PerSPecTiveS

in arousal , feeding and reward behaviours11.

sleep — opinion
Some of the genetic associations between
sleep/circadian rhythm generation and psy-
Sleep and circadian rhythm chiatric and neurological disease are listed in
Supplementary information S2 (table). It is
disruption in psychiatric and worth emphasizing that although there is an
increasing number of gene polymorphisms
neurodegenerative disease that are associated with psychiatric disor-
ders, recent studies on individuals’ resilience
to stress suggest that long-term environmen-
Katharina Wulff, Silvia Gatti, Joseph G. Wettstein and Russell G. Foster tal factors may have an epigenetic influence
on mental health12.
Abstract | Sleep and circadian rhythm disruption are frequently observed in patients A part of the problem with building spe-
with psychiatric disorders and neurodegenerative disease. The abnormal sleep that cific mechanistic links between sleep/circa-
is experienced by these patients is largely assumed to be the product of medication dian rhythm disruption and brain disorders
or some other influence that is not well defined. However, normal brain function and is that there is considerable variation among
individual phenotypes. An additional prob-
the generation of sleep are linked by common neurotransmitter systems lem is the lack of long-term and quantitative
and regulatory pathways. Disruption of sleep alters sleep–wake timing, destabilizes measures of sleep/circadian disturbances
physiology and promotes a range of pathologies (from cognitive to metabolic in brain disorders13. Patients with the same
defects) that are rarely considered to be associated with abnormal sleep. We propose diagnosis, age and gender, and even the same
that brain disorders and abnormal sleep have a common mechanistic origin and that medication, can vary greatly in the severity
of their sleep/circadian timing disruption
many co-morbid pathologies that are found in brain disease arise from a
— from severe disruption to none at all14.
destabilization of sleep mechanisms. The stabilization of sleep may be a means by This Opinion aims to provide a conceptual
which to reduce the symptoms of — and permit early intervention of — psychiatric framework for the consideration of a link
and neurodegenerative disease. between sleep/circadian rhythm disruption
and psychiatric disorder and neurologic
The association between sleep disruption (Supplementary information S1 (figure)). disease, and to draw attention to the poten-
and abnormal brain function has a long The sleep/circadian timing systems are the tial therapeutic benefits of normalizing
history. Emil Kraepelin, one of the found- product of complex interactions among sleep/circadian rhythms in individuals with
ers of modern psychiatry, noted in his first multiple brain regions, neurotransmitter brain pathologies.
textbook in 1883 (Ref. 1) that abnormal systems and modulatory hormones (BOX 1;
sleep patterns and mental health are linked. Supplementary information S1 (figure)). A conceptual framework
Throughout the 1970s and 1980s, pioneering As a consequence, abnormalities in any key At the core of any psychiatric disorder or
studies by researchers, such as Papousek2, neurotransmitter system will impinge on the neurodegenerative disease is an abnormality
Wehr 3 and Wirz-Justice4,5, highlighted the sleep/circadian timing systems at multiple in neurotransmitter signalling. Most
connections between circadian rhythm levels. However, this mechanistic connection therapeutic approaches for the treatment of
disruption, sleep timing and mental health. between primary pathology and sleep abnor- psychiatric and neurodegenerative disease
Despite this long-standing association, malities is seldom made and sleep abnormal- aim to correct such abnormalities (fIG. 1).
cause and effect between sleep disruption ities are mainly credited to a combination of As sleep/circadian timing is dependent
and brain function have been much debated secondary factors that include abnormal light on several neurotransmitter systems, it is
without any firm conclusions being reached. exposure7 (BOX 2), the side-effects of medica- not surprising that sleep complaints are
The recent advances in our understanding tion8, an abnormal social environment, and reported in more than 80% of patients with
of the neural and genetic basis of sleep and general discomfort and pain9. This view is depression or schizophrenia and that sleep
circadian (sleep/circadian) rhythm genera- changing, however, as common mechanistic abnormalities are common in patients with
tion have allowed a re-evaluation of these pathways that link brain disorders and sleep Alzheimer’s disease (AD) or Parkinson’s
connections and of our understanding of the are being identified. For example, polymor- disease (PD). Conversely, disruption of
importance of sleep to the healthy brain. phisms in clock genes (BOX 3) have been sleep/circadian control has wide-spread
Sleep is a highly complex state that associated with bipolar disorder and alcohol effects on all aspects of neural and neu-
arises from an interaction between the addiction10, and hypofunction of the orexin roendocrine function. These effects include
circadian system and a wake-dependent (hypocretin) system has been associated impaired cognition, impaired emotions,
homeostatic build-up of sleep pressure6 with narcolepsy as well as with abnormalities metabolic abnormalities, reduced immunity

