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CHRONO BIOLOGY

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CHRONOBILOGY, CIRCADIAN RHYTHMS,

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CHRONO BIOLOGY

  1. 1. - Dr.V.L.N.SEKHAR PG in Psychiatry
  2. 2.  Chronos= time; biology=study of life  Chronobiology is a field of biology that examines periodic(cyclic)phenomena in living organisms and their adoptation to solar and lunar related rhythms.  The variation of the timing and duration of biological activity in living organisms occur for many essential biological processes.
  3. 3.  These occur:- 1. In animals (eating, sleeping, mating, hibernating, migration, cellular regeneration etc.) 2. In plants (leaf movements, photosynthetic reactons etc.) 3. In microbial organisms such as fungi and protozoa.  The most important rhythm in chronobiology is the circadian rhythm.
  4. 4.  Biological clock:- - the internal physiological systems that track the environmental rhythms. Responsible for generating biological rhythms.  Biological rhythm:- is one or more biological events or functions that reoccur in time in a repeated order and with a repeated interval between occurrence.  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.
  5. 5.  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.  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
  6. 6.  Biological rhythm is one or more biological events or functions that reoccur in time in a repeated order and with a repeated interval between occurrence.  these are the ways that organisms adapt and live with the environmental rhythms around them, such as the spin of the earth, the movement of the earth around the sun, and movement of the moon around the earth.  biological rhythms allow an organism to harmonize successfully with its environment.
  7. 7.  Two types- exogenous and endogenous.  Exogenous biological rhythms are driven directly by the environment or another external influence. Eg. the hopping of sparrows on a perch when a light is turned on  Endogenous biological rhythms are driven by internal biological clocks and are maintained even when environmental cues are removed. Eg. the wake-sleep cycle and the daily body temperature cycles.
  8. 8.  the 24-hour periodicity represents a small time domain within the spectrum of temporal biology. A broad range of frequencies exist , ranging from millisecond oscillations in ocular field potentials to the 17-year cycle of emergence seen in the periodic cicada (Magicicada spp.).  Ultradian rhythm: Biologic rhythm with a period shorter than circadian (less than 20 h).  Circadian: About 24 h. The term describes rhythms with about 24 h ( > 20 to < 28 h) cycle length whether they are synchronized with a 24 h periodic surrounding or not.
  9. 9.  Infradian rhythm- Rhythm with a period longer (by definition > 28 h) than the circadian range eg. the annual migration ; reproduction cycles found in certain animals ; the human menstrual cycle.  Circaseptan: A rhythm with a period of about 7 ( ± 3) days, which may or may not be synchronized with the calendar week.  Circadiseptan: A rhythm with a period of about 14 ( ± 3) days  Circavigintan: A rhythm with a period of about 20 ( ± 3) days.  Circatrigintan or circalunar: A rhythm with a period of about 30 (± 5) days. Eg. the menstrual cycle.
  10. 10.  Circaannual -A rhythm with a period of about 1 year ( ± 2 months), synchronized with or desynchronized from the calendar year. E.g.. over-winter hibernation  Seasonal variation -Change in a biologic system brought about by seasonal changes of temperature, light-span, etc, and not observed in the absence of such changes.  Tidal rhythms - commonly observed in marine life, which follow the roughly 12-hour transition from high to low tide and back.  Gene oscillations – some genes are expressed more during certain hours of the day than during other hour
  11. 11. biological rhythms
  12. 12.  "biological clocks" - the internal physiological systems that track the environmental rhythms. Responsible for generating biological rhythms  True biological clocks has 4 characteristics 1. the clock is endogenous, meaning it gives the organism an innate ability to maintain periods of a particular length between biological functions. 2. the clock is temperature independent—a very unusual situation in biology but an essential characteristic to avoid biological rhythms being governed by the weather. 3. biological clocks have the ability to be reset in order to maintain a relationship with environmental cues. 4. biological clocks are an internal continuous monitor of the passage of time, allowing the organism to keep track of duration biologically.
  13. 13.  Two functions: 1.the capacity of the biological clock to free run (operate without external cues), 2. the ability of timing signals, known as Zeitgeber (German for "time-giver"), to synchronize the cycles to the environmental signals. Common zeitgebers include light, temperature, and social cues such as clocks, sound, or physical contact. A biological clock is said to be free running when these external cues are removed. the average free run period for circadian rhythms in humans is 25 hours. Thus, if isolated from outside input, people tend to go to sleep one hour later each day, quickly becoming out of sync with the rest of the 24 hour-based human world.
