United States Patent 19 11 Patent Number: 6,135,117 Campbell Et Al
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USOO6135117A United States Patent 19 11 Patent Number: 6,135,117 Campbell et al. (45) Date of Patent: Oct. 24, 2000 54 NON-OCULAR CIRCADIAN CLOCK OTHER PUBLICATIONS RESETTING IN HUMANS L. E. Scheving et al., “The Persistence of a Circadian (75) Inventors: Scott S. Campbell, Chappaqua; Rhythm in Histamine Response in Guinea Pigs Maintained Patricia J. Murphy, Ossining, both of Under Continuous Illumination', The Anotomical Record, N.Y. vol. 175, No. 1, 1973, pp. 1-6. P. Altmeyer et al., “Influence of Whole-Body UV Irradiation 73) Assignee: Cornell Research Foundation, Inc., on Endocrinological Parameters', Dermatologica, Vol. 166, Ithaca, N.Y. 1983, pp. 186-191. R. Woodhouse et al., “Responses of Albino and Hooded Rats Appl. No.: 09/074,455 to Various Illumination Choices in a Six-Chambered Alley way”, Perceptual and Motor Skills, vol. 61, 1985, pp. Filed: May 7, 1998 343-354. Related U.S. Application Data T. J. Savides et al., “Natural Light Exposure of Young Provisional application No. 60/046,188, May 12, 1997, Adults”, Physiology & Behavior An International Journal, abandoned, and provisional application No. 60/072,121, Jan. vol. 38, No. 4, 1986, pp. 571-574. 22, 1998, abandoned. (List continued on next page.) Int. Cl. .............................................. A61B 19/00 U.S. Cl. ............ ... 128/898; 607/88 Primary Examiner Vincent Millin Field of Search . ... 128/898; 607/88 Assistant Examiner Kelly O'Hara Attorney, Agent, or Firm Nixon Peabody LLP References Cited 57 ABSTRACT U.S. PATENT DOCUMENTS A method for resetting the phase of the human circadian 3,670, 193 6/1972 Thorington et al. clock and for enhancing alertneSS and performance in 4,600,723 7/1986 Short et al. humans. The method involves the application of non-Solar 4,858,609 8/1989 Cole . photic stimulation, in the range of 15 to 150,000 lux, to any 4,893,291 1/1990 Bicket al. non-ocular region of the human body during WakefulneSS or 5,000,752 3/1991 Hoskin et al. 5,079,682 1/1992 Roberts. during Sleep. Preferably, the photic Stimulation has a wave 5,086,770 2/1992 Prangley . length within the visible spectrum (~400–750 nm). The 5,140,562 8/1992 Moore-Ede et al. method can be used to both delay and advance the circadian 5,163,426 11/1992 CZeisler et al. clock according to a phase response curve (PRC). The 5,167,133 12/1992 Schmidt. method may also be used for acute/immediate enhancement 5,167,228 12/1992 CZeisler et al. of alertneSS and performance. The method is applicable to 5,169,380 12/1992 Brennan . alleviation of problems associated with “jet-lag”, shift work 5,176,133 1/1993 CZeisler et al. Sleep disturbance, and other Sleep disturbances involving 5,197,941 3/1993 Whitaker. misalignment of circadian rhythms. The method provides a (List continued on next page.) novel technique for shifting the phase of the circadian clock, and enhancing alertneSS and performance, using existing, or FOREIGN PATENT DOCUMENTS newly-developed devices. O 469 227A1 2/1992 European Pat. Off.. WO95/25563 9/1995 WIPO. 44 Claims, 7 Drawing Sheets 37.8 37.6 37.4 3. 37 36.8 36.6 - T 1800 2100 2400 O3OO O600 0900 1200 TIME OF DAY - PHASEDELAY = 3.06 6,135,117 Page 2 U.S. PATENT DOCUMENTS B. Iyengar, “Melanocytes-AUV Sensitive Neural Network 5.242,941 9/1993 Lewy et al.. and Circadian Rhythms”, Acta Anatomica, vol. 144, No. 4, 5,259,380 11/1993 Mendes et al.. 1992, pp. 332–335. 5,292,345 3/1994 Gerardo . R. G. Foster, “Photoreceptors and Circadian System”, 5,300,097 4/1994 Lerner et al.. American Psychological Society, vol. 2, No. 2, 1993, pp. 5,327,331 7/1994 Roberts. 34-39. 5,343,121 8/1994 Terman et al.. 5,358,503 10/1994 Bertwell et al.. B. Iyengar, “Indoleamines and the UV-Light-Sensitive 5,441,528 8/1995 Chang et al.. Photoperiodic Responses of the Melanocyte Network: A 5,447.528 9/1995 Gerardo . Biological Calendar’?” Experientia 50, 1994, pp. 733–736. 5,503,637 4/1996 Kyricos et al.. 5,545,192 8/1996 Czeisler et al.. C. A. CZeisler et al., “Suppression of Melatonin Secretion in 5,562,719 10/1996 Lopez-Claros. Some Blind Patients by Exposure to Bright Light”, New 5,589,741 12/1996 Terman et al.. England Journal of Medicine, vol. 332, No. 1, 1995, pp. 5,648,656 7/1997 Begemann et al. 6-11. 