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Chronobiology
Overview and it’srelevancein psychiatry
Presenter: Dr. Suman Pd. Adhikari
Chronobiological Terms
Term Definition
Biological clock Physiological mechanism that gives a time sense to every living
organisms i.e., when to eat, sleep/awake etc.
Biological rhythm Cyclical, repeated variation in a biological function.
Circadian rhythm Cyclical variation in a metabolic , physiological or behavioral process
with a period of about 24 hours when in constant conditions
Circannual rhythm Cyclical variation in a metabolic, physiological or behavioral process
with a period of about an year.
Diurnal activity Activity performed mainly during the daytime
Endogenous Of rhythms or other forms of biological timekeeping controlled from
within the organism by some kind of physiological ‘ biological clock ’
Entrainment Synchronization of one biological rhythm to another or to a zeitgeber
cycle, e.g. circadian rhythm are often entrained to the light-dark cycle
Term Definition
Melatonin A hormone produced rhythmically in vertebrates by the pineal gland, a
pea sized organ at the center of the human brain.
Nocturnal activity Activity performed mainly at night
Oscillator Internal and therefore unseen, or endogenous oscillator (the biological
clock ) that produces an overt measurable biological rhythm in the
organism.
Period The length of one complete cycle of a rhythm
Phase A particular reference point in the cycle of a rhythm, e.g. the daily onset
of locomotor activity, or the light-to-dark transition in a zeitgeber cycle.
Phase shift Shift in a biological rhythm along its time axis so whilst the period
remains the same the time at which the rhythm occurs changes
Zeitgeber
“time giver”
Periodic environmental signal that entrains some biological rhythm , for
example a natural or artificial day-night cycle for a circadian rhythm
 zeitgeber 
 An environmental agent or event (as the occurrence of light or dark) that
provides the stimulus for setting or resetting a biological clock of an organism
 Any external or environmental cue that entrains, or synchronizes, an
organism's biological rhythms to the earth's 24-hour light/dark cycle and 12
month cycle.
 The term "zeitgeber" (German for "time giver" or "synchronizer") was first
used by Jurgen Aschoff , one of the founders of Chronobiology
 Common zeitgeber
 Temperature
 Social interactions
 Pharmacological manipulation
 Exercise
 Eating/drinking patterns
Introduction of Chronobiology
 Study of biological time in relation with cyclic rotation of the earth in it’s axis
which is completed within 24 hrs.
 Biological rhythm varies from milliseconds in ocular field potential to years
 Circadian rhythm is the most extensively studied and best understood biological
rhythm.
 Chronobiology comes from the ancient Greek (chrónos, meaning "time"),
and biology, which means “the study, or science, of life”
History of Chronobiology
Date Literature/contributor Comment
4th
Century
BC
Androsthenes
(Ship captain of Alexandar the Great)
Described diurnal leaf movements of the
Tamarind tree.
13th
Century Noon and Midnight Manual
(Chinese)
Circadian or diurnal process in humans
mentioned
1729 Jean-Jacques d Ortous de
Mairan
(French)
Noted 24-hour patterns in the movement of
the leaves of the plant Mimosa pudica
1751 Carlous Linneaus
(Swedish Botanist and naturalist)
Designed a flower clock using certain species
of flowers. By arranging the selected species
in a circular pattern, he designed a clock
that indicated the time of day by the flowers
that were open at each given hour
1896 Patrick and Gilbert Observed that during a prolonged period of
sleep deprivation, sleepiness increases
Date Literature/contributor Comment
1918 J.S. Szymanski Showed that animals are capable of
maintaining 24-hour activity patterns in the
absence of external cues such as light and
changes in temperature
1959 Franz Halberg
(University of Minnesota-Father of
American Chronobiology)
Coined the term “Circadian”
20th
Century
Auguste Forel, Oskar Wahl Circadian rhythms were noticed in the
rhythmic feeding times of bees
1967 Erwin Bunning Described physiological clock in plant
1970s Ron Konopka, Seymour Benzer Isolated the first clock mutant in
Drosophila and mapped the “period" gene,
the first discovered genetic component of a
circadian clock
1994 Joseph Takahasi Discovered the first mammalian 'clock gene'
(CLOCK) using mice
biological rhythms
 Latin word circa means about and dies means days, which has the periodicity of one
day.
 Such rhythms persist in the absence of time cues
 Self sustained biological rhythms characterized by a free-running period of about 24
hours (circa diem)
 Circadian rhythm may be
 Diurnal: organisms active during daytime
 Nocturnal: organisms active in the night
 Crepuscular: animals primarily active during the dawn and dusk hours
(ex: white-tailed deer, some bats)
Circadian rhythms
Normal characteristics of circadian rhythm
Character Comment
Endogenous free
running period
The period of the rhythm in constant conditions is called the free-
running period and is denoted by the Greek letter τ (tau).
The rhythm persist in constant conditions, (i.e., constant
darkness)
Entrainable The rhythm can be reset by exposure to external stimuli (such as
light and heat), a process called entrainment
The external stimulus used to entrain a rhythm is called
the Zeitgeber, or "Time giver".
Exhibit temperature
compensation
They maintain circadian periodicity over a range of physiological
temperatures
Human circadian rhythms
 Sleep-wake cycle
 Body temperature
 Behaviour
 Food and water intake
 Hormones
 Metabolism
 Body fluids
 Expression of genes
Pulsatile exocrine and endocrine secretions
dependent on human circadian rhythm
functional componentsof circadian axis
 Master pacemaker situated in SCN
 Afferent-- Photoreceptive input situated
in the eye
 Efferent-- Rhythmic outputs which
provide insight into the clockwork of the
circadian pacemaker.
