Sex differences in objective measures of sleep in post-traumatic stress disorder and healthy control subjects.

A growing literature shows prominent sex effects for risk for post-traumatic stress disorder and associated medical comorbid burden. Previous research indicates that post-traumatic stress disorder is associated with reduced slow wave sleep, which may have implications for overall health, and abnormalities in rapid eye movement sleep, which have been implicated in specific post-traumatic stress disorder symptoms, but most research has been conducted in male subjects. We therefore sought to compare objective measures of sleep in male and female post-traumatic stress disorder subjects with age- and sex-matched control subjects. We used a cross-sectional, 2 × 2 design (post-traumatic stress disorder/control × female/male) involving83 medically healthy, non-medicated adults aged 19-39 years in the inpatient sleep laboratory. Visual electroencephalographic analysis demonstrated that post-traumatic stress disorder was associated with lower slow wave sleep duration (F(3,82)  = 7.63, P = 0.007) and slow wave sleep percentage (F(3,82)  = 6.11, P = 0.016). There was also a group × sex interaction effect for rapid eye movement sleep duration (F(3,82)  = 4.08, P = 0.047) and rapid eye movement sleep percentage (F(3,82)  = 4.30, P = 0.041), explained by greater rapid eye movement sleep in post-traumatic stress disorder females compared to control females, a difference not seen in male subjects. Quantitative electroencephalography analysis demonstrated that post-traumatic stress disorder was associated with lower energy in the delta spectrum (F(3,82)  = 6.79, P = 0.011) in non-rapid eye movement sleep. Slow wave sleep and delta findings were more pronounced in males. Removal of post-traumatic stress disorder subjects with comorbid major depressive disorder, who had greater post-traumatic stress disorder severity, strengthened delta effects but reduced rapid eye movement effects to non-significance. These findings support previous evidence that post-traumatic stress disorder is associated with impairment in the homeostatic function of sleep, especially in men with the disorder. These findings suggest that group × sex interaction effects on rapid eye movement may occur with more severe post-traumatic stress disorder or with post-traumatic stress disorder comorbid with major depressive disorder.

Sleep disruption is not observed with brain-responsive neurostimulation for epilepsy.

OBJECTIVE: Neurostimulation devices that deliver electrical impulses to the nervous system are widely used to treat seizures in patients with medically refractory epilepsy, but the effects of these therapies on sleep are incompletely understood. Vagus nerve stimulation can contribute to obstructive sleep apnea, and thalamic deep brain stimulation can cause sleep disruption. A device for brain-responsive neurostimulation (RNS® System, NeuroPace, Inc) is well tolerated in clinical trials, but potential effects on sleep are unknown. METHODS: Six adults with medically refractory focal epilepsy treated for at least six months with the RNS System underwent a single night of polysomnography (PSG). RNS System lead locations included mesial temporal and neocortical targets. Sleep stages and arousals were scored according to standard guidelines. Stimulations delivered by the RNS System in response to detections of epileptiform activity were identified by artifacts on scalp electroencephalography. RESULTS: One subject was excluded for technical reasons related to unreliable identification of stimulation artifact on EEG during PSG. In the remaining five subjects, PSG showed fragmented sleep with frequent arousals. Arousal histograms aligned to stimulations revealed a significant peak in arousals just before stimulation. In one of these subjects, the arousal peak began before stimulation and extended ~1 seconds after stimulation. A peak in arousals occurring only after stimulation was not observed. SIGNIFICANCE: In this small cohort of patients, brain-responsive neurostimulation does not appear to disrupt sleep. If confirmed in larger studies, this could represent a potential clinical advantage of brain-responsive neurostimulation over other neurostimulation modalities.

Validation of sleep measurement in a multisensor consumer grade wearable device in healthy young adults.

