Peter L. Franzen, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Project Summary: Sleep deprivation (SD) impairs attention, executive function, and affect regulation. Although understudied, understanding relationships between sleep and affect regulation may reveal important pathways by which sleep disturbances lead to psychiatric disorders. This is particularly relevant to the onset of depression during adolescence and early adulthood, as these developmental periods are associated with SD and increased risk for affective psychopathology. Experimental studies consistently find negative effects of SD on self-reported mood in healthy individuals. An important next step is to objectively quantify the impact of SD on affect reactivity and regulation, and to examine inter-individual variability in affective impairments using more precise objective and quantifiable methods. The candidate, Peter L. Franzen, Ph.D., has examined arousal and information processing during the sleep state in healthy and patient populations. He seeks further training to examine the pathways by which SD alters affect regulation and ultimately address the role of SD in the development of mood disorders. In the proposed research studies, the impact of SD on psychophysiological and neuroimaging indicators of affect reactivity/regulation will be examined in young adults - a developmentally vulnerable period for the development of mood disorders. It will lead to an R01 proposal investigating the impact of SD on objective indicators of affect regulation in young at adults at low and high familial risk for depression. Carefully examining the effects of SD on affect regulation under controlled conditions may reveal predictors of sleep disturbance-related trait vulnerability for psychopathology, and is a first step toward developing mechanistic models of the role of sleep in mental health. The identification of sleep-related risk factors in such vulnerable populations may suggest not only therapeutic but also preventative strategies to reduce the psychiatric and neurobehavioral consequences of sleep loss. Research will be conducted at the Department of Psychiatry, University of Pittsburgh School of Medicine, a world center for research in the areas of sleep, mood disorders, and affective neuroscience. Researchers with expertise in these areas will serve as mentors and consultants. Relevance: Many people experience negative mood effects when sleep deprived. By further understanding how sleep loss leads to emotional impairments, the relationship between sleep and healthy emotional functioning may be revealed, and prevention and intervention strategies to reduce the onset of mood disorders may be developed. This is particularly relevant in young adulthood - a time of life characterized by insufficient sleep and increased risk for the development of mood disorders. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): Sleep loss is extremely prevalent during adolescence. The causes of sleep restriction in adolescence are the result of brain/behavior/social context interactions in sleep-wake and circadian regulation. Biological changes at puberty create a natural tendency to prefer staying up late as well as increased sleepiness. However the key sleep behaviors (patterns of staying up late and erratic sleep/wake schedules) are largely an interaction between these biologic tendencies and the social environment (i.e., effects of artificial light, stimulating social media such as texting and the internet, and other highly rewarding activities combined with early school start times). Moreover, these interactions are conspiring to rob youth of sleep at a time of critical maturational changes in physical, social, and affective development. Sleep disruption in adolescence may initiate a negative cascade of impaired reward and emotion processing;affective and behavioral dysregulation;further sleep problems;and ultimately, clinical depression and substance abuse. The broad goal of this research is to elucidate potential biopsychosocial mechanisms linking sleep problems with the development of depression and substance abuse in adolescence. Understanding the mechanisms by which sleep loss contributes to vulnerabilities for affective dysfunction and behavioral and mental health problems triggered during adolescence can provide leverage for developing more effective early interventions, including both clinical and social policy-level efforts aimed at the social environment (i.e., school start times, parental and youth education programs, and behavioral interventions). As a first step to address this goal, the proposed study will evaluate the effects of well-controlled laboratory manipulations of sleep duration and social context on activity in neural systems supporting reward and emotion regulation, and on related affective behaviors. Our specific aims are: (1) to investigate the impact of transient sleep restriction and peer social context on reward and risk-taking;and (2) to investigate the impact of transient sleep restriction and peer social context on emotional reactivity/ regulation. Using a within-subjects crossover design, youth in middle adolescence will be studied under two experimental conditions: (1) sleep restriction (two nights of 4 hours time in bed) and (2) sleep extension (two nights of 10 hours time in bed). Polysomnographically-monitored sleep conditions will be followed by functional magnetic resonance imaging (fMRI) and behavioral testing the next day. We will employ validated reward and emotion processing neuroimaging tasks to examine cortical-subcortical activation in response to appetitive and aversive stimuli. Participants will be studied in pairs of friends, enabling us to examine the influence of the peer social context on affective functioning. We will also examine neural and behavioral responses to socially- relevant stimuli. PUBLIC HEALTH RELEVANCE: Biological changes at puberty create a natural tendency to prefer staying up late as well as increased sleepiness, however, these key sleep behaviors (patterns of staying up late and erratic sleep/wake schedules) are largely an interaction between these biologic tendencies and the social environment (i.e., effects of artificial light, stimulating social media such as texting and the internet, and other highly rewarding activities combined with early school start times). Moreover, these interactions are conspiring to rob youth of sleep at a time of critical maturational changes in physical, social, and affective development. Achieving a deeper and more mechanistic understanding of how sleep deprivation impacts affective function is crucial to the long-term goal of informing clinical and social policy targeting the specific aspects of the social environment and adolescent behavior that interferes with sleep, particularly at key times in the development of more serious dysfunctions, including the trajectory of affective disorders (depression, anxiety, and bipolar disorder) and substance use disorders.

