U.S. patent application number 10/435944 was filed with the patent office on 2004-02-05 for non-ocular circadian clock resetting in humans.
Invention is credited to Campbell, Scott S., Murphy, Patricia J..
Application Number | 20040020496 10/435944 |
Document ID | / |
Family ID | 26723651 |
Filed Date | 2004-02-05 |
United States Patent
Application |
20040020496 |
Kind Code |
A1 |
Campbell, Scott S. ; et
al. |
February 5, 2004 |
Non-ocular circadian clock resetting in humans
Abstract
A method for resetting the phase of the human circadian clock
and for enhancing alertness and performance in humans is disclosed.
The method involves the application of non-solar photic
stimulation, in the range of 15 to 150,000 lux, to any non-ocular
region of the human body during wakefulness or during sleep.
Preferably, the photic stimulation has a wavelength within the
visible spectrum (.about.400-750 nm). The method can be used to
both delay and advance the circadian clock according to a phase
response curve (PRC). The method may also be used for
acute/immediate enhancement of alertness and performance. The
method is applicable to alleviation of problems associated with
"jet-lag", shift work sleep disturbance, and other sleep
disturbances involving misalignment of circadian rhythms. The
method provides a novel technique for shifting the phase of the
circadian clock, and enhancing alertness and performance, using
existing, or newly-developed devices.
Inventors: |
Campbell, Scott S.;
(Chappaqua, NY) ; Murphy, Patricia J.; (Ossining,
NY) |
Correspondence
Address: |
Nixon Peabody LLP
Clinton Square
P.O. Box 31051
Rochester
NY
14603-1051
US
|
Family ID: |
26723651 |
Appl. No.: |
10/435944 |
Filed: |
May 12, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10435944 |
May 12, 2003 |
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09656409 |
Sep 6, 2000 |
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09656409 |
Sep 6, 2000 |
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09074455 |
May 7, 1998 |
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6135117 |
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60046188 |
May 12, 1997 |
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60072121 |
Jan 22, 1998 |
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Current U.S.
Class: |
128/898 |
Current CPC
Class: |
A61N 5/0618 20130101;
A61N 2005/0652 20130101 |
Class at
Publication: |
128/898 |
International
Class: |
A61B 019/00 |
Goverment Interests
[0002] This invention was made with Government support under Grant
No(s). R01MH45067 and K02MH01099, awarded by the National Institute
of Health. The Government has certain rights in the inventions.
Claims
What is claimed is:
1. A method of resetting a human circadian clock comprising the
step of exposing a non-ocular region of a human subject to a
non-solar photic stimulation during one or more circadian cycles to
reset the human circadian clock.
2. The method according to claim 1 further comprising the step of
assessing a time when a daily minimum body temperature for the
human subject occurs, wherein said step of exposing the non-ocular
region begins at an exposure time dependent upon the assessed
time.
3. The method according to claim 2 wherein said step of exposing
the non-ocular region begins before the assessed time.
4. The method according to claim 3 wherein said step of exposing
the non-ocular region begins within about six hours prior to the
assessed time.
5. The method according to claim 2 wherein said step of exposing
the non-ocular region begins after the assessed time.
6. The method according to claim 5 wherein said step of exposing
the non-ocular region begins within six hours after the assessed
time.
7. The method according to claim 1 wherein said step of exposing
the non-ocular region occurs while the human subject is awake.
8. The method according to claim 1 wherein said step of exposing
the non-ocular region occurs while the human subject is asleep.
9. The method according to claim 1 wherein said step of exposing
the non-ocular region lasts for a duration ranging from between
about 15 minutes to about 12 hours.
10. The method according to claim 9 wherein the duration of said
non-ocular exposure is about three hours.
11. The method according to claim 1 wherein said non-solar photic
stimulation has an intensity between about 15 lux to about 150,000
lux.
12. The method according to claim 11 wherein said non-solar photic
stimulation has an intensity between about 10,000 lux to about
13,000 lux.
13. The method according to claim 1 wherein said non-solar photic
stimulation has a bandwidth in the visible spectrum.
14. The method according to claim 13 wherein said non-solar photic
stimulation has a bandwidth between about 455 nanometers (nm) and
540 nm.
15. The method according to claim 1 wherein the given number of
circadian cycles is one.
16. The method according to claim 1 wherein the given number of
circadian cycles is two or more.
17. The method according to claim 1 wherein the non-ocular region
of the human subject has ample surface vasculature.
18. The method according to claim 19 wherein the non-ocular region
is a popliteal region of the human subject.
19. The method according to claim 1 wherein said step of exposing
the non-ocular region is used to treat a circadian rhythm sleep
disorder.
20. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat the circadian rhythm sleep
disorder resulting from transmeridian travel (jet-lag).
21. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat Shift Work Sleep
Disorder.
22. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat Advanced Sleep Phase
Syndrome (ASPS).
23. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat Delayed Sleep Phase Syndrome
(DSPS).
24. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat Non-24-Hour Sleep-Wake
Disorder.
25. The method according to claim 19 wherein said step of exposing
the non-ocular region is used to treat Irregular Sleep-Wake
Pattern.
26. The method according to claim 1 wherein said step of exposing
the non-ocular region is used to treat sleep and circadian rhythm
disorders associated with blindness.
27. The method according to claim 1 wherein said step of exposing
the non-ocular region is used to treat sleep and circadian rhythm
disorders in individuals for whom ocular light exposure is
contraindicated.
28. A method of enhancing nighttime alertness and performance in a
human subject comprising the step of exposing a substantially
non-ocular region of the human subject to a non-solar photic
stimulation during one or more circadian cycles.
