U.S. patent application number 16/830218 was filed with the patent office on 2020-07-16 for method and apparatus for determining circadian input.
The applicant listed for this patent is PROGRESSIVE LINGHTING AND RADIOMETRICS, LLC.. Invention is credited to George BRAINARD, Gena Glickman.
Application Number | 20200222716 16/830218 |
Document ID | / |
Family ID | 26898501 |
Filed Date | 2020-07-16 |
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United States Patent
Application |
20200222716 |
Kind Code |
A1 |
BRAINARD; George ; et
al. |
July 16, 2020 |
METHOD AND APPARATUS FOR DETERMINING CIRCADIAN INPUT
Abstract
A method and apparatus for determining the circadian input of a
light source includes selecting a circadian input to be measured
based on an action spectrum corresponding to a wavelength
sensitivity of photoreceptors for a circadian regulation system,
where the circadian input is configured to stimulate a
retinaldehyde photopigment, and for measuring spectral intensity
across the action spectrum to determine the circadian input of the
light source.
Inventors: |
BRAINARD; George;
(Haddonfield, NJ) ; Glickman; Gena; (San Diego,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
PROGRESSIVE LINGHTING AND RADIOMETRICS, LLC. |
Haddonfield |
NJ |
US |
|
|
Family ID: |
26898501 |
Appl. No.: |
16/830218 |
Filed: |
March 25, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14273971 |
May 9, 2014 |
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16830218 |
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13756401 |
Jan 31, 2013 |
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14273971 |
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12657533 |
Jan 22, 2010 |
8366755 |
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13756401 |
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09853428 |
May 10, 2001 |
7678140 |
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12657533 |
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60228493 |
Aug 28, 2000 |
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60203308 |
May 10, 2000 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 5/06 20130101; A61N
2005/0667 20130101; A61N 2005/0627 20130101; A61N 2005/0666
20130101; A61N 2005/0642 20130101; A61N 2005/0662 20130101; A61N
5/0618 20130101; A61B 5/4848 20130101 |
International
Class: |
A61N 5/06 20060101
A61N005/06; A61B 5/00 20060101 A61B005/00 |
Goverment Interests
GOVERNMENT RIGHTS IN THE APPLICATION
[0002] This invention was made with government support under grants
from NIH ROINS36590 awarded by the National Institutes of Health;
NSBIR/NASA HPF.002.08 (to GCB) awarded by the National Space
Biology Research Institute in cooperation with the National
Aeronautics and Space Administration; NSF IBN9809916 awarded by the
National Science Foundation; and DOD RO7OHY (to MDR) awarded by the
Department of Defense. The government has certain rights in the
invention.
Claims
1-23. (canceled)
24. An apparatus comprising: a light system configured to emit
polychromatic light comprising an output spectrum in a visible
region of an electromagnetic spectrum, the output spectrum
comprising a spectral region having a band of wavelengths from 424
nanometers (nm) to 505 nm, and wherein a power distribution within
the output spectrum is such that a power emitted within said
spectral region is more than a power emitted in any other region of
equal bandwidth in the output spectrum.
25. The apparatus of claim 24, wherein the power distribution
within the output spectrum is such that the power emitted within
said spectral region is more than a power emitted by the entire
output spectrum outside the spectral region.
26. The apparatus of claim 24, further comprising a housing,
wherein the light system is further configured to emit the
polychromatic light from the housing.
27. The apparatus of claim 24, wherein the light system comprises a
light source configured to emit light and at least one filtering
component configured to filter the light emitted from the light
source to produce the polychromatic light emitted from the light
system.
28. The apparatus of claim 24, wherein the light system comprises a
light source configured to emit light and a transparent composition
configured to filter the light emitted from the light source to
produce the polychromatic light emitted from the light system.
29. The apparatus of claim 24, wherein the light system comprises a
light source configured to emit light and a translucent composition
configured to filter the light emitted from the light source to
produce the polychromatic light emitted from the light system.
30. The apparatus of claim 24, wherein the light system is further
configured to allow a user to attenuate the power emitted within
the spectral region to a level where the power emitted within said
spectral region is no longer more than the power emitted in said
any other region of equal bandwidth in the output spectrum.
31. The apparatus of claim 24, wherein the light system is further
configured to allow a user to attenuate the power emitted within
the spectral region more than the power emitted in said any other
region of equal bandwidth is attenuated.
32. An apparatus, comprising: a light system configured to emit
polychromatic light, the emitted polychromatic light comprising an
output spectrum in the visible region of the electromagnetic
spectrum, the output spectrum comprising a spectral region having a
band of wavelengths from 435 nanometers (nm) to 488 nm, and wherein
the light system is further configured to attenuate the spectral
region more than any other region of equal bandwidth in the output
spectrum.
33. The apparatus of claim 32, wherein the light system is further
configured to attenuate the spectral region more than the entire
output spectrum outside the spectral region.
34. The apparatus of claim 32, further comprising a housing,
wherein the light system is further configured to emit the
polychromatic light from the housing.
35. The apparatus of claim 32, wherein the light system comprises a
transparent composition having at least one filtering component
configured to attenuate the spectral region.
36. The apparatus of claim 32, wherein the light system comprises a
translucent composition having at least one filtering component
configured to attenuate the spectral region.
37. The apparatus of claim 32, wherein the light system is further
configured such that the spectral region without attenuation is
enhanced with respect to the said any other region.
38. The apparatus of claim 37, wherein the light system comprises
at least one filtering element that allows a user to adjust the
spectral region between the enhanced spectral region and the
attenuated spectral region.
39. An apparatus, comprising: a light system configured to emit
polychromatic light, the emitted polychromatic light comprising an
output spectrum in the visible region of the electromagnetic
spectrum, the output spectrum comprising a spectral region having a
band of wavelengths from 425 nanometers (nm) to 505 nm, and wherein
the light system is further configured to attenuate the spectral
region more than any other region of equal bandwidth in the output
spectrum.
40. The apparatus of claim 39, wherein the light system is further
configured to attenuate the spectral region more than the entire
output spectrum outside the spectral region.
41. The apparatus of claim 39, further comprising a housing,
wherein the light system is further configured to emit the
polychromatic light from the housing.
42. The apparatus of claim 39, wherein the light system comprises a
transparent composition having at least one filtering component
configured to attenuate the spectral region.
43. The apparatus of claim 39, wherein the light system comprises a
translucent composition having at least one filtering component
configured to attenuate the spectral region.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
14/273,971, filed May 9, 2014 which is presently pending, which is
a continuation of application Ser. No. 13/756,401, filed Jan. 31,
2013 which is abandoned, which is a continuation of application
Ser. No. 12/657,533, filed Jan, 22, 2010, now U.S. Pat. No.
8,366,755, which is a continuation of application Ser. No.
09/853,428, filed on May 10, 2001, now U.S. Pat. No. 7,678,140,
which claims the benefit of priority to U.S. Provisional
Application No. 60/228,493, filed on Aug. 28, 2000, and U.S.
Provisional Application No. 60/203,308, filed on May 10, 2000, all
of which are expressly incorporated by reference herein in their
entirety.
TECHNICAL FIELD
[0003] The present invention generally relates to the fields of
neurology, neuroscience, and endocrinology and to light systems,
light meters, lamps, filters, transparent and translucent
materials, and methods of treating a variety of mammalian disorders
and, more particularly to a light system for stimulating or
regulating neuroendocrine, circadian, and photoneural systems in
mammals based upon the discovery of peak sensitivity ranging from
425-505 nm; a light meter system for quantifying light which
stimulates mammalian circadian, photoneural, and neuroendocrine
systems; translucent and transparent materials, and lamps or other
light sources with or without filters stimulating or regulating
neuroendocrine, circadian, and photoneural systems in mammals; and
treatment of mammals with a wide variety of disorders or deficits,
including light responsive disorders, eating disorders, menstrual
cycle disorders, non-specific alerting and performance deficit,
hormone-sensitive cancers, and cardiovascular disorders.
BACKGROUND
[0004] Light is the primary stimulus for regulating circadian
rhythms, seasonal cycles, and neuroendocrine responses in many
species including humans (Klein et al., 1991; Wehr, 1991). Further,
clinical studies have demonstrated that light therapy is effective
for treating selected affective disorders, sleep problems, and
circadian disruptions (Wenerberg, 1993; Lam, 1998), Previously, the
ocular photoreceptors which transduce light stimuli for circadian
regulation and the clinical benefits of light therapy have been
unknown.
[0005] Nonetheless, scientists have been deeply involved in
elucidating the physiologic and functional anatomic features
associated with light and vision. In fact, the underlying
neuroanatomy and neurophysiology which mediate vision have been
studied extensively over the past two centuries. More recently, the
retinohypothalamic tract (RHT), a distinct neural pathway which
mediates circadian regulation by environmental light, has been
shown to project from the retina to the suprachiasmatic nuclei
(SCN) in the hypothalamus. (Moore RY, Leon NJ. A retinohypothalamic
projection in the rat. J Comp Neurol 146:1-14, 1972; Moore RY
(1983). Organization and function of a central nervous system
circadian oscillator: the suprachiasmatic hypothalamic nucleus.
Federation Proceedings 42:2783-2789; Klein DC, Moore RY, Reppert
SM, eds. Suprachiasmatic Nucleus: The Mind's Clock. Oxford: Oxford
University Press, 5-456, 1991; Morin LP (1994) The circadian visual
system, Brain Res Brain Res Rev 19:102-127). By this pathway, light
and dark cycles are perceived through the mammalian eyes, entrain
SCN neural activity and, in turn, entrain the rhythmic secretion of
melatonin from the pineal gland. In virtually all species,
melatonin secretion is high during the night and low during the day
(Reiter, 1991; Arendt, 1998).
[0006] In addition to entraining pineal rhythms, light exposure can
acutely suppress melatonin secretion (Rollag and. Niswender, 1976;
Lewy et al., 1980). A well-defined. multisynaptic neural pathway
extends from the SCN to the pineal gland, which transmits
information about light and circadian time for entraining the
rhythmic production and secretion of the hormone melatonin. (Moore
R Y, Lenn N J. J Comp Neurol 146:114, 1972; Klein DC et al., eds.
Suprachiasmatic Nucleus: The Mind's Clock, 5-456, 1991; Schwartz W
J, Busis N A, Hedley-Whyte ET. A discrete lesion of ventral
hypothalamus and optic chiasm that disturbed the daily temperature
rhythm. J Neural 233:1-4, 1986; Arendt J. Melatonin and the pineal
gland; influence on mammalian seasonal and circadian physiology.