Scn-master pacemaker
 A group of neurons present in anterior
hypothalamus located dorsal to the optic
chiasma
 Master oscillator-- generates the mean
circadian rhythm and orchestrates a
multitudes of slave oscillators found in
peripheral tissues like kidney, liver, lungs &
other sites of the brain.
 The neurons of the SCN are among the
smallest neurons in the entire brain.
 They possess short dendrites that are not
extensively branched.
 The SCN is active during the day in both
diurnal and nocturnal animals.
 The SCN tells the animal whether it’s day or
night, but not how to behave.
 Transplants of SCN establish donor rhythms in
recipient animals.
SCN & light/dark cycles
Light
Exercise
Food
Social factors
EYE
Master clock: SCN
“Zeitgeber” (time givers)
“entrain” clock
Pineal
Gland
Regulates Hormones , Sleep/wake -
Temp
Afferent efferent and projections
Afferent Efferent
Main tract Retinohypothalamic Within the hypothalamus and to
pineal gland
Primary
neurotransmitter
Glutamate GABA
Modulator Pituitary adenylate cyclase
activating peptide(PACAP)
Efferent of SCN regulate autonomic
division of PVN--Sympathetic outflow to
pineal gland-stimulate melatonin
synthesis
Efferent parvicellular neuron of PVN has
the role in secretion of CRH which
regulates the release of cortisol
Other tract origin Ipsilateral intergeniculate
leaflet(IGL)-sub nucleus of LGN
Midbrain raphe
NT and receptor Neuropeptide Y, 5-HT1B
 Oscillations of protein production and degradation serves as the “ticking” of
the internal clock (takes about 24 hours).
 Light may participate in the triggering of some of these protein fluctuations.
How thebiological clockswork
Environmental cues
Sensory
receptors
Pace-maker
Locomotion
Hormone release
Feeding
Others
Clock-setting
pathway
Clock
mechanism
Observed
behaviour
TheBiochemistry of Circadian Rhythms
 Cortisol
 Release is highest in the morning and
drops during the day.
 Glutamate
 Released by the retinohypothalamic tract
during light
 Melatonin
 Released only at night (by the retina and
the pineal gland).
Melatonin
 Indoleamine, a circadian regulated hormone the synthesis of which is
regulated through the multisynaptic pathway from SCN to pineal gland.
 Serum level of melatonin is elevated at night and returns to baseline
during the day.
 Light shifts the phase of melatonin synthesis and suppresses the elevated
melatonin level.
Molecular clockwork
 Involves interaction and coordination
between the positive and negative
transcriptional and translational feedback
loops.
 The products of per and cry genes
translocate back into the nucleus and
repress their own transcription.
 Orphan nuclear receptor gene Rev-Erb
alpha also regulates the CLOCK-BAML1
then per and cry genes.
 Enzymes kinase and phosphatase also act
upon the gene products and has role in
molecular clock work.
per
Transcription
LIGHT
PER
Translation
Phosphorylation &
Dimerization of PER, CRY
cry
Transcription
CRY
Translation
Nucleus
Cytoplasm
CellMembrane
In all cells, the expression of many genes changes rhythmically over 24 hours.
Specific circadian genes such as CLOCK, BMAL1, and PER are responsible for the main
SCN clock working machinery as well as subsidiary clocks in other parts of the body.
Resetting thecircadian clock
sensory parameters
 The mean circadian period generated by the human SCN is of about 24.18
hours.
 In human light is the most effective agent for entraining the circadian
system
 Bilateral removal of eyes– incapable to reset circadian clock, indicating that
the photosensitive apparatus necessary for resetting must be ocular
 To maintain the proper phase relationship of behavioral and physiological
process circadian clock should be resetted in a regular basis within a
context of 24 hours a day.
 Photosensitive apparatus required for resetting the circadian clock is
different from the photoreceptors rods or cones.
 The light intensity required to activate such apparatus having high
threshold is of low i.e. 3 log unit for longer duration than of visual system.
 Eyes may retain the function in clock resetting despite being useless for
vision.
Extraocular photoreception
 Photic stimulation of extraocular tissue is sufficient to shift the human
circadian clock
 Blue light illumination of highly vascularized tissue like popliteal region
behind the knee---shown to phase shift the nightly increase of melatonin
 Currently this is not widely accepted and further research is needed
Novel classof retinal photoreceptors
 Studies in blind human and retinally degenerate animals– photoreceptors
other than rods and cones are likely to be involved in circadian system
 Rodent retinal ganglion cells found to be intrinsically photosensitive
 These cells contain Melanopsin– photo pigment initially discovered in
melanophores of tadpoles– later identified in human retina
 Melanopsin is also localized in plasma membrane of cell body, axon and
dendrites
 Plays important role in phase shifting of circadian locomotor activity
Relevancein psychiatry
 Sleep regulation
 Seasonal affective disorders
 Non seasonal depression
 Schizophrenia
Sleep regulation
Regulated by two mechanisms
 Sleep homeostat
 Related to the accumulation and
dissipation of sleep debt.
 Adenosine is supposed to be a
neuromodulator of the sleep
homeostat.
 Circadian cycle/clock
 Controls a daily rhythm in sleep
propensity or conversely, arousal.
