Mechanisms of Risky Alcohol Use in Young Adults: Linking Sleep to Reward- and Stress-Related Brain Function

Study Overview
=================
Brief Summary
-----------------
This research will use biobehavioral approaches to generate understanding about the linkages between stressful life events, sleep duration and timing, and alcohol use in young adults, with a long-term aim of developing effective preventative interventions for alcohol use disorders.

Detailed Description
-----------------
High-risk drinking (consuming ≥ 4 drinks/day or ≥ 8/week for women, ≥ 5 drinks/day or ≥ 15/week for men) is reported by one in four young adults within the past month and predicts the development and progression of alcohol use disorder (AUD). High-risk drinking can also have terrible costs beyond developing AUD, including death and disability from unintended injuries and suicide attempts, physical and sexual assault, and a wide range of acute and chronic health problems. The high degree of morbidity and mortality associated with high- risk drinking in young adulthood makes this a key developmental period for AUD research and intervention. High-risk drinking in young adults is related to high exposure to stressors, insufficient sleep duration, and late sleep timing. Alarmingly, almost half of young adults report at least moderate exposure to stressors, only 30% regularly obtain the recommended hours of sleep, and sleep timing is at its latest around age 20. Stressors and short/late sleep may also cause disruptions in reward- and stress-related brain function (e.g., medial prefrontal cortex response to monetary reward, autonomic and neuroendocrine function during stressors), which are key biobehavioral mechanisms of AUD. Short and late sleep habits are a prime target for AUD prevention in young adults; however, there is insufficient causal evidence that improving sleep opportunity and/or timing will alter the biobehavioral mechanisms of AUD or decrease high-risk drinking, particularly in at-risk young adults. The overall objective of this R01 is to evaluate a biobehavioral model whereby sufficient sleep duration and/or early sleep timing can reduce high-risk drinking by promoting reward- and stress-related brain function in young adults with high lifetime stress load. The long-term goal of this research is to leverage sleep and circadian function to promote mental health. A series of studies by the PI and Co-I Hasler demonstrate that stressful life events, short sleep, and late sleep independently predict future reward- and stress-related brain function and alcohol use and dependence symptoms in adolescents and young adults. However, these studies do not evaluate the additive and interactive effects of stressful life events and sleep/circadian function and do not include experimental designs. More recent research by the PI and Co-I Hasler uses sleep and circadian manipulation to target reward- and stress-related brain function and improve mental health in adolescents and young adults. Building from this research, this R01 will test the central hypothesis that extending and advancing sleep will alter reward- and stress-related brain function in young adults with a history of high-risk drinking and elevated lifetime exposure to stressors. This proposal is consistent with the NIAAA Strategic Objective to identify mechanisms underlying AUD and comorbid disorders.

Official Title
-----------------
Mechanisms of Risky Alcohol Use in Young Adults: Linking Sleep Duration and Timing to Reward- and Stress-Related Brain Function

Conditions
-----------------
Alcohol Use Disorder

Intervention / Treatment
-----------------
* Behavioral: Sleep extension and advance
* Behavioral: Regular sleep duration and timing


