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WO2025064827A1 - Systèmes et procédés de réglage de la phase circadienne d'un patient - Google Patents

Systèmes et procédés de réglage de la phase circadienne d'un patient Download PDF

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Publication number
WO2025064827A1
WO2025064827A1 PCT/US2024/047706 US2024047706W WO2025064827A1 WO 2025064827 A1 WO2025064827 A1 WO 2025064827A1 US 2024047706 W US2024047706 W US 2024047706W WO 2025064827 A1 WO2025064827 A1 WO 2025064827A1
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Prior art keywords
light
patient
light treatment
readable medium
computer readable
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Mark Rea
Rohan NAGARE
Mariana Figueiro
Andrew Bierman
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Icahn School of Medicine at Mount Sinai
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Icahn School of Medicine at Mount Sinai
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N5/0613—Apparatus adapted for a specific treatment
    • A61N5/0618—Psychological treatment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M16/00—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes
    • A61M16/021—Devices for influencing the respiratory system of patients by gas treatment, e.g. ventilators; Tracheal tubes operated by electrical means
    • A61M16/022—Control means therefor
    • A61M16/024—Control means therefor including calculation means, e.g. using a processor
    • A61M16/026—Control means therefor including calculation means, e.g. using a processor specially adapted for predicting, e.g. for determining an information representative of a flow limitation during a ventilation cycle by using a root square technique or a regression analysis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M21/00—Other 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
    • A61M21/02—Other 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 for inducing sleep or relaxation, e.g. by direct nerve stimulation, hypnosis, analgesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M21/00—Other 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
    • A61M2021/0005—Other 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
    • A61M2021/0027—Other 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 hearing sense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M21/00—Other 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
    • A61M2021/0005—Other 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
    • A61M2021/0044—Other 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/18—General characteristics of the apparatus with alarm
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2205/00—General characteristics of the apparatus
    • A61M2205/50—General characteristics of the apparatus with microprocessors or computers
    • A61M2205/502—User interfaces, e.g. screens or keyboards
    • A61M2205/505—Touch-screens; Virtual keyboard or keypads; Virtual buttons; Soft keys; Mouse touches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/30—Blood pressure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES 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
    • A61M2230/00—Measuring parameters of the user
    • A61M2230/50—Temperature
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0626—Monitoring, verifying, controlling systems and methods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0635—Radiation therapy using light characterised by the body area to be irradiated
    • A61N2005/0643—Applicators, probes irradiating specific body areas in close proximity
    • A61N2005/0645—Applicators worn by the patient
    • A61N2005/0647—Applicators worn by the patient the applicator adapted to be worn on the head
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/065—Light sources therefor
    • A61N2005/0651—Diodes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/06—Radiation therapy using light
    • A61N2005/0658—Radiation therapy using light characterised by the wavelength of light used
    • A61N2005/0662—Visible light

Definitions

  • the method may include determining a circadian phase of the patient and determining the light treatment to adjust the determined circadian phase.
  • the light treatment includes an amount, a duration, and a clock time relative to the determined circadian phase of light for the light treatment.
  • the method includes administering the light treatment.
  • determining the circadian phase of the patient may include monitoring, using at least one calibrated photometric device, a plurality of light exposures of the patient during at least one monitoring period of 24 hours, and/or determining a biomarker relative to clock time of the patient.
  • the light exposures may be measured as irradiance at a cornea of the patient using any metric traceable to circadian effective light based on CLA.
  • the biomarker determines DLMO and/or CBTmin.
  • the at least one calibrated photometric device is a Daysimeter.
  • the at least one photosensor is located on a wrist, a torso, a chest, or a head of the patient.
  • the light treatment is exposure to or protection from circadian effective light.
  • the light treatment predictably changes the determined circadian phase of the patient to a desired circadian phase.
  • the light treatment is outdoor light exposure.
  • the light treatment comprises limiting exposure to light.
  • a photopic illuminance traceable to CLA of “white” light delivered at eye level for the light treatment with electric room lighting is between 0 lux and 1,000 lux.
  • the duration of the light delivered for the light treatment is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours.
  • the amount of light determines the duration and clock time of the light for the light treatment, or vice versa. [0009] In an aspect, the amount of light is 700 lux and the duration is 30 minutes. In another aspect, the amount of light is 350 lux and the duration is 1 hour.
  • the light treatment is any light or dark exposure having a circadian stimulus (CS) between 0.01 and 0.7.
  • CS circadian stimulus
  • the light treatment is pure blue light provided by a pure blue light LED having a wavelength of peak emission of about 470 nm, a full- Page 2 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center width-half-maximum bandwidth of 20 nm and an irradiance of 0.5 W/m 2 .
  • the light treatment has a CLA of 0 to 1000.
  • the amount of the light is 0 to about 1000 as specified in terms of CLA.
  • the method further includes determining the effect of an amount, duration, and clock time of a light or dark exposure on the patient’s determined circadian phase.
  • the clock time, the duration, and the amount of the light delivered for the light treatment is based on the determined circadian phase of the patient and a desired circadian phase.
  • the light treatment re-aligns circadian phase as per patient’s preset goal to potentially improve population specific health outcomes including inflammation, neutropenic fever, and symptom burden of a multiple myeloma patient.
  • the light treatment comprises a 24 hour light/dark exposure plan.
  • the 24 hour light/dark exposure plan comprises a plurality of circadian effective lighting exposures and a plurality of circadian dark exposures.
  • the light treatment comprises light from naturally available daylight or an electrically powered ambient lighting device, as per patient’s preference.
  • the light treatment is provided by a white light having a correlated color temperature of about 2200 K to about 7500 K.
  • the light treatment is provided by a narrowband light source having a peak wavelength of about 380 nm to about 730 nm.
  • the light treatment is tailored and administered at a time of day preferred by the patient from 12 AM to 11:59 PM.
  • the light treatment is administered to the patient at eye level.
  • the light treatment comprises a circadian effective light period for 0 hours to 24 hours.
  • the light treatment comprises a circadian dark period for 0 hours to 24 hours.
  • the light treatment improves sleep and mood of patients with Alzheimer’s disease.
  • the light treatment comprises polychromatic white light and/or narrowband light capable of stimulating a circadian system.
  • the clock time is in the morning, the afternoon, the evening, the night, or a combination thereof.
  • the method further includes determining a new circadian phase of the patient at least one day after the light treatment has been administered.
  • the light treatment is administered every day beginning at the clock time.
  • the patient has an age of about 1 years old to about 95 years old.
  • the light treatment is provided by a lighting device.
  • the lighting device is a light box, a light mask, wearable light goggles, and LED strip, or a self-luminous tablet.
  • a non-transitory computer readable medium storing instructions thereon that when executed by at least one processor cause the at least one processor to perform operations to determine a light treatment for a patient in need thereof.
  • the operations may include determining a circadian phase of the patient and determining the light treatment to adjust the determined circadian phase.
