Article:
New research is exploring whether targeted light flashes can help reset circadian rhythms offset by traveling to new time zones. WSJ's Sumathi Reddy discusses with Tanya Rivero. Photo: iStock 
  
 Exposure to brief flashes of light during the night before a trip could help people avoid jet lag, according to a new study by Stanford University researchers. 
  
 The study, published online Monday in the Journal of Clinical Investigation, might have implications for more than just travelers. It also could point to help for people on sleep/wake schedules that don’t align with their circadian rhythms and people who suffer from seasonal affective disorder, a type of depression. The researchers also are investigating whether... ||||| Exposing people to short flashes of light while they’re sleeping could provide a fast and efficient method of preventing jet lag, according to a study by researchers at the Stanford University School of Medicine. 
  
 “This could be a new way of adjusting much more quickly to time changes than other methods in use today,” said Jamie Zeitzer, PhD, assistant professor of psychiatry and behavioral sciences. 
  
 Zeitzer is senior author of the study, which was published online Feb. 8 in the Journal of Clinical Investigation. The lead author is Raymond Najjar, PhD, a former postdoctoral scholar at Stanford now at the Singapore Eye Research Institute. 
  
 Researchers led by Zeitzer have been working on developing an optimal technique for using light exposure to help people adjust more quickly to changes in their sleep cycles. Current light-therapy treatments for sleep disturbances include sitting in front of bright lights for hours at a time during the day, which allows you to transition your body clock to a new time zone in small steps prior to taking a trip. 
  
 Night light 
  
 In an earlier study, Zeitzer and his colleagues found that light therapy works best at night because the body’s circadian rhythms, which control sleep cycles, are more sensitive to light at night, even through closed eyelids. 
  
 In the latest study, Zeitzer and Najjar found that short flashes of light at night are more effective than continuous light exposure and could further speed up the process of adjusting to a different time zone before a trip. 
  
 The transfer of light through the eyes to the brain does more than provide sight; it also changes the biological clock. A person’s brain can be tricked into adjusting more quickly to disturbances in sleep cycles by increasing how long he or she is exposed to light prior to traveling to a new time zone. 
  
 After arriving in a new time zone, the body will eventually adjust on its own, but at a slow pace of about one hour a day. Meanwhile, jet lag, which occurs because your body’s clock is still synced to your original time zone, can cause fatigue, lack of alertness, a general feeling of malaise and sometimes gastrointestinal problems. 
  
 Biological ‘hacking’ 
  
 Light therapy is designed to speed up the brain’s adjustment to time changes. By conducting light therapy at night, the brain’s biological clock gets tricked into adjusting to an awake cycle even when asleep. It’s a kind of “biological hacking” that fools the brain into thinking the day is longer while you get to sleep, Zeitzer said. ||||| This experiment demonstrates that, in direct contrast to image-forming photoreception, the human circadian timing system has the capacity to integrate light over a millisecond time scale. Furthermore, we have demonstrated that a specific temporal pattern of light has the capacity to increase the induction of circadian phase changes to a greater extent than that observed with continuous light. As opposed to the response of the circadian timing system to light flashes, other NIF responses, including increased alertness and suppressed melatonin production, failed to show consistent responsivity to light flashes. This type of sequence of light flashes would be highly improbable to occur naturally and, as such, the response we observed is likely an unintended consequence of the circuitry of the system. 
  
 Previous studies in humans have contributed to the elucidation of the characteristics of NIF photoresponses, including wavelength sensitivity (33, 36, 38), timing (49, 54), intensity (40), and photic history (41). A limited number of studies have examined the effect of the temporal pattern of light. Previous studies examining the effect of continuous long- versus short-duration (minutes) intermittent light on the NIF system have implied that the effectiveness of light in changing circadian timing declines rapidly with the duration of the light pulse (42, 43, 55). We have previously shown that much of the effectiveness of light on changing the timing of the circadian pacemaker may, in fact, be mediated within the first few milliseconds of light exposure (44). Our findings suggest that within the NIF photoresponsive structure, the circadian system appears to integrate ultrashort 2-millisecond flashes of light over time in a nonlinear fashion. This temporal integration is such that 0.95 seconds of light delivered as discreet flashes evenly distributed over an hour has the capacity to be more than 2-fold more effective on phase delaying the circadian system than an equiluminous continuous light exposure 3,800 times the duration of the flashes. This is the first demonstration to our knowledge in any species that a sequence of ultrashort intermittent light flashes can be as effective, if not more effective, in changing the phase of the circadian timing system in comparison to a continuous white light of the same spectral composition and illuminance. 
  
 Circadian integration renders ultrashort flashes more efficient than continuous light. The responsivity of the circadian system to the flash sequence could be explained by the electrophysiological properties of the ipRGCs, which have a sluggish off response, in that they continue to fire for several seconds after cessation of a light stimulus (10, 56). When flashes are separated by a short ISI, the depolarization of the ipRGCs would become sustained, similar to that evoked by continuous light exposure. The higher effectiveness of flashes on circadian photoreception could arise from the additional firing of cones, which indirectly project to ipRGCs, at light onset and offset, thus generating a continuous response boosted by superimposed multiple spiking responses at each light onset and offset. Flashes seem to offer an ideal stimulus that maximizes inputs from the visual system (cones), which is optimized to be maximally responsive to rapid temporal light fluctuations, and the more sluggish melanopsin-based system that is hypothesized to integrate light exposure of long durations so as to remove the vagaries of behavior (e.g., walking in a shaded area, weather) on light exposure and its effects on circadian timing. If the flashes are too far apart (e.g., ISI = 240 s), there may be insufficient drive on ipRGCs to evoke a change in circadian timing. Although a rapid dark regeneration of cone opsin is expected after short bleaches (57–59), if the flashes are too close together (e.g., 2.5–7.6 s), there may not be enough time for the bleached fragment of cone opsin to optimally regenerate; therefore, the loss of the superimposed boost in the response renders these sequences similar to continuous light. A similar observation has previously been noted in hamsters exposed to a train of 300-millisecond light pulses separated by 300 milliseconds of dark or 300 seconds of continuous light of equal total photon density (60). While it is a possibility that requires testing, we do not believe that rods have a substantive contribution in flashes subsequent to the first one, given that they are saturated at very low illuminances of light and regenerate at a much slower pace compared with cones. 
  
