The organization of the mammalian circadian system relies on temporal order between behavioural and physiological rhythms that are critical to the normal functioning of the body and human health. The hypothesis proposed is that a disruption in the sleep-wake cycle reflects impaired circadian clock functioning, which synergistically leads to the progression and maintenance of a variety of psychiatric disorders. The aging population is most susceptible to the depletion of chronobiological rhythms and sleep deficits, and thus, the development of psychiatric disorders in the elderly warrants attention. By evaluating previous and current literature, it was found that internal temporal disorder in humans may result from both internal and external factors that disrupt the coordinated symphony of the SCN and peripheral oscillators. Sleep disorders and neuropsychiatric illnesses transpire as a result of this chronodisruption. Evidence suggests that sleep disturbances are a causal factor of psychiatric illness, rather than being mere complications. It is proposed that senescence not only predisposes the elderly to chronodisruption and sleep deficits, but also increases their risk for developing frequently comorbid psychiatric illnesses. Increasing public awareness of the multitude of strategies available for harmonious synchronization and optimal well-being are profitable to the elderly in preventing circadian malfunction.

1. THE IMPLICATONS OF DESYNCHRONIZED CIRCADIAN
RHYTHMS IN HUMAN MENTAL HEALTH AND
SUSCEPTIBILITY IN THE AGING POPULATION
Cristina Corlito
March 2010
Supervisor: Dr. Lakin-Thomas
Advisor: Dr. Unniappan
Course Director: Dr. Noel
B.Sc. Honours Thesis
York University
Faculty of Science and Engineering
Department of Biology

2. 2
Abstract
The organization of the mammalian circadian system relies on temporal order
between behavioural and physiological rhythms that are critical to the normal functioning
of the body and human health. The hypothesis proposed is that a disruption in the sleep-
wake cycle reflects impaired circadian clock functioning, which synergistically leads to
the progression and maintenance of a variety of psychiatric disorders. The aging
population is most susceptible to the depletion of chronobiological rhythms and sleep
deficits, and thus, the development of psychiatric disorders in the elderly warrants
attention. By evaluating previous and current literature, it was found that internal
temporal disorder in humans may result from both internal and external factors that
disrupt the coordinated symphony of the SCN and peripheral oscillators. Sleep disorders
and neuropsychiatric illnesses transpire as a result of this chronodisruption. Evidence
suggests that sleep disturbances are a causal factor of psychiatric illness, rather than being
mere complications. It is proposed that senescence not only predisposes the elderly to
chronodisruption and sleep deficits, but also increases their risk for developing frequently
comorbid psychiatric illnesses. Increasing public awareness of the multitude of strategies
available for harmonious synchronization and optimal well-being are profitable to the
elderly in preventing circadian malfunction.

3. 3
Table of Contents
Introduction ....................................................................................................................... 4
Introduction and Overview of Biological Rhythms in Mammals: The Origin and Nature of
Periodicities ..............................................................................................................................4
The Light-Dark Cycle, Photoreceptors and the Retinohypothalamic Tract ..............................5
The Suprachiasmatic Nucleus and its Neural Outputs .............................................................7
Core Clock Molecular Mechanisms ..........................................................................................9
Review of Literature ....................................................................................................... 12
The Impact of Molecular Clocks on Human Physiology, Behaviour and Neuronal Function:
Circadian Regulation of Physiological Pathways ................................................................... 12
Peripheral Oscillators ............................................................................................................ 14
Clock Mechanism Disruptions and Internal Desynchrony Lead to Disease .......................... 16
Clocks and Circadian Sleep Disorders .................................................................................... 20
Clocks and Psychiatric Disorders ........................................................................................... 25
Synthesis and Summary ................................................................................................. 32
The Coalescence of Circadian Rhythms and Sleep Disorders and Their Synergistic
Neurobehavioural Consequences ......................................................................................... 32
Clocks and Aging: The Ensuing Susceptibility to Internal Desynchrony ............................... 33
The Prevalence of Sleep Disturbances in the Aging Population ............................................ 39
The Depletion of Chronobiological Rhythms and the Development of Psychiatric Disorders
with Age ................................................................................................................................. 41
Possible Treatments and Chronobiotics for Circadian Dysfunction ...................................... 44
Research Proposal........................................................................................................... 50
Alleviating Sleep Disorders to Alleviate Psychiatric Disturbances ........................................ 50
Acknowledgments ........................................................................................................... 55
References ........................................................................................................................ 56

4. 4
Introduction
Introduction and Overview of Biological Rhythms in Mammals: The
Origin and Nature of Periodicities
Cellular biology is organized in a temporal manner, with overt circadian
organization pervading all cells of the mammalian system. Virtually all organisms
exhibit behaviours that follow circadian cycles of rhythmicity, allowing them to operate
in synchrony with the environment. Such rhythmicity is the function of a biological
clock that is endogenous to the organism (Aschoff, 1965). Several lines of evidence
demonstrate that these biological clocks are inherent to living systems. First and
foremost is the fact that behaviours continue to cycle in the absence of environmental
time cues, negating the idea that rhythmicity is simply a reflexive response to
periodicities in the environment (Aschoff, 1965). Biological oscillations are defined by
periods, measured as the amount of time between two identical phases of behaviour
(Aschoff, 1965). Additional supporting evidence is observed when an organism is
exposed to an asynchronous environment lacking external time cues, such as continuous
darkness, for example, where it will reveal behavioural rhythms with a periodicity of
approximately twenty-four hours (Aschoff, 1965). These rhythms are appropriately
termed ‘circadian rhythms,’ derived from the Latin terms circa, meaning approximately,
and dies meaning day (Aschoff, 1965). Therefore, a circadian clock shows endogenous
unremitting oscillations that free-run under constant conditions and displays a periodicity
of about twenty-four hours (Aschoff, 1965).
In a synchronized state, the circadian rhythm of a mammal is entrained to the
rotation of the earth about its axis through external time cues known as Zeitgebers, of
which the light-dark cycle is dominant, followed by temperature (Aschoff, 1965). One

5. 5
theory on the origin of periodicities postulates that life originated on Earth in the face of
bombardment by cosmic rays (He et al., 2000). Those cells that attempted to replicate
during daylight were destroyed, while those replicating at night when radiation was at a
minimum proliferated (He et al., 2000). An archetypal biological clock arose in order to
confine DNA replication to the dark period as cells exploited these periodic signals for
their survival (He et al., 2000). Zeitgebers, therefore, maintain a sense of harmony
between the periodicity of mammals and that of the environment. Internal biological
timekeeping mechanisms in mammals allow them to anticipate those physiological states
which are best suited to responding to future environmental events (Aschoff, 1965).
Without Zeitgebers, circadian rhythms drift out of phase with the environment (Aschoff,
1978). In addition to the aforementioned properties of circadian clocks, clocks are
temperature compensated, maintaining constant periodicities despite changes in
physiological temperatures. The mechanisms underlying this process, however, are as of
yet unknown.
The Light-Dark Cycle, Photoreceptors and the Retinohypothalamic Tract
The sustained cyclical nature of biological systems in spite of a lack of Zeitgebers
demonstrates that these rhythms are produced by an endogenous circadian clock and not
by the daily periodicities of the environment. In mammals, the so-called master circadian
clock is located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus
(Lucas et al., 2001). The key element of circadian rhythms is the ability of the clock to
be resynchronized by photoentrainment, that is, the ability to coordinate internal
physiological rhythms with external rhythms (Lucas et al., 2001). This is done by
consulting with changes in light luminance and wavelength over the period of a twenty-

6. 6
four hour day and adjusting accordingly with phase delays or advances, allowing
mammals to perform behaviours at suitable times in correlation with different seasons
and different locations (Lucas et al., 2001). In mammals, light is the dominant Zeitgeber
for entrainment, with the retinohypothalamic tract (RHT) as the main circuit through
which light information reaches the SCN (Hattar et al., 2002). Lucas et al. (2001)
demonstrated the lack of contribution by rod and cone photoreceptors to circadian
photosensitivity by generating rodless coneless mice by combining a cl transgene with a
diphtheria-based toxin rdta. These rodless coneless mice continued to display phase
shifts of locomotor activity and suppression of pineal melatonin at night in response to
light pulses (Lucas et al., 2001). As a result, an alternative retinal component was
thought to be necessary for photoreception.
A subset of retinal ganglion cells (RGCs) containing the photopigment
melanopsin form the retinohypothalamic tract that projects to the suprachiasmatic nucleus
(Fig. 1) (Hattar et al., 2002). Hattar et al. (2002) established melanopsin as a circadian
photoreceptor by injecting RGCs with Lucifer Yellow for fluorescent labeling and then
staining them for melanopsin immunoreactivity. Melanopsin-positive RGCs appeared to
be directly sensitive to light and innervated neurons of the SCN, which then managed the
non-visual lighting information and aligned the circadian clock accordingly (Hattar et al.,
2002). RGCs thus form a large photosensitive receptive field within the outer nuclear
layer of the mammalian retina that detects environmental illumination, permitting
favourable physiological and neurobiological responses (Hattar et al., 2002).