  • the light treatment includes an amount, duration, and clock time relative to the determined circadian phase of light for the light treatment.
  • determining the circadian phase of the patient includes receiving, using at least on calibrated photometric device, a plurality of light exposures of the patient during at least one monitoring period of 24 hours and/or receiving a biomarker relative to clock time of the patient.
  • the light exposures are measured as irradiance at a cornea of the patient using any metric traceable to circadian effective light based on CLA.
  • the biomarker relative to the clock time determines DLMO and/or CBTmin.
  • the at least one calibrated photometric device is a Daysimeter.
  • the at least one photosensor is located on a wrist, a torso, a chest, or a head of the patient.
  • the light treatment is exposure to or protection from circadian effective light.
  • the light treatment predictably changes the determined circadian phase of the patient to a desired circadian phase.
  • the light treatment is outdoor light exposures.
  • the light treatment comprises limiting exposure to light.
  • a photopic illuminance traceable to CLA of “white” light delivered to at eye level for the light treatment with electric room lighting is between 0 lux and 1,000 lux.
  • the duration of the light delivered for the light treatment is about 1 hour, about 2 hours, about 3 hours, about 4 hours, about 5 hours, or about 6 hours.
  • the amount of light determines the duration and clock time of the light for the light treatment, or vice versa.
  • the amount of light is 700 lux and the duration is 30 minutes.
  • the amount of light is 350 lux and the duration is 1 hour.
  • the light treatment is any light or dark exposure having a CS between 0.01 and 0.7.
  • the light treatment is pure blue light provided Page 4 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center by a pure blue LED having a wavelength of peak emission of about 470 nm, a full- width-half-maximum bandwidth of 20 nm and an irradiance of 0.5 W/m 2 .
  • the amount of the light is 0 to about 1000 as specified in terms of CLA.
  • the operations further include determining the effect of an amount, duration, and clock time of a light or dark exposure on the patient’s determined circadian phase.
  • the clock time, the duration, and the amount of the light delivered for the light treatment is based on the determined circadian phase of the patient and a desired circadian phase.
  • the light treatment re-aligns circadian phase as per patient’s preset goal to potentially improve population specific health outcomes including inflammation, neutropenic fever, and symptom burden of a multiple myeloma patient.
  • the light treatment comprises a 24 hour light/dark exposure plan.
  • the 24 hour light/dark exposure plan comprises a plurality of circadian effective lighting exposures and a plurality of circadian dark exposures.
  • the light treatment comprises light from naturally available daylight or an electrically powered ambient lighting device, as per patient’s preference.
  • the light treatment is provided by a white light having a correlated color temperature of about 2200 K to about 7500 K.
  • the light treatment is provided by a narrowband light source having a peak wavelength of about 380 nm to about 730 nm.
  • the light treatment is tailored and administered at a time of day preferred by the patient from 12 AM to 11:59 PM.
  • the light treatment is administered to the patient at eye level.
  • the light treatment comprises a circadian effective light period for 0 hours to 24 hours.
  • the light treatment comprises a circadian dark period for 0 hours to 24 hours.
  • the light treatment improves sleep and mood of patients with Alzheimer’s disease.
  • the light treatment comprises polychromatic white light and/or narrowband light capable of stimulating a circadian system.
  • the clock time is in the morning, the afternoon, the evening, the night, or a combination thereof.
  • the operations may include determining a new circadian phase of the patient at least one day after the light treatment has been administered.
  • the light treatment is administered every day beginning at the clock time.
  • the patient has an age of about 1 years old to about 95 years old.
  • the light treatment is provided by a Page 5 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center lighting device.
  • the lighting device is a light box, a light mask, wearable light goggles, and LED strip, or a self-luminous tablet.
  • the operations further include turning on a lighting device to administer the light treatment.
  • the operations further include providing an alert to the patient indicating it is time for the light treatment.
  • the operations further include providing an audible alert to the patient that it is time for the light treatment.
  • the operations further include providing feedback to the patient of the amount of light, duration of light, and clock time of light via a display.
  • FIG. 2A is a graphical illustration of different narrowband light sources for suppressing nocturnal melatonin and predictions from a two-state circadian phototransduction model at 300 scotopic lux on the retina.
  • FIG. 2B is a graphical illustration of the absolute sensitivity for the human circadian system as characterized by light-induced nocturnal melatonin suppression.
  • FIG.3A is a bar graph of the mean absolute error (MAE) across four data sets with a modulator and without a modulator.
  • FIG.3B is a bar graph of the percent of subjects with MAE ⁇ 1 hour across four data sets with and without a modulator.
  • FIG.4 is a graphical illustration of the effect of changing CBTmin to an optimum CBTmin across four data sets.
  • FIG. 5 is a graphical illustration of changing Process L parameters on MAE across four data sets.
  • FIG. 6 is a graphical illustration of changing Process L parameters on percentage of subjects with error ⁇ 1 hour across four data sets. Page 6 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center
  • FIG.7 is a graphical illustration of changing Process P parameters on MAE across four datasets.
  • FIG. 8 is a graphical illustration of changing Process P parameters on percentage of subjects with error ⁇ 1 hour across the four datasets. [0030] FIG.
  • FIG. 9A is a graphical illustration of a phase response curve for the Kronauer99 model with photopic illuminance as light stimulus input.
  • FIG.9B is a graphical illustration of a phase response curve using circadian stimulus (CS) as light stimulus input.
  • FIG.10 is a diagram of a pacemaker model in one example.
  • FIG.11 is a flowchart for a method of adjusting the circadian phase of a patient in one example.
  • FIG.12 is a diagram of an example computing system in one example. DETAILED DESCRIPTION [0035] It will be appreciated that for simplicity and clarity of illustration, where appropriate, reference numerals have been repeated among the different figures to indicate corresponding or analogous elements.
  • connection can be such that the objects are permanently connected or releasably connected.
  • substantially is defined to be essentially conforming to the particular dimension, shape or other word that substantially modifies, such that the component need not be exact.
  • the terms “comprising,” Page 7 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center “including” and “having” are used interchangeably in this disclosure.
  • the terms “comprising,” “including” and “having” mean to include, but not necessarily be limited to the things so described. [0037]
  • “about” refers to numeric values, including whole numbers, fractions, percentages, etc., whether or not explicitly indicated.
  • pacemaker pacemaker prediction
  • pacemaker model a method of determining a light treatment for a patient in need thereof.
  • the light treatment may be configured to adjust the circadian phase of a patient to a desired circadian phase.
  • a method to determine a light treatment for a patient to adjust the circadian phase of the patient is regulated by internal clock mechanisms.
  • Various rhythmic behavioral (e.g., sleep) and physiological (e.g., melatonin) responses will cycle with a period of approximately 24 hours and are known as circadian (approximately daily) rhythms. These rhythms are, in part, regulated by different peripheral clocks in various organs and neural structures.