 Arousal steadily increases throughout
the day, reaching a maximum
immediately before the circadian
increase in plasma melatonin.
Circadian rhythm sleep disorders1
 Advanced sleep phase syndrome
 Delayed sleep phase syndrome
 Free-running type
 Irregular Sleep-Wake Disorder (ISWD)
 Jet lag
 Shift work type
1 Circadian Rhythm Sleep Disorders: Part I, Basic Principles, Shift Work and Jet Lag Disorders
An American Academy of Sleep Medicine Review
Robert L Sack, MD; Dennis Auckley, MD; R. Robert Auger, MD; Mary A. Carskadon, PhD; Kenneth P. Wright Jr, PhD; Michael V. Vitiello, PhD; Irina V. Zhdanova,
MD
 Advanced sleep phase syndrome (ASPS)
 Characterized by bedtime and wake-up time much earlier than
normal, although sleep quality is normal.
 People with ASPS may fall sleep at 6 or 8 p.m. and awaken about
eight hours later.
 An autosomal dominant familial form (FASPS): 4 hour advance of
daily sleep wake rhythm(7:30pm-4:30am)
 ASPS is related to the single nucleotide polymorphism in period
gene
 Delayed sleep phase syndrome (DSPS)
 A circadian sleep disorder in which the individual's internal body
clock is delayed with respect to the external day/night cycle
 Falls asleep late at night, typically between 1:00 am and 6:00 am,
and awakens in the late morning or in the afternoon.
 Irregular Sleep-Wake Disorder (ISWD)
 Characterized by at least three sleep episodes per 24-hour period, irregularly
from day to day.
 Most commonly occurs in elderly persons with dementia.
 Also occurs in some children with developmental disorders, including autism
spectrum disorders.
 Can be a consequence of brain tumors or traumatic brain injury
 Free running/ Non-24-Hour Sleep-Wake Disorder (Non-24)
 Rhythms, which reflect the intrinsic oscillation of the circadian pacemaker when
it is not influenced by environmental time cues.
 Circadian sleep disorder in which an individual falls asleep later each day.
 Generally the delay is about an hour or two, corresponding to a circadian cycle
of 25 - 26 hours; but some individuals with Non-24 exhibit a much longer delay,
especially those who have lived with Non-24 for many years.
 Jet lag
 When a person travels through the different time zones there would
be the phase difference.
 In jet lag the clock is slow to reset, so that after time zones have been
crossed, the endogenous signals for sleep and wakefulness do not
match the local light–dark and social schedules1
 Travelling from east to west will have phase advance while reverse
would be in opposite direction.
 Symptoms include reduced alertness, day time fatigue, loss of
appetite, reduced cognitive skills and disruption of sleep/wakefulness
 Shift work schedule
 When a person works against the natural day-night schedule he/she
would suffer from disruption of circadian rhythm.
1 The New England Journal of Medicine
Jet Lag; Robert L. Sack, M.D.
N Engl J Med 362;5 February 4, 2010
Seasonal affectivedisorders
 Seasonal affective disorder(SAD) is a form of a recurrent major
depressive episodes followed by periods of remissions that occurs in
seasonal basis.
 In DSM-IV, it is not categorized as a distinct mood disorder but as the
seasonal pattern specifiers.
 Full remissions(or a change from depression to mania or hypomania)
also occur at a characteristic time of the year.
 Two major depressive episodes meeting criteria A and B have occurred
in the last 2 yrs and no non seasonal episodes have occurred in the
same period.
 Seasonal major depressive episodes substantially outnumber the non
seasonal episodes over the individual’s lifetime.
SAD Mechanisms
 Phase Shift Hypothesis 1
 Phase delay in body
 Melatonin Dysregulation 2
 Secretion is longer than normal in winter
 Serotonin Deficiency
 L-tryptophan is a precursor of serotonin
 Genetic Abnormalities
 Based on epidemiology studies; serotonin transporter or clock gene
defects
1. Samir Malhotra, Girish Sawhney, Promila Pandhi (2004) The Therapeutic Potential of Melatonin: A Review of the
Science. MedGenMed. 6 (2): 46
2. Alfred J. Lewy, Bryan J. Lefler, Jonathan S. Emens, and Vance K. Bauer.(2006) The circadian basis of winter
depression. PNAS; 103; 7414-7419
Winter SAD
 Called as winter depression or winter blues.
 Onset in the late fall and early winter and remits in the late winter and
early summer.
 Symptoms may be atypical to major depression
 Significant increase in weight
 Increase rather than decrease in sleep
 Hyperphagia
 Heightened sensitivity to interpersonal rejection
 Leaden feeling in the extremities.
 Incidence
 4-9% of total population
 20% of population may have sub syndromal features.
 M: F=1:4
 Runs in families showing genetic or environmental influences
 Serum level of melatonin is considered as causative condition.
 Treatment
 Light therapy
 High irradiance(5,000 -10,000 lux) for about 45 – 90 minutes.
 Early morning or evening pattern of exposure.
 Pharmacotherapy
 MAO inhibitors.
 Cognitive behavioral therapy
 Comorbidity
 Bulimia nervosa
 Premenstrual dysphoric disorder
 Alcoholism
Non seasonal depression
 Depression causes the phase delay while mania causes phase advance in
sleep cycle.
 Sleep disturbances can contribute to the pathogenesis of disease.
 Total sleep deprivation provides a transient antidepressant effect in a
majority (~60%)of depressed patient.
 No difference is observed in the efficacy of such treatment with or
without medicine.