29. The method according to claim 28 wherein said step of exposing
the non-ocular region is used to enhance alertness and performance
of workers on rotating shift work schedules.
30. The method according to claim 28 wherein said step of exposing
the non-ocular region is used to enhance alertness and performance
of individuals working permanent work schedules.
31. The method according to claim 28 wherein said step of exposing
the non-ocular region lasts for a duration ranging from between
about 15 minutes to about 12 hours.
32. The method according to claim 28 wherein said non-solar photic
stimulation has an intensity between about 15 lux to about 150,000
lux.
33. The method according to claim 28 wherein said non-solar photic
stimulation has a bandwidth in the visible spectrum.
34. The method according to claim 28 wherein the non-ocular region
of the human subject has ample surface vaculature.
35. The method according to claim 28 wherein the non-ocular region
is a popliteal region of the human subject.
36. A method of resetting a human circadian clock comprising the
steps of: assessing a time when a minimum body temperature for a
human subject; and exposing a substantially non-ocular region of
the human subject to a non-solar photic stimulation for one or more
circadian cycles to reset the human circadian clock at an exposure
time dependent upon the assessed time.
37. The method according to claim 36 wherein said step of exposing
the non-ocular region begins before the assessed time.
38. The method according to claim 36 wherein said step of exposing
the non-ocular region begins about six hours prior to the assessed
time.
39. The method according to claim 36 wherein said step of exposing
the non-ocular region begins after the assessed time.
40. The method according to claim 39 wherein said step of exposing
the non-ocular region begins within six hours after the assessed
time.
41. The method according to claim 36 wherein said step of exposing
the non-ocular region occurs while the human subject is awake.
42. The method according to claim 36 wherein said step of exposing
the non-ocular region occurs while the human subject is asleep.
43. The method according to claim 36 wherein said step of exposing
the non-ocular region lasts for a duration ranging from between
about 15 minutes to about 12 hours.
44. The method according to claim 43 wherein the duration of said
non-ocular exposure is about three hours.
45. The method according to claim 36 wherein said non-solar photic
stimulation has an intensity between about 15 lux to about 150,000
lux.
46. The method according to claim 45 wherein said non-solar photic
stimulation has an intensity between about 10,000 lux to about
13,000 lux.
47. The method according to claim 36 wherein said non-solar photic
stimulation has a bandwidth in the visible spectrum.
48. The method according to claim 47 wherein said non-solar photic
stimulation has a bandwidth between about 455 nm and 540 nm .
49. The method according to claim 36 wherein the number of
circadian cycles is one.
50. The method according to claim 36 wherein the number of
circadian cycles is two or more.
51. The method according to claim 36 wherein the non-ocular region
of the human subject has ample surface vasculature.
52. The method according to claim 51 wherein the non-ocular region
is a popliteal region of the human subject.
Description
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/656,409 filed Sep. 6, 2000, which is a
divisional of U.S. patent application Ser. No. 09/074,455, filed
May 7, 1998, now U.S. Pat. No. 6,135,117, which claims the benefit
of U.S. Provisional Application No. 60/046,188 filed May 12, 1997,
and U.S. Provisional Application No. 60/072,121 filed Jan. 22,
1998.
BACKGROUND OF THE INVENTION
[0003] 1. Field of the Invention
[0004] This invention relates to a method for resetting the phase
of the human circadian clock and for enhancing alertness and
performance in humans by application of non-solar photic
stimulation, in the range of 15 to 150,000 lux, to any non-ocular
region of the human body.
[0005] 2. Related Art
[0006] As with all vertebrates, humans exhibit temporal
organization in behavior and in numerous physiological functions.
In response to the natural alternation in light and dark, virtually
all species have developed endogenous rhythms with frequencies
close to 24 hours. These internally generated, self-sustaining
rhythms are known as circadian rhythms (from the Latin circa=about,
and dies=day). The pervasive nature of such rhythms suggests that
circadian temporal organization is vital to the overall well-being
of the organism. Numerous systems and functions are mediated by the
circadian system including hormonal output, body temperature, rest
and activity, sleep and wakefulness, and motor and cognitive
performance. In all, literally hundreds of circadian rhythms in
mammalian species have been identified.
[0007] Left to run at its inherent frequency, the human biological
clock that is responsible for the generation of circadian rhythms
exhibits a daily periodicity of slightly longer than 24 hours.
Thus, a daily correction to the clock must be made for our internal
rhythms to remain synchronized or `entrained` to the natural 24
hour day. It is widely accepted that exposure to the natural
light/dark cycle provides the strongest signal to entrain the human
circadian system to the geophysical day. Inadequate exposure to
light of sufficient intensity is a contributing factor in disorders
associated with biological rhythm disturbance, such as seasonal
affective disorder (SAD), jet lag from transmeridian travel, shift
work and some types of insomnia (advanced and delayed sleep phase
syndromes). Timed exposure to artificial bright light to the eyes
has been used successfully to treat such disorders. Some examples
of studies relating to the effects of timed ocular exposure to
artificial bright light are discussed in U.S. Pat. Nos. 5,167,228
and 5,176,133 to Czeisler, which are herein incorporated by
reference.
[0008] There is compelling evidence that bright ambient
illumination on the eyes can have an immediate, acute enhancing
effect on alertness and performance. By way of example, the article
entitled, "Enhancement of Nighttime Alertness and Performance with
Bright Ambient Light" by Scott S. Campbell and Drew Dawson in
Physiology & Behavior Vol. 48, pp. 317-320, 1990, demonstrates
that ocular exposure to illumination of about 1,000 lux enhances a
human's alertness and performance. This non-circadian property of
light exposure is of particular relevance to people who must work
night or rotating shift work schedules, since declines in alertness
and performance may result in increased accident rates, reduced
productivity and increased health care costs.
