2ObjectivesUnderstand the influence of circadian rhythm disruptions on overall health.Identify clinical characteristics of circadian rhythm disturbances in older adultsRecognize the importance of chronobiology in elders’ sleep-wake disturbances.Describe results from preliminary studies assessing the use of circadian light therapy in a nursing home unit and measurement of circadian light exposure in a case study of home-dwelling older adults.
3Biological Rhythms Types of rhythms Ultradian (heart beat, respirations, appetite)Infradian (menstrual cycle)Circannual (annual breeding cycles)Circadian (sleep-wake cycle)Rhythms allow organisms to time events and anticipate change!Biological rhythms are periodic biologic fluctuations that correspond to, or are in response to, environmental changeRhythms allow organisms to time events and anticipate change; i.e., rhythms allow organism to adapt to environmental change
6Disruption of circadian rhythm Poor performance/fatigue (Reinberg et al, 2007, Laposky et al 2008)Weight gain(Knutson et al, 2007)Breast cancer (Stevens et al 2001)Other conditions
7Why older adults? Sleep disorders are common Complaints among caregivers of persons with dementia frequently revolve around disordered day/night cyclesMedications for sleep are less safe in this population
8Aging and lightOlder adults spend much of their time in muted indoor lighting.35 minutes/day of bright light exposure compared to approximately 58 minutes of bright light per day for middle-aged adults. (Sanchez 1993)Reduced light exposure compounded due to physiologic changessenile meiosis, cataract formation, and/or increased light absorption by the crystalline lens. (Charmin 2003)Attenuation of light exposure by more than 80% in normal older adults relative to young adults.
9Age related losses in retinal illumination Turner et al Br J Ophthalmol November; 92(11): 1439–1444
10Biological rhythms are endogenous but highly sensitive to environmental stimuli; i.e., light. The influence of light and darkness on circadian rhythms and related physiology and behavior through the SCN in humans.Wikipedia, accessed 10/30/09
11Role of Retinal Receptors Three known retinal receptors: process visual and circadian timing informationRods and cones: visual dataIntrinsically photosensitive retinal ganglion cells (iPRGC): primarily light-dark dataprocess visual and circadian timing information
12Spectral sensitivity of photopic, scotopic and circadian (melatonin suppression) photoreception Spectral sensitivity of photopic, scotopic and circadian (melatonin suppression) photoreception.5 7 Peak sensitivities of circadian, scotopic and photopic photoreception are 460 nm (blue), 506 nm (green) and 555 nm (green-yellow), respectively. Spectral absorptance is shown for 30D blue blocking (AcrySof SN60AT, Alcon Laboratories, Fort Worth, TX) and UV-only blocking (ClariFlex, Advanced Medical Optics, Santa Ana, CA) intraocular lenses (IOLs).8 The area between the two IOL curves is the violet, blue and green light blocked in comparison with a UV-only blocking IOL.Turner et al Br J Ophthalmol November; 92(11): 1439–1444
13iPRGCs: History1998: Melanopsin in light-sensitive cells on frog skin (Provencio et al, Proc Natl Acad Sci )2000: Melanopsin-containing cells found in retinal ganglion cell layer (Provencio et al, J Neuroscience)Most likely comprise the retinohypothalamic tractSensitive to wavelengths in the nm (blue light)2002: Light responses from melanopsin-containing ganglion cells in humans (Berson et al, Science)1998: Ignacio Provencio, U VA, first published article on melanopsin, photopigment in light-sensitive cells of frog skin. (Provencio I, Jiang G, De Grip WJ, Hayes WP, Rollag MD (January 1998). "Melanopsin: An opsin in melanophores, brain, and eye". Proc. Natl. Acad. Sci. U.S.A. 95 (1): 340–5. doi: /pnas PMID )2000: A novel human opsin in the inner retina. Provencio I, Rodriguez IR, Jiang G, Hayes WP, Moreira EF, Rollag MD. J Neurosci Jan 15;20(2):600-5.2002: Don Berson, Brown University, (Berson DM, Dunn FA, Takao M (February 2002). "Phototransduction by retinal ganglion cells that set the circadian clock". Science 295 (5557): 1070–3. doi: /science PMID )
