EP0386161A1 - Portable light unit for stimulating neuroendocrine system - Google Patents

Portable light unit for stimulating neuroendocrine system

Info

Publication number
EP0386161A1
EP0386161A1 EP19890903619 EP89903619A EP0386161A1 EP 0386161 A1 EP0386161 A1 EP 0386161A1 EP 19890903619 EP19890903619 EP 19890903619 EP 89903619 A EP89903619 A EP 89903619A EP 0386161 A1 EP0386161 A1 EP 0386161A1
Authority
EP
European Patent Office
Prior art keywords
light source
lux
patient
light
illuminance
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP19890903619
Other languages
German (de)
French (fr)
Other versions
EP0386161A4 (en
Inventor
George C. Brainard
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thomas Jefferson University
Original Assignee
Thomas Jefferson University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thomas Jefferson University filed Critical Thomas Jefferson University
Publication of EP0386161A1 publication Critical patent/EP0386161A1/en
Publication of EP0386161A4 publication Critical patent/EP0386161A4/en
Withdrawn legal-status Critical Current

Links

Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N5/0613Apparatus adapted for a specific treatment
    • A61N5/0618Psychological treatment
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M21/00Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M21/00Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis
    • A61M2021/0005Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis by the use of a particular sense, or stimulus
    • A61M2021/0044Other devices or methods to cause a change in the state of consciousness; Devices for producing or ending sleep by mechanical, optical, or acoustical means, e.g. for hypnosis by the use of a particular sense, or stimulus by the sight sense
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61NELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00Radiation therapy
    • A61N5/06Radiation therapy using light
    • A61N2005/0635Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643Applicators, probes irradiating specific body areas in close proximity
    • A61N2005/0645Applicators worn by the patient
    • A61N2005/0647Applicators worn by the patient the applicator adapted to be worn on the head
    • A61N2005/0648Applicators worn by the patient the applicator adapted to be worn on the head the light being directed to the eyes