7. 7
Figure 1 The retinohypothalamic tract and photic input pathway in the circadian
timekeeping system of mammals. Intrinsically photosensitive retinal ganglion cells
containing the photopigment melanopsin are located in the outer nuclear layer of the
mammalian retina. The axons of RGCs transmit information on the light-dark cycle in
the environment directly to the SCN via the RHT (Kavakli and Sancar, 2002).
The Suprachiasmatic Nucleus and its Neural Outputs
Numerous studies have confirmed the suprachiasmatic nucleus of the anterior
hypothalamus as the central circadian oscillator in mammals. Lesion and transplantation
studies performed by Ralph et al. (1990) produced arrhythmic mice through the ablation
of the SCN, resulting in locomotor and metabolic activities that lacked periodicities of
any kind. Subsequent tissue transplantation of a wild-type donor SCN into the host
resulted in the restoration of circadian rhythmicity as seen in overt behaviours. Through
neural projections and hormonal signals the SCN synchronizes other central oscillators in
the brain, whose efferent projections then coordinate the physiological activity of target
organs directly or indirectly (Panda and Hogenesch, 2004; Reiter, 1991). Projections
from the SCN to the subparaventricular zone of the hypothalamus are transmitted to the
medial preoptic region, which conducts thermoregulation in a circadian manner (Moore,

8. 8
1983; Panda and Hogenesch, 2004). The subparaventricular zone also projects onto the
dorsomedial nucleus of the hypothalamus, which monitors fluctuating hormone levels
and the cycle of sleep and wakefulness (Moore, 1983; Panda and Hogenesch, 2004).
Once external light-dark cues have reached the suprachiasmatic nucleus,
responses are evoked in the dorsomedial nucleus and subsequently the paraventricular
nucleus (PVN) (Klein et al., 1971). Neurons of the PVN synapse onto the preganglionic
sympathetic neurons in the intermediolateral zone of the lateral horns of the thoracic
spinal cord (Klein et al., 1971; Perreau-Lenz et al., 2003). These preganglionic neurons
influence neurons in the superior cervical ganglia whose efferent fibres innervate the
pineal gland (Fig. 2) (Klein et al., 1971). The pineal gland produces the neurohormone
melatonin from tryptophan and secretes it into the bloodstream, allowing it to mediate the
brainstem circuits that control the sleep-wake cycle as it promotes sleep (Perreau-Lenz et
al., 2003). During scotophase, or the dark period of the light-dark cycle, melatonin
secretion reaches a maximum since the SCN has reduced activation, thus removing the
inhibition of sympathetic neurons and promoting melatonin production in the pineal
gland (Perreau-Lenz et al., 2003). It follows that the neuronal and hormonal outputs of
the SCN to autonomous oscillators in the brain and their ensuing projections coordinate
the proper timing of a variety of physiological functions over the twenty-four hour
geophysical day, including but not limited to the sleep-wake control system, hormone
secretion, hunger and satiety and body temperature (Panda and Hogenesch, 2004).

9. 9
Figure 2 Brain anatomy involved in the production of the neurohormone melatonin.
Non-visual light information, or lack thereof, is transmitted to the SCN and induces a
response in the PVN. Neurons of the PVN innervate the preganglionic sympathetic
neurons of the thoracic spinal cord, which then synapse onto the superior cervical ganglia
whose efferent fibres innervate the pineal gland. The pineal gland is the production site
for melatonin and mediates its release into the bloodstream (Lewy, 2010).
Core Clock Molecular Mechanisms
Mammalian circadian rhythms of sleeping and waking, hormone secretion,
thermoregulation and the like are regulated by the molecular circadian clock mechanism,
intrinsic to every cell of the suprachiasmatic nucleus of the anterior hypothalamus and
every other cell of the human body. Historically, Drosophila melanogaster has been the
model organism in which many of the major circadian clock genes were first identified
(Clayton et al., 2001). Many homologues of the genes and proteins involved in the
generation of biological oscillations in Drosophila have now been cloned in mammals
(Clayton et al., 2001). The actions of these genes and proteins are temporally regulated,
thus giving rise to a mammalian molecular core clock mechanism that consists of

10. 10
transcription-translation autoregulatory feedback loops with both excitatory and
inhibitory components (Fig. 3) (Clayton et al., 2001; Shearman et al., 2000). The
fundamental factors in this molecular mechanism are the transcription factors CLOCK
and BMAL1, with helix-loop-helix and PAS domains that are indicative of their function
(Shearman et al., 2000). The PAS domains allow these two transcription factors to
dimerize through protein-protein interactions (Clayton et al., 2001).
In the circadian processes of the core clock molecular mechanism, Clk and Bmal1
genes are transcribed and their protein products heterodimerize when adequate
concentration levels are reached (Shearman et al., 2000). These dimers bind to
regulatory DNA sequences, or E-boxes, that initiate the transcription of the mammalian
cryptochrome genes Cry1 and Cry2, period genes Per1, Per2, and Per3 and clock-
controlled genes Ccg (Clayton et al., 2001; Shearman et al., 2000). Following post-
translational modifications, cytoplasmic PER2 and CRY heterodimerize and translocate
to the nucleus, where PER2 proteins stimulate the synthesis of BMAL1, in antiphase with
the concentration of the three PER proteins, thereby acting as a positive regulator of the
BMAL1 loop (Shearman et al., 2000). Conversely, CRY proteins bind to CLOCK-
BMAL1 dimers, inhibiting the stimulatory effect they exert on the DNA sequences
encoding PER and CRY, and forming a negative feedback loop (Shearman et al., 2000).
Consequently, as the concentrations of PER and CRY decrease, the inhibition is removed
and CLOCK-BMAL1 dimers recommence transcription and maintain the twenty-four
hour oscillation of the circadian clock mechanism (Clayton et al., 2001).
The characteristic twenty-four hour periodicity of the circadian clock mechanism
is generated through post-translational modifications, phosphorylation and cellular

11. 11
localization and stability of protein products, leading to time delays (Ikeda et al., 2003).
Cytosolic factors, such as ions and second messengers, exhibit biological oscillations and
support transcription-translation feedback loops (Ikeda et al., 2003). In this fashion, each
standalone circadian clock cell is composed of a molecular oscillator and the rhythm
maintaining effects of post-translational mechanisms. Further investigation of this
process and other clock components is currently underway. Overall, the molecular clock
produces a synchronized rhythmic output from the SCN, which is then conveyed
synaptically and humorally to other brain oscillators and peripheral tissues (Clayton et
al., 2001). In this manner, the output of the master oscillator coordinates various
physiological and behavioural mammalian systems.
Figure 3 The molecular oscillator within circadian clock cells of the SCN.
Transcription-translation feedback loops with excitatory and inhibitory components
regulate internal rhythmicity within the cell (Clayton et al., 2001).

12. 12
Mammalian physiological and behavioural systems exhibit biological oscillatory
patterns that harmonize internal conditions with the rhythmic external world. This review
will focus on the implications of desynchronized circadian rhythms in human mental
health. The hypothesis to be proposed is that a disruption in the sleep-wake cycle reflects
impaired circadian clock functioning, which synergistically leads to the progression and
maintenance of psychiatric disorders. The aging population is most susceptible to the
depletion of chronobiological rhythms, and thus, the development of psychiatric disorders
in the elderly merits attention. This will be done by evaluating previous and current
literature and proposing future directions.
Review of Literature
The Impact of Molecular Clocks on Human Physiology, Behaviour and
Neuronal Function: Circadian Regulation of Physiological Pathways
The endogenous circadian clock permeates through almost every physiological
and behavioural process in the human body and has wide implications for health.
Humans exhibit circadian rhythmicity in such behaviours and physiological processes as
sleep and wakefulness, hormone secretion, thermoregulation, feeding, metabolism,
attentiveness and memory (Clayton et al. 2001; Takahashi et al., 2008). The clock genes
that sustain biological oscillations in the suprachiasmatic nucleus also regulate the
corresponding twenty-four hour human cycle through rhythmic neural and hormonal
output signals to peripheral tissues (Yoo et al., 2004). In this manner, peripheral organs
are able to modify their temporal functioning accordingly (Fig. 4) (Yoo et al., 2004).

13. 13
Figure 4 Circadian rhythmicity in human behaviours and physiological processes.
Rhythmic solar signals entrain the cellular clocks of neurons in the SCN through afferent
retinal innervations. Neural and hormonal outputs from the SCN subsequently adjust the
phase of peripheral organs throughout the body.
The SCN employs both neural efferents and humoral signals to entrain other brain
oscillators, whose roles in coordinating various physiological processes are crucial (Silver
et al., 1996; Abe et al., 2002). Recall the abovementioned projections from the SCN to
the subparaventricular zone, medial preoptic nucleus, and dorsomedial hypothalamus,
which manage endocrine and autonomic systems, including the hypothalamic-pituitary-
adrenal axis, through supplementary neuronal projections and hormonal signals (Moore et
al., 1983; Girotti et al., 2007). The neurotransmitters glutamate and GABA mediate
synaptic transmission between the SCN and other hypothalamic areas (Hermes et al.,
1996). Using an in vitro postmortem anterograde tracing method, Jiapei and colleagues
(1998) found that the hypothalamic areas innervated by the SCN mediate
parasympathetic and sympathetic signaling centres, the sleep-wake control system, the
arousal system, locomotor activity, body temperature, cardiovascular activity and
hormone secretion. Therefore, the circadian regulation of the synthesis and release of
central nervous system neurotransmitters and neuropeptides, and the ensuing entrainment

14. 14
of brain oscillators, ensures the synchrony of tissue rhythms with the twenty-four hour
geophysical day.
The outputs of the SCN master clock not only coordinate brain oscillators but also
peripheral organs in order to orchestrate physiological oscillations. In addition to
hormonal cues, direct neural control of peripheral targets is achieved via the autonomic
nervous system (Cailotto et al., 2005). The SCN may also indirectly control the phase of
peripheral oscillators by regulating the sleep-wake cycle and therefore the rhythm of
feeding behaviour (Cailotto et al., 2005). As a result, an inconsistent feeding schedule
can disturb the harmonious alignment between the SCN and the peripheral organs
involved as it acts as an external entraining agent (Cailotto et al., 2005). Therefore, the
transcription-translation feedback loops of the core clock mechanism not only maintain
rhythmicity in the central oscillator and its clock-controlled genes but also generate
circadian outputs to peripheral targets, the details of which are as of yet not fully
understood (Duffield et al., 2002).
Peripheral Oscillators
It has been established that the clock genes expressed in the core mechanism of
the master suprachiasmatic nucleus are rhythmically expressed in peripheral circadian
oscillators located throughout the human body (Yamazaki et al., 2000; Duffield et al.,
2002; Yoo et al., 2004). Balsalobre et al. (2000) examined clock-controlled gene
expression in peripheral mammalian tissues by inducing rhythmicity in immortalized rat-
1 fibroblasts through serum shock. cDNA microarrays revealed a chronological
production of messenger RNA in response to serum shock and pharmacological
treatment, signifying the circadian regulation of gene expression (Balsalobre et al., 2000).