STUDY OBJECTIVES: Our objective was to examine the ability of a consumer-grade wearable device (Basis B1) with accelerometer and heart rate technology to assess sleep patterns compared with polysomnography (PSG) and research-grade actigraphy in healthy adults. METHODS: Eighteen adults underwent consecutive nights of sleep monitoring using Basis B1, actigraphy, and PSG; 40 nights were used in analyses. Discrepancies in gross sleep parameters and epoch-by-epoch agreements in sleep/wake classification were assessed. RESULTS: Basis B1 accuracy was 54.20 ± 8.20%, sensitivity was 98.90 ± 2.70%, and specificity was 8.10 ± 15.00%. Accuracy, sensitivity, and specificity for distinguishing between the different sleep stages were 60-72%, 48-62%, and 57-86%, respectively. Pearson correlations demonstrated strong associations between Basis B1 and PSG estimates of sleep onset latency and total sleep time; moderate associations for sleep efficiency, duration of light sleep, and duration of rapid eye movement sleep; and a weak association for duration of deep sleep. Basis B1 significantly overestimates total sleep time, sleep efficiency, and duration of light sleep and significantly underestimates wake after sleep onset and duration of deep sleep. CONCLUSIONS: Basis B1 demonstrated utility for estimates of gross sleep parameters and performed similarly to actigraphy for estimates of total sleep time. Basis B1 specificity was poor, and Basis B1 is not useful for the assessment of wake. Basis B1 accuracy for sleep stages was better than chance but is not a suitable replacement for PSG assessment. Despite low cost, ease of use, and attractiveness for patients, consumer devices are not yet accurate or reliable enough to guide treatment decision making in clinical settings.

REM sleep is associated with white matter integrity in cognitively healthy, older adults.

There is increasing awareness that self-reported sleep abnormalities are negatively associated with brain structure and function in older adults. Less is known, however, about how objectively measured sleep associates with brain structure. We objectively measured at-home sleep to investigate how sleep architecture and sleep quality related to white matter microstructure in older adults. 43 cognitively normal, older adults underwent diffusion tensor imaging (DTI) and a sleep assessment within a six-month period. Participants completed the PSQI, a subjective measure of sleep quality, and used an at-home sleep recorder (Zeo, Inc.) to measure total sleep time (TST), sleep efficiency (SE), and percent time in light sleep (LS), deep sleep (DS), and REM sleep (RS). Multiple regressions predicted fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum as a function of total PSQI score, TST, SE, and percent of time spent in each sleep stage, controlling for age and sex. Greater percent time spent in RS was significantly associated with higher FA (ß = 0.41, p = 0.007) and lower MD (ß = -0.30, p = 0.03). Total PSQI score, TST, SE, and time spent in LS or DS were not significantly associated with FA or MD (p>0.13). Percent time spent in REM sleep, but not quantity of light and deep sleep or subjective/objective measures of sleep quality, positively predicted white matter microstructure integrity. Our results highlight an important link between REM sleep and brain health that has the potential to improve sleep interventions in the elderly.

Acute cognitive effects of the hypocretin receptor antagonist almorexant relative to zolpidem and placebo: a randomized clinical trial.

STUDY OBJECTIVES: Hypnotic medications can adversely affect behavior during unanticipated awakenings during the night. Animals treated with the hypocretin (Hcrt) receptor antagonist almorexant (ALM) have less acute cognitive impairment compared to the GABAA receptor modulator zolpidem (ZOL). This study aimed to determine whether ALM produces less acute cognitive impairment than ZOL in human subjects. METHODS: Healthy, young adult, unmedicated male and female subjects participated in a controlled trial of a single dose of ALM 100 mg (N = 48), ALM 200 mg (N = 53), ZOL 10 mg (N = 49), and placebo (PBO, N = 52). RESULTS: ZOL and both doses of ALM produced similar levels of subjective sleepiness and impaired the ability of subjects to remain awake in a dark, low-stimulus setting relative to PBO. For most cognitive measures, performance under ZOL was significantly worse than ALM or PBO. For tasks involving verbal memory or visual-motor coordination, ZOL impaired performance, whereas the two doses of ALM were no different than PBO. For tasks involving higher-order executive function, ZOL produced impairment in processing speed and inhibitory control, whereas the two doses of ALM were no different than PBO. Performance decrements for ALM were less than ZOL but greater than PBO for some reaction time measures. CONCLUSIONS: The data provide support for the hypothesis that Hcrt receptor antagonists produce less functional impairment than a benzodiazepine receptor agonist (BzRA). These observations are particularly relevant to patients treated with sedative-hypnotics who are at elevated risk for falls and other untoward events during the intended hours for sleep.