Rev Reprod 3:13-22, 1998). In addition to synchronizing pineal
indolamine circadian rhythms, ocular exposure to light during the
night can acutely suppress melatonin synthesis and secretion (Klein
D C, Weller J L (1972) Rapid light-induced decrease in pineal
serotonin N- cetyltransferase activity. Science 177:532-533; Lewy A
J, Wehr T A, Goodwin F K, Newsome D A, Markey S P (1980) Light
suppresses melatonin secretion in humans. Science 210:1267-1269).
Light-induced melatonin suppression is a well-defined, broadly used
marker for photic input to the RHT and SCN (Klein D C, 1991; Arendt
J (1998) Melatonin and the pineal gland: influence on mammalian
seasonal and circadian physiology, Rev Reprod 3:13-22; Brainard G
C, Rollag M D, Hanifin J P (1997) Photic regulation of melatonin in
humans: ocular and neural signal transduction. J Bioi Rhythms
12:537-546; Lucas R J, Foster R G (1999) Neither functional rod
photoreceptors nor rod or cone outer segments are required for the
photic inhibition of pineal melatonin. Endocrinology
140:1520-1524).
[0007] Previously, it has not been known what photoreceptors
transduce light stimuli for circadian regulation. Studies on
animals with hereditary or light-induced retinal degeneration have
raised the possibility that neither the rods nor the cones used for
vision participate in light-induced melatonin suppression,
circadian locomotor phase-shifts, or photoperiodic responses
(Lucas, 1999; Webb S M, Champney T H, Lewinski A K, Reiter R1
(1985) Photoreceptor damage and eye pigmentation: influence on the
sensitivity of rat pineal N-acetyltransferase activity and
melatonin levels to light at night. Neuroendocrinology 40:205-209;
Goto M, Ebihara S (1990) The influence of different light
intensities on pineal melatonin content in the retinal degenerate
C3H mouse and the normal CBA mouse. Neurosci Lett. 108:267-272
Foster R G, Provencio I, Hudson D. Fiske S, DeGrip W, Menaker M
(1991) Circadian photoreception in the retinally degenerate mouse
(rd/rd). J Camp Physiol [A] 169:39-50; Freedman M S, Lucas R J,
Soni B, von Schantz M, Munoz M, David-Gray Z, Foster R G (1999)
Regulation of mammalian circadian behavior by non-rod, non-cone,
ocular photoreceptors. Science 284:502-504). Studies using rodents
with retinal degeneration suggest that neither the rods nor cones
used for vision participate in light-induced melatonin suppression,
circadian phase-shifts, or photoperiodic responses (Pevet et al.,
1984; Webb et al., 1985; Foster et al., 1991), Furthermore,
enucleation of rod-less, cone-less transgenic mice abolishes
light-induced circadian phase-shifts and melatonin suppression
(Lucas and Foster, 1999; Freedman et al., 1999). Recently,
light-induced melatonin suppression and circadian entrainment have
been demonstrated in humans with complete visual blindness
(Czeisler C A, Shanahan T L, Klennan E B, Martens H, Brotman D J,
Emens J S, Klein T, Rizzo J F, III (1995) Suppression of melatonin
secretion in some blind patients by exposure to bright light. (N
Engl J Med 332:6-11) and with specific color vision deficiencies.
(Ruberg, 1996). The study on humans with color vision deficiencies
showed that protanopic and deuteranopic subjects who lacked
functioning long wavelength-sensitive cones (red, or L cones), and
middle wavelength cone photoreceptors (green, or M cones),
exhibited normal light-induced melatonin suppression and
entrainment of the melatonin rhythm (Ruberg F L, Skene D J, Hanifin
J P, Rollag M D, English J, Arendt J, Brainard G C (1996) Melatonin
regulation in humans with color vision deficiencies. (J Clin
Endocrinol Metab 81:2980-2985). Thus, by themselves, neither the
red nor green cone system could be the primary input for melatonin
regulation, at least in humans with color vision deficiencies.
Together, the results from human and animal circadian studies on
different forms of visual blindness suggest that melatonin
regulation by light is controlled, at least in part, by
photoreceptors which differ from the photoreceptors that mediate
vision.
[0008] Recent studies with various vertebrate species have
identified several new molecules which may serve as circadian
photopigments. These putative photopigments include both
opsin-based molecules, such as vertebrate ancient (VA) opsin and
melanopsin, as well as non-opsin molecules like the cryptochromes
(Soni B G, Foster R G (1997) A novel and ancient vertebrate opsin.
FEBS Lett 406:279-283; Provencio I, Jiang G, De Grip W J, Hayes W
P, Rollag M D (1998) Melanopsin: an opsin in melanophores, brain,
and eye. Proc Natl Acad Sci USA 95:340-345; Miyamoto Y, Sancar A
(1998) Vitamin B2-based blue-light photoreceptors in the
retinohypothalamic tract as the photoactive pigments for setting
the circadian clock in mammals, (Proc Natl Acad Sci USA
95:6097-6102). Among these new photopigments, only melanopsin has
been specifically localized to the human retina. (Provencio I,
Rodriguez I R, Jiang G, Hayes WP, Moreira E F, Rollag M D (2000) A
novel human opsin in the inner retina. J Neurosci 20:600-605). The
molecular identification of these candidate photopigments and their
localization in the retina and/or neural components of the
circadian system make them well-suited to act as circadian
phototransducers. Functional data confirming their direct role in
circadian photoreception, however, have been lacking.
[0009] The present invention required determining whether or not
the three cone system, which supports photopic (daytime) vision,
was also the primary input for pineal melatonin suppression in
humans with normal, healthy eyes. The peak wavelength sensitivity
of the photopic visual system is near 555 nm. (Rodieck R W (1998)
The First Steps in Seeing, Sunderland, Mass.: Sinauer Associates,
Inc.). If melatonin regulation were mediated primarily by the three
cone photopic visual system, then 555 nm light would be the most
potent wavelength for regulating melatonin secretion.
[0010] In the present invention, data show that 505 nm is
approximately four times stronger than 555 nm in suppressing
melatonin. These results demonstrate that the ocular photoreceptor
primarily responsible for pineal melatonin regulation in humans, is
not the cone system that is believed to mediate photopic vision.
This present invention involved the first test of a specific
photoreceptor system for melatonin regulation in humans with
healthy, intact eyes.
[0011] Developing an action spectrum is a fundamental means for
determining the input physiology for the circadian system. This
photobiological technique has high utility for 1) defining the
relative effectiveness of photons at different wavelengths for
eliciting a biological response, and 2) identifying the specific
photopigment involved in that response. (Lipson, 1994; Coohill,
1999). The specific aim of the present study was to characterize
the wavelength sensitivity of the photoreceptor system responsible
for providing circadian input to the human pineal gland by
establishing an action spectrum for light-induced melatonin
suppression. The experiments defined an action spectrum that fits a
retinaldehyde opsin template and identified 446-477 nm as the most
potent wavelength region for regulating melatonin. Univariance
among the eight fluence-response curves suggests that a single
photopigment is primarily responsible for melatonin suppression.
These results suggest that there is a novel photopigment in the
human eye which mediates circadian photoreception.
Light as a Therapeutic Stimulus
[0012] Numerous studies have shown that environmental light is the
primary stimulus for regulating circadian rhythms, seasonal cycles,
and neuroendocrine responses in many mammalian species including
humans (Klein et al., 1991; Morin, 1994; Czeisler, 1995). During
the past 20 years, studies have tested the use of light for
treating fall and winter depression (Seasonal Affective Disorder or
SAD), nonseasonal depression, sleep disorders, menstrual
dysfunction, and eating disorders. In addition, investigators are
exploring the use of light for re-entraining human circadian
physiology relative to the challenge of shift work or
intercontinental air travel. A Congressional report estimated that
there are 20 million shift workers in the United States. (US
Congress, 1991). The two most common problems associated with shift
work are reduced alertness on the job and reduced sleep quality
after work. In addition, shift workers have increased health
problems including higher risk of cardiovascular disease and
gastrointestinal distress as well as cognitive and emotional
problems. Chronic desynchronization of the circadian system is
cited as one of the causes for these problems. (US Congress,
1991).
[0013] Light is known to be a potent stimulus for entraining and
phase-shifting circadian rhythms in many species, including humans.
(Czeisler et al., 1986; Klein et al., 1991). The circadian response
to light is dependent on the stimulus intensity, wavelength and
time of delivery. A phase-response curve (PRC) describes
light-induced shifts in rhythms relative to the circadian phase
when the light is given, and PRCs to light share similarities
across many species.
[0014] Working from the human PRC to light, some investigators have
tested strategies of light treatment to improve circadian
entrainment thereby enhancing performance, alertness, and health in
shift workers. Studying simulated shift work, different groups of
investigators have shown that workers had accelerated circadian
re-entrainment, enhanced alertness, and improved sleep quality
after treatment with bright light (2,000 lux to 12,000 lux) versus
dimmer light (10 lux to 150 lux).
Light Stimulation of the Circadian and Neuroendocrine Systems
[0015] Over the last two centuries, extensive research has
elucidated the neuroanatomy and neurophysiology which support the
sensory capacity of vision in mammals. More recently, animal
studies have demonstrated a neural pathway, named the
retinohypothalamic tract (RHT), which projects from the retina into
the hypothalamus. (Moore and Lenn, 1972; Klein et al., 1991).
Information about light is transmitted from the retina to the
hypothalamic suprachiasmatic nuclei (SCN) which are fundamental
circadian oscillators that regulate daily rhythms. (Klein et al.,
1991). The pathways supporting vision and circadian regulation are
anatomically separate, but there may be a link between these
systems by a projection from the intergeniculate leaflet to the
SCN. (Morin, 1994). Although the detailed neuroanatomy of the
circadian system primarily has been determined with animal studies,
parallel clinical and post-mortem studies suggest that humans have
a similar circadian neuroanatomy. (Schwartz et al., 1986).
[0016] The circadian system controls daily rhythms of sleep,
wakefulness, body temperature, hormonal secretion, and other
physiological parameters. (Klein et al., 1991; Morin, 1994; Lam,
1998). There is considerable evidence from studies on mammals that
the circadian and neuroendocrine effects of light are mediated via
photoreceptive physiology in the eye as opposed to photoreceptive
physiology in the skin or some other part of the body. A study by
Campbell and Murphy (1998), however, reported that a 3 hour bright
light pulse of 13,000 lux delivered to the backs of the knees of
human subjects systematically reset circadian rhythms of body
temperature and melatonin. In contrast, two recent studies failed
to elicit acute melatonin suppression with similar bright light
exposure to the backs of the knees in healthy humans and an attempt
to replicate Campbell and Murphey's findings failed to demonstrate
a phase-shift after light exposure to the back of the. Further work
is needed to determine whether or not the eyes are the exclusive
sites for circadian photoreception in humans and other mammalian
species. Data suggest that the eyes are the primary (if not
exclusive) site for circadian and neuroendocrine phototransduction.