14Intrinsically photosensitive retinal ganglion cells (iPRGCs) Timing PhotoreceptorsLocated throughout retina (~3000)Express melanopsinBlue light sensitive(peak 460nm)Regulate photoperiodism (sensitivity to length of day and night)Higher excitatory threshold than rods/conesTransmits to SCN24-hour light-dark pattern on the retina is the most efficient stimulus for entrainment of circadian rhythms in humansipRGC – intrinsically photosensitive retinal ganglion cellsNeurons: repeatedly fire electrical impulses: reset, fire, reset– light adaptation thought to occur during this process [possibly in the reset timing]Photosensitive: Respond to contrast in light levelsBerson DM, Dunn FA, Takao M. Phototransduction by retinal ganglion cells that set the circadian clock. Science Feb 8;295(5557):Melanopsin-containing cells found in monkey retinal ganglion cell layer (Provencio et al., 2000)Most likely comprise the retinohypothalamic tractSensitive to wavelengths in the nm (blue light)
15Suprachiasmatic nucleus (SCN) is master pacemaker Activity in SCN correlates with circadian rhythmsLesions of SCN abolish free-running rhythmsIsolated SCN continues to cycleTransplanted SCN imparts rhythm of the donor on the hostSCN is known to be compromised in older adults with dementia. (Harper et al 2008)SCN drives daily cycles of activity, hormonesSCN in humans have an intrinsic period slightly greater than 24 hours, and is modulated by the temporal pattern of lightand dark on the retina.Disruption of this pattern leads from flying across times zones or from shift work can lead to sleep loss, weight gain or breast cancer refStevens RG, Rea MS. Light in the built environment: potential role of circadian disruption in endocrine disruption and breast cancer. Cancer Causes Control. 2001;12:279–87. doi: /A: [PubMed] [Cross Ref]Figueiro MG, Rea MS, Bullough JD. Does architectural lighting contribute to breast cancer? J Carcinog. 2006;5:20. doi: / [PMC free article] [PubMed] [Cross Ref]Lemmer B. Importance of circadian rhythms for regulation of the cardiovascular system: studies in animal and man. Conf Proc IEEE Eng Med Biol Soc. 2006;1:168–70. full_text. [PubMed]Maemura K, Takeda N, Nagai R. Circadian rhythms in the CNS and peripheral clock disorders: role of the biological clock in cardiovascular diseases. J Pharmacol Sci. 2007;103:134–8. doi: /jphs.FMJ06003X2. [PubMed] [Cross Ref]Young ME, Bray MS. Potential role for peripheral circadian clock dyssynchrony in the pathogenesis of cardiovascular dysfunction. Sleep Med. 2007;8:656–67. doi: /j.sleep [PMC free article] [PubMed] [Cross Ref]Kreier F, Kalsbeek A, Sauerwein HP, Fliers E, Romijn JA, Buijs RM. "Diabetes of the elderly" and type 2 diabetes in younger patients: possible role of the biological clock. Exp Gerontol. 2007;42:22–7. doi: /j.exger [PubMed] [Cross Ref]Laposky AD, Bass J, Kohsaka A, Turek FW. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett. 2008;582:142–51. doi: /j.febslet [PubMed] [Cross Ref]Knutson KL, Spiegel K, Penev P, Van Cauter E. The metabolic consequences of sleep deprivation. Sleep Med Rev. 2007;11:163–78. doi: /j.smrv [PMC free article] [PubMed] [Cross Ref]
16Role of Melatonin Melatonin Primary role in humans is to convey information about the daily light-dark cycle to physiological systemsPeaks during sleep, suppressed by light.Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal environmental conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be determined by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body physiology. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas in field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlative observations, there is some evidence that melatonin stabilizes and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions could depend on the melatonin signal, for instance immune, antioxidative defenses, hemostasis and glucose regulation. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where the melatonin secretion can be disturbed. The resulting alteration could increase predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder.