[0009] It is widely accepted that the mammalian circadian clock
which is located in the brain, within the suprachiasmatic nuclei
(SCN) of the hypothalamus, receives photic information via the
eyes, by visual and/or non-visual ocular pathways originating in
the retina. It is also widely acknowledged that light acts to
enhance alertness and performance via an ocular route(s). Yet, it
has been recognized for decades that many species of birds and
reptiles possess extra-ocular photoreceptors, and it has been
demonstrated that circadian and photoperiodic response to light can
be mediated entirely by such photoreceptors. In contrast, it is
generally assumed that such nonvisual circadian photoreceptors in
mammals reside within the retina, and that mammals do not possess
the capacity for extraocular circadian photoreception. This
conclusion is based on studies showing a failure of several rodent
species to entrain to a light/dark cycle, or to respond to pulses
of light with shifts in circadian phase, following complete optic
enucleation.
[0010] Perhaps because of the widespread acceptance of the notion
that mammals have no capacity for extraocular circadian
photoreception, only two studies have examined whether extraocular
light exposure can impact brain functioning in humans. In a study
of blind subjects, Czeisler and coworkers found an absence of
light-induced melatonin suppression during ocular shielding in two
individuals who did show melatonin suppression when light fell on
their eyes. A decade earlier, Wehr and coworkers reported a lack of
clinical response in seasonal affective disorder when patients'
skin (face, neck, arms and legs) was exposed to a bright light
stimulus (2500 lux) while their eyes were shielded. No study has
examined specifically whether circadian phase resetting can be
achieved in humans via extraocular pathways.
[0011] As noted above, ocular exposure to timed bright light has
been shown to be an effective remedy for circadian rhythm
disorders. Unfortunately, treatment regimens involving ocular
exposure to bright light are tedious and time-consuming. Many
patients are simply unwilling or unable to remain relatively
stationary for extended periods gazing at a bright light
stimulus.
[0012] Additionally, the nature of the phase response curve to
light dictates that the largest shifts, both advances and delays,
are achieved at times during which people are typically asleep.
Thus, all but the most committed users of bright light treatments
fail to benefit from the most efficient temporal application of the
intervention. Attempts have been made to remedy these problems by
the development of `light visors`, which are devices worn like a
cap that are intended to permit the user more freedom of movement
while receiving light exposure. In practice, such devices are
likely to be poorly received since they also direct light toward
the eyes, and therefore, limit the visual field.
[0013] Also, as noted above, ocular light exposure has been
demonstrated to improve alertness and performance. Unfortunately,
as with circadian clock resetting, the use of ocular light in this
capacity has considerable drawbacks. By way of example, the
implementation of bright ambient light is likely to be impractical
for use in typical industrial control room settings. Rapidly
increasing utilization of computer technology for monitoring and
controlling plant operations calls for ambient lighting conditions
that take into consideration the effects of glare and contrast on
computer displays.
[0014] In summary, because light must still enter through the eyes,
unrestricted vision cannot be achieved, and mobility is limited.
Simply, any device that successfully gets light to the eyes, is
likely to interfere with normal activities. The result is reduced
compliance and limited effectiveness of light treatment
interventions as currently applied.
SUMMARY OF THE INVENTION
[0015] The present invention is a method for resetting the phase of
the human circadian clock, or enhancing alertness and performance
in humans, by application of non-solar photic stimulation, in the
range of 15 to 150,000 lux, to any non-ocular region of the human
body. Preferably, the non-solar photic stimulation is
substantially, if not solely, applied to a non-ocular region or
regions. While there is substantial evidence that the human
circadian clock can be reset with light exposure to the eyes, this
is the first demonstration that circadian clock resetting can be
achieved via non-ocular phototransduction.
[0016] The present invention is premised on the unexpected result
that substantially non-ocular presentation of appropriately timed
light in humans can induce circadian clock resetting. Specifically,
bright light transmitted through the skin, in a manner that rules
out the possibility of ocular photoreception, results in
significant clock resetting. A systematic relationship exists
between the timing of the non-ocular light stimulus and the
magnitude and direction of phase shifts, resulting in a phase
response curve. This unexpected result also underlies another
component of the present invention--that non-ocular light exposure
enhances alertness and performance. That is, it is reasonable to
conclude that non-ocular light exposure has the same physiological
consequences as ocular exposure whether impacting on the biological
clock, or on other brain areas involved in maintenance of optimal
alertness and performance.
[0017] These methods provide a number of advantages over the way in
which ocular light exposure is applied for the purposes of
resetting the circadian clock and enhancing alertness and
performance. For example, non-ocular light can be administered in
much less obtrusive ways by not restricting vision and mobility;
patients are not required to remain stationary and to stare at
lights for extended periods. Likewise non-ocular light removes the
inconvenience and potential hazards associated with glare and eye
fatigue. Another advantage of the invention is that non-ocular
light exposure can be used by individuals for whom ocular light
exposure is contraindicated. This group includes, but is not
restricted to, individuals with glaucoma, corneal pathology,
progressive retinal disease and cataracts. In addition, it is clear
that blind individuals, with no ocular light perception, could
benefit considerably from non-ocular light treatments, since many
of these individuals are unable to remain synchronized to the
environmental light/dark cycle.
[0018] Perhaps the most important advantage of this invention is
that it enables light treatments to be administered during sleep.