15. 15
Previously believed to rhythmically dampen after two to seven twenty-four hour cycles
without input from the SCN, Yoo and colleagues (2004) have demonstrated that
peripheral oscillators maintain endogenous rhythmicity whilst displaying desynchrony
amongst themselves without entraining signals (Yamazaki et al., 2000). Yoo et al.
(2004) employed the fusion of the mouse locus mPer2 with a luciferase reporter gene to
reveal strong inherent oscillations of bioluminescence in both the SCN and peripheral
tissues ex vivo. Furthermore, in SCN-lesioned mice, bioluminescence rhythms persisted
for twenty days in peripheral tissues, including the liver, lungs, pituitary and cornea,
however, with an eventual loss of phase coordination (Fig. 5).
Figure 5 Circadian rhythmicity in explanted tissues of the mouse, including the cornea,
liver, pituitary gland, kidney and lung. Luciferase reporter genes revealed inherent
oscillations of bioluminescence in these tissues (Yoo et al., 2004).
Peripheral tissues isolated in culture, including but not limited to the previously
mentioned lungs, cornea, pituitary gland and liver, express clock-controlled genes that
confer distinctive circadian period and phase properties to those structures (Yoo et al.,
2004). As such, these circadian properties are distinct in different organs and contribute
temporally to their physiological functioning (Yoo et al., 2004). The SCN does not

16. 16
generate but rather coordinates the phase of autonomous peripheral oscillators, thereby
inhibiting internal desynchrony between tissue-specific target clocks and their
synchronized phase relationship with the external environment (Yamazaki et al., 2000;
Yoo et al., 2004). The phase of each peripheral oscillator induces rhythmic gene
expression, for example that of Per1, resulting in circadian protein product activity,
which in turn regulates rhythmic metabolic events in different tissues throughout the
human body (Ripperger et al., 2000). The phase of oscillations can be altered by
adjusting the feedback of peripheral clocks characteristic of a tissue to internal and
external Zeitgebers originating from the SCN and environment, respectively (Yamazaki
et al., 2000).
Clock Mechanism Disruptions and Internal Desynchrony Lead to Disease
The organization of the mammalian circadian system, as reviewed above, relies
on temporal order between behavioural and physiological rhythms that are critical to the
normal functioning of the body and human health. Thus, the concept of the harmful
effects that would ensue as a result of disorder between these phase relationships and the
cyclical expression of clock-controlled genes readily presents itself as there are numerous
avenues through which to disrupt this fragile system (Yamazaki et al., 2000). Internal
temporal disorder in humans may result from both internal and external factors that
disrupt the coordinated symphony of the SCN and peripheral oscillators. Predominant
external factors include light deficiency and irregularity, jet lag, shift work, food intake
and social activities (Skene et al., 1999; Reddy et al., 2002; Solonin et al., 2009; Turner
and Mainster, 2008; Girotti et al., 2009). Internal factors include the disturbance of
proper photoreception, visual loss, decreased melatonin levels and circadian clock gene

17. 17
mutations (Czeisler et al., 1995; Lockley et al., 1997; Turner and Mainster, 2008). As
previously discussed, peripheral oscillators will desynchronize amongst themselves
without temporal adjustments provided by the SCN through neural and hormonal outputs
(Yoo et al., 2004). Proper SCN operations ensure good health by mediating rhythms of
sleep-wake systems, hormone secretion and metabolism, therefore, chronodisruption may
be the cause of a range of diseases (Jiapei et al., 1998; Yamazaki et al., 2000; Cailotto et
al., 2005).
Light irregularity, or improperly timed ocular light exposure, may result in
chronodisruption by modifying nocturnal melatonin synthesis in the pineal gland
depending on its duration, wavelength, intensity and time of administration (Czeisler et
al., 1995; Skene et al., 1999). Ocular light exposure in the scotophase decreases
melatonin production (Skene et al., 1999). Low circulating levels of melatonin
throughout the body may result in numerous diseases as it has been shown to contribute
beneficially to the antioxidant capability of blood plasma (Benot et al., 1999).
Environmental light is the predominant Zeitgeber in circadian timekeeping, and, for that
reason, maintains the greatest influence on human physiological and psychological
health. Photosensitive RGCs best absorb light in the blue sector of the light spectrum at
460 nm, which is quite similar to the wavelength of environmental light (Turner and
Mainster, 2008). Modern artificial lighting, unfortunately, provides only about 1% of
natural light intensity and is distinguished by red spectrum wavelengths, which is
insufficient for suitable photoreception (Turner and Mainster, 2008). Instead, optimal
photoreception requires blue light of high intensity and duration for photoentrainment and
favourable health (Turner and Mainster, 2008).

18. 18
Light deficiency fails to entrain the SCN to the geophysical day and results in a
subsequent free-running periodicity, as exemplified by blind individuals (Skene et al.,
1999). Blind individuals may be categorized, according to the extent of visual loss, as
having some light perception, and thus photoreception, and those with no light perception
capabilities and no photoreception whatsoever (Skene et al., 1999). In a study by Skene
et al. (1999), 77% of blind subjects capable of photoreception showed normal circadian
rhythmicity, while 67% of those with no light perception showed free-running period
lengths and internal desynchrony. The latter also suffered from daytime somnolence, an
excessive need for sleep during the daytime, and insomnia during the night due to the
temporal disorder of melatonin synthesis and release (Lockley et al., 1997). Further
evidence of the dire consequences of light deficiency, with light as the chief biological
Zeitgeber, is demonstrated by the fact that blind subjects who had no eyes after having
undergone bilateral enucleation showed free-running period lengths ranging from 24.13
to 24.81 hours, albeit in the presence of non-photic signals such as food intake and social
activities (Skene et al., 1999). On the whole, blind individuals incapable of
photoentrainment exhibit higher levels of circadian disruption and dampened SCN
outputs, thus making them susceptible to diseases, particularly sleeping disorders and
compromised neuropsychiatric conditions (Lockley et al., 1997; Jean-Louis et al., 2005).
Girotti and colleagues (2009) recently demonstrated the role of food intake as a
non-photic Zeitgeber. Their study revealed characteristic rhythms of clock gene
expression in each element of the hypothalamic-pituitary-adrenal axis, where a decrease
in food intake in the photophase of the light-dark cycle altered glucocorticoid secretion
and clock gene expression (Girotti et al., 2009). Physiological processes may be

19. 19
entrained to intermittent feeding schedules, with glucocorticoids synchronizing a
multitude of peripheral organs (Stephan, 1986; Girotti et al., 2009).
Shift work employees in industrial sectors, medicine and the military show signs
of considerable circadian dysfunction, including such symptoms as biochemical
disturbances, mood disorders, sleeping disorders, metabolic syndrome and an overall
feeling of malaise (Solonin et al., 2009). James et al. (2007) recently investigated the
effects of night shift work on the sleep-wake cycle, outlining desynchrony between the
master circadian clock and the night schedule as subjects maintained day active
entrainment. This was done by comparing oscillatory clock gene expression in peripheral
blood mononuclear cells with the temporally shifted sleep-wake cycle. The exposure to
artificial light at uncharacteristic times communicates odd entraining signals to the SCN
and results in perturbed circadian outputs and melatonin synthesis (James et al., 2007).
The differential responses of peripheral oscillators to the altered phase of input signals
also leads to a lack of internal coordination, hence resulting in feelings of malaise. Shift
work sleep disorder is a circadian rhythm sleep disorder in which the afflicted complain
of daytime sleepiness, insomnia and poor sleep quality (Ursin et al., 2009). Other
circadian rhythm sleep disorders will be addressed in the next section of this review.
In addition to shift work, jet lag also impairs physical and mental well-being via
circadian desynchrony. The core clock mechanism experiences much more difficulty in
acclimatization to advanced time zones rather than delayed time zones because the
former does not occur as rapidly (Reddy et al., 2002). Reddy and his colleagues (2002)
subjected mice to acute advances or delays in local time and reported that circadian
rhythms of mPer expression in the SCN adjust swiftly to advanced light pulses, while

20. 20
rhythmic mCry1 expression advanced gradually. Conversely, they found that a six hour
delay in local time entailed mPer and mCry adjusting in sequence by the second
oscillation. This study describes the different effects of traveling east or west, or
advancing or delaying, respectively, on the master clock and the prospective temporal
desynchrony between mPer and mCry expression as a result of jet lag, with ensuing
health complications (Reddy et al., 2002).
The final factor contributing to clock mechanism disruptions, internal
desynchrony, and thus, disease are genetically mutated circadian clock genes and
polymorphisms. Current research is heavily focused on identifying those clock gene
alterations that result in a variety of disrupted circadian behaviours. Clock gene
mutations may be implicated in the deterioration of the regimented functioning of both
molecular oscillators and their rhythmic neural and hormonal outputs and their effects
will be discussed in subsequent sections of this review. Cumulatively, the
aforementioned internal and external factors, particularly insufficient and temporally
displaced environmental light, may induce biological stress and disturb the coordinated
rhythmicity of physiological processes and behaviours necessary for optimal human
health. This review will now turn to those sleep disorders and neuropsychiatric illnesses
that transpire as a result of chronodisruption.
Clocks and Circadian Sleep Disorders
A profound relationship exists between clock gene variations and changes in
behavioural rhythmicity, most notably sleep parameters in humans. The timing and
amount of sleep are determined by circadian and homeostatic sleep control mechanisms,
respectively (Naylor et al., 2000). The former dictates patterns of sleep and wake at

21. 21
specific phases throughout the twenty-four hour light-dark cycle, while the latter depends
on the need for sleep (Naylor et al., 2000). In a study by Naylor et al. (2000), a mutation
in Clk in the mouse was found to alter not only the timing and length of sleep but sleep
homeostatis as well. Naylor and colleagues evaluated the effects of the CLOCK
transcription factor mutation by comparing sleep and electroencephalographic (EEG)
activity in homozygous and heterozygous mutants and wild-type mice under conditions
of entrainment, free-running rhythms and recovery from six hours of sleep deprivation.
The results indicated that heterozygotes slept one hour less per day and homozygotes two
hours less per day in contrast to wild-type mice, with lower amounts of non-rapid eye
movement sleep seen. Following periods of sleep deprivation, Clk homozygous mice
displayed 39% less sleep than heterozygotes and wild-type mice. One may attribute these
results to discrepancies of entrainment to the light-dark cycle, however, divergent sleep
behaviours were also seen when mice were free-running in continuous darkness (Naylor
et al., 2000). A study by Laposky et al. (2005) employed the same investigative
measures in mice with a deletion of Bmal1 and discovered a diminished rhythm of sleep
and wakefulness, a weakened response to sleep deprivation and lengthened sleep periods.
Whereas mutations in the mammalian cryptochrome genes Cry1 and Cry2 hold
implications for sleep homeostatis, Period genes are not essential for homeostatic sleep
regulation (Wisor et al., 2002; Shiromani et al., 2004). A study by Shiromani and
collaborators (2004) examined the effects of Per1, Per2, Per3 and double Per1-Per2
mutations on sleep factors and found that Per2-mutant and double mutant mice exhibited
longer periods of wakefulness, with less slow-wave sleep (SWS) and rapid-eve
movement (REM) sleep, than wild-type and Per1 deficient mice in states of entrainment.

