3/2/19 Circadian rhythms (very brief) intro Rhythms and reward: Do [PDF]

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3/2/19 1

Rhythms and reward: Do circadian factors contribute to risk for adolescent substance use?

Brant P Hasler, PhD, CBSM

Johns Hopkins Bloomberg School of Public Health Department of Mental Health Noon Seminar Series February 27, 2019

Circadian rhythms – (very brief) intro

º Organize physiological and behavioral processes for optimal interaction with

the environment

º “Temporal order is essential for health” - Anna Wirz-Justice (2003)

Arble & Sandoval (2013) Front. Neurosci

http://naef-lab.epfl.ch/page-34743-en.html

Clocks everywhere

October 2, 2017

Reward and circadian modulation (briefly)

Wanting Liking Pursuing rewards Consuming rewards Circadian control of reward circuitry (e.g., Logan et al, 2014, 2017;

McClung, 2007; Webb et al, 2015)

Mechanisms?

Appetitive motivation and reward processes are

modulated by the circadian system

Circadian disturbance can dysregulate appetitive

motivation and reward function

Sleep and/or circadian disturbance Mood and substance use disorders

A good overview…

Review

Impact of Sleep and Circadian Rhythms on Addiction Vulnerability in Adolescents

Ryan W. Logan, Brant P. Hasler, Erika E. Forbes, Peter L. Franzen, Mary M. Torregrossa, Yanhua H. Huang, Daniel J. Buysse, Duncan B. Clark, and Colleen A. McClung

ABSTRACT

Biological Psychiatry ª 2017 Society of Biological Psychiatry. 987 ISSN: 0006-3223 Biological Psychiatry June 15, 2018; 83:987–996 www.sobp.org/journal

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3/2/19 2 Research Strategies

1. Documenting circadian rhythmicity in affect,

behavior, and brain function

2. Examining associations between circadian

alignment (or proxies thereof), affect/motivation, and symptoms

3. Examining associations between circadian

alignment and brain function (observational and experimental)

Murray et al. (2009) Emotion Boivin et al. (1997) Arch Gen Psychiatry

“Two process model” of positive affect and reward

Diurnal rhythms in reward-related processes

Positive Affect Negative Affect

Arfken (2008); Byrne et al (2017); Hasler et al (2008; unpublished)

Hours since wake SOCIALIZING ALCOHOL USE ‘WANTING’ on BART

Time of day changes in neural response to monetary reward

Pilot fMRI study
11 healthy young adults
Morning and afternoon fMRI scans
Card guessing task (block design)
Counterbalanced order
Within-person comparison
ROI: Ventral Striatum

PM>AM in right Ventral Striatum

Hasler, et al (2014) Psychiatry Res: Neuroimaging

Reward activation

4 8 12 16 20 24 4 High reward activation – High VS Clock time Low reward activation – Low VS

Time of day changes in neural response to monetary reward: Take 2

16 right-handed males (M+/-SD 22.7 +/- 2.9 years)
Card guessing task (Delgado et al, 2000) from Human Connectome Project
Repeated-measures ANOVA model with factor Time of Day (10.00, 14.00, and 19.00 h)
mPFC, VTA, anterior cingulate cortex, caudate, NAc, and putamen

Byrne, et al (2017) J Neurosci

For a deeper dive…

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3/2/19 3 Research Strategies

1. Documenting circadian rhythmicity in affect,

behavior, and brain function

2. Examining associations between circadian

alignment (or proxies thereof), affect/motivation, and symptoms

3. Examining associations between circadian

alignment and brain function (observational and experimental)

Circadian misalignment

(working definition)

A mismatch between the timing of the behavioral sleep-wake schedule and that of the internal circadian clock

WAKE SLEEP WAKE 20 21 22 23 1 2 3 4 5 6 7 8 9 10 2 hr 6 hr 10 hr Dim Light Melatonin Onset (DLMO) Endogenous melatonin profile

“Normal” Circadian Alignment

Midsleep Sleep

ffset

Sleep

nset

Clock time (hours) Phase angles

Circadian alignment and adolescent substance abuse

Sample of 21 sleep-

disturbed adolescents with history of substance abuse

Shorter phase angles

associated with greater substance abuse and dependence

r2 = .38, p < .01

Hasler, Bootzin, et al. 2008 WAKE SLEEP WAKE 20 21 22 23 1 2 3 4 5 6 7 8 9 10 2 hr 6 hr 10 hr Dim Light Melatonin Onset (DLMO) Endogenous melatonin profile