The nature of the phase response curve to light in humans dictates
that the largest shifts, both advances and delays, are achieved at
times during which people are typically asleep. That is, phase
delays occur when light is administered during the late subjective
night (within a several-hour window prior to the daily minimum in
body temperature), whereas phase advances are achieved when light
exposure occurs during the early subjective morning (within a
several-hour window following the daily minimum in body
temperature). One advantage of the invention is that it permits
delivery of non-ocular light near the temperature minimum without
requiring wakefulness, thus insuring maximum phase shifting.
[0019] One embodiment of the invention is a method for resetting
the human circadian clock, comprising the steps of exposing the
popliteal region of an awake human subject to light at preselected
times based on the human phase response curve to non-ocular light.
The result is a rapid phase delay or advance with the intention of
resetting the circadian clock to the desired new phase.
[0020] Another embodiment of the invention is a method for
resetting the human circadian clock, comprising the steps of
exposing any non-ocular region of an awake human subject to light
at preselected times based on the human phase response curve to
non-ocular light. The result is a rapid phase delay or advance with
the intention of resetting the circadian clock to the desired new
phase.
[0021] Another embodiment of the invention is a method for
resetting the human circadian clock, comprising the steps of
exposing the popliteal region of a sleeping human subject to light
at preselected times based on the human phase response curve to
non-ocular light presented during sleep. The result is a rapid
phase delay or advance with the intention of resetting the
circadian clock to the desired new phase.
[0022] Another embodiment of the invention is a method for
resetting the human circadian clock, comprising the steps of
exposing any non-ocular region of a sleeping human subject to light
at preselected times based on the human phase response curve to
non-ocular light presented during sleep. The result is a rapid
phase delay or advance with the intention of resetting the
circadian clock to the desired new phase.
[0023] Another embodiment of the invention is a method for
enhancing alertness and/or performance, comprising the steps of
exposing the popliteal region of an awake human subject to light at
times when enhanced alertness and/or performance is desired. The
result is an immediate and acute increase in subjective and
physiological levels of alertness and performance.
[0024] Another embodiment of the invention is a method for
enhancing alertness and/or performance, comprising the steps of
exposing any non-ocular region of an awake human subject to light
at times when enhanced alertness and/or performance is desired. The
result is an immediate and acute increase in subjective and
physiological levels of alertness and performance.
[0025] Another embodiment of the invention is an apparatus that can
advantageously administer light to a non-ocular region of a human.
The apparatus may be a stationary device such as a fiber optic
phototherapy system, or it may be a portable device, such as a
battery-powered light emitting diode (LED) array.
BRIEF DESCRIPTION OF THE DRAWINGS
[0026] FIG. 1 is a perspective view of a device used to expose a
non-ocular region of a human subject to light in order to reset the
circadian clock or enhance alertness and/or performance, using the
method in accordance with the present invention;
[0027] FIGS. 2A and 2B are graphs illustrating a delay in the
circadian phase marker of minimum body temperature in one human
subject induced using the method in accordance with the present
invention;
[0028] FIGS. 3A and 3B are graphs illustrating an advance in the
circadian phase marker of minimum body temperature in one human
subject induced using the method in accordance with the present
invention;
[0029] FIG. 4A is a graph illustrating the response of the
endogenous circadian clock as measured by body temperature in a
group of human subjects, induced by a single three-hour
presentation of bright light to the popliteal region of subjects
using the method in accordance with the present invention;
[0030] FIG. 4B is a graph illustrating the response of the
endogenous circadian clock as measured by dim-light melatonin onset
in a group of human subjects induced by a single three-hour
presentation of bright light to the popliteal region of subjects
using the method in accordance with the present invention;
[0031] FIG. 4C is a graph illustrating the response of the
endogenous circadian clock as measured by body temperature, in a
group of human subjects, to a sham experimental condition (no light
presented);
[0032] FIG. 5A is a graph illustrating nighttime temperature
profiles of one human subject before (dotted line) and after (solid
line) three hours of exposure to a 10,000 lux, broad-band white
light stimulus presented to the popliteal region between 2400 h and
0300 h on one occasion;
[0033] FIG. 5B is a graph illustrating nighttime melatonin onsets
of one human subject before (dotted line) and after (solid line)
three hours of exposure to a 10,000 lux, broad-band white light
stimulus presented to the popliteal region between 2400 h and 0300
h on one occasion;
[0034] FIGS. 6A and 6B are graphs illustrating a delay in the
circadian phase marker of minimum body temperature in one sleeping
human subject induced using the method in accordance with the
present invention; and
[0035] FIGS. 7A and 7B are graphs illustrating an advance in the
circadian phase marker of minimum body temperature in one sleeping
human subject induced using the method in accordance with the
present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0036] A method for resetting the phase of the human circadian
clock and for enhancing alertness and performance in humans is
disclosed. The method involves the application of non-solar photic
stimulation to any non-ocular region of the human body. The
preferred embodiment of the invention involves non-ocular exposure
to light in a range from about 15 minutes to about 12 hours, and
most preferably for a duration of 3 hours. Preferably the photic
stimulation has an intensity in the range of 15 to 150,000 lux, and
most preferably in a range from 10,000 to 13,000 lux. Preferably,
the photic stimulation has a wavelength within the visible spectrum
(.about.400-750 nm), and most preferably within the blue-green
bandwidth (.about.455-540 nm). Preferably, the non-solar photic
stimulation is substantially, if not solely, applied to a
non-ocular region or regions. The method can be used on a sleeping
human subject. The method can be used to both delay and advance the
circadian clock according to a phase response curve (PRC). The
method may also be used for acute/immediate enhancement of
alertness and performance. The method is applicable to alleviation
of problems associated with circadian rhythm sleep disorders, such
as with "jet-lag" from transmeridian travel, shift work sleep
disorder, advanced sleep phase syndrome, delayed sleep phase
syndrome, non-24 hour sleep-wake disorder, irregular sleep-wake
pattern, circadian rhythm disorders associated with blindness,
circadian rhythm disorders in individuals for whom ocular light
exposure is contraindicated, and other sleep disturbances involving
misalignment of circadian rhythms. The method provides a novel
technique for shifting the phase of the circadian clock, and
enhancing alertness and performance, using existing, or
newly-developed devices.