 Relapse occurs after the following night sleep even day time short
napping among which early morning is critical.
 With regard to MDD, almost all patients present with sleep disturbances and
altered circadian rhythms including hormonal secretion, cardiac function, and
body temperature.
 Sleep disruption is a major symptom in depression, with over 90% of patients
showing sleep complaints that affect daytime functioning
 There may be delayed sleep onset, terminal insomnia, decreased N3-N4 sleep,
increased phasic REM density, decreased REM latency, fragmented sleep and
day time napping
 Insomnia often appears before the onset of mood disorder symptoms and
may persist into clinical remission
 Sleep difficulties are often are the key factor that causes depressed patients to
seek medical help
schizophrenia
 Sleep-onset and maintenance insomnia is a common symptom regardless of either
their medication status (previously treated) or the phase of the clinical course (acute or
chronic).
 Regarding sleep architecture, NREM-N3 sleep and REM sleep onset latency are
reduced whereas REM sleep duration tends to remain unchanged.
 Many of these sleep disturbances are caused by abnormalities of the circadian system
as indicated by misalignments of the endogenous circadian cycle and the sleep wake
cycle.
 Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep could be
partly related to a presumed hyperactivity of the dopaminergic system and dysfunction
of the GABAergic system
Sleep and circadian rhythm dysregulation in schizophrenia
Progress in Neuro-Psychopharmacology & Biological Psychiatry, Elsevier; 2013
Relevancein medical conditions
 Obesity and
metabolic
dysfunction
 Cancer
 Effect of aging
The circadian pattern of various diseases
Obesity and metabolic dysfunction
 Experimental studies showed the relation between blood lipid, glucose,
and insulin level with the circadian rhythm.
 Shift workers have more incidence of having metabolic syndrome
characterized by:
 Hyperglycemia
 Hypoinsulinemia
 Dyslipidemia
 Visceral obesity and the complications following such conditions.
Cancer
 Experimental studies showed the increased incidence of carcinomas in jet-
laged-radiation exposed animals.
 Shift working females and airhostess crossing the meridians were found to
be increased risk of breast cancer.
 Supposed to be inhibition of melatonin which augments estrogen effect.
Aging
 Experimental studies showed that phase shifting has effect in survival of
aged mice in which phase delay increased the survival but phase advance
decreased the survival.
 During aging circadian period shortens with phase advance resulting in
earlier bedtime and waking.
Pharmacological agentsaffecting circadian
rhythm
Drug Effect on rhythm
TCA Decreases elevated nocturnal body temperature in depressive patients
SSRI Decreases elevated nocturnal body temperature in depressive patients,
augment diurnal activities.
Lithium Inhibit glycogen synthase kinase 3b which stabilizes the negative
clockwork stabilizer REV-ERBa---lengthens circadian period
Benzodiazepines
Brotizolam
Act via GABA receptors in SCN– induces circadian phase advances
Reduced expression of clock genes
MDMA
Methylenedioxymethamphetamine
Phase shift in circadian locomotor activity
Terminologiesrelated to
chronotherapeutics
Terminology Comment
Chronopathology It is the study of biological rhythms in disease processes and morbid
and mortal events.
Chronopharmacology It is the study of manner and extent to which the kinetics and
dynamics of medications are directly affected by endogenous
biological rhythms, and also how the dosing time affect biological
rhythms
Chronopharmacokinetics This term includes both rhythmic changes in the drug bioavailability,
and its excretion
Chronopharmacodynamics Refers to dosing time, i.e., rhythm-dependent, differences in the
effects of medications.
Chronotoxicology Refers specifically to dosing-time, i.e., rhythm-dependent,
differences in the manifestation and severity of adverse effects and
thus intolerance of patients to medications
chronotherapeutics
Therapy Mechanism Comment
Chronotherapeutics is medical treatment administered according to a schedule that corresponds to a
persons daily, monthly, seasonal or yearly biological clock to maximize health benefits and minimize
adverse effects
Light therapy Light therapy emerged as the first successful
treatment in psychiatry based on neurobiological
principles and is now established as the treatment
of choice for SAD
Wake therapy Total sleep deprivation Improvement in depressed patients occur with
total sleep deprivation
Dark therapy Focuses on darkness, particularly
in bipolar patients
Keeping acutely manic patients in dark rooms
during the night has been shown to improve
symptoms and immediately stop rapid cycling.
Melatonin
Agomelatine
Ramelteon
Tasimelteon
If rhythms are out of sync, as in depression,
melatonin is secreted at the wrong time and the
sleep disturbance is accentuated.
Modafinil Used for excessive sleepiness associated with shift
work sleep disorder
Futureadvances
 Identification of coupling factors responsible for
communicating phase information among
biological oscillators would resolve the issues of
circadian desynchrony.
 This would give insight for pharmacological as
well as behavioral means to resolve the problems
due to circadian desynchrony.
 Impact of circadian system on the effectiveness of
pharmacological treatments would develop the
field of chronotherapy.
Summary
 Biological rhythms are the events and activities which happen in a cyclical
way in the influence of rotation of the earth in it’s axis.
 Most well studied biological rhythm is the circadian rhythm having day
night cycle.
 SCN is the master pacemaker which orchestrates other oscilators of the
body.
 Melatonin is the hormone secreted by pineal gland having role in
circadian rhythm.
 Zeitgeber is the external cue which regulates and resets the circadian
rhythm and the luminance is a Zeitgeber.
