Assessment and modification of circadian phase and amplitude

5,176,133

07/365,949

June 15, 1989

A method for accurately assessing and rapidly modifying the phase and amplitude of the endogenous circadian pacemaker is disclosed. A circadian cycle modification capacity assessment method comprises (before and after a stimulus) eliminating activity-related confounding factors associated with the sleep-rest cycle which otherwise mask the state of the endogenous circadian pacemaker. Based on either individual or normative assessment data, the circadian phase and amplitude modification method involves the application of bright (about 9,500 lux) light and, advantageously, episodes of imposed darkness, at critically chosen phases to achieve rapid and stable changes in phase and amplitude. The timing of the episodes of bright light may be chosen either by reference to empirically-derived phase response data, or by using a mathematical model in which the endogenous circadian pacemaker is a van der Pol oscillator. A forcing function in the model is substantially proportional to changes in the cube root of the surrounding illuminance, in lux. The amplitude of the endogenous circadian pacemaker may actually be reduced to substantially zero, so as to bring about dramatic phase modifications in diminishingly small periods of time. The methods find special utility in treating "jet lag" sufferers, shift workers, advanced circadian phase experienced by many elderly subjects, and those afflicted with delayed sleep phase insomnia.

Czeisler, Charles A. (Cambridge, MA); Kronauer, Richard E. (Cambridge, MA); Allan, James S. (Pittsburgh, PA)

Brigham and Women's Hospital (Boston, MA)

What is claimed is

1. A method of reducing the circadian amplitude of a human subject to approximately zero over a period of less than about 36 hours comprising the steps of

predicting the amplitude excursion, and the time of the maximum and minimum of the endogenous circadian temperature cycle of said human subject;

exposing said human subject to substantial darkness during a first period of time of approximately eight to twelve hours centered around the time of the predicted maximum of the endogenous circadian temperature cycle of said human subject;

exposing said human subject to bright light during a second time period centered around the time of the predicted minimum of the endogenous circadian temperature cycle of said human subject; and

exposing said human subject to substantial darkness during a third period of time of approximately eight to twelve hours centered around the time of the predicted maximum of the endogenous circadian temperature cycle of said human subject, to thereby reduce the circadian amplitude of said human subject to approximately zero.

2. The method of claim 1, wherein said third time period follows said second time period and said second time period follows said first time period.

3. The method of claim 1, wherein said bright light is greater than 2,000 lux.

4. A method of reducing the circadian amplitude of a human subject to approximately zero over a period of less than about 36 hours, and resetting the circadian phase of said human subject to a desired circadian phase, comprising the steps of

exposing said human subject to bright light during a second time period centered around the time of the predicted minimum of the endogenous circadian temperature cycle of said human subject;

exposing said human subject to substantial darkness during a third period of time of approximately eight to twelve hours centered around the time of the predicted maximum of the endogenous circadian temperature cycle of said human subject; and

exposing said human subject to bright light at a preselected time following said third time period to thereby reset the circadian phase of said human subject to the desired circadian phase and to reduce the circadian amplitude of said human subject to approximately zero.

5. The method of claim 4, wherein said third time period follows said second time period and said second time period follows said first time period.

6. The method of claim 4, wherein said bright light is greater than 2,000 lux.

7. A method of modifying the circadian cycle of a human subject to a desired state comprising

assessing the characteristics of the present circadian cycle of said human subject; and

applying pulses of bright light at selected times and for selected durations, wherein said assessing step comprises

modeling said human subject's desired circadian cycle as a solution to a Van der Pol differential equation, including deriving a forcing function dependent on

a) a brightness coefficient function which is a function of the present circadian cycle of said human subject; and

b) an illuminance function representing the illuminance of the scene of gaze of said human subject, the illuminance function being a function of the present circadian phase of said human subject;

whereby said preselected times and preselected durations are selected.

8. The method of claim 7, wherein said forcing function is substantially proportional to the illuminance function which comprises a subjectively assessed brightness function.

9. The method of claim 7, wherein said forcing function is substantially proportional to the illuminance function which comprises the cube root of the illuminance of light surrounding said human subject.

10. The method of claim 7, wherein said forcing function is substantially proportional to changes in the illuminance function which comprises a subjectively assessed brightness function.

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A61N 506

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