Publications

OBJECTIVE: A well-established bidirectional relationship exists between sleep and epilepsy. Patients with epilepsy tend to have less efficient sleep and shorter rapid eye movement (REM) sleep. Seizures are far more likely to arise from sleep transitions and non-REM sleep compared to REM sleep. Delay in REM onset or reduction in REM duration may have reciprocal interactions with seizure occurrence. Greater insight into the relationship between REM sleep and seizure occurrence is essential to our understanding of circadian patterns and predictability of seizure activity. We assessed a cohort of adults undergoing evaluation of drug-resistant epilepsy to examine whether REM sleep prior to or following seizures is delayed in latency or reduced in quantity.

METHODS: We used a spectrogram-guided approach to review the video-electroencephalograms of patients' epilepsy monitoring unit admissions for sleep scoring to determine sleep variables.

RESULTS: In our cohort of patients, we found group- and individual-level delay of REM latency and reduced REM duration when patients experienced a seizure before the primary sleep period (PSP) of interest or during the PSP of interest. A significant increase in REM latency and decrease in REM quantity were observed on nights where a seizure occurred within 4 h of sleep onset. No change in REM variables was found when investigating seizures that occurred the day after the PSP of interest. Our study is the first to provide insight about a perisleep period, which we defined as 4-h periods before and after the PSP.

SIGNIFICANCE: Our results demonstrate a significant relationship between seizures occurring prior to the PSP, during the PSP, and in the 4-h perisleep period and a delay in REM latency. These findings have implications for developing a biomarker of seizure detection as well as longer term seizure risk monitoring.

OBJECTIVE: The aim of the study is to identify suitable definitions and patient-reported outcome measures (PROMs) to assess each of the six core outcomes previously identified through the COMMA (Core Outcomes in Menopause) global consensus process relating to vasomotor symptoms: frequency, severity, distress/bother/interference, impact on sleep, satisfaction with treatment, and side effects.

METHODS: A systematic review was conducted to identify relevant definitions for the outcome of side-effects and PROMs with acceptable measurement properties for the remaining five core outcomes. The consensus process, involving 36 participants from 16 countries, was conducted to review definitions and PROMs and make final recommendations for the measurement of each core outcome.

RESULTS: A total of 21,207 publications were screened from which 119 reporting on 40 PROMs were identified. Of these 40 PROMs, 36 either did not adequately map onto the core outcomes or lacked sufficient measurement properties. Therefore, only four PROMs corresponding to two of the six core outcomes were considered for recommendation. We recommend the Hot Flash Related Daily Interference Scale to measure the domain of distress, bother, or interference of vasomotor symptoms and to capture impact on sleep (one item in the Hot Flash Related Daily Interference Scale captures interference with sleep). Six definitions of "side effects" were identified and considered. We recommend that all trials report adverse events, which is a requirement of Good Clinical Practice.

CONCLUSIONS: We identified suitable definitions and PROMs for only three of the six core outcomes. No suitable PROMs were found for the remaining three outcomes (frequency and severity of vasomotor symptoms and satisfaction with treatment). Future studies should develop and validate PROMs for these outcomes.

STUDY OBJECTIVES: We previously reported that during a 45-day simulated space mission, a dynamic lighting schedule (DLS) improved circadian phase alignment and performance assessed once on selected days. This study aimed to evaluate how DLS affected performance on a 5-minute psychomotor vigilance task (PVT) administered multiple times per day on selected days.

METHODS: Sixteen crewmembers (37.4 ± 6.7 years; 5F) underwent six cycles of 2 × 8-hour/night followed by 5 × 5-hour/night sleep opportunities. During the DLS (n = 8), daytime white light exposure was blue-enriched ( 6000 K; Level 1: 1079, Level 2: 76 melanopic equivalent daytime illuminance (melEDI) lux) and blue-depleted ( 3000-4000 K; L1: 21, L2: 2 melEDI lux) 3 hours before bed. In the standard lighting schedule (SLS; n = 8), lighting remained constant ( 4500K; L1: 284, L2 62 melEDI lux). Effects of lighting condition (DLS/SLS), sleep condition (5/8 hours), time into mission, and their interactions, and time awake on PVT performance were analyzed using generalized linear mixed models.