  • peripheral clocks each have slightly different intrinsic periods and would be, therefore, asynchronous with differently timed peaks and troughs without a master clock that orchestrates them all so that human behavior and physiology work in concert.
  • the master clock located in the suprachiasmatic nuclei sends neural signals to other parts of the brain which then send humoral signals to the peripheral clocks.
  • the phase changes in the core body temperature (CBT) are modulated by a rhythmic input from the SCN acting upon the thermoregulatory centers within the hypothalamus, in turn modulating the set point and altering the thresholds for sweating and cutaneous vasodilation.
  • V( ⁇ ) represents the combined action spectrum of the middle-wavelength (M) cone sensitivity and the long- wavelength (L) cone sensitivity of the human macula, peaking at 555 nm.
  • M middle-wavelength
  • L long- wavelength
  • the intrinsically photosensitive retinal ganglion cells ipRCGs
  • the axions which form the RHT connecting the retina to the SCN cannot account for the peak spectral sensitivity at 460 nm because the in vivo ipRGC photopigment, melanopsin, exhibits an action spectrum peaking at or near 490 nm (after being filtered by the crystalline lens).
  • Utilizing all five retinal photoreceptors, together with a neural circuit consistent with orthodox retinal neurophysiology, provides a more accurate, but non-linear characterization of the spectral sensitivity of the circadian system.
  • the non-linear aspects of observed responses may need a model having different retinal phototransduction circuit pathways depending on the stimulus and resulting in different spectral sensitivity to polychromatic and narrowband light sources.
  • Model predictions of spectral sensitivity at one scotopic (rod spectral sensitivity) light level for both narrowband and polychromatic sources are shown in FIG.2A.
  • the blue versus yellow (b-y) spectral opponent mechanism underlying one channel of human color vision, is an important element of the modeled retinal circadian phototransduction circuit.
  • This spectral opponent mechanism results in a two-state model, one state for “cool” sources where the spectral power distribution of the source results in a channel response of b > y, and the other for “warm” sources where the same channel Page 10 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center response is b ⁇ y.
  • subadditivity is a characteristic of the circadian phototransduction circuit for “cool” sources as illustrated by the negative lobe in FIG.2A.
  • Equation A1.1 mathematically describes circadian-effective light (CLA 2.0) based on the modeled spectral sensitivity of the human circadian phototransduction circuit, which includes the b-y spectral opponent mechanism shared with the visual system.
  • shunting inhibition a retinal mechanism called shunting inhibition.
  • the high threshold results from rod activation of a specific type of amacrine cell.
  • the modeled electrical shunt limits direct Page 11 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center depolarization of the ipRGC in response to photon absorption and thereby, from sending any neural signals to the SCN.
  • rods provide direct input to the ipRGC in nocturnal rodents, resulting in high sensitivity to light of the circadian phototransduction circuit.
  • Another feature of the model is the compression of neural response to light at high levels.
  • FIG.2B illustrates the model predictions for different light levels, ranging from outdoors at night, to residential interiors, to commercial interiors, to outdoors during the day as a function of optical radiation spectrally weighted by CLA 2.0. Equation A1.2 mathematically describes the circadian stimulus (CS) to the human SCN.
  • CS circadian stimulus
  • Most pacemaker models use photopic illuminance (lux) as input (S). In instances where only one light source is used, inaccurate characterization of spectral sensitivity is not important because the relative effectiveness of different light sources is irrelevant. Thus, only the amount of light needed to stimulate the pacemaker is relevant, irrespective of the units used to characterize the photic stimulus.
  • V( ⁇ ) Even for instances where different “white” polychromatic lights generated by commercial light sources were used, the error in characterizing V( ⁇ ) is small, particularly when the amount of light is quite large with respect to dim baseline conditions. In other words, where “white” lights are used differences in their relative spectral power distribution are less important than differences in their absolute spectral power distribution. Where narrowband light sources are used, however, erroneous characterization of the spectral sensitivity of the system can lead to larger errors. [0051] For example, the efficacy of a “blue” light for stimulating the SCN can be several orders of magnitude greater than that of a “red” light of the same photopic illuminance at the eye.
  • a function that compresses the raw spectrally weighted irradiance, usually photopic illuminance, as S input may be used in the pacemaker model. As illustrated in FIG. Page 12 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center 2B, CS is a biophysically grounded compressive function of spectrally weighted irradiance, CLA 2.0.
  • a separate, arbitrary compressive function of spectrally weighted irradiance e.g., V( ⁇ ) or CLA
  • V( ⁇ ) or CLA a separate compressive function of spectrally weighted irradiance
  • CLA 2.0 and CS are grounded in the neurophysiology of the retina, these characterizations of the photic stimulus (S) to the pacemaker (O) are inherently better than a pacemaker model that utilizes an arbitrary compressive function for photopic illuminance or even for irradiance spectrally weighted by a different function such as CLA.
  • the daily rhythm of melatonin concentration is currently the most acceptable marker of circadian phase and is widely used because it can be reliably assayed in blood, saliva, or urine.
  • Dim light melatonin onset usually gets precedence over other circadian phase markers because it exhibits relatively greater robustness in the wake of various external influences. For instance, too much carbohydrate intake can significantly affect CBT and heart rate rhythms. Inherent changes to CBT are further essential to trigger master clock mediated immune response to any external threats that may compromise immune health. Cortisol and CBT parameters can also be masked by sleep, stress, and activity. On the other hand, melatonin concentration and secretion remain relatively uninfluenced by these factors. This also accords greater reliability for melatonin, over other circadian markers, to track circadian phase position.
  • DLMO Dim light melatonin onset
  • the method described herein uses novel techniques for pacemaker models known in the art to determine more accurate circadian phase predictions and therefore more effective light treatments to shift circadian phase.
  • the pacemaker models known in the art may be modified to use various parameters described herein.
  • the pacemaker model may use CS as photic input (l).
  • the equations for CLA 2.0 and CS are mathematically described above.
  • the importance is the use of circadian effective lighting based on CS to adjust the circadian phase of the patient, as well as making accurate estimates of the relevant clock time of the circadian phase.
  • the pacemaker model described herein can predict the effect of light and dark exposures, as quantified in terms of CS, within 30 minutes of a patient’s actual circadian phase.
  • FIG.11 illustrates a method 1100 for determining a light treatment for a patient in need thereof.
  • the method 1100 may include determining a circadian phase of the patient. Determining the circadian phase of the patient may include taking biological samples from the patient to measure the response (R) of the patient. These biological samples may be any biological sample that is operable as a marker for Page 13 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center circadian phase.
  • the biological sample may be blood, saliva, or urine.
  • the biological sample of the patient may be used to determine the daily rhythm of melatonin content.
  • dim light melatonin onset may be used as the marker for circadian phase.
  • DLMO dim light melatonin onset
  • DLMO may be the preferred marker for determining the circadian phase of the patient.
