Performing Department
(N/A)
Non Technical Summary
Walnuts are a nutrient-rich food that provides melatonin and polyphenols. We haveevidence that dietary intakes of foods high in these components can have a good impact on sleep but we don't know if includingwalnuts in the diet influences sleep. We propose to fill this knowledge gap by testing the effects of walnut consumption on blood levels of melatonin and sleep. We expect that walnut consumption for 4 days will increase melatonin levels and lead to better sleep quality compared to a food with a high amount of carbohydrates and sugar (HCHS). This is very important for the general community because a large portion of American adults experience sleep difficulties. With this study, we will be able to provide useful information to the American population about the potential benefits of walnuts for improving their sleep. To accomplish this goal, we will conduct a trial in middle-aged to older adults who have sleep difficulties.Adults will be recruited and tested under 2 conditions: walnut or HCHS. In each conditionthey will eat three servings per day of walnuts or HCHS food for four days. Sleep quality will be measured every night using a questionnaire and a wrist monitor. We will also measure time spent in deep and light sleep on night 3. Other measures of sleep quality will be measured in the laboratoryon day 4. These will include blood melatonin levels and body temperature. We will also measure overnight production of melatonin from urine collected on the morning of day 5. Given the extent of poor sleep, our findings will provide information on natural ways to improve sleep health from increased walnut consumption. This will have high public health relevance given the importance of good sleep for overall health and wellbeing.
Animal Health Component
0%
Research Effort Categories
Basic
100%
Applied
0%
Developmental
0%
Goals / Objectives
Objectives: The overall goal of this study is to conduct a randomized crossover dietary intervention to evaluate the causal impact of walnut consumption, compared to an energy-matched high-carbohydrate, high-sugar (HCHS) alternative, representative of a common American snack food, on sleep quality in adults with habitually poor sleep quality. Furthermore, we aim to evaluate the effect of walnut vs. HCHS consumption on key markers of circadian rhythmicity that are involved in the sleep/wake cycle. These objectives will be accomplished within the framework of a randomized, controlled, crossover dietary intervention study with 2 phases of 4 days each comprising either 3 servings/day of walnuts (3 oz/d) or 3 equicaloric servings of a HCHS food. The goals of this project will address the following specific aims:Specific Aim 1: To determine the effect of walnut consumption, compared to a HCHS food on circadian physiology.Hypothesis 1a: Walnut consumption for 4 days will lead to higher serum melatonin (primary outcome) and overnight melatonin production, assessed from urinary 6-sulfatoxymelatonin (secondary outcome), compared to an equicaloric amount of a HCHS food.Hypothesis 1b: Walnut consumption will lead to more robust circadian rhythms, reflected by a higher proximal to distal body temperature gradient (secondary outcome), compared to an equicaloric amount of a HCHS food.Specific Aim 2: To determine the effect of short-term walnut consumption, compared to a HCHS food, on sleep quality.Hypothesis 2a: Walnut consumption will lead to better sleep quality, assessed using questionnaire (secondary outcome: sleep quality on Karolinska Sleep Diary) and wrist actigraphy (primary outcomes: lower sleep fragmentation index, sleep efficiency), compared to diet enriched with an equivalent amount of a HCHS food.Hypothesis 2b: Walnut consumption will lead to better sleep quality, assessed using polysomnography (primary outcome: SWS), compared to a diet enriched with an equicaloric amount of a HCHS food.We will enroll 24 participants (50% females; expecting 20 participants to complete both study phases) into a randomized crossover trial with two study phases: walnut and HCHS. Each study phases will be 4 days in duration and separated by a 2-3-week washout period. During the walnut phase, participants will be given walnuts and instructed to consume one serving at each of three separate eating occasions every day. During the HCHS (control) phase, participants will be given a commonly consumed snack food and instructed to consume an amount equal in calories to a serving of walnuts at each of 3 eating occasions every day.In Year 1, we