  14. 14.  Entrainment is the process of aligning a biological rhythm with an environmental stimulus. There are limits to the time periods that biological rhythms can be entrained.  For circadian rhythms in most animals, 18 hours is the shortest period tolerated, with an upper limit of about 28-30 hours. If zeitgebers are provided for shorter or longer intervals, the organism reverts back to free running.  A good example of entrainment is the acquisition of the 24-hour wake-sleep schedule by human infants after birth. Newborn circadian rhythms free run, significantly disrupting the sleeping patterns of their parents. However, as they mature and become responsive to zeitgebers such as light and dark, infants gradually adopt the 24-hour schedule of adults.
  15. 15.  Latin: circa=about; dies=day  the most extensively studied and best understood biological rhythms.  Rhythms that fluctuate on a 24-hour time scale are known as circadian rhythms.  Physiologic or behavioral cycles with a period of 24 hrs produced by endogenous pacemaker.  Franz Halberg who coined the word circadian, is widely considered the "father of American chronobiology.“  The best-known circadian rhythms  body temperature  hormone secretion  metabolism  sleep/wake cycle
  16. 16.  Ubiquitous (cyanobacterias, plants, rodents, humans)  Endogenous (persist in the absence of environmental cycles) circadian rhythm can further be broken down into routine cycles during the 24-hour day:  Diurnal- which describes organisms active during daytime  Nocturnal- which describes organisms active in the night  Crepuscular- which describes animals primarily active during the dawn and dusk hours (ex: white-tailed deer, some bats)  Prominent daily variations also occur in  endocrine,  thermoregulatory,  cardiac,  pulmonary,  renal,  gastrointestinal,  neurobehavioral functions.
  17. 17.  Measurement of circadian phase and its changes can be obtained through the assessment of proxy- markers which are: 1.Core body temperature minimum(CBTM) –which occurs approximately 2 hrs before awakening from nocturnal sleep. 2.Dim light melatonin onset (DLMO)- the time at which endogenous melatonin begins to climb which takes place approximately 2-3 hr before routine bedtime.
  18. 18.  Sleep-wake cycle  Body temperature  Behaviour  Food and water intake  Hormones  Metabolism  Body fluids  Expression of genes
  19. 19.  Taken together, the circadian axis of mammals can be divided into three distinct functional components:  (1) a master pacemaker situated in the SCN,  (2) a photoreceptive input to the SCN that originates in the eye, and  (3) the myriad of rhythmic outputs that provide insight into the clockwork of the circadian pacemaker.
  20. 20. Anatomy  The mammalian circadian system is organized as a hierarchy of pacemakers.  The SCN is the master oscillator that orchestrates a multitude of slave oscillators.  These slave oscillators are found in a wide range of peripheral tissues including the kidney, liver, lung, and other sites in the brain.  Most of these studies were conducted in rodents.
  21. 21.  The SCNs are small, paired, hypothalamic structures situated immediately dorsal to the optic chiasm.  They were recognized as the site of the primary circadian pacemaker, because lesions in the ventral hypothalamus that encompassed the SCN rendered rodents behavioraly arrhythmic.  Transplantation of SCN tissue from mutant hamsters that expressed abnormally short circadian periods into the brains of SCN-lesioned host hamsters with normal prelesion circadian periods resulted in a transfer of the abnormally short period.  SCN is a true biological pacemaker and not simply a neural relay for a rhythm generator located elsewhere in the brain.
  22. 22.  SCN neurons that are isolated and maintained in culture for several days also continue to show approximately 24-hour rhythms in action potential frequency.  The neurons of the SCN are among the smallest neurons in the entire brain.  They possess short dendrites that are not extensively branched.  A consequence of these cellular dimensions is the high packing density of the nucleus.  Virtually every neuron in the SCN is immunopositive for the inhibitory neurotransmitter γ-aminobutyric acid (GABA).
  23. 23.  the most obvious anatomical subdivision is the core of the SCN, defined by the presence of calbindin- positive neurons.  The remainder of the SCN that surrounds the core is considered the shell.  Discrete functions have not been firmly assigned to subdivisions of the SCN, but the afferent and efferent projections to and from these subdivisions are beginning to provide insights into their putative functions.