Definitions

  • This invention relates to apparatus and treatments for phototherapy and in particular to more convenient treatments for affecting the neuroendocrine system, circadian rhythms and circannual rhythms in humans.
  • Phototherapy the use of light as a treatment, has been successfully used to treat a number of diseases including psoriasis and rickets. More recently, scientists have discovered that sunlight plays a critical role in the regulation of circadian and circannual rhythms in humans. Accordingly, increased attention is being paid to the use of phototherapy in diseases influenced by daily and seasonal rhythms. Phototherapy has been demonstrated to have significant effects in the treatments of several diseases of particular interest to psychiatrists, including affective illness and chronolbiological disorders.
  • One currently prescribed treatment for phototherapy is to have patients sit approximately three feet from a light box which typically has dimensions of about 2* by 4* . These light boxes are generally awkward and cumbersome to use. Furthermore, the patients are required to sit in one spot for approximately one to five hours, depending on their specific therapy. This has been found to be restrictive and limiting. Additionally, these devices are difficult to transport due to their size and weight and generally require an external power source.
  • an improved phototherapeutic device and phototherapy method are provided.
  • the invention is designed to stimulate the neuroendocrine and circadian systems circannual of the patient with a very bright light of at least 200 lux.
  • This light is portably mounted to a portion of the patient's body, preferably the head, and is directed towards the patient's eyes.
  • the light preferably uses a full white light spectrum and is supplied with power by a battery which is preferably rechargeable.
  • the invention also may chose to deflect heat generated from the light away from the person wearing the unit. It is envisioned that the light can be equipped with a dimmer switch or rheostat so that the user may reduce the intensity of the bulbs.
  • the device can be equipped with filters, such as dichroic filters, neutral density filters and those filters designed to block or screen designated radiation, such as infrared or ultraviolet light. Such filters can be interposed between the lamp of the light and the user's eyes.
  • a phototherapeutic device and method which permit uninterrupted patient activity during treatment.
  • the device can be used for the treatment of depression, such as SAD, or used by healthy people involved in shift work to overcome resistance by their internal clocks.
  • Shift work challenges the normal biological rhythms of human beings. People who change work shifts often report psychological discomfort and negative health consequences. Accidents and health related absenteeism are often higher among shift-workers due to the stress in changing schedules.
  • the use of the phototherapeutic device of this invention may prove beneficial in resetting the person's biological clock when he or she changes shifts.
  • an estimated 20-25% of the work force in the United States is involved in some form of shift work.
  • the phototherapeutic device of this invention may be useful for people who travel by plane over multiple time zones. Such travelers experience a malady known as "jet-lag" which can debilitate the traveler for one to four days after the flight. As with shift workers, the device of this invention might be used for a more rapid, effective resetting of the internal biological clock, allowing prevention or quicker recovery from jet lag.
  • an object of this invention to provide a portable, head-mounted phototherapeutic device for the treatment of psychiatric disorders.
  • FIG. 1 is a perspective illustration of a preferred portable phototherapeutic device of this invention, equipped with a side-mounted battery pack, dimmer switch, light source and heat deflector;
  • FIG. 2 is perspective illustration of another preferred, portable, phototherapeutic embodiment having a top-mounted battery pack and front-mounted light source;
  • FIG. 3 is a perspective view of another photo- therapeutic embodiment of this invention including a front mounted light source and filter; and FIG. 4 : is a transverse view of another phototherapeutic embodiment of this invention which includes a front mounted light source and remote battery pack for providing a lighter weight construction.
  • FIG. 1 there is shown a portable phototherapeutic device 10 having a heat deflector .16. and head mounting device 5.
  • the device .3-0 s provided with a light source .12. and battery pack JL4.. It becomes readily apparent that this device 10. overcomes the problems of excessive size and weight and limited mobility by being light weight, self- contained and head-mounted.
  • the device 10 can also be fitted with a rheostat Ig. for permitting a patient to adjust the intensity of the light source 12.
  • FIG. 2 An alternative embodiment is illustrated in FIG. 2 which describes a phototherapeutic device 0. having a light source mounted on an extension of the head mounting means 5..
  • the battery pack 24. of this embodiment 2J) is located along the top portion of the head mounting means j.
  • a phototherapeutic device 3_p_ having a radiation shield ⁇ 36. is described.
  • the light source 3_2., of this embodiment is attached to the head mounting means 5.
  • Disposed between the eyes of the user and the light source 32 is a filter designed to block or screen designated radiation, such as infrared or ultraviolet light.
  • the filter 3 could also be a dichroic or neutral density filter.
  • a light-weight phototherapeutic device 43 having a remote battery back 4 .
  • the light source 4_2. is disposed on a mounting means 4J3., which can generally assume the shape of a sun visor.
  • the device £0 is equipped with a member 4j5 which can correspond to a radiation filter and/or a heat deflection shield.
  • a strap 48. can be provided for adjustment to various head sizes.
  • the light sources JL2, £2., 32 or 42 preferably comprises an incandescent lamp, preferably a quartz halogen lamp.
  • the intensity of the illuminance produced by these lamps 1J2, _2, 3Z, and £2. should be at least 200 lux, although more preferable ranges include from about 200 lux to about 10,000 lux, from about 1000 lux to about 3000 lux, from about 1500 lux to about 2700 lux, and most preferably from about 2000 lux to about 2500 lux. The latter range has been recognized as acceptable. For instance, studies of phototherapy with S.A.D. patients have concluded that bright light (2500 lux) is significantly more effective as an antidepressant than the intensity of light ordinarily found in a home or office (100-300 lux) . See F.M. Jacobsen, "Seasonal Affective Disorder and the Use of Light as an Anti-Depressant", Directions in Psychiatry. Vol. 6, 1986 which is hereby incorporated by reference.
  • One acceptable treatment for the symptoms of Seasonal Affective Disorder could be to expose patients to the bright artificial light produced by the phototherapeudic devices of this invention for a period of 5 to 6 hours per day. It is understood that the anti- depressant effects could appear within 2 to 6 days after the commencement of"treatment, and a relapse often could occur 2-4 days after light treatment is discontinued.
  • this invention provides portable, light-weight phototherapeutic devices for stimulating a patient's circadian system and associated neuroendocrine parameters.

Abstract

On décrit des appareils photothérapeutiques de faible poids qui émettent des rayons lumineux d'au moins 200 lux sur les yeux du porteur. L'appareil décrit est portable et peut servir pour le traitement photothérapeutique de patients dépressifs, de travailleurs postés et de personnes souffrant des décalages horaires et de troubles affectifs saisonniers.Light weight phototherapeutic devices are described which emit light rays of at least 200 lux on the wearer's eyes. The apparatus described is portable and can be used for the phototherapeutic treatment of depressed patients, shift workers and people suffering from jet lag and seasonal affective disorders.