 Integration of light information in the retina, however, does not exclude the possibility of integration of photic drive by neurons in the SCN (61). As with the ipRGCs, SCN neurons exhibit persistent firing, even after cessation of a light stimulation (62), providing a substrate for temporal integration. Alternatively, some neurons in the SCN are activated by phases of darkness (61). While the role of these neurons and their implication in entrainment remain unclear, it is possible that the combination of the excitation by flashes of light with interspersed darkness is able to mediate the observed effects. 
  
 A circadian critical fusion frequency. When flashes were separated by 2.5 to 7.6 seconds, circadian phase shift was reduced to a similar magnitude as the shift induced by continuous light. Thus, the circadian system may “perceive” this frequency of stimulation the same as it would continuous light. This is akin to the phenomenon of flicker fusion in image-forming vision, in which scotopic, rod-mediated vision has a critical fusion frequency (CFF) near 15 Hz, while cone-mediated vision reaches a CFF near 60 Hz (63). Based on our findings, we suggest that circadian CFF, after dark adaptation and under a broad band full retinal exposure to a pattern of 2-millisecond stimuli, occurs around 0.13 Hz (7.6 s ISI). As with CFF, we expect circadian CFF to vary across species (64). 
  
 A dichotomy in the NIF retinohypothalamic pathways. Given the technical difficulties in assessing the effect of individual 2-millisecond light flashes on melatonin suppression or alertness changes, we cannot exclude that transient changes in these functions have occurred following each brief light exposure. Nevertheless, the absence of an ISI-dependent change in melatonin suppression and alertness over a 60-minute period under different ISIs supports the idea that light-induced circadian phase shifting is not subserved by the same neural pathways as either light-induced melatonin suppression or light-induced changes in alertness. Light-induced changes in melatonin production, alertness, and phase shift are all thought to be communicated to the brain by the ipRGCs (16, 21, 65). While light-induced melatonin suppression is often used as a proxy for the effect of light on the circadian system, our data indicate that there are at least some circumstances in which this is inaccurate. It is possible that distinct subtypes of ipRGCs in the human retina (66, 67) may subserve different NIF functions. The M1 subtype of ipRGCs is implicated mainly in phase shifting the circadian system and has a faster response, a lower intrinsic threshold, and similar extrinsic input compared with other ipRGC subtypes (67). It is therefore possible that temporal integration is limited to M1 ipRGCs and that activation of these ipRGCs with light flashes is insufficient to induce light-induced melatonin suppression or alertness. An alternative possibility is that, as discussed above, the temporal integration of light is occurring at the level of the SCN. While the retinohypothalamic tract, which arises from the ipRGCs, projects to and conveys light information to the SCN, it also projects to other brain nuclei, including the paraventricular nucleus of the hypothalamus (PVN) (68), pretectal area (16), lateral hypothalamic area (LHA) (69), and ventrolateral preoptic nucleus (VLPO) (68, 70). The PVN is involved in the control of melatonin secretion, while the other areas (pretectal area, LHA, VLPO) are all implicated in the regulation of sleep or wake. If temporal integration in the SCN is required for the phase shifting response to flashes, despite whether similar integration occurs in the retina, it is not altogether unexpected that NIF responses, such as light-induced melatonin suppression and changes in alertness, which may not depend on the SCN, are not affected by the flashes in a dose-dependent manner. 
  
 Technical considerations. There was considerable variability associated with responses to very short ISIs between the flashes of light. Some of this variability may be explained by difficulties in maintaining eyes open due to sleep inertia or anticipatory blinking, which is more likely to occur when the ISI is very short (e.g., every 2.5 s) rather than long (e.g., every 240 s). We did not record eyelid movement but did discuss with the participants the importance of remaining awake with their eyes open in the Ganzfeld dome. Light is able to penetrate through the closed eyelid in a wavelength-dependent fashion, such that approximately 3% to 14% of light is transmitted (71). We have recently shown that, given sufficient intensity, millisecond light flashes passing through the eyelid have the capacity to induce changes in circadian timing (72). Nevertheless, if a participant had his eyes closed, the retinal illuminance of the stimulus would differ from the corneal measured illuminance and could contribute to the variability of the responses to the short ISI. Future studies are necessary to discover, and potentially remove, this source of variability in the response to short ISI. 
  
 It is worth mentioning that, even though we fit the observed phase shift as a function of ISI with a linear rise and exponential decay function, it is quite possible that other functions may be more appropriate for these data. This phenomenological fit, however, was chosen as most suitable after multiple tests with various models, based on known retinal and neuronal physiology. Further studies on NIF photoreception are necessary to refine these models and consecutively the fit of our data. 
  
 Flashes that are 2 milliseconds in duration, such as those used in this study, are faster than the pupil constriction response (73). While the pupil constricts after the flash occurs, we have found (data not shown) that there is a persistent pupillary constriction for 29.5 ± 3.24 seconds (n = 4) after an individual flash, thereby reducing the overall input to the retina, especially for flashes with an ISI under 15 seconds. Taking into account pupillary constriction induced by both continuous and different sequences of light flashes, continuous light would still contain 850 to 18,000 times more light than the sequences of flashes used in this study. We could have, as many laboratories do, used an antimuscarinic agent to dilate the pupils to avoid the pupillary light reflex and keep it from interfering with the amount of light striking the retina. Given the potential effect of antimuscarinics on the physiologic properties of retinal ganglion cells (74), we feel that the use of such agents would have created greater uncertainty in the interpretation of our results. 
  
 A final consideration is that the phase shift observed in our study under continuous light was smaller than that observed in previous studies (41, 49). This difference, however, is likely due to protocol dissimilarities in the intensity of the light exposure (49) and light history of the participants that could lead to a different sensitization of the photoreceptive system (41). 
  
