• Save
The Implications of Desynchronized Circadian Rhythms in Human Mental Health and Susceptibility in the Aging Population
Upcoming SlideShare
Loading in...5
×
 

The Implications of Desynchronized Circadian Rhythms in Human Mental Health and Susceptibility in the Aging Population

on

  • 2,916 views

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 ...

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.

Statistics

Views

Total Views
2,916
Views on SlideShare
2,883
Embed Views
33

Actions

Likes
0
Downloads
0
Comments
0

3 Embeds 33

http://www.techgig.com 18
http://www.linkedin.com 14
http://www.docshut.com 1

Accessibility

Upload Details

Uploaded via as Adobe PDF

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

    The Implications of Desynchronized Circadian Rhythms in Human Mental Health and Susceptibility in the Aging Population The Implications of Desynchronized Circadian Rhythms in Human Mental Health and Susceptibility in the Aging Population Document Transcript

    • 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 Abstract The organization of the mammalian circadian system relies on temporal orderbetween behavioural and physiological rhythms that are critical to the normal functioningof 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 tothe progression and maintenance of a variety of psychiatric disorders. The agingpopulation is most susceptible to the depletion of chronobiological rhythms and sleepdeficits, and thus, the development of psychiatric disorders in the elderly warrantsattention. By evaluating previous and current literature, it was found that internaltemporal disorder in humans may result from both internal and external factors thatdisrupt the coordinated symphony of the SCN and peripheral oscillators. Sleep disordersand neuropsychiatric illnesses transpire as a result of this chronodisruption. Evidencesuggests that sleep disturbances are a causal factor of psychiatric illness, rather than beingmere complications. It is proposed that senescence not only predisposes the elderly tochronodisruption and sleep deficits, but also increases their risk for developing frequentlycomorbid psychiatric illnesses. Increasing public awareness of the multitude of strategiesavailable for harmonious synchronization and optimal well-being are profitable to theelderly in preventing circadian malfunction.
    • 3 Table of ContentsIntroduction ....................................................................................................................... 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 ..........................................................................................9Review 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 ........................................................................................... 25Synthesis 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 ...................................... 44Research Proposal........................................................................................................... 50 Alleviating Sleep Disorders to Alleviate Psychiatric Disturbances ........................................ 50Acknowledgments ........................................................................................................... 55References ........................................................................................................................ 56
    • 4IntroductionIntroduction and Overview of Biological Rhythms in Mammals: TheOrigin and Nature of Periodicities Cellular biology is organized in a temporal manner, with overt circadianorganization pervading all cells of the mammalian system. Virtually all organismsexhibit behaviours that follow circadian cycles of rhythmicity, allowing them to operatein synchrony with the environment. Such rhythmicity is the function of a biologicalclock that is endogenous to the organism (Aschoff, 1965). Several lines of evidencedemonstrate that these biological clocks are inherent to living systems. First andforemost is the fact that behaviours continue to cycle in the absence of environmentaltime cues, negating the idea that rhythmicity is simply a reflexive response toperiodicities in the environment (Aschoff, 1965). Biological oscillations are defined byperiods, measured as the amount of time between two identical phases of behaviour(Aschoff, 1965). Additional supporting evidence is observed when an organism isexposed to an asynchronous environment lacking external time cues, such as continuousdarkness, for example, where it will reveal behavioural rhythms with a periodicity ofapproximately twenty-four hours (Aschoff, 1965). These rhythms are appropriatelytermed ‘circadian rhythms,’ derived from the Latin terms circa, meaning approximately,and dies meaning day (Aschoff, 1965). Therefore, a circadian clock shows endogenousunremitting oscillations that free-run under constant conditions and displays a periodicityof about twenty-four hours (Aschoff, 1965). In a synchronized state, the circadian rhythm of a mammal is entrained to therotation of the earth about its axis through external time cues known as Zeitgebers, ofwhich the light-dark cycle is dominant, followed by temperature (Aschoff, 1965). One
    • 5theory on the origin of periodicities postulates that life originated on Earth in the face ofbombardment by cosmic rays (He et al., 2000). Those cells that attempted to replicateduring daylight were destroyed, while those replicating at night when radiation was at aminimum proliferated (He et al., 2000). An archetypal biological clock arose in order toconfine DNA replication to the dark period as cells exploited these periodic signals fortheir survival (He et al., 2000). Zeitgebers, therefore, maintain a sense of harmonybetween the periodicity of mammals and that of the environment. Internal biologicaltimekeeping mechanisms in mammals allow them to anticipate those physiological stateswhich 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 aretemperature compensated, maintaining constant periodicities despite changes inphysiological temperatures. The mechanisms underlying this process, however, are as ofyet unknown.The Light-Dark Cycle, Photoreceptors and the Retinohypothalamic Tract The sustained cyclical nature of biological systems in spite of a lack of Zeitgebersdemonstrates that these rhythms are produced by an endogenous circadian clock and notby the daily periodicities of the environment. In mammals, the so-called master circadianclock 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 tobe resynchronized by photoentrainment, that is, the ability to coordinate internalphysiological rhythms with external rhythms (Lucas et al., 2001). This is done byconsulting with changes in light luminance and wavelength over the period of a twenty-
    • 6four hour day and adjusting accordingly with phase delays or advances, allowingmammals to perform behaviours at suitable times in correlation with different seasonsand different locations (Lucas et al., 2001). In mammals, light is the dominant Zeitgeberfor entrainment, with the retinohypothalamic tract (RHT) as the main circuit throughwhich light information reaches the SCN (Hattar et al., 2002). Lucas et al. (2001)demonstrated the lack of contribution by rod and cone photoreceptors to circadianphotosensitivity by generating rodless coneless mice by combining a cl transgene with adiphtheria-based toxin rdta. These rodless coneless mice continued to display phaseshifts of locomotor activity and suppression of pineal melatonin at night in response tolight pulses (Lucas et al., 2001). As a result, an alternative retinal component wasthought to be necessary for photoreception. A subset of retinal ganglion cells (RGCs) containing the photopigmentmelanopsin form the retinohypothalamic tract that projects to the suprachiasmatic nucleus(Fig. 1) (Hattar et al., 2002). Hattar et al. (2002) established melanopsin as a circadianphotoreceptor by injecting RGCs with Lucifer Yellow for fluorescent labeling and thenstaining them for melanopsin immunoreactivity. Melanopsin-positive RGCs appeared tobe directly sensitive to light and innervated neurons of the SCN, which then managed thenon-visual lighting information and aligned the circadian clock accordingly (Hattar et al.,2002). RGCs thus form a large photosensitive receptive field within the outer nuclearlayer of the mammalian retina that detects environmental illumination, permittingfavourable physiological and neurobiological responses (Hattar et al., 2002).
    • 7Figure 1 The retinohypothalamic tract and photic input pathway in the circadiantimekeeping system of mammals. Intrinsically photosensitive retinal ganglion cellscontaining the photopigment melanopsin are located in the outer nuclear layer of themammalian retina. The axons of RGCs transmit information on the light-dark cycle inthe 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 anteriorhypothalamus as the central circadian oscillator in mammals. Lesion and transplantationstudies performed by Ralph et al. (1990) produced arrhythmic mice through the ablationof the SCN, resulting in locomotor and metabolic activities that lacked periodicities ofany kind. Subsequent tissue transplantation of a wild-type donor SCN into the hostresulted in the restoration of circadian rhythmicity as seen in overt behaviours. Throughneural projections and hormonal signals the SCN synchronizes other central oscillators inthe brain, whose efferent projections then coordinate the physiological activity of targetorgans directly or indirectly (Panda and Hogenesch, 2004; Reiter, 1991). Projectionsfrom the SCN to the subparaventricular zone of the hypothalamus are transmitted to themedial preoptic region, which conducts thermoregulation in a circadian manner (Moore,
    • 81983; Panda and Hogenesch, 2004). The subparaventricular zone also projects onto thedorsomedial nucleus of the hypothalamus, which monitors fluctuating hormone levelsand 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 paraventricularnucleus (PVN) (Klein et al., 1971). Neurons of the PVN synapse onto the preganglionicsympathetic neurons in the intermediolateral zone of the lateral horns of the thoracicspinal cord (Klein et al., 1971; Perreau-Lenz et al., 2003). These preganglionic neuronsinfluence neurons in the superior cervical ganglia whose efferent fibres innervate thepineal gland (Fig. 2) (Klein et al., 1971). The pineal gland produces the neurohormonemelatonin from tryptophan and secretes it into the bloodstream, allowing it to mediate thebrainstem circuits that control the sleep-wake cycle as it promotes sleep (Perreau-Lenz etal., 2003). During scotophase, or the dark period of the light-dark cycle, melatoninsecretion reaches a maximum since the SCN has reduced activation, thus removing theinhibition of sympathetic neurons and promoting melatonin production in the pinealgland (Perreau-Lenz et al., 2003). It follows that the neuronal and hormonal outputs ofthe SCN to autonomous oscillators in the brain and their ensuing projections coordinatethe proper timing of a variety of physiological functions over the twenty-four hourgeophysical day, including but not limited to the sleep-wake control system, hormonesecretion, hunger and satiety and body temperature (Panda and Hogenesch, 2004).
    • 9Figure 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 aresponse in the PVN. Neurons of the PVN innervate the preganglionic sympatheticneurons of the thoracic spinal cord, which then synapse onto the superior cervical gangliawhose efferent fibres innervate the pineal gland. The pineal gland is the production sitefor 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 andevery other cell of the human body. Historically, Drosophila melanogaster has been themodel 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 thegeneration 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
