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Circadian Rhythm Disorder: When the Brain's Clock Tells the Wrong Time
- 1. Biology, Neurophysiology and Treatment of Circadian Rhythm Sleep-Wake Disorders Yonah Ziemba When the Brain’s Clock Tells the Wrong Time Third year medical student Dept. of Psychiatry Thomas Jefferson University Hospital
- 2. Patient Presentation • AL is a 18F, can’t fall asleep before 2am and has difficulty waking up before 10am. • Recurrent episodes of falling asleep during her morning college classes. • During her previous semester, her classes were all in the afternoon. She slept from 2-10am without any trouble. • Her friends tease that she thinks she is in California, but she never lived in a different time zone and has no desire to move.
- 5. Entrainment • The human’s natural body clock is approx. 25 hours. • In order to function, our brain uses external light to adjust the circadian rhythm to external day/night cycles. • This adjustment is called “Entrainment”.
- 6. • Question: Is entrainment via rods & cones, or are there a separate set of photosensitive ganglion cells dedicated to circadian rhythm? • Study Design: Develop knockout mice without rods & con es, and see whether they are capable of entrainment. • Results: Entrainment can be done without rods & cones. Entrainment can not be done without eyes.
- 8. Press play to watch music video
- 9. Circadian Rhythm Sleep-Wake Disorders Diagnostic Criteria • Persistent pattern of sleep disruption that is due to a misalignment between the endogenous circadian rhythm and the sleep-wake schedule required by an individual’s environment. • The sleep disruption leads to excessive sleepiness or insomnia, causing impairment.
- 10. CRSWD- Delayed Sleep Phase Type • Delay in the timing of the major sleep period in relation to the desired sleep and wake- up time • When allowed to set their own schedule, patients will exhibit normal sleep quality and duration. • Symptoms of sleep-onset insomnia, difficulty waking in the morning, and excessive early day sleepiness are prominent.
- 11. Excerpt of DSM
- 12. Excerpt of DSM
- 13. Excerpt of DSM
- 14. Treatment • Minimize or eliminate caffeine, nicotine, and alcohol • Avoid daytime naps • Refrain from engaging in stimulating activity for at least two hours prior to the desired sleep onset time. • No after-dinner screen time! • Timed Melatonin • Light therapy • Find a new high school!
- 17. • Question: Is any particular color most potent in setting our circadian rhythm? • Study Design: Expose subjects to different color light and measure blood levels of melatonin. • Results: Blue light is most potent
- 19. click here for video
- 20. Thanks to our teachers and mentors who helped us at this clerkship: Dr. Abbasi Dr. Denysenko Dr. Chism Dr. Chandi Dr. Neff Dr Greene
Editor's Notes
- Every animal has cicadian rhythm without outside input, even in cave or outer space Biomarkers such as salivary dim light melatonin onset should be obtained only when the diagnosis is unclear.
- How
- XXXXXxxxx Studies published in the early 1970’s established the suprachiasmatic nucleus of the hypothalamus as the central circadian pacemaker in mammals (1–5). This pacemaker is comprised of individual cells which, when isolated, can oscillate independently with a near-24- hour period (5;6). The SCN receives direct input from the retina (7–9), providing a mechanism by which entrainment to light-dark cycles occurs. Recently, a subset of retinal ganglion cells has been described that serve as photoreceptors for circadian and other non-image-forming responses (10–12). These specialized retinal ganglion cells are distributed throughout the retina, project to the SCN, are photosensitive, and contain melanopsin as their photopigment (13;14). While the photosensitive retinal ganglion cells can mediate circadian responses to light, there is also evidence that rod and cone photoreceptors can play a role in circadian responses to light (15;16). The relative contribution of different photoreceptors to circadian responses is not yet well understood, and this is an area of intense research currently. It is likely that the intensity, spectral distribution, and temporal pattern of light can all affect the relative contribution of different photoreceptors to circadian responses. The same neuroanatomical features of the circadian system described in mammals are also present in humans (17–24). Sleep Med Clin. Author manuscript; available in PMC 2010 June 1.