 Ultrashort flashes revolutionize light therapy for chronobiological disorders. Whether for mood (23, 28, 75) or circadian disorders (26), light has been shown to be an effective and safe, yet challenging therapy. Multiple modulations have been suggested for the chromaticity (76–78), intensity (79), and pattern (55, 80) of light exposures to render them optimal for clinical and personal use. Here, we show that modulation of the temporal pattern of light at the millisecond time scale can be manipulated to isolate and optimize the effects of light on the circadian timing system. Using modern lighting technologies, such as ultra-bright light-emitting diodes, flashes can also be incorporated into portable mask designs that could be controlled and timed via smart phone software to proactively phase shift and resynchronize jet-lagged travelers to their new time zone, help individuals who want to go to sleep earlier on a regular basis do so (e.g., adolescents), and work in conjunction with daytime light/dark exposure to aid adjusting shift workers. The efficiency of this light treatment is especially pronounced, as flashes have been shown to be able to phase delay the circadian system, even during sleep, when the circadian system is most sensitive to light (54), while the eyelids are closed and without altering sleep (72). This type of light exposure, therefore, opens new treatment possibilities for circadian disorders that will need to be tested in real-world clinical trials as well as possibilities for the alleviation of associated sleep, mood, cognitive, and metabolic declines. |||||Summary:
– Researchers at Stanford University have discovered what a press release calls a "fast and efficient" way to stop jet lag before it starts: repeatedly flashing light into your eyes while you sleep. "If you are flying to New York tomorrow, tonight you use the light therapy," Dr. Jamie Zeitzer says. "If you normally wake up at 8am, you set the flashing light to go off at 5am. When you get to New York, your biological system is already in the process of shifting to East Coast time." A flash every 10 seconds for one hour, used toward the end of the night, will push the body's circadian rhythm forward by about two hours, the Wall Street Journal explains. Using the flashes of light at the beginning of the night, on the other hand, will delay the circadian clock and could be helpful when the aforementioned traveler heads back to the West Coast. Current in-advance methods for dealing with jet lag and sleep-cycle issues involve continuous light administered while awake. Not only did the study find flashing lights to be more effective—they change the body's circadian rhythm up to three times faster than a steady light—they don't interrupt a person's life. "Most people can sleep through the flashing light just fine," Zeitzer says in the press release. Researchers are hoping to have a light-flashing sleep mask available for consumers later this year. This same method could be used to help people who work the night shift or have seasonal affective disorder. And researchers are currently testing it on a group of teens to improve school performance. "We’re basically looking to intentionally jet lag teens so that they can go to bed at a reasonable time," Zeitzer tells the Journal. (This family of five gave itself perpetual jet lag by switching to Martian time.)
Artikel: Ny forskning undersöker om riktade ljusblixtar kan bidra till att återställa dygnsrytmerna kompenseras genom att resa till nya tidszoner. WSJ:s Sumathi Reddy diskuterar med Tanya Rivero. Foto: iStock Exponering för korta ljusblixtar under natten före en resa kan hjälpa människor att undvika jetlag, enligt en ny studie av Stanford University forskare. Studien, som publiceras på nätet måndag i Journal of Clinical Investigation, kan ha konsekvenser för mer än bara resenärer. Det kan också peka på att hjälpa människor på sömn / vakna scheman som inte överensstämmer med deras dygnsrytmer och människor som lider av säsongsbunden affektiv störning, en typ av depression. Forskarna undersöker också om ... <unk> <unk> Att exponera människor för korta ljusblixtar medan de sover kan ge en snabb och effektiv metod för att förhindra jetlag, enligt en studie av forskare vid Stanford University School of Medicine. – Det här kan vara ett nytt sätt att anpassa sig mycket snabbare till tidsförändringar än andra metoder som används idag, säger Jamie Zeitzer, doktorand, biträdande professor i psykiatri och beteendevetenskap. Zeitzer är huvudförfattare till studien, som publicerades online 8 feb i Journal of Clinical Investigation. Huvudförfattare är Raymond Najjar, PhD, en före detta postdoktor vid Stanford nu vid Singapore Eye Research Institute. Forskare ledda av Zeitzer har arbetat med att utveckla en optimal teknik för att använda ljusexponering för att hjälpa människor att snabbare anpassa sig till förändringar i sina sömncykler. Aktuella ljusbehandlingar för sömnstörningar inkluderar att sitta framför starkt ljus i timmar vid en tidpunkt på dygnet, vilket gör att du kan flytta din kroppsklocka till en ny tidszon i små steg innan du tar en resa. Nattljus I en tidigare studie fann Zeitzer och hans kollegor att ljusterapi fungerar bäst på natten eftersom kroppens dygnsrytmer, som styr sömncyklerna, är känsligare för ljus på natten, även genom slutna ögonlock. I den senaste studien fann Zeitzer och Najjar att korta ljusblixtar på natten är effektivare än kontinuerlig ljusexponering och skulle ytterligare kunna påskynda processen att anpassa sig till en annan tidszon innan en resa. Överföringen av ljus genom ögonen till hjärnan gör mer än att ge syn; det förändrar också den biologiska klockan. En människas hjärna kan luras att snabbare anpassa sig till störningar i sömncyklerna genom att öka hur länge hon eller han utsätts för ljus innan han reser till en ny tidszon. Efter ankomsten till en ny tidszon kommer kroppen så småningom att anpassa sig på egen hand, men i en långsam takt av omkring en timme om dagen. Under tiden kan jetlag, som uppstår på grund av att kroppens klocka fortfarande är synkroniserad till din ursprungliga tidszon, orsaka trötthet, brist på vakenhet, en allmän känsla av sjukdomskänsla och ibland gastrointestinala problem. Biologisk ”hackande” Ljusterapi är utformad för att påskynda hjärnans anpassning till tidsförändringar. Genom att genomföra ljusterapi på natten blir hjärnans biologiska klocka lurad att anpassa sig till en vaken cykel även när man sover. Det är en sorts ”biologisk