  24. 24.  Retinohypothalamic tract is the primary afferent input originating from retinal ganglion cells innervating SCN, excitatory glutamate is the primary NT  Ipsilateral intergeniculate leaflet (IGL) of the lateral geniculate complex receives input directly from the retina, providing a secondary indirect pathway from the retina to the SCN. Neuropeptide Y is the predominant NT  Distinct serotonergic projection from the midbrain raphe. Serotonin modulates light's effect on SCN function.
  25. 25.  Main efferant pathway Within the hypothalamus and to pineal gland.for this primary neurotransimitter GABA. Efferent of SCN regulate autonomic division of PVN-- Sympathetic outflow to pineal gland- stimulate melatonin synthesis.  A second, less understood efferent pathway from the SCN plays an important role in the control of cortisol. Systemic cortisol levels increase in response to stress. However, these levels also have a strong circadian component, being highest in the early morning in humans. Peak cortisol levels occur at approximately 6 AM to 8 AM, just as melatonin levels approach baseline
  26. 26.  The mean circadian period generated by the human SCN is approximately 24.18 hours.  Like a watch that ticks 10 minutes and 48 seconds too slowly per day, an individual with such a period gradually comes out of synchrony with the astronomical day.  In slightly more than 3 months, a normally diurnal human would be in antiphase to the day– night cycle and thus would become transiently nocturnal.  Therefore, a circadian clock must be reset on a regular basis to be effective at maintaining the proper phase relationships of behavioral and physiological processes within the context of the 24-hour day.
  27. 27.  The circadian clock drives many rhythms, including rhythms in behavior, core body temperature, sleep, feeding, drinking, and hormonal levels.  One such circadian-regulated hormone is the indoleamine, melatonin.  Melatonin synthesis is controlled through a multisynaptic pathway from the SCN to the pineal gland.  Exposure to light elicits two distinct effects on the daily melatonin profile.
  28. 28.  First, light acutely suppresses elevated melatonin levels, immediately decreasing them to baseline levels  Second, light shifts the phase of the circadian rhythm of melatonin synthesis.  Because melatonin can be assayed easily, it provides a convenient window into the state of the circadian pacemaker.  Any perturbation of the clock is reflected in the melatonin profile; thus, melatonin offers an output that can be used to study the regulation of the central circadian pacemaker
  29. 29.  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).
  30. 30.  Growth hormone –increase during sleep; decrease during wakeful state.  Prolactin –resembles like growth hormone cycle.  Aldosterone – peaks in afternoon; declines in evening.  Testosterone – low in afternoon; high in night
  31. 31.  A cohort of principal clock genes has been identified in mammals since 1997.  Many of these molecular components were initially discovered in the fruit fly, Drosophila melanogaster, leading to the discovery of mammalian orthologs.  The mammalian circadian clockwork consists of interacting positive and negative transcriptional and translational feedback loops .  The expression of multiple homologs of the Drosophila period gene and cryptochrome genes are positively regulated by the binding of CLOCK-BMAL1 (Bmal1 is also known as Mop3) heterodimers to E-box enhancers in the promoters of these genes.  The products of the Per and Cry genes translocate back into the nucleus and repress their own transcription.  This series of events constitutes the negative feedback limb of the core oscillation.
  32. 32.  In addition to activating the transcription of the Per and Cry genes, the CLOCK-BMAL1 complex also activates expression of the orphan nuclear receptor gene Rev-Erbα. The gene product of Rev-Erbα, in turn, translocates into the nucleus and represses transcription of the Bmal1 gene through Rev- Erb/ROR response elements in the Bmal1 gene promoter. BMAL1 subsequently hetero-dimerizes with CLOCK and again activates expression of the Per, Cry, and Rev-Erbα genes.  This derepression (or activation) of the Bmal1 gene, subsequent hetero dimerization with CLOCK, and activation of the Per, Cry, and Rev-Erbα genes constitutes the positive feedback limb of the core oscillator.  Regulation: by posttranslational modifications. eg, phosphorylation of some of the PER proteins by casein kinase Iε or δ is important for their translocation into the nucleus or their degradation in the cytoplasm. Other kinases, and presumably phosphatases, are emerging as critical regulators of the circadian molecular clockwork. Histone acetylation or phosphorylation likely to control the rhythmic expression and function of clock genes
  33. 33.  In humans and other mammals, light perceived through the eyes is the most effective agent for entraining (synchronizing) the circadian system to the 24- hour day.  Bilateral removal of the eyes renders an individual incapable of resetting the circadian clock, indicating that the photosensitive apparatus necessary for resetting must be ocular.  The photic sensitivities of the visual and circadian systems are quite different  The visual system can be activated by intensities of light ranging from dim starlight to bright daylight.  This dynamic range represents approximately 14 log units of light intensity measured in photons per second per square centimeter.  The dynamic range of the circadian system is only 3 log units, and the activation threshold is much higher than that of the visual system.  Additionally, the circadian system requires light stimuli of much longer duration to activate clock resetting than that required by the visual system to construct images.
