Sleep/Wake Disorders and Brain Injury

Transcription

1 Sleep/Wake Disorders and Brain Injury Anthony H. Lequerica, PhD Neuropsychologist & Clinical Research Scientist North American Brain Injury Society Conference New Orleans, Louisiana - September 18-21, 2013

2 What is this thing called SLEEP? Naturally recurring state Diminished consciousness Relatively suspended sensory activity Inactivity of nearly all voluntary muscles Growth and rejuvenation of immune, nervous, skeletal and muscular systems Occurs in all mammals and birds, and many reptiles, amphibians, and fish

3 Sleep as a Circadian Rhythm circa (around) + diem (day) endogenous (built in) adjusted by environmental cues & behavior Light and darkness One decide when to sleep to some extent temporal isolation studies Free running at > 24 hours Sleep period staring at 11:00pm Monday may drift to 11:30pm Tuesday, etc. Sleep only one of many circadian rhythms

4 Circadian Rhythm Generation Suprachiasmatic nucleus Melatonin is secreted Neurotransmitters Dopamine Acetylcholine Epiniphrine Norepinephrine Serotonin Orexins or hypocretins pineal gland

5 Sleep Architecture Sleep cycle can be broken down into parts NREM = Non-rapid eye movement sleep Characterized by gradual increase in depth Decrease in consciousness Relaxing of muscles Slowing of breathing and heart rate REM = Rapid eye movement sleep More central nervous system activation Greater heart rate variability Dreaming

6 Stage 1 Sleep Stages: Non-REM Usually slow rolling eye movements Alpha brainwaves on EEG Fragmented images Stage 2 Brainwaves slow down Sleep spindles and K-complexes on EEG Heart rate and breathing slows Body temperature decreases

7 Stages 3 and 4 Sleep Stages: Non-REM Slow wave sleep Delta brainwaves Difficult to awaken Deepest, restful Groggy and disoriented upon waking Decreases with each sleep cycle

8 Sleep Stages: Rapid Eye Movement (REM) Begins ~ 90 minutes after sleep onset Increases with each sleep cycle Heightened CNS Activation Breathing rapid, irregular, shallow Limb muscles temporarily paralized Heart rate & blood pressure increase Eyes dart around rapidly Associated with dreams Sensitive to deprivation REM rebound

9 Sleep Measurement Tools Subjective measurement Sleep Logs/Diaries to record sleep/wake behavior Questionnaires regarding sleep/wake history Pittburgh Sleep Quality Index (PSQI) Insomnia Severity Inventory (ISI) Epworth Sleepiness Scale (ESS) Valid in the general population BUT Less reliable for individuals with cognitive impairment or decreased self-awareness Best if used in conjunction with objective measures Some great smart phone apps for logging sleep

10 SLEEP LOG DATES PM SAMPLE C Midnight 1 2 AM Noon SAMPLE C A Sunday Monday Tuesday Wednesday Thursday Friday Saturday C = Caffeine A = Alcohol = LIGHTS OUT: The time you get into bed to TRY to fall asleep = LIGHTS ON: The time you get out of bed in the morning = SLEEP ONSET: This symbol indicates falling asleep. = AWAKENING: This symbol indicates waking up. = ASLEEP: Time spent asleep (no line = awake)

11 Sleep Measurement Tools Objective measurement Polysomnography is gold standard To measures sleep stages & diagnose sleep disorders Not great for naturalistic observation Can be intrusive or disrupt daily routines Can be uncomfortable Is labor intensive and expensive Actigraphy Wrist accelerometer Measures rest/activity cycle Uses algorithm to determine sleep vs. wake Unable to determine sleep stages

12 Polysomnography Core electrodes for sleep staging Electroencephalogram (EEG) brainwaves Electrooculogram (EOG) eye movements Electromyogram (EMG) muscle activity

13 Polysomnography Other electrodes Indicators of heart function Electrocardiogram (EKG) Pulse Oximetry Indicators of breathing Respiratory Airflow Respiratory Effort Indicators of leg movement Over anterior tibialis muscle Comprehensive Used for diagnosis

14 Polysomnography Example Sleep Apnea Example Airflow ceases Labored respiratory effort Decreased O2 saturation Signs of arousal Breathing catches up Multiple Sleep Latency Test Maintenance of Wakefulness Test

15 Actigraphy Accelerometer worn on the wrist like a watch Sensitive tri-axial motion detection Measures rest/activity cycle Can collect up to 22 days of data Correlates with PSG sleep/wake parameters Sleep latency, duration, efficiency Number of awakenings, time awake after sleep onset. Computer software analysis of motion/rest patterns More cost-effective, convenient, less intrusive Some also measure light intensity and participant responses (momentary assessment)

16 Actigraphy Example 1: consistent

17 Actigraph Example 2: daysleeper DOB: 1/1/1965

18 Sleep After TBI Increased interest over the past several years. 45 Peer Reviewed Publications on Sleep and Brain Injury Number of Publications Time (in 5 year intervals)