22. 22
Double mutant strains became arrhythmic in aperiodic conditions, however, the amount
of time spent awake, in SWS and in REM sleep was equivalent to that in an entrained
state even after 36 days, thus signifying the maintenance of total sleep levels. Per genes
are more so involved in altering the phase position of the sleep-wake cycle (Shiromani et
al., 2004). In conclusion, circadian clock gene alterations have profound implications for
both rhythms of sleep and wakefulness and sleep propensity, although knowledge as to
their exclusivity to one or the other is currently unknown.
Variations in circadian clock genes have a variety of effects on the configuration
of human sleep. Delayed sleep phase syndrome (DSPS) is the most commonly reported
circadian rhythm sleep disorder whose features include sleep periods delayed by 2 to 6
hours, the inability to fall asleep, difficulty waking and a lack of feeling well rested
(Campbell and Murphy, 2007; Chang et al., 2009). One study investigated a 30 year old
graduate student with DSPS whose average bedtime was 3:38 a.m. and usually awoke at
1:47p.m. in order to feel replenished (Campbell and Murphy, 2007). Campbell and
Murphy (2007) examined the sleep and body temperature rhythms of the subject in
comparison to those of 3 normal age-matched subjects with both parties in aperiodic
conditions free from environmental cues. Whereas the time between the core body
temperature minimum and sleep onset in control subjects was 1.63 hours, the graduate
student displayed a phase angle of 3.62 hours. Furthermore, the DSPS patient had a free-
running period length of 25.38 hours compared to an average of 24.44 hours for the
control subjects. One may refute these results by suggesting that the lighting conditions
in temporal isolation contributed to the lengthening of the free-running period in the
DSPS subject, however, the authors noted that illumination was below 50 lux, which is

23. 23
insufficient for optimal photoreception (Campbell and Murphy, 2007). Therefore, DSPS
causes an abnormal endogenous period length and internal desynchrony between sleep
and body temperature rhythms, resulting in poor sleep efficiency and duration.
The previous findings may be attributed to a polymorphism in the circadian clock
gene Per3 or a missense mutation in the casein kinase I epsilon gene CKI ε. Archer et al.
(2003) have found a correlation between a length polymorphism in Per3 and DSPS,
particularly the shorter allele for which 75% of DSPS patients were homozygous. They
found that the 4-repeat allele, as opposed to the 5-repeat allele, was substantially
prevalent in DSPS patients in contrast to the control group. Recall post-translational
mechanisms, such as phosphorylation, affect the stability of protein products and function
to create time delays in the circadian clock mechanism. PER is targeted for degradation
through phosphorylation by CKI ε, making it unavailable for dimerization and subsequent
nuclear localization and thus causing it to oscillate (Archer et al., 2003).
The shorter variation of PER3 contains fewer phosphorylation sites than its longer
counterpart and may be the cause of polymorphic differences in function and hence
longer endogenous period length seen in DSPS (Archer et al., 2003). A study by Takano
and associates (2004) revealed that a missense mutation in the N408 allele in CKI ε
functions as a safeguard against DSPS by modifying its autophosphorylation activity.
In contrast to DSPS, advanced sleep phase syndrome (ASPS) dictates human
behaviours marked by early bedtimes, early morning waking and a short endogenous
period length (Xu et al., 2005). ASPS is caused by a mutation in a residue in the casein
kinase I binding site of the Per2 gene and results in attenuated phosphorylation levels
(Archer et al., 2003). The reduction in phosphorylation seen in both DSPS and ASPS is

24. 24
indicative of the different pathological symptoms that may occur as a result of
phosphorylation levels in different PER proteins. In another case, through mutagenesis
screenings of related ASPS patients, Xu et al. (2005) found a threonine to alanine
missense mutation at amino acid 44 in the human CKIδ gene. Subjects under study had
an average bedtime of 6:12 p.m., compared to the control average of 11:24 p.m., and an
average rising time of 4:06 a.m. compared to the control average of 8:00 a.m. Overall,
this T44A mutation decreases CKIδ enzyme activity in ASPS patients and consequently
leads to a shortened activity rhythm and advanced phase of activity in an entrained setting
of 12 hours of light and 12 hours of dark (Xu et al., 2005).
The etiology of the abovementioned circadian rhythm sleep disorders may be
attributed to circadian clock gene polymorphisms and mutations, whereas obstructive
sleep apnea syndrome (OSAS) and its symptoms produce arrythmicity in clock gene
functioning. This arrythmicity may be credited to fluctuating levels of factors circulating
through the blood (Burioka et al., 2008). Burioka et al. (2008) have measured Per1
mRNA expression in peripheral blood mononuclear cells in those patients with severe
OSAS using polymerase chain reaction analysis over a twenty-four hour period. In
contrast to similar healthy controls, the eight OSAS participants showed no circadian
rhythms of Per1 mRNA expression throughout the day and abnormal elevations of
plasma noradrenaline. Elevated noradrenaline levels and sympathetic activity contributed
to an increase in the transcription of Per1 during sleep (Burioka et al., 2008).
Interestingly, continuous positive airway treatment for a period of three months improved
not only shallow sleep with frequent waking due to hypoxic episodes, but also daily
oscillations of Per1 transcription (Burioka et al., 2008). The effects of continuous

25. 25
positive airway treatment on clock gene transcription thereby illustrate a mechanism by
which a circadian rhythm sleeping disorder may be managed by improving clock gene
function.
Fatal familial insomnia (FFI) is a debilitating disorder marked by sleep
deficiency. FFI is a prion disease distinguished by a 178 codon prion protein gene
mutation (Reder et al., 1995). A study by Sforza et al. (1995) studied six subjects with
this disease using twenty-four hour polygraphic recordings in a sleep laboratory. Their
findings revealed severe reductions in total sleep time, impairments in the circadian
regulation of the sleep-wake cycle and abrupt alterations from wakefulness to sleep.
Positron emission topography uncovered atrophy in the thalamus, particularly the antero-
ventral and dorso-medial thalamic nuclei, which take part in regulating the sleep-wake
cycle (Sforza et al., 1995). Over the course of the disease, symptoms of insomnia
progressively worsen and circadian rhythms dampen substantially until the total sleep
time is reduced to about 50 minutes per day and the subject dies (Sforza et al., 1995).
Portaluppi et al. (1994) conducted assays for melatonin in the blood plasma of two FFI
patients and found that concentrations of the hormone decreased in accordance with
disease progression, further compromising circadian rhythmicity.
Clocks and Psychiatric Disorders
Just as the misalignment of the circadian pacemaker and clock gene mutations and
polymorphisms have been associated with circadian rhythm sleep disorders, these factors
are implicated in psychiatric disorders. A variety of abnormal endogenous circadian
rhythms underlie major depressive disorder (MDD), particularly the sleep-wake cycle
(Gordijn et al., 1994; Emens et al., 2009). Emens and colleagues (2009) set out to

26. 26
demonstrate a correlation between MDD and improper coordination between the
circadian pacemaker and sleeping schedule. Study subjects were comprised of eighteen
females ranging from 19 to 60 years of age who had been diagnosed with MDD
according to the Diagnostic and Statistical Manual of Mental Disorders (DSM),
excluding those with suicidal tendencies, jet lag, shift work positions and medications
that would impede melatonin production. Emens et al. (2009) calculated circadian
misalignment according to the time difference between melatonin production and the
midpoint of sleep. Those with larger time differences exhibited a phase delay in central
pacemaker rhythmicity in comparison to the timing of sleep and a higher severity of
symptoms (Fig. 6). These results demonstrate the interaction between circadian
desynchrony, poor sleep and mild to moderate symptoms of depression, though future
studies should be conducted on a more representative sample population (Emens et al.,
2009).
Figure 6 The larger the time difference between melatonin synthesis and the midpoint
of sleep, also known as the phase angle difference (PAD), the higher the severity of
depressive symptoms according to the Hamilton Depression Rating Scale (HAM-D).
Following a clinical assessment by a health professional, a score higher than 7 on the
HAM-D constitutes a diagnosis of MDD (Emens et al., 2009).
An alternative route by which disrupted circadian oscillations may facilitate MDD
is through the deregulation of mood by the mesolimbic dopaminergic system (Hampp et

27. 27
al., 2008). Hampp and associates (2008) ascertained that Per2 mutant mice have reduced
levels of expression of monoamine oxidase A in the mesolimbic dopaminergic system,
which is an enzyme that mediates dopamine metabolism. The atypical mood behaviours
observed in these mice may be attributed to this clock gene mutation. Polymorphisms
and mutations in the Clock gene have been connected to bipolar disorder (Benedetti et al.,
2003; Roybal et al., 2007). Roybal and colleagues created Clock mutant mice through
mutagenesis, thereby inhibiting its transcriptional activation of molecular rhythms. The
mice were subjected to tests in which they were able to induce rewarding electrical
stimulation to themselves via electrodes implanted in the medial forebrain bundle. Clock
mutant mice were able to experience euphoria at lower currents than wild type mice and
cocaine decreased these current thresholds substantially in the mutants. This response is
predictive of substance abuse as the mice experienced a greater sense of reward upon
stimulation because of their hypersensitivity, making them more inclined to abuse such
stimulants (Roybal et al., 2007). These states of ecstasy and substance abuse mimic the
condition of bipolar patients (Roybal et al., 2007).
The mood-related behaviours of Clock mutant mice parallel those humans with
bipolar disorder, including less depression and less anxiety (Roybal et al., 2007). This
was discerned as mice showed little anxiety when subjected to an unprotected arm of a
raised platform. Conversely, when treated with lithium, a mood stabilizer given to
bipolar patients, the mutant mice displayed more wild-type behaviours of high anxiety in
this situation (Roybal et al., 2007). Like the previously mentioned MDD patients, Clock
mutant mice have compromised dopaminergic systems, although with increased firing of
dopaminergic neurons that is diminished through the viral insertion of a gene coding for a