An Open-Label Study of Doxazosin Extended-Release for PTSD: Findings and Recommendations for Future Research on Doxazosin.

OBJECTIVE: This report presents findings from an eight-week, open-label study of doxazosin extended-release for nightmares, sleep disturbance, and overall clinical symptoms in posttraumatic stress disorder (PTSD). Recommendations for future studies of doxazosin are provided. METHOD: Fifteen male and female adults were enrolled. The primary endpoints were change in Clinician-Administered PTSD Scale total, nightmare, and sleep disturbance scores from pretreatment to end of treatment. Self-report data on PTSD, sleep quality, depression, and quality of life collected at three time points and sleep diary data collected daily were analyzed secondarily. RESULTS: Eight participants completed eight weeks of study treatment. Among completers, significant changes in nightmares and overall PTSD symptoms were found. Secondary analyses using data from completers and noncompleters demonstrated improvements in all secondary outcomes. Of the participants who dropped out of the study, four participants discontinued because of side effects, and three participants discontinued because of other barriers to study participation. CONCLUSIONS: These findings indicate that doxazosin may be of value for some individuals with PTSD but problematic for others. Alternative formulations of doxazosin, such as the immediate-release formulation, should be studied. Future research should examine moderators of treatment tolerability and treatment effects to best identify those who will or will not benefit from doxazosin.

Cognitive Behavioral Therapy for Insomnia Reduces Fear of Sleep in Individuals With Posttraumatic Stress Disorder.

STUDY OBJECTIVES: Our study aims were to examine (1) the association between fear of sleep and posttraumatic stress disorder (PTSD) symptoms, (2) the association between fear of sleep and subjective and objective insomnia symptoms and disruptive behaviors during sleep, and (3) whether fear of sleep decreases following cognitive behavioral therapy for insomnia (CBT-I). METHODS: Forty-five adults with PTSD and insomnia participated in the study. Fear of sleep was assessed using the Fear of Sleep Inventory; PTSD symptoms were assessed using the Clinician Administered PTSD Scale; and sleep disturbance symptoms were assessed using the Insomnia Severity Index, polysomnography, sleep diaries, and the Pittsburgh Sleep Quality Index Addendum for PTSD. Participants were randomly assigned to 8 weeks of CBT-I (n = 29) or a waitlist control condition (n = 16). RESULTS: Greater fear of sleep was associated with greater PTSD symptom severity, greater nightmare frequency, and greater hypervigilance intensity. Greater fear of sleep was associated with decreased wake after sleep onset (WASO), reduced total sleep time, and greater disruptive nocturnal behaviors. Following CBT-I, there was a significant reduction in fear of sleep compared to the waitlist condition. These improvements persisted 6 months later. CONCLUSIONS: Fear of sleep was related to sleep disturbances specific to trauma rather than "classic" insomnia symptoms. Unexpectedly, greater fear of sleep was associated with reduced WASO. These results may be related to having a truncated sleep period and thus more consolidated sleep. Fear of sleep deceased following CBT-I despite not being a permissible target for this research protocol and not being related to insomnia symptoms. CLINICAL TRIAL REGISTRATION: Registry: CinicalTrials.gov; Name: Treating People with Post-traumatic Stress Disorder with Cognitive Behavioral Therapy for Insomnia; Identifier: NCT00881647; URL: https://clinicaltrials.gov/ct2/show/NCT00881647.