5,716,978 2/1998 Lewy et al.. D. A. Golombek et al., “Let There Be Light: Signal Trans OTHER PUBLICATIONS duction in a Mammalian Circadian System”, Brazilian Jour nal of Medicine and Biological Research, vol. 29, No. 1, C. A. CZeisler et al., “Bright Light Resets the Human 1996, pp. 1-148. Circadian Pacemaker Independent of the Timing of the Sleep-Wake Cycle”, Science, vol. 233, 1986, pp. 667-671. A. E. Reinberg et al., “Synchronisation Et Dyschronisme T. A. Wehr et al., “Eye Versus Skin Phototherapy of Seasonal Des Rythmes Circadiens Humains”, Pathologie Biologie, Affective Disorder”, American Journal of Psychiatry, vol. vol. 44, No. 6, 1996, pp. 487-495. 144, No. 6, 1987, pp. 753–757. S. Reuss, “Components and Connections of the Circadian C. A. CZeisler et al., “Bright Light Induction of Strong (Type Timing System in Mammals”, Cell & Tissue Research, vol. 0) Resetting of the Human Circadian Pacemaker”, Science, 285, No. 3, 1996, pp. 353–378. vol. 244, 1989, p. 1328. E. Van Cauter et al., “Strategies for Resetting the Human D.A. Oren, "Humoral Phototransduction Blood is a Mes Circadian Clock”, The New England Journal of Medicine, senger', The Neuroscientist, vol. 2, No. 4, 1996, pp. vol. 322, No. 18, 1990, pp. 1306–1308. 207-21 O. A. T. Winfree, “Resetting the Human Clock', Nature Inter S. Campbell et al., “Extraocular Circadian Phototransduc national Weekly Journal of Science, vol. 350, No. 6313, tion in Humans”, Submitted to Science Aug. 11, 1997, pp. 1991, p. 18. 1-21. U.S. Patent Oct. 24, 2000 Sheet 1 of 7 6,135,117 FIG. I. U.S. Patent Oct. 24, 2000 Sheet 2 of 7 6,135,117 37.4 37.2- . 36.8 a lf. A 36.6 36.4 FIG. 2A 1800 2foo 2400 0300 0600 0900 1200 TIME OF DAY EäSi3S3:.............. -- 37.8 37.6 37.4 37.2 37 36.8 36.6 FIG. 92B 1800 2100 2400 O300 O600 O900 1200 TIME OF DAY - PHASEDELAY = 3.06h U.S. Patent Oct. 24, 2000 Sheet 3 of 7 6,135,117 36.8 36.4 36 FIG. 3A 1800 2100 2400 0300 0600 : 0900 1200 TIME OF DAY r i 37.2 36.8 36.4 36 FIG. 3B 1800 2100 24OO O300 O600 0900 1200 TIME OF DAY - PHASE ADVANCE = 2.43h U.S. Patent Oct. 24, 2000 Sheet 4 of 7 6,135,117 ADVANCE (hrs) DELAY (hrs) -12 -8 -4 4 8 12 TIMING OF LIGHT RELATIVE TOTmin (hrs) ADVANCE (hrs) DELAY (hrs) -12 -8 -4 d 4 8 12 TIMING OF LIGHT RELATIVE TOTmin (hrs) ADVANCE (hrs) DELAY (hrs) FIG. 4C -12 8 -4 O TIMING OF LIGHT RELATIVE TOTmin (hrs) U.S. Patent Oct. 24, 2000 Sheet 5 of 7 6,135,117 37.5 PHASEDELAY = 163 MIN. 35.5 22 24 O2 04 08 10 TIME OF DAY FIG. 5A NINOIVIEW(||||ßd) TIME OF DAY FIG. 5B U.S. Patent Oct. 24, 2000 Sheet 6 of 7 6,135,117 37.6 3.4 37.2 37 36.8 36.6 36.4 36.2 36 : 16:00:00 20:00:00 24:00:00 28:00:00 32:00:00 37.6 37.4 37.2 37 36.8 36.6 36.4 36.2 16:00:00 20:00:00 24:00:00 28:00:00 32:00:00 U.S. Patent Oct. 24, 2000 Sheet 7 of 7 6,135,117 37.6 37.4 37.2 37 36.8 36.6 36.4 36.2 36 FIG. 7A 16:00:00 22:00:00 26:00:00 30-odo 34:00:00 1. - - - - - - - - - 1. 37.6 37.4 37.2 37 36.8 36.6 36.4 36.2 36 16:00:00 22:00:00 26:00:00 30:00:00 34:00:00 6,135,117 1 2 NON-OCULAR CIRCADIAN CLOCK It is widely accepted that the mammalian circadian clock RESETTING IN HUMANS which is located in the brain, within the Suprachiasmatic nuclei (SCN) of the hypothalamus, receives photic informa This application claims the benefit of U.S. Provisional tion via the eyes, by visual and/or non-visual ocular path Application No. 60/046,188 filed May 12, 1997 now aban ways originating in the retina. It is also widely acknowl doned and U.S. Provisional Application No. 60/072,121 edged that light acts to enhance alertneSS and performance filed Jan. 22, 1998 now abandoned. via an ocular route(s). Yet, it has been recognized for This invention was made with Government support decades that many species of birds and reptiles possess under Grant No(s). R01MH45067 and K02MH01099, extra-ocular photoreceptors, and it has been demonstrated awarded by the National Institute of Health. The Govern that circadian and photoperiodic response to light can be ment has certain rights in the inventions. mediated entirely by Such photoreceptors. In contrast, it is BACKGROUND OF THE INVENTION generally assumed that Such nonvisual circadian photore ceptors in mammals reside within the retina, and that mam 1. Field of the Invention mals do not possess the capacity for extraocular circadian This invention relates to a method for resetting the phase 15 photoreception.