28. 28
wild type CLOCK protein (Roybal et al., 2007). As the name implies, bipolar disorder
alternates between states of mania and depression, with depressive states being
predominant in the winter months (Roybal et al., 2007).
Winter depression, also known as seasonal affective disorder (SAD), involves
changes in circadian genetic factors, the external environment and circulating melatonin
(Wehr et al., 2001; Johansson et al.., 2003; Partonen et al., 2007). Certain animals
display photoperiodism, that is, the ability to infer the time of year based on the length of
the day. Such information is made available by measuring the duration of melatonin
release during the night, the duration of which is longer in the winter (Wehr et al., 2001).
Wehr et al. (2001) found that variations in season affect patients with SAD but not
similar healthy subjects. Their study measured the duration of melatonin release in dim
light in 55 SAD patients and 55 equivalent healthy subjects throughout the summer and
winter months, with plasma samples being taken every 30 minutes all through the day. In
SAD subjects, melatonin release in the scotophase was much more pronounced in the
winter rather than summer, however, no change was observed in those without SAD
diagnoses.
In regards to circadian genetic mechanisms, Partonen et al. (2007) surmised the
genes Per2, Bmal1 and Npas2, whose products function mutually in the core circadian
oscillator, are compromised in SAD. As previously mentioned, BMAL1 is a PAS protein
that interacts with other proteins, and as such, dimerizes with NPAS2 and binds to DNA
(Partonen et al., 2007). Single nucleotide polymorphisms were assessed in each of the
three genes in 189 patients and 189 symptom-free controls. Gene-wise logistic regression
analysis revealed SAD to be related to polymorphisms within all three genes and posing

29. 29
the greatest chance of illness due to their magnified cumulative effects (Partonen et al.,
2007). When genetic variations in all three were present, patients had a 10 times greater
chance of developing SAD compared to the controls, while those with less severe allelic
combinations had a 4 times greater chance. Recently, point mutations have been located
in the melanopsin gene Opn4 in retinal ganglion cells, which serve to decrease
photosensitivity (Roecklein et al., 2009). As the contrast between light intensities is
already reduced in the winter, these point mutations aggravate that effect as dusk and
dawn Zeitgebers cannot be detected and proper photoentrainment cannot occur
(Roecklein et al., 2009). Such a hindrance in phototransduction may result in internal
desynchrony, and thus, clinical symptoms of depression in the winter months.
Deteriorations in mood behaviours are often accompanied by substance abuse,
most likely due to the fact that circadian rhythmicity and dopaminergic systems are
confounded in these patients. Abarca et al. (2002) investigated cocaine addiction in Per
mutant mice in order to ascertain the circadian control of cocaine-induced reward and
behavioural sensitization. A single cocaine injection produced a fivefold increase in
locomotion in Per1 and Per2 knockout and wild type mice compared to saline injections.
During cocaine administration, mice were placed in boxes with two floor divisions in
which one consisted of a rod pattern of texture and the other of circles. Cocaine
administration was always associated with the same floor division. After repeated
cocaine injections, wild type mice became sensitized to cocaine-associated factors, Per1
mutants showed no sensitization and Per2 mutants showed an intense sensitized
behavioural reaction. While both wild type and Per2 mutant mice preferred the division
associated with cocaine injections, Per1 mutants did not prefer the side associated with

30. 30
reward. In addition, stronger behavioural responses to the drug were seen in the morning
than at night. Since all three groups displayed similar levels of locomotor activity in
response to a single cocaine injection, it may be inferred that cocaine addiction, rather
than acute application, is managed by the clock genes Per1 and Per2 with opposing
effects in the circadian system (Abarca et al., 2002).
Previous discussions highlighted aberrant dopaminergic systems and clock gene
mutations in MDD and bipolar disorder mice models. These same conditions are
observed in mice addicted to cocaine. McClung and colleagues (2005) found that a loss
of function point mutation in Clock results in the same cocaine sensitization behaviours
outlined by Abarca et al. (2002), with Clock mutants displaying a greater degree of
sensitivity to the rewarding feelings of cocaine. This may be credited to increased levels
of tyrosine hydroxylase activity, an enzyme involved in dopamine metabolism, and
therefore, heightened amounts of dopaminergic transmission in the reward centres of
mice without functional CLOCK proteins (McClung et al., 2005). Alcoholism, another
form of substance abuse possibly under circadian control in humans, may be associated
with excessive levels of glutamate in the extracellular fluid, as suggested by Per2 mutant
mice whose levels of glutamate reuptake transporters in the nervous system are
significantly reduced (Spanagel et al., 2005). These mice display augmented levels of
voluntary alcohol consumption when offered ethanol in comparison to wild type controls
(Spanagel et al., 2005).
Malformed circadian rhythms of activity, body temperature and sleep are often
prevalent in patients with Alzheimer’s disease, which is common in the elderly. Many
victims of this neurodegenerative illness exhibit what is referred to as ‘sundowning’, or

31. 31
the worsening of Alzheimer’s behaviours in the afternoon and evening (Volicer et al.,
2001). Volicer et al. (2001) sought to decipher the relationship, if any, between
sundowning and circadian rhythms in a cohort of 25 Alzheimer’s patients and nine
healthy subjects. Their results revealed that those Alzheimer’s patients who undergo
sundowning showed increased nocturnal locomotor activity, with lower amplitudes
during the day, and major phase delays in both activity and body temperature in
comparison to controls. Furthermore, these subjects had severely reduced amplitudes of
body temperature and disrupted sleep parameters. These results imply that patients who
sundown may be suffering from disturbances in their rhythms, however, other
environmental factors must be considered in these habitual states of aggravation (Volicer
et al., 2001). One study that has shed some light on this issue is by Mahlberg and
associates (2008), in which cranial computed tomography revealed significant levels of
pineal calcification in AD patients, thereby limiting melatonin synthesis to sup-optimal
levels and inhibiting the coordination of the circadian system.
Schizophrenia is a neuropsychiatric illness characterized by distorted cognition,
abnormal affect and social withdrawal (Wulff et al., 2006). Schizophrenic patients show
strong disturbances in their sleep-wake cycles, melatonin patterns and light exposure, yet
research in this area remains vague (Wulff et al., 2006). Wulff et al. (2006) studied a 27-
year old male patient for six weeks, documenting gradually delayed bedtimes and risings,
which culminated in the eventual reversal of night and day activities and low sleep
efficiency. His free-running period length was longer than 24 hours, as well as a free-
running melatonin rhythm of 24.29 hours. Instead of being coordinated with the light-
dark cycle of the environment, the patient’s light exposure was synchronized with his

32. 32
own activity, and the temporal misalignment of these input light signals may exacerbate
his established desynchrony even further (Wulff et al., 2006).
Synthesis and Summary
The Coalescence of Circadian Rhythms and Sleep Disorders and Their
Synergistic Neurobehavioural Consequences
There is a widely held assumption that sleep deficits are the secondary effects of
psychiatric disorders. While this may certainly be the case under some circumstances,
evidence would lead one to speculate that sleep disturbances are a causal factor of
psychiatric illness, rather than being mere complications. A disruption in the sleep-wake
cycle reflects impaired circadian clock functioning, which synergistically leads to the
progression and maintenance of a variety of psychiatric disorders. Sleep-wake cycles are
perturbed in most if not all of the previously mentioned psychiatric disorders, and many
of the studies discussed implicated irregular clock gene functioning. Recall the study by
Emens et al. (2009), whose results demonstrated a temporal misalignment between the
central circadian pacemaker and the sleep-wake cycle, the degree of which corresponded
to the severity of clinical psychiatric symptoms experienced. Over 10 years earlier,
Boivin and collaborators (1997) released similar findings from a study in which 24
healthy adults were subjected to internal desynchrony by living according to 30 hour and
28 hour sleep-wake cycles. Through the use of psychometric response scales, they too
showed varying mood states based on the degree of displacement between the sleep-wake
cycle and circadian rhythmicity.
The successful treatment of MDD seems to involve the management of sleep
disturbances, indicating their contribution to this psychiatric disorder (Ohayon and Roth,

33. 33
2003). In 2003, Ohayon and Roth interviewed a representative sample of the population
of the United Kingdom, Germany, Italy and Portugal, totaling 14,915 participants.
Participants were questioned about their sleep habits, sleep symptoms, current mental
health status and history and subsequently diagnosed according to the Diagnostic and
Statistical Manual of Mental Disorders if need be. Symptoms of insomnia arose in 19.1%
of the sample, with 90% of this 19.1% cohort experiencing severe insomnia in excess of
six months. Among those suffering from severe insomnia for six months to five years,
28% held concomitant psychiatric diagnoses, and of those suffering for more than five
years 25.8% held diagnoses. Furthermore, insomnia preceded states of relapse in 56.2%
of interviewees and came about concurrently in 22.1% of states of reversion. Taken as a
whole, subjects afflicted with sleep disturbances show evidence of higher rates of
psychiatric disorders than the general population and these disturbances may be presumed
to be the cause of their onset or recurrence rather than transpiring as symptoms (Ohayon
and Roth, 2003).
Clocks and Aging: The Ensuing Susceptibility to Internal Desynchrony
The aging population is most susceptible to the depletion of chronobiological
rhythms. The elderly are predisposed to chronodisruption due to ocular aging and
suboptimal photoreception necessary for circadian photoentrainment (Turner and
Mainster, 2008). Ocular aging consists of the aging of the crystalline lens and the
decreasing size of the pupil, culminating in a significant reduction of phototransduction
by RGCs, with the former blocking the absorption of favourable blue light (Turner and
Mainster, 2008). In 2008, Turner and Mainster calculated the levels of circadian
photoreception decrease experienced throughout the aging process by multiplying human