Although light is the principal stimulus for regulating the
circadian system, other external stimuli such as sound,
temperature, social cues and conditioning may also influence
physiological timing functions.
Light Regulation of Melatonin
[0017] A well-defined neural pathway carries photic information
about light extends from the SCN to the pineal gland via a
multisynaptic pathway with connections being made sequentially in
the paraventricular hypothalamus, the upper thoracic
intermediolateral cell column, and the superior cervical ganglion.
(Moore, 1983). By way of this neuroanatomy, cycles of light and
dark which are perceived through the eyes entrain SCN neural
activity which, in turn, entrains the rhythmic synthesis and
secretion of melatonin from the pineal gland. In virtually all
species including humans, high levels of melatonin are secreted
during the night and low levels are secreted during the day.
[0018] In addition to entraining the melatonin circadian rhythm,
light can acutely suppress melatonin secretion. Specifically,
exposure of the eyes to light during the night causes a rapid
decrease in the high activity of the pineal enzyme
serotonin-N-acetyltransferase and subsequent inhibition of
synthesis and secretion of melatonin. The acute light-induced
suppression of melatonin was first observed in rats and later in
humans (Klein and Weller, 1972; Lewy et al., 1980). This response
has been used as a tool by the PI (GCB) and many other
investigators to help determine the ocular, neural and biochemical
physiology for melatonin regulation. (Klein et al., 1991; Brainard
et al., 1997). In addition, seasonal changes in photoperiod length
alters the duration of the elevated melatonin production.
Specifically, in a number of mammalian species including humans,
the duration of increased nocturnal melatonin secretion is shorter
in the summer due to shortened night time periods. In summary, many
studies have shown that light stimuli are the strongest and most
consistent regulators of melatonin. In addition, certain drugs can
powerfully impact melatonin secretion, while other non-photic and
non-pharmacologic stimuli that may modify melatonin levels include
body posture and exercise.
Phototransduction and Action Spectrum Analysis
[0019] The overall aim of the present invention is the
identification of the photoreceptor(s) for applications in the
areas of circadian regulation, neuroendocrine regulation, and the
clinical benefits of light therapy in humans. Fundamentally, all
photobiological responses are mediated by specific organic
molecules that absorb photons and then undergo physical-chemical
changes which, in turn, lead to broader physiological changes
within the organism. This photobiological process is termed
phototransduction and the organic molecules which absorb light
energy to initiate photobiological responses are called
photopigments. Generally, these photoactive molecules do not absorb
energy equally across the electromagnetic spectrum. Each
photoreceptor molecule or complex has a characteristic absorption
spectrum which depends on its atomic structure. An action spectrum
is one of the main tools for identifying the photopigment which
initiates a photobiological response. The simplest definition of an
action spectrum is the relative response of an organism to
different wavelengths. (Lipson, 1994;Coohill, 1999).
[0020] Photobiologists have evolved a refined set of practices and
guidelines for determining analytical action spectra which are
applicable to all organisms from plants to humans. (Coohill, 1991;
Lipson, 1994). Analytical action spectra are developed using two or
more monochromatic light stimuli with half-peak bandwidths of 15 nm
or less. Generally, these action spectra are determined by
establishing a set of dose-response curves (fluence-response
curves) at different wavelengths for a specific biological
response. The action spectrum is then formed by plotting the
reciprocal of incident photons required to produce the criterion
biological response versus wavelength. This fundamental
photobiological technique has high utility for 1) defining the
relative effectiveness of different wavelengths for eliciting a
biological response, and 2) identifying the specific photosensitive
molecules involved in biological responses.
Action Spectra for Circadian Regulation in Rodents
[0021] As in other fields of photobiology, the initial attempts to
define circadian and neuroendocrine responses to wavelength began
with polychromatic action spectra which tested broader bandwidths
of light in various rodent species (Coohill, 1991). These
polychromatic action spectra were published mainly during the early
1970's through the mid 1980's and were reasonably consistent in
indicating that the spectral region between 450 nm and 550 nm
provides the strongest stimulation of circadian and neuroendocrine
responses in rodents (for review: Brainard et al., 1999). Analytic
action spectra, however, are superior to polychromatic action
spectra for identifying the photopigments that mediate
photobiological responses.
[0022] In a landmark study, Takahashi and colleagues determined an
analytic action spectrum for circadian wheel running behavior in
Syrian hamsters (Takahashi et al., 1984). Their study established
fluence-response functions for a set of monochromatic wavelengths
and then formed an action spectrum from those fluence-response
functions. Their action spectrum had a spectral peak (.lamda.max)
around 500 nm and seemed similar in shape to the absorption
spectrum for rhodopsin. Although they found these data to support
the hypothesis that a rhodopsin-based photopigment and rod cells in
the retina mediate circadian entrainment in hamsters, they were
careful to point out that the participation of a cone mechanism
could not be excluded. Since then, three other analytic action
spectra have been published on circadian and neuroendocrine
regulation in rodents. (Bronstein et al., 1987; Provencio and
Foster, 1995; Yoshimura and Ebihara, 1996). Data from these action
spectra have been fitted to spectral sensitivity curves for
retinal-based visual photopigments. This curve fitting is
predicated on the assumption that a retinal-based molecule
transduces light stimuli for circadian regulation, and allows the
prediction of the shape of the photopigment absorption spectrum as
well as its peak sensitivity (.lamda.max). Across these rodent
studies, the predicted max ranges from 480 nm to 511 nm and is
surrounded by a broad region of high sensitivity. From these
studies, different photopigments have been suggested to be
responsible for circadian regulation including rhodopsin, a
rhodopsin-like molecule, a middle wavelength cone photopigment, or
a UV cone photopigment. Furthermore, preliminary data from other
investigators working with Takahashi, showed that the action
spectrum for photoperiod-dependent reproductive development
response of male Siberian hamsters and light-induced phase-shifting
of circadian locomotor activity has its .lamda.max: in the range of
475 nm. The investigators interpret their unpublished action
spectra to support the hypothesis that a short wavelength-sensitive
photoreceptor mediates both functions. (Fred Turek, PhD, personal
communication).
Circadian Regulation in Rodents with Loss of Cone and Rod
Photorecemors
[0023] It is important to note that there is considerable diversity
in the cellular structure and function of the retina across
mammalian species, and that in rodents the retina contains both
cone and rod photoreceptors. (Rodieck, 1998). Early studies with
blind mole rats and rats with destruction of retinal photoreceptors
due to prolonged light exposure raised the possibility that neither
the rods nor the cones used for vision participate in regulating
the circadian and neuroendocrine systems. (Pevet et al., 1984;Webb
et al., 1985). Despite profound loss of photoreceptors and vision,
light detection for circadian and photoperiodic regulation was
preserved. It remained possible, however, that a small population
of surviving rods or cones could still be responsible for circadian
photoreception.
[0024] Studies in mice with hereditary retinal disorders (rd/rd and
rds/rds) have shown that these animals still exhibit normal
light-induced melatonin suppression and circadian locomotor
phase-shifts despite a nearly total loss of classical visual
photoreceptors. The data support the conclusion that circadian
photoreception is maintained either by 1) a very small number of
rod or cone cells, or 2) an unrecognized class of retinal
photoreceptors. (Foster et al., 1991; Provencio et al., 1994;
Yoshimura et al., 1994). Further work with rd mice suggested that
middle-wavelength sensitive (M-cones) and/or S-cones may be
responsible for circadian photoreception. (Provencio and Foster,
1995; Yoshimura and Ebihara, 1996). Recent studies with transgenic
coneless (cl) mice which have extensive loss of M-cones and S-cones
show that these mice exhibit normal sensitivity for light-induced
melatonin suppression and circadian phase-shifting of locomotion.
(Lucas et al., 1999; Freedman et al., 1999). Similarly, coneless,
rodless mice (rd/rd cl) also appeared to exhibit normal sensitivity
for light-induced melatonin suppression and phase-shifting of
wheel-running behavior. These results indicate that rods, M-cones
and S-cones are not required for circadian photoreception. Removal
of the eyes however, abolished light-induced circadian
phase-shifting. (Freedman et al., 1999). Overall the results
suggest that the mouse eye contains specific photoreceptors for
circadian regulation different from the visual photoreceptors. A
study on normal rats, however, shows that the rod and cone
photoreceptors for vision provide input to SCN neurons.
(Aggelopoulos and Meissl, 2000). Thus, it is premature to rule out
the visual photoreceptors from playing a role in circadian
regulation in animals with normal, intact eyes.
[0025] If the rods and cones that mediate vision in rodents are not
the primary photoreceptors for circadian regulation in rodents,
what are the alternative candidates? Recent studies with various
vertebrate species have identified several new molecules which may
serve as circadian photopigments. These putative photopigments
include both opsin-based molecules such as vertebrate ancient (VA)
opsin (Soni and Foster, 1997), melanopsin (Provencio et al., 1998),
and peropsin (Sun et al., 1997) as well as non-opsin molecules like
biliverdin (Oren, 1996) and cryptochrome (Miyamoto and Sancar,
1998). Among these new photopigments, only melanopsin has been
specifically localized to the human neural retina (Provencio et
al., 2000) and cryptochrome has been localized to the mouse neural
retina (Miyamoto and Sancar, 1998). The molecular identification of
these candidate photoreceptors and their localization in the retina
and/or neural components of the circadian system, make them
well-suited to act as circadian phototransducers.
[0026] In summary, the present invention involves a light system
for stimulating or regulating neuroendocrine, circadian, and
photoneural systems in mammals based upon the discovery of peak
sensitivity ranging from 425-505 nm. Also, the present invention
involves a light meter system for quantifying light which
stimulates mammalian circadian, photoneural, and neuroendocrine
systems, wherein the light meter has at least one light metering
device to match peak wavelength sensitivity of mammalian
photoreceptors for mammalian circadian, photoneural, and
neuroendocrine systems, Furthermore, the present invention exploits
this peak wavelength sensitivity for novel light systems, novel
translucent and transparent materials, and novel lamps or other
light sources with or without filters. The present invention also
involves the peak sensitivity as the focal point for treatment of
mammals with a wide variety of disorders or deficits, including but
not limited to, light responsive disorders, eating disorders,
menstrual cycle disorders, non-specific alerting and performance
deficit, hormone-sensitive cancers, and cardiovascular
disorders.