    • 10transcription-translation autoregulatory feedback loops with both excitatory andinhibitory components (Fig. 3) (Clayton et al., 2001; Shearman et al., 2000). Thefundamental factors in this molecular mechanism are the transcription factors CLOCKand 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 todimerize through protein-protein interactions (Clayton et al., 2001). In the circadian processes of the core clock molecular mechanism, Clk and Bmal1genes are transcribed and their protein products heterodimerize when adequateconcentration levels are reached (Shearman et al., 2000). These dimers bind toregulatory DNA sequences, or E-boxes, that initiate the transcription of the mammaliancryptochrome 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 translocateto the nucleus, where PER2 proteins stimulate the synthesis of BMAL1, in antiphase withthe concentration of the three PER proteins, thereby acting as a positive regulator of theBMAL1 loop (Shearman et al., 2000). Conversely, CRY proteins bind to CLOCK-BMAL1 dimers, inhibiting the stimulatory effect they exert on the DNA sequencesencoding 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 removedand CLOCK-BMAL1 dimers recommence transcription and maintain the twenty-fourhour oscillation of the circadian clock mechanism (Clayton et al., 2001). The characteristic twenty-four hour periodicity of the circadian clock mechanismis generated through post-translational modifications, phosphorylation and cellular
    • 11localization and stability of protein products, leading to time delays (Ikeda et al., 2003).Cytosolic factors, such as ions and second messengers, exhibit biological oscillations andsupport transcription-translation feedback loops (Ikeda et al., 2003). In this fashion, eachstandalone circadian clock cell is composed of a molecular oscillator and the rhythmmaintaining effects of post-translational mechanisms. Further investigation of thisprocess and other clock components is currently underway. Overall, the molecular clockproduces a synchronized rhythmic output from the SCN, which is then conveyedsynaptically and humorally to other brain oscillators and peripheral tissues (Clayton etal., 2001). In this manner, the output of the master oscillator coordinates variousphysiological and behavioural mammalian systems.Figure 3 The molecular oscillator within circadian clock cells of the SCN.Transcription-translation feedback loops with excitatory and inhibitory componentsregulate internal rhythmicity within the cell (Clayton et al., 2001).
    • 12 Mammalian physiological and behavioural systems exhibit biological oscillatorypatterns that harmonize internal conditions with the rhythmic external world. This reviewwill focus on the implications of desynchronized circadian rhythms in human mentalhealth. The hypothesis to be proposed is that a disruption in the sleep-wake cycle reflectsimpaired circadian clock functioning, which synergistically leads to the progression andmaintenance of psychiatric disorders. The aging population is most susceptible to thedepletion of chronobiological rhythms, and thus, the development of psychiatric disordersin the elderly merits attention. This will be done by evaluating previous and currentliterature and proposing future directions.Review of LiteratureThe Impact of Molecular Clocks on Human Physiology, Behaviour andNeuronal Function: Circadian Regulation of Physiological Pathways The endogenous circadian clock permeates through almost every physiologicaland behavioural process in the human body and has wide implications for health.Humans exhibit circadian rhythmicity in such behaviours and physiological processes assleep and wakefulness, hormone secretion, thermoregulation, feeding, metabolism,attentiveness and memory (Clayton et al. 2001; Takahashi et al., 2008). The clock genesthat sustain biological oscillations in the suprachiasmatic nucleus also regulate thecorresponding twenty-four hour human cycle through rhythmic neural and hormonaloutput signals to peripheral tissues (Yoo et al., 2004). In this manner, peripheral organsare able to modify their temporal functioning accordingly (Fig. 4) (Yoo et al., 2004).
    • 13Figure 4 Circadian rhythmicity in human behaviours and physiological processes.Rhythmic solar signals entrain the cellular clocks of neurons in the SCN through afferentretinal innervations. Neural and hormonal outputs from the SCN subsequently adjust thephase of peripheral organs throughout the body. The SCN employs both neural efferents and humoral signals to entrain other brainoscillators, whose roles in coordinating various physiological processes are crucial (Silveret al., 1996; Abe et al., 2002). Recall the abovementioned projections from the SCN tothe 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 etal., 1983; Girotti et al., 2007). The neurotransmitters glutamate and GABA mediatesynaptic 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 mediateparasympathetic and sympathetic signaling centres, the sleep-wake control system, thearousal system, locomotor activity, body temperature, cardiovascular activity andhormone secretion. Therefore, the circadian regulation of the synthesis and release ofcentral nervous system neurotransmitters and neuropeptides, and the ensuing entrainment
    • 14of brain oscillators, ensures the synchrony of tissue rhythms with the twenty-four hourgeophysical day. The outputs of the SCN master clock not only coordinate brain oscillators but alsoperipheral organs in order to orchestrate physiological oscillations. In addition tohormonal cues, direct neural control of peripheral targets is achieved via the autonomicnervous system (Cailotto et al., 2005). The SCN may also indirectly control the phase ofperipheral oscillators by regulating the sleep-wake cycle and therefore the rhythm offeeding behaviour (Cailotto et al., 2005). As a result, an inconsistent feeding schedulecan disturb the harmonious alignment between the SCN and the peripheral organsinvolved as it acts as an external entraining agent (Cailotto et al., 2005). Therefore, thetranscription-translation feedback loops of the core clock mechanism not only maintainrhythmicity in the central oscillator and its clock-controlled genes but also generatecircadian outputs to peripheral targets, the details of which are as of yet not fullyunderstood (Duffield et al., 2002).Peripheral Oscillators It has been established that the clock genes expressed in the core mechanism ofthe master suprachiasmatic nucleus are rhythmically expressed in peripheral circadianoscillators located throughout the human body (Yamazaki et al., 2000; Duffield et al.,2002; Yoo et al., 2004). Balsalobre et al. (2000) examined clock-controlled geneexpression in peripheral mammalian tissues by inducing rhythmicity in immortalized rat-1 fibroblasts through serum shock. cDNA microarrays revealed a chronologicalproduction of messenger RNA in response to serum shock and pharmacologicaltreatment, signifying the circadian regulation of gene expression (Balsalobre et al., 2000).
    • 15Previously believed to rhythmically dampen after two to seven twenty-four hour cycleswithout input from the SCN, Yoo and colleagues (2004) have demonstrated thatperipheral oscillators maintain endogenous rhythmicity whilst displaying desynchronyamongst 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 toreveal strong inherent oscillations of bioluminescence in both the SCN and peripheraltissues ex vivo. Furthermore, in SCN-lesioned mice, bioluminescence rhythms persistedfor 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 inherentoscillations of bioluminescence in these tissues (Yoo et al., 2004). Peripheral tissues isolated in culture, including but not limited to the previouslymentioned lungs, cornea, pituitary gland and liver, express clock-controlled genes thatconfer distinctive circadian period and phase properties to those structures (Yoo et al.,2004). As such, these circadian properties are distinct in different organs and contributetemporally to their physiological functioning (Yoo et al., 2004). The SCN does not
    • 16generate but rather coordinates the phase of autonomous peripheral oscillators, therebyinhibiting internal desynchrony between tissue-specific target clocks and theirsynchronized phase relationship with the external environment (Yamazaki et al., 2000;Yoo et al., 2004). The phase of each peripheral oscillator induces rhythmic geneexpression, for example that of Per1, resulting in circadian protein product activity,which in turn regulates rhythmic metabolic events in different tissues throughout thehuman body (Ripperger et al., 2000). The phase of oscillations can be altered byadjusting the feedback of peripheral clocks characteristic of a tissue to internal andexternal Zeitgebers originating from the SCN and environment, respectively (Yamazakiet al., 2000).Clock Mechanism Disruptions and Internal Desynchrony Lead to Disease The organization of the mammalian circadian system, as reviewed above, relieson temporal order between behavioural and physiological rhythms that are critical to thenormal functioning of the body and human health. Thus, the concept of the harmfuleffects that would ensue as a result of disorder between these phase relationships and thecyclical expression of clock-controlled genes readily presents itself as there are numerousavenues through which to disrupt this fragile system (Yamazaki et al., 2000). Internaltemporal disorder in humans may result from both internal and external factors thatdisrupt the coordinated symphony of the SCN and peripheral oscillators. Predominantexternal factors include light deficiency and irregularity, jet lag, shift work, food intakeand social activities (Skene et al., 1999; Reddy et al., 2002; Solonin et al., 2009; Turnerand Mainster, 2008; Girotti et al., 2009). Internal factors include the disturbance ofproper photoreception, visual loss, decreased melatonin levels and circadian clock gene
    • 17mutations (Czeisler et al., 1995; Lockley et al., 1997; Turner and Mainster, 2008). Aspreviously discussed, peripheral oscillators will desynchronize amongst themselveswithout temporal adjustments provided by the SCN through neural and hormonal outputs(Yoo et al., 2004). Proper SCN operations ensure good health by mediating rhythms ofsleep-wake systems, hormone secretion and metabolism, therefore, chronodisruption maybe the cause of a range of diseases (Jiapei et al., 1998; Yamazaki et al., 2000; Cailotto etal., 2005). Light irregularity, or improperly timed ocular light exposure, may result inchronodisruption by modifying nocturnal melatonin synthesis in the pineal glanddepending on its duration, wavelength, intensity and time of administration (Czeisler etal., 1995; Skene et al., 1999). Ocular light exposure in the scotophase decreasesmelatonin production (Skene et al., 1999). Low circulating levels of melatoninthroughout the body may result in numerous diseases as it has been shown to contributebeneficially to the antioxidant capability of blood plasma (Benot et al., 1999).Environmental light is the predominant Zeitgeber in circadian timekeeping, and, for thatreason, maintains the greatest influence on human physiological and psychologicalhealth. Photosensitive RGCs best absorb light in the blue sector of the light spectrum at460 nm, which is quite similar to the wavelength of environmental light (Turner andMainster, 2008). Modern artificial lighting, unfortunately, provides only about 1% ofnatural light intensity and is distinguished by red spectrum wavelengths, which isinsufficient for suitable photoreception (Turner and Mainster, 2008). Instead, optimalphotoreception requires blue light of high intensity and duration for photoentrainment andfavourable health (Turner and Mainster, 2008).
    • 18 Light deficiency fails to entrain the SCN to the geophysical day and results in asubsequent free-running periodicity, as exemplified by blind individuals (Skene et al.,1999). Blind individuals may be categorized, according to the extent of visual loss, ashaving some light perception, and thus photoreception, and those with no light perceptioncapabilities and no photoreception whatsoever (Skene et al., 1999). In a study by Skeneet al. (1999), 77% of blind subjects capable of photoreception showed normal circadianrhythmicity, while 67% of those with no light perception showed free-running periodlengths and internal desynchrony. The latter also suffered from daytime somnolence, anexcessive need for sleep during the daytime, and insomnia during the night due to thetemporal disorder of melatonin synthesis and release (Lockley et al., 1997). Furtherevidence of the dire consequences of light deficiency, with light as the chief biologicalZeitgeber, is demonstrated by the fact that blind subjects who had no eyes after havingundergone bilateral enucleation showed free-running period lengths ranging from 24.13to 24.81 hours, albeit in the presence of non-photic signals such as food intake and socialactivities (Skene et al., 1999). On the whole, blind individuals incapable ofphotoentrainment exhibit higher levels of circadian disruption and dampened SCNoutputs, thus making them susceptible to diseases, particularly sleeping disorders andcompromised neuropsychiatric conditions (Lockley et al., 1997; Jean-Louis et al., 2005). Girotti and colleagues (2009) recently demonstrated the role of food intake as anon-photic Zeitgeber. Their study revealed characteristic rhythms of clock geneexpression in each element of the hypothalamic-pituitary-adrenal axis, where a decreasein food intake in the photophase of the light-dark cycle altered glucocorticoid secretionand clock gene expression (Girotti et al., 2009). Physiological processes may be