[0037] Empirical Basis for Clock Resetting with Non-Ocular Light
Exposure
[0038] Circadian rhythms are endogenously generated oscillations of
about twenty-four hours that provide temporal structure to a wide
range of behavioral and physiological functions. Because the
endogenous clock tends to run at a period close to, but not exactly
24 hours, a daily adjustment is required to synchronize, or entrain
circadian rhythms to the external environment. The natural
light/dark cycle is the most important signal for ensuring such
entrainment, and many vertebrate and non-vertebrate species possess
multiple photoreceptor systems through which circadian entrainment
may be achieved. In the house sparrow, for example, three discrete
input pathways for light to act on the circadian system have been
identified. Similarly, a number of fish, amphibian and reptile
species have extraocular and extrapineal pathways for circadian
light transduction. Indeed, a host of species possess functional
extraocular pathways for circadian entrainment by light, even in
the presence of ocular photoreceptors that are capable of mediating
the entraining influence of light.
[0039] In recent years, it has been suggested that the
photoreceptors responsible for entraining the mammalian biological
clock may not be the same cells that mediate vision. It has been
shown, for example, that mice homozygous for the autosomal
recessive allele rd ("retinally degenerate"), with no
electrophysiological or behavioral visual responses to bright
light, can be entrained to a light/dark cycle. Likewise, bright
light exposure suppresses melatonin output in some totally blind
human subjects, despite the fact that they have no conscious light
perception and no pupillary light reflex. Such findings support the
hypothesis that all vertebrates, including mammals, have
specialized nonvisual photoreceptors that mediate circadian
responses to the light-dark cycle. It is generally assumed,
however, that such nonvisual circadian photoreceptors in mammals
reside within the retina, and that mammals do not possess the
capacity for extraocular circadian photoreception. This conclusion
is based on studies showing a failure of several rodent species to
entrain to a light/dark cycle, or to respond to pulses of light
with shifts in circadian phase, following complete optic
enucleation.
[0040] Perhaps because of the widespread acceptance of the notion
that mammals have no capacity for extraocular circadian
photoreception, only two studies have examined whether extraocular
light exposure can impact brain functioning in humans. In their
study of blind subjects, Czeisler and coworkers found an absence of
light-induced melatonin suppression during ocular shielding in two
of their subjects who did show melatonin suppression when light
fell on their eyes. A decade earlier, Wehr and coworkers reported a
lack of clinical response in seasonal affective disorder when
patients' skin (face, neck, arms and legs) was exposed to a bright
light stimulus (2500 lux) while their eyes were shielded. Detailed
examination of the methods used in these studies makes it clear
that they did not adequately test the ability of the human
circadian timing system to respond to non-ocular light; in neither
study was the output of the circadian clock actually measured.
Likewise, there are problems of interpretation in most studies
using non-human mammals. Furthermore, the comparative literature on
circadian rhythms indicates that in a vast majority of instances,
there is no fundamental difference in the manner in which mammalian
and non-mammalian species respond to manipulations of the circadian
clock. For these reasons, we decided to re-examine the issue of
extraocular photoreception in humans.
[0041] Method for Non-Ocular Circadian Clock Resetting in
Humans
[0042] Set forth below are some examples of using the method to
reset the circadian clock in human subjects via a non-ocular
pathway. The first two examples involve subjects who were awake
during the non-ocular light exposure interval; the third example
describes effects of non-ocular light exposure in sleeping
subjects.
EXAMPLE 1
[0043] A total of 33 phase-shifting trials was carried out in 15
healthy subjects (mean age: 35.7 years; range: 22-67; 13 males, 2
females). Each laboratory session lasted for four consecutive days
and nights, during which subjects were assigned randomly to either
a control or an active condition. Successive laboratory visits were
separated by at least 10 days. During the active sessions (phase
delay, n=13; phase advance, n=11), light was presented at varying
times relative to baseline circadian phase, in order to examine the
response of the circadian clock throughout the 24-hour circadian
cycle. A circadian cycle is one complete cycle of a circadian
variable, such as body temperature. Under normal conditions a
circadian cycle is about twenty-four hours. Light can be applied
during one or more circadian cycles. The extraocular light stimulus
in this example comprised a 3-hour pulse of light presented to the
popliteal region, the area directly behind the knee joint.
[0044] In this particular example, the light source 10 was a
BiliBlanket Plus (Ohmeda, Inc.), a fiber optic phototherapy device
commonly used for home treatment of hyperbilirubinemia, as shown in
FIG. 1. The light source 10 includes a halogen lamp (not shown) in
a vented metal housing 12, which also contains a small fan to
disperse heat generated by the lamp. Illumination from the halogen
bulb leaves the housing 12 via 2400 optic fibers encased in a
flexible plastic tube 14 about one meter (m) in length. The optic
fibers terminate in a 4".times.6" woven pad 16 approximately 0.25"
thick. Because the light source 10 is remote, the fiber optic pad
16 generates no heat. The pad 16 was placed over the popliteal area
of each leg which has ample surface vasculature and secured in
place with a polyester athletic knee brace. During the 3-hour light
exposure interval, subjects remained seated in a reclining chair,
with a table positioned over their laps.