DEFINITIONS
[0027] "Light responsive disorders" means any disorder responding
to or preventable by phototherapy and includes, but is not limited
to, seasonal affective disorders, sleep disorders, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers (including, but not limited to, breast cancers), and
cardiovascular disorders.
[0028] "Light system" means a lamp, a lamp with filters, or another
system or source for delivering light.
[0029] "Translucent or transparent material component" or
"translucent or transparent material" includes, but is not limited
to, at least one of the following: glasses, visors, windows,
contacts, and filters. These materials may shape natural or
artificial light.
[0030] "Light source" includes, but is not limited to, at least one
of the following light sources: artificial light, natural light,
and lamps.
SUMMARY
[0031] The present invention involves a light system for
stimulating or regulating neuroendocrine, circadian, and
photoneural systems in mammals based upon the discovery of peak
sensitivity ranging from 425-505 nm. Also, the present invention
involves a light meter system for quantifying light which
stimulates mammalian circadian, photoneural, and neuroendocrine
systems, wherein the light meter has at least one light metering
device to match peak wavelength sensitivity of mammalian
photoreceptors for mammalian circadian, photoneural, and
neuroendocrine systems, said peak wavelength ranging between
425-505 nm. Furthermore, the present invention exploits this peak
wavelength sensitivity for novel light systems, novel translucent
and transparent materials, and novel lamps or other light sources
with or without filters. The present invention also involves
exploiting this peak sensitivity for treatment of mammals with a
wide variety of light responsive disorders or deficits, including
but not limited to, light responsive disorders, eating disorders,
menstrual cycle disorders, non-specific alerting and performance
deficit, hormone-sensitive cancers, and cardiovascular
disorders.
[0032] The light metering device is specifically configured to
accurately quantify electromagnetic radiation that stimulates or
regulates the circadian, photoneural, and neuroendocrine systems of
healthy mammals or mammals having a variety of disorders. The
meter's wavelength sensitivity matches the wavelength sensitivity
of the photoreceptors for circadian, photoneural, and
neuroendocrine regulation in mammals. This device is also used to
quantify electromagnetic radiation which is optimum for treating
Seasonal Affective Disorders (SAD) or other light-responsive
disorders.
BRIEF DESCRIPTION OF THE FIGURES
[0033] FIG. 1: In this graph the bars represent group mean +SEM
plasma melatonin values (N=8) before and after monochromatic :light
exposure at 505 nm. There were no significant variations across
mean melatonin pre-light exposure values (F=0.85). Paired,
two-tailed Students' t tests demonstrated which light intensities
elicited a significant melatonin suppression.
[0034] FIG. 2: This graph illustrates group mean +SEM
control-adjusted melatonin change values (N=8) at 505 nm
monochromatic light exposure. The figure shows that progressively
higher light irradiance exposure produces increasingly greater
melatonin suppression.
[0035] FIG. 3: This figure demonstrates the fitted fluence-response
curve for photon density and % control-adjusted melatonin
suppression (N=8). Each data point represents one group mean
.+-.SEM.
[0036] FIG. 4: The bars represent group mean +SEM values relative
to an equal photon dose of 4.2.times.10.sup.13 photons/cm.sup.2.
These data show that the 505 nm % control-adjusted plasma melatonin
suppression is significantly stronger than that for 555 nm.
[0037] FIG. 5: This diagram illustrates the experimental
electronic, optic and ganzfeld dome exposure array. This apparatus
provides a uniform, patternless stimulus that encompasses the
subject's entire visual field. For clarity, the subject's head is
shown slightly withdrawn from the opening of the ganzfeld dome.
During all light exposures, the subjects' bony orbits are
completely enclosed in the dome walls providing complete exposure
of their visual fields.
[0038] FIG. 6: In this graph the bars represent group mean +SEM
plasma melatonin values before and after monochromatic light
exposure at 460 nm in eight healthy subjects. There were no
significant differences (F=0.70, p=0.69) across pre-exposure mean
melatonin values. Light irradiances at or above 3.1 .mu./cm.sup.2
elicited significant melatonin suppression.
[0039] FIG. 7: This figure illustrates the mean +SEM plasma
melatonin percent control-adjusted change scores from eight healthy
subjects exposed to different irradiances of monochromatic light at
460 nm. Progressively higher irradiance exposures at 460 nm produce
progressively greater plasma melatonin percent control-adjusted
change scores (p<0.0001).
[0040] FIG. 8: This graph demonstrates the best fit thence-response
curve for 460 nm exposures and percent control-adjusted melatonin
suppression (R.sup.2=0.97). Each data point represents one group
mean .+-.SEM from eight healthy subjects.
[0041] FIGS. 9A-9H: These figures illustrate the fitted univariant
fluence-response curves for monochromatic light exposures and
percent control-adjusted melatonin suppression for eight
wavelengths of visible light ranging from 440 nm to 600 nm. Each
fluence-response curve is derived from eight healthy volunteers who
participated in a complete, within-subjects experimental design. In
each graph, the data points represent group means .+-.SEM. Each
curve has a high coefficient of correlation (0.95 to 0.81).
[0042] FIG. 10: In this graph the bars represent group mean +SEM
plasma melatonin values before and after exposure to 31.8
.mu./cm.sup.2 monochromatic light at 420 nm in eight healthy
subjects. This light irradiance induced a significant melatonin
suppression (p<0.003).
[0043] FIG. 11: This graph demonstrates the action spectrum for
percent control-adjusted melatonin suppression in 72 healthy human
subjects, The filled circles represent the half-saturation
constants of eight wavelengths from 440 to 600 nm which were
normalized to the maximum response and plotted as log relative
sensitivity. The open circle represents the estimated
half-saturation constant derived from the 420 nm data. The line in
the graph portrays the best fit template for vitamin A.sub.1
retinaldehyde photopigments which predicts a maximal spectral
absorbance (1 max) of 464 nm (Partridge and De Grip, 1991). There
is a high coefficient of correlation for fitting this opsin
template to the melatonin suppression data (R.sup.2=0.91). The
basis for the balanced wavelength peak sensitivity range is a
calculation of approximately two standard deviations from 464
nm.
[0044] FIG. 12: This figure illustrates a comparison of the
melatonin suppression and visual action spectra. The maximal
spectral response and long wavelength limb of the melatonin
suppression template is plotted along with the maximal spectral
response and long wavelength limbs of the human rods and cones that
support vision (Stockman and Sharpe, 1999). The shaded area around
the 464 nm template represents .+-.SD from the data presented
above.
DETAILED DESCRIPTION
[0045] The science of photobiology involves the study of how the
infrared, visible and ultraviolet portions of the electromagnetic
spectrum influence biological processes. There are two broad
categories of light measurement techniques: radiometric and
photometric. Each measurement technique has its merits and
drawbacks relative to circadian regulation, neuroendocrine
regulation and light therapy. Radiometry is based exclusively on
the physical properties of light--its energy and wavelength. A
radiometer measures the radiant power of a light source over a
defined range of wavelengths. Radiometers can be configured to
measure different bandwidths across the electromagnetic spectrum.
The wavelengths within the designated bandwidth can be detected
equally, or they can be filtered for differential sensitivity
across the various wavelengths.
[0046] In contrast to radiometry, photometry is based on the
selective responsiveness of the human visual system. A photometer
is simply a radiometer that has filters added to the detector which
"shape" the detector sensitivity to resemble the luminance
(brightness) response of the human visual system. Thus, photometry
is a special branch of radiometry. Between individual humans, there
are substantial differences in visual responses. The average
photopic and scotopic visual functions are defined with reference
to the adaptive state of the rod and cone photoreceptors in the
human retina. Radiometers can be filtered to detect only those
relative proportions of wavelengths that comprise the photopic or
scotopic visual response. Photometers will detect photopic lux or
scotopic lux, respectively. Specifically defined, lux measures are
measures of illuminance--the amount of light, or luminous flux,
falling on a surface. One photopic lux is one lumen per square
meter (1 m/m.sup.2). The new metering system is configured to
measure a new lighting unit which could be called "circadian lux"
as opposed to photopic lux or scotopic lux.
[0047] Most investigators have operated from the assumption that
light therapy is mediated via a photoreceptive mechanism in the
human eye as opposed to a photoreceptive mechanism in the skin or
some other part of the body. The data of the present invention
demonstrate that the photoreceptive mechanism for the circadian and
neuroendocrine system or the photoreceptive mechanism that mediates
light therapy is not identical to the photoreceptive system that
mediates the sensory capacity of vision.
Subjects, Materials and Methods
Subjects
[0048] The healthy females (N=6) and males (N=10) in this study had
a mean .+-.SEM age of 25.7.+-.0.8 yrs, demonstrated normal color
vision as measured by the Ishihara and Farnsworth Munsell D-100
tests (mean FM score: 64.2.+-.11.5), had a stable sleeping pattern
(mean wake-up time 7:30 AM.+-.12 min), and signed an approved IRB
consent document before participating.
Light Exposure Protocol
[0049] Each experiment began at midnight when subjects entered a
dimly lit room (10 lux). One drop of 0.5% Cyclopentolate HCI was
placed in each eye to dilate the pupils, and blindfolds were placed
over subjects' eyes. Subjects remained sitting upright in darkness
for 120 min. While still blindfolded and just prior to 2:00 AM, a
blood sample was taken by venipuncture. During light exposure, each
subject's head rested in an ophthalmologic head holder facing a
Ganzfeld apparatus that provided a concave, patternless, white
reflecting surface encompassing the subject's entire visual field.
The subjects were exposed to the light stimulus from 2:00 to 3:30
AM. During this 90 min exposure, subjects sat quietly, kept their
eyes open and gazed at a fixed target dot in the center of the
Ganzfeld dome. Subject compliance for keeping their eyes open and
the subjects' pupil size were monitored by a miniature video
camera. At 3:30 AM, a second blood sample was taken. Each subject
was exposed to complete darkness from 2:00 to 3:30 AM on their
control night and was tested with at least 6 days between each
nighttime exposure. Plasma samples were assayed for melatonin by
RIA. (Rollag, 1976). The minimum detection limit of the assay was
0.5-2.0 pg/mL. Control samples had 8% and 14% intra-assay
coefficients of variation.