    • 19entrained to intermittent feeding schedules, with glucocorticoids synchronizing amultitude of peripheral organs (Stephan, 1986; Girotti et al., 2009). Shift work employees in industrial sectors, medicine and the military show signsof considerable circadian dysfunction, including such symptoms as biochemicaldisturbances, mood disorders, sleeping disorders, metabolic syndrome and an overallfeeling of malaise (Solonin et al., 2009). James et al. (2007) recently investigated theeffects of night shift work on the sleep-wake cycle, outlining desynchrony between themaster circadian clock and the night schedule as subjects maintained day activeentrainment. This was done by comparing oscillatory clock gene expression in peripheralblood mononuclear cells with the temporally shifted sleep-wake cycle. The exposure toartificial light at uncharacteristic times communicates odd entraining signals to the SCNand results in perturbed circadian outputs and melatonin synthesis (James et al., 2007).The differential responses of peripheral oscillators to the altered phase of input signalsalso leads to a lack of internal coordination, hence resulting in feelings of malaise. Shiftwork sleep disorder is a circadian rhythm sleep disorder in which the afflicted complainof daytime sleepiness, insomnia and poor sleep quality (Ursin et al., 2009). Othercircadian 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 viacircadian desynchrony. The core clock mechanism experiences much more difficulty inacclimatization to advanced time zones rather than delayed time zones because theformer 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 circadianrhythms of mPer expression in the SCN adjust swiftly to advanced light pulses, while
    • 20rhythmic mCry1 expression advanced gradually. Conversely, they found that a six hourdelay in local time entailed mPer and mCry adjusting in sequence by the secondoscillation. This study describes the different effects of traveling east or west, oradvancing or delaying, respectively, on the master clock and the prospective temporaldesynchrony between mPer and mCry expression as a result of jet lag, with ensuinghealth complications (Reddy et al., 2002). The final factor contributing to clock mechanism disruptions, internaldesynchrony, and thus, disease are genetically mutated circadian clock genes andpolymorphisms. Current research is heavily focused on identifying those clock genealterations that result in a variety of disrupted circadian behaviours. Clock genemutations may be implicated in the deterioration of the regimented functioning of bothmolecular oscillators and their rhythmic neural and hormonal outputs and their effectswill be discussed in subsequent sections of this review. Cumulatively, theaforementioned internal and external factors, particularly insufficient and temporallydisplaced environmental light, may induce biological stress and disturb the coordinatedrhythmicity of physiological processes and behaviours necessary for optimal humanhealth. This review will now turn to those sleep disorders and neuropsychiatric illnessesthat transpire as a result of chronodisruption.Clocks and Circadian Sleep Disorders A profound relationship exists between clock gene variations and changes inbehavioural rhythmicity, most notably sleep parameters in humans. The timing andamount 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
    • 21specific phases throughout the twenty-four hour light-dark cycle, while the latter dependson the need for sleep (Naylor et al., 2000). In a study by Naylor et al. (2000), a mutationin Clk in the mouse was found to alter not only the timing and length of sleep but sleephomeostatis as well. Naylor and colleagues evaluated the effects of the CLOCKtranscription factor mutation by comparing sleep and electroencephalographic (EEG)activity in homozygous and heterozygous mutants and wild-type mice under conditionsof 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 twohours less per day in contrast to wild-type mice, with lower amounts of non-rapid eyemovement sleep seen. Following periods of sleep deprivation, Clk homozygous micedisplayed 39% less sleep than heterozygotes and wild-type mice. One may attribute theseresults to discrepancies of entrainment to the light-dark cycle, however, divergent sleepbehaviours were also seen when mice were free-running in continuous darkness (Nayloret al., 2000). A study by Laposky et al. (2005) employed the same investigativemeasures in mice with a deletion of Bmal1 and discovered a diminished rhythm of sleepand wakefulness, a weakened response to sleep deprivation and lengthened sleep periods. Whereas mutations in the mammalian cryptochrome genes Cry1 and Cry2 holdimplications for sleep homeostatis, Period genes are not essential for homeostatic sleepregulation (Wisor et al., 2002; Shiromani et al., 2004). A study by Shiromani andcollaborators (2004) examined the effects of Per1, Per2, Per3 and double Per1-Per2mutations on sleep factors and found that Per2-mutant and double mutant mice exhibitedlonger periods of wakefulness, with less slow-wave sleep (SWS) and rapid-evemovement (REM) sleep, than wild-type and Per1 deficient mice in states of entrainment.
    • 22Double mutant strains became arrhythmic in aperiodic conditions, however, the amountof time spent awake, in SWS and in REM sleep was equivalent to that in an entrainedstate even after 36 days, thus signifying the maintenance of total sleep levels. Per genesare more so involved in altering the phase position of the sleep-wake cycle (Shiromani etal., 2004). In conclusion, circadian clock gene alterations have profound implications forboth rhythms of sleep and wakefulness and sleep propensity, although knowledge as totheir exclusivity to one or the other is currently unknown. Variations in circadian clock genes have a variety of effects on the configurationof human sleep. Delayed sleep phase syndrome (DSPS) is the most commonly reportedcircadian rhythm sleep disorder whose features include sleep periods delayed by 2 to 6hours, 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 oldgraduate student with DSPS whose average bedtime was 3:38 a.m. and usually awoke at1:47p.m. in order to feel replenished (Campbell and Murphy, 2007). Campbell andMurphy (2007) examined the sleep and body temperature rhythms of the subject incomparison to those of 3 normal age-matched subjects with both parties in aperiodicconditions free from environmental cues. Whereas the time between the core bodytemperature minimum and sleep onset in control subjects was 1.63 hours, the graduatestudent 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 thecontrol subjects. One may refute these results by suggesting that the lighting conditionsin temporal isolation contributed to the lengthening of the free-running period in theDSPS subject, however, the authors noted that illumination was below 50 lux, which is
    • 23insufficient for optimal photoreception (Campbell and Murphy, 2007). Therefore, DSPScauses an abnormal endogenous period length and internal desynchrony between sleepand body temperature rhythms, resulting in poor sleep efficiency and duration. The previous findings may be attributed to a polymorphism in the circadian clockgene 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. Theyfound that the 4-repeat allele, as opposed to the 5-repeat allele, was substantiallyprevalent in DSPS patients in contrast to the control group. Recall post-translationalmechanisms, such as phosphorylation, affect the stability of protein products and functionto create time delays in the circadian clock mechanism. PER is targeted for degradationthrough phosphorylation by CKI ε, making it unavailable for dimerization and subsequentnuclear localization and thus causing it to oscillate (Archer et al., 2003).The shorter variation of PER3 contains fewer phosphorylation sites than its longercounterpart and may be the cause of polymorphic differences in function and hencelonger endogenous period length seen in DSPS (Archer et al., 2003). A study by Takanoand associates (2004) revealed that a missense mutation in the N408 allele in CKI εfunctions as a safeguard against DSPS by modifying its autophosphorylation activity. In contrast to DSPS, advanced sleep phase syndrome (ASPS) dictates humanbehaviours marked by early bedtimes, early morning waking and a short endogenousperiod length (Xu et al., 2005). ASPS is caused by a mutation in a residue in the caseinkinase 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
    • 24indicative of the different pathological symptoms that may occur as a result ofphosphorylation levels in different PER proteins. In another case, through mutagenesisscreenings of related ASPS patients, Xu et al. (2005) found a threonine to alaninemissense mutation at amino acid 44 in the human CKIδ gene. Subjects under study hadan average bedtime of 6:12 p.m., compared to the control average of 11:24 p.m., and anaverage 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 consequentlyleads to a shortened activity rhythm and advanced phase of activity in an entrained settingof 12 hours of light and 12 hours of dark (Xu et al., 2005). The etiology of the abovementioned circadian rhythm sleep disorders may beattributed to circadian clock gene polymorphisms and mutations, whereas obstructivesleep apnea syndrome (OSAS) and its symptoms produce arrythmicity in clock genefunctioning. This arrythmicity may be credited to fluctuating levels of factors circulatingthrough the blood (Burioka et al., 2008). Burioka et al. (2008) have measured Per1mRNA expression in peripheral blood mononuclear cells in those patients with severeOSAS using polymerase chain reaction analysis over a twenty-four hour period. Incontrast to similar healthy controls, the eight OSAS participants showed no circadianrhythms of Per1 mRNA expression throughout the day and abnormal elevations ofplasma noradrenaline. Elevated noradrenaline levels and sympathetic activity contributedto an increase in the transcription of Per1 during sleep (Burioka et al., 2008).Interestingly, continuous positive airway treatment for a period of three months improvednot only shallow sleep with frequent waking due to hypoxic episodes, but also dailyoscillations of Per1 transcription (Burioka et al., 2008). The effects of continuous
    • 25positive airway treatment on clock gene transcription thereby illustrate a mechanism bywhich a circadian rhythm sleeping disorder may be managed by improving clock genefunction. Fatal familial insomnia (FFI) is a debilitating disorder marked by sleepdeficiency. FFI is a prion disease distinguished by a 178 codon prion protein genemutation (Reder et al., 1995). A study by Sforza et al. (1995) studied six subjects withthis disease using twenty-four hour polygraphic recordings in a sleep laboratory. Theirfindings revealed severe reductions in total sleep time, impairments in the circadianregulation 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-wakecycle (Sforza et al., 1995). Over the course of the disease, symptoms of insomniaprogressively worsen and circadian rhythms dampen substantially until the total sleeptime 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 FFIpatients and found that concentrations of the hormone decreased in accordance withdisease progression, further compromising circadian rhythmicity.Clocks and Psychiatric Disorders Just as the misalignment of the circadian pacemaker and clock gene mutations andpolymorphisms have been associated with circadian rhythm sleep disorders, these factorsare implicated in psychiatric disorders. A variety of abnormal endogenous circadianrhythms 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