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PersPectives

and elevated risks of cancer and coronary sleep in psychiatric disease cognitive performance in healthy individuals
heart disease (fIG. 2). A spectrum of clini- Abnormalities in sleep timing and sleep have all been shown to vary with the time of
cal symptoms that are reported for sleep architecture are recognized as common day. Mood is generally low in the morning,
disruption are also routinely reported for co-morbidities in numerous psychiatric dis- best towards the evening and declines with
pathologies that are co-morbid with brain orders. Indeed, changes in sleep behaviour extended wakefulness. This has led to the
disorders. However, these pathologies are are listed as key criteria for the diagnosis proposal that mood and cognition, like sleep
rarely considered to be associated with of affective (mood) disorders in current and wakefulness, are partly regulated by
sleep disruption. Sleep/circadian rhythm classification schemes, which include the circadian and homeostatic processes (BOX 1;
disruption leads to abnormal light exposure Diagnostic and Statistical Manual of Mental Supplementary information S1 (figure)),
and atypical patterns of social behaviour. Disorders (DSM-Iv) of the American and that mood instability arises from an
These disturbances may further destabilize Psychiatric Association and the International abnormal phase relationship between cir-
sleep/circadian physiology, exacerbating an Classification of Disorders (ICD-10) of the cadian and homeostatic processes. This
already abnormal pattern of neurotrans- World Health Organization. The common abnormal phase relationship is similar to
mitter release in the brain. This could lead patterns of abnormal sleep that are found the condition of jet lag. After travel across
to a state of internal de-synchronization in psychiatric disorders have been summa- multiple time zones, the peripheral clocks
of numerous hormonal and behavioural rized elsewhere13. In fIG. 3 we exemplify one (BOX 3) receive conflicting timing cues from
rhythms15. In addition, medication, addic- of these patterns, namely the delayed sleep the suprachiasmatic nucleus (SCn; which
tion to drugs and substance abuse may phase in schizophrenia. It is important is itself in the process of resetting) and from
also affect the pattern of neurotransmit- to stress that sleep disruption is tightly the environment (owing to irregular sleep
ter release. The net result might be the associated with an increased susceptibility and or activity schedules), abnormal light
substantial disruption of multiple neural to a broad range of psychopathological and exposure and food intake (BOX 2). resetting
and neuroendocrine pathways (fIG. 1). Sets somatic conditions (fIG. 2) and is not merely the normal temporal alignment can take days
of interacting factors, such as those men- the result of an individual’s frustration at and during this time period cognitive sys-
tioned above , would explain the variable failing to initiate or sustain sleep, or at tems and mood are severely assaulted16. The
nature of sleep disruptions in psychiatric feeling sleepy at an inappropriate time. rapid antidepressant effects of sleep depri-
disorders and neurodegenerative disease. Despite the recognition of an association vation, light therapy and an imposed sleep
relatively small changes in the environ- between sleep/circadian rhythm disruption schedule at night17 have been interpreted as
ment could be amplified and increase an and mental health, mechanistic links remain the beneficial effects of re-aligning circadian
individual’s vulnerability to a pathological poorly understood. Interestingly, several and homeostatic processes18. This supports
state. The relationships that are outlined of the clock genes (BOX 3) have been linked the idea that there are tangible links between
in fIG. 1 highlight the problem of assigning with abnormal sleep timing and affective sleep/circadian processes and affective disor-
simple ‘cause and effect’ interpretations to disorders (Supplementary information S2 ders19. unfortunately, this idea has not been
any abnormal sleep phenotype. (table)). Furthermore, mood, alertness and examined in any detail. Furthermore, results
relating to the role of sleep disturbance as a
risk factor in mental health, as a contributing
Box 1 | neurotransmitter activation and inactivation during sleep and wakefulness factor in disease progression — or even as a
target for treatment — remain sparse. Some
Sleep and wakefulness are two mutually exclusive vigilance states. Sleep is characterized by poor of the more robust associations between
responsiveness to external stimuli and wakefulness is characterized by consciousness. These sleep/circadian rhythm disruption and
vigilance states are the product of the alternated release and inhibition of neurotransmitters. This
psychiatric disease are outlined below.
is regulated by the action of sleep-promoting neurons in the anterior hypothalamus and
sleep-inhibiting neurons in the lateral and posterior hypothalamus on the arousal-promoting
systems in the brainstem106–108. Major depressive disorder. up to 90% of
During wake the excitatory neurotransmitters noradrenaline, serotonin, histamine, acetylcholine patients who suffer from an acute depres-
and orexin are released from their respective neurons in the brainstem, midbrain and basal sive episode report changes in their sleep
forebrain structures. The release of the inhibitory neurotransmitters GABA (γ-aminobutyric acid) profile. These changes are usually described
and galanin from the ventrolateral preoptic nucleus (VLPO) is also suppressed. as difficulties in initiating and maintaining
During sleep the non-rapid eye movement (NREM) and REM states of sleep arise from differential sleep during the night. Importantly, persist-
patterns of neurotransmitter release. First, during NREM sleep all aminergic and cholinergic ent insomnia increases the risk of relapse
neurotransmitters, and orexin are inhibited through VLPO-mediated GABA and galanin release. into a new major depressive disorder (MDD)
This decreases arousal. Once NREM sleep has been initiated, thalamo-cortical rhythms that include
episode20. Increased sleep disruption — for
θ and δ oscillations and sleep spindles can be detected by electroencephalography (EEG). Second,
during REM sleep the release of aminergic neurotransmitters of the brainstem is inhibited. However,
example, that experienced by mothers after
acetylcholine that originates from neurons in the brainstem, midbrain and basal forebrain is childbirth — raises the risk of post-partum
released. Orexin is also released. The GABA and galanin that are released from the brainstem and depression, with poorer sleep quality corre-
VLPO act to inhibit aminergic brainstem neurons. lating with more severe depression21.
The transition from wake to sleep is dependent on the build-up of the ATP breakdown product Interestingly, some of the tricyclic anti-
adenosine during wakefulness. This occurs in specific brain regions, especially the basal forebrain. depressants (for example, amitriptyline,
High levels of adenosine are correlated with increased sleep pressure. A key function of adenosine imipramine, clomipramine and non-tricyclic
is its inhibition of GABAergic basal forebrain neurons, which act to inhibit the sleep-promoting antidepressants (for example, trazodone or
neurons of the VLPO. Disinhibition of the VLPO promotes the release of GABA and galanin, which mirtazapine) have very pronounced sedative
inhibit the arousal-promoting systems in the brainstem, midbrain and basal forebrain, thereby
effects, and are commonly used as hypnotic
initiating NREM sleep.
agents in individuals without depression.