17Melatonin Rhythms and Aging Average (±SEM) plasma melatonin in young (top, n=90) and older (bottom, n=29) subjects during a normally phased sleep episode (closed boxes) and a constant routine where they remained awake at the same clock hours (open circles). Data were aligned such that each subject's wake time was graphically adjusted to 08:00 and the data from the baseline day and night and from the CR(constant routine) expressed relative to wake time; sleep time is from 24:00 to 08:00. Melatonin data were averaged hourly within and then across subjectsAge , mean 68Average (±SEM) plasma melatonin in young (top, n=90) and older (bottom, n=29) subjects during a normally phased sleep episode (closed boxes) and a constant routine where they remained awake at the same clock hours (open circles). Data were aligned such that each subject's wake time was graphically adjusted to 08:00 and the data from the baseline day and night and from the CR expressed relative to wake time; sleep time is from 24:00 to 08:00. Melatonin data were averaged hourly within and then across subjects.Zeitzer et al Sleep November 1; 30(11): 1437–1443.
18Plasma melatonin suppression by bright light in 65 year old man Plasma melatonin data from subject 19G7, a 65 year old man who was exposed to a 3,527 lux light stimulus. Upper panel: plasma melatonin data from the initial circadian phase estimation procedure (CR1); middle panel: plasma melatonin data from the intervention day, with the 6.5-h experimental light exposure indicated by the open box; lower panel: plasma melatonin data from the final circadian phase estimation procedure (CR2) shown in the solid symbols, with data from CR1 replotted from above in the open symbols. During CR1, the fitted peak of the melatonin secretion (MELmax) occurred at 03:45, 3.5 h before habitual wake time. During CR2 MELmax occurred at 06:30, a 3.5 h phase delay. Melatonin was suppressed by 78% during the 6.5-h 3,527 lux light stimulus.Plasma melatonin data from subject 19G7, a 65 year old man who was exposed to a 3,527 lux light stimulus. Upper panel: plasma melatonin data from the initial circadian phase estimation procedure (CR1); middle panel: plasma melatonin data from the intervention day, with the 6.5-h experimental light exposure indicated by the open box; lower panel: plasma melatonin data from the final circadian phase estimation procedure (CR2) shown in the solid symbols, with data from CR1 replotted from above in the open symbols. During CR1, the fitted peak of the melatonin secretion (MELmax) occurred at 03:45, 3.5 h before habitual wake time. During CR2 MELmax occurred at 06:30, a 3.5 h phase delay. Melatonin was suppressed by 78% during the 6.5-h 3,527 lux light stimulus.Duffy et al Neurobiol Aging May; 28(5): 799–807.
19Melatonin suppression with bright light Phase shift of fitted plasma melatonin peak (MELmax) vs. illuminance of experimental light stimulus. Data from each of the ten subjects are plotted individually and shown with square symbols. Solid line represents the 4-parameter logistic model fit to the data, with the 95% confidence interval of the model shown in the dotted lines. For comparison, the 4-parameter logistic model fit to the data from our previous study in younger adults  is shown in the dashed line.Phase shift of fitted plasma melatonin peak (MELmax) vs. illuminance of experimental light stimulus. Data from each of the ten subjects are plotted individually and shown with square symbols. Solid line represents the 4-parameter logistic model fit to the data, with the 95% confidence interval of the model shown in the dotted lines. For comparison, the 4-parameter logistic model fit to the data from our previous study in younger adults  is shown in the dashed line.Duffy et al Neurobiol Aging May; 28(5): 799–807.