    • 26demonstrate a correlation between MDD and improper coordination between thecircadian pacemaker and sleeping schedule. Study subjects were comprised of eighteenfemales ranging from 19 to 60 years of age who had been diagnosed with MDDaccording to the Diagnostic and Statistical Manual of Mental Disorders (DSM),excluding those with suicidal tendencies, jet lag, shift work positions and medicationsthat would impede melatonin production. Emens et al. (2009) calculated circadianmisalignment according to the time difference between melatonin production and themidpoint of sleep. Those with larger time differences exhibited a phase delay in centralpacemaker rhythmicity in comparison to the timing of sleep and a higher severity ofsymptoms (Fig. 6). These results demonstrate the interaction between circadiandesynchrony, poor sleep and mild to moderate symptoms of depression, though futurestudies 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 midpointof sleep, also known as the phase angle difference (PAD), the higher the severity ofdepressive symptoms according to the Hamilton Depression Rating Scale (HAM-D).Following a clinical assessment by a health professional, a score higher than 7 on theHAM-D constitutes a diagnosis of MDD (Emens et al., 2009). An alternative route by which disrupted circadian oscillations may facilitate MDDis through the deregulation of mood by the mesolimbic dopaminergic system (Hampp et
    • 27al., 2008). Hampp and associates (2008) ascertained that Per2 mutant mice have reducedlevels of expression of monoamine oxidase A in the mesolimbic dopaminergic system,which is an enzyme that mediates dopamine metabolism. The atypical mood behavioursobserved in these mice may be attributed to this clock gene mutation. Polymorphismsand 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 throughmutagenesis, thereby inhibiting its transcriptional activation of molecular rhythms. Themice were subjected to tests in which they were able to induce rewarding electricalstimulation to themselves via electrodes implanted in the medial forebrain bundle. Clockmutant mice were able to experience euphoria at lower currents than wild type mice andcocaine decreased these current thresholds substantially in the mutants. This response ispredictive of substance abuse as the mice experienced a greater sense of reward uponstimulation because of their hypersensitivity, making them more inclined to abuse suchstimulants (Roybal et al., 2007). These states of ecstasy and substance abuse mimic thecondition of bipolar patients (Roybal et al., 2007). The mood-related behaviours of Clock mutant mice parallel those humans withbipolar disorder, including less depression and less anxiety (Roybal et al., 2007). Thiswas discerned as mice showed little anxiety when subjected to an unprotected arm of araised platform. Conversely, when treated with lithium, a mood stabilizer given tobipolar patients, the mutant mice displayed more wild-type behaviours of high anxiety inthis situation (Roybal et al., 2007). Like the previously mentioned MDD patients, Clockmutant mice have compromised dopaminergic systems, although with increased firing ofdopaminergic neurons that is diminished through the viral insertion of a gene coding for a
    • 28wild type CLOCK protein (Roybal et al., 2007). As the name implies, bipolar disorderalternates between states of mania and depression, with depressive states beingpredominant in the winter months (Roybal et al., 2007). Winter depression, also known as seasonal affective disorder (SAD), involveschanges in circadian genetic factors, the external environment and circulating melatonin(Wehr et al., 2001; Johansson et al.., 2003; Partonen et al., 2007). Certain animalsdisplay photoperiodism, that is, the ability to infer the time of year based on the length ofthe day. Such information is made available by measuring the duration of melatoninrelease 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 notsimilar healthy subjects. Their study measured the duration of melatonin release in dimlight in 55 SAD patients and 55 equivalent healthy subjects throughout the summer andwinter months, with plasma samples being taken every 30 minutes all through the day. InSAD subjects, melatonin release in the scotophase was much more pronounced in thewinter rather than summer, however, no change was observed in those without SADdiagnoses. In regards to circadian genetic mechanisms, Partonen et al. (2007) surmised thegenes Per2, Bmal1 and Npas2, whose products function mutually in the core circadianoscillator, are compromised in SAD. As previously mentioned, BMAL1 is a PAS proteinthat 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 thethree genes in 189 patients and 189 symptom-free controls. Gene-wise logistic regressionanalysis revealed SAD to be related to polymorphisms within all three genes and posing
    • 29the 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 greaterchance of developing SAD compared to the controls, while those with less severe alleliccombinations had a 4 times greater chance. Recently, point mutations have been locatedin the melanopsin gene Opn4 in retinal ganglion cells, which serve to decreasephotosensitivity (Roecklein et al., 2009). As the contrast between light intensities isalready reduced in the winter, these point mutations aggravate that effect as dusk anddawn Zeitgebers cannot be detected and proper photoentrainment cannot occur(Roecklein et al., 2009). Such a hindrance in phototransduction may result in internaldesynchrony, 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 areconfounded in these patients. Abarca et al. (2002) investigated cocaine addiction in Permutant mice in order to ascertain the circadian control of cocaine-induced reward andbehavioural sensitization. A single cocaine injection produced a fivefold increase inlocomotion 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 inwhich one consisted of a rod pattern of texture and the other of circles. Cocaineadministration was always associated with the same floor division. After repeatedcocaine injections, wild type mice became sensitized to cocaine-associated factors, Per1mutants showed no sensitization and Per2 mutants showed an intense sensitizedbehavioural reaction. While both wild type and Per2 mutant mice preferred the divisionassociated with cocaine injections, Per1 mutants did not prefer the side associated with
    • 30reward. In addition, stronger behavioural responses to the drug were seen in the morningthan at night. Since all three groups displayed similar levels of locomotor activity inresponse to a single cocaine injection, it may be inferred that cocaine addiction, ratherthan acute application, is managed by the clock genes Per1 and Per2 with opposingeffects in the circadian system (Abarca et al., 2002). Previous discussions highlighted aberrant dopaminergic systems and clock genemutations in MDD and bipolar disorder mice models. These same conditions areobserved in mice addicted to cocaine. McClung and colleagues (2005) found that a lossof function point mutation in Clock results in the same cocaine sensitization behavioursoutlined by Abarca et al. (2002), with Clock mutants displaying a greater degree ofsensitivity to the rewarding feelings of cocaine. This may be credited to increased levelsof tyrosine hydroxylase activity, an enzyme involved in dopamine metabolism, andtherefore, heightened amounts of dopaminergic transmission in the reward centres ofmice without functional CLOCK proteins (McClung et al., 2005). Alcoholism, anotherform of substance abuse possibly under circadian control in humans, may be associatedwith excessive levels of glutamate in the extracellular fluid, as suggested by Per2 mutantmice whose levels of glutamate reuptake transporters in the nervous system aresignificantly reduced (Spanagel et al., 2005). These mice display augmented levels ofvoluntary 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 oftenprevalent in patients with Alzheimer’s disease, which is common in the elderly. Manyvictims of this neurodegenerative illness exhibit what is referred to as ‘sundowning’, or
    • 31the 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, betweensundowning and circadian rhythms in a cohort of 25 Alzheimer’s patients and ninehealthy subjects. Their results revealed that those Alzheimer’s patients who undergosundowning showed increased nocturnal locomotor activity, with lower amplitudesduring the day, and major phase delays in both activity and body temperature incomparison to controls. Furthermore, these subjects had severely reduced amplitudes ofbody temperature and disrupted sleep parameters. These results imply that patients whosundown may be suffering from disturbances in their rhythms, however, otherenvironmental factors must be considered in these habitual states of aggravation (Voliceret al., 2001). One study that has shed some light on this issue is by Mahlberg andassociates (2008), in which cranial computed tomography revealed significant levels ofpineal calcification in AD patients, thereby limiting melatonin synthesis to sup-optimallevels 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 showstrong disturbances in their sleep-wake cycles, melatonin patterns and light exposure, yetresearch 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 sleepefficiency. 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
    • 32own activity, and the temporal misalignment of these input light signals may exacerbatehis established desynchrony even further (Wulff et al., 2006).Synthesis and SummaryThe Coalescence of Circadian Rhythms and Sleep Disorders and TheirSynergistic Neurobehavioural Consequences There is a widely held assumption that sleep deficits are the secondary effects ofpsychiatric disorders. While this may certainly be the case under some circumstances,evidence would lead one to speculate that sleep disturbances are a causal factor ofpsychiatric illness, rather than being mere complications. A disruption in the sleep-wakecycle reflects impaired circadian clock functioning, which synergistically leads to theprogression and maintenance of a variety of psychiatric disorders. Sleep-wake cycles areperturbed in most if not all of the previously mentioned psychiatric disorders, and manyof the studies discussed implicated irregular clock gene functioning. Recall the study byEmens et al. (2009), whose results demonstrated a temporal misalignment between thecentral circadian pacemaker and the sleep-wake cycle, the degree of which correspondedto the severity of clinical psychiatric symptoms experienced. Over 10 years earlier,Boivin and collaborators (1997) released similar findings from a study in which 24healthy adults were subjected to internal desynchrony by living according to 30 hour and28 hour sleep-wake cycles. Through the use of psychometric response scales, they tooshowed varying mood states based on the degree of displacement between the sleep-wakecycle and circadian rhythmicity. The successful treatment of MDD seems to involve the management of sleepdisturbances, indicating their contribution to this psychiatric disorder (Ohayon and Roth,
    • 332003). In 2003, Ohayon and Roth interviewed a representative sample of the populationof the United Kingdom, Germany, Italy and Portugal, totaling 14,915 participants.Participants were questioned about their sleep habits, sleep symptoms, current mentalhealth status and history and subsequently diagnosed according to the Diagnostic andStatistical 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 ofsix 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 fiveyears 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 awhole, subjects afflicted with sleep disturbances show evidence of higher rates ofpsychiatric disorders than the general population and these disturbances may be presumedto be the cause of their onset or recurrence rather than transpiring as symptoms (Ohayonand Roth, 2003).Clocks and Aging: The Ensuing Susceptibility to Internal Desynchrony The aging population is most susceptible to the depletion of chronobiologicalrhythms. The elderly are predisposed to chronodisruption due to ocular aging andsuboptimal photoreception necessary for circadian photoentrainment (Turner andMainster, 2008). Ocular aging consists of the aging of the crystalline lens and thedecreasing size of the pupil, culminating in a significant reduction of phototransductionby RGCs, with the former blocking the absorption of favourable blue light (Turner andMainster, 2008). In 2008, Turner and Mainster calculated the levels of circadianphotoreception decrease experienced throughout the aging process by multiplying human