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Box 2 | light, circadian rhythms, sleep and arousal abnormal electroretinograms36, and poly-
morphisms in the melanopsin photopig-
Under normal circumstances, exposure to the 24-hour pattern of light and dark aligns (entrains) ment gene (BOX 2) have been linked to SAD
biological rhythms to environmental time. The suprachiasmatic nuclei (SCN) receives light and (Supplementary information S2 (table)).
dark information from the eyes via a direct projection termed the retinohypothalamic tract. In
The melanopsin-containing retinal ganglion
addition, light also modulates arousal brain systems through direct and indirect projections from
cells encode the level of environmental light
the eyes37 (Supplementary information S1 (figure)). In humans and other diurnal species, increased
levels of light elevate alertness and low light decreases sleep latency109. Thus, inappropriate light and project to a range of retino-recipient
exposure not only disrupts the circadian timing of sleep, but also alters levels of alertness, nuclei that include the SCn and the ventro-
vigilance and performance. Exposure to a normal light–dark schedule ensures a stable phase lateral preoptic nucleus (vlPO)37. The SCn
relationship of internal rhythms with the external environment110. The recent discovery of a new controls the timing and the vlPO acts as a
photoreceptor system that is maximally sensitive to blue light in the mammalian eye has switch between wakefulness and sleep. These
profoundly altered our understanding of ocular light detection and has provided a new anatomical and mechanistic facts provide
mechanistic understanding of how circadian and sleep processes are regulated by light37. evidence that the pathology of SAD might
Blue-light photosensitive retinal ganglion cells (pRGCs), which use the photopigment melanopsin, be the result of a circadian/sleep rhythm
trigger a cascade of neuronal activities in the SCN that are critical for the entrainment of the
abnormality. Polymorphisms in some of the
molecular clock to the local light cycle111. The SCN then regulates peripheral clocks via both
key clock genes have also been linked to SAD
humoral and neuronal pathways112. The pRGCs also project to sleep-promoting neurons in the
superior colliculus and the ventrolateral preoptic nucleus (VLPO). These structures are associated (Supplementary information S2 (table)).
with the regulation of sleep, emotions, arousal and higher cognitive function113.
Bipolar disorder. Bipolar disorder is asso-
ciated with a spectrum of symptoms that
As a result, part of the efficacy of some been suggested as a biological endophenotype range from major or minor depression to
antidepressants can be attributed to their to reduce the heterogeneity in the diagnosis major or minor mood elevation (mania
direct action on sleep. Indeed, hypnotic of depression30,32. It is worth noting, how- and hypomania) and from low-grade mood
agents (for example, zolpidem) or agonists ever, that only a small number of individuals cycling to full psychosis. Major differences
of melatonin (for example, agomelatine (10–80) has been included in these studies. in the frequency of mood cycling and the
(valdoxan/Melitor/Tymanax; Servier); a simultaneous occurrence of depressive
synthetic melatonin receptor agonist with Seasonal affective disorder. Seasonal affec- mood and manic episodes (mixed states)
additional serotonin 2C-receptor blocking tive disorder (SAD), also known as winter add to the complexity of a psychiatric
potential that is marketed as an antidepres- depression or winter blues, is a mood dis- diagnosis. Irregular sleep timing and a
sant) have been linked to an improvement order in which individuals have normal reduction in total sleep time are triggers for
in the quality of sleep, the latency to sleep, mental health throughout most of the year manic episodes38. Indeed, disruption of the
sleep consolidation22–24 and the stability of but experience depressive symptoms during 24-hour sleep–wake cycle, shortened sleep
non-rapid eye movement sleep (nrEM sleep)25 a specific season — usually in the winter — and travel across multiple time zones seem
(Supplementary information S1 (figure)). year after year. In the DSM-Iv, SAD is not to act as important triggers for a relapse into
This realization has allowed insomnia and a unique mood disorder but is a specifier mania in individuals who are predisposed
daytime sleepiness in MDD to be man- of major depression. Individuals with SAD to manic episodes (in 77% of patients)39.
aged and, crucially, has led to an improved tend to show excessive daytime sleepiness, Consequently, instability in the 24-hour
treatment strategy for affective and neu- have little energy and crave sweets and sleep–wake cycle is postulated as an impor-
rovegetative (physical, emotional and cog- carbohydrates. They may also feel pro- tant component of bipolar disorder, and
nitive) symptoms26,27. In another study the foundly depressed. Although there seems to therapies for the disorder involve regimes of
wake-promoting agent modafinil (Provigil/ be an overall increase in the prevalence of stable and adequate sleep39.
Modavigil; Cephalon) was administered to SAD with increasing latitude and with the One of the consequences of sleep/circa-
patients with MDD who were only partially shortened daily light periods of the winter dian disruption might be abnormalities in
responsive to selective serotonin reuptake inhib- season, there is considerable country to the stress axis, with particular emphasis on
itor (SSrI) antidepressants. Patients showed country variation33,34. These inconsistencies atypical neurotransmitter release (fIG. 1). For
significantly improved daytime wakefulness in the prevalence of SAD may be the result example, hypercortisolaemia can arise from
(measured using the Epworth Sleepiness of the condition being a more severe expres- a breakdown in glucocorticoid receptor-
Scale), reduced depressive symptoms (meas- sion of the naturally occurring seasonal mediated negative feedback mechanisms in
ured using the Hamilton rating Scale for variation in mood that is experienced by a the hypothalamic–pituitary–adrenal axis (HPA
Depression) and reduced fatigue (measured large percentage of the general population axis). Such pathogenesis has been impli-
using the Fatigue Severity Scale)28. These as well as the result of variation in the clas- cated as a major factor in the development
treatment strategies seem to improve the sification of SAD versus depression from of bipolar disorder and of the neurocogni-
quality of life for these patients and hint at country to country. The very high success tive deficits that are associated with this
possible mechanistic links between the biol- rate of phototherapy is the strongest evi- condition40. Substantial therapeutic
ogy of sleep and depression. Interestingly, dence for a recurrent, seasonally influenced benefits for the treatment of bipolar disor-
shortened latency to rEM sleep, increased depressive condition that is a function of der have been obtained by lowering the
rEM density and increased rEM sleep are an interaction between light and internal circulating cortisol levels or by blocking
phenotypes that are predictive for unipolar circadian and/or circannual rhythms35. In the effects of elevated cortisol with antago-
but not bipolar depression29–31. These sleep addition, eye defects have been associated nists (for example, mifepristone or ru-486
phenotypes, which also occur in first-degree with SAD. For example, patients with SAD (Mifegyne/Mifepres; Danco laboratories
relatives of patients in these studies , have show a higher frequency of reduced and and Exelgyn)40.