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: 18-24 years of age; NIAAA criteria for past-month high-risk drinking (i.e., ≥ 4 drinks/day or ≥ 8/week for women, ≥ 5 drinks/day or ≥ 15/week for men); short and late sleep (weekday sleep duration ≤ 6 h & midpoint ≥ 4 am; n=60) or long and early sleep (weekday sleep duration ≥ 8h & midpoint ≤2:30 am; n=30), which will be determined with the Munich Chronotype Questionnaire; at least moderate lifetime exposure to stressors (>6 events on the 20-item Adult Stress and Adversity Inventory-Screener); not currently in high school; and English language fluency. Exclusion Criteria: Severe alcohol use disorder (AUD) and/or substance use disorder (SUD), defined as ≥6 AUD/SUD criteria in the Diagnostic and Statistical Manual-5; acute alcohol intoxication on the days of the laboratory post-intensive visits, operationalized as a blood alcohol concentration of .02 or higher during Breathalyzer saliva screen; current sleep disorders other than insomnia and delayed sleep phase disorder; lifetime diagnosis of bipolar or schizophrenia spectrum disorder; moderate to high suicide risk; certain medical conditions (e.g., neurological disorder, heart failure or trouble, high blood pressure, history of head injury with unconsciousness > 5 minutes); conditions that are contraindicated for MRI (e.g., ferrous metal in the body); positive screen for participant-reported eye disease, epilepsy, or photosensitizing medications that are contraindicated during the manipulation condition when bright light is administered (e.g., psychiatric neuroleptic drugs [e.g., phenothiazine], psoralen drugs, antiarrhythmic drugs [e.g., amiodarone], antimalarial and antirheumatic drugs, porphyrin drugs used in photodynamic treatment of skin diseases); travel across two or more time zones within the month prior to the overnight study visits. begin/end a prescribed medication within 2 months of the observational study; medication dose changes within the timeframe calculated as 5x the drug's half-life [the time to reach pharmacokinetic steady-state] before the initiation of the observational or experimental studies; participant-anticipated changes in prescribed medications or medication dosing during the observational or experimental studies; self-reported use of opioids, benzodiazepines, hallucinogens, or stimulants (other than caffeine and nicotine) within 24 hours of study visits; self-reported symptoms of withdrawal from depressants or stimulants on days of study visits; and use of melatonin if participant is not willing to discontinue use for the duration of the study. If possible, participants who are excluded for positive breathalyzer screen, self-reported substance use within 24 hours of study visits, or symptoms of withdrawal during study visits will be rescheduled for an alternative overnight visit within 2-3 days. Participants who are excluded for moderate to high suicide risk, recent or anticipated changes in medications, or travel across time-zones will become eligible for the study when they no longer meet these exclusion criteria.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 24 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sleep extension and advance Lark Routine<br>Participants go to bed 90 minutes earlier than their typical average bedtime to extend sleep duration and advance sleep timing | Behavioral: Sleep extension and advance<br>* Participants in the sleep extension and advance condition will maintain a stable sleep schedule that extends sleep duration and advances bedtime by 90 min relative to weekday bedtime. This chronotherapeutic manipulation will include blocking phase-delaying light in the evening using goggles with orange lenses (blue blockers) beginning 2 h prior to bedtime, and 30 min of 506 lux blue-green light exposure in the morning beginning at rise time using bright light goggles (ReTimer Pty Ltd., Australia). Schedule and chronotherapy adherence will be reinforced using motivational techniques (e.g., securing motivation, preplanning, problem-solving), requiring participants to text the study coordinator and complete morning assessments at rise time, and monetary incentives.<br>|
| Active Comparator: Regular sleep duration and timing Owl Routine<br>Participants go to bed at their typical average bedtime | Behavioral: Regular sleep duration and timing<br>* Participants in the regular sleep duration and timing condition will keep a stable sleep schedule that matches their typical weekday sleep opportunity and timing. Schedule adherence will be reinforced using motivational techniques (e.g., securing motivation, preplanning, problem-solving), requiring participants to text the study coordinator and complete morning assessments at rise time, and monetary incentives.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Alcohol use | The Alcohol Timeline Follow-Back (TLFB) will be administered electronically to assess the quantity (number of standard drinks) and frequency of alcohol use over the past 2 months, beginning at screening and continuing at least every 2 months through the follow-up assessment. The TLFB uses a calendar, anchor dates, and standard drink conversions to obtain retrospective estimates of alcohol use. | 2 months | 
| Reward-related brain function | fMRI during the Monetary Incentive Delay task (MID, 92) will be used to measure BOLD regional response and functional connectivity related to anticipation and receipt of monetary rewards. This task reliably elicits activation in neural reward circuitry | 2 weeks | 
| Stress-related brain function | Stress-related brain function will be indexed using autonomic and neuroendocrine measures taken before and during the Trier Social Stress Task. The TSST is a lab-based social-evaluative threat task that reliably elicits subjective stress and increases in the stress-hormone cortisol. | 2 weeks | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
circadian, adolescence, substance use, stress, reward, sleep