“Normal” Circadian Alignment

Midsleep Sleep

ffset

Sleep

nset

Clock time (hours) Phase angles WAKE SLEEP WAKE 20 21 22 23 1 2 3 4 5 6 7 8 9 10 Dim Light Melatonin Onset (DLMO) Endogenous melatonin profile

Circadian Misalignment due to Delayed Phase

Midsleep Sleep

ffset

Sleep

nset

Clock time (hours) Phase angles

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3/2/19 4

Adolescents are subject to chronic circadian misalignment (aka social jet lag)

Circadian and preferred sleep timing shift later (delay) post-puberty
Shift towards evening chronotype
Mismatch with early school start times

Monday Tuesday Wednesday Thursday Friday Saturday Sunday

12 14 16 18 20 22 2 4 6 8 10 12 Clock Time

Better alignment; make up sleep Circadian misalignment; insomnia and sleep loss

Preferred s/w timing

Proxies for circadian misalignment:

Evening chronotype

Chronotype (sleep timing preference) on a continuum
Morning-types (larks) and evening-types (owls)
Chronotype correlates with (physiological) circadian phase

– Morning- and evening-types have different phase alignment

Evening types tend to exhibit more disrupted

sleep, depression, and substance involvement

Evening types tend to report more

impulsivity, risk-taking, and sensation and/or novelty seeking

Healthy young adults

(n=62)

Hasler (unpublished) Adults with primary insomnia

(n=100)

Hasler et al (2012) J Sleep Res Miller et al (2015) Chrono Int

5 10 15 20 Clock Time (hours) 17 18 19 20 21

Evening-types exhibit delayed and blunted rhythms in positive affect

Healthy middle-aged adults

(n=408)

SJL = difference in sleep timing on school/work days and free days*
Tends to be worse for evening-types/late chronotypes

10 teens (15-16 y/o) from Crowley & Carskadon (2010)

In 1,456 11-17 y/o’s from the NSF 2006 Sleep in America poll, teens went to bed ~90 minutes later and slept ~75 minutes more on non-school days (137 and 93 min for 17 y/os) Mean DLMO delay of 45 min

Proxies for circadian misalignment:

Social jet lag

Wittman et al (2006)

Childhood and adolescent sleep characteristics predict later substance involvement

Insomnia Poor sleep quality Restless sleep Short sleep duration Daytime sleepiness Evening chronotype Weekend delays (SJL)

Variable sleep timing AUD diagnosis or symptoms Alcohol use Binge drinking Alcohol intoxication Marijuana use Onset of alcohol involvement Onset of marijuana involvement Alcohol-related problems Marijuana-related problems SUD diagnosis or symptoms Nicotine/tobacco use Other illicit drug use SLEEP DISTURBANCE SLEEP LOSS “CIRCADIAN” CHARACTERISTICS

Hasler et al, 2014; 2016, 2017; Haynie et al, 2018, Mike et al, 2016; Miller et al, 2017; Pasch et al, 2015; Pieters et al 2015; Roane and Taylor 2008 ; Tavernier et al, 2015; Warren et al , 2017; Wong et al, 2004; 2010; 2016

Eveningness, late sleep timing, and short sleep, but not social jet lag, predict heavy alcohol use @ 1-year

Binge alcohol use @ 1-year

Hasler et al (2017) ACER 729 adolescents 12-21 y/o’s from NCANDA study, baseline and 1-year follow-up

Covariates: age, sex, race, ethnicity, SES, and baseline substance use N-CANDA

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Eveningness, late sleep timing, and short sleep, but not social jet lag, predict marijuana use @ 1-year

Marijuana use @ 1 year

Hasler et al (2017) ACER 729 adolescents 12-21 y/o’s from NCANDA study, baseline and 1-year follow-up

Covariates: age, sex, race, ethnicity, SES, and baseline substance use N-CANDA

Naturalistic study of circadian alignment in late adolescent drinkers (R21)

36 18-22 y/o drinkers (light, moderate, heavy) over 14 days
Weekday-weekend transition as “natural experiment”

Does pre-weekend DLMO-midsleep predict weekend alcohol use?