  34. 34.  The different sensory demands of the circadian and visual systems raise the possibility that a novel photoreceptive apparatus subserves light- mediated entrainment of the circadian system to the day–night cycle.  Visually blind rodents that have a genetically induced loss of rods and cones remain capable of light-mediated circadian clock resetting.  A similar situation has been observed in blind humans. A subset of blind individuals retains the ability to photically regulate the rhythmic synthesis of melatonin.
  35. 35.  It has been suggested that photic stimulation of extra ocular tissues is sufficient to shift the human circadian clock.  Specifically, blue light illumination of highly vascularized tissue, such as the popliteal region behind the knee, was shown to phase shift the nightly increase of melatonin.  Many studies were done but none of them have given a conclusive evidence.
  36. 36.  The findings from retinally degenerate animal models and blind humans indicate that photoreceptors other than rods and cones are likely to be involved in the photoregulation of the circadian axis  A small subset of rodent retinal ganglion cells recently has been shown to be intrinsically photosensitive. The spectral sensitivity of these cells matches the spectral sensitivity of the circadian system  Intrinsically photosensitive retinal ganglion cells project directly to the SCN. They also project to the IGL and the olivary pretectal nuclei, other brain structures involved in the interpretation of illuminance information.
  37. 37.  The intrinsically photosensitive cells contain melanopsin, a photopigment initially discovered in the pigmented skin cells (melanophores) of tadpoles and subsequently identified in human and mouse retinas  The melanopsin-containing ganglion cells are significantly less sensitive to light compared to the rod and cone photoreceptors of the visual system, and they require light stimuli of relatively long duration to be activated.  Finally, these cells are maximally sensitive to wavelengths of light similar to those required to acutely suppress nocturnal melatonin levels in humans.
  38. 38. Function:  Although the anatomy and physiology of melanopsin retinal ganglion cells are highly suggestive that these cells function as circadian photoreceptors, recent studies provide the most compelling evidence.  Mice with a targeted disruption of both copies of the melanopsin gene show profound deficits in their ability to phase-shift circadian loco motor rhythms in response to pulses of light.  These deficits were observed at all irradiances tested  Thus, the photopigment melanopsin and, presumably, the retinal ganglion cells containing melanopsin are required for normal photic regulation of circadian rhythms.
  39. 39.  Restful consolidated sleep is most appreciated when sleep disturbances are experienced.  Sleep is the integrated product of two oscillatory processes.  The first process, frequently referred to as the sleep homeostat, is an oscillation that stems from the accumulation and dissipation of sleep debt.  The biological substrates encoding sleep debt are not known, although adenosine is emerging as a primary candidate neuromodulator of the sleep homeostat.
  40. 40.  The second oscillatory process is governed by the circadian clock and controls a daily rhythm in sleep propensity or, conversely, arousal.  The circadian cycle in arousal (wakefulness) steadily increases throughout the day, reaching a maximum immediately before the circadian increase in plasma melatonin.  Arousal subsequently decreases to coincide with the circadian trough in core body temperature.  Experiments imposing forced sleep schedules throughout the circadian day have shown that an uninterrupted 8-hour bout of sleep can only be obtained if sleep is initiated approximately 6 hours before the temperature nadir.  This nadir typically occurs at approximately 5:00 AM to 6:00 AM.  In healthy individuals, initiating sleep between 11:00 PM and 12:00 AM affords the highest probability of getting 8 solid hours of sleep.
  41. 41.  Diurnal preference varies among individuals as a function of age, endogenous circadian periods, and other factors.  Clinically, diurnal preference can be quantified using the Horne–Östberg (HO) questionnaire.  In qualitative terms, morning people or morning larks tend to awaken earlier and experience the core body temperature minimum at an earlier clock time relative to night people or night owls.
