U.S. patent application number 10/690483 was filed with the patent office on 2004-12-09 for rem sleep augmentation with extra-ocular light.
This patent application is currently assigned to Cornell University Research Foundation. Invention is credited to Campbell, Scott S., Murphy, Patricia J..
Application Number | 20040249237 10/690483 |
Document ID | / |
Family ID | 22503110 |
Filed Date | 2004-12-09 |
United States Patent
Application |
20040249237 |
Kind Code |
A1 |
Campbell, Scott S. ; et
al. |
December 9, 2004 |
REM sleep augmentation with extra-ocular light
Abstract
The invention provides for exposing an extraocular (i.e.,
non-ocular) region of a human to light during sleep, which enhances
REM sleep. Also provided are devices to carry out the methods. Key
timing parameters ensure effective REM enhancement without
adversely impacting a subject's circadian clock. The invention
provides for improving cognitive function and performance in
healthy individuals and in individuals suffering from a disease or
disorder in which mental status is compromised.
Inventors: |
Campbell, Scott S.;
(Chappaqua, NY) ; Murphy, Patricia J.; (Chappaqua,
NY) |
Correspondence
Address: |
DARBY & DARBY P.C.
P. O. BOX 5257
NEW YORK
NY
10150-5257
US
|
Assignee: |
Cornell University Research
Foundation
|
Family ID: |
22503110 |
Appl. No.: |
10/690483 |
Filed: |
October 20, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10690483 |
Oct 20, 2003 |
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09937324 |
Sep 20, 2001 |
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6669627 |
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09937324 |
Sep 20, 2001 |
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PCT/US00/18820 |
Jul 7, 2000 |
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60143217 |
Jul 9, 1999 |
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Current U.S.
Class: |
600/27 |
Current CPC
Class: |
A61N 5/0618 20130101;
A61N 2005/0662 20130101 |
Class at
Publication: |
600/027 |
International
Class: |
A61M 021/00 |
Goverment Interests
[0002] The research leading to the present invention was supported
in part by the National Institutes of Health Grants R01-AG15370,
R01-MH45067, R01-AG12112, R01-MH45617, P20-MH45762, R03-AG15370,
K02-MH01099, and M01-RR00047. The United States Government has
certain rights in the invention.
Claims
What is claimed is:
1. A method for enhancing REM sleep in a subject, which method
comprises exposing a non-ocular region of a subject to photic
stimulation for an interval during a sleep period.
2. The method according to claim 1, wherein enhancing REM sleep
comprises increasing the number of minutes spent in REM sleep
during the interval of photic stimulation.
3. The method according to claim 2, wherein the number of minutes
in REM sleep increases by at least about 30%.
4. The method according to claim 2, wherein the number of minutes
in REM sleep increases by at most about 200%.
5. The method according to claim 1, wherein enhancing REM sleep
comprises increasing the frequency of REM periods during the
interval of photic stimulation.
6. The method according to claim 5, wherein the frequency of REM
periods increases by about 40%.
7. The method according to claim 1, wherein the non-ocular region
is a region of ample surface vasculature.
8. The method according to claim 7, wherein the region of ample
surface vasculature is the popliteal fossa.
9. The method according to claim 1, wherein the interval lasts for
a duration ranging from between about 15 minutes to about 12
hours.
10. The method according to claim 9, wherein the duration is about
three hours.
11. The method according to claim 1, wherein the photic stimulation
has an intensity ranging from about 15 lux to about 150,000
lux.
12. The method according to claim 11, wherein the photic
stimulation has an intensity ranging from about 10,000 lux to about
13,000 lux.
13. The method according to claim 1, wherein the photic stimulation
has a bandwidth in the visible spectrum.
14. The method according to claim 13, wherein the photic
stimulation has a bandwidth between about 455 nanometers (nm) and
540 nm.
15. The method of claim 1, which method further comprises enhancing
cognitive function in a subject.
16. The method according to claim 15, wherein the subject suffers
from a medical disorder in which mental status is compromised.
17. The method according to claim 15, wherein the subject is a
normal individual.
18. The method according to claim 15, wherein cognitive function is
enhanced to a degree comparable to that achieved with a cholinergic
agonist.
19. A method for extending a REM cycle of a person, comprising the
steps of: a) sensing the start of the REM cycle; b) sensing the end
of the REM cycle; c) determining the time interval of the REM
cycle; and d) augmenting the time interval of the REM cycle by
selectively providing non-ocular photic stimulation for a
predetermined interval.
20. An article for extending a REM cycle of a person, comprising:
a) a sensor which provides phasic activity signals; b) a timing
circuit connected to the sensor and outputting an elapsed-interval
signal indicative of the magnitude of the REM cycle; c) a
comparator which compares the elapsed-interval signal to a
predetermined-interval signal and outputs a shortfall signal; d) a
controller responsive to the shortfall signal to generate a control
signal; e) a photic stimulator positionable in contact with the
person's skin and being actuated in response to the control
signal.
21. The article as in claim 20, wherein the controller further
generates an update signal which is provided to the comparator as
the predetermined-interval signal during a subsequent REM cycle.
Description
[0001] This is a continuation of application Ser. No. 09/937,324,
filed Sep. 20, 2001, which is incorporated herein by reference in
its entirety, which is the national phase of PCT/US00/18820, filed
Jul. 7, 2000, which claims priority to U.S. application Ser. No.
60/143,217 filed Jul. 9, 1999.
FIELD OF THE INVENTION
[0003] The invention relates to a non-drug alternative to enhance
cognitive function. In particular, the invention provides for
exposing an extraocular (i.e., non-ocular) region of a human to
light during sleep, which enhances REM sleep. Also provided are
devices to carry out the methods. Key timing parameters ensure
effective REM enhancement without adversely impacting a subject's
circadian clock. The invention provides for improving cognitive
function and performance in healthy individuals and in individuals
suffering from a disease or disorder in which mental status is
compromised.