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PersPectives

Box 3 | The molecular clock and the role of the suprachiasmatic nuclei in sleep density as a vulnerability marker for affective
disorders46. Biological markers allow early
A paired cluster of approximately 50,000 neurons within the anterior hypothalamus termed the detection of disorders in high-risk subjects
suprachiasmatic nuclei (SCN) coordinate the circadian rhythm of sleep and act to drive wakefulness and provide cues for useful endophenotypes
throughout the day and sleep during the night. The generation of circadian rhythms at the
in genetic association studies.
subcellular level is thought to depend on the activity of a key group of clock genes114. At the core is a
molecular feedback loop in which the proteins brain and muscle ARNT-like 1 (BMAL1; also known as
ARNTL) and CLOCK act as transcriptional regulators and drive the expression of the period Alcoholism. Sleep is disturbed in patients
homologue 1 (PER1), PER2, PER3 and cryptochrome 1 (CRY1) and CRY2 genes. A complex that is with alcohol problems, on drinking nights
formed by PER1, PER2, PER3, CRY1 and CRY2 proteins enters the nucleus and then impedes the and on nights with no alcohol. During
BMAL1 and CLOCK-mediated transcriptional drive. The complex therefore acts as a transcriptional periods of heavy drinking and up to two
repressor of its own genes. Additional feedback loops have been identified that regulate the years after the discontinuation of alcohol
resetting properties of the core feedback loop and thereby stabilize 24-hour periodicity114. Such intake, patients’ sleep phases show reduced
molecular clocks are not confined to the neurons of the SCN but occur in most cells of the body. slow wave sleep (SWS) states, suppressed
Thus, the conceptual view of the mammalian circadian system has changed markedly in the last rEM sleep, fragmented sleep during the
decade — from a central clock in the SCN driving 24-hour rhythmicity to a more hierarchical
second half of a normal 8-hour bedtime and
arrangement of multiple peripheral clocks that are synchronized by the SCN115. Under pathological
shortened overall sleep durations47. rates of
conditions the SCN and peripheral clocks lose their normal phase relationship and a state of
internal desynchronization may develop. If sustained, this state may predispose individuals to insomnia in these patients are reported to
disease116. The SCN is also thought to receive multiple feedbacks from the periphery that include be between 40–70%. Interestingly, patients
information regarding metabolic status117 and the levels of activity118. The net result is a complex with alcohol addictions who have a good
arrangement of reciprocal interactions that all contribute to the period, phase and amplitude of an prognosis for recovery are those individu-
individual’s circadian phenotype15. Several of these clock genes have been linked directly to als who tend to return to normal ratios of
abnormal sleep/circadian phenotypes6. For example, in humans a specific point mutation in DEC2 nrEM to rEM sleep and who sleep well
— a gene encoding a transcriptional repressor — causes a short sleep duration phenotype119. In in general47. Altered sleep patterns, such as
mice, a loss of function in FBXL3 (which is involved in phosphorylation-dependent ubiquitination) short rEM latencies and high rEM densi-
leads to a stabilization of the CRY proteins, which then leads to a global transcriptional repression
ties, are thought to predispose individuals
of the Per and Cry genes and a long period (26-hour) circadian phenotype120,121. In humans, the long
to a relapse as they may be more prone to
allele variant of PER35/5, which is encoded by PER3 with five repetitions of the variable number
tandem repeat (VNTR), has been linked to extreme morning chronotypes, whereas the shorter allele use ethanol to induce sleep48. Excessive
(PER34/4) is associated with extreme eveningness and delayed sleep phase syndrome122. These alcohol consumption in addicted and non-
variant forms of PER3 gene are also associated with homeostatic processes of sleep. Homozygosity addicted individuals can cause depressive-
for either variant allele contributes to differences in sleep homeostasis and electroencephalography like states. Indeed, ethanol is classified as
(EEG) sleep structure: the longer allele (PER35/5) is associated with a more rapid sleep onset (which a depressant drug as it has sedative effects
indicates greater sleep pressure) as well as a longer time spent in slow wave sleep (SWS) states and owing to its facilitation of the response
increased θ and α activity during wakefulness (again a strong indication of higher levels of sleep at gABA (γ-aminobutyric acid)-ergic
pressure). In addition, subjects who inherited the longer allele performed very poorly in cognitive synapses and inhibition of glutamatergic
tests after periods of extended wakefulness122. This was correlated with increased θ activity and
nMDAr (N-methyl-d-aspartate recep-
slow eye rolling (both objective markers for sleepiness and inattention). Interestingly, when these
tor) signalling 47. Co-morbid addiction to
allele frequencies of PER3 were examined in patients who were diagnosed with bipolar disorder, the
data suggested that early onset bipolar disorder is associated with the longer allele (PER35/5) and later alcohol in patients with bipolar disorder is
onset with the shorter allele (PER34/4)43. common and seems to influence circadian
preference: patients who are addicted to
alcohol show a predominance of morn-
Mice that carry a mutation in the circa- long allele variant of the period homologue 3 ing chronotypes, whereas patients who are
dian Clock gene (BOX 3) show a decreased (PER3) clock gene (PER35/5) has been linked not addicted to alcohol show a predomi-
need for sleep, increased motor activity, to the early onset of bipolar disorder type I nance of evening chronotypes49. Studies
lower anxiety and an increased preference (Ref. 43) (BOX 3; Supplementary information in mice have indicated a strong indirect
for cocain intake — behaviours that are S2 (table)). Early onset of bipolar disorder association between alcohol consumption
comparable to the mania-state of bipolar type I (diagnosis before the age of 18 years) and Per2 variant(Supplementary informa-
disorder. Mood-stabilizing drugs, such as is considered to be a predictor for a more tion S2 (table)). In Per2-mutant mice, the
lithium, restore normal behaviour in these severe course of the disorder with more psy- expression of the membrane glutamate
mice41. However, in patients with severe chotic features, a higher frequency of mixed transporter excitatory amino acid receptor 1
mania (for example, in bipolar disorder episodes and a poorer overall prognosis. (EAA1; also known as grIK4) is reduced.
type I) sleep/circadian abnormalities persist This prediction is based on the poorer pro- EAA1 is primarily expressed in astroglia
after mood stabilization and apparent clini- phylactic lithium response of patients with and acts to clear excess glutamate from
cal recovery 42. This suggests that multiple early onset bipolar disorder type I compared the synaptic cleft and to transport gluta-
interactions contribute to this spectrum with patients with late onset of the disorder mate back into the neuron. The resulting
disorder. genetic association studies of (diagnosis above the age of 40 years)44. The hyperglutamatergic state in Per2-mutant
patients with bipolar disorder have sug- importance of early detection and interven- mice has been implicated in the aetiology
gested that polymorphisms in some of the tion in the treatment of bipolar affective of alcohol dependence50. Thus, increased
clock genes are linked to the frequency of disorder has led to attempts to identify pro- alcohol consumption seems to be linked to
depressive relapses, to positive responses to dromal features of the disorder in high-risk a dysfunction of the Per2 gene. Additional
sleep deprivation and to improved responses subjects45. For example, an analysis of sleep associations between alcohol preference and
to long-term lithium treatment. recently, the microstructure has identified increased rEM both clock genes and sleep genes have been