Description

-I-
PORTABLE LIGHT UNIT FOR STIMULATING NEUROENDOCRINE SYSTEM
FIELD OF THE INVENTION This invention relates to apparatus and treatments for phototherapy and in particular to more convenient treatments for affecting the neuroendocrine system, circadian rhythms and circannual rhythms in humans.
BACKGROUND OF THE INVENTIONS The biological effects of light are increasingly being recognized as playing an important role in modern healthcare. Phototherapy, the use of light as a treatment, has been successfully used to treat a number of diseases including psoriasis and rickets. More recently, scientists have discovered that sunlight plays a critical role in the regulation of circadian and circannual rhythms in humans. Accordingly, increased attention is being paid to the use of phototherapy in diseases influenced by daily and seasonal rhythms. Phototherapy has been demonstrated to have significant effects in the treatments of several diseases of particular interest to psychiatrists, including affective illness and chronolbiological disorders. It has also been used with some success in the treatment of psychiatric disorders which have a "seasonal component", for example, seasonal affective disorder "S.A.D". Light has been shown to have a number of psychological effects on the human central nervous system which may be separate from its visual effects. Very bright light, i.e. above about 2000 lux, is capable of suppressing the production and release of the pineal hormone and can set the internal "clock", within a certain range, for circadian rhythms. Reference is herein made to F.M. Jacobsen et al., "Seasonal Affective Disorder and the Use of Light as an Antidepressant" , Directions in Psychiatry. Vol 6, 1986, which is herein incorporated by reference.
One currently prescribed treatment for phototherapy is to have patients sit approximately three feet from a light box which typically has dimensions of about 2* by 4* . These light boxes are generally awkward and cumbersome to use. Furthermore, the patients are required to sit in one spot for approximately one to five hours, depending on their specific therapy. This has been found to be restrictive and limiting. Additionally, these devices are difficult to transport due to their size and weight and generally require an external power source.
Accordingly, a need exists for a mobile phototherapy treatment which would not require patient inactivity. In addition, a need exists for a phototherapeutic device which is lightweight and self- contained.
SUMMARY OF THE INVENTION In accordance with the teachings of this invention, an improved phototherapeutic device and phototherapy method are provided. The invention is designed to stimulate the neuroendocrine and circadian systems circannual of the patient with a very bright light of at least 200 lux. This light is portably mounted to a portion of the patient's body, preferably the head, and is directed towards the patient's eyes. The light preferably uses a full white light spectrum and is supplied with power by a battery which is preferably rechargeable. The invention also may chose to deflect heat generated from the light away from the person wearing the unit. It is envisioned that the light can be equipped with a dimmer switch or rheostat so that the user may reduce the intensity of the bulbs. In addition, the device can be equipped with filters, such as dichroic filters, neutral density filters and those filters designed to block or screen designated radiation, such as infrared or ultraviolet light. Such filters can be interposed between the lamp of the light and the user's eyes.
Accordingly, a phototherapeutic device and method are provided which permit uninterrupted patient activity during treatment. The device can be used for the treatment of depression, such as SAD, or used by healthy people involved in shift work to overcome resistance by their internal clocks.
Shift work challenges the normal biological rhythms of human beings. People who change work shifts often report psychological discomfort and negative health consequences. Accidents and health related absenteeism are often higher among shift-workers due to the stress in changing schedules. The use of the phototherapeutic device of this invention may prove beneficial in resetting the person's biological clock when he or she changes shifts. Currently, an estimated 20-25% of the work force in the United States is involved in some form of shift work.
Finally, the phototherapeutic device of this invention may be useful for people who travel by plane over multiple time zones. Such travelers experience a malady known as "jet-lag" which can debilitate the traveler for one to four days after the flight. As with shift workers, the device of this invention might be used for a more rapid, effective resetting of the internal biological clock, allowing prevention or quicker recovery from jet lag.
It is, therefore, an object of this invention to provide a portable, head-mounted phototherapeutic device for the treatment of psychiatric disorders.