hacking” som lurar hjärnan att tänka att dagen är längre medan man får sova, sade Zeitzer. Detta experiment visar att, i direkt kontrast till bildbildande fotoreception, har det mänskliga dygnstidsbestämningssystemet kapacitet att integrera ljus över en millisekunds tidsskala. Vidare har vi visat att ett specifikt tidsmässigt ljusmönster har kapacitet att öka induktionen av dygnsfasförändringar i större utsträckning än vad som observeras med kontinuerligt ljus. I motsats till det cirkadiska timingsystemets respons på ljusblixtar, visade andra NIF-svar, inklusive ökad vakenhet och undertryckt melatoninproduktion, inte konsekvent respons på ljusblixtar. Denna typ av sekvens av ljusblixtar skulle vara mycket osannolikt att uppstå naturligt och, som sådan, den reaktion vi observerade är sannolikt en oavsiktlig följd av systemets kretsar. Tidigare studier på människa har bidragit till att klargöra egenskaperna hos NIF-fotosvar, inklusive våglängdskänslighet (33, 36, 38), timing (49, 54), intensitet (40) och fotisk historia (41). Ett begränsat antal studier har undersökt effekten av ljusets temporalmönster. Tidigare studier som undersökte effekten av kontinuerligt intermittent ljus under lång tid jämfört med kort tid (minuter) på NIF-systemet har inneburit att ljusets effektivitet vid förändring av dygnstimulation minskar snabbt med ljuspulsens varaktighet (42, 43, 55). Vi har tidigare visat att mycket av ljusets effektivitet när det gäller att ändra tidpunkten för dygnspacemakern i själva verket kan förmedlas inom de första millisekunderna av ljusexponering (44). Våra fynd tyder på att inom NIF fotoresponsive struktur verkar dygnssystemet integrera ultrakorta 2-millisekundersblixtar av ljus över tid på ett ickelinjärt sätt. Denna tidsmässiga integration är sådan att 0,95 sekunders ljus som levereras som diskreta blixtar jämnt fördelade över en timme har kapacitet att vara mer än två gånger mer effektiv på fasfördröjning av dygnssystemet än en equaluminous kontinuerlig ljusexponering 3,800 gånger blixtarnas varaktighet. Detta är den första demonstrationen till vår kunskap hos någon art att en sekvens av ultrakorta intermittenta ljusblixtar kan vara lika effektiv, om inte mer effektiv, när det gäller att ändra fasen av det cirkadiska timingssystemet i jämförelse med ett kontinuerligt vitt ljus av samma spektralsammansättning och belysning. Circadisk integration gör ultrakorta blixtar effektivare än kontinuerligt ljus. Cirkadiska systemets ansvar för blixtsekvensen kan förklaras med de elektrofysiologiska egenskaperna hos ipRGC, som har en trög reaktion, i det att de fortsätter att avfyra i flera sekunder efter att en ljusstimulus (10, 56) upphört. När blixtar separeras av en kort ISI, skulle depolariseringen av IPRGCs bli ihållande, liknande den som framkallas av kontinuerlig ljusexponering. Den högre effektiviteten av blixtar på cirkadian fotoreception kunde uppstå från den ytterligare avfyrning av koner, som indirekt projicerar till ipRGCs, vid ljusdebut och offset, vilket genererar en kontinuerlig respons som ökas av överlagrade multipla spejande svar vid varje ljusdebut och offset. Flashes verkar erbjuda en idealisk stimulans som maximerar ingångar från det visuella systemet (koner), som är optimerad för att vara maximalt lyhörd för snabba temporala ljusfluktuationer, och den mer tröga melanopsin-baserade systemet som är hypothesized att integrera ljusexponering av långa varaktigheter för att ta bort vagaries av beteende (t.ex., gå i ett skuggat område, väder) på ljusexponering och dess effekter på dygns timing. Om blixtarna är för långt ifrån varandra (t.ex. ISI = 240 s), kan det finnas otillräcklig drift på ipRGCs för att framkalla en förändring i dygnstiming. Även om en snabb mörk regenerering av kon opsin förväntas efter korta blekmedel (57–59), om blixtarna är för nära varandra (t.ex. 2,5–7,6 s), finns det kanske inte tillräckligt med tid för att det blekta fragmentet av kon opsin optimalt ska kunna regenerera; därför återger förlusten av den överlagrade boosten i responsen dessa sekvenser liknande kontinuerligt ljus. En liknande observation har tidigare noterats hos hamstrar som exponerats för ett tåg med 300 millisekunders ljuspulser separerade med 300 millisekunders mörker eller 300 sekunders kontinuerligt ljus med lika total fotontäthet (60). Även om det är en möjlighet som kräver testning, tror vi inte att stavar har ett väsentligt bidrag i blixtar efter den första, med tanke på att de är mättade vid mycket låga belysningar av ljus och regenerera i en mycket långsammare takt jämfört med koner. Integration av ljusinformation i näthinnan utesluter dock inte möjligheten att neuroner integrerar photisk drivning i SCN (61). Liksom med IPRGCs, SCN neurons uppvisar ihållande bränning, även efter upphörande av en ljusstimulering (62), som ger ett substrat för temporal integration. Alternativt aktiveras vissa neuroner i SCN av faser av mörker (61). Även om dessa neuroners roll och deras betydelse för entraineringen fortfarande är oklar, är det möjligt att kombinationen av excitation genom ljusblixtar med varvat mörker kan medla de observerade effekterna. En dygnskritisk fusionsfrekvens. När blixtar separerades med 2,5 till 7,6 sekunder reducerades dygnsfasförskjutningen till en liknande magnitud som förskjutningen framkallad av kontinuerligt ljus. Således kan dygnssystemet “uppfatta” denna frekvens av stimulering på samma sätt som det skulle kontinuerlig ljus. Detta liknar fenomenet flimmerfusion i bildbildande syn, där scotopisk, stavmedierad syn har en kritisk fusionsfrekvens (CFF) nära 15 Hz, medan konmedierad syn når en CFF nära 60 Hz (63). Baserat på våra resultat, föreslår vi att dygns CFF, efter mörk anpassning och under ett brett band full näthinneexponering för ett mönster av 2-millisekunders stimuli, inträffar runt 0,13 Hz (7,6 s ISI). Precis som med CFF förväntar vi oss att dygnscancern CFF varierar mellan olika arter (64). En dikotomi i NIF:s retinohypotalamusvägar. Med tanke på de tekniska svårigheterna att bedöma effekten av individuella 2-millisekunders ljusblixtar på melatonindämpning eller vakenhetsförändringar kan vi inte utesluta att övergående förändringar i dessa funktioner har inträffat efter varje kort ljusexponering. Avsaknaden av en ISI-beroende förändring i melatoninsuppression och vakenhet under en 60-minutersperiod under olika ISI-nivåer stöder dock tanken att ljusinducerad dygnsfasförskjutning inte underställs av samma neurala vägar som vare sig ljusinducerad melatoninsuppression eller ljusinducerade