BACKGROUND OF THE INVENTION
[0004] Rapid eye movement, or REM sleep, is a discrete sleep state
characterized by muscle atonia (i.e., flaccid paralysis), low
voltage, desynchronized EEG, and phasic activity such as increased
respiratory activity, muscle twitches and burst of rapid eye
movement. In humans, REM sleep comprises about 20-25% of a normal
night's sleep and it is during this time that dreams typically
occur.
[0005] There is a vast body of literature documenting an intimate
relationship between the occurrence of REM sleep on one hand, and
learning and memory on the other. For example, rodents undergoing
intensive water maze learning trials, and humans exposed to
high-intensity learning and memory regimens exhibit increased REM
sleep amounts in subsequent sleep episodes. Likewise, deprivation
of REM sleep inhibits learning and memory on subsequent tasks and
retention of learned information is compromised when followed by
REM deprivation.
[0006] Presentation of auditory, visual, and somatosensory stimuli
just prior to or during sleep has been reported to enhance REM
sleep in laboratory animals and humans, typically without altering
non-REM (NREM) sleep (Block et al., In: Neurobiology of Sleep and
Memory, Drucker-Colin and MacGaugh, eds., New York: Academic Press,
1977, pp. 255-72; Drucker-Colin et al., Brain Res. 278:308, 1983;
Guerrien et al., Physiol. Beh. 45:947, 1988; Mandai et al., Sleep
'86 Sutttgart: Gustav Fischer Verlag, 1988, pp. 382-4;
Merchant-Nancy et al., Brain Res. 681:15, 1988; Vazquez et al.,
Sleep 21:138, 1988). One sensory stimulus that has not been tested
in this regard is photic stimulation. Although rats maintained in
conditions of constant light exhibit more REM sleep per 24 hours
(Vazquez and Neuhaus, J. Comp. Physiol. 128:37, 1978), there is no
report of alteration of REM sleep by administration of a pulse of
light during sleep. Naturally the disruptive effect on sleep of
light administration to the eyes argues against conducting such a
study at all.
[0007] In previous work, the inventors have shown that light
applied to the popliteal fossa (the area directly behind the
kneecap) can affect the biological clock in the same way as light
presented to the eyes (co-owned, co-pending U.S. patent application
Ser. No. 09/074,455 and International Application No.
PCT/US98/09550, Publication No. WO 98/51372, filed May 7 and 11,
1998, respectively, both entitled "Non-ocular Circadian Clock
Resetting in Humans"; Campbell et al., Science 279:376, 1998).
However, there was no indication that non-ocular light exposure
would in any way affect sleep stages or patterns, and particularly
no indication that it could enhance REM sleep.
[0008] Moreover, the discovery that non-ocular light exposure can
shift the circadian cycle cautions against doing anything that
would unintentionally disrupt the circadian cycle in the absence of
an external disruption, such as trans-meridian travel or shift
work.
[0009] As described below, the present invention advantageously
permits enhancement of REM sleep, and concomitant enhancement of
cognitive function. Moreover, by applying the strategies and
devices of the invention, these enhancements can be achieved
without adversely modifying the circadian rhythm.
SUMMARY OF THE INVENTION
[0010] The present invention advantageously provides a method for
enhancing REM sleep in a subject, preferably a human subject. The
method comprises exposing a non-ocular region of a subject to
photic stimulation for an interval during a sleep period. In
particular, this method can increase the number of minutes spent in
REM sleep during the interval of photic stimulation, e.g., by
increasing the frequency of REM periods. The method of the
invention advantageously provides for enhancing cognitive function
in a subject, particularly memory processes. Subjects whom the
invention can assist include those who suffer from a medical
disorder in which mental status is compromised, as well as normal
individuals.
[0011] In a specific embodiment, the invention provides a method
for increasing REM sleep of a person, which method comprises the
steps of sensing the start of the REM cycle; sensing the end of the
REM cycle; determining the time and interval of the REM cycle; and,
augmenting the time interval of the REM cycle by selectively
providing non-ocular photic stimulation for a predetermined
interval. Also provided is a device or an article for increasing
REM sleep of a person. Such an article, which may be adapted to be
worn or attached to the person, includes a sensor which provides
phasic activity signals; a timing circuit connected to the sensor
and outputting an elapsed-interval signal indicative of the
magnitude of the REM cycle; a comparator which compares the
elapsed-interval signal to a predetermined-interval signal and
outputs a shortfall signal; a controller responsive to the
shortfall signal to generate a control signal; and, a photic
stimulator positionable in contact with the person's skin and being
actuated in response to the control signal.
DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1. (Prior art) Perspective view of a device used to
expose a non-ocular region of a human subject to light.
[0013] FIGS. 2A, B, and C. Views of a light-emitting diode (LED)
array device for exposing skin to light. 2A. View of the complete
device. 2B. View of diode array. 2C. Perspective view of the device
attached to the popliteal fossa.
[0014] FIG. 3. Perspective view of a sock article for controlled
delivery of non-ocular light to the top surface of the foot.
[0015] FIG. 4. Block diagram of a circuit for controlling exposer
to non-ocular light.
[0016] FIGS. 5A and 5B. (A) Difference in the percentage of REM
sleep during light exposure in control versus active conditions.
Values from matched control and active sessions are connected.
Dotted lines indicate the three light stimulus intervals during
which the percentage of REM sleep was decreased in active relative
to control sessions. The wide range of percent REM values (e.g.,
0-44% for control intervals) reflects the fact that, while the
clock times of light exposure were identical for the active and
control sessions for a given subject, the 3-hr light stimulus
intervals occurred at varying clock times/circadian phases across
subjects, i.e., at times during which the propensity for REM sleep
is both high and low. (B) Percentage change in minutes of REM sleep
during the light stimulus interval for individual subjects,
arranged in order of magnitude, from -41% to +209%. The median
change in minutes of REM during light exposure was an increase of
30%; denoted by arrow. The mean change was +47%.