[0045] To ensure that the light stimulus did not reach the retina,
a 10'.times.10' black, opaque, double thickness polyester "skirt"
was draped over the table, reaching the floor on all sides, and was
secured with Velcro around the subject's waist. An exhaust fan (in
addition to those in each BiliBlanket housing) was placed beneath
the skirt to evacuate any heat produced by the halogen light
source. The lamp housing 12 was placed beneath the table and under
the skirt, so that any light escaping through the housing vents was
obscured from the subject's eyes. Illumination at the subject's eye
level never exceeded 20 lux. Accordingly, the illumination from
light source 10 is substantially applied to a non-ocular region.
Throughout their stay in the laboratory, when not sleeping and not
involved in the experimental light manipulation, subjects were
maintained in constant illumination of less than 50 lux.
[0046] Each light source 10 provided approximately 13,000 lux to
the popliteal region in a bandwidth between approximately 455 and
540 nm. Although in this example one type of light source 10
operating within a particular bandwidth and at a particular
intensity is disclosed, other types of light systems with other
bandwidths and other intensities, such as broad-band white light
provided by commercial fluorescent light boxes, may be used as
needed or desired (see Example 2, below).
[0047] On the night prior to (night 1 in the lab) and the nights
following the light stimulus (nights 3 and 4) subjects were
required to remain in bed (and were allowed to sleep) from 2400 h
until noon the following day. On the light exposure night (night 2
in the lab) sleep was necessarily displaced to accommodate
presentation of the 3-hour light pulse. With the exception of this
interval, subjects were in bed from 2400 h until noon on night 2,
as well. Sleep was not permitted during the light exposure interval
and continuous EEG and video monitoring of subjects throughout the
exposure interval ensured compliance.
[0048] Body core temperature was recorded continuously. In a subset
of sessions (n=18), hourly saliva samples were also collected for
melatonin assay. Body core temperature was recorded in 2-minute
epochs, using disposable rectal thermistors (Yellow Springs, Inc.)
attached to MiniLogger ambulatory recording devices (Mini-Mitter,
Inc., Sun River, Oreg.). Saliva samples were collected under dim
light from 1800 h until 2400 h on night 2 (prior to light exposure)
and on night 4.
[0049] Melatonin levels were measured by radioimmunoassay (ALPCO,
Inc., Windham, N.H.) using the Kennaway G280 antibody. All samples
from a given subject during a given laboratory session were
analyzed in the same assay. We have calculated an intraassay
coefficient of variation of 2.1%; the inter-assay precision has
been reported as 10.4%.
[0050] The nadir of the temperature rhythm and the dim light
melatonin onset (DLMO) were used to evaluate circadian phase prior
to and following presentation of the light pulse. The magnitude of
phase shift achieved in each trial was determined by comparing
subjects' baseline circadian phase (during the first 24 hours in
the lab), with phase determined during the final 24 hours in the
lab.
[0051] Referring to FIGS. 2A and 2B, an example of a delay in
circadian phase in one subject in response to a 3-hour bright light
presentation to the popliteal region is illustrated. Light was
presented on one occasion between 0100 h and 0400 h on night 2 in
the laboratory (black bar) while the subject (a 29 year-old male)
remained awake and seated in a dimly lit room (ambient
illumination<20 lux). Circadian phase was determined by fitting
a complex cosine curve (dotted line) to the raw body core
temperature data (solid line). Resulting phase estimates are
indicated by vertical dotted lines. Baseline (night 1) circadian
phase occurred at 0404 h as shown in FIG. 2A; circadian phase
following light presentation (last 24 hours in the lab) occurred at
0708 h as shown in FIG. 2B. The phase angle between the mid-point
of the light stimulus and the fitted body temperature minimum at
baseline was 1.57 hours. The resulting phase delay was 3.06
hours.
[0052] Referring to FIGS. 3A and 3B, an example of an advance in
circadian phase in one subject in response to a 3-hour bright light
presentation to the popliteal region is illustrated. Light was
presented on one occasion between 0600 h and 0900 h, following
night 2 in the laboratory (black bar) while the subject (a 44
year-old male) remained awake and seated in a dimly lit room
(ambient illumination<20 lux). Circadian phase was determined by
fitting a complex cosine curve (dotted line) to the raw body core
temperature data (solid line). Resulting phase estimates are
indicated by vertical dotted lines. Baseline (night 1) circadian
phase occurred at 0713 h as shown in FIG. 3A; circadian phase
following light presentation (last 24 hours in the lab) occurred at
0453 h as shown in FIG. 3B. The phase angle between the mid-point
of the light stimulus and the fitted body temperature minimum at
baseline was 0.28 h. The resulting phase advance was 2.34
hours.
[0053] Response of the endogenous circadian pacemaker, as measured
by body core temperature to a single 3-hour presentation of bright
light to the popliteal region is illustrated in FIG. 4A. Each point
represents the phase shift observed (advances are designated by
positive numbers, delays by negative numbers on the y-axis) in
response to bright light presented at a given time relative to the
phase of body core temperature at baseline. "Timing of light
relative to Tmin" (x-axis) refers to the interval between the
mid-point of light presentation and the fitted temperature minimum.
Magnitude of the observed phase shifts varied systematically as a
function of this relationship, resulting in the generation of a
classic phase response curve.
[0054] In 18 of trials, the phase response of a second circadian
marker, the onset of the endogenous melatonin rhythm under dim
light conditions (DLMO) was assessed. The results of these
assessments are shown in FIG. 4B. Each point represents the phase
shift observed (advances are designated by positive numbers, delays
by negative numbers on the y-axis) in response to bright light
presented at a given time relative to the phase of body core
temperature at baseline.