19 Research Findings Within 3 months of TBI (Rao, et al., 2008) N=54 admitted to trauma or TBI unit Age: M = 43.2, SD = 17.7; 59% males 65% mild, 11% moderate, 19% severe Sleep disturbance & daytime sleepiness were associated with post-tbi depression & anxiety No relationship found with severity (consistent with numerous studies in chronic TBI) High prevalence of sleep/wake cycle disturbances in TBI rehab unit (Makley et al., 2008) Patients w/swcd=longer stays in acute & rehab Studies show sleep can improve over time after TBI

20 Prospective Evaluation of Acute Sleep Abnormality Participants (N=205) (Nakase-Richardson, et al., 2013) 71% Male, 68% Caucasian Primarily severe TBI (Median ED GCS = 7) Measure (administered weekly in rehab hospital) Delirium Rating Scale-Revised-98 (DelRS-R98) Item 1 - sleep-wake cycle disturbance (SWCD) Rated as none, mild, moderate, and severe Ratings analyzed serially & 1-month post-injury

21 Findings Prospective Evaluation of Acute Sleep Abnormality (Nakase-Richardson, et al., 2013) Sleep abnormalities prevalent after TBI 66% had SWCD on rehab admission 63% had moderate to severe ratings Presence of mod to severe at 1 month post-injury associated with duration of post-traumatic amnesia Sleep abnormalities decrease over time but many remain with SWCD throughout course of rehabilitation

22 Insomnia and Fatigue after TBI Cross sectional study (Cantor et al., 2012) Sponsored by the National Institute of Disability and Rehabilitation Research (NIDRR) 5 TBI Model Systems (TBIMS) led by NY TBIMS (Mount Sinai School of Medicine) Collaborating Sites: Carolinas TBI Rehabilitation & Research System JFK-Johnson Rehabilitation Institute TBI Model System Northern California TBI Model System (Santa Clara Valley Medical Center) Northern New Jersey TBI System (Kessler Foundation Research Center)

23 Insomnia and Fatigue after TBI Participants (N=334) Individuals with TBI completing1-year (n = 213) or 2-year (n = 121) follow-up interviews between 2008 and Results (Cantor et al., 2012) Insomnia occurred in 11% to 24% Post-TBI Fatigue (PTBIF) in 33% to 44% Insomnia and fatigue were both related to sleep disturbance, sleep hygiene, satisfaction with life, anxiety, and depression.

24 Insomnia and Fatigue after TBI Results (continued) (Cantor et al., 2012) PTBIF associated with greater disability and sleepiness. Insomnia without fatigue was rare (2%-3%) PTBIF without insomnia occurred in 21% to 23% of the individuals. Comorbidity occurred in 9% to 22% of the individuals

25 Sleep and Melatonin after TBI Recent study by Shekleton and colleagues (2010) Study sample composed of 23 individuals with TBI Average of days post injury Mean age years old 17 males, 6 females Moderate to Severe TBI Compared with age/gender matched healthy controls Decreased sleep efficiency Increased wake after sleep onset and slow wave sleep Reduced evening melatonin production Melatonin production correlated with amount of REM sleep Higher levels of depression and anxiety symptoms

26 Summary of Findings Survey and subjective measures: 30% - 70% of individuals w/tbi have sleep problems well beyond the acute phase of recovery Difficulty falling asleep or staying asleep Disrupted or low quality sleep Daytime sleepiness and fatigue Physiological Findings Reduced evening melatonin production More slow wave sleep Increase waking after sleep onset Reduced sleep efficiency Better regulation of sleep architecture correlates with recovery

27 Consequences of Sleep/Wake Disturbances Impact can be extreme in individuals who already have cognitive impairment after TBI. Cognitive dysfunction and activity limitations Trouble concentrating or sustaining attention Slowed reaction time Impaired problem solving Difficulty completing tasks Safety issues Problems can interfere with Neurorehabilitation and recovery Social functioning Emotional functioning Return to work or school Depression Sleep/Wake Disturbance Irritability Anxiety

28 Current Treatments Many sleep medications not optimal after TBI Hypnotics/benzodazepines common side effects Daytime grogginess Impaired occupational performance Risk of dependence Daytime sleepiness often treated with psychostimulants with no focus on treating disrupted sleep throughout the night

29 Ramelteon Pilot Study Funded by The New Jersey Commission on Brain Injury Research Ramelteon is a melatonin agonist Uses brain s natural biochemical sleep-wake pathways May provide a more homeopathic treatment Decreased sleep latency and increased total sleep time Less likely to cause hang-over effect lagging into daytime Cognitive and motor impairments Abuse or dependence compared with other sleep meds Only drug indicated by FDA for long-term treatment Has not yet been studied in humans with TBI