[0017] FIG. 6. REM/NREM cycle length in active versusl control
conditions for the segments of sleep that occurred prior to,
during, and after administration of 3 hours of extraocular light
during sleep. Only cycles that occurred completely within the
period indicated were analyzed (e.g., cycles included in the
"pre-lights" cycle length average started and ended in the period
before light exposure commenced). Mean cycle length was
significantly shorter during light administration relative to the
pre- and post-light cycles within the active condition as well as
compared to the light stimulus interval in the control condition
(*<0.05).
DETAILED DESCRIPTION
[0018] The present invention is based, in part, on the recent
discovery that non-ocular (i.e., extraocular) presentation of light
during sleep can increase REM sleep during the time of exposure by
at least about 30%, and by as much as about 200%, with an average
of about 50%. Enhancement of REM sleep results from an increase in
the frequency of REM periods, e.g., by about 40%. This REM sleep
enhancement was found to occur over the entire period of light
administration, up to the entire sleep period. No other sleep
stages were significantly affected during light administration, nor
was sleep architecture altered following the light interval.
[0019] These results confirm that extraocular light is transduced
into a signal that is received and processed by the human central
nervous system. This unexpected and robust finding has potentially
important implications in a number of areas. Perhaps the most
exciting involves the treatment of cognitive deficits associated
with Alzheimer's Disease (AD) and other dementing illnesses, as
well as major depression. The current treatment strategy for
improving mental functioning in such disorders involves the use of
a class of medications referred to as cholinergic agonists, which
have their effect by increasing the bioavailability of
acetylcholine in the brain. Unfortunately, these drugs have
unwanted side effects, particularly in older individuals.
[0020] Because it is well demonstrated that REM sleep is mediated
by cholinergic activity in the brainstem, our working hypothesis is
that extra-ocular light activates cholinergic pathways in the pons,
as well as other areas of the brain including the suprachiasmatic
nuclei (i.e., the biological clock). Thus, although not intending
to be limited by any particular theory, we hypothesize that
extra-ocular light presented during sleep will have the same effect
on the cholinergic system as the currently used medications.
However, the effects mediated by extra-ocular light can be
achieved, without the side effects associated with such medications
and complications of interactions with other medications. In
addition, compliance problems with the treatment regimen will be
reduced or eliminated, since light is administered during sleep.
The result is enhanced REM sleep and, consequently, enhanced waking
function.
[0021] Cognitive performance can be enhanced in healthy individuals
of all ages by increasing the amount of REM sleep in a nighttime
sleep period. Medications that affect the cholinergic system are
not appropriate for healthy individuals. Thus, any individual who
requires, or desires, enhanced waking function stands to benefit
from this discovery.
[0022] A non-drug alternative to enhance cognitive functioning has
significant appeal, both with respect to treatment of medical
disorders in which mental status is compromised, and in terms of
general use for boosting productivity.
[0023] The invention thus has broad applicability for mentally
impaired and normal individuals. This invention is particularly
useful in the timing of photic stimulation, relative to the
disclosures of co-owned, co-pending U.S. patent application Ser.
No. 09/074,455 and International Application No. PCT/US98/09550
(PCT Publication No. WO 98/51372), filed May 7 and 11, 1998,
respectively, both entitled "Non-ocular Circadian Clock Resetting
in Humans", the disclosures of each of which are incorporated
herein by reference in their entirety. Preferably, to enhance REM
sleep and cognitive function with minimum impact on the circadian
clock, exposing a non-ocular region to photic stimulation occurs
both before and after the critical inflection point during sleep:
daily minimum body temperature. This point is achieved at roughly
the same time for each individual, although the time can vary
widely between individuals. The advantage of providing photic
stimulation before and after this point is that biological clock
resetting is minimized, since the prior and subsequent exposures
offset each other's effects. The devices of the invention
advantageously control for the timing of exposure to avoid
circadian clock resetting.
Definitions
[0024] "REM sleep" refers to the period of sleep characterized by
specific phasic activities, including rapid eye movement (REM),
flaccid paralysis (decreased muscle tone), middle ear muscle
activity, twitching of the extremities (such as the big toe), etc.
This is the sleep cycle in which most dreams occur. REM sleep
generally occurs in regular intervals of about 90 minutes, and
lasts about 20 minutes. Increasing the amount of REM sleep has
positive effects on cognitive function, particularly on memory
processes. The present invention increases the frequency of REM
episodes, i.e., it decreases the interval to less than 90 minutes.
By shortening this cycle time, the invention increases the total
number of REM episodes, and thus the total amount of REM sleep. It
may also be possible to increase the length of a REM episode or
episodes. The increase in REM sleep appears to be offset for the
most part by a decrease in stage 2 sleep, and to some degree stage
1 sleep.
[0025] "Cognitive function" includes, but is not necessarily
limited to, the ability to reason and solve problems, short term
and long term memory processes, visual discrimination and
perceptual skill, and learning.
[0026] A "medical disease or disorder in which mental status is
compromised" can include a neurodegenerative disease, such as
Alzheimer's Disease, Parkinson's Disease, and senile dementia;
major depression; schizophrenia; stroke; childhood learning
disorders such as attention deficit disorder (ADD) and, possibly,
dyslexia (in which improvement may result from increasing
compensation skills rather than directly correcting dyslexia);
alcohol and drug abuse; and normal aging.
[0027] A "normal" individual is a person whose cognitive function
and overall mental status is within normal ranges, and who would
not be diagnosed with or assessed as having a disease or disorder
in which mental status is compromised.
[0028] A "subject" is any animal, preferably a mammal, and more
preferably a human, who undergoes or experiences REM sleep. The
term "subject" specifically excludes newborns suffering from
hyperbilirubinemia, who receive 24-hour light therapy for a few
days to two weeks after developing jaundice. In addition to humans,
which are exemplified herein, the methods of the invention are
expected to enhance REM sleep and cognitive function in any animal
that undergoes REM sleep, such as but not limited to, dogs, cats,
horses, circus animals, etc., particularly to enhance learning
during training of the animal. Thus, although the focus of the
methods and devices of the invention is on modulation of REM sleep
in humans, it can be extended to other animal species, particularly
the species enumerated above.