  • the marker for circadian phase of the patient may be cortisol or CBT (core body temperature).
  • the marker for circadian phase of the patient may be any biomarker known to determine circadian phase. These circadian phase markers may be used to determine the original (e.g., initial) circadian phase of the patient.
  • the DLMO may determine the baseline CBTmin of a patient for use in a pacemaker model.
  • the use of a baseline CBTmin in a pacemaker model increases the accuracy of the pacemaker model predictions.
  • the initial phase may be estimated using a patient’s sleep/rest pattern.
  • the method may include determining a desired circadian phase (e.g., preset goal) for the patient. For example, humans who spend most of their time indoors may have disrupted circadian phases due to inadequate light exposures during daytime or light exposures occurring during the night.
  • the desired circadian phase of a patient may take into account a desired sleep start time and a desired sleep end time.
  • the sleep start time and sleep end time may be related to a DLMO which can be input into the pacemaker model described herein (e.g., as a CBTmin value).
  • the method 1100 may include determining a light treatment to adjust (e.g., change) the circadian phase of the patient. Determining the light treatment may include inputting the desired sleep start time and desired sleep end time of the patient, as defined in terms of DLMO (or CBTmin using Equation 1), as well as the calculated/measured current CBTmin into a pacemaker model.
  • CS and thereby CL A 2.0 for a light treatment may be determined from the pacemaker model. Variations in CS determine the exact parameters of the light treatment.
  • the pacemaker model described herein determines the effect on circadian phase for any type of light exposure or dark Page 14 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center exposure. Therefore, the pacemaker model is operable to determine any number of different light and/or dark exposures necessary to adjust the circadian phase of the patient to a desired phase.
  • the CS needed to change the circadian phase of the patient may be used to determine a light treatment having various parameters.
  • these parameters may be the amount, duration, and clock time of a circadian effective light.
  • the light treatment may further include limiting exposures to circadian effective light at certain times.
  • the light treatment may be tailored to the patient’s social schedule or other preferences. It will be appreciated that a variety of different light treatments may be used depending on the patient’s desired circadian phase. For example, in some patients full 24 hour control of CS may be obtainable, and therefore a 24 hour light treatment plan comprising various lighting characteristics may be administered.
  • a light treatment may comprise a singular light event (e.g., a light treatment having a set amount, duration, and clock time).
  • a light treatment may include one or more light treatments (e.g., light treatments having a set amount, duration, and clock time).
  • the amount, duration, and clock time of the circadian effective light may be related to one another. Therefore, many different light treatment options may be presented to a patient in order to allow the patient to fit the treatment into their daily schedule. For example, a greater amount of light may be administered for a shorter duration to effect a change in the circadian phase of the patient.
  • the light treatment may comprise administering a plurality of circadian effective lighting exposures and a plurality of circadian dark exposures throughout a 24 hour period.
  • a light treatment may include light having a CS of 0.3 for 2 hours starting at 9 am followed by typical daily light exposures and then circadian dark exposures occurring before a desired sleep start time.
  • the light treatment may include exposure to a light source having a specific CS (e.g., 0.01 to 0.7) for a specific duration and at a specific clock time to adjust the patient’s circadian phase in view of the patient’s initial phase.
  • the pacemaker model may indicate the certain parameters (e.g., CS value, duration, and clock time) to adjust the circadian phase of the patient Page 15 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center given the patient’s initial circadian phase.
  • the light treatment may comprise a plurality of CS light exposures throughout a day.
  • CS may be directly related to melatonin suppression.
  • CLA relates directly to a CS value, therefore the pacemaker models’ outputted CS value at a necessary time may correlate to a CLA value which then may be transformed into the desired lighting treatment.
  • being outdoors at night may correspond to a CS of about 0, while being outdoors during the day may correspond to a CS of about 0.7.
  • Being outdoors at night may have a melatonin suppression percentage of about 0%, whereas being outdoors during the day may have a melatonin suppression percentage of about 70%.
  • These two light/dark exposures may comprise the minimum and maximum CS values.
  • In between outdoor light during the day and outdoor light at night are a variety of different CS light values.
  • These different CS light values may provide the basis for the light treatment necessary to adequately suppress melatonin for a duration at a clock time to adjust the circadian phase of the patient.
  • the light treatment may provide the patient with a variety of options including different amounts, durations, and clock times.
  • the light treatment may be provided by a lighting device, outdoor light, or by limiting light exposure.
  • the lighting device may be any device that provides light.
  • the lighting device may be a light mask operable to deliver light directly to a patient’s eyes.
  • the light mask may be operable to deliver light even when the patient’s eyes are closed.
  • the lighting device may be configured to provide pulses of light. For example, the lighting device may provide a 1 second pulse of 0.65 CS light every 30 seconds. The pulsing may limit heat buildup while producing similar effectiveness of continuous radiation.
  • the lighting device may be electric room lighting, a self- luminous tablet, a light box, electrically powered ambient lighting devices, a linear source (e.g., LED strip) or other lighting devices known in the art.
  • the light box may be a diffused light box such as a ganzfeld sphere.
  • the light treatment may be going outside for a duration at a given clock time depending on the patient’s desired circadian phase.
  • the necessary CS for the light treatment may be converted into photopic illuminance of “white” light delivered to the eyes of the patient with electric room lighting between about 0 lux to 1000 lux.
  • the light treatment may Page 16 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center be a white light having an amount of about 0 lux to about 100 lux, about 100 lux to about 200 lux, about 200 lux to about 300 lux, about 300 lux to about 400 lux, about 400 lux to about 500 lux, about 500 lux to about 600 lux, about 600 lux to about 700 lux, about 700 lux to about 800 lux, about 800 lux to about 900 lux, or about 900 lux to about 1,000 lux all correlating to different CS values and therefore different effects on the patient’s circadian phase.
  • the light treatment may be administered via a white light source with correlated color temperatures (CCTs) ranging from about 2200 K to about 7500 K, where each value in the range provides a different effect on the patient’s circadian phase.
  • CCTs correlated color temperatures
  • the light treatment may comprise pure blue light from a blue LED having a particular wavelength (e.g., peak emission of 470 nm), full-width-half- maximum bandwidth (e.g., FWHM of 20 nm), and irradiance (e.g., 0.5 W/m 2 ).
  • other light treatments may be given in terms of CS and thereby CLA.
  • the light treatment may be a polychromatic white light and/or narrowband light.
  • a narrow-band light source may have a peak wavelength between 380 nm and 730 nm, corresponding to different CS values and therefore having differing effects on the patient’s circadian phase.
  • the duration of the light may be about 1 minute to about 30 minutes, about 30 minutes to about 1 hour, about 1 hour to about 1.5 hours, about 1.5 hours to about 2 hours, about 2 hours to about 2.5 hours, about 2.5 hours to about 3 hours, about 3 hours to about 3.5 hours, about 3.5 hours to about 4 hours, about 4 hours to about 4.5 hours, about 4.5 hours to about 5 hours, about 5 hours to about 5.5 hours, about 5.5 hours to about 6 hours, or more.