 There are genetic events which act as work clock.
 There is definite role of circadian rhythm in causation, course and
outcome of various psychiatric and medical conditions.
 Aging is a process which affects circadian rhythm of an individual.
 There is significant interaction between pharmacological agents and
circadian rhythm.
Chronobiology overview and its relevance in psychiatry

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Chronobiology overview and its relevance in psychiatry

  • 1. Chronobiology Overview and it’srelevancein psychiatry Presenter: Dr. Suman Pd. Adhikari
  • 2. Chronobiological Terms Term Definition Biological clock Physiological mechanism that gives a time sense to every living organisms i.e., when to eat, sleep/awake etc. Biological rhythm Cyclical, repeated variation in a biological function. Circadian rhythm Cyclical variation in a metabolic , physiological or behavioral process with a period of about 24 hours when in constant conditions Circannual rhythm Cyclical variation in a metabolic, physiological or behavioral process with a period of about an year. Diurnal activity Activity performed mainly during the daytime Endogenous Of rhythms or other forms of biological timekeeping controlled from within the organism by some kind of physiological ‘ biological clock ’ Entrainment Synchronization of one biological rhythm to another or to a zeitgeber cycle, e.g. circadian rhythm are often entrained to the light-dark cycle
  • 3. Term Definition Melatonin A hormone produced rhythmically in vertebrates by the pineal gland, a pea sized organ at the center of the human brain. Nocturnal activity Activity performed mainly at night Oscillator Internal and therefore unseen, or endogenous oscillator (the biological clock ) that produces an overt measurable biological rhythm in the organism. Period The length of one complete cycle of a rhythm Phase A particular reference point in the cycle of a rhythm, e.g. the daily onset of locomotor activity, or the light-to-dark transition in a zeitgeber cycle. Phase shift Shift in a biological rhythm along its time axis so whilst the period remains the same the time at which the rhythm occurs changes Zeitgeber “time giver” Periodic environmental signal that entrains some biological rhythm , for example a natural or artificial day-night cycle for a circadian rhythm
  • 4.  zeitgeber   An environmental agent or event (as the occurrence of light or dark) that provides the stimulus for setting or resetting a biological clock of an organism  Any external or environmental cue that entrains, or synchronizes, an organism's biological rhythms to the earth's 24-hour light/dark cycle and 12 month cycle.  The term "zeitgeber" (German for "time giver" or "synchronizer") was first used by Jurgen Aschoff , one of the founders of Chronobiology  Common zeitgeber  Temperature  Social interactions  Pharmacological manipulation  Exercise  Eating/drinking patterns
  • 5. Introduction of Chronobiology  Study of biological time in relation with cyclic rotation of the earth in it’s axis which is completed within 24 hrs.  Biological rhythm varies from milliseconds in ocular field potential to years  Circadian rhythm is the most extensively studied and best understood biological rhythm.  Chronobiology comes from the ancient Greek (chrónos, meaning "time"), and biology, which means “the study, or science, of life”
  • 6. History of Chronobiology Date Literature/contributor Comment 4th Century BC Androsthenes (Ship captain of Alexandar the Great) Described diurnal leaf movements of the Tamarind tree. 13th Century Noon and Midnight Manual (Chinese) Circadian or diurnal process in humans mentioned 1729 Jean-Jacques d Ortous de Mairan (French) Noted 24-hour patterns in the movement of the leaves of the plant Mimosa pudica 1751 Carlous Linneaus (Swedish Botanist and naturalist) Designed a flower clock using certain species of flowers. By arranging the selected species in a circular pattern, he designed a clock that indicated the time of day by the flowers that were open at each given hour 1896 Patrick and Gilbert Observed that during a prolonged period of sleep deprivation, sleepiness increases
  • 7. Date Literature/contributor Comment 1918 J.S. Szymanski Showed that animals are capable of maintaining 24-hour activity patterns in the absence of external cues such as light and changes in temperature 1959 Franz Halberg (University of Minnesota-Father of American Chronobiology) Coined the term “Circadian” 20th Century Auguste Forel, Oskar Wahl Circadian rhythms were noticed in the rhythmic feeding times of bees 1967 Erwin Bunning Described physiological clock in plant 1970s Ron Konopka, Seymour Benzer Isolated the first clock mutant in Drosophila and mapped the “period" gene, the first discovered genetic component of a circadian clock 1994 Joseph Takahasi Discovered the first mammalian 'clock gene' (CLOCK) using mice
  • 9.  Latin word circa means about and dies means days, which has the periodicity of one day.  Such rhythms persist in the absence of time cues  Self sustained biological rhythms characterized by a free-running period of about 24 hours (circa diem)  Circadian rhythm may be  Diurnal: organisms active during daytime  Nocturnal: organisms active in the night  Crepuscular: animals primarily active during the dawn and dusk hours (ex: white-tailed deer, some bats) Circadian rhythms
  • 10. Normal characteristics of circadian rhythm Character Comment Endogenous free running period The period of the rhythm in constant conditions is called the free- running period and is denoted by the Greek letter τ (tau). The rhythm persist in constant conditions, (i.e., constant darkness) Entrainable The rhythm can be reset by exposure to external stimuli (such as light and heat), a process called entrainment The external stimulus used to entrain a rhythm is called the Zeitgeber, or "Time giver". Exhibit temperature compensation They maintain circadian periodicity over a range of physiological temperatures
  • 11. Human circadian rhythms  Sleep-wake cycle  Body temperature  Behaviour  Food and water intake  Hormones  Metabolism  Body fluids  Expression of genes
  • 12. Pulsatile exocrine and endocrine secretions dependent on human circadian rhythm
  • 13. functional componentsof circadian axis  Master pacemaker situated in SCN  Afferent-- Photoreceptive input situated in the eye  Efferent-- Rhythmic outputs which provide insight into the clockwork of the circadian pacemaker.