  42. 42.  Adult short sleepers habitually get 5-6 or fewer hours of sleep per 24 hours, without impairment in daytime functioning. Their sleep is typically unbroken and, although short, is not a result of voluntarily restricted sleep.In children, short sleepers are those who get three hours or less than the norm for their age group.  A “long sleeper” is an individual who sleep longer than average, but feels well and functions without impairment. Long sleep is different from idiopathic hypersomnia where a person sleeps long hours but still does not feel refreshed. Long sleepers are adults who typically sleep 9-10 hours (or more) when not previously sleep- deprived, and children who sleep 2 hours more than the age-appropriate norm.
  43. 43.  Defined as an alteration of the phase relationship between the intrinsic circadian system & the extrinsic light-dark cycle resulting in an unconventional or abnormal sleep-wake pattern  leads to symptoms of insomnia ,excessive sleepiness or impairment of occupational/academic/social functioning.  Included in sleep disorders but differ from others as the defect is in the circadian clock and the circadian rhythm of sleep-wake cycle.
  44. 44.  Alteration of endogenous circadian system  Delayed sleep phase Syndrome  Advanced sleep phase syndrome  Non 24hr sleep-wake syndrome  Irregular sleep-wake rhythm Change in timing of environmental light-dark or social activity cycles(circadian desynchrony)  Shift work sleep disorder  Jet lag disorder
  45. 45.  Advanced sleep phase syndrome (ASPS) is a pathological extreme of the morning lark phenotype.  An autosomal-dominant familial form of ASPS (FASPS) recently has been genetically characterized.  Afflicted family members exhibit a striking 4-hour advance of the daily sleep–wake rhythm.  They typically fall asleep at approximately 7:30 PM and spontaneously awaken at approximately 4:30 AM.  Affected individuals have a single nucleotide polymorphism in the gene encoding hPER2, the human homolog of the mouse Per2 clock gene.
  46. 46.  Functional impairment occur in the late afternoon & evening when sleepiness begins.  Diagnosis include confirmation of advanced timing of sleep period with a sleep log for 7 days with exclusion of other causes.  Prevalence is about 1 % in middle aged individuals ,appears more common with advancing age.  Elderly vulnerable to reduction of light transmission due to various eye conditions like cataracts , glaucoma , senile miosis
  47. 47.  Light therapy used in the evening to delay the circadian phase eg. 4000 lux artificial light source over 12 consecutive days from 7 – 9 pm resulted in decreased awakenings and phase advancement.  Only drawback is compliance with usage of bright light boxes in older subjects  Melatonin taken in the morning delays the sleep schedule but side effects may limit this use.  Most efficacious is chronotherapy in which sleep onset is advanced 3 hrs at a time to an interval of 2 days until desired sleep-wake cycle timing is obtained.
  48. 48.  A circadan sleep disorder in which the individual ‘s internal body clock is delayed with respect to external day/night cycle.  Falls asleep late at night,typically betwwen 1:00am and 6:00am and awakens in the late morning or in the afternoon.  Delayed sleep phase syndrome (DSPS) has been shown to be influenced by genetics. A length polymorphism in a repeat region of the hPER3 gene appears to be associated with diurnal preference in DSPS patients, the shorter allele being associated with evening preference.  Functional impairment is seen in daytime if total sleep time is reduced.
  49. 49.  Diagnosis by stable sleep delay in at least 1 week of sleep log along with delay in CBTM & DLMO with exclusion of other causes.  Prevalence of 5-10% and more common in adolescents & young adults.  Unusually long endogenous circadian period that maintains its entrainment may be the underlying patho-physiology
  50. 50.  Light therapy for 2 wks with 2500 lux given for 2 hrs b/w 6 – 9 am with evening light restriction showed an improvement in multiple sleep latencies.  Melatonin given at night time at a dose of 5 mg for 6 wks 5 hrs before the mean sleep onset time.  Vit B12 has been reported as effective in advancing sleep phase.  Avoidance of napping to enhance homeostatic drive to sleep during the night and avoidance of bright light exposure in evening hrs.  Addressing concurrent stressors is also part of treatment.
  51. 51.  Circadian rhythm that free runs at a period of its endogenous circadian clock even in the presence of time cues. So, sleep wake period gradually shifts to later in day as time advances.  Hallmark is the episodic symptom presentation depending on the phase of patient’s clock at any given time. If the phase is out of sync with the desired sleep-wake cycle ,symptoms are maximum but if phase identical, then symptoms are not present at all.  Diagnosis by progressively delayed sleep-wake times with a period of greater than 24 hrs for 7 days in sleep log.  Most common in blind because light signals fail to transmit to SCN.In sighted, secondary to diminished sensitivity to light as an entraining agent or exceedingly long intrinsic circadian rhythm.  Melatonin dosed at 0.5 mg-10mg at night within an hr of bed time over 1-3 wks in the blind. In sighted. artificial light given may be effective in slowing down the clock.  Vitamin B12 has been reported to be effective.