  • the duration of the light treatment in combination with the amount, as measured by CS, have differing effects on the adjustment of the patient’s circadian rhythm. For example, a higher CS for a short duration may have a similar effect to a lower CS for a longer duration.
  • the model can predict change in circadian phase for each administered CS at each duration, thereby providing a variety of CS values and durations to adjust a patient’s circadian phase.
  • the clock time of the light treatment may be any time from 12:00 am to 11:59 pm (e.g., the morning, the afternoon, the evening, the night, or combinations thereof). The clock time may be important for the light treatment.
  • the patient may be exposed to a higher CS light or a CS light for a longer duration earlier in the day.
  • the model may provide Page 17 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center another option where an even higher CS light is necessary to advance the patient’s circadian phase at a later clock time.
  • the amount of light and the duration of light may be related. For example, a light treatment having 700 lux for 30 minutes may be roughly equivalent to a light treatment having 350 lux for 1 hour and walking outside will correspond to an even shorter duration than 30 minutes.
  • equivalent light treatments may be administered on different days due to a patient’s schedule or preference.
  • equivalent light treatments e.g., one light treatment with a certain amount, duration, and clock time may be equivalent to a different amount, duration, and time
  • the pacemaker model may determine the effect of any type of light or dark exposure in terms of CS for a specific duration and clock time.
  • the above examples for light and dark sources, durations, and clock times are examples only.
  • the pacemaker model provides accurate predictions of light and dark exposure effects on the circadian phase of the patient and therefore is operable to determine numerous different combinations of light sources, durations, and clock times to adjust the patient’s circadian phase to the desired circadian phase.
  • the pacemaker model is operable to provide the patient with a plurality of light treatment options.
  • the method 1100 may further include monitoring the patient’s light/dark exposures throughout the day using the at least one photosensor.
  • the photosensor may be in communication with a computing device.
  • the computing device may be in communication with a lighting device or other wearable device.
  • the computing device may be in communication with a display.
  • the Page 18 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center display may provide haptic feedback to the user related to the light treatment.
  • the display may provide feedback that the light from the lighting device or outdoor lighting is an insufficient amount of light.
  • the display may also provide guidance on the light treatment.
  • the display may indicate that it is the correct clock time to begin the light treatment.
  • the display may indicate that it is time for circadian dark exposure (e.g., no light provided).
  • the display may indicate the duration of the light treatment and may provide a timer to indicate when the light treatment is completed.
  • the display may be a mobile device.
  • an audible alert may be given to a patient related to duration, amount, and clock time of the light treatment.
  • the audible alert may be produced by a mobile device.
  • the computing device may be in communication with a lighting device. The computing device may control the amount, duration, and clock time of light to provide a light treatment.
  • the computing device may be able to adjust ambient light to provide the light treatment.
  • the ambient light may be adjusted by the computing device to provide the light treatment to change the patient’s circadian phase.
  • the computing device may be operable to turn the lighting device on and provide CS light at a desired clock time for a desired duration, thereby fully automating the light treatment.
  • the lighting device, the display, and the computing device may all be one component, such that the device is operable to determine the light treatment parameters, provide the light treatment, and provide feedback related to the light treatment.
  • the method 1100 may further include determining a patient’s circadian phase (e.g., new circadian phase) at least one day after the light treatment has started. In this manner, the patient’s progress towards their desired circadian phase may be determined. The light treatments may then be adjusted to enhance progress or maintain the current circadian phase of the patient.
  • the method 1100 may be conducted on patients of any age. In an example, the age of the patient may be about 1 year old to about 95 years old.
  • determining the patient’s circadian phase may also optionally include monitoring a plurality of light exposures of the patient during at least one monitoring period of 24 hours.
  • more than one monitoring Page 19 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center period may be used.
  • Monitoring the plurality of light exposures may be conducted using at least one calibrated photosensor.
  • the photosensor may be a calibrated photometric device.
  • the photosensor may be a Daysimeter.
  • the Daysimeter may contain a red-green-blue (RGB) solid-state photosensor package with an infrared (IR) filter.
  • RGB reading may allow a computing system to compute a variety of spectrally weighted irradiance values such as photopic illuminance (lux), CLA, and CS.
  • the Daysimeter may also contain a three-axis, solid-state accelerometer package to measure a behavior response (R) influenced by the circadian system, called Activity Index (AI), simultaneous with the light stimulus (S). Sampling rates of the light exposures may occur every second or less. Storage rates may be between every 30 seconds to every 180 seconds.
  • the light exposure measurements may be sent to the computing system, such that the light exposure measurements are stored and/or analyzed by the computing system.
  • the light exposures may be measured as irradiance at a cornea of the patient weighted by circadian effective light (CLA). In other examples, the light exposures may be measured using any metric traceable to circadian effective light.
  • the photosensor may be located on the patient’s body.
  • the photosensor may be located on a wrist, torso, chest, or head of a patient.
  • monitoring the patient’s light exposure throughout a day may improve the efficacy of the light treatment. For example, by monitoring the patient’s light exposures, more effective CS light treatments may be determined. For example, if a patient is working outdoors for an entire morning, a higher CS for a light treatment may not be necessary around noon. Whereas if the patient is inside for the entire morning, a higher CS around noon may help adjust the patient’s circadian phase to the desired circadian phase. The information gathered from the patient’s light exposures may improve the treatment by more accurately determining the circadian phase and predicting necessary light exposures for circadian phase adjustment.
  • the light treatment may be configured to re-align the circadian phase of the patient to improve population specific health outcomes.
  • the light treatment may improve inflammation, neutropenic fever, and symptom burden of a multiple myeloma patient.
  • the light treatment may improve sleep and mood of patients with Alzheimer’s disease.
  • the light treatment may improve the sleep schedule for any human.
  • the light treatment may be used to change the circadian phase of a patient who has been traveling between time zones.
  • the light treatment may be configured to help submariners adjust their circadian phase to a desired schedule depending on the demands of their job.
  • Office workers may adjust their circadian phase by, for example, going on a walk every day at noon or being exposed to other circadian effective light for longer durations, such as a lighting device in their office.
  • school students may adjust their circadian phase by going on walk outdoors around noon or being exposed to other circadian effective light earlier in the day and then limiting light exposures later in the day.
  • the method provided herein may be operable to predictably shorten the re-entrainment period for a regularly commuting daytime worker following daylight savings transition by providing a light treatment to adjust the worker’s circadian phase.
  • FIG.12 is a diagram illustrating an example of a system for implementing certain aspects of the present technology.
  • FIG.12 illustrates an example of computing system 1200, which can be for example any computing device making up an internal computing system, a remote computing system, a camera, or any component thereof in which the components of the system are in communication with each other using connection 1205.