  • 14. Scn-master pacemaker  A group of neurons present in anterior hypothalamus located dorsal to the optic chiasma  Master oscillator-- generates the mean circadian rhythm and orchestrates a multitudes of slave oscillators found in peripheral tissues like kidney, liver, lungs & other sites of the brain.  The neurons of the SCN are among the smallest neurons in the entire brain.  They possess short dendrites that are not extensively branched.
  • 15.  The SCN is active during the day in both diurnal and nocturnal animals.  The SCN tells the animal whether it’s day or night, but not how to behave.  Transplants of SCN establish donor rhythms in recipient animals. SCN & light/dark cycles
  • 16. Light Exercise Food Social factors EYE Master clock: SCN “Zeitgeber” (time givers) “entrain” clock Pineal Gland Regulates Hormones , Sleep/wake - Temp
  • 17. Afferent efferent and projections Afferent Efferent Main tract Retinohypothalamic Within the hypothalamus and to pineal gland Primary neurotransmitter Glutamate GABA Modulator Pituitary adenylate cyclase activating peptide(PACAP) Efferent of SCN regulate autonomic division of PVN--Sympathetic outflow to pineal gland-stimulate melatonin synthesis Efferent parvicellular neuron of PVN has the role in secretion of CRH which regulates the release of cortisol Other tract origin Ipsilateral intergeniculate leaflet(IGL)-sub nucleus of LGN Midbrain raphe NT and receptor Neuropeptide Y, 5-HT1B
  • 18.  Oscillations of protein production and degradation serves as the “ticking” of the internal clock (takes about 24 hours).  Light may participate in the triggering of some of these protein fluctuations. How thebiological clockswork Environmental cues Sensory receptors Pace-maker Locomotion Hormone release Feeding Others Clock-setting pathway Clock mechanism Observed behaviour
  • 19. TheBiochemistry of Circadian Rhythms  Cortisol  Release is highest in the morning and drops during the day.  Glutamate  Released by the retinohypothalamic tract during light  Melatonin  Released only at night (by the retina and the pineal gland).
  • 20. Melatonin  Indoleamine, a circadian regulated hormone the synthesis of which is regulated through the multisynaptic pathway from SCN to pineal gland.  Serum level of melatonin is elevated at night and returns to baseline during the day.  Light shifts the phase of melatonin synthesis and suppresses the elevated melatonin level.
  • 21. Molecular clockwork  Involves interaction and coordination between the positive and negative transcriptional and translational feedback loops.  The products of per and cry genes translocate back into the nucleus and repress their own transcription.  Orphan nuclear receptor gene Rev-Erb alpha also regulates the CLOCK-BAML1 then per and cry genes.  Enzymes kinase and phosphatase also act upon the gene products and has role in molecular clock work.
  • 22. per Transcription LIGHT PER Translation Phosphorylation & Dimerization of PER, CRY cry Transcription CRY Translation Nucleus Cytoplasm CellMembrane In all cells, the expression of many genes changes rhythmically over 24 hours. Specific circadian genes such as CLOCK, BMAL1, and PER are responsible for the main SCN clock working machinery as well as subsidiary clocks in other parts of the body.
  • 23. Resetting thecircadian clock sensory parameters  The mean circadian period generated by the human SCN is of about 24.18 hours.  In human light is the most effective agent for entraining the circadian system  Bilateral removal of eyes– incapable to reset circadian clock, indicating that the photosensitive apparatus necessary for resetting must be ocular  To maintain the proper phase relationship of behavioral and physiological process circadian clock should be resetted in a regular basis within a context of 24 hours a day.
  • 24.  Photosensitive apparatus required for resetting the circadian clock is different from the photoreceptors rods or cones.  The light intensity required to activate such apparatus having high threshold is of low i.e. 3 log unit for longer duration than of visual system.  Eyes may retain the function in clock resetting despite being useless for vision.
  • 25. Extraocular photoreception  Photic stimulation of extraocular tissue is sufficient to shift the human circadian clock  Blue light illumination of highly vascularized tissue like popliteal region behind the knee---shown to phase shift the nightly increase of melatonin  Currently this is not widely accepted and further research is needed
  • 26. Novel classof retinal photoreceptors  Studies in blind human and retinally degenerate animals– photoreceptors other than rods and cones are likely to be involved in circadian system  Rodent retinal ganglion cells found to be intrinsically photosensitive  These cells contain Melanopsin– photo pigment initially discovered in melanophores of tadpoles– later identified in human retina  Melanopsin is also localized in plasma membrane of cell body, axon and dendrites  Plays important role in phase shifting of circadian locomotor activity
  • 27. Relevancein psychiatry  Sleep regulation  Seasonal affective disorders  Non seasonal depression  Schizophrenia
  • 28.
  • 29. Sleep regulation Regulated by two mechanisms  Sleep homeostat  Related to the accumulation and dissipation of sleep debt.  Adenosine is supposed to be a neuromodulator of the sleep homeostat.  Circadian cycle/clock  Controls a daily rhythm in sleep propensity or conversely, arousal.  Arousal steadily increases throughout the day, reaching a maximum immediately before the circadian increase in plasma melatonin.