    • 34crystalline lens transmission by pupil diameter and subsequently measuring melatoninsuppression sensitivity from light sources with wavelengths between 350 and 700nanometres (Table 1). The results illustrated an age-dependent reduction in melatoninsuppression in response to blue light. From Table 1, it may be estimated that a person 95years 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 a15 year old in order to attain equivalent levels of photoreception.Table 1 Circadian photoreception at different ages. The numbers in the table indicatethe level of retinal illumination achieved by the ages listed in the top row in contrast tothose in the left column. They also indicate the relative level of light exposure requiredby those in the left column to achieve similar levels of effective photoreception as thosein the top row (Turner and Mainster, 2008). In addition to ocular aging, the elderly are particularly prone to insufficient lightexposure because of their habitual lifestyles (Turner and Mainster, 2008). Reducedcrystalline lens transmission and pupil diameter require brighter light exposures for theelderly in order to maintain sufficient photoreception, however, residential lighting isexcessively dim and lacking in blue spectrum wavelengths compared to environmental
    • 35light (Fig 7) (Turner and Mainster, 2008). The link between circadian desynchrony andscarce bright light exposure was investigated by Campbell et al. (1988), who recordedlevels of light exposure in 13 Alzheimer’s patients and 10 healthy elderly controls ofsimilar ages. The data, based on five days of recording subjects in their natural routinesat home, revealed that subjects rarely received exposure to ambient light in excess of2000 lux. Furthermore, Alzheimer’s patients received 0.5 hours of bright illumination incomparison 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 figuresare even lower in those elderly subjects who are institutionalized in nursing homes andretirement living centres (Turner and Mainster, 2008). Campbell et al. (1988) noted thesleep deficits prevalent in both of these groups, therefore, light deficiency may beimplicated in circadian rhythm disturbances in the elderly, as well as the potentialneuropsychiatric illnesses in which they are involved.Figure 7 Illuminance levels in a variety of settings. Residential lighting typicallyranges from 100 to 500 lux, however, proper physical and especially mental health
    • 36require environmental light exposures exceeding 1000 to 3000 lux, such as sunlight andother sources of bright light (Turner and Mainster, 2008). Like the aging population, those with cataracts have inadequate levels of circadianphotoreception due to reduced ocular light transmission and smaller pupils (Turner andMainster, 2008). In these cases, the crystalline lens is surgically replaced with anintraocular lens (IOL), which typically blocks ultra-violet radiation and restores bluelight-inducing photoreception, however, some IOLs block blue light, resorting toprevious ophthalmologic standards (Turner and Mainster, 2008). Although some patientswith IOLs are lacking in circadian light exposures, IOLs have proven to be beneficial forphotoreception in the aging population (Turner and Mainster, 2008). As of yet, researchon the effects of aging on photosensitive RGCs remains controversial. Together, ocularaging and light deficiency are responsible for the dampening of SCN output signals andcircadian amplitudes in the elderly to some extent, consequently leading to internaldesynchrony. An alternative region that appears to be associated with the attenuation of thebiological timekeeping system in the aging population is the SCN. Nygard et al. (2005)attributed the weakened ability of the central oscillator to synchronize with externalstimuli, 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 spontaneousfiring and synaptic transmissions in the ventrolateral region of the SCN. Theventrolateral portion of the SCN receives input from the RHT and neurons in this regionmediate inhibitory synaptic transmission by expressing vasoactive intestinal polypeptide(VIP) (Nygard et al., 2005). Single neurons in the ventrolateral region rhythmically
    • 37alternate between periods of silence and activity (Nygard et al., 2005). Recordingsconducted on slices of the SCN in vitro showed that young mice have a smallerproportion of silent cells during the day, whereas such rhythmicity appeared to be absentin 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 targetof the aging process as seen by the modified firing properties of individual neurons andsubsequently changed SCN output signals (Nygard et al., 2005). A recent study by Biello et al. (2009) demonstrated that the aging process altersthe central pacemaker by diminishing its response to phase shifting stimuli. This may bethe reason why the elderly exhibit advanced behavioural rhythms and lose the capacity totemporally adapt to the environment (Biello et al., 2009). Biello et al. (2009) comparedthe phase shifting properties of various neurotransmitters thought to be involved inentraining the SCN in young and old mice. Glutamate, histamine and NMDA all delayedthe phase of rhythmicity in young mice, and thus are thought to be involved in photicpathways, however, older mice did not respond as strongly (Biello et al., 2009). Theapplication of neurotransmitters thought to be involved in non-photic signaling pathways,Muscimol, a GABA agonist, and 8-OH DPAT, a serotonin agonist, resulted in phaseadvances in young mice, whereas older mice showed lesser responses. Gastrin-releasingpeptide 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 agingSCN to phase shift in response to some stimuli, though not all, perhaps implicating thedisruption of particular synaptic pathways and neurotransmitter systems in the
    • 38dysfunction 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 pinealproduction 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 majorurinary metabolite 6-hydroxymelatonin, and hence measuring the total nocturnalproduction of melatonin. Sack and collaborators conducted assays for three consecutivenights in the summer and winter across a wide range of healthy adults, including medicalstudents, hospital personnel and retirement home residents. After adjusting fordemographic variables of height, weight, gender, sleep patterns, smoking, alcohol andcoffee consumption, a significant negative correlation was found between age andmelatonin 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 declinein cyclic melatonin production begins in middle-age, with these subjects having 60% ofthe amplitude measured in young controls. Consideration must be given to the possibilitythat such weakened melatonin levels in old age may be due to light deficits. Collectively, the age-related factors of light deficiency, ocular aging, deterioratedelectrical SCN rhythms, altered neurotransmitter signaling and diminished melatoninproduction may be responsible for the vast array of circadian perturbations observed inthe elderly. Such perturbations include the dampening of circadian amplitudes and outputsignals, the inability to synchronize with the environment, cognitive impairment,advanced activity phases, lengthened free-running circadian period lengths, sleepdisturbances and psychiatric disorders (Nygard et al., 2005; Turner and Mainster, 2008;
    • 39Biello et al., 2009). The most frequently reported sleep-wake cycle alterations in old ageinclude fragmented sleep with less restoration, an overall phase advance of the sleep-wake cycle with earlier bedtimes and earlier awakenings, increased daytime drowsinessand 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 andhomeostatic sleep control mechanisms, respectively (Naylor et al., 2000). Dijk et al.(1999) investigated the interplay of the circadian pacemaker and homeostatic factors insleep regulation and how they change with aging. The circadian rhythms of 13 oldersubjects, ranging from 65 to 75 years old, and 11 younger subjects, ranging from 20 to 30years old, were assessed using polysomnographic recordings and it was found that olderpeople wake up one hour earlier than predicted by the endogenous rhythms of core bodytemperature and plasma melatonin with which sleep is normally synchronized. Thesubjects were placed in states of temporal disorder and the amplitude of the core bodytemperature rhythm in the elderly was reduced by 20 to 30% compared to youngersubjects. The older subjects exhibited high levels of sleep fragmentation and shorterperiods of sleeping, with the most fragmentation taking place when body temperature wason the rise, thus suggesting that they are more sensitive to waking signals from the centraloscillator (Dijk et al., 1999). Following sleep deprivation, Dijk et al. (1999) observedhomeostatic control systems in operation, however, deep slow-wave sleep on EEGs wasmarkedly less in older subjects. These results indicate that the age-dependent decrease insleep quality and earlier sleep onset and wake times are due to the hindered ability of
    • 40circadian mechanisms to promote sleep during the geophysical morning and the hinderedability of homeostatic mechanisms in enforcing sleep propensity (Dijk et al., 1999). The degeneration of the circadian timing system in the elderly was depicted in astudy by Huang et al. (2002), in which sleep-wake cycles and phases of rest and activitywere measured in routine settings. The study employed the use of wrist actigraphy overtwenty-four hour periods for five to seven consecutive days in young subjects rangingfrom 21 to 34 years old, middle-aged subjects of 36 to 44 years old, old subjects of 61 to79 years old and the oldest subjects of 80 to 91 years old. Those subjects showingextreme preferences for activity in the morning or evening were excluded from theinvestigation. In comparison to the young and middle-aged subjects, the old and oldestsubjects exhibited decreased sleep time, decreased sleep efficiency, longer sleep latency,a higher number of nocturnal awakenings, a higher number of naps and the highest levelsof sleep fragmentation (Table 2) (Huang et al., 2002). Actigraph readings revealedattenuated rhythms of rest and activity in the old and oldest subjects, with the lowestdaytime activity and the highest levels of activity during the night. In addition, the datafrom these two subject groups are indicative of minimal coupling between sleep andenvironmental Zeitgebers (Huang et al., 2002). These results are suggestive of theimpairment 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 fourage groups under study. The old and oldest subjects spent the most time in bed, however,
    • 41with the lowest amounts of actual sleep time. The old and oldest subjects took thelongest to fall asleep, had the lowest levels of sleep efficiency, the highest numbers ofnocturnal awakenings, the highest number of naps and the highest sleep fragmentationindices (Huang et al., 2002). Recent research has given credence to the potential involvement of circadianclock gene alterations and their profound implications for rhythms of sleep andwakefulness in the aging population. Malatesta et al. (2007) analyzed CLOCK proteinlevels in the neurons of the medullary reticular formation, the brain centre thatparticipates in the regulation of the sleep-wake cycle, in both young and old rats.Immunocytochemical techniques were applied at different phases of the light-darkcircadian cycle. Low CLOCK levels were found in the old rats in the nerve cellcompartments under scrutiny, including the cytoplasm, rough endoplasmic reticulum,nucleus, nucleolus and chromatin. Malatesta and colleagues (2007) speculate that thesedepressed levels of CLOCK protein in the neurons of the medullary reticular formationare associated with significantly disturbed sleep-wake cycles in the elderly.The Depletion of Chronobiological Rhythms and the Development ofPsychiatric Disorders with Age The aging population is most susceptible to the depletion of chronobiologicalrhythms, and thus, the development of psychiatric disorders in the elderly meritsattention. Previous sections have outlined the relationships between circadian rhythmabnormalities, perturbed sleep-wake cycles and aging. It may be hypothesized thatsenescence not only predisposes the elderly to chronodisruption and sleep deficits, butalso increases their risk for developing frequently comorbid psychiatric illnesses (Fig. 8).The relationship between aging and depression via ocular dysfunction was evaluated byJean-Louis and colleagues (2005). Recall ocular aging results in suboptimal