will obtain IRB and institutional approvals for the study. This will be accomplished within the first 3 months. Staff will be trained in the study procedures, including recruitment process, scheduling, and testing. They will receive training in sample processing. Study initiation will follow IRB approval. For this study, wewill recruit 12 men and 12 women, aged 45-65 years, equally distributed among those with normal weight (18.5-24.9 kg/m2) and overweight (25-29.9 kg/m2).Women will be postmenopausal (i.e., absence of a menstrual period for a ≥12 months). All participants will report poor sleep quality, reflected by a global score >5 on the PSQI (44). Participants with conditions that could affect sleep will be excluded. This includes, but is not limited to: smoking, excessive caffeine intake (>300 mg/day), shift work, chronic pain, diagnosis of a chronic disease (e.g., uncontrolled hypertension, pre-diabetes, type 2 diabetes, chronic kidney disease, chronic obstructive pulmonary disease), autoimmune diseases, cardiovascular event or cancer in the past 24 months, psychiatric/neurologic disease or disorder, or sleep disorder (diagnosed or high risk for sleep apnea, chronic insomnia, restless leg syndrome, narcolepsy). In addition, individuals who have nut allergies or intolerances or who report disliking the taste of walnuts (i.e., pleasantness of taste rated <50 mm on 100-mm visual analog scale) will be excluded.Once enrolled into the study, participants will be randomly assigned to walnuts or HCHS for the first phase of the study. During the walnut condition, participants will add one serving (1 oz) of walnuts at their self-defined breakfast, lunch, and dinner for 4 days. In the HCHS condition, participants will add one HCHS food (one PopTarts® pastry) to each of their self-defined breakfast, lunch, and dinner for 4 days.During the week prior to the start of each study phase, participants will be asked to avoid consumption of any variety of nut. Additionally, during each phase, participants will be asked to stop all caffeine intake at noon and to refrain from drinking alcohol. Compliance with dietary intake recommendations will be assessed with daily food records using the 24-hour Automated Self-Administered (ASA-24) software. Sleep will be assessed objectively using wrist actigraphy (Actigraph GT3X+, Actigraph, LLC, Pensacola, FL), worn at all times during each study phase, and by questionnaires (Consensus Sleep Diary and Karolinska Sleep Scale) completed each night.On days 1-3 of each study phase, participants will be asked to go to bed and wake up at their typicaltimes and not to deviate from their usual physical activity habits. Sleep will be monitored using wrist actigraphy and, on night 3, using in-home polysomnography. On the morning of day 4, participants will be admitted to the inpatient unit of the Irving Institute for Clinical and Translational research in the fasted state. During the inpatient visit, participants will follow a modified constant routine protocol. Lights will not be dimmed during the day; however, participants will be asked to wear blue light blocking glasses (amber lens glasses, S1601, Uvex by Sperian) from 9 AM to 7 PM. An in-dwelling catheter will be inserted in an antecubital vein to facilitate frequent blood sampling. Blood samples will be drawn from their catheter at hourly intervals starting at 9 AM until midnight. At the same time, High-Resolution Thermochron iButtons (DS1921H, Maxim Integrated, San Jose, CA) will be affixed to the skin at 9 locations using medical tape: hands (2), feet (2), subclavicular (2), thighs (2), and sternum (1). Regular hospital meals will be provided, and participants will be given their food supplement at breakfast, lunch, and dinner served at 9 AM, 1 PM, and 6 PM, respectively. Starting at 7 PM, lights will be dimmed to <5 lux and use of electronic devices will be forbidden until lights off at 11 PM (46). The midnight blood draw will be taken from an adjacent room through a port in the wall. Lights will be turned on the next morning at 8 AM. Upon awakening, participants will provide a urine sample, be given a standard hospital breakfast, and will be discharged. Participants will undergo a 2-3-week washout period prior to repeating the procedures highlighted above with the alternate food.Participant testing will occur throughout Years 1 & 2. In Year 3, samples will be assayed and data will be analyzed. We anticipate abstract submissions to occur early in Year 3 and full manuscripts to be to submitted for publication in mid-Year 3.
