Dean W. Beebe, PhD 4/26/2019

1. Poor Sleep After Pediatric Brain Injury: Symptom and Contributor to Other Symptoms Dean W. Beebe, PhD 4/26/2019

2. Poor Sleep After Pediatric Brain Injury: Symptom and Contributor to Other Symptoms I have no relevant conflicts of interest to disclose.

3. Overview • Sleep as Biobehavioral Phenomenon • Sleep after TBI • Effects of Poor Sleep • Treatment Evidence • Where we stand, what to do

4. Sleep as Biobehavioral Phenomenon

5. Sleep as Biobehavioral Phenomenon Visible/Behavioral Aspects • Duration • Timing (onset, offset, midsleep) • Latency to fall asleep when trying • Quality (movement, wake after sleep onset, snoring, subjective restfulness) • Sleep-affecting behaviors (“sleep hygiene”, bedtime resistance) and mood • Environmental factors affecting sleep

6. Sleep as Biobehavioral Phenomenon Physiological Aspects • Duration • Timing (onset, offset, melatonin rhythm) • Latency to fall asleep when trying • Quality (wake after sleep onset, arousals) • Sleep stages or “architecture” • Breathing during sleep • Movement during sleep

7. Sleep as Biobehavioral Phenomenon Stages of Sleep • Non-REM • Stage N1 • Stage N2 • Stage N3 (SWS) • REM sleep (Carskadon & Dement, 2011)

8. Sleep as Biobehavioral Phenomenon • Arousal largely determined by 2 processes. (Borbely et al., 2016)

9. Sleep as Biobehavioral Phenomenon • Arousal largely determined by 2 processes. • Homeostatic Sleep Drive • Neuro substrate unclear • Adenosine in basal forebrain? • Builds with time awake, dissipates rapidly during sleep, especially during Slow Wave Sleep

10. Sleep as Biobehavioral Phenomenon • Arousal largely determined by 2 processes. (Borbely et al., 2016)

11. Sleep as Biobehavioral Phenomenon • Arousal largely determined by 2 processes. • Circadian Rhythm • Suprachiasmatic nucleus • Core Body Temp and Melatonin (Borbely et al., 2016)

12. Sleep as Biobehavioral Phenomenon • Arousal largely determined by 2 processes. (Borbely et al., 2016)

13. Sleep as Biobehavioral Phenomenon (Espana & Scammell, 2011)

14. Sleep as Biobehavioral Phenomenon (Espana & Scammell, 2011) (Espana & Scammell, 2011)

15. Sleep as Biobehavioral Phenomenon (Espana & Scammell, 2011) (Espana & Scammell, 2011)

16. Sleep After TBI Part 1: Adults

17. Sleep After Adult TBI: Self-Report (All p < .01) Pooled % Reporting (Mathias & Alvaro, 2012)

18. Sleep After Adult TBI: Formal Diagnosis (All p < .01) Pooled % Diagnosed (Mathias & Alvaro, 2012)

19. Sleep After Adult TBI: Actigraphy * p < .05 ** p < .01 ** * * * * Effect Size (.5 = medium) 24-hr Sleep Nighttime Sleep (El-Khatib et al., 2019)

20. Sleep After Adult TBI: Sleep Architecture Effects on REM (Mantua et al., 20118 Sleep Med Rev)

21. Sleep After Adult TBI: Sleep Architecture Effects on SWS (Mantua et al., 20118 Sleep Med Rev)

22. Sleep After Adult TBI: Sleep Architecture • A lot of variation across studies • Slow Wave Sleep increased in Mod-Severe TBI, not mild TBI (Mantua et al., 20118 Sleep Med Rev)

23. Sleep After TBI Part 2: Children

24. Sleep After Pediatric TBI: Parent Report (Beebe et al., 2007)

25. Sleep After Pediatric TBI: Parent Report (Beebe et al., 2007)

26. Sleep After Pediatric TBI: Parent Report Sleep Fxn (higher = better) (Tham et al., 2012)

27. Sleep After Pediatric TBI: Self-Report (20 years later) * * * *p < .06 * * (Botchway et al., 2019)

28. Sleep After Pediatric TBI: Actigraphy • 5 studies, no direct severity comparisons *Kaufman et al. study clear had a clear recruitment bias

29. Sleep After Pediatric TBI: Most Common Concerns • Insomnia • More common and more problems with sleep maintenance after mTBI? • Sleep onset more a problem after severe TBI? • Excessive daytime sleepiness • Possibly sleep-disordered breathing • Insufficient evidence re: parasomnias, movement disorders, circadian rhythm disorders (Botchway et al., 2018)

30. Sleep After TBI: Possible Contributors • Sleep is a biobehavioral phenomenon, so causes vary case-by-case • Direct structural injury (e.g., hypothalamus, pineal gland, basal forebrain, brainstem) • Alterations in neurochemistry or metabolism • Neuroendocrine changes • Pain (though findings inconsistent) • Medication side effects • Emotional disruption and/or PTSD • Changes in sleep-related behavior (Botchway et al., 2018; Howell & Griesbach, 2018; Sandsmark, et al., 2017; Wickwire et al., 2016 )