  • 30. Circadian rhythm sleep disorders1  Advanced sleep phase syndrome  Delayed sleep phase syndrome  Free-running type  Irregular Sleep-Wake Disorder (ISWD)  Jet lag  Shift work type 1 Circadian Rhythm Sleep Disorders: Part I, Basic Principles, Shift Work and Jet Lag Disorders An American Academy of Sleep Medicine Review Robert L Sack, MD; Dennis Auckley, MD; R. Robert Auger, MD; Mary A. Carskadon, PhD; Kenneth P. Wright Jr, PhD; Michael V. Vitiello, PhD; Irina V. Zhdanova, MD
  • 31.  Advanced sleep phase syndrome (ASPS)  Characterized by bedtime and wake-up time much earlier than normal, although sleep quality is normal.  People with ASPS may fall sleep at 6 or 8 p.m. and awaken about eight hours later.  An autosomal dominant familial form (FASPS): 4 hour advance of daily sleep wake rhythm(7:30pm-4:30am)  ASPS is related to the single nucleotide polymorphism in period gene  Delayed sleep phase syndrome (DSPS)  A circadian sleep disorder in which the individual's internal body clock is delayed with respect to the external day/night cycle  Falls asleep late at night, typically between 1:00 am and 6:00 am, and awakens in the late morning or in the afternoon.
  • 32.  Irregular Sleep-Wake Disorder (ISWD)  Characterized by at least three sleep episodes per 24-hour period, irregularly from day to day.  Most commonly occurs in elderly persons with dementia.  Also occurs in some children with developmental disorders, including autism spectrum disorders.  Can be a consequence of brain tumors or traumatic brain injury  Free running/ Non-24-Hour Sleep-Wake Disorder (Non-24)  Rhythms, which reflect the intrinsic oscillation of the circadian pacemaker when it is not influenced by environmental time cues.  Circadian sleep disorder in which an individual falls asleep later each day.  Generally the delay is about an hour or two, corresponding to a circadian cycle of 25 - 26 hours; but some individuals with Non-24 exhibit a much longer delay, especially those who have lived with Non-24 for many years.
  • 33.  Jet lag  When a person travels through the different time zones there would be the phase difference.  In jet lag the clock is slow to reset, so that after time zones have been crossed, the endogenous signals for sleep and wakefulness do not match the local light–dark and social schedules1  Travelling from east to west will have phase advance while reverse would be in opposite direction.  Symptoms include reduced alertness, day time fatigue, loss of appetite, reduced cognitive skills and disruption of sleep/wakefulness  Shift work schedule  When a person works against the natural day-night schedule he/she would suffer from disruption of circadian rhythm. 1 The New England Journal of Medicine Jet Lag; Robert L. Sack, M.D. N Engl J Med 362;5 February 4, 2010
  • 34. Seasonal affectivedisorders  Seasonal affective disorder(SAD) is a form of a recurrent major depressive episodes followed by periods of remissions that occurs in seasonal basis.  In DSM-IV, it is not categorized as a distinct mood disorder but as the seasonal pattern specifiers.  Full remissions(or a change from depression to mania or hypomania) also occur at a characteristic time of the year.  Two major depressive episodes meeting criteria A and B have occurred in the last 2 yrs and no non seasonal episodes have occurred in the same period.  Seasonal major depressive episodes substantially outnumber the non seasonal episodes over the individual’s lifetime.
  • 35. SAD Mechanisms  Phase Shift Hypothesis 1  Phase delay in body  Melatonin Dysregulation 2  Secretion is longer than normal in winter  Serotonin Deficiency  L-tryptophan is a precursor of serotonin  Genetic Abnormalities  Based on epidemiology studies; serotonin transporter or clock gene defects 1. Samir Malhotra, Girish Sawhney, Promila Pandhi (2004) The Therapeutic Potential of Melatonin: A Review of the Science. MedGenMed. 6 (2): 46 2. Alfred J. Lewy, Bryan J. Lefler, Jonathan S. Emens, and Vance K. Bauer.(2006) The circadian basis of winter depression. PNAS; 103; 7414-7419
  • 36. Winter SAD  Called as winter depression or winter blues.  Onset in the late fall and early winter and remits in the late winter and early summer.  Symptoms may be atypical to major depression  Significant increase in weight  Increase rather than decrease in sleep  Hyperphagia  Heightened sensitivity to interpersonal rejection  Leaden feeling in the extremities.
  • 37.  Incidence  4-9% of total population  20% of population may have sub syndromal features.  M: F=1:4  Runs in families showing genetic or environmental influences  Serum level of melatonin is considered as causative condition.  Treatment  Light therapy  High irradiance(5,000 -10,000 lux) for about 45 – 90 minutes.  Early morning or evening pattern of exposure.  Pharmacotherapy  MAO inhibitors.  Cognitive behavioral therapy  Comorbidity  Bulimia nervosa  Premenstrual dysphoric disorder  Alcoholism
  • 38. Non seasonal depression  Depression causes the phase delay while mania causes phase advance in sleep cycle.  Sleep disturbances can contribute to the pathogenesis of disease.  Total sleep deprivation provides a transient antidepressant effect in a majority (~60%)of depressed patient.  No difference is observed in the efficacy of such treatment with or without medicine.  Relapse occurs after the following night sleep even day time short napping among which early morning is critical.