[0029] The terms "non-ocular" and "extra-ocular" refer to any part
of the body besides the eyes. It is possible that during the sleep
period a subject may observe the light source. However, such visual
stimulation would not alter the invention, since by definition the
person stimulated visually must be conscious, not asleep. The REM
enhancement occurs in sleeping individuals. Preferably, the
non-ocular region has ample surface vasculature, so that
light-responsive factors present in blood can react to the photic
stimulation. Non-ocular regions of the body include, but are by no
means limited to, the ear/inner ear; feet, especially the top
surface of the feet; arms, especially the inner elbow; legs,
especially the inner knee (popliteal fossa); and abdomen. The head
is also rich in vasculature, which suggest that cranial exposure
may be useful, particularly for people who have lost their hair or
have very short or thinning hair. Alternative sites on the head
include the forehead, the temples, and the neck. Naturally, the
adopted strategy for delivering photic stimulation preferably
avoids awaking the subject, so should be administered away from the
eyes or in such a way that the eyes are not likely to detect the
stimulation.
[0030] The term "photic stimulation" as used herein refers to the
exposure of a non-ocular region of the body to light, i.e.,
irradiation by photons. In a specific embodiment, the term "photic
stimulation" means non-solar light, i.e., excludes sunlight. For
example, solar photic stimulation might occur during a nap on the
beach (if such a nap lasted long enough for REM sleep to occur).
However, sunlight carried on optical fibers, e.g., from an aperture
in an otherwise darkened room, is regarded as non-solar light.
Preferably the light is not accompanied by heat. If there is any
heat generated by the photic stimulation, it should be minimized. A
number of strategies can be used to deliver the photic stimulation,
i.e., the light, including fiber optics, light emitting diodes
(LEDs), chemiluminescent molecules, etc. Light sources for fiber
optics include incandescent, fluorescent, and halogen lamps.
Preferably, the photic stimulation is in the visible range, e.g.,
broad-band white light, more preferably in the blue-green portion
of the spectrum (e.g., from about 455 to about 540 nm). It may also
be possible to use harmonics of these wavelengths. The intensity of
photic stimulation, which depends on the power of the light source
and the proximity of the non-ocular region to the light source, can
range from about 15 lux to about 150,000 lux, and preferably ranges
from about 10,000 lux to about 13,000 lux.
[0031] The term "interval" is used herein to refer to the time of
photic stimulation. There may be one interval or more than one
interval during any sleep period. The interval or intervals have a
period of photic stimulation, i.e., light exposure. The duration of
an interval of photic stimulation can range from about 15 minutes
to about 12 hours; multiple short duration intervals are possible.
In a specific embodiment, infra, the duration is about three hours.
Preferably, for maximum enhancement of REM sleep, the interval
starts when the subject retires to sleep, and continues until the
subject arises. This strategy ensures that exposure will proceed
and follow the critical inflection point. Alternatively, the
interval and duration can be determined by detecting the onset and
duration of natural REM sleep, as described below.
[0032] The term "sleep period" is used herein to refer to the time
in which a subject is asleep, i.e., from the time of falling asleep
after going to bed until arising. While sleep periods generally
occur at night, REM sleep can be enhanced during daytime sleep as
well, e.g., for a shift worker or someone taking a nap. Indeed,
shorter sleep periods may be more effective if REM sleep is
enhanced.
[0033] As used herein, the term "about" or "approximately" means
that a value can fall with an acceptable range or acceptable
standard deviation for the nature of the particular value and its
measurement, e.g., 20%, preferably 10%, more preferably 5%, of a
defined value.
Devices for Enhancing REM Sleep
[0034] The method described herein requires that a sleeping human
subject be exposed to a non-ocular light source under conditions
sufficient to enhance REM sleep. Thus, the invention contemplates
various devices, apparatus, articles, and the like to supply
extraocular light in a controlled manner, i.e., to avoid disrupting
circadian rhythms. The terms device, apparatus, and article are
used herein interchangeably, although an article can specifically
refer to clothing or some other body covering specifically modified
to provide non-ocular light.
[0035] The invention envisions several different mechanisms for
transmission of the light, including but not limited to, fiber
optic configurations (see U.S. Pat. No. 5,300,097), light emitting
diode (LED) arrays (see U.S. Pat. No. 5,259,380; preferably held on
a flexible pad or appliance, e.g., as described in U.S. Pat. No.
5,358,503), and bioluminescent or chemiluminescent derivations.
Light sources, e.g., for use with fiber optics, include but are by
no means limited to incandescent, halogen, and fluorescent light
lamps that produce light in the visible, and preferably blue-green,
wavelengths (see U.S. Pat. No. 3,670,193). Preferably, such light
sources are part of a device, which may operate on an automatic
timer or under computer control.
[0036] More preferably, the device includes a feedback mechanism so
that exposure occurs during a sleep period for a desired interval.
The feedback mechanism may comprise a sensor for detecting phasic
activity associated with REM sleep. Through microprocessor control,
the frequency and duration of REM sleep can be monitored and, by
activating the light source, frequency or duration, or both, of REM
sleep modified to increase total REM sleep a desired amount, e.g.,
by turning on the light to increase the frequency of REM sleep
periods. Thus, a device of the invention may be operated by a
pre-programmed or programmable microprocessor that regulates the
time and interval of light exposure. Such a program can monitor:
(1) the length of REM cycles; (2) the length of REM periods; (3)
the total amount of REM sleep over a defined time, and judge
whether and how much to enhance REM sleep.
[0037] In a specific embodiment, controlling exposure of the photic
stimulation in response to phasic stimuli can extend the REM period
or increase REM frequency, or both. As demonstrated in the
examples, non-ocular photic stimulation increases REM frequency (by
decreasing the NREM periods).
[0038] The sensor for detecting a phasic event can be vibration
sensitive, e.g., for toe twitches, or an electromyographic (EMG)
electrode to evaluate muscle tone, middle ear muscle activity, eye
twitching, or other phasic activity.