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 PersPectives

identified. For example, enforced wakeful- Neuropathology

ness leads to changes in the expression of Addiction or
Psychiatric disorder and Medication
substance abuse
Per2 and the Clock-controlled D site albu- neurodegenerative disease
min promoter-binding protein gene (Dbp;
a Pro- and acidic-rich region (PAr) leu
zipper transcription factor and a component
Abnormal neurotransmitter release
of the circadian output pathway) in the
forebrain of mice, suggesting that these cir-
cadian genes may have a role in the homeo-
static regulation of sleep51. Importantly, Dbp Sleep/circadian rhythm disruption
expression is increased in the frontal cortex
of alcohol-preferring rats52, and in humans
this gene has been mapped closely to a
genetic linkage locus for bipolar disorder on • Co-morbid pathologies
• Abnormal light–dark exposure
chromosome 19q13 (Ref. 53). • Disrupted social behaviour Stress axis activation

Schizophrenia. The neuropathology Figure 1 | The complex relationship between neuropathology (psychiatric disorder or neuro-
of schizophrenia is characterized by the degenerative disease), an abnormal pattern of neurotransmitterNature release and circadian
Reviews and
| Neuroscience
dysfunction of inhibitory neuronal circuits, sleep timing. At the core of all neurological disease is an abnormality (of some level) in one or more
reduction of cortical neuropil, a lower of the neurotransmitter systems. Such an abnormality probably impinges on the circadian and sleep
number of neurons in the hippocampus and (circadian/sleep) timing as this system is itself regulated across different brain regions and by a range
childhood-onset cortical grey matter loss54. of neurotransmitters123. Disruption of sleep/circadian control all aspects of neural and neuroendocrine
function. This will result in co-morbid pathologies (FiG. 2). Sleep/circadian rhythm disruption commonly
Elevated cortisol levels are also reported
leads to abnormal social behaviour and light exposure and will feedback to further destabilize sleep/
in patients with schizophrenia. However, circadian physiology. Many of these abnormalities will activate the stress axis, which will distort physi-
many treatment paradigms focus exclu- ological responses even further. This distortion, the impact of medication, and perhaps addiction and
sively on the modulation of dopamine- and substance abuse contribute to the disruption of the major neural and neuroendocrine networks.
serotonin-mediated synaptic signalling,
often with only limited success55. In view of
such wide-spread alterations in brain archi- sleep problems have been shown in patients humans SnAP25 has been linked to schizo-
tecture and physiology, it is hardly surprising who follow a fixed routine, whereas phrenia by genetic association and linkage
that abnormal sleep has been described in individuals without schizophrenia and analysis and levels of SnAP25 have been
patients with schizophrenia since the 1920s who are released from any fixed routine do shown to be reduced in the hippocampus
and, more recently, has been documented not show such severe sleep–wake timing of patients with schizophrenia66. In mice,
as a common feature in previously unmedi- disruption (K.W. and r.g.F, unpublished abnormalities in SnAP25 induced a range
cated patients who are now undergoing observations). of psychiatric-like phenotypes, which
treatment 56 and in patients who are under- genome-wide association studies have included hyperactivity, alterations in social
going long-term antipsychotic treatment 23. suggested that numerous genes may be interaction and deficits in spatial mem-
Abnormal sleep patterns in schizophrenia involved in the development of schizophre- ory 67. In recent in vitro studies, inhibition
include reductions in rEM latency, rEM nia. Several of these genes are linked to of synaptic vesicle recycling by botulinum
density, sleep efficiency, total sleep time sleep and/or circadian regulation. For exam- toxin A or dynasore (which block exocyto-
and the duration of nrEM stage 4, and ple, variants of disrupted in schizophrenia 1 sis and endocytosis, respectively) in orga-
an increase in sleep latency 57 (fIG. 3b,3d). (DISC1) have been linked to an inability to notypic cultures of the SCn resulted
Multiple circadian abnormalities have also experience pleasure (anhedonia)60 and the in abnormal patterns of circadian gene
been recorded and these include delayed homeostatic regulation of sleep in animal expression in SCn neurons68.
phase, advanced phase, free-running and/ models61. A polymorphism in cyclic AMP
or irregular sleep timing patterns (K.W. and (cAMP)-specific 3′,5′-cyclic phosphodieste- Anxiety, panic, obsessive-compulsive dis-
r.g.F, unpublished observations). Sleep rase 4D (PDE4D) has been associated order and post-traumatic stress disorder.
disorders are reported in 30–80% of patients with sleepiness in one cohort study 62 The relationship between disrupted sleep
with schizophrenia and are one of the most and with schizophrenia in another study 63. and various anxiety-related disorders is well
common symptoms of the disorder. Patients Furthermore, the T3111C single nucle- recognized and is part of the current, text-
with poor sleep also score badly on many otide polymorphism of the human CLOCK revised DSM-Iv (DSM-Iv-Tr) diagnosis
‘quality of life’ clinical subscales57. Adults gene has been linked to abnormalities in for post-traumatic stress disorder (PTSD).
and older patients with schizophrenia com- dopamine regulation38 and to schizophre- Cause and effect, however, can be diffi-
ment that an improvement in sleep is one of nia64. Synaptosomal-associated protein 25 cult to untangle — for example, insomnia
their highest priorities during treatment 58. (SnAP25) is a neuron-specific SnAP recep- predisposes individuals to anxiety, which
Improvement of sleep quality is frequently tor (SnArE) protein that is essential for precipitates sleep disruption and this disrup-
correlated with an improvement in negative normal synaptic vesicle release from presy- tion then increases the likelihood of panic.
symptoms59. Social isolation and/or a lack of naptic nerve terminals (Supplementary Conversely, clinical research has shown that
social constraint are routinely suggested as information S2 (table)) and has been shown sleep problems may actually precede condi-
the cause of the sleep disruption in schizo- to play an important part in light-signalling tions such as anxiety and depression21,69. In
phrenia. This seems unlikely, however, as to the circadian system65. Interestingly, in contrast to MDD, patients with PTSD and