It is another object of this invention to provide a self-containing phototherapeutic device for delivering bright light to the users eye's for stimulating the circadian and neuroendocrine system of the user. It is still another object of this invention to provide an improved method of phototherapy for treating both psychiatric disorders and negative health consequences associated with shift work or jet lag. With these and other objects in view, this invention resides in the novel construction, combination, arrangement of parts and methods substantially as hereinafter described and more particularly defined by the attached claims. BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings illustrate a complete embodiment of the invention according to the best mode so far devised for the practical application of the principles thereof and in which: FIG. 1 : is a perspective illustration of a preferred portable phototherapeutic device of this invention, equipped with a side-mounted battery pack, dimmer switch, light source and heat deflector;
FIG. 2 : is perspective illustration of another preferred, portable, phototherapeutic embodiment having a top-mounted battery pack and front-mounted light source;
FIG. 3 : is a perspective view of another photo- therapeutic embodiment of this invention including a front mounted light source and filter; and FIG. 4 : is a transverse view of another phototherapeutic embodiment of this invention which includes a front mounted light source and remote battery pack for providing a lighter weight construction. DETAILED DESCRIPTION OF THE INVENTION Referring now to the figures and particularly to
FIG. 1, there is shown a portable phototherapeutic device 10 having a heat deflector .16. and head mounting device 5.. The device .3-0 s provided with a light source .12. and battery pack JL4.. It becomes readily apparent that this device 10. overcomes the problems of excessive size and weight and limited mobility by being light weight, self- contained and head-mounted. The device 10 can also be fitted with a rheostat Ig. for permitting a patient to adjust the intensity of the light source 12.
An alternative embodiment is illustrated in FIG. 2 which describes a phototherapeutic device 0. having a light source mounted on an extension of the head mounting means 5.. In this fashion, the light source 22. can be more appropriately focused on the eyes of the user. The battery pack 24. of this embodiment 2J) is located along the top portion of the head mounting means j. In FIG. 3, a phototherapeutic device 3_p_ having a radiation shield ^36. is described. The light source 3_2., of this embodiment is attached to the head mounting means 5. Disposed between the eyes of the user and the light source 32 is a filter designed to block or screen designated radiation, such as infrared or ultraviolet light. The filter 3; could also be a dichroic or neutral density filter.
Referring now to FIG. 4, a light-weight phototherapeutic device 43 is illustrated having a remote battery back 4 . The light source 4_2. is disposed on a mounting means 4J3., which can generally assume the shape of a sun visor. The device £0 is equipped with a member 4j5 which can correspond to a radiation filter and/or a heat deflection shield. In accordance with this particular embodiment, a strap 48. can be provided for adjustment to various head sizes.
The light sources JL2, £2., 32 or 42 preferably comprises an incandescent lamp, preferably a quartz halogen lamp. The intensity of the illuminance produced by these lamps 1J2, _2, 3Z, and £2. should be at least 200 lux, although more preferable ranges include from about 200 lux to about 10,000 lux, from about 1000 lux to about 3000 lux, from about 1500 lux to about 2700 lux, and most preferably from about 2000 lux to about 2500 lux. The latter range has been recognized as acceptable. For instance, studies of phototherapy with S.A.D. patients have concluded that bright light (2500 lux) is significantly more effective as an antidepressant than the intensity of light ordinarily found in a home or office (100-300 lux) . See F.M. Jacobsen, "Seasonal Affective Disorder and the Use of Light as an Anti-Depressant", Directions in Psychiatry. Vol. 6, 1986 which is hereby incorporated by reference.
One acceptable treatment for the symptoms of Seasonal Affective Disorder could be to expose patients to the bright artificial light produced by the phototherapeudic devices of this invention for a period of 5 to 6 hours per day. It is understood that the anti- depressant effects could appear within 2 to 6 days after the commencement of"treatment, and a relapse often could occur 2-4 days after light treatment is discontinued.
In the treatment of manic-depressive patients, an exposure to 500 lux has been known to cause a 50% suppression of melatonin levels, but produced no effect in the controls. A.J. Lewy, et alr "Manic-depressive Patients May Be Supersensitive to Light", the Lancet. p. 384, February 14, 1981. It has also been demonstrated that when manic-depressants were exposed to a light intensity of 1500 lux, almost complete suppression of melatonin secretion was noted, resulting in levels of approaching those observed during daytime in two healthy subjects. Accordingly, the use of the devices of this invention could be used to suppress human melatonin secretion in manic-depressants and alter the environmental light-cycle which generates their circadian rhythm.
From the foregoing, it has been demonstrated that this invention provides portable, light-weight phototherapeutic devices for stimulating a patient's circadian system and associated neuroendocrine parameters. Although various embodiments have been illustrated, this was for the purpose of describing, but not limiting the invention. Various modifications, which will become apparent to one skilled in the art, are within the scope of this invention described in the attached claims.