34. 34
crystalline lens transmission by pupil diameter and subsequently measuring melatonin
suppression sensitivity from light sources with wavelengths between 350 and 700
nanometres (Table 1). The results illustrated an age-dependent reduction in melatonin
suppression in response to blue light. From Table 1, it may be estimated that a person 95
years of age exhibits one-tenth of the level of photoreception seen in a ten year old.
Likewise, a person who is 85 years old requires 7.58 times brighter light exposures than a
15 year old in order to attain equivalent levels of photoreception.
Table 1 Circadian photoreception at different ages. The numbers in the table indicate
the level of retinal illumination achieved by the ages listed in the top row in contrast to
those in the left column. They also indicate the relative level of light exposure required
by those in the left column to achieve similar levels of effective photoreception as those
in the top row (Turner and Mainster, 2008).
In addition to ocular aging, the elderly are particularly prone to insufficient light
exposure because of their habitual lifestyles (Turner and Mainster, 2008). Reduced
crystalline lens transmission and pupil diameter require brighter light exposures for the
elderly in order to maintain sufficient photoreception, however, residential lighting is
excessively dim and lacking in blue spectrum wavelengths compared to environmental

35. 35
light (Fig 7) (Turner and Mainster, 2008). The link between circadian desynchrony and
scarce bright light exposure was investigated by Campbell et al. (1988), who recorded
levels of light exposure in 13 Alzheimer’s patients and 10 healthy elderly controls of
similar ages. The data, based on five days of recording subjects in their natural routines
at home, revealed that subjects rarely received exposure to ambient light in excess of
2000 lux. Furthermore, Alzheimer’s patients received 0.5 hours of bright illumination in
comparison to one hour in the control group and, in turn, the control group received one-
third to two-thirds less the amount encountered by healthy younger people. These figures
are even lower in those elderly subjects who are institutionalized in nursing homes and
retirement living centres (Turner and Mainster, 2008). Campbell et al. (1988) noted the
sleep deficits prevalent in both of these groups, therefore, light deficiency may be
implicated in circadian rhythm disturbances in the elderly, as well as the potential
neuropsychiatric illnesses in which they are involved.
Figure 7 Illuminance levels in a variety of settings. Residential lighting typically
ranges from 100 to 500 lux, however, proper physical and especially mental health

36. 36
require environmental light exposures exceeding 1000 to 3000 lux, such as sunlight and
other sources of bright light (Turner and Mainster, 2008).
Like the aging population, those with cataracts have inadequate levels of circadian
photoreception due to reduced ocular light transmission and smaller pupils (Turner and
Mainster, 2008). In these cases, the crystalline lens is surgically replaced with an
intraocular lens (IOL), which typically blocks ultra-violet radiation and restores blue
light-inducing photoreception, however, some IOLs block blue light, resorting to
previous ophthalmologic standards (Turner and Mainster, 2008). Although some patients
with IOLs are lacking in circadian light exposures, IOLs have proven to be beneficial for
photoreception in the aging population (Turner and Mainster, 2008). As of yet, research
on the effects of aging on photosensitive RGCs remains controversial. Together, ocular
aging and light deficiency are responsible for the dampening of SCN output signals and
circadian amplitudes in the elderly to some extent, consequently leading to internal
desynchrony.
An alternative region that appears to be associated with the attenuation of the
biological timekeeping system in the aging population is the SCN. Nygard et al. (2005)
attributed the weakened ability of the central oscillator to synchronize with external
stimuli, the dampening of activity and temperature cycles and disruptions in the sleep-
wake cycle to the altered electrophysiology of the aging SCN. Nygard and colleagues
(2005) used cell-attached and whole cell recordings to study the rhythm of spontaneous
firing and synaptic transmissions in the ventrolateral region of the SCN. The
ventrolateral portion of the SCN receives input from the RHT and neurons in this region
mediate inhibitory synaptic transmission by expressing vasoactive intestinal polypeptide
(VIP) (Nygard et al., 2005). Single neurons in the ventrolateral region rhythmically

37. 37
alternate between periods of silence and activity (Nygard et al., 2005). Recordings
conducted on slices of the SCN in vitro showed that young mice have a smaller
proportion of silent cells during the day, whereas such rhythmicity appeared to be absent
in older mice as a higher proportion of silent cells fired both during the day and the night.
These results point to an altered response to light in aged mice, with the SCN as a target
of the aging process as seen by the modified firing properties of individual neurons and
subsequently changed SCN output signals (Nygard et al., 2005).
A recent study by Biello et al. (2009) demonstrated that the aging process alters
the central pacemaker by diminishing its response to phase shifting stimuli. This may be
the reason why the elderly exhibit advanced behavioural rhythms and lose the capacity to
temporally adapt to the environment (Biello et al., 2009). Biello et al. (2009) compared
the phase shifting properties of various neurotransmitters thought to be involved in
entraining the SCN in young and old mice. Glutamate, histamine and NMDA all delayed
the phase of rhythmicity in young mice, and thus are thought to be involved in photic
pathways, however, older mice did not respond as strongly (Biello et al., 2009). The
application of neurotransmitters thought to be involved in non-photic signaling pathways,
Muscimol, a GABA agonist, and 8-OH DPAT, a serotonin agonist, resulted in phase
advances in young mice, whereas older mice showed lesser responses. Gastrin-releasing
peptide and neuropeptide Y induced comparable phase shifts in both young and old mice.
These results are consistent with previous findings and signify the ability of the aging
SCN to phase shift in response to some stimuli, though not all, perhaps implicating the
disruption of particular synaptic pathways and neurotransmitter systems in the

38. 38
dysfunction of the aging SCN (Penev et al., 1995; Palomba et al., 2008; Biello et al.,
2009).
Since its discovery over twenty years ago, evidence demonstrating that the pineal
production of melatonin declines with aging is now a widely accepted fact. Sack et al.
(1986) demonstrated this concept by performing periodic assays for melatonin’s major
urinary metabolite 6-hydroxymelatonin, and hence measuring the total nocturnal
production of melatonin. Sack and collaborators conducted assays for three consecutive
nights in the summer and winter across a wide range of healthy adults, including medical
students, hospital personnel and retirement home residents. After adjusting for
demographic variables of height, weight, gender, sleep patterns, smoking, alcohol and
coffee consumption, a significant negative correlation was found between age and
melatonin for both men and women. The same results were attained by Zhou et al.
(2003) by performing assays for melatonin on saliva, which also revealed that the decline
in cyclic melatonin production begins in middle-age, with these subjects having 60% of
the amplitude measured in young controls. Consideration must be given to the possibility
that such weakened melatonin levels in old age may be due to light deficits.
Collectively, the age-related factors of light deficiency, ocular aging, deteriorated
electrical SCN rhythms, altered neurotransmitter signaling and diminished melatonin
production may be responsible for the vast array of circadian perturbations observed in
the elderly. Such perturbations include the dampening of circadian amplitudes and output
signals, the inability to synchronize with the environment, cognitive impairment,
advanced activity phases, lengthened free-running circadian period lengths, sleep
disturbances and psychiatric disorders (Nygard et al., 2005; Turner and Mainster, 2008;

39. 39
Biello et al., 2009). The most frequently reported sleep-wake cycle alterations in old age
include fragmented sleep with less restoration, an overall phase advance of the sleep-
wake cycle with earlier bedtimes and earlier awakenings, increased daytime drowsiness
and insomnia (Campbell et al., 1988; Biello et al., 2009).
The Prevalence of Sleep Disturbances in the Aging Population
Recall that the timing and amount of sleep are determined by circadian and
homeostatic sleep control mechanisms, respectively (Naylor et al., 2000). Dijk et al.
(1999) investigated the interplay of the circadian pacemaker and homeostatic factors in
sleep regulation and how they change with aging. The circadian rhythms of 13 older
subjects, ranging from 65 to 75 years old, and 11 younger subjects, ranging from 20 to 30
years old, were assessed using polysomnographic recordings and it was found that older
people wake up one hour earlier than predicted by the endogenous rhythms of core body
temperature and plasma melatonin with which sleep is normally synchronized. The
subjects were placed in states of temporal disorder and the amplitude of the core body
temperature rhythm in the elderly was reduced by 20 to 30% compared to younger
subjects. The older subjects exhibited high levels of sleep fragmentation and shorter
periods of sleeping, with the most fragmentation taking place when body temperature was
on the rise, thus suggesting that they are more sensitive to waking signals from the central
oscillator (Dijk et al., 1999). Following sleep deprivation, Dijk et al. (1999) observed
homeostatic control systems in operation, however, deep slow-wave sleep on EEGs was
markedly less in older subjects. These results indicate that the age-dependent decrease in
sleep quality and earlier sleep onset and wake times are due to the hindered ability of

40. 40
circadian mechanisms to promote sleep during the geophysical morning and the hindered
ability of homeostatic mechanisms in enforcing sleep propensity (Dijk et al., 1999).
The degeneration of the circadian timing system in the elderly was depicted in a
study by Huang et al. (2002), in which sleep-wake cycles and phases of rest and activity
were measured in routine settings. The study employed the use of wrist actigraphy over
twenty-four hour periods for five to seven consecutive days in young subjects ranging
from 21 to 34 years old, middle-aged subjects of 36 to 44 years old, old subjects of 61 to
79 years old and the oldest subjects of 80 to 91 years old. Those subjects showing
extreme preferences for activity in the morning or evening were excluded from the
investigation. In comparison to the young and middle-aged subjects, the old and oldest
subjects exhibited decreased sleep time, decreased sleep efficiency, longer sleep latency,
a higher number of nocturnal awakenings, a higher number of naps and the highest levels
of sleep fragmentation (Table 2) (Huang et al., 2002). Actigraph readings revealed
attenuated rhythms of rest and activity in the old and oldest subjects, with the lowest
daytime activity and the highest levels of activity during the night. In addition, the data
from these two subject groups are indicative of minimal coupling between sleep and
environmental Zeitgebers (Huang et al., 2002). These results are suggestive of the
impairment of sleep-wake cycles and rest-activity rhythms with aging.
Table 2 Characteristics of the sleep-wake cycle are presented in the context of the four
age groups under study. The old and oldest subjects spent the most time in bed, however,