31. Effects of Poor Sleep in Children

32. What is Good Sleep? See also https://www.cdc.gov/chronicdisease/resources/infographic/children-sleep.htm • Schedule matches demands • No chronic, loud snoring • <20 min to fall asleep • Only a few brief awakenings • Calm to modestly restless

33. Effects of Poor Sleep: Correlational Data Short/disrupted sleep in kids correlates with: • ↑ Daytime sleepiness • ↓ Attention • ↓ Regulation of Impulses, Mood, Behaviors • ↓ School performance • ↑ Risky behaviors and accidental injuries • ↑ Accidents in teen drivers • ↑ Negative mood (Beebe, 2006, 2011; Vriend et al., 2015)

34. Effects of Poor Sleep: A Cautionary Tale (r=.64) (http://www.tylervigen.com/) (Beebe, 2016, SLEEP)

35. Effects of Poor Sleep: Experimental Data • Hundreds of studies on adults • A couple dozen published pediatric studies • In children and adolescents, sleep restriction causes: • ↑ Daytime sleepiness • ↓ Attentive behaviors (office tests less sensitive) • ↑ In negative mood, especially when challenged • ↓ Regulation of behavior or impulses • ↓ Some higher-level cognitive skills (Beebe, 2011, Ped Clin North Am; Vriend et al., 2015, Sleep Med Clin)

36. Effects of Poor Sleep: Sleepy Teens Study • Healthy teens ages 14 - 17 years (Baum et al., 2014; Beebe et al, 2008, 2009, 2010, 2011, 2013, 2015, 2017, 2018; Garner et al., 2015; Simon et al., 2015)

37. Effects of Poor Sleep: Sleepy Teens Study (Baum et al., 2014; Beebe et al., 2008, 2017, 2018; DiFrancesco et al, under review) *** *** *** * p < .05 ** p < .01 *** p < .001 ** Raw Score * ***

38. Effects of Poor Sleep: Sleepy Teens Study (Baum et al., 2014; Beebe et al., 2008, 2017, 2018; DiFrancesco et al, under review) * *** *** * p < .05 ** p < .01 *** p < .001 * Raw Score ***

39. Effects of Poor Sleep: Sleepy Teens Study (Baum et al., 2014; Beebe et al., 2008, 2017, 2018; DiFrancesco et al, under review) p < .001 # of Seconds Behavior Shown p < .001 p >.05

40. Effects of Poor Sleep: Sleepy Teens Study (Baum et al., 2014; Beebe et al., 2008, 2017, 2018; DiFrancesco et al, under review) p = .006 p = .007 Milliseconds p = .003

41. Effects of Poor Sleep: Sleepy Teens Study (Baum et al., 2014; Beebe et al., 2008, 2017, 2018; DiFrancesco et al, under review) %

42. Effects of Poor Sleep: Sleepy Teens Study p = .007 p = .003 Raw Score p < .06 Pain and Symptom Assessment Q-aire

43. Effects of Poor Sleep: Can Worsen Symptoms Further reduces attention in kids with ADHD: Inattention (Omission Errors) T-Scores (Gruber et al., 2011)

44. Effects of Poor Sleep: Can Worsen Symptoms Further reduces attention in kids with ADHD: *** *** * p < .05 ** p < .01 *** p < .001 ** Item Average ** * Hyper ODD SCT Attention (Becker et al., 2019)

45. Effects of Poor Sleep: Effects in TBI? • Research promising but limited • Almost exclusively correlational work • Reporter/measurement effect major concern • Self-report of poor sleep often correlates with self-report of pain, mood, fatigue, QOL • Parent-report of sleep often correlates with parent-report of pain, behavior, mood, QOL • Correlations often much weaker across informants or between objective & reports. (Botchway et al., 2018)

46. Treatment Options State of the Evidence

47. Treatment Options: Adult Research “The treatment of Sleep-Wake Disturbances after TBI usually requires a multifactorial approach. First-line treatments should focus on non-pharmacologic interventions.” (Driver & Stork, 2018)

48. Treatment Options: Adult Research • Treatment remains largely symptom-driven and extrapolated from non-TBI research • Side effects poorly understood after TBI • Side effects of sleep meds are often areas of vulnerability after TBI • Benzodiazepines  poorer cognition in neurologically intact groups • Anticholinergic side effects (e.g., memory) • Protracted carry-over of even short-acting hypnotics (Driver & Stork, 2018)

49. Treatment Options: Adult Research • Some promise for melatonin and melatonin agonists, but more research needed • Other meds may be used for comorbid conditions, but not on-label for sleep in any population, let alone in TBI • Non-pharmacologic medical interventions can, however, have a clear role (e.g., CPAP for obstructive sleep apnea) (Driver & Stork, 2018)

50. Treatment Options: Adult Research • Environmental and behavioral Rx derived from non-neuro populations promising • Sleep hygiene as foundation • Cognitive-behavioral treatment for insomnia (CBT-I) in chronic phase if >4 sessions • Blue-light therapy • Problem-solving treatment • Evidence of sustained effects over time • Evidence base still limited (Bogdenov et al., 2017; Driver & Stork, 2018)