förändringar i vakenhet. Ljusinducerade förändringar i melatoninproduktion, vakenhet och fasförskjutning anses alla kommuniceras till hjärnan av ipRGC (16, 21, 65). Medan ljusinducerad melatoninsuppression ofta används som en proxy för ljusets effekt på dygnssystemet, indikerar våra data att det åtminstone finns vissa omständigheter under vilka detta är felaktigt. Det är möjligt att distinkta subtyper av ipRGC i människans näthinna (66, 67) kan underställa olika NIF-funktioner. M1-subtypen av ipRGC är främst inblandad i fasförskjutning av dygnssystemet och har ett snabbare svar, en lägre inneboende tröskel och liknande yttre ingång jämfört med andra subtyper av ipRGC (67). Det är därför möjligt att temporal integration begränsas till M1 ipRGC och att aktivering av dessa ipRGC med ljusblixtar är otillräcklig för att inducera ljusinducerad melatoninsuppression eller vakenhet. En alternativ möjlighet är att ljusets temporala integration, som diskuterats ovan, sker på SCN-nivå. Även om retinohypotalamuskanalen, som uppstår från ipRGC, projekterar till och förmedlar ljusinformation till SCN, projekterar den också till andra hjärnkärnor, inklusive paraventrikulärkärnan i hypotalamus (PVN) (68), pretektal area (16), lateral hypotalamus area (LHA) (69) och ventrolateral preoptical nuclear (VLPO) (68, 70). PVN är involverat i kontrollen av melatoninsekretionen, medan de andra områdena (pretectal area, LHA, VLPO) alla är inblandade i regleringen av sömn eller vakning. Om temporal integration i SCN krävs för det fasförskjutna svaret på blixtar, trots att liknande integration sker i näthinnan, är det inte helt oväntat att NIF-svaren, såsom ljusinducerad melatoninsuppression och förändringar i vakenhet, som kanske inte beror på SCN, inte påverkas av blixtarna på ett dosberoende sätt. Tekniska överväganden. Det fanns en avsevärd variation i samband med reaktioner på mycket korta ISI mellan ljusblixtarna. En del av denna variabilitet kan förklaras med svårigheter att hålla ögonen öppna på grund av sömntröghet eller förutseende blinkande, vilket är mer sannolikt att inträffa när ISI är mycket kort (t.ex. var 2,5:e s) snarare än lång (t.ex. var 240:e s). Vi spelade inte in ögonlocksrörelse men diskuterade med deltagarna vikten av att hålla sig vaken med ögonen öppna i Ganzfeld kupolen. Ljuset kan tränga igenom det slutna ögonlocket på ett våglängdsberoende sätt, så att cirka 3% till 14% av ljuset överförs (71). Vi har nyligen visat att, med tillräcklig intensitet, millisekundersblixtar som passerar genom ögonlocket har kapacitet att framkalla förändringar i dygnstiming (72). Men om en deltagare hade ögonen stängda, skulle stimulusens retinal illuminans skilja sig från hornhinnan mätt illuminans och kunde bidra till variabiliteten i svaren på den korta ISI. Framtida studier är nödvändiga för att upptäcka, och potentiellt ta bort, denna källa till variabilitet i svaret på kort ISI. Det är värt att nämna att även om vi passar den observerade fasförskjutningen som en funktion av ISI med en linjär uppgång och exponentiell sönderfallsfunktion, är det fullt möjligt att andra funktioner kan vara lämpligare för dessa data. Denna fenomenologiska passform valdes dock som mest lämplig efter flera tester med olika modeller, baserade på känd retinal och neuronal fysiologi. Ytterligare studier av NIF-fotomottagning är nödvändiga för att förfina dessa modeller och på varandra följande passa våra data. Blixtar som är 2 millisekunder långa, såsom de som används i denna studie, är snabbare än pupillens sammandragningsrespons (73). Medan pupillen drar sig tillbaka efter blixten inträffar, har vi funnit (data ej visat) att det finns en ihållande pupillförträngning i 29,5 ± 3,24 sekunder (n = 4) efter en individuell blixt, och därmed minskar den totala inmatningen till näthinnan, särskilt för blixtar med en ISI under 15 sekunder. Med hänsyn till pupillsammandragning framkallad av både kontinuerliga och olika sekvenser av ljusblixtar, skulle kontinuerligt ljus fortfarande innehålla 850 till 18 000 gånger mer ljus än de sekvenser av blixtar som används i denna studie. Vi kunde, som många laboratorier gör, ha använt ett antimuskarinmedel för att vidga pupillerna för att undvika pupillljusreflexen och hindra den från att störa den mängd ljus som träffar näthinnan. Med tanke på den potentiella effekten av antimuskarinika på de fysiologiska egenskaperna hos retinala ganglioner (74), anser vi att användningen av sådana medel skulle ha skapat större osäkerhet i tolkningen av våra resultat. Ett sista övervägande är att den fasförskjutning som observerades i vår studie under kontinuerligt ljus var mindre än den som observerats i tidigare studier (41, 49). Denna skillnad beror dock sannolikt på protokollskillnader i intensiteten av ljusexponeringen (49) och ljushistorien hos deltagarna som kan leda till en annan sensibilisering av fotoreceptorsystemet (41). Ultrakorta blixtar revolutionerar ljusterapi för kronobiologiska störningar. Vare sig det gäller humör (23, 28, 75) eller dygnsstörningar (26) har ljus visat sig vara en effektiv och säker, men ändå utmanande terapi. Flera moduler har föreslagits för kromaticitet (76–78), intensitet (79) och mönster (55, 80) för ljusexponering för att göra dem optimala för kliniskt och personligt bruk. Här visar vi att modulering av ljusets temporala mönster vid millisekundsskalan kan manipuleras för att isolera och optimera ljusets effekter på det dygnsbaserade timingssystemet. Med hjälp av modern belysningsteknik, såsom ultraljusavgivande dioder, kan blixtar också införlivas i bärbara maskdesigner som kan styras och tidsbestämmas via smarttelefonprogramvara för att proaktivt fasskifta och synkronisera jetlaggade resenärer till sin nya tidszon, hjälpa personer som vill gå och lägga sig tidigare på regelbunden basis göra det (t.ex. ungdomar), och arbeta i samband med dagtid ljus/mörk exponering för att hjälpa justera skiftarbetare. Effektiviteten i denna ljusbehandling är särskilt uttalad, då blixtar har visat sig kunna fasfördröja dygnssystemet, även under sömn, då dygnssystemet är som känsligast för ljus (54), medan ögonlocken är stängda och utan att ändra sömnen (72). Denna typ av ljusexponering öppnar därför nya behandlingsmöjligheter för dygnssjukdomar som kommer att behöva testas i verkliga kliniska prövningar samt möjligheter för lindring av tillhörande sömn, humör, kognitiva och metaboliska nedgångar. ••••••••••••••••••••••
