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.
– 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.)