    • 42photoreception necessary for circadian photoentrainment. Study subjects’ ages averaged68.3 years, with 27% being visually impaired according to ophthalmologic assessments.Low ambient light exposures corresponded with depressed mood states when controllingfor demographic factors and medical complications (Jean-Louis et al., 2005). Ocularpathologies such as glaucoma, ocular hypertension and cataracts appear to intensify thisrelationship by negating light input to the master oscillator, thereby compromising soundmental health in the elderly (Jean-Louis et al., 2005).Figure 8 The implications of circadian rhythms in human mental health. A disruptionin the sleep-wake cycle reflects impaired circadian clock functioning, whichsynergistically leads to the progression and maintenance of psychiatric disorders. Theaging population is most susceptible to the depletion of chronobiological rhythms andsleep deficits, and thus, the development of psychiatric disorders in the elderly meritsattention. Malformed circadian rhythms and disrupted sleep parameters were previouslydiscussed in regards to Alzheimer’s disease, which is common in the elderly. A study by
    • 43Mishima et al. (1999) evaluated fluctuating levels of melatonin, which is thought todecline with age (Sack et al., 1986), and rest-activity rhythms in elderly patients withAlzheimer’s disease. Wrist actigraphy was used to assess circadian rest-activity rhythmsand blood samples were assayed for plasma melatonin concentrations. The first studygroup consisted of Alzheimer’s patients with ages averaging 75.7 years and the secondgroup consisted of dementia-free residents of the same nursing-home facility whose agesaveraged 78.3 years, with the latter being free of disturbed sleep-wake cycles. The studywas conducted in conditions of light below 150 lux and minimal physical exercise inorder to prevent the suppression of melatonin. The Alzheimer’s patients showedconsiderably reduced amplitudes of melatonin secretion, with several patients displayingatypical peak secretion levels during the day, and less total daily secretions in comparisonto the control group (Mishima et al., 1999). In addition, the rest-activity rhythms of theAlzheimer’s patients proved to be quite erratic. A similar study reported insufficient lightexposure in these patients (Ancoli-Israel et al., 1997). This study establishes a positivecorrelation between dampened melatonin rhythms and disturbed sleep-wake patterns andrest-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, consistingof 14 men and 14 women whose ages averaged 58.3 years. An Actillume wrist monitorwas used to measure both light exposure and activity levels. The dramatic resultsindicated that reduced light exposure was linked to weakened circadian rhythms and
    • 44sleep fragmentation, especially with age. The mean light exposure among the 28 subjectswas less than 1000 lux, which worsened with age, and correlated with depressed moodand increased severity of psychiatric symptoms. These patients exhibited an excessivenumber of nocturnal awakenings, sometimes leading to insomnia for more than threehours per night. These sleep disturbances resulted in more daytime napping, andtherefore, less daytime activity with substandard neuropsychological functioning andpoor cognition. Actigraph recordings produced one-fifth of the robust amplitudemeasured in control participants. Collectively, these findings suggest possible roles forlight deficiency, sleep disturbances, attenuated circadian rhythms, lifestyle and age statusin this psychiatric disorder (Martin et al., 2001). However, the administration of anti-psychotic medications in many of the subjects may have confounded the results andfurther studies are required to delineate their contribution, if any, to these disturbedbehavioural 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 disordersand psychiatric disorders, an assortment of chronobiological therapies has been proposedto alleviate their symptoms. The major internal Zeitgeber melatonin has been suggestedas an effective pharmacological treatment for a range of circadian disruptions, includingcircadian rhythm sleep disorders, jet lag, shift-work maladaptation and free-runningrhythms in the blind (Fischer et al., 2003). Recall that blind individuals are susceptible tosleep disorders and compromised neuropsychiatric conditions. Fischer et al. (2003)investigated whether a single one-time melatonin administration could temporarily
    • 45entrain blind individuals, thus synchronizing their sleep-wake cycles and melatoninrhythms and improving sleep conditions. Twelve men ages 18 to 40, incapable ofphotoentrainment, were given 5mg of melatonin one hour before bedtime, with both thesubjects and administrators being unaware if the substance being given was melatonin ora placebo. In contrast to the placebo, melatonin increased total sleep time and sleepefficiency while decreasing the number of nocturnal awakening episodes. In regards toendocrine processes, adrenocorticotropic (ACTH) hormone and cortisol secretion arenormally 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, asingle dose of melatonin improved sleep by realigning these hormonal rhythms. In light of its ability to synchronize circadian rhythms, improve sleep quality andregulate the hypothalamic-pituitary-adrenal axis, melatonin has the potential to serve asan anti-depressant (Fischer et al., 2003). This prospect is further supported in a study byBenedetti et al. (2001), in which similar results as Fischer and colleagues (2003) wereobtained, however, with the additional finding that melatonin decreased the need for theuse of benzodiazepines. In the context of this study, psychoactive benzodiazepine drugswere being taken by elderly subjects in order to treat insomnia (Benedetti et al., 2001).Melatonin administration before bedtime eliminated the use of benzodiazepines entirelyin 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 depressivedisorders. Recently, the new chronobiotic agomelatine has been put forward as a potentialanti-depressant because of its coordinating effects on the circadian rest-activity rhythm
    • 46and 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 anantagonist at serotonin receptors (Kasper et al., 2010). A study by Kasper and colleagues(2010) compared the effects of agomelatine with sertraline, a selective serotonin reuptakeinhibitor (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 andthe ease of falling asleep, and relieved feelings of depression and anxiety without anymajor adverse effects. Further research is required to establish agomelatine as aneffective treatment for sleep disorders and affective disorders. Selective serotonin reuptake inhibitors are often employed in the treatment ofaffective disorders, including major depressive disorder, seasonal affective disorder andbipolar disorder. Sprouse et al. (2006) demonstrated the ability of fluoxetine, an SSRI, toalter firing activity of neurons in the SCN, and hence, circadian rhythmicity. At first,extracellular recordings of spontaneous neuron firing in the hypothalamic SCN slices ofrats in vitro revealed no change in rhythm in response to fluoxetine. This was thought tobe due to the loss of endogenous serotonin levels in culture conditions in vitro (Sprouse etal., 2006). When fluoxetine was paired with tryptophan, a serotonin precursor,microelectrode recordings revealed concentration-dependent phase advances in SCNrhythms (Sprouse et al., 2006). Further research is being conducted to ascertain themagnitude and direction of circadian phase shifts in clinical applications of fluoxetine(Sprouse et al., 2006).
    • 47 As a mood stabilizer, lithium is used in the treatment of bipolar disorder as itcounteracts both mania and depression (Hafen and Wollnik, 1994). Lithium lengthensthe 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, anenzyme which targets the transcription factors of the molecular oscillator for degradationvia phosphorylation, thereby slowing the molecular oscillator and relieving the advancedrhythm disturbances often seen in bipolar patients (Hafen and Wollnik, 1994; Iwahana etal., 2004). Most antidepressants, including lithium, need 2 to 8 weeks in order to exerttheir 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 depressionand a treatment regimen that evokes a rapid response and maintains this response isnecessary (Wu et al., 2009). Despite its transient effects, sleep deprivation has been discovered as one of themost prompt and efficient chronotherapeutics, reducing depressive symptoms in 40 to60% 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 chronotherapeuticaugmentation treatment (CAT), consisting of medications, sleep deprivation, bright lighttherapy and sleep phase advances. Forty-nine patients diagnosed with bipolar disorderaccording to the DSM were randomly assigned to either the medication group or the CATgroup. CAT subjects were kept awake for 33 hours and then exposed to 5000 lux lightfor two hours for three consecutive days following sleep deprivation, as well as threedays of gradual sleep phase advances. The CAT group exhibited a substantial relief ofdepressive symptoms as early as two days into treatment, and this effect lasted for seven
    • 48weeks, at which time 12/19 CAT subjects had gone into remission (Fig. 9). Acombination of established chronotherapies appears to be most effective in alleviating thesymptoms 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 andsleep phase advances, displayed a considerable reduction in depressive symptoms incomparison to those solely on medications. This difference was seen as early as Day 2and was maintained for 7 weeks (Wu et al., 2009). Bright light therapy in the morning has long been known as an effective treatmentfor both MDD and SAD patients. A study by Lewy et al. (1998) demonstrated thesuperior efficacy of morning versus evening bright light therapy. This was based on theprediction 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 winterseasonal pattern and 49 controls participated in the study for six weeks. The participantswere 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 oflight withdrawal, and then treated with light in the opposing time period. Blood sampleswere taken once a week in dim light and assayed for melatonin in order to determine
    • 49circadian phase positions relative to nocturnal melatonin onset. Morning bright lighttherapy, which phase advanced patients, proved more effective than that in the evening,which phase delayed patients, with the former inducing a 27% decrease in depressivesymptoms and intensifying those symptoms during the withdrawal period (Lewy et al.,1998). The authors of this study suggest the application of bright light therapy withoutdelay upon awakening for the best results in patients with SAD (Lewy et al., 1998). Thephase advancing and phase delaying effects of bright light therapy may be applied intreatment 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 circadianrhythm disorders. Recall that photosensitive RGCs best absorb light in the blue sector ofthe light spectrum at 460 nm, which is quite similar to the wavelength of environmentallight (Turner and Mainster, 2008). A study by Glickman et al. (2006) investigated theoptimal spectral wavelength for phototherapy in 24 SAD patients. Blue light emittingdiode boxes gave off 468 nm light to 11 subjects, while the red light emitting diode boxesgave off 654 nm to 13 subjects. Light therapy was administered everyday for threeweeks for durations of 45 minutes between 6 to 8 AM. According to the HamiltonDepression Rating Scale, subjects who had been given short blue wavelength lighttreatments scored 7.3 points lower on depressive symptoms than those who had beenexposed to longer red wavelength light, thus confirming blue light as optimal for lighttherapy (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