Sleepless Night and Day, the Plight of Progressive Supranuclear Palsy.

Objectives: To elucidate the unique sleep and waking characteristics in progressive supranuclear palsy (PSP), a neurodegenerative disease associated with motor deficits and dementia that largely affects the brainstem and thalamic regions. Methods: A total of 20 PSP and 16 healthy older adult controls participated in this study. The participants underwent an overnight polysomnography and multiple sleep latency test (MSLT) the following day. Prior to the MSLT last trial, they were asked to complete the Stanford Sleepiness Scale. Data were assessed for measures of latency to sleep onset, sleep duration, waking, and sleep staging during the night. Mean sleep latency, a measure of daytime sleepiness, sleep onset rapid eye movement (REM) periods, and microsleeps were studied with the MSLT. Spectral analysis of wake electroencephalogram (EEG) was performed for 30-second periods at the start of each MSLT trial. Results: PSP took significantly longer time to fall asleep (p < .001), slept less during the night (p ≤ .001), and had more wake after sleep onset than controls (p ≤ .001). PSP had less N2 sleep (p < .05) and N3 sleep (p < .05), and REM sleep (p < .001) than controls. During the MSLT, PSP took significantly longer to fall asleep (p < .001), did not have microsleeps when they remained awake throughout the assessment periods, but were subjectively sleepier than controls (p < .05). Gamma power was increased during wake EEG in PSP (p < .01). Conclusions: Sleep/waking regulation and REM sleep regulation are disrupted in PSP, leading to profound sleep deprivation without recuperation. Our findings suggest a diminished homeostatic sleep drive in PSP. This hyperaroused state is unique and is a severely disabling feature of PSP.

Rest-activity rhythm disruption in progressive supranuclear palsy.

OBJECTIVE/BACKGROUND: The brainstem is among the first regions affected in progressive supranuclear palsy (PSP) and is part of the sleep/circadian regulation network. In two small studies, blood pressure and core body temperature circadian patterns were disrupted in PSP; however, it is unclear if circadian activity rhythms are also affected. Our objective was to perform circadian analyses of the rest-activity rhythms in PSP and determine the association with increasing disease severity. PATIENTS/METHODS: Individuals with a clinical PSP diagnosis (n = 17; nine men) and healthy older adults (n = 17; nine men) were selected for this study. Participants wore actigraphy wristbands and completed sleep diaries for up to 14 consecutive days. Data were analyzed to assess circadian activity strength (amplitude, mesor, f-ratio), phase (acrophase), and circadian stability (intradaily variability, interdaily stability, relative amplitude). Analyses controlled for sleep fragmentation, cognition, and self-reported depression. The association between disease severity using the PSP rating scale and circadian activity rhythm disruption was assessed. RESULTS: Individuals with PSP had significantly lower circadian activity mesor (p ≤ 0.001), amplitude (p ≤ 0.001), robustness (f-ratio, p <0.01), relative amplitude (p ≤ 0.001), and interdaily stability (p ≤ 0.01), with increased intradaily variability (p <0.05). CAR remained weaker in PSP after controlling for sleep fragmentation, and again when also controlling for cognitive impairment and depression. Weaker circadian activity (mesor, amplitude, f-ratio, and relative amplitude) was associated with increased disease severity. CONCLUSIONS: Circadian activity rhythms are disrupted in individuals with PSP as compared to controls, and worsen with disease severity. This is the first study of its kind to describe circadian activity rhythms in PSP.