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Emotional responses sleep in neurodegenerative disease

Abnormal patterns of sleep timing and
sleep architecture are consistently asso-
ciated with neurodegenerative disease.
Feeling states Stress Overt behaviour
The phenotype is variable and the spe-
cific mechanistic connections remain
poorly defined, in the same way as mental
• Frustration, anger health77. unsurprisingly, when neurode-
• Exhaustion • Increased impulsivity
• Increased irritability
Disorders of the
• Mania and increased risk taking generative disease affects brain structures
hypothalamo-pituitary
• Mood fluctuations
adrenal axis
• Decreased motor performance and the neurotransmitters that are involved
• Depressed mood • Increased stimulant and sedative use in sleep/circadian rhythms, sleep disrup-
• Alcohol use and misuse
tion is the result (BOX 1). neurodegenerative
disease is usually progressive and irrevers-
ible, but the treatment of sleep abnormali-
Cognitive responses ties is emerging as a possible approach for
the improvement of the overall condition
of patients. In some neurodegenerative dis-
eases the treatment of sleep abnormalities
Attention Memory Executive functions
may even slow the progression of physical
and mental decline. Below, we consider
several neurodegenerative diseases that
• Decreased working memory are commonly associated with sleep/circa-
• Reduced ability to concentrate • Reduced ability to multi task dian rhythm disruption as well as those in
capacity
and to continue performing • Reduced decision making
• Difficulties sustaining attention
• Reduced memory of facts
• Reduced creativity and which sleep stabilization has been shown
• Reduced recall of events
and alertness
or episodes
productivity to be beneficial.

Alzheimer’s disease. The impact of frag-

mented night-time sleep in patients with
AD is very debilitating to both patients
• Drowsiness Risk of
• Microsleep
Somatic responses
diabetes II
and care-givers and is a primary reason
for patient institutionalization. The gen-
eral neurodegenerative process in AD
Bodily sensations of pain Reduced immunity to undoubtedly alters many aspects of sleep
and being chilled disease and viral infection
and circadian control, and certain changes
have been suggested as markers of disease
Cardiovascular Metabolic progression78. Brain nuclei in the anterior
disease Risk of cancer problems hypothalamus (for example, vlPO and
SCn), lateral and posterior hypothalamus
Figure 2 | The health consequences of shortened or reduced sleep and desynchronized circa- and the basal forebrain contain key regula-
Nature Reviews
dian rhythms, classified by emotional, cognitive and somatic responses. For a full| Neuroscience
list and refer- tory circuits for the control of sleep and vig-
ences see Supplementary information S3 (table). ilance, and degeneration of these regions in
patients with AD almost certainly contrib-
utes to their sleep problems. Specifically, the
obsessive-compulsive disorder (OCD) fre- are located in the amygdala (the centre for SCn shows a higher level of neuropathology
quently show hyper-vigilance and problems emotional processing) and the nearby locus in patients with AD compared with
in falling asleep70. As a result, the diagnostic coeruleus (the arousal-promoting area). individuals without AD who were of the
discrimination between anxiety disorder nPS has also been shown to co-localise with same age79. In addition, degeneration of
and delayed sleep phase syndrome (DSPS) is glutamate, which is the main excitatory cholinergic neurons in the basal forebrain is
difficult. neurotransmitter of the brain. A specific one of the first biochemical changes
neuropeptide S (nPS) has been linked polymorphism in the nPSr (Asn107Ile) that is noted in patients with AD. Activation
in recent studies to anxiety and sleep. For of men but not of women results in a gain of the cerebral cortex during rEM sleep is
example, rodent studies have shown that of function of the receptor by increasing dependent on the basal forebrain’s cholin-
nPS suppresses anxiety and appetite71, its sensitivity approximately tenfold. The ergic innervations to the cerebral cortex. A
induces wakefulness and hyperactivity 72,73 less active isoform of the nPSr (Asn107) disruption in this circuit is the likely cause
and plays a substantial part in the ameliora- occurs less frequently in male patients with of rEM sleep disruption in AD patients80.
tion of conditioned fear 74. In humans, nPS panic disorder and this suggests that nPS Key interactions that ensure nrEM sleep
suppresses sleep and promotes wakefulness, may have a potential protective function in promotion include the disinhibition of
and has been implicated in the modulation panic disorders76. Collectively, these results vlPO neurons by adenosinergic inhibi-
of emotional energy and arousal states75. support the idea that nPS may be part of tion of gABA-containing basal forebrain
nPS receptors (nPSrs) are widely distrib- a neurotransmitter system that modulates neurons and the subsequent vlPO-driven
uted in the brain — for example nPSrs sleep and wake timings, and anxiety levels. gABA-mediated inhibition of diencephalic

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 PersPectives

and ascending brainstem arousal systems a Local clock time Local clock time
b
(BOX 1). If the basal forebrain and the vlPO