  • 39.  With regard to MDD, almost all patients present with sleep disturbances and altered circadian rhythms including hormonal secretion, cardiac function, and body temperature.  Sleep disruption is a major symptom in depression, with over 90% of patients showing sleep complaints that affect daytime functioning  There may be delayed sleep onset, terminal insomnia, decreased N3-N4 sleep, increased phasic REM density, decreased REM latency, fragmented sleep and day time napping  Insomnia often appears before the onset of mood disorder symptoms and may persist into clinical remission  Sleep difficulties are often are the key factor that causes depressed patients to seek medical help
  • 40. schizophrenia  Sleep-onset and maintenance insomnia is a common symptom regardless of either their medication status (previously treated) or the phase of the clinical course (acute or chronic).  Regarding sleep architecture, NREM-N3 sleep and REM sleep onset latency are reduced whereas REM sleep duration tends to remain unchanged.  Many of these sleep disturbances are caused by abnormalities of the circadian system as indicated by misalignments of the endogenous circadian cycle and the sleep wake cycle.  Circadian disruption, sleep onset insomnia and difficulties in maintaining sleep could be partly related to a presumed hyperactivity of the dopaminergic system and dysfunction of the GABAergic system Sleep and circadian rhythm dysregulation in schizophrenia Progress in Neuro-Psychopharmacology & Biological Psychiatry, Elsevier; 2013
  • 41. Relevancein medical conditions  Obesity and metabolic dysfunction  Cancer  Effect of aging The circadian pattern of various diseases
  • 42. Obesity and metabolic dysfunction  Experimental studies showed the relation between blood lipid, glucose, and insulin level with the circadian rhythm.  Shift workers have more incidence of having metabolic syndrome characterized by:  Hyperglycemia  Hypoinsulinemia  Dyslipidemia  Visceral obesity and the complications following such conditions.
  • 43. Cancer  Experimental studies showed the increased incidence of carcinomas in jet- laged-radiation exposed animals.  Shift working females and airhostess crossing the meridians were found to be increased risk of breast cancer.  Supposed to be inhibition of melatonin which augments estrogen effect.
  • 44. Aging  Experimental studies showed that phase shifting has effect in survival of aged mice in which phase delay increased the survival but phase advance decreased the survival.  During aging circadian period shortens with phase advance resulting in earlier bedtime and waking.
  • 45. Pharmacological agentsaffecting circadian rhythm Drug Effect on rhythm TCA Decreases elevated nocturnal body temperature in depressive patients SSRI Decreases elevated nocturnal body temperature in depressive patients, augment diurnal activities. Lithium Inhibit glycogen synthase kinase 3b which stabilizes the negative clockwork stabilizer REV-ERBa---lengthens circadian period Benzodiazepines Brotizolam Act via GABA receptors in SCN– induces circadian phase advances Reduced expression of clock genes MDMA Methylenedioxymethamphetamine Phase shift in circadian locomotor activity
  • 46. Terminologiesrelated to chronotherapeutics Terminology Comment Chronopathology It is the study of biological rhythms in disease processes and morbid and mortal events. Chronopharmacology It is the study of manner and extent to which the kinetics and dynamics of medications are directly affected by endogenous biological rhythms, and also how the dosing time affect biological rhythms Chronopharmacokinetics This term includes both rhythmic changes in the drug bioavailability, and its excretion Chronopharmacodynamics Refers to dosing time, i.e., rhythm-dependent, differences in the effects of medications. Chronotoxicology Refers specifically to dosing-time, i.e., rhythm-dependent, differences in the manifestation and severity of adverse effects and thus intolerance of patients to medications
  • 47. chronotherapeutics Therapy Mechanism Comment Chronotherapeutics is medical treatment administered according to a schedule that corresponds to a persons daily, monthly, seasonal or yearly biological clock to maximize health benefits and minimize adverse effects Light therapy Light therapy emerged as the first successful treatment in psychiatry based on neurobiological principles and is now established as the treatment of choice for SAD Wake therapy Total sleep deprivation Improvement in depressed patients occur with total sleep deprivation Dark therapy Focuses on darkness, particularly in bipolar patients Keeping acutely manic patients in dark rooms during the night has been shown to improve symptoms and immediately stop rapid cycling. Melatonin Agomelatine Ramelteon Tasimelteon If rhythms are out of sync, as in depression, melatonin is secreted at the wrong time and the sleep disturbance is accentuated. Modafinil Used for excessive sleepiness associated with shift work sleep disorder
  • 48. Futureadvances  Identification of coupling factors responsible for communicating phase information among biological oscillators would resolve the issues of circadian desynchrony.  This would give insight for pharmacological as well as behavioral means to resolve the problems due to circadian desynchrony.  Impact of circadian system on the effectiveness of pharmacological treatments would develop the field of chronotherapy.
  • 49. Summary  Biological rhythms are the events and activities which happen in a cyclical way in the influence of rotation of the earth in it’s axis.  Most well studied biological rhythm is the circadian rhythm having day night cycle.  SCN is the master pacemaker which orchestrates other oscilators of the body.  Melatonin is the hormone secreted by pineal gland having role in circadian rhythm.
  • 50.  Zeitgeber is the external cue which regulates and resets the circadian rhythm and the luminance is a Zeitgeber.  There are genetic events which act as work clock.  There is definite role of circadian rhythm in causation, course and outcome of various psychiatric and medical conditions.  Aging is a process which affects circadian rhythm of an individual.  There is significant interaction between pharmacological agents and circadian rhythm.