  • Connection 1205 can be a physical connection using a bus, or a direct connection into processor 1210, such as in a chipset architecture.
  • Connection 1205 can also be a virtual connection, networked connection, or logical connection.
  • computing system 1200 is a distributed system in which the functions described in this disclosure can be distributed within a datacenter, multiple data centers, a peer network, etc.
  • Example computing system 1200 includes at least one processing unit (CPU or processor) 1210 and connection 1205 that couples various system components including system memory 1215, such as ROM 1220 and RAM 1225 to processor 2310.
  • Computing system 1200 can include a cache 1212 of high-speed memory connected directly with, in close proximity to, or integrated as part of processor 1210.
  • Processor 1210 can include any general purpose processor and a hardware service or software service, such as services 1232, 1234, and 1236 stored in storage device 1230, configured to control processor 1210 as well as a special-purpose processor where software instructions are incorporated into the actual processor design.
  • Processor 1210 may essentially be a completely self-contained computing system, containing multiple cores or processors, a bus, memory controller, cache, etc.
  • a multi-core processor may be symmetric or asymmetric.
  • computing system 1200 includes an input device 1245, which can represent any number of input mechanisms, such as a microphone for speech, a touch-sensitive screen for gesture or graphical input, keyboard, mouse, motion input, speech, etc.
  • Computing system 1200 can also include output device 1235, which can be one or more of a number of output mechanisms.
  • output device 1235 can be one or more of a number of output mechanisms.
  • multimodal systems can enable a user to provide multiple types of input/output to communicate with computing system 1200.
  • Computing system 1200 can include communications interface 1240, which can generally govern and manage the user input and system output.
  • the communication interface may perform or facilitate receipt and/or transmission wired or wireless communications using wired and/or wireless transceivers, including those making use of an audio jack/plug, a microphone jack/plug, a universal serial bus (USB) port/plug, an Apple® Lightning® port/plug, an Ethernet port/plug, a fiber optic port/plug, a proprietary wired port/plug, a Bluetooth® wireless signal transfer, a BLE wireless signal transfer, an IBEACON® wireless signal transfer, an RFID wireless signal transfer, near-field communications (NFC) wireless signal transfer, dedicated short range communication (DSRC) wireless signal transfer, 802.11 WiFi wireless signal transfer, WLAN signal transfer, Visible Light Communication (VLC), Worldwide Interoperability for Microwave Access (WiMAX), IR communication wireless signal transfer, Public Switched Telephone Network (PSTN) signal transfer, Integrated Services Digital Network (ISDN) signal transfer, 3G/4G/5G/LTE cellular data network wireless signal transfer, ad-hoc network signal transfer, radio wave signal transfer
  • the communications interface 1240 may also include one or more Global Navigation Satellite System (GNSS) receivers or transceivers that are used to determine a location of the Page 22 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center computing system 1200 based on receipt of one or more signals from one or more satellites associated with one or more GNSS systems.
  • GNSS systems include, but are not limited to, the US-based GPS, the Russia-based Global Navigation Satellite System (GLONASS), the China-based BeiDou Navigation Satellite System (BDS), and the Europe-based Galileo GNSS.
  • GLONASS Russia-based Global Navigation Satellite System
  • BDS BeiDou Navigation Satellite System
  • Galileo GNSS Europe-based Galileo GNSS
  • Storage device 1230 can be a non-volatile and/or non-transitory and/or computer-readable memory device and can be a hard disk or other types of computer readable media which can store data that are accessible by a computer, such as magnetic cassettes, flash memory cards, solid state memory devices, digital versatile disks, cartridges, a floppy disk, a flexible disk, a hard disk, magnetic tape, a magnetic strip/stripe, any other magnetic storage medium, flash memory, memristor memory, any other solid-state memory, a compact disc read only memory (CD-ROM) optical disc, a rewritable compact disc (CD) optical disc, digital video disk (DVD) optical disc, a blu-ray disc (BDD) optical disc, a holographic optical disk, another optical medium, a secure digital (SD) card, a micro secure digital (microSD) card, a Memory Stick® card, a smartcard chip, a EMV chip, a subscriber identity module (SIM) card, a mini
  • the storage device 1230 can include software services, servers, services, etc., that when the code that defines such software is executed by the processor 1210, it causes the system to perform a function.
  • a hardware service that performs a particular function can include the software component stored in a computer-readable medium in connection with the necessary hardware components, such as processor 1210, connection 1205, output device 1235, etc., to carry out the function.
  • computer-readable medium includes, but is not limited to, portable or non-portable storage devices, optical storage devices, and various other mediums Page 23 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center capable of storing, containing, or carrying instruction(s) and/or data.
  • a computer- readable medium may include a non-transitory medium in which data can be stored and that does not include carrier waves and/or transitory electronic signals propagating wirelessly or over wired connections. Examples of a non-transitory medium may include, but are not limited to, a magnetic disk or tape, optical storage media such as CD or DVD, flash memory, memory or memory devices.
  • a computer- readable medium may have stored thereon code and/or machine-executable instructions that may represent a procedure, a function, a subprogram, a program, a routine, a subroutine, a module, a software package, a class, or any combination of instructions, data structures, or program statements.
  • a code segment may be coupled to another code segment or a hardware circuit by passing and/or receiving information, data, arguments, parameters, or memory contents. Information, arguments, parameters, data, etc. may be passed, forwarded, or transmitted via any suitable means including memory sharing, message passing, token passing, network transmission, or the like.
  • the computing device or apparatus may include various components, such as one or more input devices, one or more output devices, one or more processors, one or more microprocessors, one or more microcomputers, one or more cameras, one or more sensors, and/or other component(s) that are configured to carry out the steps of processes described herein.
  • the computing device may include a display, one or more network interfaces configured to communicate and/or receive the data, any combination thereof, and/or other component(s).
  • the one or more network interfaces can be configured to communicate and/or receive wired and/or wireless data, including data according to the 3G, 4G, 5G, and/or other cellular standard, data according to the Wi-Fi (802.11x) standards, data according to the Bluetooth TM standard, data according to the IP standard, and/or other types of data.
  • the components of the computing device can be implemented in circuitry.
  • the components can include and/or can be implemented using electronic circuits or other electronic hardware, which can include one or more programmable electronic circuits (e.g., microprocessors, GPUs, DSPs, CPUs, and/or other suitable electronic circuits), and/or can include and/or be implemented using computer Page 24 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center software, firmware, or any combination thereof, to perform the various operations described herein.
  • the computer-readable storage devices, mediums, and memories can include a cable or wireless signal containing a bit stream and the like.
  • non-transitory computer-readable storage media expressly exclude media such as energy, carrier signals, electromagnetic waves, and signals per se.
  • a major goal of any model is to predict data that are not part of the model development.
  • the accuracy of model predictions is not isolated to the master clock (O) alone.
  • O master clock
  • S photopic illuminance
  • S photic stimulus
  • R phase markers to characterize the response (R) of the master clock.
