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1.  [No title available] 
PMCID: PMC3933955  PMID: 24424100
2.  [No title available] 
PMCID: PMC3940266  PMID: 24380782
3.  [No title available] 
PMCID: PMC3946296  PMID: 24360982
4.  Controlling light–dark exposure patterns, rather than sleep schedules, determines circadian phase 
Sleep medicine  2013;14(5):456-461.
Examine, in a field study, circadian phase changes associated with two different light–dark exposures patterns, one that was congruent with a phase advanced sleep schedule and the other that was incongruent with an advanced schedule.
Twenty-one adults (mean age ± SD = 22.5 ± 3.9 years; 11 women) participated in the 12 day study. After a five day baseline period, participants were all given individualized, fixed, 90 minute advanced sleep schedules for one week. Participants were randomly assigned to one of two groups, an advance group with a light–dark exposure prescription designed to advance circadian phase or a delay group with light–dark exposure prescription designed to delay circadian phase. The advance group received two morning hours of short-wavelength (blue) light (λmax ≈ 476 ± 1 nm, full-width-half-maximum ≈ 20 nm) exposure and three evening hours of light restriction (orange-filtered light, λ < 525 nm = 0). The delay group received blue light for three hours in the evening and light restriction for two hours in the morning. Participants led their normal lives while wearing a calibrated wrist-worn light exposure and activity monitor.
After seven days on the 90 minute advanced sleep schedule, circadian phase advanced 132 ± 19 minutes for the advance group and delayed 59 ± 7.5 minutes for the delay group.
Controlling the light–dark exposure pattern shifts circadian phase in the expected direction irrespective of the fixed advanced sleep schedule.
PMCID: PMC4304650  PMID: 23481485
5.  Valid measures of periodic leg movements (PLMs) during a suggested immobilization test using the PAM-RL leg activity monitors require adjusting detection parameters for noise and signal in each recording 
Sleep medicine  2013;15(1):132-137.
Objective and background
Individuals with restless legs syndrome (RLS) (Willis-Ekbom disease [WED]) usually have periodic leg movements (PLMs). The suggested immobilization test (SIT) measures sensory and motor features of WED during wakefulness. Surface electromyogram (EMG) recordings of the anterior tibialis (AT) are used as the standard for counting PLMs. However, due to several limitations, leg activity meters such as the PAM-RL were advanced as a potential substitute. In our study, we assessed the validity of the measurements of PLM during wakefulness (PLMW) in the SIT for PAM-RL using both default and custom detection threshold parameters compared to AT EMG.
Data were obtained from 39 participants who were diagnosed with primary WED and who were on stable medication as part of another study using the SIT to repeatedly evaluate WED symptoms over 6–12 months. EMG recordings and PAM-RL, when available, were used to detect PLMW for each SIT. Complete PAM-RL and polysomnography (PSG) EMG data were available for 253 SITs from that study. The default PAM-RL (dPAM-RL) detected leg movements based on manufacturer's noise (resting) and signal (movement) amplitude criteria developed to accurately detect PLM during sleep (PLMS). The custom PAM-RL (cPAM-RL) similarly detected leg movements except the noise and movement detection parameters were adjusted to match the PAM-RL data for each SIT.
The distributions of the differences between either dPAM-RL or cPAM-RL and EMG PLMW were strongly leptokurtic (Kurtosis >2) with many small differences and a few unusually large differences. These distributions are better described by median and quartile ranges than mean and standard deviation. Despite an adequate correlation (r = 0.66) between the dPAM-RL and EMG recordings, the dPAM-RL on average significantly underscored the number of PLMW (median: quartiles = −13: −51.2, 0.0) and on Bland–Altman plots had a significant magnitude bias with greater underscoring for larger average PLMW/h. There also was an adequate correlation (r = 0.70) between cPAM-RL and EMG but with minimal underscoring of PLMW (median quartiles = 0.0; −20, 10) and no significant magnitude bias. Two scorers independently scoring 13% of the SITs showed an adequate interscorer reliability of 0.96–0.98.
Our study confirms our expectation that measuring PLMW in a SIT using dPAM-RL is not valid and that adjustments to the detection threshold criteria are required. The PAM-RL, using parameters customized for each SIT provided a valid and reliable measure of PLMW with minimal magnitude bias compared to the AT EMG recordings.
PMCID: PMC3921115  PMID: 24332046
Restless Legs Syndrome (RLS); Willis Ekbom disease (WED); Leg activity monitors; Suggested immobilization test (SIT); Periodic leg movements during wakefulness (PLMW); Polysomnography; PAM-RL
6.  Associations of Self-Reported and Actigraphy-Assessed Sleep Characteristics with Body Mass Index and Waist Circumference in Adults: Moderation by Gender 
Sleep medicine  2013;15(1):64-70.
Self-reported sleep duration has been linked to body mass index (BMI) and waist circumference in previous work; however, data regarding whether these associations are stronger in men or women have been mixed, and few studies have measured sleep objectively. We investigated self-reported and actigraphy-assessed sleep characteristics in relation to BMI and waist circumference, and examined the extent to which these associations differ by gender.