    • 50with chronic MDD diagnoses for five weeks. The results indicated substantialimprovement in symptoms, with depression scores improving by 53.7 % and withremission rates of 50%. Light therapy is predicted to be most effective in conjunctionwith the abovementioned treatment strategies of melatonin and sleep deprivation (Goel etal., 2006). The widespread success of light therapy is derived from its ability to phase shiftthe endogenous circadian pacemaker, and so it is used to alleviate the detrimental effectsof jet lag, shift-work, circadian rhythm sleep disorders, Alzheimer’s disease and bipolardisorder, to name a few. Optimal photoreception may be achieved in the agingpopulation with ample natural light exposure, IOLs and bright, appropriately timedresidential lighting (Turner and Mainster, 2008). Structural designs that allow for brightenvironmental light exposure during the geophysical day and limited light exposure in theevening would allow for most advantageous entrainment and internal synchrony (Oren etal., 1997; Turner and Mainster, 2008). Increasing public awareness of these strategies forharmonious synchronization and optimal well-being are not only profitable to the elderlyin preventing circadian malfunction but to all age groups.Research ProposalAlleviating Sleep Disorders to Alleviate Psychiatric DisturbancesRationale Circadian dysfunction, notably decreased circulating melatonin levels anddisturbed rest-activity rhythms, and the deterioration of the sleep-wake cycle arecharacteristic of the aging population (Campbell et al., 1988; Zhou et al., 2003; Nygard etal., 2005; Turner and Mainster, 2008). In light of those previously mentioned studies that
    • 51have enhanced sleeping conditions and alleviated depressive symptoms through the useof melatonin and light therapy, future studies warrant investigating whether correctingcircadian misalignment with these circadian resetting agents will attenuate sleepdisturbances 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 treatmentcombining timed bright light exposure and exogenous melatonin, two primary Zeitgebers,in consolidating circadian rhythms and alleviating sleep disturbances and psychiatricsymptoms in elderly patients with Alzheimer’s disease.ParticipantsParticipants will be gathered from a geriatric facility and will be comprised ofAlzheimer’s patients ranging from the ages of 60 to 90 years old. Written consent formsand approval from an institutional ethics board will be attained prior to commencing thestudy.Preliminary AssessmentPrior to commencing treatment, initial assessments of sleep-wake cycles and rest-activityrhythms will be made for a duration of one week. This information will be gatheredthrough nurse and staff ratings, subject interviews and with the use of Actillume wristmonitors (Martin et al., 2001). Actillume recordings will also indicate the amount oflight exposure obtained by the participants. Saliva samples will be taken every 30minutes during the daytime in dim light conditions within a 24 hour period and assayedfor melatonin concentrations in order to assess the level of circadian misalignment (Zhouet al., 2003). In addition, the total amount of nocturnal melatonin production will be
    • 52measured by performing assays for its major urinary metabolite 6-hydroxymelatonin(Sack et al., 1986). Cognitive tests and psychiatric assessments will be applied to assessthe severity of psychiatric symptoms.MethodsThe study will be conducted in a double-blind manner using placebos. Participants willrandomly be assigned to one of two groups. The first group will receive bright lightexposure of 3000 lux daily between the hours of 6AM and 9AM and 3 mg of melatoninone hour before bedtime for one month (Lewy et al., 1998; Fischer et al., 2003; Turnerand Mainster, 2008). The use of blue light emitting diodes would be best (Glickman etal., 2006). The second group will receive light exposure of 100 lux daily between thehours of 6AM and 9AM and a placebo pill one hour before bedtime for one month. Theuse of red light emitting diodes would be best (Glickman et al., 2006). The study will beconducted in a double-blind manner since the nurses and staff, as well as the participantsthemselves, will be unaware as to whether they are administering a treatment regimen orplacebo. A final assessment will be made after one month of treatment by applying thesame procedures as outlined in the preliminary assessment. The healthcare professionalsperforming the final cognitive tests and psychiatric assessments will be uninformed as towhich group participants were assigned.ControlsThe only difference between the two groups will be the treatment regimen administeredas they will otherwise be living in the same geriatric facility, be age-matched and have adiagnosis of dementia. The placebo pills will serve as controls for exogenous melatonin.
    • 53The use of longer wavelength light will serve as a control as it has been established thatlight of this intensity and of the red spectrum are insufficient for the body’s circadiandemands (Glickman et al., 2006; Turner and Mainster, 2008).Predicted OutcomesThe combined treatment of bright morning light therapy and exogenous melatonin willmost likely result in improved central pacemaker functioning, which will be evident withdecreased activity during the night and increased activity during the day. Treatment willlead to an increase in sleep efficiency, sleep duration, and deep sleep, with a decrease indaytime napping, nocturnal awakenings and agitation. Nocturnal melatonin levels willincrease, not only due to the application of exogenous melatonin, but also due toimproved sleeping parameters and light exposure. Cognition and mood will be enhancedas 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).LimitationsThe placebo effect, medications and the severity of dementia-related symptoms mayprove to be limitations in this study. This study may be expanded to test for the placeboeffect by including an additional age-matched control group living in the same geriatricfacility with diagnoses of dementia, however, this group would receive neither thetreatment regimen nor placebos. This control group would account for other variablesthat may lead to improvements in participants, for example, the context of the facility in
    • 54which they are residing and being cared for. The administration of medications in manyof the subjects may confound the results if they contribute to disturbed behaviouralrhythms in comparison to those subjects who are not taking medication. This study maybe revised by differentiating between those subjects taking medication and those who arenot. In regards to the severity of dementia-related symptoms, the participants should becomparable in their states of disease progression and those exhibiting the later stages ofAlzheimer’s should be excluded as they are characterized by severe impairments. Lastly,environmental outdoor light would be optimal for treatment, however, its effects mayconfound the results of the control group since the differences between natural lightingand residential lighting of low lux levels would be quite obvious and possibly skewparticipant and administrator treatment perceptions.
    • 55Acknowledgments My deepest gratitude to Dr. Lakin-Thomas for her continuous guidance,assistance and feedback throughout this project. It is most appreciated.
    • 56References Abarca C, Albrecht U, Spanagel R (2002) Cocaine sensitization and reward areunder the influence of circadian genes and rhythm. Proc Natl Acad Sci U S A 99: 9026–9030. Abe M, Herzog ED, Yamazaki S, Straume M, Tei H, et al. (2002) Circadianrhythms in isolated brain regions. Journal of Neuroscience 22(1): 350-356. Ancoli-Israel S, Klauber MR, Jones DW, Kripke DF, Martin J. (1997) Variationsin circadian rhythms of activity, sleep, and light exposure related to dementia in nursing-home patients. Sleep 20(1): 18-23. Archer SN, Robilliard DL, Skene DJ, Smits M, Williams A, et al. (2003) A lengthpolymorphism in the circadian clock gene Per3 is linked to delayed sleep phasesyndrome and extreme diurnal preference. Sleep 26: 413–415. Aschoff J. (1965) Circadian rhythms in man. Science 148: 1427-1432. Aschoff J. (1978) Phase relations between a circadian rhythm and its zeitgeberwithin the range of entrainment. Naturwissenschaften 65(2): 80-84. Balsalobre A, Marcacci L, Schibler U. (2000) Multiple signaling pathways elicitcircadian gene expression in cultured Rat-1 fibroblasts. Current Biology 10(20): 1291-1294. Benedetti C, Siegrist C, Orlando A, Beltran JM, Tuchscherr L. (2001) Lack ofchanges in serum prolactin, FSH, TSH, and estradiol after melatonin treatment in dosesthat improve sleep and reduce benzodiazepine consumption in sleep-disturbed, middle-aged, and elderly patients. Journal of Pineal Research 30(1): 34-42. Benedetti F, Serretti A, Colombo C, Barbini B, Lorenzi C, et al. (2003) Influenceof CLOCK gene polymorphism on circadian mood fluctuation and illness recurrence inbipolar depression. Am J Med Genet B Neuropsychiatr Genet 123: 23–26. Benot S, Goberna R, Reiter RJ, Garcia-Maurino S, Osuna C, Guerrero JM.(1999) Physiological levels of melatonin contribute to the antioxidant capacity of humanserum. Journal of Pineal Research 27(1): 59-64. Biello SM. (2009) Circadian clock resetting in the mouse changes with age. Age13(4): SI 293-303. Boivin DB, Czeisler CA, Dijk D, Duffy JF, Folkard S, et al. (1997) Complexinteraction of the sleep-wake cycle and circadian phase modulates mood in healthysubjects. Archives of General Psychiatry 54(2): 145-152.
    • 57 Burioka N, Koyanagi S, Endo M, Takata M, Miyata M et al. (2008) Clock genedysfunction in patients with OSAS. Eur. Respir. J. 32:105-112. Cailotto C, La Fleur SE, Van Heijningen C, Wortel J, Kalsbeek A, et al. (2005)The suprachiasmatic nucleus controls the daily variation of plasma glucose via theautonomic output to the liver: are the clock genes involved? European Journal ofNeuroscience 22(10): 2531-2540. Campbell SS, Kripke DF, Gillin JC, Hrubovcak JC. (1988) Exposure to light inhealthy elderly subjects and Alzheimer’s patients. Physiology and Behaviour 42(2): 141-144. Campbell SS, Murphy PJ. (2007) Delayed sleep phase disorder in temporalisolation. Sleep 30(9): 1225-1228. Chang A, Reid KJ, Gourineni R, Zee PC. (2009) Sleep timing and circadianphase in delayed sleep phase syndrome. Journal of Biological Rhythms 24(4): 313-321. Clayton JD, Kyriacou CP, Reppert SM. (2001) Keeping time with the humangenome. Nature 409(6822): 829-831. Czeisler CA, Shanahan TL, Klerman EB, Martens H, Brotman DJ, et al. (1995)Suppression of melatonin secretion in some blind patients by exposure to bright light.New England Journal of Medicine 332(1): 6-11. Dijk D, Duffy JF, Riel E, Shanahan TL, Czeisler CA. (1999) Ageing and thecircadian and homeostatic regulation of human sleep during forced desynchrony of rest,melatonin and temperature rhythms. Journal of Physiology 516(2): 611-627. Duffield GE, Best JC, Meurers BH, Bittner A, Loros JJ, Dunlap JC. (2002)Circadian programs of transcriptional activation, signaling, and protein turnover revealedby microarray analysis of mammalian cells. Current Biology 12(7): 552-557. Emens J, Lewy A, Kinzie JM, Arntz D, Rough J. (2009) Circadian misalignmentin major depressive disorder. Psychiatry Research 168(3): 259-261. Fischer S, Smolnik R, Herms M, Born J, Fehm HL. (2003) Melatonin acutelyimproves the neuroendocrine architecture of sleep in blind individuals. Journal ofClinical Endocrinology and Metabolism 88(11): 5315-5320. Girotti M, Weinberg MS, Spencer RL. (2007) Differential responses ofhypothalamus-pituitary-adrenal axis immediate early genes to corticosterone andcircadian drive. Endocrinology 148(5): 2542-2552. Girotti M, Weinberg MS, Spencer RL. (2009) Diurnal expression of functionaland clock-related genes throughout the rat HPA axis: system-wide shifts in response to a