Smaller weekday DLMO-midsleep phase angles predicts greater weekend alcohol use

Findings hold when accounting for weekday alcohol use, sex, and/or TST

Hasler et al (in press) Chrono Int

SMALLER DLMO- MIDSLEEP LARGER DLMO- MIDSLEEP

p<0.001 p=0.33

Social jet lag and alcohol use? Less clear…

Covariates: weekday alcohol use, sex, and/or TST Hasler et al (in press) Chrono Int

LATER MIDSLEEP ON SUNDAY LATER MIDSLEEP ON THURSDAY LATER DLMO ON SUNDAY LATER DLMO ON THURSDAY

More “classic” social jet lag ~ more alcohol use More “objective” social jet lag ~ LESS alcohol use

p=0.004 p=0.35 p=0.03 p=0.04

Questions about social jet lag

10 mid-adolescents (age 15-16) from Crowley & Carskadon (2010) 31 late adolescents (age 18-22) Hasler et al (in press) Mean DLMO delay of 45 min Mean DLMO delay of 8 min

Mixed results
Timing vs duration
Importance of context

– e.g., atypical social jet lag in mostly-undergrad sample

Late sleep timing and stimulation response to alcohol

Hasler,…., Pedersen (in revision)

1.0
0.5

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Pre-drink 5 20 35 Stimulartion (Alcohol-Control) Minutes post-drink Whites

1.0
0.5

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Pre-drink 5 20 35 Stimulartion (Alcohol-Control) Minutes post-drink Blacks Early midsleep Late midsleep

1.0
0.5

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Pre-drink 5 20 35 Stimulartion (Alcohol-Control) Minutes post-drink Females

1.0
0.5

0.0 0.5 1.0 1.5 2.0 2.5 3.0 Pre-drink 5 20 35 Stimulartion (Alcohol-Control) Minutes post-drink Males Early midsleep Late midsleep

Later midsleep in Whites predicts greater stimulation ratings after alcohol consumption Later midsleep in Males predicts greater stimulation ratings throughout the Alcohol session 144 young adult social drinkers; 10 days sleep diary; Alcohol and Control lab sessions Self-reported stimulation based on Biphasic Alcohol Effects Scale (Alcohol-Control)

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3/2/19 6 Research Strategies

1. Documenting circadian rhythmicity in affect,

behavior, and brain function

2. Examining associations between circadian

alignment (or proxies thereof), affect/motivation, and symptoms

3. Examining associations between circadian

alignment and brain function (observational and experimental)

Impaired reward processing may mediate link between circadian misalignment and substance use

Internal factors

(Delayed sleep phase)

External factors

(Early school start times)

Reward dysfunction

impulsivity, reward sensitivity
mPFC, striatum

Substance involvement Circadian misalignment

“Social jet lag” and eveningness associated with altered reward function in adolescents

56 teens (aged 11-13)
fMRI monetary reward task
Weekday-weekend shifts in

midsleep (actigraphy)

Hasler et al. Biol Psychol. 2012

all 20 y/o males
fMRI monetary reward task
21 E-types vs 13 M-types

Medial PFC Ventral striatum

Hasler et al. (2013) Psychiatry Res Neuroimag Alcohol Use Alcohol Dependence

Chronotype and “dual systems” models

Subcortical Prefrontal cortex INCREASING EVENINGNESS Chronotype DEVELOPMENT AGE 10 12 14 16 18 20 22 24 26 Reward sensitivity Cognitive control

Casey, 2015; Roenneberg, 2003; Steinberg, 2010; Hasler (in preparation)

Does circadian misalignment lead to altered reward function (or vice versa)?

Causal direction?

K01 - Circadian misalignment and reward function in adolescents

ºExperimental study in healthy adolescents ºPrimary aim: To probe the effects of circadian misalignment on reward-related brain functioning. ºWithin-person experimental design, comparing:

Aligned Condition

(sleep/wake aligned with internal timing)

vs

Misaligned Condition

(sleep/wake mismatched with internal timing)

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3/2/19 7

N1 N2 Time of Day

fMRI scan

f f f

Dark/sleep phase in lab Recovery sleep

DLMO assessment

MISALIGNED CONDITION “School day”

10 12 14 16 18 20 22 2 4 6 8 10 N1 N2 Dark/sleep phase in lab Recovery sleep 10 12 14 16 18 20 22 2 4 6 8 10

DLMO assessment

f f

ALIGNED CONDITION “Weekend”

K01 Protocol: Aligned vs Misaligned

1 2 3 4 5 6 7 10 12 14 16 18 20 22 2 4 6 8 10 Dark/sleep phase at home

STABILIZATION WEEK (at home)

EACH CONDITION STARTS WITH: FOLLOWED BY EITHER… …OR…

Light/wake phase at home

Study Days

Does circadian misalignment impact the neural response to reward?