  52. 52.  Lack of clearly distinct sleep-wake cycles resulting in symptoms of insomnia or sleepiness.  Nighttime sleep is truncated and shows poor consolidation,daytime has frequent,irregualar napping.  Total amount of sleep over 24 hrs is normal ,but sleep tends to be divided into among 3 or more erratic sleep periods  Sleep logs shows at least three irregular sleep bouts during 24-hr period over a week.  M/c in institutionalised patients with dementia & in children with MR
  53. 53.  Desynchrony between and among the SCN and the various oscillators in peripheral tissues result in circadian-associated maladies.  Travel across multiple time zones (jet-lag) and shift work are the most common causes of circadian desynchrony.  Cardiovascular disease risk factors such as obesity, low high-density lipoprotein (HDL) cholesterol levels, and high triglycerides are more prevalent among shift workers than day workers. Furthermore, many of these associations increase in aged shift workers.  Epidemiological studies have shown that women working night shifts have a significantly elevated risk of breast cancer.
  54. 54.  Jet lag is the condition of one's circadian clock being desynchronized from the local time resulting from rapid long- distance trans meridian (east–west or west–east) travel, as on a jet plane.  The condition of jet lag may last several days, and a recovery rate of one day per time zone crossed is a fair guideline .  It is not linked to the length of flight, but to the trans-meridian (west–east) distance traveled.  Eg: A ten-hour flight from Europe to southern Africa does not cause jet lag, as travel is primarily north–south. A five-hour flight from the east to the west coast of the United States may well result in jet lag.  Air travellers who fly west typically complain of difficulty maintaining sleep & early morning awakenings whereas those flying east have difficulty with initiating sleep.  Symptom severity dependent on number of time zones crossed.
  55. 55.  Symptoms include headaches , fatigue , irregular sleep patterns, insomnia , disorientation , grogginess, irritability , mild depression , constipation or diarrhea.  the guide for calculating jet lag is the number of time zones crossed, and the maximum possible disruption is plus or minus 12 hours.  for most people, traveling west to east is more disruptive. This may be because most people have a circadian period which is a bit longer than 24 hours, making it easier to stay up later than to get up earlier.  It may also be that flights to the east are more likely to require people to stay awake more than one full night in order to adjust to the local time zone.  To catch up with local time upon eastward travel, a phase advance must occur whereas a phase delay occurs in westward travel. Since phase advances are more difficult than phase delays , eastward travel is more difficult.
  56. 56. Before the flight- 1. to visit the doctor to plan a coping strategy for medical conditions that require monitoring & regarding meds. 2.attempt to partially adapt to the destination time zone in advance by starting the daily routine one hour before or after one normally does during the week before departure. During the flight- not to take alcoholic beverages and caffeine, as caffeine disrupts sleeping schedules & to drink plenty of water.2. to break the trip into smaller segments if it is too long and stay overnight in some city. Also, to adjust sleeping times in plane to destination time. Upon arrival- to adapt to the local time and eat accordingly. Also, exposure to sunlight during the day is helpful.[  the recommended dose of melatonin is 0.3–0.5 mg, to be taken the first day of traveling.  Light therapy can speed up to one hour per time zone when used at the correct time, combined with avoiding light during specific periods.[1
  57. 57.  Artificial lighting has permitted the manufacturing and service industries to work around the clock. As a result, shift workers are constantly experiencing the effects of circadian desynchrony as they try to entrain to an ever-changing light–dark cycle.  Deleterious effects of shift work include elevated stress, deficits in alertness, decreased cognitive function, and gastric distress. Prevalence of about 10% in night shift workers.  Diagnostic criteria include either insomnia or excessive sleepiness , temporal relationship with work , present for at least 1 month,7-day sleep log or actigraph revealing disturbed sleep circadian/sleep alignment.  Total sleep time is reduced, reporting 10 fewer sleep hrs/week.Shift workers fail to delay their circadian rhythm b’cos of exposure to bright light in morning.  At increased risk of development of disease in other organ systems.