20Circadian light transfer function Figueiro, et al. 2006
22Light levels in contemporary and natural environments39 54–57 and also in phototherapy for seasonal affective disorder, which is typically 2500 lux for 2 h/day or 10 000 lux for 30 min/day.44 Illuminances are given in units of photopic lux. Photopic lux accurately describe the effectiveness of a particular light exposure for overall cone photoreception, which has a peak sensitivity at 555 nm in the green–yellow part of the spectrum (cf, fig 1). A standard circadian lux unit is needed10 40 but has not been adopted yet for comparing the effectiveness of different light exposures for circadian photoreception, which has peak sensitivity at 460 nm in the blue part of the spectrum (cf, fig 1).Turner et al Br J Ophthalmol November; 92(11): 1439–1444
23Therapeutic light 2 Hours bright light in AM Improved sleep efficiency in NH residentsFetveit et al, 200330 minutes sunlight for five daysDecreased nappingIncreased participationAlessi et al, 2005Daytime bright lightImproved sleep/wake cycle in persons with dementia (van Someren et al,1997)Studies using bright white light have demonstrated that light treatment can help reduce the negative impact of aging on circadian rhythms of sleep and wake, and thus, improve the quality and quantity of sleep in older adults, including those with dementia. Bright white light exposure in the morning improved sleep in institutionalized older adults. Fetveit et al12 demonstrated that exposure to 2 hours of bright light in the morning for at least 2 weeks substantially improved sleep efficiency of older adults living in nursing homes. Alessi et al.11 showed that five consecutive days of 30-minute exposure to sunlight, increased physical activity, structured bedtime and control of light and noise at night resulted in a significant decrease in daytime sleeping in intervention participants compared to controls. Further, they showed that intervention participants had increased participation in social and physical activities as well as social conversation. Murphy and Campbell49 have shown that light exposure in the evening can delay the circadian clock and help older adults sleep better at night and be more awake during the day.
24Riemersma-van de Lek et al JAMA 2008 6/12 Homes randomized for lighting interventionInstalled fluorescent fixtures, both real and sham1000 lux horizontal at eyes in interventionCaregivers unaware which arm randomized toMelatonin randomized by patient3.5 year follow upLight exposure was manipulated byinstalling a large number of ceilingmountedfixtures with Plexiglas diffuserscontaining an equal amount of PhilipsTLD 840 and 940 fluorescent tubes(Philips Lighting BV, Eindhoven, theNetherlands) in the common livingroom. Lights were on daily between approximately9 AM and 6 PM. The aim wasan exposure of ±1000 lux, measuredbefore the eyes in the gaze direction. Thisintensity is technically feasible and hasin previous studies been confirmedto synchronize circadian rhythms inhealthy people in temporal isolation31and to improve circadian activity rhythmdisturbances in elderly patients withmoderate to severe dementia.32
25MMSE, DepressionADLs improved Less irritability, less inability to sleep in those with the lighting.5%without decelerating the progressive cognitive worsening (as is also the case foracetylcholinesteraseinhibitors8).Light also reduced depressive symptoms by a relative 19% and attenuated the gradual increase in functional limitationsby53%.A similar increase in efficacy over time by 2% was found foRiemersma-van der Lek, R. F. et al. JAMA 2008;299:
26Schedule change: Shift work Light at night (LAN)Nurses’ Health Study (Willet, PI)Effects of Light at Night on Circadian System in Nurses (Schernhammer, PI, RO1-OH008171)30 year studyEvaluate light exposure in rotating shift workers based on the recent information on the specific wavelengths that affect melatonin levels in humans, and will relate those measures to the response of their circadian system, as measured by melatonin levels in urine. Specifically, we will measure light exposure by applying a new device, a circadian light meter that captures the short wavelength portion of visible light, which has been described to most strongly suppress melatonin levels and phase shift the circadian pace maker as part of the light's influence on non-image forming function in humans. Urine collections will be conducted during three of the overall 7 days of study period.Sample 180Approx 15 million shift workers in US: self selecting nurses, safety officers