09:00
07:00
23:00
19:00
15:00
9:00
are impaired, the basal forebrain-mediated 1:00 2:00 3:00 4:00 5:00 6:00 7:00 8:00
disinhibition and the inhibition that the
vlPO exerts on the ascending brainstem MVT
arousal systems may also be weakened. This REM
leads to the observed diminution of SWS Awake

and the increased nrEM stage 1 sleep. In S1

NREM
addition, K complexes and sleep spindles, S2
S3
which are specific features of nrEM stage 2
S4
sleep, are poorly formed, are of low ampli-
tude, have a shorter duration and are less c d Local clock time
Local clock time
numerous. A link between sleep spindle

09:00
07:00
23:00
19:00
15:00
9:00
number and verbal memory consolidation 2:00 3:00 4:00 5:00 6:00 7:00 8:00 9:00 10:00 11:00
during sleep has been proposed in healthy
MVT
subjects81. Patients with AD also have a high
REM
prevalence of day-time sleeping 82 and this Awake
can disrupt the homeostatic drivers for sleep S1
(Supplementary information S1 (figure)).

NREM
S2
A notable feature of AD is ‘sundowning’ S3
which is a tendency to be confused and S4
agitated in the late afternoon and evening.
This could be related to mental and physi- Figure 3 | rest–activity profiles and hypnograms from two human subjects, illustrating
cal exhaustion at the end of the day, how- normal and disrupted circadian behaviour. a | rest–activity cycles were recorded using wrist
Nature Reviews | Neuroscience
ever, reduced light at this time of day could actigraphs from a healthy unemployed subject with a regular sleep phase between 22:00 and 08:00
also contribute to impaired levels of cogni- local time. each row represents a day of 24 hours and each line starts at 09:00. The green shaded
tive alertness. In addition, patients who are area highlights sleep in the normal range (23:00–07:00) and bedtime (23:00) is indicated by the red
line. b | electroencephalography (eeG)-derived hypnogram from a home, overnight recording of a
institutionalized show a greater lack of
41-year-old healthy, unemployed man showing a normal sleep structure across the entire sleep
a robust daytime light signal. This lack
period (from 01:00 to 08:00). The sleep hypnogram illustrates the cyclical pattern of brain activity,
of a robust signal promotes daytime som- which consists of four basic vigilance states: wakefulness (shown in red); non-rapid eye movement
nolence and fragmented bouts of sleep at sleep (NreM) stages one (S1) and S2 (shown in yellow); slow wave sleep (SWS; also referred to as
night, predisposes individuals to free- deep sleep), which consists of S3 and S4 of NreM (shown in green); and reM sleep (shown in blue).
running sleep patterns (BOX 2), and c | rest–activity from a subject with schizophrenia. This shows circadian rhythm disruption with a
ultimately results in internal temporal delayed sleep phase. Sleep onset times range between 04:00 and 06:00 and wake times occur
desynchrony, not least in the pattern of between 1500 and 1600 hours on most days. d | Hypnogram from a home, overnight recording of a
melatonin release from the pineal gland. 49-year-old patient with schizophrenia. it is important to note the longer sleep duration and reduc-
Melatonin release is known to be lower tion in SWS (no stage four sleep) that is often seen in schizophrenia. MvT, movement (physical
activity without waking up).
than normal in patients with AD83. In
age-matched, healthy individuals, the
administration of melatonin has been
shown to decrease sleep onset latency bright light exposure could prove to be a body formation in the substantia nigra
and increase daytime alertness, whereas valuable therapeutic tool for the improve- leading to striatal dopamine deficiency 89.
results in patients with AD are mixed. ment of sleep quality in patients with AD. However, degeneration with lewy body
After melatonin treatment some patients formation also occurs in the brainstem
with AD show improved sleep quality (less Parkinson’s disease. The earliest descrip- nuclei (for example, the pedunculopontine
interrupted sleep and reduced daytime tion of the ‘shaking palsy’ by James nucleus), which are critical in thalamo-
sleepiness and agitation), some show no Parkinson included a reference to dis- cortical arousal77. Degeneration of these
effects on sleep and some become more turbed sleep86. night-time sleep distur- nuclei seems to lead to the disruption of
aggressive. Melatonin effects are, in part, bances as well as daytime sleepiness occur basic rEM and nrEM sleep architec-
dependent on the phase of the circadian in PD87. It has been estimated that 80–90% ture. Substantial evidence suggests that
cycle84 and so the different responses to of patients with PD have a sleep disorder abnormal rEM sleep behaviour precedes
melatonin treatment may be due to dif- that affects their ability to fall asleep and Parkinsonism and dementia by several
ferences in the internal circadian phase of stay asleep, their dreams, motor activity years87. It might therefore provide a useful
patients when melatonin is administered. during sleep, post-sleep behaviour or day- marker during the early phase of PD and
This hypothesis is supported by the obser- time somnolence. There is also some evi- present an opportunity for early interven-
vation that melatonin administration in dence for a disrupted pattern of melatonin tion of this disease. Preliminary studies
combination with light therapy in insti- release and that weak light entrainment show that the use of melatonin in combina-
tutionalized patients with AD results in signals (for example, in the winter or dur- tion with bright light exposure is useful for
improved night-time sleep, higher daytime ing institutionalization) can exacerbate improving sleep quality in PD, but more
activity and less daytime sleep85. Thus, the condition88. Pathologically, PD is char- studies are needed to provide statistically
the use of melatonin in combination with acterized by neuronal cell loss with lewy robust conclusions88.