Project Methods
Serum melatonin (primary outcome) will be measured hourly from 9 AM to midnight during the inpatient day of each phase (day 4). Participants will wear blue-blocking lenses during the daytime (9 AM to 7 PM) and will be placed in dim light (<5 lux) with no electronic device use from 7 PM until lights out at 11 PM. Circulating melatonin will be compared between conditions (walnuts vs HCHS) using 4-hour postprandial area under the curve after each eating occasion.Estimates of circadian phase in each phase will be derived from measures of serum melatonin drawn at hourly intervals. Time of fitted maximum and amplitude will be determined using a 3-harmonic regression model applied to individual melatonin curves. Circadian melatonin profile will be further characterized by determining dim light melatonin onset, defined as the clock time of the upward crossing of 25% of the fitted amplitude. This value will be compared between each phase.Urinary 6-sulfatoxymelatonin (secondary outcome) will be measured by competitive ELISA and urine creatinine by clinical chemistry analyzer. The ratio of urinary 6-sulfatoxymelatonin to creatinine is used to standardize for variations in urine concentrations when total 24-hour urinary output is unknown. Participants will be instructed to collect all urine from voids occurring after bedtime on day 4 in the laboratory until the first, next-morning void.In addition, circadian rhythmicity of skin temperature (secondary outcome) will be measured using High-Resolution Thermochron iButtons DS1921H (Maxim Integrated, San Jose, CA). These noninvasive wireless temperature loggers, affixed to the skin with medical tape, will be used to continuously measure skin temperature throughout the 24-hour period from 8 AM on day 4 until discharge (~8 AM) the following morning. Core body temperature peaks during the wake period and reaches its minimum value during the sleep period (48). Proximal skin temperature followed a similar rhythm as core body temperature, reaching its minimum value during the sleep period and maximum value during the wake period. Distal skin temperature exhibits the opposite phase, reaching its minimum during the wake period and its maximum value during the sleep period. As the difference between distal and proximal temperatures increases at sleep onset, the distal to proximal gradient increases. The circadian rhythmicity of core and skin temperature is necessary to induce sleep and wakefulness. A decrease in core body temperature is associated with a decrease in self-assessed alertness. In contrast, core body temperature elevation throughout the 24 hour period is associated with insomnia. Studies have found that an increase in distal skin temperature and distal vasodilation is the best predictor of sleep initiationand short sleep onset latency.Sleep quality will be monitored both via self-report and objective measures. Sleep times and duration will be monitored using wrist actigraphy in conjunction with a sleep diary. The actigraph monitor (ActiGraph GT3X+, ActiLife LLC, Pensacola, FL) will be worn on the non-dominant wrist 24 h/day. Actigraphy variables (primary outcomes: sleep fragmentation index, sleep efficiency; secondary outcome: sleep quality) will be analyzed using the ActiLife Data Analysis Software with the Cole-Kripke algorithm. In conjunction with actigraphy, and to assist with actigraphy scoring, participants will complete a daily sleep diary (recording time to bed, time of awakening, time to sleep onset and number of nighttime awakenings, and the number and duration of daytime naps). The ambient light sensor on the monitor will provide additional information confirming bedtimes and light exposure. Actigraphy is endorsed by the American Academy of Sleep Medicine for free-living assessment of sleep. We have much experience using this method to track sleep in study participants. In previous studies (AHA16SRFN27950012 and R01HL128226), adult males and females have worn the actigraph monitor for 2 periods of 6 weeks each, differing in mandated sleep duration: either sleep restriction (1.5 hours/night less than usual) or adequate sleep (habitual sleep duration verified to be between 7 and 9 hours/night).The zMachine Synergy (General Sleep, Cleveland, OH) will be used to assess sleep duration and architecture at home on night 3 of study phase. We chose to perform this test at home to reduce sleep disturbances that may occur from sleeping in an unfamiliar environment and from the catheter used to collect blood samples throughout the day. This 8-channel sleep staging device is designed to characterize sleep architecture and detect apneas. All recordings will be scored automatically for sleep staging, arousals, and respiratory events. The primary outcome to be collected is deep sleep but we will also have information on time to fall asleep, time in rapid-eye movement sleep, and time in light sleep. We are currently using this device to assess sleep architecture in other studies conducted under my supervision (R01HL142648 and UH3DK128302). Self-reported sleep quality (secondary outcome) will be assessed using the Karolinska Sleep Diary, a self-report measure consisting of 12 items (54). Participants will use this diary to rate various aspects of their sleep experience, including bedtime, time of awakening, sleep duration, sleep efficiency, sleep latency, and ease of waking up compared to falling asleep. The Karolinska Sleep Diary provides a subjective measure of sleep quality, capturing the characteristics of participants' nightly sleep and revealing any fluctuations that may occur. We are not using the PSQI to assess sleep in this study because the PSQI is designed to capture sleep information over the past month (44) and is therefore not appropriate for short-term sleep assessments.?