[0055] "Timing of light relative to Tmin" (x-axis) refers to the
interval between the mid-point of light presentation and the fitted
temperature minimum. As with body temperature, the timing of human
subjects' nightly melatonin onset was shifted by the non-ocular
light stimulus according to a phase response curve. The direction
and magnitude of the shifts in DLMO were equivalent to those for
temperature. Indeed, there was a significant correlation between
the shift in body core temperature and the shift in melatonin onset
(Spearman rank-order correlation: rho=0.704; P=0.009). The strong
correlation between the two phase markers employed strongly
suggests that the non-ocular light stimulus directly influenced the
endogenous circadian clock and not simply the output variables.
[0056] The phase shifts in the active sessions were the consequence
of the light administration, and not systematically influenced by
the experimental procedure itself. In the control condition,
subjects underwent the identical protocol as in the delay
condition, including application of the fiber optic pad and
activation of the exhaust fans. However, in the control condition,
the halogen bulb providing illumination to the optic pad was
disconnected. Because in all conditions the light source was not
turned on until they were seated and an opaque "skirt" was in
place, subjects were unaware of whether light was actually being
presented during a given session. Comparison of the phase of body
temperature at baseline and following the control manipulation
revealed no systematic phase shifts as a result of exposure to this
protocol, as illustrated in FIG. 4C. Each point represents the
change in phase following the control stimulus compared to baseline
temperature phase. All no-light presentations occurred prior to
baseline temperature minimum and therefore only that portion of the
x-axis is shown.
[0057] Selection of the popliteal region for the site of light
exposure in this study ensured (for methodological control) that
light would not reach the retina. There is every reason to believe
that timed light exposure presented to any non-ocular area of the
body with adequate surface vasculature would result in similar
circadian phase resetting.
EXAMPLE 2
[0058] In another example, six subjects (mean age 45.4 yrs; range,
30-71 yrs) were used to examine effects of non-ocular circadian
clock resetting. As in Example 1, the popliteal region (the area
directly behind the knee joint), was the site for the non-ocular
light administration.
[0059] Illumination was provided by a light box (Apollo, Inc., Orem
Utah) situated directly beneath the exposed knees (i.e. subjects
wore short pants) of a subject sitting upright in a comfortable
chair. At a distance of 18 inches, the light source provided about
10,000 lux illumination. The subjects' eyes were shielded from
illumination by a blackout `skirt` secured around the seated
subject at the level of the rib cage, and extending to the floor
surrounding the light. There was no other light source in the room
besides the television situated 2 meters away from the subject and
providing less than 5 lux at eye level. The bright light stimulus
was presented from 2400 h to 0300 h.
[0060] For the group, the average phase delay was 2.27 hrs in
response to the non-ocular bright light stimulus. Four of the 5
subjects showed a delay, with phase-shifts ranged from 1.8 hrs to
4.7 hrs (one subject showed no phase-shift). FIG. 5A shows pre- and
post-temperature plots obtained from one subject. The effects of
the non-ocular light stimulus are apparent. This subject showed a
clear phase-delay.
[0061] In this study, we also measured salivary melatonin levels
collected each hour, beginning at 1800 h and continuing until
subjects' bedtimes. Thus, on the light exposure night, samples were
collected from 1800 h-0300 h; on the following day they were
collected from 1800 h to 2400 h. Melatonin profiles from the same
subject whose temperature is depicted in FIG. 5A, are shown in FIG.
5B. As with body temperature, nighttime melatonin onset showed a
substantial phase-delay when measured on the evening following the
3-hr bright light stimulus to the popliteal region.
EXAMPLE 3
[0062] In another example, non-ocular light was administered to 10
subjects while they were asleep. As in Examples 1 and 2, the
popliteal region (the area directly behind the knee joint), was the
site for the non-ocular light administration. Each laboratory
session lasted for four consecutive days and nights. Light was
presented at varying times relative to baseline circadian phase, in
order to examine phase response throughout the circadian cycle. The
extraocular light stimulus consisted of a pulse of light presented
to the popliteal region while subjects were sleeping. Subjects were
asleep during the non-ocular light presentation as verified by
conventional sleep laboratory techniques (electroencephalography).
The magnitude of phase shift achieved in each trial was determined
by comparing subjects' baseline circadian phase (during the first
24 hours in the lab), with phase determined during the final 24
hours in the lab.
[0063] Referring to FIGS. 6A and 6B, an example of a delay in
circadian phase in one subject (a 24 year-old male) in response to
a 1.25-hour bright light presentation to the popliteal region
during sleep is illustrated. Light was presented on two consecutive
days between 0930 h and 1045 h (black bar) in a darkened room.
Circadian phase was determined by fitting a complex cosine curve
(dotted line) to the raw body core temperature data (solid line).
Resulting phase estimates are indicated by vertical dotted lines.
Baseline (night 1) circadian phase occurred at 0336 h as shown in
FIG. 6A; circadian phase following light presentation (last 24
hours in the lab) occurred at 0517 h as shown in FIG. 6B. The phase
angle between the mid-point of the light stimulus and the fitted
body temperature minimum at baseline was 6.52 hours (i.e., light
was presented following the temperature minimum). The resulting
phase delay was 1.68 hours. There was a corresponding delay in the
onset of the melatonin rhythm (DLMO) of 1.87 hours.
[0064] Referring to FIGS. 7A and 7B, an example of an advance in
circadian phase in one subject (a 54 year-old male) in response to
a 3-hour bright light presentation to the popliteal region during
sleep is illustrated. Light was presented on two consecutive nights
between 0400 h and 0700 h, (black bar) in a darkened room.
Circadian phase was determined by fitting a complex cosine curve
(dotted line) to the raw body core temperature data (solid line).