41. 41
with the lowest amounts of actual sleep time. The old and oldest subjects took the
longest to fall asleep, had the lowest levels of sleep efficiency, the highest numbers of
nocturnal awakenings, the highest number of naps and the highest sleep fragmentation
indices (Huang et al., 2002).
Recent research has given credence to the potential involvement of circadian
clock gene alterations and their profound implications for rhythms of sleep and
wakefulness in the aging population. Malatesta et al. (2007) analyzed CLOCK protein
levels in the neurons of the medullary reticular formation, the brain centre that
participates in the regulation of the sleep-wake cycle, in both young and old rats.
Immunocytochemical techniques were applied at different phases of the light-dark
circadian cycle. Low CLOCK levels were found in the old rats in the nerve cell
compartments under scrutiny, including the cytoplasm, rough endoplasmic reticulum,
nucleus, nucleolus and chromatin. Malatesta and colleagues (2007) speculate that these
depressed levels of CLOCK protein in the neurons of the medullary reticular formation
are associated with significantly disturbed sleep-wake cycles in the elderly.
The Depletion of Chronobiological Rhythms and the Development of
Psychiatric Disorders with Age
The aging population is most susceptible to the depletion of chronobiological
rhythms, and thus, the development of psychiatric disorders in the elderly merits
attention. Previous sections have outlined the relationships between circadian rhythm
abnormalities, perturbed sleep-wake cycles and aging. It may be hypothesized that
senescence not only predisposes the elderly to chronodisruption and sleep deficits, but
also increases their risk for developing frequently comorbid psychiatric illnesses (Fig. 8).
The relationship between aging and depression via ocular dysfunction was evaluated by
Jean-Louis and colleagues (2005). Recall ocular aging results in suboptimal

42. 42
photoreception necessary for circadian photoentrainment. Study subjects’ ages averaged
68.3 years, with 27% being visually impaired according to ophthalmologic assessments.
Low ambient light exposures corresponded with depressed mood states when controlling
for demographic factors and medical complications (Jean-Louis et al., 2005). Ocular
pathologies such as glaucoma, ocular hypertension and cataracts appear to intensify this
relationship by negating light input to the master oscillator, thereby compromising sound
mental health in the elderly (Jean-Louis et al., 2005).
Figure 8 The implications of circadian rhythms in human mental health. A disruption
in the sleep-wake cycle reflects impaired circadian clock functioning, which
synergistically leads to the progression and maintenance of psychiatric disorders. The
aging population is most susceptible to the depletion of chronobiological rhythms and
sleep deficits, and thus, the development of psychiatric disorders in the elderly merits
attention.
Malformed circadian rhythms and disrupted sleep parameters were previously
discussed in regards to Alzheimer’s disease, which is common in the elderly. A study by

43. 43
Mishima et al. (1999) evaluated fluctuating levels of melatonin, which is thought to
decline with age (Sack et al., 1986), and rest-activity rhythms in elderly patients with
Alzheimer’s disease. Wrist actigraphy was used to assess circadian rest-activity rhythms
and blood samples were assayed for plasma melatonin concentrations. The first study
group consisted of Alzheimer’s patients with ages averaging 75.7 years and the second
group consisted of dementia-free residents of the same nursing-home facility whose ages
averaged 78.3 years, with the latter being free of disturbed sleep-wake cycles. The study
was conducted in conditions of light below 150 lux and minimal physical exercise in
order to prevent the suppression of melatonin. The Alzheimer’s patients showed
considerably reduced amplitudes of melatonin secretion, with several patients displaying
atypical peak secretion levels during the day, and less total daily secretions in comparison
to the control group (Mishima et al., 1999). In addition, the rest-activity rhythms of the
Alzheimer’s patients proved to be quite erratic. A similar study reported insufficient light
exposure in these patients (Ancoli-Israel et al., 1997). This study establishes a positive
correlation between dampened melatonin rhythms and disturbed sleep-wake patterns and
rest-activity cycles, all of which are characteristic of elderly Alzheimer’s patients
(Mishima et al., 1999; Volicer et al., 2001; Mahlberg et al., 2008).
As previously described, there is a temporal misalignment of circadian rhythms,
sleep-wake cycles and light exposures observed in schizophrenic patients. Martin et al.
(2001) evaluated these factors in an aged population of schizophrenic patients, consisting
of 14 men and 14 women whose ages averaged 58.3 years. An Actillume wrist monitor
was used to measure both light exposure and activity levels. The dramatic results
indicated that reduced light exposure was linked to weakened circadian rhythms and

44. 44
sleep fragmentation, especially with age. The mean light exposure among the 28 subjects
was less than 1000 lux, which worsened with age, and correlated with depressed mood
and increased severity of psychiatric symptoms. These patients exhibited an excessive
number of nocturnal awakenings, sometimes leading to insomnia for more than three
hours per night. These sleep disturbances resulted in more daytime napping, and
therefore, less daytime activity with substandard neuropsychological functioning and
poor cognition. Actigraph recordings produced one-fifth of the robust amplitude
measured in control participants. Collectively, these findings suggest possible roles for
light deficiency, sleep disturbances, attenuated circadian rhythms, lifestyle and age status
in this psychiatric disorder (Martin et al., 2001). However, the administration of anti-
psychotic medications in many of the subjects may have confounded the results and
further studies are required to delineate their contribution, if any, to these disturbed
behavioural rhythms in comparison to those subjects who are not taking medication
(Martin et al., 2001).
Possible Treatments and Chronobiotics for Circadian Dysfunction
With circadian rhythm disturbances as characteristic of various sleep disorders
and psychiatric disorders, an assortment of chronobiological therapies has been proposed
to alleviate their symptoms. The major internal Zeitgeber melatonin has been suggested
as an effective pharmacological treatment for a range of circadian disruptions, including
circadian rhythm sleep disorders, jet lag, shift-work maladaptation and free-running
rhythms in the blind (Fischer et al., 2003). Recall that blind individuals are susceptible to
sleep disorders and compromised neuropsychiatric conditions. Fischer et al. (2003)
investigated whether a single one-time melatonin administration could temporarily

45. 45
entrain blind individuals, thus synchronizing their sleep-wake cycles and melatonin
rhythms and improving sleep conditions. Twelve men ages 18 to 40, incapable of
photoentrainment, were given 5mg of melatonin one hour before bedtime, with both the
subjects and administrators being unaware if the substance being given was melatonin or
a placebo. In contrast to the placebo, melatonin increased total sleep time and sleep
efficiency while decreasing the number of nocturnal awakening episodes. In regards to
endocrine processes, adrenocorticotropic (ACTH) hormone and cortisol secretion are
normally inhibited during the first half of sleep and rise in the latter half (Fischer et al.,
2003). With this normally entrained rhythm being desynchronized in blind individuals, a
single dose of melatonin improved sleep by realigning these hormonal rhythms.
In light of its ability to synchronize circadian rhythms, improve sleep quality and
regulate the hypothalamic-pituitary-adrenal axis, melatonin has the potential to serve as
an anti-depressant (Fischer et al., 2003). This prospect is further supported in a study by
Benedetti et al. (2001), in which similar results as Fischer and colleagues (2003) were
obtained, however, with the additional finding that melatonin decreased the need for the
use of benzodiazepines. In the context of this study, psychoactive benzodiazepine drugs
were being taken by elderly subjects in order to treat insomnia (Benedetti et al., 2001).
Melatonin administration before bedtime eliminated the use of benzodiazepines entirely
in 65% of subjects, while reducing their use by 25 to 66% in 20% of subjects. Anti-
depressants that improve sleep quality could therefore be crucial to treating depressive
disorders.
Recently, the new chronobiotic agomelatine has been put forward as a potential
anti-depressant because of its coordinating effects on the circadian rest-activity rhythm

46. 46
and its mitigating effects on symptoms of depression and anxiety (Kasper et al., 2010).
Agomelatine acts as an agonist at melatonin receptors MT1 and MT2 and as an
antagonist at serotonin receptors (Kasper et al., 2010). A study by Kasper and colleagues
(2010) compared the effects of agomelatine with sertraline, a selective serotonin reuptake
inhibitor (SSRI) known by its trade name as Zoloft, on patients with MDD. Agomelatine,
in contrast to sertraline, increased the amplitude of rest-activity rhythms within one week.
According to wrist actigraphs and sleep diaries, agomelatine improved sleep quality and
the ease of falling asleep, and relieved feelings of depression and anxiety without any
major adverse effects. Further research is required to establish agomelatine as an
effective treatment for sleep disorders and affective disorders.
Selective serotonin reuptake inhibitors are often employed in the treatment of
affective disorders, including major depressive disorder, seasonal affective disorder and
bipolar disorder. Sprouse et al. (2006) demonstrated the ability of fluoxetine, an SSRI, to
alter firing activity of neurons in the SCN, and hence, circadian rhythmicity. At first,
extracellular recordings of spontaneous neuron firing in the hypothalamic SCN slices of
rats in vitro revealed no change in rhythm in response to fluoxetine. This was thought to
be due to the loss of endogenous serotonin levels in culture conditions in vitro (Sprouse et
al., 2006). When fluoxetine was paired with tryptophan, a serotonin precursor,
microelectrode recordings revealed concentration-dependent phase advances in SCN
rhythms (Sprouse et al., 2006). Further research is being conducted to ascertain the
magnitude and direction of circadian phase shifts in clinical applications of fluoxetine
(Sprouse et al., 2006).