  • CBTmin minimum core body temperature
  • a variety of metrics can be used to assess the accuracy of S-O-R model predictions, but two of particular importance, and utilized here, when possible, are (1) mean absolute error (MAE), which characterizes the variance in the actual values with respect to the modeled values and (2) the amount of data within an accuracy criterion.
  • MAE mean absolute error
  • pacemaker model predictions can be independently tested and compared, thus avoiding the possibility of “getting lucky” in predicting just one data set.
  • All four data sets were obtained under Page 25 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center field conditions, not under controlled experiments. As such, these data should be inherently more variable than laboratory data because light exposures, as well as other potential influences on circadian phase, were not controlled. If pacemaker models can predict phase changes for ambulatory data, they should also be able to predict phase changes in controlled laboratory experiments. Therefore, these four data sets represent a “worst-case” test of pacemaker models. Fourth, the proper specification of S and R is critical in testing pacemaker models.
  • a Daysimeter contains a red- green-blue (RGB), solid-state photosensor package, with an infrared (IR) filter.
  • the R, G, and B reading from a calibrated light source enable software to compute a variety of spectrally weighted irradiance values such as photopic illuminance (lux), CLA and CS.
  • These sensors also contain a three-axis, solid-state accelerometer package to measure a behavioral response (R) influenced by the circadian system, called Activity Index (AI), simultaneous with the light stimulus (S). Sampling rates were once every second, while storage rates (average values) varied between once every 30 seconds to once every 180 seconds (depending upon the study). The lab maintains a calibration file for each of the units developed.
  • ⁇ DLMO is a considered to be the best measure of circadian phase change.
  • a trained nurse collected and stored all samples for biomarker Page 26 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center assessments. Table 1 summarizes the four data sets used in assessments of model prediction accuracy.
  • Two points should be noted regarding the light measurements in these four studies.
  • Step 1 was to determine whether predictions are better with or without Process L for the original limit-cycle oscillator model.
  • Step 2 was to determine whether CLA was better than photopic illuminance for prediction accuracy.
  • Step 3 was to determine whether CS as photic input obviates Process L.
  • Step 4 was to determine whether considering only the morning light exposure period can improve prediction accuracy.
  • Step 5 was to determine the importance of the sensitivity modulator and the initial estimate of clock time for the CBT min .
  • Step 6 was to determine if the Kronauer99 model parameters still hold given the change in characterization of the light stimulus input.
  • FIG.10 is a graphical illustration of the Kronauer99 framework.
  • CR Constant routine
  • Step 1 Determine whether predications are better with or without Process L for the original limit-cycle oscillator model.
  • the impact of prior light exposures was investigated by including and excluding Process L in the working model framework for each of the data sets.
  • Process L was simply bypassed, inputting the Page 31 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center light data into Process P directly.
  • the light data from the Daysimeter has a relatively high temporal bandwidth being sampled at 3-min intervals or less.
  • the importance of the high frequency content for accurate predictions helped us determine the importance of the temporal dynamics of Process L and values of the involved time constants in a subsequent analysis. For example, Process L does not treat each light stimulus to the pacemaker independently.
  • Process L improves the circadian phase prediction accuracy. This means, in effect, that light exposures are not independent when driving the SCN and sampling intervals should be short ( ⁇ 180 s). Rather, one must know with relatively high precision the previous light exposure before the impact of the next light exposure can be predicted.
  • Model Data Set R 2 Mean absolute Subjects with error (MAE) in error ⁇ 1.0 hours hours (%) Kronauer99 Rea et al., 0.07 1.48 45 without 2016 Process L Figueiro et al., 0.11 1.16 60 2014 Sharkey et al., 0.11 1.58 32 2011 Average 0.10 1.41 46 Kronauer99 Rea et al., 0.11 0.91 55 with Process 2016 L Figueiro et al., 0.42 0.86 67 2014 Page 32 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center Sharkey et al., 0.21 1.43 36 2011 Average 0.25 1.07 53
  • Step 3 Determine whether circadian stimulus as photic input obviates Process L.
  • CS replaced photopic illuminance as the input light parameter “I” as specified in the Kronauer99 framework (Eq. A2.6).
  • I0 Eq. A2.6
  • CS is a sigmoid function, inherently rendering every weak light stimulus equal (below threshold) and every strong light stimulus equal (above saturation). If, for example, the light stimuli were always either above saturation or below threshold, characterizing light exposures in units of CS would reduce the significance of Process L for model predictions.
  • Step 4 Determine whether considering only the morning light exposure period can improve prediction accuracy. Diurnal species, including humans, typically exhibit intrinsic periods slightly longer than 24 h. To entrain to local time, morning light exposure is particularly important because it will advance the clock phase and the majority of humans free run with a period slightly longer than 24 h. Whether measuring morning light exposure alone would accurately predict phase changes was examined.
  • Step 5 Determine the importance of the sensitivity modulator and the initial estimate of the CBTmin.
  • the Kronauer99 model included a sensitivity modulator between Process L and Process P which controls the relative effectiveness of photic exposures depending upon the circadian phase of the pacemaker at the time of exposure. For example, a light exposure in the early morning should be more effective for inducing a phase change than that very same light exposure mid-day. Values generated by the sensitivity modulator depend upon the value of the circadian phase marker, CBTmin.
  • the circadian phase marker was initially estimated to occur at 0400 (4:00 AM) to depict a “typical” CBTmin for people entrained to the solar day; that is, 4 h after midnight.
  • this assumed value of 0400 (4:00 AM) also sets the values for the light drive terms, x and x c , quite apart from the sensitivity modulator, as illustrated in FIG.10, where x is a variable proportional to endogenous core body temperature and x c is a complementary variable.
  • x is a variable proportional to endogenous core body temperature
  • x c is a complementary variable.
  • the four data sets employed DLMO as the phase marker, but the analysis is based upon light- induced changes in DLMO (i.e., ⁇ DLMO).
  • ⁇ DLMO light- induced changes in DLMO
  • the absolute values of DLMO are unimportant, and all phase changes are evaluated relative to the phase determined at the end of the baseline period.
  • MAE across the four data sets dropped from 0.79 to 0.75 h with exclusion of the sensitivity modulator.
  • the percentage of subjects with error ⁇ 1 h decreased from 75 to 71%.
  • a closer look at these two metrics for the individual data sets shows that including the sensitivity modulator improved both MAE and the percentage of subjects with error ⁇ 1 h for three of the four data sets.
  • the revised pacemaker model has been referred to as the CS-oscillator model.
  • the CS-oscillator model [0123]
  • Kronauer99 introduced Process L to account for hysteresis by the circadian- phototransduction mechanisms. In effect, this means that the effectiveness of a given Page 41 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center light pulse is not independent of the effectiveness of the previous light pulse. All neural systems, including those in the retina, adapt to repeated stimulation.
