Role of Photic and Non-photic Time Cues in Resetting Circadian Rhythms

Study Overview
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Brief Summary
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The aim of this study is to determine the principal time cue (light or meals) for resetting circadian rhythms in melatonin and metabolic outcomes.

Detailed Description
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The objective of this proposal is to construct and compare PRCs describing the relationship between the timing of light exposure and meals across the 24-hour day and the size and direction of shift in circadian rhythms of circulating lipids and melatonin in humans. Completion of the work will provide mechanistic insight on the role of photic and non-photic cues mediating entrainment of circadian rhythms in humans besides that of melatonin. In this proposal, we will use the same experimental paradigm that we have successfully used previously to characterize and compare PRCs for shifts in melatonin in response to light exposure of different durations and spectra, and as used in our pilot trials demonstrating a robust PRC of lipid circadian rhythms in response to combined photic and non-photic stimuli across the day. We will achieve our objective using a randomized controlled trial in young healthy adults (n=48, 18-30 years) that systematically manipulates the timing of 6.5-hour bright light exposure and 6.5-hour time restricted eating across the 24-hour circadian cycle to specifically: Aim 1: Determine if light is the primary time cue for resetting melatonin but not lipid circadian rhythms. Hypothesis: The resetting response of circadian rhythms in melatonin but not cholesterol and triglycerides is dependent upon the circadian phase at which a 6.5-hour bright light exposure occurs. Aim 2: Determine if meal timing is the primary time cue for resetting lipid but not melatonin circadian rhythms. Hypothesis: The resetting response of circadian rhythms in cholesterol and triglycerides but not melatonin is dependent upon the circadian phase at which a 6.5-hour time restricted eating occurs. Aim 3 (Exploratory): Evaluate the acute effects of eating across the 24-hour day on circulating lipid levels. Hypothesis: The acute effects of 6.5-hour time restricted eating on circulating cholesterol and triglycerides levels are dependent on the circadian phase at which meals are eaten.

Official Title
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Determining the Role of Photic and Non-photic Time Cues in Resetting Circadian Rhythms in Humans

Conditions
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Light Exposure, Meal Timing

Intervention / Treatment
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* Behavioral: Bright Light
* Behavioral: Time-restricted eating
* Behavioral: Dim light
* Behavioral: 12-h meal window


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged between 18-30 years Healthy (no medical, psychiatric or sleep disorders; Non-smoking for at least 6 months; Body Mass Index of >18 or <30 kg/m2; Able to maintain 8-hour consistent sleep schedule during the study Able to refrain from caffeine, alcohol, medication and supplements during the study Exclusion Criteria: History of alcohol or substance abuse; Positive result on drugs of abuse urine toxicology; Current or past history of sleep disorders, including but not limited to obstructive sleep apnea, narcolepsy, insomnia, or any significant sleep complaint Psychiatric disorder, or first degree relative with a psychiatric disorder Recent acute or chronic medical disorder Use of drugs or medication (birth control OK) likely to affect sleep, alertness or light sensitivity, as determined by the investigators Visual disorder, including but not limited to color blindness, or family history of glaucoma Pregnancy or lactation Shift work (past 3 years) Transmeridian travel (2 or more time zones) in the past 3 months Any other reason as determine by the Principal Investigator

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: 3 condition, parallel arm randomized control trial
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Bright light<br>Participants will receive a 6.5-hour 10,000 lux light pulse (4100K fluorescent light) centered within the 16-hour wake episode (start 4.75 hour after wake and end 11.25 hour after wake). Participants will receive 4 identical meals (equal calories and macronutrient content), over a 12-hour interval (meals at 2, 6, 10, and 14 hours after waking) centered within the 16-hour wake episode. | Behavioral: Bright Light<br>* 6.5-hour 10,000 lux light pulse (4100K fluorescent light) centered within the 16-hour wake episode (start 4.75 hour after wake and end 11.25 hour after wake).<br>Behavioral: 12-h meal window<br>* 12-hour restricted meal window (4 meals at 2, 6, 10, and 14 hours after waking) centered within the 16-hour wake episode.<br>|
| Experimental: Time-restricted eating<br>Participants will consume 4 identical meals, as in the other groups, except that the meal window will be restricted to 6.5 hours instead of 12 hours (meals at 4.75, 6.9, 9.1, 11.25 hours after waking) centered within the 16-hour wake episode. Participants will remain in dim light (<3 lux) throughout the 16-hour wake episode. | Behavioral: Time-restricted eating<br>* 6.5-hour restricted meal window (4 meals at 4.75, 6.9, 9.1, 11.25 hours after waking) centered within the 16-hour wake episode.<br>Behavioral: Dim light<br>* dim light (<3 lux) throughout the 16-hour wake episode<br>|
| Sham Comparator: Control<br>Participants will receive 4 identical meals (equal calories and macronutrient content), over a 12-hour interval (meals at 2, 6, 10, and 14 hours after waking) centered within the 16-hour wake episode. Participants will remain in dim light (<3 lux) throughout the 16-hour wake episode. | Behavioral: Dim light<br>* dim light (<3 lux) throughout the 16-hour wake episode<br>Behavioral: 12-h meal window<br>* 12-hour restricted meal window (4 meals at 2, 6, 10, and 14 hours after waking) centered within the 16-hour wake episode.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Amplitude of Phase Response Curve of melatonin | Amplitude of phase response curve of melatonin derived by fitting a sinusoidal regression to the individual phase shift data across  24 hours | 24 hours | 
| Amplitude of Phase Response Curve of triglyceride | Amplitude of phase response curve of triglyceride derived by fitting a sinusoidal regression to the individual phase shift data across  24 hours | 24 hours | 
| Amplitude of Phase Response Curve of cholesterol | Amplitude of phase response curve of cholesterol derived by fitting a sinusoidal regression to the individual phase shift data across  24 hours | 24 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the curve (AUC) of melatonin | AUC of melatonin | 6.5 hours during intervention | 
| Area under the curve (AUC) of triglyceride | AUC of triglyceride | 6.5 hours during intervention | 
| Area under the curve (AUC) of cholesterol | AUC of cholesterol | 6.5 hours during intervention |