Hasler (in preparation)

Circadian misalignment reduces neural response during response inhibition

18 healthy teens

Aligned > Misaligned - AM

Logan, Barlow, and Hasler (in preparation)

Go/No-Go task; No-Go vs Rest

249 voxel cluster peaking in left inferior frontal gyrus (t=7.25, cluster pFWE < 0.001)

No difference on behavioral

measure of accuracy during No-Go trials; no differences on Delay Discounting Task

No regions showed greater

activation during Misaligned condition (AM or PM)

Included DLMO covariate
Strong evidence of circadian-reward links in animal lit
Growing evidence of circadian-reward links in humans
Next steps

– More experimental designs and use of physiological measures

Advance sleep timing & extend sleep duration to reduce risk

– More focus on circadian phenotype – Unpacking of “eveningness”—addiction association using objective sleep and circadian measures- Is it all about circadian misalignment? – Drilling down into social jet lag construct – timing vs duration; context – Research on caffeine’s role in teen circadian misalignment and addiction

Conclusions; what’s next Ongoing adolescent studies

Short-term 8-day protocol Long-term 3- and 6- month follow-ups Day of Study 1 2 3 4 5 6 7 8

Current self-reported

sleep/circadian function

Current self-reported

reward function

Alcohol and drug use
ver past 3 months

Day of Week M T W Th F Sa Su M Sleep Diary and actigraphy daily Circadian phase DLMO DLMO gene expression Neural activity fMRI Experience Positive & negative affect, craving –every ~3h during waking Behavior Alcohol and drug use, social context – every ~3h during waking

SOCIAL JET LAG STUDY: 150 high school drinkers (stratified across sleep timing) DELAYED SLEEP PHASE STUDY: 150 high schoolers (100 “delayed” phase 50 “normal” phase)

R01 AA025626; R01 DA 044143

Daniel Buysse, MD

Erika Forbes, PhD

Peter Franzen, PhD

Stephanie Holm, MD

Ron Dahl, MD

Richard Bootzin, PhD

Wambui Ngari

Grants from the National Institutes of Health: K01DA032557 (Hasler), R21AA023209 (Hasler), R01AA025626 (Hasler), R01 DA044143 (Hasler), U01AA021690 (Clark), K24AA0202840 (Martin), R01AA13397, K01MH077106 (Franzen), R01DA018910 (Dahl), R01DA026222 (Forbes, Shaw), K01MH074769 (Forbes), T32HL082610 (Buysse), R01MH024652 (Buysse)

Dissertation Research Awards from American Psychological Association, Society for a Science of Clinical Psychology, and the Social and Behavioral Sciences Research Institute, University of Arizona.

Contract from Office of National Drug Control and Policy

Acknowledgments

Duncan Clark, PhD, MD

Sarah Pedersen, PhD

Daniel Shaw, PhD

Stephanie Sitnick, PhD

Happy Fletcher

Scott Bruce, PhD

Deb Scharf, PhD

SLIDE 8

3/2/19 8 Don’t forget about caffeine!

Common among adolescents

– ~75% consume caffeine daily (Branum et al, 2014 Pediatrics) – 30% of 12th graders report past-month energy drink use (Terry-McElrath et al., 2014)

Disturbs sleep and circadian rhythms

– Double shot 3 h before habitual bedtime à 40 m phase delay in DLMO (Burke et al,

2015)

– Caffeine enhanced light-induced phase delays in mice (Ruby et al, 2018)

May increase substance use risk

– High school students who mix alcohol and energy drinks also report more alcohol use and problems (Tucker et al., 2016) – In adolescent rats, caffeine use enhanced dopaminergic response to cocaine (O’Neil et al, 2015)

Start with the sleep/circadian phenotype:

Circadian misalignment increases prevalence of depression in DSPD

p<0.001 p<0.001

Murray et al (2017) SLEEP