[0039] A preferred timer element of a device of the invention will
function to provide non-ocular photic stimulation for a period that
extends through the daily minimum body temperature. This point is
achieved at roughly the same time each day for each individual,
although the time can vary widely between individuals. In any
event, the point of daily minimum body temperature can be
calibrated for any given individual and used to set a timer control
on the device.
[0040] The invention envisions the use of these various devices
designed to facilitate light exposure to a wide range of non-ocular
sites. For example, a device is envisioned by which the foot or
hand is covered (like a sock or glove), thereby exposing the entire
area to illumination; another device is one by which the tympanic
membrane is illuminated by LEDs incorporated in headphones or
earplugs; another device is one by which the midriff is exposed to
light by an illuminated wrap; another device is envisioned in which
the source of illumination is not worn by the subject but
illuminates a non-ocular site, for example, partially-illuminated
bed linens.
[0041] Energy to operate the aforementioned devices may be provided
by a variety of power sources that would enable the devices to be
stationary or portable, for example a standard AC outlet or a
battery. For example, a 6.times.4 blue LED array device of the
invention can be powered by a battery pack comprising 6 "AA" 1.5
volt batteries, or one or more 9 volt batteries in parallel.
Examples of Devices and Articles to Enhance REM Sleep
[0042] The device 100 shown in FIG. 1, which was originally used to
reduce the method to practice as described in the example infra,
can be altered in a number of ways to facilitate various
applications of the method. As described in the Example, the fiber
optic pad 160 can be wrapped against the popliteal fossa, or
alternatively the inside of the elbow, the calf or thigh, or around
the abdomen. Alternatively, this device can be attached to fabric
article, such as but by no means limited to, a sheet, blanket,
and/or pillow case; undergarments and/or t-shirts; or a nightgown
or pajamas (preferably removably attached so that the fabric
article can be laundered). Preferably, the fiber optic cable 140 is
positioned to minimize contact with the subject. The lamp housing
120 can be plugged into an electrical outlet.
[0043] An LED device 200 is shown in FIG. 2A. This device comprises
an array 210 of 24 blue, high intensity LEDs 220 (FIG. 2B). The LED
array may be supported on a flexible backing 220. In a specific
embodiment, the flexible backing can be a black cloth fabric to
which the array is adhered with bath tub caulk or an equivalent
composition. The array 210 has an area of approximately
2.5".times.2.5". It can be run by ten "AA" batteries, or two 9V
batteries, placed in pack 230. As shown in FIG. 2C, the LED array
and batteries can be strapped onto the leg or other non-ocular
region using for example, but not by way of limitation, velcro
straps 240, or an elastic wrapping or brace, or sock, e.g., as
described below.
[0044] An apparatus in accordance with another aspect of the
invention can be worn as an article of clothing, such as a sock, a
pair of pajamas, or a band of some sort, or otherwise can be
positioned in proximity to a person's skin, for example, through a
pillow, sweat band, or chair. With reference to FIG. 3, an article
300 constructed in accordance with this aspect of the invention
includes a housing 310 which can be affixed to a person in any
conventional manner such as by a strap or by a hook-and-loop
attachment to a conventional article of clothing; the manner of
attaching the article 300, however, forms no part of the present
invention. As shown in FIG. 3, hooks 320 are supported on a front
face of the housing and loops 330 are provided on a sock 340. (By
placing the loops on the sock, the sock will not stick to other
articles of clothing when washed.)
[0045] The article 300 includes a sensor 350 which is provided to
sense the onset and completion of a natural REM cycle. As
understood by those of skill in the art, during a REM cycle there
are a variety of muscle groups that are active and which can be
monitored to gauge the beginning and end of a REM cycle. For
example, muscles undergo flaccid paralysis during a REM cycle.
Other muscle groups demonstrate twitching phenomenon. Changes from
active to inactive and from inactive to active can be monitored to
gauge the length of a REM cycle. A presently preferred method
monitors the inactive to active transition as indicating the start
of a REM cycle and active to inactive as indicating the end of the
cycle. For example, a person's toes twitch during REM but not
otherwise. The sensor may take on a variety of forms but preferably
is suitable for sensing phasic activity, and most preferably is an
electromyographic (EMG) electrode.
[0046] The sensor 350 communicates with circuitry, for example,
circuitry within the housing, by way of an insulated connecting
wire 360. The housing further includes a light source which may be
within the housing behind a light-transmissive window 370 (as
shown) or which may be flush with or project from the housing. In
use, the housing 310 is mounted on an article of clothing such as
the sock 340 by connecting the hooks 320 to the loops 330 which
preferably causes the window 370 or light source to shine directly
on the person's skin. Thus, for example, the article of clothing
340 may have an aperture 380 in register with the window 370 or
light source, or may have a light-transmissive material positioned
to permit light to shine on the person's skin (e.g., the clothing
may include stretched rayon or the like).
[0047] With reference now to FIG. 4, a block diagram of a circuit
400 in accordance with this aspect of the invention is illustrated.
The circuit includes the sensor 350 described above and a light
source 410 which may be positioned behind the window 370 of the
housing 310 or be exposed exteriorly of the housing. The phasic
activity detected or sensed by the sensor 350 are provided to a
timing circuit 420 for the purpose of determining the length of the
person's REM cycle or period of the REM episode, or both. The
timing circuit 420 may take on a variety of forms, the particulars
of which are not material to the invention. The timing circuit most
preferably is implemented using digital circuitry and may comprise
a clocking circuit, an interval timer, or pulses stored in a
digital circuit from which the passage of time can be gauged by a
digital processor. Alternatively, however, the timing circuit can
be implemented using analog components such as an RC timing circuit
and voltage detector arrangement as understood by those of skill in
the art. In either case, the timing circuit outputs an
elapsed-interval signal which is indicative of the magnitude (that
is, length) of the REM cycle or REM period, or both.
[0048] The elapsed-interval signal is provided as an input to a
comparator circuit. The comparator also receives a reference signal
from a data store 435, preferably, a reference signal which
represents a predetermined-interval of time or other determined
interval, as described below. The comparator compares these signals
and outputs a shortfall signal which is indicative of the degree to
which the person's REM cycle varies in time from the reference
signal setting.