27Circadian phase shifters Can have negative effects on healthAbrupt: jet lag, shift workGradual: institutionalizationTimed light exposure: reset clockSensitivity age-relatedBright light in morning advances the clockBright light in evening delays the clockDelays easier than advancesJet lag: Adjusting to new schedule can cause daytime sleepiness, insomnia, irritability, stomach upset
28Circadian Lighting in Long-term Care: A feasibility study
32Lighting Installation VAMC safety standards1st phase: 3 ‘blue lamp’ prototypes by GE: 8000 Kelvin (K); 14,000K;16,000K2nd: 13 standard fluorescent lighting ceiling light fixtures in Dayroom7 of 13 changed to 14,000 K ( K)Timer controlled blue lighting on, 8a-6pLighting after 6pm: sufficient for visual acuityRegular lighting is 5000 Kelvin (color correlated temperature, hot body radiation)
34Mean of light measurements taken at eye level (horizontally) at 8 points in the room in the 4 cardinal directions, using PMA 2200 Photoradiometer, SnP Meter Photopic SL , S/N 9829Light ConditionsPhotopic (cones) LuxScotopic (rods)LuxS/PRatioBrightnessVisual Effectivenessall on51711782.24781181814,000 K only3819182.26606759standard3337252.14491609all off2224892.17328412Lux – SI unit of illuminance [human brightness perception] as measured by a light meter1 lux = 1 lumen/square meterTwo types of photoreceptors: Rods/cones ratio = ~10/1Photopic - brightness perceived by conesScotopic – brightness perceived by rods [more sensitive to bluish-white light]Historically, light meters measured eye’s cone sensitivity to lamps/lighting = photopic dataMore accurate measure combines the two [rods and cones] into a measure that more reflects what the human eye perceives in terms of light S/P ratioStudies indicate that lighting that provides higher S/P ratio provides better visual acuityVisual effectiveness: “a measure of how the appearance of information and the use of visual elements within it affect the ease with which users can find, understand, and use the information. Because most… users use their eyes to access your information, the visual impact of that information can be an important factor in its general quality.”
35Results & Conclusions Wrist actigraph well accepted Light sensor on wrist covered much of the time by clothing?New blue lighting well received3 subjects exposure to blue lighting (time in Dayroom/ 10 hr period):77 minutes, 371 mins, 373 minsNext time: Change installation pattern?, use DaysimeterTM
36Rest-Activity and Light Exposure Patterns in the Home Setting: A Methodological Study P. Higgins, T. Hornick, M. FigueiroAmerican J Alzheimer’s Disease and Other Dementias, 2010
37PurposeAssess the feasibility and reliability of using a circadian light meter (DaysimeterTM) in a field setting and use the human circadian phototransduction model’s analyses to provide clinically relevant results
38DyadCaregiver – Wife, 73 years, “good health”, no vision problems, no sleep-aid meds. Primary caregiverElder – Husband, 80 years, vascular dementia plus multiple co-morbidities, continent, needed assistance for all ADL’s and IADL’s, multiple meds included antidepressant but no sleep-aidElder received all primary care from the Cleveland VA Geriatrics Clinical team.The couple had been married for approximately 50 years. Mr. X was diagnosed with probable vascular dementia three years previously and the couple had recently moved into an independent housing community for elders. Neither had significant visual problems and neither were taking medications for sleep or behavior disorders. Mr. X, who was continent, needed assistance for bathing, dressing, transfer, toileting and feeding and was dependent in all independent activities of daily living. His last Mini Mental Status Exam, 25/30, was completed more than three years before the study and he had resisted all repeat attempts at testing. Besides dementia syndrome, Mr. X had aortic stenosis, hyperaldosteronism, s/p CVA with right hemiparesis, diabetes mellitus, hypertension, gastritis, hyperlipidemia, and a history of depression. Mr X was on ASA, losartan, metformin, omeprazole, simvastatin, and citalopram, and no over the counter agents. Mrs. X, who was not a patient in the LSCVAMC geriatrics clinic, rated her health as good and reported that she was on medications for hypertension and hyperlipidemia but did not take any sleep-aid medication. She provided all care for her husband.Recruited on a routine visit to clinic. Informed written consent obtained from wife for both parties. Assent obtained for elder.