Hyperinsulinemic response to oral glucose challenge in individuals with posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with a 2-4 fold increased risk of developing Type 2 diabetes mellitus. However, detailed assessments of glucose metabolism and insulin secretion in a study designed to minimize confounders are lacking. Furthermore, few studies examine potential mechanisms involved. We analyzed data from a case-control study of medically healthy, medication-free adults to determine whether individuals with PTSD had abnormal glucose or insulin response to oral glucose tolerance test (OGTT) compared to controls. Secondarily, we assessed potential mediators such as sleep, cortisol and adiponectin. METHODS: Data was analyzed from 92 age and gender-matched subjects (44 PTSD, 48 controls). Chronic PTSD was diagnosed using the Structured Clinical Interview for DSM-IV and Clinician Administered PTSD Scale. Subjects underwent 75-g OGTT, actigraphy and sleep diary (to quantify sleep duration), polysomnography (to assess slow wave sleep [SWS] and delta power), and overnight blood sampling (for cortisol and adiponectin). RESULTS: At baseline, individuals with PTSD had mildly increased insulin levels (by 19%, compared to controls, p=0.048) that was mediated primarily by weight. In response to OGTT, the PTSD group had higher levels of insulin at 120 min (by 44%, p=0.03) and insulin AUC (by 43%, p=0.015) compared to controls, after adjusting for confounders. Glucose levels were similar in the two groups. Although self-reported sleep duration, SWS, and delta power differed between PTSD subjects and controls, they did not mediate the effects of PTSD status on insulin response. CONCLUSION: In this case-control study, individuals with PTSD had a hyperinsulinemic response to oral glucose challenge compared to controls, suggestive of insulin resistance.

Cognitive behavioral therapy for insomnia in posttraumatic stress disorder: a randomized controlled trial.

STUDY OBJECTIVES: Examine whether cognitive behavioral therapy for insomnia (CBT-I) improves sleep in posttraumatic stress disorder (PTSD) as well as nightmares, nonsleep PTSD symptoms, depression symptoms, and psychosocial functioning. DESIGN: RANDOMIZED CONTROLLED TRIAL WITH TWO ARMS: CBT-I and monitor-only waitlist control. SETTING: Department of Veterans Affairs (VA) Medical Center. PARTICIPANTS: Forty-five adults (31 females: [mean age 37 y (22-59 y)] with PTSD meeting research diagnostic criteria for insomnia, randomly assigned to CBT-I (n = 29; 22 females) or monitor-only waitlist control (n = 16; nine females). INTERVENTIONS: Eight-session weekly individual CBT-I delivered by a licensed clinical psychologist or a board-certified psychiatrist. MEASUREMENTS AND RESULTS: Measures included continuous monitoring of sleep with diary and actigraphy; prepolysomnography and postpolysomnography and Clinician-Administered PTSD Scale (CAPS); and pre, mid, and post self-report questionnaires, with follow-up of CBT-I participants 6 mo later. CBT-I was superior to the waitlist control condition in all sleep diary outcomes and in polysomnography-measured total sleep time. Compared to waitlist participants, CBT-I participants reported improved subjective sleep (41% full remission versus 0%), disruptive nocturnal behaviors (based on the Pittsburgh Sleep Quality Index-Addendum), and overall work and interpersonal functioning. These effects were maintained at 6-mo follow-up. Both CBT-I and waitlist control participants reported reductions in PTSD symptoms and CAPS-measured nightmares. CONCLUSIONS: Cognitive behavioral therapy for insomnia (CBT-I) improved sleep in individuals with posttraumatic stress disorder, with durable gains at 6 mo. Overall psychosocial functioning improved following CBT-I. The initial evidence regarding CBT-I and nightmares is promising but further research is needed. Results suggest that a comprehensive approach to treatment of posttraumatic stress disorder should include behavioral sleep medicine. CLINICAL TRIAL INFORMATION: TRIAL NAME: Cognitive Behavioral Treatment Of Insomnia In Posttraumatic Stress Disorder. URL: http://clinicaltrials.gov/ct2/show/NCT00881647. REGISTRATION NUMBER: NCT00881647.