Article: New research examines whether directed light flashes can help restore circadian rhythms to be compensated by travelling to new time zones. WSJ's Sumathi Reddy discusses with Tanya Rivero. Photo: iStock Exposure to short light flashes during the night before a trip can help people avoid jet lag, according to a new study by Stanford University researchers. The study, published online Monday in the Journal of Clinical Investigation, can have consequences for more than just travellers. It may also point to helping people on sleep/wake schedules that do not correspond to their circadian rhythms and people suffering from seasonal affective disorder, a type of depression. The researchers are also investigating whether exposure to short light flashes while asleep can provide a quick and effective method to prevent jet lag, according to a study by researchers at Stanford University School of Medicine. “This may be a new way to adapt much faster to time changes than other methods used today,” says Jamie Zeitzer, PhD student, Associate Professor of Psychiatric and Behavioural Sciences. Zeitzer is the lead author of the study, which was published online Feb 8 in the Journal of Clinical Investigation. The lead author is Raymond Najjar, PhD, a former postdoctoral fellow at Stanford now at the Singapore Eye Research Institute. Scientists led by Zeitzer have worked to develop an optimal technique for using light exposure to help people adapt more quickly to changes in their sleep cycles. Current lighting treatments for sleep disorders include sitting in front of bright light for hours at a time of day, allowing you to move your body watch to a new time zone in small steps before taking a trip. Nightlights In a previous study, Zeitzer and his colleagues found that light therapy works best at night because the body's circadian rhythms, which control sleep cycles, are more sensitive to light at night, even through closed eyelids. In the latest study, Zeitzer and Najjar found that short light flashes at night are more effective than continuous light exposure and could further accelerate the process of adapting to another time zone before a trip. The transmission of light through the eyes to the brain does more than give sight; it also changes the biological clock. A person’s brain can be tricked into adapting more quickly to sleep cycle disturbances by increasing how long he or she is exposed to light before travelling to a new time zone. After arriving at a new time zone, the body will eventually adapt on its own, but at a slow rate of about an hour a day. Meanwhile, jet lag, which occurs because the body's clock is still synchronized to your original time zone, can cause fatigue, lack of alertness, a general feeling of malaise and sometimes gastrointestinal problems. Biological “hacking” Light therapy is designed to accelerate the brain's adaptation to time changes. By conducting light therapy at night, the brain’s biological clock is tricked into adapting to a awake cycle even when you sleep. It is a kind of ‘biological hacking’ that tricks the brain into thinking that the day is longer while you sleep, Zeitzer said. This experiment shows that, in direct contrast to image forming photoreception, the human circadian time determination system has the capacity to integrate light over a millisecond's time scale. Furthermore, we have shown that a specific temporal pattern of light has the capacity to increase the induction of circadian phase changes to a greater extent than is observed with continuous light. Contrary to the response of the circadian timing system to light flashes, other NIF responses, including increased alertness and suppressed melatonin production, did not consistently respond to light flashes. This type of sequence of light flashes would be very unlikely to occur naturally and, as such, the reaction we observed is likely an unintended consequence of the system's circuits. Previous studies in humans have helped clarify the properties of NIF photoresponses, including wavelength sensitivity (33, 36, 38), timing (49, 54), intensity (40) and photonic history (41). A limited number of studies have investigated the effect of light temporal patterns. Previous studies investigating the effect of continuous intermittent light over a long period of time compared to short time (minutes) on the NIF system have meant that the efficiency of light in changing daily stimulation decreases rapidly with the duration of the light pulse (42, 43, 55). In the past, we have shown that much of the efficiency of light in changing the timing of the circadian spacemaker can in fact be conveyed within the first milliseconds of light exposure (44). Our findings suggest that within the NIF photoresponsive structure, the circadian system seems to integrate ultrashort 2-millisecond flashes of light over time in a nonlinear manner. This temporal integration is such that 0.95 seconds of light delivered as discrete flashes evenly distributed over one hour has the capacity to be more than twice more effective on phase delay of the circadian system than an equiluminous continuous light exposure 3.800 times the duration of the flashes. This is the first demonstration to our knowledge of any species that a sequence of ultrashort intermittent light flashes can be equally effective, if not more effective, in changing the phase of the circadian timing system in comparison to a continuous white light of the same spectral composition and illumination. Circadic integration makes ultra-short flashes more efficient than continuous light. The responsibilities of the circadian system for the lightning sequence can be explained by the electrophysiological properties of the ipRGC, which has a sluggish reaction, in that they continue to fire for several seconds after a light stimulus (10, 56) ceases. When lightning is separated by a short ISI, the depolarization of IPRGCs would become persistent, similar to that induced by continuous light exposure. The higher efficiency of lightning on the circadian photoreception could occur from the further firing of cones, indirectly projecting to ipRGCs, at light onset and offset, generating a continuous response increased by superimposed multiple scouting responses at each light debut and offset. Flashes seems to offer an ideal stimulus that maximizes inputs from the visual system (cones), which is optimized to be maximally responsive to rapid temporal light fluctuations, and the more sluggish melanopsin-based system that is hypothesized to integrate light exposure of long durations to remove vagaries of behavior (e.g., walk in a shaded