Light Production and Measurement
[0050] Experimental light stimuli were produced by xenon arc lamps
(Photon Technology Intl, Inc., Princeton, N.J.) enclosed in a
light-proof chamber and cooled by high-speed fans and water
circulation. An exit beam of light from each source was directed by
a parabolic reflector, and excess heat in this beam was reduced by
a water filter. Monochromatic wavelengths (10-11 nm half-peak
bandwidth) were produced by a grating monochromator and light
irradiance was controlled by a manual diaphragm. The resulting
light beam was directed into the top area of a Ganzfeld dome and
reflected evenly off the walls into volunteers' eyes. The entire
reflecting surface of the dome was coated with a white surface with
a 95-99% reflectance efficiency over the 400 to 760 nm range.
Routine measurement of the light irradiance (.mu.W/cm.sup.2) was
done with a J16 Meter with a J6512 irradiance probe (Tektronix,
Beaverton, Oreg.). Experimental light stimuli reflected from the
Ganzfeld domes were measured at volunteers' eye level immediately
before and after the 90 min exposure. Additional measures were
taken each half hour of the exposure to insure stimulus stability
and enable intensity readjustment. Subjects in the 505 nm series
were exposed to intensities ranging from 0.011 to 97 .mu.W/cm.sup.2
(a 3 log unit photon density range of 10.sup.10 to 10.sup.13
photons/cm.sup.2).Subjects exposed to 555 nm received control or a
15 82 W/cm.sup.2 (4.2.times.10.sup.13 photons/cm.sup.2)
exposure.
Statistics
[0051] Two-tailed, Students' t tests were used to assess
significance of raw melatonin change from 2:00 to 3:30 AM. These
data were then converted to % control-adjusted melatonin change
scores as described elsewhere. (Gaddy, 1993). For the 505 nm data,
sets of pre-exposure melatonin values and % control-adjusted
melatonin change scores were analyzed with one-way, repeated
measures ANOVA. Significant differences between groups were
assessed with post-hoc Scheffe F-tests; alpha was set at 0.05. For
the 505 nm mean % control-adjusted melatonin suppression data, the
computer program Origin 6.0 (Microcal, Northampton, Mass.) was used
to fit a fluence-response curve to a 4 parameter model as described
elsewhere (Brainard, 19893), and to test for goodness-of-fit of the
data by coefficient of correlation.
Results
[0052] The full 505 nm data complement, from raw melatonin values
to a final fluence-response curve, is illustrated in FIGS. 1-3.
Across all nights of testing, there were no significant differences
(F=0.85) between sets of pre-exposure melatonin values indicating
that plasma levels were consistent across the different study
nights. FIG. 1 shows the mean .+-.SEM pre- and post-exposure
melatonin values. One-way, repeated measures ANOVA showed a
significant effect of light intensity on plasma melatonin % change
scores (F=17.17, P<0.0001). Paired t tests demonstrated that
compared to the 0 .mu.W/cm.sup.2 control night, all intensities at
or above 5.5 .mu.W/cm.sup.2 significantly suppressed melatonin
(P<0.05 or less). In contrast, irradiances of 2.8, 1.4 and 0.011
.mu.W/cm.sup.2 did not suppress melatonin compared to the control
night (Scheffe F values: 0.97, 0.01 and 0.02, respectively). As
illustrated in FIG. 2, all melatonin data were converted to
control-adjusted % change scores. As with the melatonin % change
scores, ANOVA showed a significant effect of light intensity on
plasma melatonin % control-adjusted change scores (F=13.59,
P<0.0001). FIG. 3 illustrates a best fit, sigmoidal
fluence-response curve which plots melatonin % control-adjusted
scores against stimulus photon density. The specific formula for
this curve is included in the figure.
[0053] Subjects exposed to 555 nm received both control (0
.mu.W/cm.sup.2) and 15 .mu.W/cm.sup.2 (4.2.times.10.sup.13
photons/cm.sup.2) exposures. For the control and light exposure
nights, the mean pre-exposure raw melatonin scores were
64.4.+-.12.5 and 59.6.+-.6.2, while the mean post-exposure scores
were 62.6.+-.10.5 and 49.1.+-.6.0, respectively. The modest drop in
melatonin over the 90 min 555 nm light exposure period was not
statistically significant (t=1.69, df=7, P=0.14). For comparison of
responses to 505 nm and 555 nm, FIG. 4 illustrates %
control-adjusted melatonin suppression relative at equal photon
densities across the two wavelengths. These data reveal that 505 nm
is significantly stronger than 555 nm in suppressing melatonin
(t=-3.04, df=14, P<0.01).
Discussion
[0054] The data presented here demonstrate that: 1) there is a
clear fluence-response relationship between graded light
intensities of 505 nm light and melatonin suppression, and 2) that
505 nm light is significantly stronger than 555 nm light for
suppressing melatonin in healthy, human subjects. Previous studies
with animals and humans have illustrated fluence-response
relationships for melatonin suppression and circadian
phase-shifting with exposure to monochromatic light (Podolin, 1987;
Brainard, 1988; Nelson, 1991) as well as white light (Brainard,
1983; Boivin, 1996). A recent study on human subjects suggests that
a four parameter curve is optimal for modeling light-induced
melatonin suppression and circadian phase shifting. (Zeitzer,
1997). That contention matches earlier animal data (Brainard, 1983)
as well as the 505 nm data reported here.
[0055] The demonstration that 505 nm light is more potent than 555
nm light for controlling melatonin has important basic science and
clinical implications. In humans, it is well-established that
higher levels of ocular illumination are required for stimulating
the circadian system than for supporting vision. (Lewy, 1980,
Nelson, 1991; Czeisler, 1986). Consequently, many investigators
have considered the three cone photopic visual system to be
responsible for stimulating circadian and neuroendocrine responses
since this part of the visual system is responsive to "bright"
daytime levels of illumination. Over the past 20 years most of the
published literature on human circadian responses to light reports
light levels in terms of illuminance (lux, lumens) which is a
specific measure based on the traditional sensitivity curve of the
photopic visual system. The peak wavelength sensitivity of that
curve is 555 nm. (Rodieck, 1998). Indeed, some researchers have
argued that their data support the notion that the visual cones are
involved in circadian phase-shifting in humans. (Zeitzer, 1997). If
melatonin regulation is mediated primarily by the three cone
photopic visual system, then 555 nm light should be the most potent
wavelength for regulating melatonin. The data here do not support
this view. On the contrary, 505 nm is significantly stronger,
photon for photon, than 555 nm in suppressing melatonin. The
clinical implication of this result is that it is not optimum to
use photometric values (lux) for quantifying light used
therapeutically in patients with certain sleep disorders or
circadian disruption due to shiftwork or intercontinental jet
travel as is the current standard practice. (1995 Special Issue, J
Bioi).
[0056] Ultimately, these studies open the door for redefining how
light should be measured relative to the circadian system. The best
circadian measurement system would match the action spectrum for
human circadian regulation. That action spectrum would not only
elucidate the relative circadian potencies of different
wavelengths. but it should help identify the photoreceptor that
initiates signals from the retina to the SCN.
[0057] In summary, monochromatic 505 nm light suppressed melatonin
in a fluence-response manner, and is approximately four times
stronger than a 555 nm stimulus at an equal photon dose for
melatonin suppression. These data demonstrate that the three cone
system that is believed to mediate human photopic vision is not the
primary photoreceptor system to transduce light stimuli for
melatonin regulation.
Action Spectra Study Design
[0058] Action spectra are determined by comparing the number of
photons required for the same biological effect at different
wavelengths (Lipson, 1994; Coohill, 1999). The melatonin
suppression action spectrum described here was formed from fluence-
response curves at 8 wavelengths between 440 nm and 600 nm. A
within-subjects design was used for each fluence-response curve.
For each wavelength studied, a set of 8 volunteers was exposed to a
minimum of 8 different light irradiances on separate nights with at
least 6 days between exposures. At the completion of that work, it
was determined that a probe of sensitivity to monochromatic light
below 440 nm was needed. Consequently, a group of 8 subjects was
exposed to a single night of no light exposure and a single night
of exposure to one irradiance of 420 nm light.
Subjects
[0059] Volunteers who were involved in shift work, planned long
distance jet travel before or during the study period, or had
irregular sleeping schedules were excluded from this study. The
subject drop-out rate was 7.9%. The ethnic distribution of the 72
subjects who completed this study included 55 Caucasians, 9 Asians,
4 African Americans, 3 Hispanics and 1 individual of unknown
ethnicity. Subjects who had a relatively stable daily sleeping
pattern, passed a physical exam for general and ocular health, and
signed an approved IRB consent document were accepted into this
study. A total of 37 females and 35 males between 18-30 years old
(mean .+-.SEM age=24.5.+-.0.3) completed the study. The
self-reported mean .+-.SE weekday wake-up time among subjects was
7:06 AM.+-.18 min. All subjects were normal on the Ishihara and
Farnsworth Munsell D-100 tests for color vision (mean .+-.SEM FM
score: 51.4.+-.4.3).
Light Exposure Protocol for Action Spectra
[0060] Each experiment began at midnight when subjects entered a
dimly lit room (10 lux or less). One drop of 0.5% Cyclopentolate
HCI was placed in each eye to dilate the subjects' pupils and
blindfolds were placed over their eyes. Subjects remained sitting
upright for 120 minutes and listened to music on headphones or
engaged in quiet conversation. While still blindfolded and just
prior to 2:00 AM, a 10 ml blood sample was taken by venipuncture of
the antecubital vein. Subjects' blindfolds were then removed and
the subjects were exposed to the monochromatic light stimulus from
2:00 to 3:30 AM. During light exposure, each subject's head rested
in an ophthalmologic head holder facing a ganzfeld apparatus that
provided a concave, patternless reflecting surface encompassing
each subject's entire visual field (see FIG. 1). During this 90
minute exposure, subjects sat quietly, kept their eyes open and
gazed at a fixed target dot in the center of the ganzfeld dome.
Subject compliance for keeping their eyes open and the subjects'
pupil size were monitored by a miniature video camera inside the
ganzfeld dome. If the subjects began to close their eyes during the
exposure period, the experimenters reminded them to keep their eyes
completely open. At 3:30 AM, a second 10 ml blood sample was taken
by venipuncture and the subjects were then permitted to leave the
laboratory. Eight wavelengths were studied for this action spectrum
(440, 460, 480, 505, 530, 555, 575 and 600 nm). Across these
wavelengths, each subject was exposed to complete darkness from
2:00 to 3:30 AM on their control night and to a set of irradiances
covering a 4 log unit photon density range of 10.sup.10 to
10.sup.14 photons/cm.sup.2 on exposure nights. For the probe of
sensitivity to monochromatic light at 420 nm, a group of 8 subjects
were exposed to a single night of no light exposure and a single
night of exposure to 420 nm light at 31.8 .mu.W/cm.sup.2
(5.58.times.10.sup.13 photons/cm.sup.2).