42Built Environment Independent living complex for seniors Apartment: 640 square feetBrown paneling and beige paint and carpetOne south facing window in bedroomSliding glass door onto porch (south facing)Standard florescent lighting: kitchen and bathIncandescent lighting: floor and table lamps
43Ambient light exposure/24 hrs when out of bed (lux) RangeMean mins:> 20 lux> 500 lux>1000 luxElder0-449191.50.0Caregiver0-3990635.518.08.0Dyad dataLight Norms (in lux)*Sunlight/reflective surfaces ,000Overcast Day 1,000Avg nursing home 50Avg living roomTwilight 10Full Moon 1*From Turner, Br J Opthalmology
44- Mean sleep efficiency % - Mean night sleep (mins) ACTIGRAPHYCaregiver wifeDemented husbandSleep-rest- Mean sleep efficiency %- Mean night sleep (mins)- Mean sleep latency (mins)- Mean wake after sleep onset [WASO] (mins)- Mean napping/24 hr (mins)7025781119314461710596Intra-daily variability (0-2)0.710.95Inter-daily stability (0-1)0.690.76Caregiver 4.3 hoursElder – 7.4 hoursNighttime sleep: number of minutes scored as sleeping at night.Sleep latency: number of minutes until sleep onset scored (first interval with > 20 minutes sleep).>60 minsimpaired*Sleep efficiency: percent of time scored as sleep beginning with first sleep interval. <70%impaired*Napping: number of minutes scored as sleeping when not in bed.WASO: number of minutes scored as awake after sleep onset to end of sleep; indication of sleep fragmentation. >90 minutesimpaired sleep*Intra-daily variability (IV): indication of fragmentation of rest-activity/24 hours; theoretical range 0-2; a good r-a rhythm has low IV (Carvalho-Bos et al 2007)Inter-daily stability (IS): indication of the strength of the coupling between the light-dark cycle and rest-activity cycle; theoretical range 0-1; good r-a rhythm\ has high IS (Carvalho-Bos et al 2007)*”Cutpoints” used to provide “clinically meaningful” norms per Yaffee et al, p 238.
4524-hour Sleep and Light Caregiver Elder Caregiver 1112 wake minutes 328 sleep minutes(7 episodes)22.8% sleep
46CaregiverPer Daysimeter: caregiver phasor magnitude of [norms ] Indication of circadian entrainment/disruption
47Entrained vs Disrupted HumanWould like to talk about two specific environmental phase shifters: jet lag and shift work
48Conclusions Daily light levels are very low Little variation in light levelsSleepNeither caregiver or elder sleep wellCaregiver: poor circadian entrainmentSleep disruption causesLow lighting, little contrastFrequent wake times at night
49Support VISN 10 GRECC, Cleveland VAMC Frances Payne Bolton School of Nursing, Case Western Reserve University, Cleveland, OHLighting Research Center, Rensselear Polytechnic Institute, Troy NYGeneral Electric Company, Nela Park, East Cleveland, OH49
50Team Tom Hornick, MD1,2 Patricia Higgins, PhD1,2 Mariana Figueiro, PhD3Mark Rea, PhD3Andy Bierman, MS3John Bullough, PhD3Bill Biers, PhD4Mark Duffy, PhD4Ed Yandek, BS41Case Western Reserve University2Cleveland Veterans Affairs Medical Center3Lighting Research Center, Rensselaer Polytechnic Institute4General Electric Lighting, Nela Park
51Next Steps“Methodology issues in a tailored light treatment for persons with dementia" R01 – M. Figueiro, PI