    • 58restricted feeding schedule. American Journal of Physiology-Endocrinology andMetabolism 296(4): E888-E897. Glickman G, Byrne B, Pineda C, et al. (2006) Light therapy for seasonal affectivedisorder with blue narrow-band light-emitting diodes (LEDs). Biological Psychiatry59(6): 502-507. Goel N, Etwaroo GR. (2006) Bright light, negative air ions and auditory stimuliproduce rapid mood changes in a student population: a placebo-controlled study.Psychological Medicine 36(9): 1253-1263. Gordijn MCM, Beersma DGM, Bouhuys AL, Reinink E, Van Den HoofdakkerRH. (1994) A longitudinal study of diurnal mood variation in depression; characteristicsand significance. Journal of Affective Disorders 31(4): 261-273. Hafen T, Wollnik F. (1994) Effect of lithium carbonate on activity level andcircadian period in different strains of rats. Pharmacology Biochemistry and Behaviour49(4): 975-983. Hampp G, Ripperger JA, Houben T, Schmutz I, Blex C, et al. (2008) Regulationof monoamine oxidase A by Circadian clock components implies clock influence onmood. Curr. Biol. 18:678-83. Hattar S, Liao HW, Takao M, Berson DM, Yau KW. (2002) Melanopsin-containing retinal ganglion cells: architecture, projections, and intrinsic photosensitivity.Science 295: 1065–1070. He YJ, Qi F, Qi SC. (2000) Periodicity of Earth’s orbital chirality and possiblemechanism of biological rhythms. Medical Hypotheses 55(3): 253-256. Hermes MLHJ, Coderre EM, Buijs RM, Renaud LP. (1996) GABA andglutamate mediate rapid neurotransmission from suprachiasmatic nucleus tohypothalamic paraventricular nucleus in rat. Journal of Physiology 496(3): 749-757. Huang Y, Liu R, Wang Q, Van Someren EJW, Xu H, et al. (2002) Age-associateddifference in circadian sleep-wake and rest-activity rhythms. Physiology and Behaviour76(4-5): 597-603. Ikeda M, Sugiyama T, Wallace CS, Gompf HS, Yoskioka T, et al. (2003)Circadian dynamics of cytosolic and nuclear Ca2+ in single suprachiasmatic nucleusneurons. Neuron 38(2): 253-263.
    • 59 Iwahana E, Akiyama M, Miyakawa K, et al. (2004) Effect of lithium on thecircadian rhythms of locomotor activity and glycogen synthase kinase-3 proteinexpression in the mouse suprachiasmatic nuclei. European Journal of Neuroscience19(8): 2281-2287. James FO, Cermakian N, Boivin DB. (2007) Circadian rhythms of melatonin,cortisol, and clock gene expression during simulated night shift work. Sleep 30(11):1427-36. Jean-Louis G, Kripke D, Zizi F, Wolintz A. (2005) Associations of ambientillumination with mood: Contribution of ophthalmic dysfunctions. Physiology andBehaviour 84(3): 479-487. Jiapei D, Van Der Vliet J, Swaab DF, Buijs RM. (1998) Humanretinohypothalamic tract as revealed by in vitro postmortem tracing. The Journal ofComparative Neurology 397(3): 357-370. Johansson C, Willeit M, Smedh C, Ekholm J, Paunio T, et al. (2003) Circadianclock-related polymorphisms in seasonal affective disorder and their relevance to diurnalpreference. Neuropsychopharmacology 28: 734–739. Kasper S, Hajak G, Wulff K, Hoogendijk WJ, Montejo AL, et al. (2010) Efficacyof the novel antidepressant agomelatine on the circadian rest-activity cycle anddepressive and anxiety symptoms in patients with major depressive disorder: arandomized, double-blind comparison with sertraline. Journal of Clinical Psychiatry71(2): 109-120. Kavakli IH, Sancar A. (2002) Circadian photoreception in humans and mice.Molecular Interventions 2(8): 484-492. Klein DC, Weller JL, Moore RY. (1971) Melatonin metabolism: neural regulationof pineal serotonin: acetyl coenzyme A N-acetyltransferase activity. Proceedings of theNational Academy of Sciences of the United States of America 68: 3107-3110. Laposky A, Easton A, Dugovic C, Walisser J, Bradfield C, et al. (2005) Deletionof the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architectureand the response to sleep deprivation. Sleep 28: 395–409. Lewy AJ, Bauer VK, Cutler NL, Sack RL, Ahmed S, et al. (1998) Morning vsevening light treatment of patients with winter depression. Archives of GeneralPsychiatry 55(10): 890-896. Lewy AJ. (2010) To sleep, perchance to reset your body clock. PsychiatricTimes 27(1). Lockley SW, Skene DJ, Tabandeh H, Bird AC, Defrance R, Arendt J. (1997)
    • 60Relationship between napping and melatonin in the blind. Journal of Biological Rhythms12(1); 16-25. Lucas RJ, Freedman MS, Lupi D, Munoz M, David-Gray ZK, Foster RG. (2001)Identifying the photoreceptive inputs to the mammalian circadian system using transgenicand retinally degenerate mice. Behav. Brain Res. 125: 97-102. Mahlberg R, Walther S, Kalus P, Bohner G, Haedel S, et al. (2008) Pinealcalcification in Alzheimers disease: An in vivo study using computed tomography.Neurobiology of Aging 29(2): 203-209. Malatesta M, Fatoretti P, Baldelli B, Battistelli S, Balietta M, et al. (2007) Effectsof ageing on the fine distribution of the circadian CLOCK protein in reticular formationneurons. Histochemistry and Cell Biology 127(6): 641-647. Martin J, Jeste DV, Caliguiri MP, Patterson T, Heaton R. (2001) Actigraphicestimates of circadian rhythms and sleep/wake in older schizophrenia patients.Schizophrenia Research 47(1): 77-86. McClung CA, Sidiropoulou K, Vitaterna M, Takahashi JS, White FJ, et al. (2005)Regulation of dopaminergic transmission and cocaine reward by the Clock gene. ProcNatl Acad Sci U S A 102: 9377–9381. Mishima K, Tozawa T, Satoh K, Matsumoto Y, Hashikawa Y. (1999) Melatoninsecretion rhythm disorders in patients with senile dementia of Alzheimers type withdisturbed sleep-waking. Biological Psychiatry 45(4): 417-421 Moore RY. (1983) Organization and function of a central nervous systemcircadian oscillator: the suprachiasmatic hypothalamic nucleus. Fed Proc 42: 2783–2789. Naylor E, Bergmann BM, Krauski K, Zee PC, Takahashi JS, Vitaterna MH, TurekFW. (2000) The circadian clock mutation alters sleep homeostasis in the mouse. Journalof Neuroscience 20(21): 8138-8143. Nygard M, Hill RH, Wikstrom MA, Kristensson K. (2005) Age-related changes inelectrophysiological properties of the mouse suprachiasmatic nucleus in vitro. BrainResearch Bulletin 65(2): 149-154. Ohayon MM, Roth T. (2003) Place of chronic insomnia in the course ofdepressive and anxiety disorders. Journal of Psychiatric Research 37(1): 9-15. Oren DA, Giesen HA, Wehr TA. (1997) Restoration of detectable melatonin afterentrainment to a 24-hour schedule in a free-running man. Psychoneuroendocrinology22(1): 39-52.
    • 61 Palomba M, Nygard M, Florenzano F, Bertini G, Kristensson K, et al. (2008)Decline of the presynaptic network, including GABAergic terminals, in the agingsuprachiasmatic nucleus of the mouse. Journal of Biological Rhythms 23(3): 220-231. Panda S, Hogenesch JB. (2004) It’s all in the timing: Many clocks, manyoutputs. Journal of Biological Rhythms 19(5): 374-387. Partonen T, Treutlein J, Alpman A, Frank J, Johansson C, et al. (2007) Threecircadian clock genes Per2, Arntl, and Npas2 contribute to winter depression. Ann Med39: 229–238. Penev PD, Zee PC, Wallen EP, Turek FW. (1995) Aging alters the phase-resettingproperties of a serotonin agonist on hamster circadian rhythmicity. American Journal ofPhysiology 268(1): R293-R298. Perreau-Lenz S, Kalsbeek A, Garidou M, Wortel J, Van Der Vliet J, et al. (2003)Suprachiasmatic control of melatonin synthesis in rats: Inhibitory and stimulatorymechanisms. European Journal of Neuroscience 17(2): 221-228. Portaluppi F, Cortelli P, Avoni P, Vergnani L, Maltoni P, et al. (1994) Progressivedisruption of the circadian rhythm of melatonin in fatal familial insomnia. J ClinEndocrinol Metab 78: 1075–1078. Ralph MR, Foster RG, Davis FC, Menaker M. (1990). Transplantedsuprachiasmatic nucleus determines circadian period. Science 247: 975-8. Reddy AB, Field MD, Maywood ES, Hastings MH. (2002) Differentialresynchronisation of circadian clock gene expression within the suprachiasmatic nuclei ofmice subjected to experimental jet lag. Journal of Neuroscience 22(17): 7326-7330. Reder AT, Mesnick AS, Brown P, Spire JP, Van Cauter E, Wollman RL,Cervenakova L, Goldfarb LG, Garay A, Ovsiew F, Gajdusek DC, Roos RP. (1995)Clinical and genetic studies of fatal familial insomnia. Neurology 45(6): 1068-1075. Reiter RJ. (1991) Neuroendocrine effects of light. International Journal ofBiometeorology 35(3):169-175. Ripperger JA, Shearman LP, Reppert SM, Schibler U. (2000) CLOCK, anessential pacemaker component, controls expression of the circadian transcription factorDBP. Genes and Development 14(6): 679-689. Roecklein KA, Rohan KJ, Duncan WC, Rollag MD, Rosenthal NE. (2009) Amissense variant (P10L) of the melanopsin (OPN4) gene in seasonal affective disorder.Journal of Affective Disorders 114(1-3): 279-285. Roybal K, Theobold D, Graham A, DiNieri JA, Russo SJ, et al. (2007) Mania-like
    • 62behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 104: 6406–6411. Sack RL, Lewy AJ, Erb DL, Vollmer MW, Singer CM. (1986) Human melatoninproduction decreases with age. Journal of Pineal Research 3(4): 379-388. Sforza E, Montagna P, Tinuper P, Cortelli P, Avoni P, Ferillo F, Petersen R,Gambetti P, Lugaresi E. (1995) Sleep-wake cycle abnormalities in fatal familialinsomnia. Evidence of the role of the thalamus in sleep regulation. ElectroencephalogrClin Neurophysiol 94(6): 398-405. Shearman LP, Sriram S, Weaver DR, Maywood ES, Chaves I, et al. (2000)Interacting molecular loops in the mammalian circadian clock. Science 288: 1013-1019. Shiromani PJ, Xu M, Winston EM, Shiromani SM, Gerashchenko D, Weaver DR.(2004) Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriodgenes. Am J Physiol Regul Integr Comp Physiol 287: R47–R57. Silver R, Lesauter J, Tresco PA, Lehman MN. (1996) A diffusible couplingsignal from the transplanted suprachiasmatic nucleus controlling circadian locomotorrhythms. Nature 382(6594): 810-813. Skene DJ, Lockley SW, Thapan K, Arendt J. (1999) Effects of light on humancircadian rhythms. Reproduction Nutrition Development 39(3): 295-304. Solonin YG, Boiko ER, Loginova TP, Ketkina OA. (2009) Circadian rhythms ofphysiological functions in men and women as related to shift work. Human Physiology35(4): 437-441. Spanagel R, Pendyala G, Abarca C, Zghoul T, Sanchis-Segura C, et al. (2005)The clock gene Per2 influences the glutamatergic system and modulates alcoholconsumption. Nat Med 11: 35–42. Sprouse J, Braselton J, Reynolds L. (2006) Fluoxetine modulates the circadianbiological clock via phase advances of suprachiasmatic nucleus neuronal firing.Biological Psychiatry 60(8): 896-899. Stephan FK (1986) Coupling between feeding and light-entrainable circadianpacemakers in the rat. Physiology and Behaviour 38(4): 537-544. Takahashi JS, Hong H, Ko CH, McDearmon EL. (2008) The genetics ofmammalian circadian order and disorder: implications for physiology and disease.Nature Reviews Genetics 9: 764-775.
    • 63 Takano A, Uchiyama M, Kajimura N, Mishima K, Inoue Y, et al. (2004) Amissense variation in human casein kinase I epsilon gene that induces functionalalteration and shows an inverse association with circadian rhythm sleep disorders.Neuropsychopharmacology 29(10):1901-1909. Turner PL, Mainster MA. (2008) Circadian photoreception: ageing and the eyesimportant role in systemic health. British Journal of Ophthalmology 92(11): 1439-1444. Ursin R, Baste V, Moen BE. (2009) Sleep duration and sleep-related problems indifferent occupations in the Hordaland Health Study. Scandinavian Journal of WorkEnvironment & Health 35(3): 193-202. Volicer L, Harper DG, Manning BC, Goldstein R, Satlin A (2001) Sundowningand circadian rhythms in Alzheimer disease. Am J Psychiatry 158: 704–711. Wehr TA, Duncan WC Jr, Sher L, Aeschbach D, Schwartz PJ, Turner EH,Postolache TT, Rosenthal NE. (2001) A circadian signal of change of season in patientswith seasonal affective disorder. Arch. Gen. Psychiatry 58:1108-1114. Wisor JP, O’Hara BF, Terao A, Selby CP, Kilduff TS, Sancar A, Edgar DM,Franken P. (2002) A role for cryptochromes in sleep regulation. BMC Neuroscience3(20). Wu JC, Kelsoe JR, Schachat C, et al. (2009) Rapid and sustained antidepressantresponse with sleep deprivation and chronotherapy in bipolar disorder. BiologicalPsychiatry 66(3): 298-301. Wulff K, Joyce E, Middleton B, Dijk D, Foster RG. (2006) The suitability ofactigraphy, diary data, and urinary melatonin profiles for quantitative assessment of sleepdisturbances in schizophrenia: A case report. Chronobiology International 23(1-2): 485-495. Xu Y, Padiath QS, Shapiro RE, Jones CR, Wu SC, et al. (2005) Functionalconsequences of a CKIdelta mutation causing familial advanced sleep phase syndrome.Nature 434: 640–644. Yamazaki S, Numano R, Abe M, Hida A, Takahashi R, Ueda M, et al. (2000)Resetting central and peripheral circadian oscillators in transgenic rats. Science288(5466): 682-685. Yoo S, Yamazaki S, Lowrey PL, Shirnomura K, Ko CH, et al. (2004)PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistentcircadian oscillations in mouse peripheral tissues. Proceedings of the National Academyof Sciences of the United States of America 101(15): 5339-5346.
    • 64 Zhou J, Liu R, Van Heerikhuize J, Hofman MA, Swaab DF. (2003) Alterations inthe circadian rhythm of salivary melatonin begin during middle-age. Journal of PinealResearch 34(1): 11-16.