30 Aims and Hypotheses Aims Examine effect of Ramelteon on sleep quality Measure impact on cognitive functioning in individuals with TBI reporting sleep disturbance Hypotheses Ramelteon improves sleep quality and reduces daytime fatigue in individuals reporting sleep difficulties after TBI Actigraphy measures of sleep quality should correlate with cognitive functioning among individuals with TBI

31 Study Design Double blinded placebo controlled study Both objective & subjective measures allow for a high level of scientific rigor but still captures subjective experience of participants Cross-over design allows all participants to receive the actual treatment (all get treatment and placebo)

32 Protocol PHASE 0 PHASE 1 PHASE 2 PHASE 3 Baseline Pill within 30 min. of bedtime Washout Period Pill within 30 min. of bedtime Week 0 Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 Week 7 Week 8 VISITS => MEASURES: Demographic and Health Questionnaire Physical Examination by Physician Pregnancy Test (if applicable) Blood Draw For Liver Functioning Cognitive Tests and Questionnaires X - Week Supply of Study Pill Actigraph & Log Provided or Collected (P or C) Participant Payments t = -1 t = 0 t = 1 t = 2 t = 3 t = 4 t = 5 t = 6 t = 7 t = 8 Initial End Baseline Check In No Visit End Phase 1 No Visit End Phase 2 Check In No Visit End Phase 3 x x x x x x x x x x x x P C P C P $10 $20 $20

33 Measures Sleep Log or Sleep Diary Completed daily by subject to record Bedtime, uptime, sleep latency, wake after sleep onset Subjective sleep quality Levels of pain and anxiety experienced overnight. Includes questions about Intake of caffeine and alcohol Time spent napping during the day Empirical Fatigue Scale Actigraphy

34 Initial Visit Complete Medical History To identify pre-morbid / coexisting conditions potentially associated with sleep problems Information about medications collected Pittsburgh Sleep Quality Index (PSQI) Sent home with Actigraph Sent home with Pulse Oximeter Screening for sleep apnea

35 Assessment at Visits 2, 3, & 5 30-minute cognitive test battery via computer Subtests included Verbal & Visual Memory Tests Finger Tapping Test Symbol Digit Coding, Continuous Performance Test Stroop Test, Shifting Attention Test Subjective questionnaires included Sleep (Insomnia Severity Index, Epworth Sleepiness Scale) Fatigue (Fatigue Assessment Scale) Mood (Brunel Mood Scale, Positive and Negative Affect Schedule)

36 Findings from Baseline Visit Based on N=10 Sleep Efficiency = Total Sleep Time Total Time in Bed Objective sleep efficiency from the night before baseline testing correlated with: Psychomotor Speed SS (r = 0.67, p = 0.048) Complex Attention SS (r = 0.58, p = 0.079) CPT commission errors (r = -0.57, p = 0.083) CPT choice reaction time correct (r = -0.61, p = 0.064)

37 Findings from Baseline Visit Based on N=10 Sleep Efficiency = Total Sleep Time Total Time in Bed Subjective sleep efficiency from the night before baseline testing correlated: BRUMS depression (r= -0.93, p = 0.002) BRUMS confusion(r = -0.81, p =.029) Psychomotor Speed SS (r = 0.90, p = 0.005) BRUMS tension (r = -0.68, p = 0.093)

38 Findings from Baseline Week Objective sleep efficiency from the WEEK before baseline testing correlated: Neurocognitive Index SS (r = 0.62, p = 0.059) Executive Function SS (r = 0.55, p = 0.080) Cognitive Flexibility SS (r = 0.57, p = 0.065) Subjective sleep efficiency from the WEEK before baseline testing correlated: FAS (r = -0.73, p = 0.016) Executive Function (r = 0.63, p = 0.053) Cognitive Flexibility (r = 0.59, p = 0.075)

39 PURPOSE OF BASELINE ANALYSIS Validation of measures for this study Sleep measured via actigraphy and sleep log correlates with cognitive and subjective measures in expected ways.

40 Time (min) Preliminary Findings Analysis of Week 3: Findings not yet significant at p<.05 (N=12) Change in Total Sleep Time with Ramelteon placebo ramelteon 350 objective Measurement Method subjective

41 Standard Score Preliminary Findings Changes in Cognitive Performance with Ramelteon placebo ramelteon nci ca cf ef pmrs ps rt verm vism Cognitive Tests

42 Next Steps Complete enrollment for Ramelteon Study Analyze all data Identify characteristics of responders and non-responders Think about how poor sleep hygiene can impact efficacy of medication for circadian rhythm disorders Examine light data from actigraphs

43 Research Assistants Silvio Lavrador Jaclyn Portelli Gabriel Felix Thank You Belinda Washington, TBI Lab Coordinator Neil Jasey, MD, Consultant Dedicated to the memory of Joshua Cantor who was a leader in sleep/wake disorders after TBI and a well-respected mentor