area, weather) on light exposure and its effects on daily timing. If the flashes are too far apart (e.g. ISI = 240 s), there may be insufficient operation on ipRGCs to induce a change in circadian timing. Although a rapid dark regeneration of con opsin is expected after short bleaches (57–59), if the flashes are too close to each other (e.g. 2.5–7.6 s), there may not be enough time for the bleached fragment of con opsin to optimally regenerate; therefore, the loss of the superimposed boost in the response renders these sequences similar continuous light. A similar observation has previously been noted in hamsters exposed to a train with 300 milliseconds of light pulses separated by 300 milliseconds of darkness or 300 seconds of continuous light with equal total photon density (60). Although it is an opportunity that requires testing, we do not believe that rods have a significant contribution in lightning after the first, given that they are saturated at very low lights of light and regenerate at a much slower rate compared to cones. However, integration of light information into the retina does not preclude the possibility of neurons integrating phototic drive into SCN (61). As with IPRGCs, SCN neurons exhibit persistent burning, even after cessation of a light stimulation (62), which provides a substrate for temporal integration. Alternatively, some neurons in SCN are activated by phases of darkness (61). Although the role of these neurons and their importance to entrainment are still unclear, it is possible that the combination of excitation by light flashes with interspersed darkness can mediate the observed effects. One-day critical fusion frequency. When lightning was separated by 2.5 to 7.6 seconds, the circadian phase shift was reduced to a similar magnitude as the displacement induced by continuous light. Thus, the daily system can “perceive” this frequency of stimulation in the same way as it would continuous light. This is similar to the phenomenon of flicker fusion in image forming vision, where scotopic, rod-mediated vision has a critical fusion frequency (CFF) near 15 Hz, while conmediated vision reaches a CFF near 60 Hz (63). Based on our results, we suggest that the daily CFF, after dark adaptation and under a wide band full retinal exposure to a pattern of 2-millisesecond stimuli, occurs around 0.13 Hz (7.6 s ISI). As with CFF, we expect that the circadian cancer CFF varies between different species (64). A dichotomy of the NIF's retinohypothalamus pathways. Given the technical difficulties in assessing the effect of individual 2-millisecond light flashes on melaton attenuation or alertness changes, we cannot rule out that transient changes in these functions have occurred after each short light exposure. However, the absence of an ISI-dependent change in melatonin suppression and alertness over a 60-minute period during different ISI levels supports the idea that light-induced circadian shift is not subject to the same neural pathways as neither light-induced melatonin suppression nor light-induced changes in alertness. Light-induced changes in melatonin production, alertness, and phase displacement are all considered to be communicated to the brain by ipRGC (16, 21, 65). While light-induced melatonin suppression is often used as a proxy for the effect of light on the daily system, our data indicate that there are at least certain circumstances under which this is incorrect. It is possible that distinct subtypes of ipRGC in the human retina (66, 67) can submit to different NIF functions. The M1 subtype of ipRGC is primarily involved in phase displacement of the circadian system and has a faster response, a lower intrinsic threshold and similar external input compared to other subtypes of ipRGC (67). It is therefore possible that temporal integration is limited to M1 ipRGC and that activation of these ipRGC with light flashes is insufficient to induce light-induced melatonin suppression or alertness. An alternative possibility is that the temporal integration of light, as discussed above, takes place at SCN level. Although the retinohypothalamus canal, which occurs from ipRGC, projects to and conveys light information to SCN, it also projects to other brain nuclei, including the paraventricular nucleus of the hypothalamus (PVN) (68), pretectal area (16), lateral hypothalamus area (LHA) (69) and ventrolateral preoptical nuclear (VLPO) (68, 70). PVN is involved in the control of melatonin secretion, while the other areas (pretectal area, LHA, VLPO) are all involved in the regulation of sleep or wake. If temporal integration into SCN is required for the phase-shifted response to lightning, despite similar integration occurring in the retina, it is not entirely unexpected that the NIF responses, such as light-induced melatonin suppression and changes in alertness, which may not be due to SCN, are not affected by the lightning in a dose-dependent manner. Technical considerations. There was a considerable variation in reactions to very short ISIs between light flashes. Some of this variability can be explained by difficulties in keeping your eyes open due to sleep inertia or foresight flashing, which is more likely to occur when the ISI is very short (e.g. every 2.5 s) rather than long (e.g. every 240 s). We did not record eyelid movement but discussed with the participants the importance of staying awake with our eyes open in the Ganzfeld dome. The light can penetrate the closed eyelid in a wavelength-dependent manner, transferring approximately 3% to 14% of light (71). We have recently shown that, with sufficient intensity, millisecond flashes passing through the eyelid have the capacity to induce changes in circadian timing (72). But if a participant had his eyes closed, the retinal illuminance of the stimulus would differ from the cornea measured illuminance and could contribute to the variability of responses to the short ISI. Future studies are necessary to detect, and potentially remove, this source of variability in response to short ISI. It is worth mentioning that while we fit the observed phase shift as a function of ISI with a linear rise and exponential decay function, it is quite possible that other functions may be more suitable for these data. However, this phenomenological fit was chosen as most suitable after several tests with different models, based on known retinal and neuronal physiology. Further studies of NIF photo reception are necessary to refine these models and successively fit our