Resulting phase estimates are indicated by vertical dotted lines.
Baseline (night 1) circadian phase occurred at 0725 h as shown in
FIG. 7A; circadian phase following light presentation (last 24
hours in the lab) occurred at 0545 h as shown in FIG. 7B. The phase
angle between the mid-point of the light stimulus and the fitted
body temperature minimum at baseline was -1.92 h (i.e., light was
presented prior to the temperature minimum). The resulting phase
advance was 1.67 hours.
EXAMPLE 4
[0065] Ocular exposure to light results in increased brain
electrical activity. When EEG data are collected during ocular
light exposure, then subjected to spectral analysis (Fast Fourier
Transform method), power density in the higher frequency ranges
(beta frequency band, approximately 21-32 Hz) is enhanced relative
to EEG activity during dim light exposure. This increase in beta
activity is indicative of higher levels of alertness, and has been
associated with increased levels of psychomotor and cognitive
performance. It is reasonable to assume that in the same manner as
non-ocular exposure results in phase shifts similar to those
achieved with ocular light pulses, non-ocular light exposure will
also affect EEG beta activity in a manner similar to ocular
exposure. The following example describes a pilot study that was
undertaken to determine whether non-ocular light exposure resulted
in acute increases in brain electrical activity.
[0066] Multiple samples of waking EEG data from one subject were
collected during exposure of the popliteal region to a non-ocular
light source, and during a control condition. In the control
condition, electrical power was provided to the light source, but
the halogen lamp providing illumination to the fiber optic cables
was unplugged. The subject (a 25-year-old female) was seated in a
dimly lit (<20 lux) room, with a double-thickness, black
polyester `skirt` fastened with Velcro around her waist. Two
Biliblanket phototherapy devices were attached to the popliteal
region of each leg as described earlier in Example 1. The devices
were placed underneath the `skirt` and behind the chair in which
the subject was seated. The halogen lamp was unplugged or plugged
in by the experimenter out of view of the subject. The black skirt
ensured that the subject was not aware of whether the light source
was activated or deactivated. The subject was instructed as
follows: "Sit as still as possible, with your feet on the floor and
arms at your side. Avoid any head or body movements and keep your
eyes closed. We will inform you when you may open your eyes." Two
EEG sites (C3 and 01) were referenced to linked mastoids;
impedances for all were below 2 k.OMEGA.. Three minute intervals of
EEG data were collected and digitized at a rate of 256 samples per
second. The three minute samples were collected in the following
order:
[0067] A) Eyes closed, light source activated.
[0068] B) Eyes closed, light source deactivated.
[0069] C) Eyes closed, light source deactivated.
[0070] D) Eyes closed, light source activated.
[0071] The average of the data from conditions A+D (light source
`on`) and B+C (light source `off`) were used to investigate the
effects of non-ocular light on EEG activity. After removal of
visually detected eyeblink and muscle artifact, the data set from
each of the conditions were subjected to spectral analysis (FFT),
yielding the average power density (.mu.V.sup.2), in 2-second
epochs. Both absolute and relative power density in predefined
frequency bands (delta=1.54 Hz, theta=4-7 Hz, alpha=8-13 Hz,
beta1=13-20 Hz, beta2=21-32 Hz) were calculated.
[0072] Total absolute power was higher when the non-ocular light
source was activated relative to the control condition (15.4 vs.
10.6_V.sup.2 for site C3; 11.8 vs 6.6_V.sup.2 for site 01).
Relative power in the alpha (16.1 vs 17.2 for site C3; 23.9 vs 24.0
for site 01) and theta (15.1 vs 15.2 for site C3; 11.5 vs. 10.4 for
site 01) frequency bands did not differ between lights on and
lights off conditions. However, delta power was substantially lower
(24.0 vs. 31.6, while activity in both the low and high beta
frequency bands was higher (23.5 vs. 17.4 for B1 at site C3; 23.7
vs. 19.6 for B1 at site 01; 22.7 vs. 18.0 for B2 at site C3; 27.0
vs. 22.2 for B2 at site 01) when the lights were activated.
[0073] These preliminary results indicate that non-ocular light
exposure, even when the eyes are completed shielded from the light
stimulus, may result in EEG activation at frequencies associated
with higher alertness.
[0074] Devices for Facilitating the Method
[0075] The method described herein requires that a human subject be
exposed to a non-ocular light source under conditions sufficient to
reset the human circadian clock, or to acutely enhance alertness
and performance. The device originally used to reduce the method to
practice, as described in the examples above, can be altered in a
number of ways to facilitate various applications of the method.
The invention envisions several different means by which the light
may be transmitted, including fiber optic configurations, light
emitting diode (LED) arrays, bioluminescent derivations, and
incandescent and fluorescent light sources.
[0076] The invention envisions the use of these various light
sources designed to facilitate light exposure to a wide range of
non-ocular sites. For example, a device is envisioned by which the
foot or hand is covered (like a sock or glove), thereby exposing
the entire area to illumination; another device is one by which the
tympanic membrane is illuminated by LEDs incorporated in headphones
or earplugs; another device is one by which the midriff is exposed
to light by an illuminated wrap; another device is envisioned in
which the source of illumination is not worn by the subject but
illuminates a non-ocular site, for example, partially-illuminated
bed linens.
[0077] Energy to operate the aforementioned devices may be provided
by a variety of power sources that would enable the devices to be
stationary or portable, for example a standard AC outlet or a
battery.
[0078] We have described a variety of specific embodiments of the
invention, but the method and device are not limited to these
embodiments. The claims set forth below incorporate the full scope
and definition of the invention.
* * * * *