Light Production and Measurement
[0061] As shown in FIG. 5, experimental light stimuli were produced
by a 450 or 1200 W xenon arc lamp (Photon Technology Inc.,
Princeton, N.J.). Each lamp was enclosed in a light proof chamber
and cooled by water circulation. An exit beam of light from each
source was directed by a parabolic reflector and, for the 1200 W
lamps, excess heat in the light beam was reduced by a water filter.
Monochromatic wavelengths (10-14.5 nm half peak bandwidths) were
produced by a grating monochromator and light irradiance was
controlled by a manual diaphragm. The resulting light beam was
directed into the top area of a ganzfeld apparatus and reflected
evenly off the walls of the ganzfeld dome into volunteers' eyes.
The entire reflecting surface of the dome was coated with a white
material (Spectralite) with a 95-99% reflectance efficiency over
the 400 to 760 nm range. Routine measurement of the light
irradiance (.mu.W/cm.sup.2) was done with a Tektronix J16
Radiometer/Photometer with a J6512 irradiance probe (Tektronix,
Beaverton, Oreg.). Experimental light stimuli reflected from the
ganzfeld dome was measured at volunteers' eye level immediately
before and after the 90 minute exposure. Additional measures were
taken each half hour of the exposure to insure stimulus stability
and enable readjustment of the intensity if it varied. These spot
measures were taken with a ft-1.degree. meter (Minolta, Osaka,
Japan). Spectroradiometric assessment of the monochromatic
wavelengths at the level of subjects' corneas was done with a
portable spectroradiometer with a fiber optic sensor (Ocean Optics
S2000). This equipment was calibrated with a standard lamp
traceable to the National Institute of Standards and Technology
(NIST).
[0062] In action spectroscopy, it is critical that the measured
light stimuli are representative of the stimuli which actually
reach the photoreceptors that mediate the photobiological response.
In studies on light regulation of the circadian system, factors
which can modify the measured stimulus before it reaches the
photoreceptors include head and eye motion, squinting and eye
closure, pupillary reflexes, and light transduction through the
ocular media (Caddy et al., 1993; Brainard et al., 1997). Most of
these factors are controlled in the experimental technique
described above. Concerning !light transmission through ocular
media, the cornea and aqueous and vitreous humors normally transmit
nearly 100% of visible wavelengths to the retina and do not change
substantively as the eyes age (Boettner and Wolter, 1962). In
contrast, the aging human lens develops pigmentation that
attenuates the transmission of shorter visible wavelengths to the
retina (Lerman, 1987; Brainard et al., 1997). In the present study,
restricting the age of volunteers to 18-30 years controlled this
factor. Measurements of mean transmittance of 36 postmortem human
lenses in this age range showed relatively even transmission from
440 to 600 nm. In contrast, there was a mean 45% reduction in lens
transmission at 420 nm compared to 460 nm (Brainard et al., 1997).
Consequently, measured corneal light irradiances at 420 nm had to
be adjusted to compensate for reduced stimulus transmission to the
retina even in this relatively young study group.
Blood Samples and Melatonin Assay
[0063] Blood samples were collected in glass vacutainers which
contained EDTA. Plasma was separated by refrigerated
centrifugation, aliquoted into cryogenic vials and stored at
-20.degree. C. until assay. Melatonin concentrations were assayed
by radioimmunoassay using antiserum described by Rollag and
Niswender, (1976). Radiolabeled ligand was prepared by adding 10 82
l of a dioxane solution containing 1 .mu.mole 5-methoxytryptamine
and 1 .mu.mole tri-N-butylamine to 250 .mu.Ci (0.1 nmole) dried
Bolton-Hunter Reagent (New England Nuclear Corp., Boston, Mass.).
The reaction was allowed to proceed for one hour before adding 50
.mu.l of aqueous sucrose (16 gm/ml electrophoresis buffer) and
purifying product by disc gel electrophoresis. Duplicate aliquots
of 200 .mu.l of each unknown and control sample were extracted into
2 ml of chloroform. The chloroform was removed in a SpeedVac
centrifuge (Savant Instruments, Holbrook, N.Y.) and resuspended in
200 .mu.l of assay buffer (phosphate buffered saline, pH 7.4,
containing 0.1% gelatin with 1.00 mg thimerosal/liter as a
preservative). The extracts were washed twice with 3 ml of
petroleum ether, then evaporated to dryness in a SpeedVac before
being resuspended in 200 .mu.l of deionized water. Approximately
50,000 cpm of radiolabeled ligand and a 1:256,000 dilution of
antiserum (R1055, 9/16/74) was added to each unknown and a
triplicate 2-fold geometric series of standards ranging in
concentration from 0.201 to 200 pg per 200 .mu.l assay buffer. The
final assay volume of buffer in each tube was 400 .mu.l. At the end
of the 48 hour incubation period, three ml of 95% ethanol
(4.degree. C.) was added to each assay tube and the bound
radioactivity precipitated by centrifugation at 2000.times.g for 30
minutes. The supernatant was decanted and radioactivity in the
precipitate was quantified. The quantity of melatonin
immunoreactivity in the samples was calculated with the use of a
computer program (M. L. Jaffe and Associates, Silver Spring, Md.;
see Davis et al., 1980). All solutions were maintained at 4.degree.
C. throughout the radioimmunoassay procedure. Assay results were
not corrected for recovery (which has proven to be >95% in
independent trials). The minimum detection limit of the assay is
0.5-2.0 pg/ml.
Statistics for Action Spectra
[0064] Two-tailed, paired Student's t tests were used to assess
statistical significance of raw melatonin change from 2:00 to 3:30
AM. Percent melatonin change scores were determined by the
following formula:
Percent Melatonin Change Score = 100 .times. 03 : 30 h melatonin -
02 : 00 h melatonin 02 : 00 h melatonin ##EQU00001##
[0065] Percent melatonin change scores then were normalized to
percent control-adjusted change scores by subtracting the control
(no light) condition percent change scores for each subject from
that same subject's light exposure score. This technique accounts
for the normal individual rise or fall in plasma melatonin levels
with respect to the light-induced changes (Gaddy et al. 1993;
Brainard et al., 1997). For data from each wavelength, complete
sets of pre-exposure melatonin values, percent melatonin change
scores, and percent control-adjusted melatonin change scores were
analyzed with one way, repeated-measures ANOVA. Significant
differences between groups were assessed with post-hoc Scheffe
F-tests with alpha set at 0.05. The group of single
fluence-response curves (one for each wavelength) was fitted to a
parametric model in which the melatonin response (Y) to a photon
dose (X) is predicted by: the theoretical initial Y-response (0
dose) for the curve (A.sub.1); the theoretical final Y-response
("infinite" dose) for the curve (A.sub.2); the dose producing a
response halfway between A.sub.1 and A.sub.2 (X.sub.50 or
ED.sub.50; and the slope estimator (p) for the slope of the curve
between A.sub.1 and A.sub.2. The equation is:
Y = A 1 - A 2 1 + ( X / X 5 0 ) P + A 2 ##EQU00002##
[0066] The computer program Origin 6.0 (Microcal, Northampton,
Mass.) was used to fit the fluence-response curves to the data.
From extensive experience in our laboratory, a saturating 90 minute
light exposure produces a maximum mean percent control-adjusted
plasma melatonin suppression ranging from 60 to 80% depending on
the particular group of subjects being tested (Gaddy et al., 1993;
Ruberg et al., 1996; Wang et al., 1999; Brainard et al., 2000;
2001). To form an analytical action spectrum, it is necessary to
determine if all fluence-response curves can be fit to a univariant
sigmoidal curve (Lipson, 1994; Coohill, 1991; 1999). To do this,
sigmoid curves were fitted to the five fluence-response curves
between 440 nm and 530 nm which reached a mean percent
control-adjusted melatonin suppression of 60-80% by constraining
the At factor (theoretical initial Y-response) to 0 since no light
exposure should yield a 0% control-adjusted plasma melatonin
suppression. From this set of curves, a mean A.sub.2 (theoretical
final Y-response or "infinite" dose for the curve and a mean p
(slope estimator) was calculated. Subsequently, all 8 data sets
(including the data sets which did not reach saturation) were then
fitted to sigmoid curves that constrained A.sub.2 and p to these
means and constrained A.sub.1 to 0. Each calculated curve was
tested for goodness-of-fit of the data by coefficient of
correlation.
Melatonin Action Spectrum
[0067] This action spectrum was formed from the photon density
which elicited the half-saturation constant (ED.sub.50) of the
percent control-adjusted melatonin suppression for each of the 8
wavelengths. These half-saturation constants were derived from the
8 univariant fluence-response curves described above. The
half-saturation constants were then normalized to the maximum
response and plotted as relative sensitivity. The relative quantum
sensitivity from each group of subjects was then graphically
plotted (quanta/wavelength) to illustrate the resultant action
spectra for melatonin suppression in humans. A predicted peak
sensitivity for this action spectrum was determined by fitting a
vitamin A.sub.1-retinaldehyde photopigment template to the data by
a modification of the method described by MacNichol (1983).
Specifically, the long wavelength limb of vitamin A.sub.1-based
photopigments can be considered linear within the 10-90%
sensitivity range when plotted on a frequency abscissa. To select
the best fit vitamin A.sub.1 template, the normalized 10-90% long
wavelength melatonin ED.sub.50 data were fitted to a series of
vitamin A.sub.1-based templates within the 10-90% sensitivity range
of the templates' long-wavelength limbs (Partridge and De Grip,
1991). Pearson correlation coefficients derived from fitting the
melatonin data to the templates indicated the optimum fitting
template.
Results of Action Spectra
Variations in Pupillary Dilation, Exposure Time and Melatonin
Assay
[0068] Individuals vary slightly in their pupil size and response
to mydriatic agents. Mean.+-.SD pupillary dilation was 7.19.+-.0.88
mm for all 72 subjects across all nights of exposures. There were
no significant pupil size changes during the light exposures.
Similarly, there is a small degree of variability in exact light
exposure durations due to slight experimental delays. Across 627
single-subject experiments, the mean.+-.SD exposure duration was
90.6.+-.2.1 minutes. A total of 53 assays were run to quantify
melatonin in plasma samples collected during this project.
Coefficients of variation calculated from control samples assayed
as 19.2 pg/ml and 90.0 pg/ml had 10.8% and 4.0% for intra-assay
coefficients of variation, respectively. The inter-assay
coefficients of variation were 13.5% and 10.2%.