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© 2010 Macmillan Publishers Limited. All rights reserved

PersPectives

Huntington’s disease. In addition to PD, with the conditions and diseases that are light, melatonin can also act to entrain the
other diseases of the basal ganglia, such described above should have a positive effect. circadian system. Melatonin administration
as Huntington’s disease (HD), also show Evidence is emerging that such stabilization in conjunction with phototherapy has shown
progressive abnormalities of sleep and does indeed prove beneficial. For example, some promising — albeit preliminary —
circadian function as well as atrophy in bright-light phototherapy has been used improvement of sleep patterns in dementia85.
key brain structures that are involved in as an entrainment signal for the circadian However, melatonin administration seems
the regulation of sleep — for example, the system and has been shown to alleviate some not to be a powerful therapeutic agent for
brain stem and lateral hypothalamus90–93. of the symptoms of several mood disorders mood regulation7. The value of melatonin
Transgenic r6/2 mice that carry the HD that include SAD, unipolar depression treatment for sleep stabilization in affective
mutation have provided important insights and bipolar depression102. In addition to disorders and schizophrenia remains to
into the molecular basis of circadian
rhythm disruption in HD (Supplementary
information S2 (table)). In this mouse Glossary
model, pharmacological restoration and Bipolar disorder International Classification of Disorders
maintenance of rest-activity cycles corre- A disorder characterized by abrupt mixed states of mood (ICD-10). A disease classification published by the World
late with a normalized pattern of circadian from an energetic elevated mood (termed mania or, if Health Organization that provides diagnostic criteria for
gene expression in the SCn and a marked milder, hypomania) to a deep depressive state. Bipolar mental health disorders. The ICD-10 classification consists
disorder type 1 classification is based on the occurrence of 10 main groups.
improvement in the cognitive deficits that
of at least one manic episode, with or without the
are seen in these animals94, 95. occurrence of a major depressive episode. Bipolar K complexes
disorder type 2 is characterized by at least one A brief, negative high-voltage peak, usually greater than
Multiple sclerosis. reduced sleep latency hypomania episode and one major depressive state. 100 μV. Like sleep spindles, K-complexes are another
characteristic of stage two sleep.
and daytime sleepiness are common fea-
Chronotype
tures of multiple sclerosis (MS) and cor- An individual’s preference for daytime or night-time Light therapy
relate with increased levels of pain, fatigue activities (also referred to as morningness and eveningness (Also known as phototherapy). Consists of exposure to
and depression96–98. It should also be noted or larks and owls, respectively). Morning types wake up daylight or artificial light (provided by a light box). Light
that treatment with β-interferon (IFnβ), early and are most alert in the first part of the day, whereas exposure is of a defined intensity and is given at a specific
evening types are most alert in the late evening hours and time. Light therapy has been used to treat circadian rhythm
which is thought to suppress autoimmune
prefer to go to bed late. disorders, such as delayed sleep phase syndrome, and can
responses in MS, may exacerbate sleep also be used to treat seasonal affective disorder.
disruption because sleep efficiency is mark- Circadian phase
edly decreased on the night following IFnβ A particular reference point in the circadian cycle. for Major depressive disorder
example, the onset of sleep. A disorder characterized by severe, highly persistent
injections99. Circadian rhythm disruption
depression and a loss of interest or pleasure in everyday
has not been widely reported in MS96, Circadian system activities. It is often associated with lack of appetite,
suggesting that MS lesions do not occur (Also known as process C). The entire molecular, cellular chronic fatigue and sleep disturbances. There is an
frequently within the SCn100. By contrast, and physiological basis for the generation of circadian increased risk of suicide.
brainstem demyelination and midbrain rhythms in an organism.
Narcolepsy
lesions are common in MS and are associ-
Diagnostic and statistical manual of mental disorders A chronic sleep disorder (or dyssomnia). In
ated with migraines and headaches but not (DSM-IV). A manual published by the American Psychiatric relation to sleep, the condition is characterized by
with sleep disturbance. However, lesions to Association that provides diagnostic criteria for mental excessive daytime sleepiness whereby the individual
the lateral hypothalamus result in low orexin health disorders. DSM-IV-TR is the most recent, experiences extreme fatigue at inappropriate times and
text-revised version published in 2000. may fall asleep.
(hypocretin) levels in the cerebrospinal fluid
and result in hypersomnia, which has been Diurnal Non-rapid eye movement sleep
treated successfully with the anti-inflam- An activity or process that occurs during the daytime (NReM). There are four distinct stages of NReM
matory drug prednisolone. lesions in the (during light). sleep (NReM 1–4) defined on the basis of eeG or
reticular formation of the medulla oblongata polysomnography and other characteristics that are seen
Electroencephalography in each stage.
(the centre for automatic breathing control)
(eeG). A measure of the electrical activity of the brain that
give rise to sleep-disordered breathing 101. can be used to define different wake, NReM and ReM Prodromal
As the interactions of the multiple neuronal sleep states. An early symptom (or set of symptoms) that might indicate
systems that are involved in sleep generation the start of a disease before specific symptoms occur.
and sleep–wake control are complex, demy- Endophenotype
A special type of biomarker. In mental health, it is the Selective serotonin reuptake inhibitors
elination in one or more of these neuronal division of behavioural symptoms into recognizable (Also known as serotonin-specific reuptake inhibitors). A
systems could profoundly affect sleep and phenotypes with a clear genetic association. class of compounds typically used as antidepressants in
arousal in MS. In patients with MS, sleep the treatment of depression, anxiety disorders and some
stabilization may improve the quality of life, Entrainment personality disorders. These inhibitors increase the
The process by which an organism’s circadian rhythm is extracellular level of the neurotransmitter serotonin by
but to our knowledge no systematic
synchronized to an environmental rhythm such as the inhibiting its reuptake into the presynaptic cell. This
studies have investigated the effectiveness light–dark cycle. increases the level of serotonin that is available to bind to
of this treatment . the postsynaptic receptor.
Hypothalamic-pituitary-adrenal axis
sleep as a therapeutic target A complex set of direct influences and feedback Sleep spindles
interactions among the hypothalamus, pituitary gland and Stage 2 sleep is characterized by sleep spindles that signify
If the relationships that are depicted in adrenal glands. The hypothalamic-pituitary-adrenal (HPA) a burst of brain activity which is visible on an electroen-
fIG.1 are broadly correct, then stabilization axis constitutes a major part of the neuroendocrine system cephalogram (eeG) ranging from 11 to
of the sleep/circadian system in patients that controls reactions to stress. 16 Hz.

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 PersPectives

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 PersPectives

117. Yi, C. X. et al. Ventromedial arcuate nucleus Acknowledgements

communicates peripheral metabolic information to the The work is supported by the National Institute for Health
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