RESULTS: The DLS was associated with fewer attentional lapses (reaction time [RT] > 500 milliseconds) compared to SLS. Lapses, mean RT, and 10% fastest/slowest RTs were worse following 5 compared to 8 hours of sleep but not between lighting conditions. There was an effect of time into mission on RTs, likely due to sleep loss. Overall performance differed by time of day, with longer RTs at the beginning and end of the day. There were more lapses and slower RTs in the afternoon in the SLS compared to the DLS condition.

CONCLUSIONS: Future missions should incorporate DLS to enhance circadian alignment and performance. This paper is part of the Sleep and Circadian Rhythms: Management of Fatigue in Occupational Settings Collection.

STUDY OBJECTIVES: Menopause is associated with nighttime sleep fragmentation, declining estradiol, and impaired cognition. In a model of pharmacologically induced estradiol suppression mimicking menopause, we examined the impact of menopause-pattern sleep fragmentation on daytime neurobehavioral performance and sleepiness in premenopausal women.

METHODS: Twenty premenopausal women completed two five-night inpatient studies in the mid-to-late follicular phase (estrogenized) and after pharmacological estradiol suppression (hypo-estrogenized). During each study, participants had an uninterrupted 8-hour sleep opportunity for two nights, followed by three nights where sleep was experimentally fragmented to mimic menopause-pattern sleep disturbance, and during which the sleep opportunity was extended to prevent shortening of the sleep duration. Neurobehavioral performance and subjective sleepiness were measured using the Psychomotor Vigilance Task and Karolinska Sleepiness Scale (KSS).

RESULTS: Compared to unfragmented sleep, sleep fragmentation increased attentional lapses (+ 0.6 lapses, p < .05), slowed reaction time (+ 9.4 milliseconds, p < .01), and increased daytime sleepiness (+ 0.5 KSS score, p < .001). Estradiol suppression increased attentional lapses (+ 0.8; p < .001) and reaction time (+ 12.3, p < .01) but did not significantly affect daytime sleepiness. The effect of sleep fragmentation on neurobehavioral performance differed by estradiol state, such that the adverse effects of sleep fragmentation on attentional lapses (+ 0.9, trend p = .06) and reaction time (+ 15, p < .05) were observed only when estrogenized.

CONCLUSIONS: Menopause-pattern sleep fragmentation and estradiol suppression worsened neurobehavioral performance and daytime sleepiness, even while sleep duration was not reduced. The adverse effects of sleep fragmentation in the context of an adequate sleep duration highlight the importance of sleep continuity as a vital aspect of good sleep health.

Robust circadian rhythms are essential for optimal health. The central circadian clock controls temperature rhythms, which are known to organize the timing of peripheral circadian rhythms in rodents. In humans, however, it is unknown whether temperature rhythms relate to the organization of circadian rhythms throughout the body. We assessed core body temperature amplitude and the rhythmicity of 929 blood plasma metabolites across a 40-h constant routine protocol, controlling for behavioral and environmental factors that mask endogenous temperature rhythms, in 23 healthy individuals (mean [± SD] age = 25.4 ± 5.7 years, 5 women). Valid core body temperature data were available in 17/23 (mean [± SD] age = 25.6 ± 6.3 years, 1 woman). Individuals with higher core body temperature amplitude had a greater number of metabolites exhibiting circadian rhythms (R2 = 0.37, p = .009). Higher core body temperature amplitude was also associated with less variability in the free-fitted periods of metabolite rhythms within an individual (R2 = 0.47, p = .002). These findings indicate that a more robust central circadian clock is associated with greater organization of circadian metabolite rhythms in humans. Metabolite rhythms may therefore provide a window into the strength of the central circadian clock.

IMPORTANCE: Safe and effective nonhormonal treatments for menopausal vasomotor symptoms (VMS) are needed.