[0049] A controller 440 responds to the shortfall signal by
generating a control signal which, in turn, controls actuation of
the light source 410 by completing a circuit which includes the
light source 410 and its power supply 450. The circuit is completed
by closing a switch 460 which may be a relay switch or transistor.
When the light source is positioned in contact with or proximate to
the person's skin (e.g., when connected to an article of clothing
such as sock 340), the actuated light has an effect on the brain
mechanisms controlling sleep of the person such that the REM
episode, as detected by the sensor 350, is extended for a period of
time thereafter or a new REM episode is initiated sooner.
[0050] Optionally, the controller 440 can provide updated
information to the data store 350 as the person advances through
one or more complete sleep cycles by way of connection 470 (shown
in phantom). The updated information can be used to modify the
natural period, frequency, or both, of REM sleep.
EXAMPLES
[0051] The invention will be better understood by reference to the
following examples, which are provided as exemplary of the
invention and not by way of limitation.
Example 1
Enhancement of REM Sleep During Extra-Ocular Light Exposure
[0052] Administration of sensory stimuli just prior to or during
sleep has been shown to enhance REM sleep in humans and other
mammals (DeGennaro et al., Int. J. Neurosci. 82:163-8, 1995;
Merchant-Nancy et al., Brain Res. 681:15-22, 1995; Vazquez et al.,
Sleep 21:138-42, 1998). Such changes in REM sleep do not appear to
be modality-dependent, as auditory, somatosensory, and visual
stimuli enhance REM to similar degrees (ibid). This Example shows
that sensory stimuli, in the form of light presented to a
non-ocular site during sleep, results in acute changes in REM sleep
during the stimulus interval.
Methods
[0053] A total of 16 individuals were studied on two occasions,
separated by at least 10 days. During one lab session, subjects
were exposed to a 3-hr light stimulus during sleep; the other
session was identical with the exception that a sham light stimulus
was administered during sleep instead. The clock times of active
and control light exposure were matched for each individual.
Following an adaptation night in the laboratory, 4 of the 16
individuals studied were exposed to the stimulus during one sleep
period at each session; the other 12 subjects were exposed to the
stimulus on two consecutive nights at each session. Polysmnography
(PSG) was recorded throughout each of the sleep episodes in which a
light stimulus was administered.
[0054] The protocols were approved by the Institutional Review
Board of Weill Medical College of Cornell University, and
participants gave written informed consent prior to participation
in each laboratory session.
[0055] In the active condition, one fiber optic light source
(Biliblanket Plus Phototherapy System, Ohmeda Inc.) which emitted
approximately 13,000 lux was placed on the popliteal fossa of each
leg prior to bedtime. Each light delivery device consists of a
halogen lamp in a vented metal housing, which also contains a small
fan to disperse heat generated by the lamp. Illumination from the
halogen bulb leaves the housing through 2400 optic fibers encased
in a flexible plastic tube. The optic fibers terminate in a woven
pad, approximately 10 cm.times.15 cm and 0.64 cm thick, that
provides illumination without generating heat. The light pads were
completely covered by athletic bandages wrapped around the legs.
Automatic timers activated the light delivery devices at
predetermined clock times and extinguished them 3 hours later. In
the control condition, the light pads were placed in a manner
identical to the active condition, with the exception that opaque
black fabric sheaths were placed over the pads to insure that no
light reached the skin. While the clock times of light exposure
were identical for the active and control sessions for a given
subject, the 3-hr. light interval was scheduled to occur at a
variety of clock times across subjects. Thus, sleep and light
exposure occurred at varying times throughout the 24-hour day.
[0056] A total of 28 pairs of PSG records (i.e., matched pairs of
active and control light nights from the 16 subjects), were scored
according to standard criteria (Rechtschaffer and Kales, A manual
of standardized terminology, techniques and scoring system for
sleep stages of human subjects, Washington, D.C.: National
Institute of Health, 1968 vol., publ. 204) in 30-sec epochs by
trained scorers who were blind to subject and condition. Because
the primary aim of this study was to assess the effects of
extraocular light presented during sleep, if the proportion of time
spent asleep during the light interval was less than 80%, or if the
proportion of time spent asleep throughout the entire sleep period
(from sleep onset to terminal awakening) was less than 80%, the
data from that night and the subject's matching record from the
corresponding condition were excluded from analysis. Application of
this criterion resulted in the exclusion of 5 pairs of records from
analysis. The remaining 23 matched pairs of records included in all
analyses were from 14 subjects (mean age 37.4 years, range 25-68
years; 13M, 1F).
[0057] Primary analyses focused on whether sleep was altered during
the light stimulus administration. Of secondary interest was
whether there were changes in sleep following the light stimulus
interval. Thus, sleep parameters were compared across active and
control conditions first for the 3-hr light versus sham stimulus
interval and then across the post-stimulus intervals. The frequency
and duration of discrete episodes of REM sleep (Webb and Dreblow,
Sleep, 5:372, 1982) were similarly analyzed for the segments of
sleep that occurred during the light stimulus interval and
post-lights. Of interest with regard to the REM/NREM cycle length
was the change in cycle length within the sleep period during which
active lights were administered, from pre-, to during-, to
post-light stimulation. Therefore, the REM/NREM cycle length across
the sleep period relative to light administration was analyzed. In
addition, a comparison of the length of REM/NREM cycles that
occurred completely within the light stimulus intervals between
active and control conditions was performed.
Results
[0058] Comparisons of sleep stage variables across experimental
conditions indicated that the number of minutes spent in REM during
the 3-hour light interval increased significantly from a group
average of 27.0.+-.13 min in the control condition to 35.5.+-.14
min in the active condition (t(22)=3.06, p<0.01). This 8.5
minute change in the group average represents a 31% increase in REM
sleep over control levels. The significant increase in percentage
of REM was observed in 12 of the 14 subjects studied (in 19 of the
23 matched pairs of sleep periods) (binomial test p(12)=0.006).