  58. 58.  Exposure to bright light during nighttime work shift has been efficacious.Light exposure between 7000 & 12000 lux during night and complete darkness during day on subjects for 1 week.  Intermittent exposure to light of 20 min/hr appears to be effective in producing desired phase shifts in night workers.  Exogenous melatonin is used by shift workers during the morning to improve the timing & quality of sleep.  Modafinil (wakefulness promoting agent)is approved for shift work disorder and is useful to improve alertness at desired times without adversely affecting daytime sleep when taken at beginning of night shift  Caffeine at 250 mg to 400mg may aid in increasing alertness.
  59. 59.  M/C monthly cycle in humans is the menstrual cycle linked with changes in the mental state.  Premenstrual syndrome : recurrence of symptoms in the pre – menstruum 5-10 days (luteal phase) with absence in the post- menstruum (follicular phase). Seen in 30-80% of reproductive women.  Psychological symptoms : disabling tension , severe & sudden mood swings , suicidal depression and incapacitating lethergy  Physical symptoms : headache , bloated feeling , loss of energy , cyclic acne  It is the timing rather than the nature of symptoms that indicates the diagnosis. To establish a pattern, keep a prospective record of her symptoms on a calendar for at least two menstrual cycles. PMS has increased risk for clinical depression.  PMDD: severe form of PMS with predominant mood symptoms and disruption of personal relationships. Seen in 3-8% women.
  60. 60.  Supportive therapy includes evaluation, reassurance, and informational counseling.  Healthy lifestyle: Reduction of caffeine, sugar, and sodium intake and increase of fiber, adequate rest and sleep with aerobic exercise. Dietary intervention studies indicate that calcium supplementation, vitamin E (400 IU/d) has shown some effectiveness along with Vitamin B6, magnesium, manganese and tryptophan.  SSRIs can be used to treat severe PMS ,medication taken only on the days when symptoms are expected to occur.  Spironolactone has been shown to be useful for water retention.  NSAIDs; e.g., ibuprofen have been used to treat pain.  Evening primrose oil, which contains gamma-Linolenic acid (GLA),phenyl alanine and chasteberry are found helpful
  61. 61.  Early morning awakening & mood most depressed in morning d/t phase advance of sleep wake cycle.  REM sleep occurs earlier in the night in depression along with changes of body temperature & cortisol levels.  Travel from east to west a/w depression and from west to east a/w hypomania.  Shortened rhythm of less than 24 hrs seen in long term schizophrenia  Abnormal circadian rhythms in anorexia nervosa
  62. 62.  The Earth's axis is tilted 23.45 degrees from the plane of its own orbit around the sun (the ecliptic).  As a result, the relative proportion of daytime to nighttime within the 24-hour astronomical day varies as the Earth proceeds through its orbit of the sun.  Many organisms are capable of synchronizing physiology to the seasonal cycle to maximize survival.
  63. 63.  Large mammals that typically have long gestation periods, such as sheep, conceive in the fall when the nights are long and the days are short, so birth occurs during the relatively mild season of spring. These animals are referred to as short-day breeders.  Conversely, mammals with gestation periods of only a few weeks, such as hamsters, conceive and give birth during spring and summer, when the days are long and the nights are short. Hence, these animals are referred to as long-day breeders
  64. 64.  The most reliable environmental parameter providing a faithful representation of the solar day is the day–night cycle.  In seasonally breeding animals, day length is physiologically encoded through the melatonin profile.  A long night, such as that experienced during the short day lengths of winter, results in an elevated melatonin profile of a relatively long duration.  A short summer night, by contrast, results in a short duration of elevated melatonin. This seasonal signal is interpreted by the reproductive axis, resulting in an appropriate reproductive response
  65. 65.  Reproductive responses to changing day length can be dramatic.  A male Siberian hamster (Phodopus sungorus) maintained in long days is reproductively competent and typically has a testicular weight of approximately 250 mg per testis.  Under short days, however, the testes regress to approximately 15 mg per testis, representing a 94 percent decrease in testicular mass.  The same degree of regression is observed in response to melatonin infusions that mimic short days.
  66. 66.  Whether humans are truly seasonal is still a point of considerable debate.  Several lines of evidence exist that suggest the presence of a residual tendency toward seasonality.  A peak in the rate of suicide occurs in the summer; this peak is cross-cultural.  Birth rates also tend to show a seasonal variation; a small but distinguishable peak in the rate of births occurs in spring and summer.
  67. 67.  SAD is the most overt manifestation of seasonality in humans.  It is characterized by recurrent major depressive episodes followed by periods of remission that occur on a seasonal basis.  In DSM IV, it is not categorized as a distinct mood disorder but as the seasonal pattern specifiers.
