Experimental Manipulation of Sleep and Circadian Rhythms and the Role Played on Reward Function in Teens (CARRS-P2)

Experimental Manipulation of Sleep and Circadian Rhythms and the Role Played on Reward Function in Teens

Adolescence is a time of heightened reward sensitivity and greater impulsivity. On top of this, many teenagers experience chronic sleep deprivation and misalignment of their circadian rhythms due to biological shifts in their sleep/wake patterns paired with early school start times. Many studies find that this increases the risk for substance use (SU). However, what impact circadian rhythm and sleep disruption either together or independently have on the neuronal circuitry that controls reward and cognition, or if there are interventions that might help to modify these disruptions is unknown. Project 2 (P2) of the CARRS center will test an innovative and mechanistic model of brain circuitry that uses multi-method approaches, takes a developmental perspective, and incorporates key sleep and reward constructs.

Substance use (SU) and substance use disorders (SUD) pose devastating health, financial, and societal costs. The incidence of SU and SUDs increases across adolescence, making this sensitive developmental period one of both heightened risk-and heightened opportunity for prevention and intervention. However, to develop effective interventions investigators need to identify novel and modifiable risk factors and mechanisms for SUD. Sleep and circadian rhythm disturbances are such risk factors, and the reward system, with its increasing sensitivity during adolescence, provides a plausible mechanistic substrate. The focus on sleep, circadian rhythms, and reward system function is particularly salient given the extensive, parallel development of these systems during adolescence, and the plausible linkages between sleep and circadian rhythms, reward function, and SUD risk. Late sleep timing, short sleep duration and circadian misalignment are associated with increased substance use in teenagers and young adults. The central hypothesis of the Center for Adolescent Reward, Rhythms and Sleep (CARRS) is that adolescent development acts on underlying sleep and circadian traits to modify homeostatic sleep drive, circadian phase, and circadian alignment, which in turn impact cortico-limbic functions critical to SU risk (e.g., reward and cognitive control). Investigators further hypothesize that specific manipulations of sleep and circadian rhythms during adolescence will affect reward responsivity and cognitive control in either positive or negative directions. These manipulations will provide experimental support for our model, and proof of concept for novel clinical interventions to reduce the risk of SU and SUDs. Most previous studies have examined individual components of circadian rhythms, sleep, and reward function in adolescence. Project 2 (P2) of CARRS will test an innovative and mechanistic model of brain circuitry that uses multi-method approaches, takes a developmental perspective, and incorporates key sleep and reward constructs. Most notably, P2 improves upon past observational work by testing an experimental intervention that manipulates sleep and circadian rhythms to directly examine its impact on reward function and cognitive control. P2 will study 150 adolescents (age 13-15, 50% female) across two key sleep phenotypes: early sleep timing (low risk, n=50) and late sleep timing (high risk, n=100). All participants will complete the observational study: 2 weeks of home sleep monitoring (actigraphy), followed by an overnight laboratory visit to assess self-report, behavioral, and neuroimaging (fMRI) tasks tapping cognitive control and reward function, as well as circadian phase via salivary melatonin and molecular rhythms via hair follicles. The Late group will continue to the experimental study, each participant randomized to manipulation or attentional control conditions (n=50 each). Investigators will probe whether advancing sleep/circadian timing and extending sleep duration via sleep scheduling and chronotherapeutic approaches (reducing PM light exposure; administering AM bright light) improves sleep, circadian, and neurobehavioral function relevant to SUD risk. Finally, repeated 6-month follow-up assessments of sleep and SU for all participants are included to examine longitudinal associations.

adolescence, sleep, substance use, reward sensitivity and motivation, circadian phase and alignment, inhibition

For ~2 weeks, Advance/Extend participants will advance bedtime and regularize wake time. The first night of the manipulation will be conducted in the lab under tightly-controlled experimental conditions. Participants will then go home and for the next 12 days will be instructed to: Sleep scheduling-- advance bedtime by 1.5 hours ( + sleep duration) Decrease evening blue light exposure via blue blocker goggles (2 hrs before bed) Increase morning bright light exposure via bright light goggles (30 min after rise) Monitor sleep, mood, and substance use via smartphone-based platform and wrist actigraph

Control participants will complete the baseline laboratory study, then maintain their habitual sleep schedules over the next 13 days at home, with no instruction on sleep timing or light exposure. Control participants will complete smartphone-and text-based assessments, thereby controlling for effort.

Assessed by adjusted average pumps on Balloon Analogue Risk Task, a computerized measure of risk taking behavior in which participants are presented with a series of balloons and offered the chance to earn money by pumping each balloon up by clicking a button.

Assessed by accuracy on Cued Go/No-Go Task, specifically correct response (withholding response) on go trials with no/go target

This outcome will be measured during the Stop Signal Task, which is a computerized an fMRI behavioral task. It will be assessed by activation within the Executive Control Network, specifically, activation is defined as bold signal in regions of the Executive Control Network (particularly the inferior frontal gyrus) on correct Stop trials versus correct Go trials.

This outcome will be measured during the Money Incentive Delay Task, which is a computerized an fMRI behavioral task. It will be assessed by activation within the reward network, specifically, activation is defined as bold signals in regions of the reward network (particularly the ventral striatum) on reward anticipation trials versus no money trials.

Substance use on Time Line Follow Back interview. Specifically, the frequency (# of days) of substance use (yes/no) in the past 6 months.

Inclusion Criteria: Typically enrolled in a traditional high-school with synchronous learning (in-person or online synchronous learning, but not cyber- or home-schooling) [school closures during the COVID-19 pandemic are an exception to this] Physically and psychiatrically healthy Provision of written informed consent and assent Additional inclusion criterion for Experimental protocol: Meets operational definition of late sleep timing (>11:15PM habitual bedtime) Exclusion Criteria: History of alcohol, cannabis, or illicit drug use in the past month, or greater than monthly use in the past year Significant or unstable acute or chronic medical conditions Frequent headaches or migraines History of seizures Current serious psychiatric disorder (e.g., depressive disorder, bipolar disorder, eating disorder, psychotic disorder diagnosis, alcohol use disorder or substance use disorder) that would interfere with completion of study procedures Family history of bipolar disorder among first degree relative Current syndromal sleep disorders other than insomnia and delayed sleep phase disorder MRI contraindications (ie, absence of metal in the body, pregnancy, claustrophobia) Pregnancy Medications that increase sensitivity to blue light/photosensitizing medications, including psychiatric neuroleptic drugs, psoralen drugs, antiarrhythmic drugs, etc. Changes to psychotropic medication regimen in the 2 weeks prior to enrollment, and/or major changes to medications during the study protocol If participants have an average bedtime that is later than 3:00AM or an average wake time later than 11:00AM they cannot participate in the study Participants should be EXCLUDED for other sleep disorders that require ongoing treatment Participants should be EXCLUDED for other sleep disorders that cause significant distress or impairment, per DSM 5 criteria in the Sleep SCID.

Current and future investigators, both internal and external, may have access to de-identified data; however only group data would be shared.