OBJECTIVE: To evaluate the efficacy and safety of elinzanetant, a selective neurokinin-1,3 receptor antagonist, for the treatment of moderate to severe menopausal vasomotor symptoms.

DESIGN, SETTING, AND PARTICIPANTS: Two randomized double-blind phase 3 trials (OASIS 1 and 2) included postmenopausal participants aged 40 to 65 years experiencing moderate to severe vasomotor symptoms (OASIS 1: 77 sites in the US, Europe, and Israel from August 27, 2021, to November 27, 2023, and OASIS 2: 77 sites in the US, Canada, and Europe from October 29, 2021, to October 10, 2023).

INTERVENTION: Once daily oral elinzanetant, 120 mg, for 26 weeks or matching placebo for 12 weeks followed by elinzanetant, 120 mg, for 14 weeks.

MAIN OUTCOMES AND MEASURES: Primary end points included mean change in frequency and severity of moderate to severe vasomotor symptoms from baseline to weeks 4 and 12, measured by the electronic hot flash daily diary. Secondary end points included Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b total T score and Menopause-Specific Quality of Life questionnaire total score from baseline to week 12.

RESULTS: Eligible participants (mean [SD] age, OASIS 1: 54.6 [4.9] years; OASIS 2: 54.6 [4.8] years) were randomized to elinzanetant (OASIS 1: n = 199; OASIS 2: n = 200) or placebo (OASIS 1: n = 197; OASIS 2: n = 200). A total of 309 (78.0%) and 324 (81.0%) completed OASIS 1 and 2, respectively. For the elinzanetant and placebo groups, the baseline mean (SD) VMS per 24 hours were 13.4 (6.6) vs 14.3 (13.9) (OASIS 1) and 14.7 (11.1) v 16.2 (11.2) (OASIS 2). Baseline VMS severity was 2.6 (0.2) vs 2.5 (0.2) (OASIS 1) and 2.5 (0.2) vs 2.5 (0.2) (OASIS 2). Elinzanetant significantly reduced VMS frequency at week 4 (OASIS 1: -3.3 [95% CI, -4.5 to -2.1], P < .001; OASIS 2: -3.0 [95% CI, -4.4 to -1.7], P < .001) and at week 12 (OASIS 1: -3.2 [95% CI, -4.8 to -1.6], P < .001; OASIS 2: -3.2 [95% CI, -4.6 to -1.9], P < .001). Elinzanetant also improved VMS severity at week 4 (OASIS 1: -0.3 [95% CI, -0.4 to -0.2], P < .001; OASIS 2: -0.2 [95 CI, -0.3 to -0.1], P < .001) and week 12 (OASIS 1: -0.4 [95% CI, -0.5 to -0.3], P < .001; OASIS 2: -0.3 [95% CI, -0.4 to -0.1], P < .001). Elinzanetant improved sleep disturbances and menopause-related quality of life at week 12, and the safety profile was favorable.

CONCLUSIONS AND RELEVANCE: Elinzanetant was well tolerated and efficacious for moderate to severe menopausal VMS.

TRIAL REGISTRATION: ClinicalTrials.gov Identifier: OASIS 1: NCT05042362, OASIS 2: NCT05099159.

BACKGROUND: In residency programs, the availability of faculty mentors for traditional dyadic mentorship relationships may be limited. Few frameworks exist for mentorship programs with a combined faculty and peer mentorship approach. The authors developed the Mentorship Families Program (MFP), a faculty-resident group mentorship program within a psychiatry residency program to meet the need for mentorship for a large cohort of residents. A cross-sectional survey was used to evaluate the impact of the MFP after its first implementation year.

METHODS: Eleven mentorship families were created with 11 faculty members and 45 residents; each mentorship family consisted of one faculty member and 4-5 residents. A cross-sectional survey characterized the one-year perceived impact (2021-2022) of the MFP on resident and faculty mentoring experiences, with questions about the content, frequency, and quality of the MFP meetings and the strengths and areas of improvement for the MFP. Descriptive statistics were used to summarize quantitative feedback; directed content analysis was performed on open-ended feedback.