  68. 68.  Regular temporal relationship between the onset of major depressive episodes and a particular time of the year (unrelated to obvious season-related psychosocial stressors).  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 years, and no non seasonal episodes have occurred in the same period.  Seasonal major depressive episodes substantially outnumber the nonseasonal episodes over the individual's lifetime.
  69. 69.  Also called Winter depression, or the Winter blues.  The most prevalent form of SAD has an onset in the late fall and early winter and remits in the late spring and early summer  Symptoms atypical of major depression can present with winter SAD.  These include, but are not restricted to, 1. significant increase in weight, 2. hyperphagia, 3. an increase rather than decrease in sleep, 4. a heightened sensitivity to interpersonal rejection, 5. and a leaden feeling in the extremities.  Most distinct, however, is a craving for carbohydrates.
  70. 70.  Prevalence of winter SAD among the general population to be between 4 and 9 percent. Women are four times as likely as men to be affected.  The gold standard treatment for winter SAD is light therapy.  A typical prescription for light therapy involves 45 to 90 minutes daily exposure to a broad spectrum, ultraviolet-filtered, white light source of relatively high irradiance (5,000 to 10,000 lux).
  71. 71.  Recent studies have suggested that a combination treatment of light therapy in conjunction with cognitive-behavioral therapy may be more efficacious than light therapy alone.  Monoamine oxidase inhibitors (MAOIs) have also been used successfully to treat winter SAD.  In some winter SAD patients, bright light administered during the evening is also antidepressant.
  72. 72.  Aberrations in the timing and amount of sleep are frequently part of the symptomology of depression, including nonseasonal depression.  For example, the circadian phase angle of sleep onset can vary in bipolar I disorder, depending on the state; depression causes a phase delay, whereas mania results in a phase advance.  In addition, sleep disturbances can contribute to the pathogenesis of the disease
  73. 73.  A curious phenomenon related to depression and sleep is that total sleep deprivation can provide a transient antidepressant effect in a majority (approximately 60 percent) of depressed patients.  Relapse occurs after the following night of sleep. Even short, daytime naps can cause relapse.  This tendency of nap-induced relapse varies as a function of the time of day during which the nap is taken.  Early morning appears to be a critical time during which naps have a high tendency of causing relapse
  74. 74.  A peak in the rate of suicide occurs in the summer  Birth rates also tend to show a small but distinguishable peak in spring and summer.  In schizophrenia , patients show an excess of birth dates in the winter months in northern & southern hemispheres.  Higher rate of psychiatric admissions in summer months  Depression and ECT more in spring & autumn.  Female manic patients peak admissions in Aug & Sep.
  75. 75.  Metabolic syndrome is characterized by hyperglycemia, hypoinsulinemia, dyslipidemia, and visceral obesity. Furthermore, it is frequently associated with cardiovascular disease.  Shift workers may also suffer a greater risk of metabolic syndrome.  Obesity has been linked to reduced sleep, suggesting a role for the circadian clock.  This has also been demonstrated in mutated mice too.
  76. 76.  Female flight attendants suffer an increased incidence of breast cancer.  In several studies, cancer patients with altered daily rhythms had poor survival relative to those patients with nearly normal 24-hour rhythms.  Long-term shift work also has been shown to be correlated with increased incidence of colorectal and breast cancer.  Supposed to be inhibition of melatonin which augments estrogen effect
  77. 77.  In general, as humans age, circadian period shortens, circadian phase advances resulting in earlier waking times and bedtimes, the amplitudes of most circadian rhythms decrease, and dramatic phase shifts such as those caused by jet-lag are less tolerated.
  78. 78.  Circadian rhythmicity can be affected by drugs, and conversely, the circadian clock can modulate the efficacy of drugs throughout the course of the day.  Some of the best-studied interactions between medications and the circadian clock have included the circadian effects of antidepressants.  Elevated nocturnal body temperature is a common feature among depressed patients.
  79. 79. 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 clock work stabilizer REV-ERBa—lengthens the cercarion period. BENZODIZEPINE S(short acting) triazolam or brotizolam Act via GABA receptors in SCN- induces circadian phase advances Brotizolam has been shown to reduce the light-induced expression of clock genes Per1 and Per2 in the SCN
  80. 80. 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
  81. 81.  Kaplan & Sodock’s Comprehensive Textbook of Psychiatry  Sims Symptoms of mind  Pubmed  Google images

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