  • the present technology may be presented as including individual functional blocks including functional blocks comprising devices, device components, steps or routines in a method embodied in software, or combinations of hardware and software. Additional components may be used other than those shown in the figures and/or described herein. For example, circuits, systems, networks, processes, and other components may be shown as components in block diagram form in order not to obscure the aspects in unnecessary detail. In other instances, well-known circuits, processes, algorithms, structures, and techniques may be shown without unnecessary detail in order to avoid obscuring the aspects. [0129] Individual aspects may be described above as a process or method which is depicted as a flowchart, a flow diagram, a data flow diagram, a structure diagram, or a block diagram.
  • a process is terminated when its operations are completed but may have additional steps not included in a figure.
  • a process may correspond to a method, a function, a procedure, a subroutine, a subprogram, etc.
  • a process corresponds to a function
  • its termination can correspond to a return of the function to the calling function or the main function.
  • Such instructions can include, for example, instructions and data which cause or otherwise configure a general purpose computer, special purpose computer, or a processing device to perform a certain function or group of functions. Portions of computer resources used can be accessible over a network.
  • the computer executable instructions may be, for example, binaries, intermediate format instructions such as assembly language, firmware, source code, etc. Examples of computer-readable media that may be used to store instructions, information used, and/or information created during methods according to described examples include magnetic or optical disks, flash memory, USB devices provided with non-volatile memory, networked storage devices, and so on.
  • Devices implementing processes and methods according to these disclosures can include hardware, software, firmware, middleware, microcode, hardware Page 43 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center description languages, or any combination thereof, and can take any of a variety of form factors.
  • the program code or code segments to perform the necessary tasks e.g., a computer- program product
  • a processor(s) may perform the necessary tasks.
  • form factors include laptops, smart phones, mobile phones, tablet devices, or other small form factor personal computers, personal digital assistants, rackmount devices, standalone devices, and so on.
  • the functionality described herein also can be embodied in peripherals or add-in cards. Such functionality can also be implemented on a circuit board among different chips or different processes executing in a single device, by way of further example.
  • the instructions, media for conveying such instructions, computing resources for executing them, and other structures for supporting such computing resources are example means for providing the functions described in the disclosure.
  • Coupled to refers to any component that is physically connected to another component either directly or indirectly, and/or any component that is in communication with another component (e.g., connected to the other component over a wired or wireless connection, and/or other suitable communication interface) either directly or indirectly.
  • Claim language or other language reciting “at least one of” a set and/or “one or more” of a set indicates that one member of the set or multiple members of the set (in any combination) satisfy the claim. For example, claim language reciting “at least one of A and B” or “at least one of A or B” means A, B, or A and B.
  • claim language reciting “at least one of A, B, and C” or “at least one of A, B, or C” means A, B, C, or A and B, or A and C, or B and C, or A and B and C.
  • the language “at least one of” a set and/or “one or more” of a set does not limit the set to the items listed in the set.
  • claim language reciting “at least one of A and B” or “at least one of A or B” can mean A, B, or A and B, and can additionally include items not listed in the set of A and B.
  • Such techniques may be implemented in any of a variety of devices such as general purposes computers, wireless communication device handsets, or integrated circuit devices Page 45 of 58 98666117.2 PATENT Atty Docket: 093698-822897 Via Patent Center having multiple uses including application in wireless communication device handsets and other devices. Any features described as modules or components may be implemented together in an integrated logic device or separately as discrete but interoperable logic devices. If implemented in software, the techniques may be realized at least in part by a computer-readable data storage medium comprising program code including instructions that, when executed, performs one or more of the methods described above.
  • the computer-readable data storage medium may form part of a computer program product, which may include packaging materials.
  • the computer-readable medium may comprise memory or data storage media, such as RAM such as synchronous dynamic random access memory (SDRAM), ROM, non- volatile random access memory (NVRAM), EEPROM, flash memory, magnetic or optical data storage media, and the like.
  • RAM such as synchronous dynamic random access memory (SDRAM), ROM, non- volatile random access memory (NVRAM), EEPROM, flash memory, magnetic or optical data storage media, and the like.
  • SDRAM synchronous dynamic random access memory
  • ROM read-only memory
  • NVRAM non- volatile random access memory
  • EEPROM electrically erasable programmable read-only memory
  • flash memory such as electrically erasable programmable read-only memory
  • magnetic or optical data storage media such as magnetic or optical data storage media, and the like.
  • the techniques additionally, or alternatively, may be realized at least in part by a computer-readable communication medium that carries or communicates program code in the form of instructions or data structures and that can be accessed, read, and/or executed by a computer, such as propag
  • the program code may be executed by a processor, which may include one or more processors, such as one or more DSPs, general purpose microprocessors, an application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry.
  • processors such as one or more DSPs, general purpose microprocessors, an application specific integrated circuits (ASICs), field programmable logic arrays (FPGAs), or other equivalent integrated or discrete logic circuitry.
  • a general purpose processor may be a microprocessor; but in the alternative, the processor may be any conventional processor, controller, microcontroller, or state machine.
  • a processor may also be implemented as a combination of computing devices, e.g., a combination of a DSP and a microprocessor, a plurality of microprocessors, one or more microprocessors in conjunction with a DSP core, or any other such configuration. Accordingly, the term “processor,” as used herein may refer to any of the foregoing structure, any combination of the foregoing structure, or any other structure or apparatus suitable for implementation of the techniques described herein. [0141] The disclosures shown and described above are only examples.

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Abstract

L'invention divulgue des systèmes et des procédés pour fournir un traitement lumineux à un patient en ayant besoin. Le procédé peut comprendre la détermination d'une phase circadienne du patient et la détermination d'un traitement lumineux sur la base d'une phase circadienne souhaitée du patient.
PCT/US2024/047706 2023-09-20 2024-09-20 Systèmes et procédés de réglage de la phase circadienne d'un patient Pending WO2025064827A1 (fr)

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WO2020236958A1 (fr) * 2019-05-20 2020-11-26 University Of Washington Dispositifs, systèmes et procédés d'éclairage servant à stimuler les rythmes circadiens
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WO2022178250A1 (fr) * 2021-02-18 2022-08-25 Charles Jarboe Luminaire à efficacité circadienne
US20230268050A1 (en) * 2022-02-21 2023-08-24 Serca Science LLC Circadian Rhythm Recommendation Model Using Light Sensors and an Intelligent Light Box
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WO2015011652A1 (fr) * 2013-07-25 2015-01-29 Koninklijke Philips N.V. Système et procédé pour administrer une luminothérapie et modifier le rythme circadien
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WO2020236958A1 (fr) * 2019-05-20 2020-11-26 University Of Washington Dispositifs, systèmes et procédés d'éclairage servant à stimuler les rythmes circadiens
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WO2022178250A1 (fr) * 2021-02-18 2022-08-25 Charles Jarboe Luminaire à efficacité circadienne
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