- Confirmation of the diagnosis includes a complete history and use of a sleep diary or actigraphy (i.e., a wrist-wom motion detector that monitors motor activity for prolonged periods and can be used as a proxy for sleep-wake patterns for at least 7 days). The period covered should include weekends, when social and occupational obligations are less strict, to ensure that the individual exhibits a consistently delayed sleep-wake pattern. Biomarkers such as salivary dim light melatonin onset should be obtained only when the diagnosis is unclear.
- When allowed to make own sched: NOT excessive sleep inertia
- Alterations in response to light – Hypersensitivity to nocturnal light exposure has been proposed in DSWPD, although the evidence is mixed. In one study, 2000 lux-hours of nocturnal light exposure was associated with a greater degree of melatonin suppression in adults with DSWPD compared with controls, suggestive of excessive circadian sensitivity to light [35]. Other studies have failed to find similar effects but may not have controlled for differences in daytime light exposure, which can alter the melatonin response [12,22,36]. Alternatively, a blunted phase-advance response to morning light has also been proposed in DSWPD [37-39]. ●Changes in light exposure – Increased evening light exposure or decreased morning light exposure could theoretically contribute to the DSWPD phenotype, independent of issues regarding sensitivity to light [40,41]. However, a prospective cohort study of light exposure patterns among adolescents found comparatively less pre-sleep light intensity (lux) exposure in those with DSWPD compared with controls, and no differences in the amount of post-sleep light exposure [36]. Psychoactive medications have occasionally been implicated in circadian rhythm disturbances. In a study of seven adults with schizophrenia, receipt of typical antipsychotics (haloperidol and flupenthixol) was associated with circadian dyssynchrony, including delayed and free-running patterns, but no such association was found with clozapine
- Developmental changes in sleep-wake timing – A delay in preferred bedtimes and wake times during the adolescent period has been demonstrated across varying societies worldwide [12-21]. This coincides with a variety of pubertal changes, both physiologic and social [22]. A systematic assessment of circadian preference in >20,000 individuals demonstrated a crescendo pattern of increasing "eveningness" until the age of approximately 20 years, followed by a gradual decline [23]. Adolescent DSWPD may represent an extreme expression of this scheduling preference [5,24-29]. American and Norwegian adolescents: 7 percent [7,8], Japanese young people estimated a prevalence <1 percent, A systematic study involving over 1000 Western European adolescents, aged 15 to 18 years, reported a similarly low rate of circadian disorders of any type (<1 percent) [9]. Differences in school start times (later in Western Europe compared with many high schools in the United States) may explain some of the regional variability.
- Xxxxxxxxxxxxxxxxx The photopigment in the human eye that transduces light for circadian and neuroendocrine regulation, is unknown. The aim of this study was to establish an action spectrum for light- induced melatonin suppression that could help elucidate the ocular photoreceptor system for regulating the human pineal gland. Subjects (37 females, 35 males, mean age of 24.5 0.3 years) were healthy and had normal color vision. Full-field, monochromatic light exposures took place between 2:00 and 3:30 A.M. while subjects’ pupils were dilated. Blood samples collected before and after light exposures were quantified for melatonin. Each subject was tested with at least seven different irradiances of one wavelength with a minimum of 1 week between each nighttime exposure. Nighttime melatonin supression tests (n 627) were completed with wavelengths from 420 to 600 nm. The data were fit to eight univariant, sigmoidal fluence–response curves (R2 0.81–0.95). The action spec- trum constructed from these data fit an opsin template (R2 0.91), which identifies 446–477 nm as the most potent wave- length region providing circadian input for regulating melatonin secretion. The results suggest that, in humans, a single pho- topigment may be primarily responsible for melatonin suppres- sion, and its peak absorbance appears to be distinct from that of rod and cone cell photopigments for vision. The data also suggest that this new photopigment is retinaldehyde based. These findings suggest that there is a novel opsin photopig- ment in the human eye that mediates circadian photoreception.
- Why care about color? color is NOT physical reality Thought experiment: Bat might see sound and hear color most potent wavelength = 446–477 nm = blue light.
- http://www.businessinsider.com/iphone-sleeping-night-shift-mode-2016-1#ooid=1pNmo3MDE6SwWVu9wiBxmHuATQfzFzBN