Nearly two-thirds of the subjects (9 out of 14) exhibited increases
in REM greater than the group average. For individual subjects, the
absolute change in minutes of REM ranged from -19 to +35 during
light exposure (see FIG. 5A). The percentage change in REM sleep
from the control to the active condition averaged 47% and ranged
from -41% to +209% (median=+43%) (FIG. 5B).
[0059] Only REM sleep was significantly altered by light
administration. The increase in REM was accompanied by small
decreases in wakefulness and all NREM sleep stages (Table 1). None
of the changes in other sleep stages or in wakefulness during the
light interval was significant. In addition, the changes in sleep
were limited to the light stimulus interval. There were no
differences in the amount of wakefulness or in any stage of sleep
prior to or following light administration (Table 1).
1TABLE 1 Sleep stage variables for segments of sleep periods
occurring before, during, and after a 3-hr interval of light
exposure to the popliteal fossa of human subjects during sleep.
Sleep Percent (SD) of polysommnographically- period segment
(relative to scored sleep stage* light exposure interval Wake 1 2
3/4 5 pre-lights Control 35 (34) 6 (4) 26 (14) 26 (18) 8 (9) Active
31 (28) 7 (7) 28 (14) 26 (21) 8 (12) during lights Control 12 (10)
6 (3) 41 (11) 27 (15) 14 (5) Active 8 (5) 6 (3) 38 (14) 28 (27) 20
(6) post-lights Control 15 (12) 9 (9) 44 (12) 11 (7) 21 (11) Active
17 (24) 6 (4) 42 (20) 11 (9) 24 (20) entire sleep Control 11 (5) 6
(2) 41 (11) 24 (12) 21 (6) period Active 14 (8) 6 (2) 41 (8) 25
(13) 18 (5) *Wake and sleep stage percentages expressed as a
proportion of minutes during the indicated segment (e.g., for
entire sleep period, percentages were calculated as: (minutes of
stage X/minutes from bedtime until final awakening) .times.
100).
[0060] Likewise, for those subjects who received light pulses on
two consecutive nights, there were no first versus second night
differences in sleep. While, as expected, the absolute amount of
REM was influenced by the time of day during which the light
stimulus occurred, the enhancement of REM sleep was not time-of-day
dependent (i.e., REM sleep enhancement occurred during times when
the propensity for REM sleep is both high and low).
[0061] The mean duration of individual REM periods (REMP) during
the control versus the active condition did not differ
(22.4.+-.12.4 min vs. 22.8.+-.13.5 min, n.s.). Rather, the observed
augmentation of REM sleep was due to an increase in the number of
discrete REM sleep episodes that occurred during the 3-hour light
stimulus intervals (Wilcoxon signed rank test of REM episode
frequency in the control vs. active light conditions: 1.17.+-.0.72
vs. 1.59.+-.0.59 episodes; z=2.11, p<0.05). The number of REM
periods occurring in the rest of the sleep period (i.e., before
lights on and following lights off) did not differ between
conditions. The increase in REM period frequence necessarily
resulted in a shortening of the REM/NREM cycle length during the
fixed duration light stimulus interval (FIG. 6). Indeed, an
unpaired t-test comparing the duration of REM/NREM cycles that
occurred completely within the light stimulus interval revealed
that the mean cycle length was significantly shorter during the
active (n=14; 84.4.+-.7/6 min) than during the control condition
(n=11; 103.7.+-.6.5 min)(t(23)=2.33, ; p<0.05). The mean
REM/NREM cycle length did not differ as a function of condition
either prior to or following the light stimulus interval (FIG.
6).
[0062] While, as expected, the absolute amount of REM sleep
obtained in a given sleep period was influenced by the time of
day/circadian phase during which the sleep period and the light
stimulus occurred, the enhancement of REM sleep was not time-of-day
dependent. That is, REM sleep enhancement occurred during times
when the propensity for REM sleep is both high and low. For
example, three individuals who received a light pulse at either
2200-0100 h, 0500-0800 h, or 1630-1930 h, exhibited changes in
percentage of REM sleep during the light interval of +30%, +39%,
and +44%, respectively.
[0063] Comparisons of sleep variables on the first versus second
night of light administration (for the 9 subjects who received
light pulses on two consecutive nights) revealed no significant
night-to-night differences. The lack of night-to-night variation in
sleep parameters in the active condition suggests that there was no
"habituation effect" to the photic stimulus, as there was no
decrease in REM sleep amounts from the first to the second stimulus
periods.
[0064] Because extraocular light administration affects the
circadian timing system in vertebrates, including humans (Campbell
and Murphy, Science, 279:376, 1998; Underwood and Groos,
Experientia, 38:989, 1982), it is conceivable that the increase of
REM sleep was due to an immediate shift in the timing of REM sleep,
either within or following the light exposure interval. To evaluate
the possible immediate effects of extraocular light exposure on REM
period timing, the latency from lights-on to the first occurrence
of REM sleep during the first light presentation was calculated.
The timing of the first REM period during light administration did
not differ between active and control conditions (control: 63.+-.50
min vs. active: 62.+-.36 min, n.s.), suggesting that a shift in the
timing of REM sleep was not responsible for the observed
enhancement of REM sleep during light exposure. Moreover, an
immediate phase shift (advance or delay) in REM sleep expression
would presumably result in differences in the amount of REM sleep
or distribution of REM periods not only during the 3-hr light
interval, but in the remainder of the sleep period following light
exposure, as well. Such was not the case (Table 1; FIG. 6).
[0065] Preliminary analysis of four subjects' data, who were
exposed to light throughout their sleep periods (as opposed to the
3-hour exposures described in the paper), revealed that REM sleep
continued to be enhanced by an average of about 30%.
Discussion
[0066] The data reported here provide additional, strong evidence
that light presented to a site other than the eye is transduced
into a signal that can influence brain function. Unexpectedly, in
this case, the light signal administered to a peripheral site was
transmitted to brain structures involved in REM sleep. Thus,
surprisingly like other modes of sensory stimulation (DeGennaro et
al., supra; Merchant-Nancy et al., supra; Vazquez et al., supra),
extra-ocular light presented to sleeping subjects had a significant
effect on REM sleep. The known modes to alter REM sleep generally
increase the REM period. In contrast, at least in some cases, the
present invention increases REM frequency, although the ability of
extraocular light to increase the REM period must be
considered.