47. 47
As a mood stabilizer, lithium is used in the treatment of bipolar disorder as it
counteracts both mania and depression (Hafen and Wollnik, 1994). Lithium lengthens
the circadian period of the central pacemaker through direct pharmacological effects
(Iwahana et al., 2004). The drug inhibits the action of a glycogen synthase kinase 3, an
enzyme which targets the transcription factors of the molecular oscillator for degradation
via phosphorylation, thereby slowing the molecular oscillator and relieving the advanced
rhythm disturbances often seen in bipolar patients (Hafen and Wollnik, 1994; Iwahana et
al., 2004). Most antidepressants, including lithium, need 2 to 8 weeks in order to exert
their effects and induce a favourable response in patients (Wu et al., 2009).
Unfortunately, there is a high risk for suicide in patients with bipolar disorder depression
and a treatment regimen that evokes a rapid response and maintains this response is
necessary (Wu et al., 2009).
Despite its transient effects, sleep deprivation has been discovered as one of the
most prompt and efficient chronotherapeutics, reducing depressive symptoms in 40 to
60% of patients within 24 to 48 hours (Wu et al., 2009). A study by Wu et al. (2009)
evaluated the standard medications lithium and sertraline against a chronotherapeutic
augmentation treatment (CAT), consisting of medications, sleep deprivation, bright light
therapy and sleep phase advances. Forty-nine patients diagnosed with bipolar disorder
according to the DSM were randomly assigned to either the medication group or the CAT
group. CAT subjects were kept awake for 33 hours and then exposed to 5000 lux light
for two hours for three consecutive days following sleep deprivation, as well as three
days of gradual sleep phase advances. The CAT group exhibited a substantial relief of
depressive symptoms as early as two days into treatment, and this effect lasted for seven

48. 48
weeks, at which time 12/19 CAT subjects had gone into remission (Fig. 9). A
combination of established chronotherapies appears to be most effective in alleviating the
symptoms of this particular psychiatric disorder.
Figure 9 In accordance with the Hamilton Rating Scale for Depression, CAT subjects,
whose treatment consisted of medications, sleep deprivation, bright light therapy and
sleep phase advances, displayed a considerable reduction in depressive symptoms in
comparison to those solely on medications. This difference was seen as early as Day 2
and was maintained for 7 weeks (Wu et al., 2009).
Bright light therapy in the morning has long been known as an effective treatment
for both MDD and SAD patients. A study by Lewy et al. (1998) demonstrated the
superior efficacy of morning versus evening bright light therapy. This was based on the
prediction that SAD patients would have phase delayed rhythms during winter depression
(Lewy et al., 1998). Forty-five patients with MDD or bipolar disorder with a winter
seasonal pattern and 49 controls participated in the study for six weeks. The participants
were treated with bright light therapy in their homes for two weeks either in the morning,
between 6 to 8 AM, or in the evening, between 7 to 9 PM, then subjected to a week of
light withdrawal, and then treated with light in the opposing time period. Blood samples
were taken once a week in dim light and assayed for melatonin in order to determine

49. 49
circadian phase positions relative to nocturnal melatonin onset. Morning bright light
therapy, which phase advanced patients, proved more effective than that in the evening,
which phase delayed patients, with the former inducing a 27% decrease in depressive
symptoms and intensifying those symptoms during the withdrawal period (Lewy et al.,
1998). The authors of this study suggest the application of bright light therapy without
delay upon awakening for the best results in patients with SAD (Lewy et al., 1998). The
phase advancing and phase delaying effects of bright light therapy may be applied in
treatment regimens for the circadian rhythm sleep disorders DSPS and ASPS as well.
With light as the dominant Zeitgeber in the human circadian timekeeping system,
it is no surprise that light exposure is one of the most potent treatments for circadian
rhythm disorders. Recall that photosensitive RGCs best absorb light in the blue sector of
the light spectrum at 460 nm, which is quite similar to the wavelength of environmental
light (Turner and Mainster, 2008). A study by Glickman et al. (2006) investigated the
optimal spectral wavelength for phototherapy in 24 SAD patients. Blue light emitting
diode boxes gave off 468 nm light to 11 subjects, while the red light emitting diode boxes
gave off 654 nm to 13 subjects. Light therapy was administered everyday for three
weeks for durations of 45 minutes between 6 to 8 AM. According to the Hamilton
Depression Rating Scale, subjects who had been given short blue wavelength light
treatments scored 7.3 points lower on depressive symptoms than those who had been
exposed to longer red wavelength light, thus confirming blue light as optimal for light
therapy (Glickman et al., 2006). As previously outlined in bright morning light therapy,
the timing of light exposure is critical in light therapy. A recent study by Goel et al.
(2006) applied 10 000 lux light for one hour immediately upon awakening to patients

50. 50
with chronic MDD diagnoses for five weeks. The results indicated substantial
improvement in symptoms, with depression scores improving by 53.7 % and with
remission rates of 50%. Light therapy is predicted to be most effective in conjunction
with the abovementioned treatment strategies of melatonin and sleep deprivation (Goel et
al., 2006).
The widespread success of light therapy is derived from its ability to phase shift
the endogenous circadian pacemaker, and so it is used to alleviate the detrimental effects
of jet lag, shift-work, circadian rhythm sleep disorders, Alzheimer’s disease and bipolar
disorder, to name a few. Optimal photoreception may be achieved in the aging
population with ample natural light exposure, IOLs and bright, appropriately timed
residential lighting (Turner and Mainster, 2008). Structural designs that allow for bright
environmental light exposure during the geophysical day and limited light exposure in the
evening would allow for most advantageous entrainment and internal synchrony (Oren et
al., 1997; Turner and Mainster, 2008). Increasing public awareness of these strategies for
harmonious synchronization and optimal well-being are not only profitable to the elderly
in preventing circadian malfunction but to all age groups.
Research Proposal
Alleviating Sleep Disorders to Alleviate Psychiatric Disturbances
Rationale
Circadian dysfunction, notably decreased circulating melatonin levels and
disturbed rest-activity rhythms, and the deterioration of the sleep-wake cycle are
characteristic of the aging population (Campbell et al., 1988; Zhou et al., 2003; Nygard et
al., 2005; Turner and Mainster, 2008). In light of those previously mentioned studies that

51. 51
have enhanced sleeping conditions and alleviated depressive symptoms through the use
of melatonin and light therapy, future studies warrant investigating whether correcting
circadian misalignment with these circadian resetting agents will attenuate sleep
disturbances and psychiatric pathologies in the elderly (Lewy et al., 1998; Fischer et al.,
2003; Goel et al., 2006). The proposed study will evaluate the efficacy of a treatment
combining timed bright light exposure and exogenous melatonin, two primary Zeitgebers,
in consolidating circadian rhythms and alleviating sleep disturbances and psychiatric
symptoms in elderly patients with Alzheimer’s disease.
Participants
Participants will be gathered from a geriatric facility and will be comprised of
Alzheimer’s patients ranging from the ages of 60 to 90 years old. Written consent forms
and approval from an institutional ethics board will be attained prior to commencing the
study.
Preliminary Assessment
Prior to commencing treatment, initial assessments of sleep-wake cycles and rest-activity
rhythms will be made for a duration of one week. This information will be gathered
through nurse and staff ratings, subject interviews and with the use of Actillume wrist
monitors (Martin et al., 2001). Actillume recordings will also indicate the amount of
light exposure obtained by the participants. Saliva samples will be taken every 30
minutes during the daytime in dim light conditions within a 24 hour period and assayed
for melatonin concentrations in order to assess the level of circadian misalignment (Zhou
et al., 2003). In addition, the total amount of nocturnal melatonin production will be

52. 52
measured by performing assays for its major urinary metabolite 6-hydroxymelatonin
(Sack et al., 1986). Cognitive tests and psychiatric assessments will be applied to assess
the severity of psychiatric symptoms.
Methods
The study will be conducted in a double-blind manner using placebos. Participants will
randomly be assigned to one of two groups. The first group will receive bright light
exposure of 3000 lux daily between the hours of 6AM and 9AM and 3 mg of melatonin
one hour before bedtime for one month (Lewy et al., 1998; Fischer et al., 2003; Turner
and Mainster, 2008). The use of blue light emitting diodes would be best (Glickman et
al., 2006). The second group will receive light exposure of 100 lux daily between the
hours of 6AM and 9AM and a placebo pill one hour before bedtime for one month. The
use of red light emitting diodes would be best (Glickman et al., 2006). The study will be
conducted in a double-blind manner since the nurses and staff, as well as the participants
themselves, will be unaware as to whether they are administering a treatment regimen or
placebo. A final assessment will be made after one month of treatment by applying the
same procedures as outlined in the preliminary assessment. The healthcare professionals
performing the final cognitive tests and psychiatric assessments will be uninformed as to
which group participants were assigned.
Controls
The only difference between the two groups will be the treatment regimen administered
as they will otherwise be living in the same geriatric facility, be age-matched and have a
diagnosis of dementia. The placebo pills will serve as controls for exogenous melatonin.

53. 53
The use of longer wavelength light will serve as a control as it has been established that
light of this intensity and of the red spectrum are insufficient for the body’s circadian
demands (Glickman et al., 2006; Turner and Mainster, 2008).
Predicted Outcomes
The combined treatment of bright morning light therapy and exogenous melatonin will
most likely result in improved central pacemaker functioning, which will be evident with
decreased activity during the night and increased activity during the day. Treatment will
lead to an increase in sleep efficiency, sleep duration, and deep sleep, with a decrease in
daytime napping, nocturnal awakenings and agitation. Nocturnal melatonin levels will
increase, not only due to the application of exogenous melatonin, but also due to
improved sleeping parameters and light exposure. Cognition and mood will be enhanced
as well. Melatonin rhythms and light exposure are dampened in Alzheimer’s patients,
therefore, this treatment has the potential to restore the compromised rest-activity cycles,
sleep-wake patterns and neuropsychiatric functioning seen in these elderly patients
(Ancoli-Israel et al., 1997; Mishima et al., 1999).
Limitations
The placebo effect, medications and the severity of dementia-related symptoms may
prove to be limitations in this study. This study may be expanded to test for the placebo
effect by including an additional age-matched control group living in the same geriatric
facility with diagnoses of dementia, however, this group would receive neither the
treatment regimen nor placebos. This control group would account for other variables
that may lead to improvements in participants, for example, the context of the facility in