Fluence-Response Data at 460 Nm
[0069] Since the predicted peak of the final action spectrum is 464
nm, the full data complement. from raw melatonin values to a final
fluence-response curve for the nearby monochromatic stimulus at 460
nm, is illustrated in FIGS. 2-4. This fluence-response study at 460
nm was done with 8 subjects (4 males, 4 females). Across these
subjects on all nights of testing, there were no significant
differences (F=0.70, p=0.69) between sets of pre-exposure values
indicating that baseline nocturnal melatonin levels were consistent
across the different nights of study. FIG. 6 shows the mean+SEM
pre- and post-exposure (2:00 to 3:30 AM) melatonin values (mean
range 72.1-29.3 pg/ml). At 460 nm, exposure to irradiances of 2.3
.mu.W/cm.sup.2 and lower did not significantly suppress plasma
melatonin. In contrast, exposures of 3.1 .mu.W/cm.sup.2 and higher
elicited significant melatonin suppressions (p<0.03 or
less).
[0070] For comparative purposes, all melatonin data were converted
to plasma melatonin percent control-adjusted change scores. As
illustrated in FIG. 7, one-way, repeated measures ANOVA showed a
significant effect of light intensity on plasma melatonin percent
control-adjusted change scores (F=14.92, p<0.0001). Post-hoc
tests on plasma melatonin percent control-adjusted scores
demonstrated that all intensities at or above 3.1 .mu.W/cm.sup.2
significantly suppressed melatonin more than 0.012 .mu.W/cm.sup.2
(p<0.05 or less). Similarly, all irradiances at or above 12.1
.mu.W/cm.sup.2 significantly suppressed melatonin more than 1.5
.mu.W/cm.sup.2. Finally, both 24.2 and 42.2 .mu.W/cm.sup.2
exposures elicited significantly higher plasma melatonin percent
control-adjusted change scores compared to an irradiance of 2.3
.mu.W/cm.sup.2.
[0071] The data from FIG. 7 can be mathematically converted into a
best fit, sigmoidal curve which plots melatonin suppression against
stimulus photon density. The specific formula for this curve is
shown below and has a 0.97 coefficient of correlation
(R.sup.2).
y = 7 . 1 7 - 73.4 1 + ( x / 8.29 ) 1.23 + 7 3 . 4 ##EQU00003##
[0072] As shown in FIG. 8, this curve illustrates the
fluence-response interaction between mean.+-.SEM melatonin percent
control-adjusted change scores and the photon density of the
monochromatic light.
Fluence-Response Data for All 8 Wavelengths
[0073] As shown in FIGS. 6-8, there is a clear, fluence-response
relationship between graded photon densities of monochromatic 460
nm light and melatonin suppression. Data from each of the 8
wavelengths tested in this study fit four-parameter sigmoidal
curves with high coefficients of correlation. Specifically,
wavelengths at 440, 460, 480, 505, 530, 555, 575 and 600 nm had
respective coefficients of correlation (R.sup.2): 0.99, 0,97, 0.95,
0.97, 0.98, 0,92, 0.96, and 0.97. As described in the Methods, to
form an analytical action spectrum, all fluence-response curves
must be fit to a univariant sigmoidal curve (Lipson, 1994; Coohill,
1999). The univariant curve model for the data in this study has
the factors of A.sub.1=0, A.sub.2=66.9, and p=1.27. FIG. 5
illustrates all 8 univariant fluence-response curves from this
study. As with previous circadian analytical action spectra
(Takahashi et al., 1984; Provencio and Foster, 1995; Yoshimura and
Ebihara, 1996), full range fluence-response curves were not
elicited above 550 nm. Despite this, standard photobiological curve
fitting methods could be used to fit the data from all eight
wavelengths in the present study to univariant, sigmoidal
functions. When fit to a univariant fluence-response curve with
these factors, the data from exposures to 440, 460, 480, 505, 530,
555, 575 and 600 nm have high coefficients of correlation of 0.91,
0.95, 0.93, 0.94, 0.92, 0.90, 0.95, and 0.81, respectively.
Melutonir Suppression Response to 420 Nm at a Single Intensity
[0074] Given the high sensitivity of subjects to short wavelength
light as shown in FIG. 9, it was determined that a probe of
sensitivity to monochromatic light below 440 nm was needed. On the
control night when the eight volunteers were exposed to darkness
only, their raw mean melatonin levels at 2:00 and 3:30 AM were 69.4
and 76.0 pg/ml, respectively. That small increase was not
statistically significant (t=-1.15, p=0.29). As shown in FIG. 10,
when these volunteers were exposed to 420 nm light at 31.8
.mu.W/cm.sup.2 (5.58.times.10.sup.13 photons/cm.sup.2), raw mean
melatonin levels at 2:00 and 3:30 AM were 76.4 and 47.6 pg/ml,
respectively. That decrease in melatonin was statistically
significant (t=4.67, p<0.003). For comparative purposes, this
single melatonin suppression response was fitted to the univariant
fluence-response curve formula used for all of the data in FIG. 9.
The resulting curve estimated a half-maximum (X.sub.50 or
ED.sub.50) melatonin suppression response for 420 nm of
1.83.times.10.sup.13 photons/cm.sup.2.
Action Spectrum for Melatonin Suppression
[0075] Action spectra ace determined by comparing the number of
photons required for the same biological effect at different
wavelengths (Smith, 1989; Coohill, 1999). For this experiment, the
action spectrum was formed from the photon density which elicited
the half-saturation constant (X.sub.50 or ED.sub.50) of the percent
control-adjusted melatonin suppression for each of the eight
wavelengths. The half-saturation constants were derived from the
eight univariant fluence-response curves shown in FIG. 9 and the
one estimated half-saturation constant from the data shown in FIG.
10. The relative quantum sensitivity from each group of subjects
was plotted in FIG. 11 (quanta/wavelength) to illustrate the
resultant action spectra for human melatonin suppression. When the
data were aligned to the best-fit template for vitamin
A.sub.1-retinaldehyde photopigments, this action spectrum predicted
a peak spectral sensitivity (1 max) of 464 nm. There was a strong
coefficient of correlation between the data and this fitted opsin
nomogram (R.sup.2=0.91).
Comparison of Action Spectra
[0076] The action spectrum for the photoreceptor system which
provides input to the pineal gland appears to be distinct from the
action spectra for the classical human visual photoreceptor
systems. To illustrate this, the maximal spectral absorbencies and
long wavelength limbs of the human rod and cone photoreceptors that
support vision (Stockman and Sharpe, 1999) are illustrated in FIG.
8 along with the maximal spectral absorbence and long wavelength
limb of the melatonin action spectrum. The shaded area around the
melatonin action spectrum illustrates .+-.SD for this function.
Discussion of Action Spectra
[0077] The action spectrum presented here is based on univariant
fluence-response curves for melatonin suppression by eight
monochromatic light wavelengths in healthy subjects. These data fit
a vitamin A.sub.1 opsin template with 446-477 nm providing the
strongest circadian input for melatonin regulation. These results
suggest a novel photopigment in the human eye may be primarily
responsible for melatonin regulation and may be distinct from the
individual rod and cone photoreceptors for vision.
[0078] In developing a fluence-response curve, a complete
within-subjects experimental design produces the most reliable
results. When subjects are studied over a two to four month period,
however, lack of stability in the subjects' circadian entrainment
can introduce variability in light-induced melatonin suppression.
This study accepted only volunteers who reported regular bed and
wake times and their melatonin rhythms appeared to have been stable
during the course of the study. As shown in the 2:00 AM melatonin
values (FIG. 6), there were no significant differences between sets
of pre-exposure values indicating that baseline melatonin levels
were consistent across the different study nights. This phenomenon
has been documented for the 505 nm fluence-response group as well
as in other similarly controlled studies (Brainard et al., 1997;
2000; 2001; Wang et al., 1998). This within-subject stability of
the melatonin rhythm over time has been frequently confirmed in the
literature (Waldhauser and Dietzel, 1985; Arendt, 1988; 1998).
[0079] The data from each wavelength studied fit a univariant four
parameter sigmoidal curve with a high coefficient of correlation.
The univariance of these curves is consistent with, but does not
prove, the hypothesis that melatonin suppression is modulated by a
single photoreceptor type. Previous studios with animals and humans
have illustrated similar fluence-response relationships for
melatonin suppression and other circadian responses with
monochromatic and broad spectrum light (Brainard et al., 1983;
1988; Podolin et al., 1987; Mcintyre et al., 1989; Nelson and
Takahashi, 1991; Zeitzer al., 2000; Dkhissi-Benyahya et al., 2000).
The initial attempts to define circadian and neuroendocrine
responses to photons of different wavelength began with
polychromatic action spectra which tested single irradiances of
broader light bandwidths in various rodent species. These
polychromatic action spectra were reasonably consistent in
indicating that the spectral region between 450-550 nm provides the
strongest stimulation of circadian and neuroendocrine responses in
rodents (for review: Brainard et al., 1999). Analytic action
spectra, based on sets of fluence-response curves at different
monochromatic wavelengths, are superior for identifying
photoreceptors that mediate photobiological responses (Lipson,
1994; Coohill, 1999).
[0080] There are four analytic action spectra on circadian and
neuroendocrine regulation in hamsters, rats and mice (Takahashi et
al. 1984; Bronstein et al., 1987; Provencio and Foster, 1995;
Yoshimura and Ebihara, 1996). Data from these action spectra have
been fitted to spectral sensitivity curves for retinal-based visual
photopigments. This curve fitting is predicated on the assumption
that a retinal-based molecule transduces light stimuli for
circadian regulation, and allows the prediction of the shape of the
photopigment absorption spectrum as well as its peak sensitivity (1
max). Across these studies which employed different circadian
endpoints, the predicted 1 max ranges from 480-511 nm and is
surrounded by a broad region of high sensitivity, From these
results, different photopigments have been suggested to be
responsible for circadian regulation, including rhodopsin, a
rhodopsin-like molecule, a middle wavelength cone photopigment, or
an ultraviolet cone photopigment.
[0081] It is commonly believed that the photopic, visual system has
a peak wavelength sensitivity around 555 nm (Rodieck, 1998). Many
investigators have hypothesized that the photopic visual system
mediates circadian and neuroendocrine responses, since this part of
the visual system is responsive to "bright" daytime levels of
illumination. Previous data (Brainard et al., 2001) and those
presented above do not support this view. The results clearly
demonstrate that 555 nm is significantly weaker in suppressing
melatonin compared to an equal photon density of 460 nm. Thus, the
photopic system is not likely to be the primary input for circadian
regulation. Demonstrating that the photopic visual system is not
the principal phototransducer for melatonin regulation does not
preclude it from having any role in circadian input. Indeed, recent
studies suggest that visual cones may be involved in circadian
regulation. Recordings from SCN neurons in rats indicate that the
visual rods and cones provide input to cells of the rat SCN
(Aggelopoulos and Meissl, 2000). Similarly, a human phase-shifting
study suggests that, under some circumstances, the visual long
wavelength-sensitive cone may also mediate circadian vision in
humans (Zeitzer et al., 1997).