data. Lightnings 2 milliseconds long, such as those used in this study, are faster than the pupil contraction response (73). While the pupil retreats after lightning occurs, we have found (data not shown) that there is a sustained pupil narrowing in 29.5 ± 3.24 seconds (n = 4) after an individual flash, thus reducing the total input to the retina, especially for flashes with an ISI for 15 seconds. Taking into account pupil contraction induced by both continuous and different sequences of light flashes, continuous light would still contain 850 to 18,000 times more light than the sequences of lightning used in this study. As many laboratories do, we could have used an antimuscarinic agent to widen the pupils to avoid the pupil light reflex and prevent it from interfering with the amount of light that hits the retina. Given the potential effect of antimuscarinics on the physiological properties of retinal ganglions (74), we believe that the use of such agents would have created greater uncertainty in the interpretation of our results. A final consideration is that the phase shift observed in our study under continuous light was less than that observed in previous studies (41, 49). However, this difference is likely due to protocol differences in the intensity of light exposure (49) and the light history of participants that may lead to a different sensitisation of the photoreceptor system (41). Ultrashort flashes revolutionize light therapy for chronobiological disorders. Whether in mood (23, 28, 75) or circadian disorders (26), light has proved to be an effective and safe, yet challenging therapy. Several modules have been proposed for chromaticity (76–78), intensity (79) and pattern (55, 80) of light exposure to make them optimal for clinical and personal use. Here we show that modulation of the temporal patterns of light at the millisecond scale can be manipulated to isolate and optimize the effects of light on the daily timing system. Using modern lighting technologies, such as ultralight-emitting diodes, lightning can also be incorporated into portable mask designs that can be controlled and timed through smartphone software to proactively phase-shift and synchronize jet-lagged travelers to their new time zone, helping people who want to go to bed earlier on a regular basis do so (e.g. young people), and working in conjunction with daytime light/dark exposure to help adjust shift workers. The effectiveness of this light treatment is particularly pronounced, as lightning has been shown to be able to phase-delay the circadian system, even during sleep, when the circadian system is at its most sensitive to light (54), while the eyelids are closed and without changing sleep (72). This type of light exposure therefore opens up new treatment opportunities for circadian diseases that will need to be tested in real-life clinical trials as well as opportunities for relief of associated sleep, mood, cognitive and metabolic declines. <unk> <unk> <unk> <unk> <unk> <unk> <unk> <unk> <unk>
– Forskare vid Stanford University har upptäckt vad ett pressmeddelande kallar ett "snabbt och effektivt" sätt att stoppa jetlag innan det börjar: upprepade gånger blinkande ljus i ögonen medan du sover. "Om du flyger till New York i morgon, i kväll använder du ljusterapin", säger dr Jamie Zeitzer. "Om du normalt vaknar klockan 8 ställer du in det blinkande ljuset som ska tändas klockan 5. När du kommer till New York är ditt biologiska system redan i färd med att flytta till östkusttid." En blixt var tionde sekund i en timme, som används mot slutet av natten, kommer att driva kroppens dygnsrytm framåt med ungefär två timmar, förklarar Wall Street Journal. Att använda ljusblixtarna i början av natten, å andra sidan, kommer att fördröja dygnsklockan och kan vara till hjälp när den ovan nämnda resenären beger sig tillbaka till västkusten. Aktuella metoder i förväg för att hantera jetlag- och sömncykelfrågor innefattar kontinuerligt ljus som administreras medan man är vaken. Studien fann inte bara blinkande ljus vara mer effektiva – de förändrar kroppens dygnsrytm upp till tre gånger snabbare än ett stadigt ljus – de avbryter inte en människas liv. "De flesta kan sova genom det blinkande ljuset alldeles utmärkt", säger Zeitzer i pressmeddelandet. Forskare hoppas att ha en lätt flammande sömnmask tillgänglig för konsumenter senare i år. Samma metod skulle kunna användas för att hjälpa personer som arbetar nattskiftet eller har säsongsbunden affektiv störning. Och forskare testar den för närvarande på en grupp tonåringar för att förbättra skolprestationerna. "Vi är i princip ute efter att avsiktligt jetlag tonåringar så att de kan gå till sängs i rimlig tid," Zeitzer berättar Journal. (Denna familj på fem gav sig själv evig jet lag genom att byta till marsian tid.)
“Scientists at Stanford University have discovered what a press release calls a “fast and effective” way to stop jet lag before it begins: repeatedly flashing light in your eyes while you sleep. "If you fly to New York tomorrow, tonight you'll use the light therapy," said Dr. Jamie Zeitzer. "If you normally wake up at 8 am, set the flashing light to light at 5 am. When you get to New York, your biological system is already moving to East Coast time." A flash every ten seconds in an hour, used towards the end of the night, will push the body's circadian rhythm forward by about two hours," explains the Wall Street Journal. Using the light flashes at the beginning of the night, on the other hand, will delay the daily clock and may be helpful when the above-mentioned traveller heads back to the West Coast. Current methods in advance to deal with jet lag and sleep cycle issues include continuous light administered while awake. The study not only found flashing light to be more effective—they change the body's circadian rhythm up to three times faster than a steady light—they don't interrupt a person's life. "Most people can sleep through the flashing light just fine," says Zeitzer in the press release. Scientists hope to have a lightly flaming sleep mask available to consumers later this year. The same method could be used to help people who work the night shift or have seasonal affective disorder. And scientists are currently testing it on a group of teenagers to improve school performance. "We're basically looking to intentionally jet lag teenagers so they can go to bed in a reasonable time," Zeitzer tells the Journal. (This family of five gave itself eternal jet team by switching to Martian time.)