RESULTS: Twenty-seven residents (60%) and 8 faculty members (73%) responded to the survey. 70% of mentorship families met at least once. The MFP helped foster resident-faculty connections and provided an environment to gain career advice. However, residents and faculty reported challenges with scheduling meetings and a lack of meeting structure as barriers to effective engagement with the MFP. Most residents recommended that other training programs implement a program like the MFP as it offered multidimensional opportunities for connections between residents and faculty.

CONCLUSIONS: A faculty-resident group mentorship program like the MFP can be implemented in residency training programs when traditional one-to-one faculty mentorship is often limited.

BACKGROUND: Women may be vulnerable to elevated depressive symptoms during the menopause transition (MT). Studies generally have not considered premenopausal depressive symptom history or examined symptoms in relation to the final menstrual period (FMP).

OBJECTIVE: To identify specific time points in relation to the FMP when depressive symptoms increase or decrease.

METHODS: Participants were 1582 multiracial/ethnic women from the longitudinal Study of Women's Health Across the Nation (SWAN). Biological, psychosocial, and depressive symptom data were collected approximately annually. Depressive symptoms were measured by the Center for Epidemiological Studies-Depression (CESD) scale.

RESULTS: Women with high baseline depressive symptoms (CES-D ≥ 16) declined in symptoms (M = -1.04/yr., 95 % CI = -1.58, -0.50) until 4 years before the FMP, followed by a smaller decrease (M = -0.50/yr., 95 % CI = -0.72, -0.28) until 18 months after the FMP. Depressive symptoms increased (M = 0.21/yr., 95 % CI = 0.11, 0.30) in those with low baseline symptoms until 1 year before the FMP, and decreased (M = -0.06/yr., 95 % CI = -0.11, -0.008) going forward. Greater social support, higher levels of follicle stimulating hormone and estradiol, and less sleep disturbance contributed to greater decline in depressive symptoms among those with high baseline depressive symptoms. Anxiety, experiencing stressful life events, lower body mass index, and poor role-physical function contributed to an increase in depressive symptoms among those with low baseline symptoms.

LIMITATIONS: Excluded women had higher baseline CES-D scores. Lacked pre-MT depression for pre/early perimenopausal women at baseline.

CONCLUSION: Accounting for baseline depressive symptom level and focusing on the FMP more precisely characterize depressive symptom change over the MT.

OBJECTIVES: To examine the associations of actigraphy-assessed sleep timing and regularity with psychological health in early late life women, whose circadian rhythms may be impacted by aging.

DESIGN: Cross-sectional.

PARTICIPANTS: A racially/ethnically diverse sample of 1197 community-dwelling women (mean age 65 years) enrolled in the Study of Women's Health Across the Nation.

MEASURES: Actigraphy-assessed sleep measures included timing (mean midpoint from sleep onset to wake-up) and regularity (standard deviation of midpoint in hours). Psychological health measures included a composite well-being score, the Center for Epidemiological Studies Depression Scale, and the Generalized Anxiety Disorder-7 Scale. Linear and logistic regression models, adjusted for covariates (including sleep duration), tested associations between sleep and psychological health measures.

RESULTS: After covariate adjustment, a sleep midpoint outside of 2:00-4: 00 AM was significantly associated with depressive symptoms (β = 0.88, 95% CI = 0.06, 1.70) and scoring above the cut-point for clinically significant depressive symptoms (OR = 1.72, 95% CI = 1.15, 2.57). Sleep irregularity was significantly associated with lower psychological well-being (β = -0.18, 95% CI = -0.33, -0.03), depressive (β = 1.36, 95% CI = 0.29, 2.44) and anxiety (β = 0.93, 95% CI = 0.40, 1.46) symptoms, and scoring above the cut-point for clinically significant depressive (OR = 1.68, 95% CI = 1.01, 2.79) and anxiety (OR = 1.62, 95% CI = 1.07, 2.43) symptoms.

CONCLUSION: Above and beyond sleep duration, a sleep midpoint outside of 2:00-4:00 AM was associated with depressive symptoms while sleep irregularity was associated with multiple psychological health domains in late life women.