[0082] The data presented here do not support the view that any of
the known visual photoreceptors provide the primary input for
melatonin regulation. FIG. 10 shows that none of the action spectra
for individual visual photoreceptor systems match the action
spectrum for melatonin suppression. If the photoreceptors that
mediate vision in humans are not the primary photoreceptors for
circadian regulation, what are the alternative candidates? Recent
studies with various vertebrate species have identified several new
molecules which may serve as circadian photopigments. These
putative photopigments include both opsin-based molecules such as
vertebrate ancient (VA) opsin (Soni and Foster, 1997), melanopsin
(Provencio et al., 1998), and peropsin (Sun et al., 1997), as well
as non-opsin molecules like biliverdin (Oren, 1996) and
cryptochrome (Miyamoto and Sancar, 1998). Among these new
photopigments, only melanopsin has been specifically localized to
the human neural retina (Provencio et al., 2000) and cryptochrome
has been localized to the mouse neural retina (Miyamoto and Samar,
1998). Cryptochromes have been studied extensively as circadian
photoreceptors in plants and insects (Ahmad and Cashmore, 1993;
Stanewsky et al., 1998), and have been proposed as circadian
photoreceptors in mammals (Miyamoto and Sancar, 1998; Thresher et
al., 1998). The contention that cryptochromes serve as circadian
photoreceptors in humans or other mammals, however, remains
controversial (van der Horst et al., 1999; Griffin et al., 1999;
von Schantz et al., 2000).
[0083] The action spectrum presented here matches a vitamin
A.sub.1-retinaldehyde photopigment template which supports the
hypothesis that one of the new opsin photopigment candidates
provides primary photic input for melatonin regulation in humans.
The molecular identification of candidate opsin or non-opsin
photoreceptors and their localization in the retina and/or neural
components of the circadian system make them well-suited to act as
circadian phototransducers.
[0084] Are the effects of light on melatonin suppression relevant
to general circadian regulation? Studies have shown that hamsters
have a higher intensity threshold for light-induced phase-shifts of
wheel running rhythms than for melatonin suppression (Nelson and
Takahashi, 1991). Recently, however, a study on humans showed that
the 50% response sensitivity for circadian phase-shifting (119 lux)
was only slightly higher than that for melatonin suppression (106
lux) with white light (Zeitzer et al., 2000). It is possible that
there are separate photoreceptors for mediating circadian
entrainment versus acute suppression of melatonin. It is
reasonable, however, to conclude that a variety of non-visual
effects of light such as melatonin suppression, entrainment of
circadian rhythms, and possibly some clinical responses to light
are mediated by a shared photoreceptor system.
[0085] In general, relatively high light illuminances ranging from
2,500 to 12,000 lux are used for treating winter depression,
selected sleep disorders and circadian disruption (Wetterberg,
1993; Lam, 1998). Although these light levels are therapeutically
effective, some patients complain that they produce, side effects
of visual glare, visual fatigue, photophobia, ocular discomfort,
and headache. Determining the action spectrum for circadian
regulation can lead to improvements in light therapy. Total
illuminances for treating a given disorder can be reduced as the
wavelength emissions of the therapeutic equipment are
optimized.
[0086] Modem industrialized societies employ light extensively in
homes, schools, work places and public facilities to support visual
performance, visual comfort, and aesthetic appreciation within the
environment. Since light is also a powerful regulator of the human
circadian system, future lighting strategies will need to provide
illumination for human visual responses as well as homeostatic
responses. The action spectrum presented here suggests that there
are separate photoreceptors for visual and circadian responses to
light in humans. Hence, new approaches to architectural lighting
may be needed to optimally stimulate both the visual and circadian
systems.
[0087] In conclusion, this study characterizes the wavelength
sensitivity of the ocular photoreceptor system for regulating the
human pineal gland by establishing an action spectrum for
light-induced melatonin suppression. The results identify 446-477
nm portion of the spectrum as the most potent wavelengths providing
circadian input for regulating melatonin secretion. These data
suggest that the primary photoreceptor system for melatonin
suppression is distinct from the rod and cone photoreceptors for
vision. Finally, this action spectrum suggests that there is a
novel retinaldehyde photopigment which mediates human circadian
photoreception. These findings open the door for optimizing the
utilization of light in both therapeutic and architectural
applications.
Embodiments include: [0088] (a) A method of treating or preventing
a light responsive disorder in a mammal, comprising administration
of a therapeutically effective amount of light to said mammal, said
light being generated by a light system, wherein said light system
emits a balance of wavelengths to stimulate a circadian,
photoneural, or neuroendocrine system of said mammal, said balance
of wavelengths having a peak sensitivity ranging from 425-505 nm:
optionally, wherein said light responsive disorder is at least one
of the group of seasonal affective disorder (SAD), a sleep
disorder, circadian disruption, eating disorders, menstrual cycle
disorders, non-specific alerting or performance deficits,
hormone-sensitive cancers, or cardiovascular disorders. [0089] (b)
A method of treating a light responsive disorder in a mammal,
comprising administration of a therapeutically effective amount of
light to said mammal, said light being generated by a light system,
wherein said light system excludes emission of a balance of
wavelengths to stimulate a circadian, photoneural, or
neuroendocrine system of said mammal, said balance of wavelengths
having a peak sensitivity ranging from 425-505 nm: optionally,
wherein said light responsive disorder is at least one of the group
of seasonal affective disorder (SAD), a sleep disorder, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers, or cardiovascular disorders. [0090] (c) A light system,
comprising at least one light source, said light source emitting a
balance of wavelengths to stimulate a mammalian circadian,
photoneural, or neuroendocrine system, said balance of wavelengths
having a peak sensitivity ranging from 425-505 nm. [0091] (d) A
light system, comprising at least one light source, said light
source excluding emission of a balance of wavelengths to stimulate
a mammalian circadian, photoneural, or neuroendocrine system, said
balance of wavelengths having a peak sensitivity ranging from
425-505 nm. [0092] (e) A transparent composition, comprising at
least one light filtering component, said light filtering component
specifically transmitting a balance of wavelengths for stimulating
a mammalian circadian, photoneural, or neuroendocrine system, said
balance of wavelengths having a peak transmittance ranging from
425-505 nm, [0093] (f) A translucent composition, comprising at
least one light filtering component, said light filtering component
specifically transmitting a balance of wavelengths for stimulating
a mammalian circadian, photoneural, or neuroendocrine system, said
balance of wavelengths having a peak transmittance ranging from
425-505 nm, [0094] (g) A transparent composition, comprising at
least one light filtering component, said light filtering component
specifically blocking a balance of wavelengths for stimulating a
mammalian circadian, photoneural, or neuroendocrine system, said
balance of wavelengths having a peak sensitivity ranging from
425-505 nm, [0095] (h) A translucent composition, comprising at
least one light filtering component, said light filtering component
specifically blocking a balance of wavelengths for stimulating a
mammalian circadian, photoneural, or neuroendocrine system, said
balance of wavelengths having a peak sensitivity ranging from
425-505 nm, [0096] (i) A method of treating a light responsive
disorder in a mammal, comprising administration of a
therapeutically effective amount of light to said mammal, said
light being generated by a light system, wherein said light system
comprises at least one light source and at least one transparent
material component, said light source emitting light through said
transparent material component, said transparent material component
comprising at least one light filtering component, said light
filtering component specifically transmitting a balance of
wavelengths to stimulate a circadian, photoneural, or
neuroendocrine system of said mammal, said balance of wavelengths
having a peak sensitivity ranging from 425-505 nm: optionally,
wherein said light responsive disorder is at least one of the group
of seasonal affective disorder (SAD), a sleep disorder, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers, or cardiovascular disorders. [0097] (j) A method of
treating a light responsive disorder in a mammal, comprising
administration of a therapeutically effective amount of light to
said mammal, said light being generated by a light system, wherein
said light system comprises at least one light source and at least
one translucent material component, said light source emitting
light through said translucent material component, said translucent
material component comprising at least one light filtering
component, said light filtering component specifically transmitting
a balance of wavelengths to stimulate a circadian, photoneural, or
neuroendocrine system of said mammal, said balance of wavelengths
having a peak sensitivity ranging from 425-505 nm: optionally,
wherein said light responsive disorder is at least one of the group
of seasonal affective disorder (SAD), a sleep disorder, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers, or cardiovascular disorders. [0098] (k) A method of
treating a light responsive disorder in a mammal, comprising
administration of a therapeutically effective amount of light to
said mammal, said light being generated by a light system, wherein
said light system comprises at least one light source and at least
one transparent material component, said light source emitting
light through said transparent material component, said transparent
material component comprising at least one light filtering
component, said light filtering component specifically blocking a
balance of wavelengths to stimulate a circadian, photoneural, or
neuroendocrine system of said mammal, said balance of wavelengths
having a peak sensitivity ranging from 425-505 nm: optionally,
wherein said light responsive disorder is at least one of the group
of seasonal affective disorder (SAD), a sleep disorder, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers, or cardiovascular disorders. [0099] (l) A method of
treating a light responsive disorder in a mammal, comprising
administration of a therapeutically effective amount of light to
said mammal, said light being generated by a light system, wherein
said light system comprises at least one light source and at least
one translucent material component, said light source emitting
light through said translucent material component, said translucent
material component comprising at least one light filtering
component, said light filtering component specifically blocking a
balance of wavelengths to stimulate a circadian, photoneural, or
neuroendocrine system of said mammal, said balance of wavelengths
having a peak sensitivity ranging from 425-5055 nm: optionally,
wherein said light responsive disorder is at least one of the group
of seasonal affective disorder (SAD), a sleep disorder, circadian
disruption, eating disorders, menstrual cycle disorders,
non-specific alerting or performance deficits, hormone-sensitive
cancers, or cardiovascular disorders. [0100] (m) A light meter
system for quantifying light which stimulates a mammalian
circadian, photoneural, or neuroendocrine system under normal
conditions or which provides light therapy, said light meter system
comprising at least one light metering device configured to match
wavelength sensitivity of mammalian photoreceptors for circadian
and neuroendocrine regulation, said wavelength having a peak
sensitivity ranging from 425-505 nm.
* * * * *