[0067] There is ample evidence to indicate that photoreceptors
exist in the largest sense organ--the skin--and that the sequelae
of phototransduction via dermal light receptors includes effects on
central nervous system processes and on behavior (Steven, Biol.
Rev. (Camb. Philos. Soc.) 38:204, 1963; Tosini and Avery, Physiol.
Beh. 59:195, 1996; Ullen et al., Behav. Brain Res. 54:107, 1993).
In the current study, the light signal administered to a peripheral
site during sleep was transmitted to the central nervous system and
influenced the generation of REM sleep. The enhancement of REM
sleep observed during exposure to extraocular light in this study
appears to reflect an acute effect of light administration on the
REM sleep generating system, rather than a "downstream" result of
manipulating the circadian clock.
[0068] These results may be explained by several possible
mechanisms. Cholinergic pathways that are activated by sensory
stimuli (Merchant-Nancy, el al., Brain Res. 681:15-22, 1995), and
possibly involved in the transduction of photic information to the
circadian timing system (Earnest, et al., Proc. Nat'l. Acad. Sci.
USA, 82:4277-81, 1985) could account in part for both the observed
effects on REM sleep as well as the phase-shifting effects of
extra-ocular light in awake individuals (Campbell, et al., Science,
279:376-9, 1998). Alternatively, serotonergic modulation of
responses to light (Challet, et al., J. Biological Rhythms,
13:410-21, 1998), as well as serotonergic transmission from the
dorsal raphe during sleep (Meyer-Bernstein, et al., J. Neurosci.,
16:2097-1111, 1996) might underlie the REM enhancement resulting
from administration of light to sleeping humans.
[0069] With regard to the effects of decreased REM sleep, it is
well-established that experimentally induced REM sleep deprivation
in animals and humans has detrimental effects on memory (Smith,
Neurosci. Biobeh. Rev. 9:157, 1985; Vogel, Arch. Gen. Psychiatry,
32:749, 1975). Further, while there are only slight decreases in
typical REM sleep amounts in healthy older humans relative to their
younger counterparts, a significant decrease in the proportion of
REM sleep, as well as a delay in the onset of the first REM period,
are hallmarks of age-related dementing disorders (Montplaisir et
al., Sleep, 18:145, 1995). Indeed, the proportion of REM sleep, REM
density (i.e., the number of rapid eye movements per unit of time),
and REM latency have been used to distinguish normal, depressed,
and demented older individuals (Dykierek et al., J. Psychiatric
Res. 32:1, 1998; Vitiello et al., Biol. Psychiatry, 19:721,
1984).
[0070] That REM sleep is altered in demented patients is consistent
with the "cholinergic hypothesis" of Alzheimer's disease, which
posits that a deficiency in cholinergic transmission and/or
production in the central nervous system is responsible for many of
the symptoms of the disease. Accordingly, the treatment of dementia
in Alzheimer's disease relies heavily on cholinomimetic agents and
aceylcholinesterase inhibitors (Peskind, J. Clin. Psychiatry 59
(Suppl. 9):22, 1998; Polinsky, Clinical Therapeutics 20:634, 1998).
These drugs have also been shown to enhance REM sleep
(Holsboer-Trachsler et al., Neurophyschopharm. 8:87, 1993; Riemann
et al., Psychiatry Res. 51:253, 1994), a feature that places them
among the few means by which REM sleep can be augmented. Yet, the
decreased metabolism of drugs in aging, as well as an increased
risk of side effects and multiple drug interactions in the elderly
make non-pharmacological therapies attractive for this population.
Thus while cholinergic drugs may effectively increase REM sleep and
also attenuate symptoms of dementia, a non-invasive,
nonpharmacological technique by which this could be accomplished is
highly desirable. In this regard, the finding that REM sleep is
enhanced during extraocular light exposure can be utilized to
develop a novel approach to ameliorating symptoms of dementia.
[0071] In the current study, administration of extraocular light
resulted in an average increase in REM sleep of 31% during the
light exposure interval. This degree of enhancement is comparable
to or larger than the increase in REM sleep following
administration of cholinergic agents, DHEA, or other modalities of
sensory stimulation. Means of augmenting REM sleep are rare,
warranting elaboration of the initial discovery.
[0072] A longer interval of light exposure led to proportional
increases in REM sleep. Previous studies in which REM sleep was
altered by sensory stimulation have yielded results suggesting that
determinants of the manner in which REM sleep is influenced are
numerous and complex. For example, sensory stimuli have been
reported to alter REM period frequency, REM period duration, or
phasic REM events (e.g. eye movements, muscle twitches). The effect
on REM sleep induced by sensory stimulation appears to depend on
several factors, including pre-sleep brain activation levels,
stimulation modality, the timing of sensory stimulation relative to
individual rapid eye movements, and whether or not the sleep period
was preceded by an intensive learning session. A study using
auditory stimulation for varying durations and across multiple
sleep periods in rats indicated that there was no habituation
effect, which is consistent with our observation that further
increases in REM sleep are possible with more prolonged non-ocular
light stimulation.
[0073] Further analyses of these data focused on the composition of
sleep, particularly the effects of extra-ocular light on the
frequency, duration, and consolidation of discrete REM periods, may
elucidate additional benefits of this treatment. In addition,
relationships between circadian phase-resetting effects and
alterations in sleep resulting from administration of extra-ocular
light during sleep may be examined.
[0074] The present invention is not to be limited in scope by the
specific embodiments described herein. Indeed, various
modifications of the invention in addition to those described
herein will become apparent to those skilled in the art from the
foregoing description and the accompanying figures. Such
modifications are intended to fall within the scope of the appended
claims.
[0075] It is further to be understood that all values are
approximate, and are provided for description.
[0076] All patents, patent applications, publications, and other
materials cited herein are hereby incorporated by reference in
their entireties.
* * * * *