Claims

We claim:
1. A phototherapeutic device for treating a patient comprising:
(a) a light source for producing an illuminance of at least 200 lux on the eyes of said patient; and
(b) mounting means for affixing said light source to a portion of the patient's body.
2. The device of claim 1 wherein said mounting means comprises means for attaching said light source to a patient's head.
3. The device of claim 1 wherein said light source comprises means for producing an illuminance of at least about 200 lux to about 10,000 lux.
4. The device of claim 1 wherein said light source comprises means for producing an illuminance of about 1000 lux to about 3000 lux.
5. The device of claim 1 wherein said light source comprises means for producing an illuminance of about 1500 lux to about 2700 lux.
6. The device of claim 1 wherein light source comprises means for producing an illuminance of about 2000 lux to about 2500 lux.
7. The device of claim 1 wherein said light source comprises means for producing light having a broad- spectrum white light component.
8. The device of claim 4 wherein said light source comprises means for producing green light.
9. The device of claim 1 wherein said light source comprises means for producing blue-green light.
10. The device of claim 7 further comprising heat deflector means for deflecting a portion of the heat from said light source away from the head of said patient.
11. The device of claim 10 wherein said heat deflection means comprises a reflector.
12. The device of claim 10 wherein said heat deflection means comprises a dichroic filter.
13. The device of claim 7 further comprises an ultraviolet filter.
14. The device of claim 7 further comprising a neutral density filter disposed between said light source and said eyes of said patient.
15. A method of phototherapy comprising:
(a) providing a light source having an illuminance of at least about 200 lux,
(b) mounting said light source to the head of a patient; and
(c) illuminating the eyes of said patient with said light source for a time sufficient to stimulate said patient's circadian system.
16. The method of claim 15 wherein said illuminating step comprises stimulating the neuroendocrine system of the patient.
17. The method of claim 15 wherein said providing step provides a light source having an illuminance of at least about 1500 lux to about 2700 lux.
18. The method of claim 15 wherein said providing step provides a light source having an illuminance of at least about 2000 to about 2500 lux.
19. The method of claim 18 wherein said providing step provides a light source having a white light spectrum.
EP19890903619 1988-03-08 1989-03-08 Portable light unit for stimulating neuroendocrine system Withdrawn EP0386161A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US16528588A 1988-03-08 1988-03-08
US165285 1988-03-08

Publications (2)

Publication Number Publication Date
EP0386161A1 true EP0386161A1 (en) 1990-09-12
EP0386161A4 EP0386161A4 (en) 1992-02-19

Family

ID=22598265

Family Applications (1)

Application Number Title Priority Date Filing Date
EP19890903619 Withdrawn EP0386161A4 (en) 1988-03-08 1989-03-08 Portable light unit for stimulating neuroendocrine system

Country Status (4)

Country Link
EP (1) EP0386161A4 (en)
JP (1) JP2513876B2 (en)
CA (2) CA1327231C (en)
WO (1) WO1989008475A1 (en)

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US5503637A (en) * 1987-06-26 1996-04-02 Light Sciences, Inc. Apparatus for producing and delivering high-intensity light to a subject
JPH09213101A (en) * 1995-11-27 1997-08-15 Matsushita Electric Works Ltd Portable light irradiation device
WO2001085254A1 (en) * 2000-05-10 2001-11-15 Thomas Jefferson University Photoreceptor system for melatonin regulation and phototherapy
US6488698B1 (en) 2000-08-16 2002-12-03 Henry H. Hyman Portable light unit for treatment of seasonal affective disorders
US7276025B2 (en) 2003-03-20 2007-10-02 Welch Allyn, Inc. Electrical adapter for medical diagnostic instruments using LEDs as illumination sources
US10252079B2 (en) 2003-06-06 2019-04-09 Koninklijke Philips N.V. Hand-held light therapy apparatus
US8459844B2 (en) 2010-07-01 2013-06-11 Welch Allyn, Inc. Replacement light assembly
JP2013541977A (en) * 2010-09-29 2013-11-21 ユマライト インコーポレイティッド Head-mounted phototherapy

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US4315502A (en) * 1979-10-11 1982-02-16 Gorges Denis E Learning-relaxation device

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US4057054A (en) * 1976-05-20 1977-11-08 Giannone Frank C Eye treatment apparatus
JPS5318288A (en) * 1976-08-02 1978-02-20 Tokuji Suzuki Mental rest or sleep inducing apparatus
JPS58173563A (en) * 1982-04-06 1983-10-12 三菱電機株式会社 Sleep inducer
AT382784B (en) * 1982-06-16 1987-04-10 Stiegler Reinhard Dr DEVICE FOR REDUCING MENTAL TENSIONS
AU614800B2 (en) * 1987-12-24 1991-09-12 Optron Pty Ltd Chromo therapy device

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Publication number Priority date Publication date Assignee Title
CH455071A (en) * 1967-11-30 1968-04-30 Castells Toha Luis Device for sending monochromatic radiation into the eye for therapeutic purposes
US4315502A (en) * 1979-10-11 1982-02-16 Gorges Denis E Learning-relaxation device

Non-Patent Citations (1)

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Title
See also references of WO8908475A1 *

Also Published As

Publication number Publication date
CA1339384E (en) 1997-08-26
EP0386161A4 (en) 1992-02-19
JP2513876B2 (en) 1996-07-03
CA1327231C (en) 1994-02-22
WO1989008475A1 (en) 1989-09-21
JPH03501936A (en) 1991-05-09

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