Project Summary Adolescence begins a period of vulnerability for depression and suicidality, as well as for sleep loss. Short sleep duration is extremely common in youth (i.e., 44% of high school students report 6 or less hours of sleep on school nights), and is a risk factor for depression, suicidality, and other negative outcomes. Sleep loss is hypothesized to exert an influence on internalizing symptoms by disrupting reward and cognitive control neural pathways. These brain networks continue to develop during adolescence, are implicated in the development and maintenance of depression, and have been shown to be sensitive to acute sleep restriction in our prior experimental work. Our findings of blunted activation within both reward and cognitive control circuitry following sleep restriction (as compared to sleep extension) provide plausible mechanisms by which sleep loss is involved in the pathway to developing internalizing psychopathology. The next critical step to extend this line of work is to examine the cumulative effects of insufficient sleep, to examine sleep-brain relationships naturalistically during the school year, and to examine the extent to which these predict longitudinal changes in depression and suicidality. These are the goals of our proposed study. We propose to enroll a sample of 210 youth ages 11.5? 14.5 (66% female), who are currently in the 7th, 8th, or 9th grades, representing a continuum of habitual sleep duration, but ensuring 50% with 7 or fewer hours of sleep. Participants will then be followed for the next 4 years during the peak risk for depression onset during adolescence, with annual assessments of sleep via actigraphy and behavioral measures (reward learning, cognitive control), along with fMRI scans at baseline (7th?9th grade) and repeated 2 years later (in 9th?11th grade). Self-report internet-based assessments will be collected quarterly (every 3 months; 14?16 in total) to examine more nuanced temporal associations between changes in sleep duration, depression symptoms, and suicidal ideation. In this longitudinal 4-year design, we will examine how declining sleep duration influences reward and cognitive control, and whether sleep and these mechanisms jointly predict subsequent depression symptoms and suicidal ideation. Insufficient sleep may be an important? yet modifiable?vulnerability factor for psychopathology. Understanding the temporal associations linking sleep and mental health?as well as the role of neural mechanisms?will help better target sleep-focused interventions by determining when, and in whom, they would best be directed. Study findings will provide leverage for developing novel interventions, augmenting existing (sleep or mental health) treatments, and/or changing public policy (i.e., later school start times) to improve adolescent sleep, and ultimately, prevent internalizing disorders.

PROJECT SUMMARY PROJECT 1 (P1) Substance use disorders (SUD) are widely prevalent and pose devastating health, financial, and societal costs. The incidence of SU 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, we need to identify novel and modifiable risk factors and mechanisms for SUD. Circadian rhythm and sleep disturbances have strong ties to SU risk, and their effects on intermediary markers of SU risk in adolescence?reward and inhibitory control systems?provides a plausible mechanistic substrate. The Center?s conceptual model posits that adolescent development is associated with enhanced reward function relative to cognitive control, phase delay in endogenous circadian rhythms, and lower homeostatic sleep drive. Environmental and social factors interact with these developmental processes, often resulting in late sleep timing, short sleep duration, and circadian misalignment?each of which is associated with increased substance use in teens and young adults. P1 will utilize the constant routine paradigm to rigorously characterize circadian rhythms and homeostatic sleep drive by controlling for masking influences of physical activity, posture, meals, and light levels. We will examine their individual and combined effects on measures of reward and cognitive control, and in combination with P2, on the development of substance use, to test the underlying mechanisms involved in the CARRS conceptual model. P1 will enroll 96 adolescents ages 13?15 (50% female) stratified by habitual sleep timing (early, intermediate, late, N=32 each). Participants will monitor sleep patterns at home with actigraphy and sleep diary, then complete fMRI measures of reward and cognitive control and a 60-hour lab session. The lab session includes two nights of polysomnographic (PSG) sleep studies, separated by 36 hours of sleep deprivation. After the first PSG, participants will follow a constant routine for the next 24 hours with wakeful bedrest; semi-recumbent posture; constant dim light; and hourly nutritional supplements. After 24 hours, participants will remain awake, but not confined to bed. Physiological circadian measures include salivary melatonin; core body temperature; and molecular rhythms from hair follicle cells (examined in P3). Physiological sleep homeostatic measures include waking EEG theta power. and delta sleep EEG response following 36 hours of wakefulness. Behavioral tests indexing cognitive control performance with and without reward modulation along with self-reports of mood and sleepiness will be collected every 2 hours. Finally, online surveys will index substance use every 6 months through study conclusion. P1 will draw directly on resources provided by the Center Cores. CARRS and P1 will innovatively advance understanding of distinct circadian and sleep homeostatic effects on reward-cognitive control function and the development of adolescent SU.

ABSTRACT Suicide is the second leading cause of death among young people age 14?24, and rates in this age group are increasing. Most suicide risk factors are distal (i.e., long-standing, static), thus informative regarding who is at risk, but not when. As such, our ability to reliably predict near-term suicide risk among vulnerable populations remains grossly inadequate. Studies consistently demonstrate a link between subjective sleep disturbances and the continuum of suicidality. Yet, sleep is a complex behavior that can be measured along multiple dimensions and at varying levels of analysis. Furthermore, little attention has been paid to the role of normative biological and psychosocial developmental processes that further contribute to dynamic changes in risk related to sleep disturbance. Such changes in sleep are particularly dramatic during adolescence. Studies also have not examined how sleep interacts with other known pathways, such as dysregulation in affective, cognitive and arousal-related systems, to lead to suicidality in vulnerable youth. We thus propose to conduct an 8-week prospective multi-method study of sleep health and suicidal thoughts and behavior in a transdiagnostic sample of ultra-high risk adolescents (14-18) who have recently enrolled in an Intensive Outpatient or Partial Hospitalization Program. We will capitalize on the extant clinical and research infrastructures to compare sleep-suicide associations and plausible affective, cognitive and arousal-related mechanisms using self-report, behavioral, lab task paradigms and physiology in adolescents at ultra-high risk for suicide.