Archived, cross-sectional data from the National Survey of Midlife Development in the United States (MIDUS) Biomarkers Study, collected in 2004–2006, were used. Participants included 1248 adults (43% male) who reported their habitual sleep duration, and a subset of participants (n = 441, 40% male) who underwent seven nights of wrist actigraphy.
Self-reported total sleep time, actigraphy-assessed total sleep time, and actigraphy-assessed sleep efficiency were inversely associated with BMI in the full sample of both men and women. Gender moderated associations between actigraphy assessments of sleep and anthropometric variables, however, such that total sleep time and sleep efficiency were related to BMI and waist circumference in women only. Associations between sleep and waist circumference were independent of BMI.
Sleep duration and sleep continuity are associated with body weight and distribution of body fat, but these associations are stronger, or only present, in women.
PMCID: PMC3926516  PMID: 24239499
sleep duration; actigraphy; body mass index; waist circumference; gender; women
7.  Agreement Between Stroke Patients and Family Members For Ascertaining Pre-Stroke Risk of Sleep Apnea 
Sleep medicine  2013;15(1):121-124.
Ascertaining self-reported information about pre-stroke obstructive sleep apnea (OSA) risk in the acute stroke period is challenging as many stroke patients have deficits that hinder communication. We examined agreement between stroke patients without communication limitations and family members (proxy) with respect to pre-stroke risk of OSA.
Patient-proxy pairs (n = 42) were interviewed independently as part of the Brain Attack Surveillance in Corpus Christi Project from May 2010 - April 2011. The Berlin questionnaire was used to measure a high risk of OSA defined as the presence of at least two of the following conditions: 1) snoring behaviors/witnessed apneas, 2) daytime sleepiness, and 3) hypertension or obesity. Patient-proxy agreement was assessed using a kappa coefficient.
Forty-three percent of patients self-identified as high risk for sleep apnea, and 45% of proxies identified patients as high risk. Patient-proxy agreement for high risk of pre-stroke OSA was fair (kappa = 0.28) with better agreement for spouses and children proxies (kappa = 0.38) than for other family members. Agreement was also fair for most individual questions.
Spouse and child proxy use of the Berlin questionnaire may be an option to assess a patient's pre-stroke likelihood of sleep apnea. Whereas prospective studies of incident stroke in patients with and without objectively confirmed sleep apnea would require formidable resources, the present results suggest that an alternative strategy may involve proxy use of the Berlin in a retrospective study design.
PMCID: PMC3959892  PMID: 24238964
Obstructive sleep apnea; Stroke; Proxy; Berlin Questionnaire
8.  Obstructive sleep apnea and neurocognitive performance: the role of cortisol 
Sleep medicine  2013;15(1):27-32.
Obstructive sleep apnea (OSA) is a prevalent disorder with multiple consequences including negative effects on neurocognitive function. Several domains of cognitive function are impaired in OSA patients, but the mechanisms through which this sleep disorder results in impairment are not clear. Given the well-known effects of cortisol on cognitive function, in particular memory, the dysregulating effects of OSA on cortisol levels is hypothesized as a potential pathway leading to cognitive impairment.
Fifty-five participants with OSA (mean apnea-hypopnea index [AHI], 30.3) were assessed over 2 days. Over a 24-hour period, blood was collected every 2 hours to examine cortisol levels. The following night, sleep was monitored with polysomnography (PSG). Participants were given a battery of neurocognitive tests, which assessed 7 cognitive domains.
OSA severity assessed by oxygen desaturation index (ODI) was associated with 24-hour cortisol levels. AHI, ODI, and nighttime cortisol levels were associated with global deficit scores (GDS) in cognitive functioning, particularly in domains of learning, memory, and working memory (P<.05 for all). Hierarchical linear regression analysis revealed that nighttime cortisol accounted for 9% to 16% of variance in learning (P=.018), memory (P=.003), and working memory (P=.016) domains, though apnea severity did not significantly predict any additional variance.
In our sample of patients with OSA, nocturnal cortisol levels were associated with neuropsychologic functioning above and beyond the influence of covariates and apnea severity. These findings suggest that OSA-related alterations in cortisol activity may partially explain the pathophysiology of neuropsychologic impairments in sleep apnea.
PMCID: PMC3906433  PMID: 24269133
Obstructive sleep apnea; sleep; neurocognitive function; memory; cortisol; hypothalamic-pituitary-adrenal axis
9.  Prevalence of Insomnia Symptoms in a General Population Sample of Young Children and Preadolescents: Gender Effects 
Sleep medicine  2013;15(1):91-95.
This population-based study examines the prevalence of insomnia symptoms as well as its sociodemographic, subjective, and polysomnographic (PSG) sleep risk factors in young and preadolescent children.
Cross-sectional study of 700 children, ages 5–12 who underwent a 9-hour PSG and parent completed sleep and development questionnaires (Penn State Child Cohort). Insomnia symptoms were defined as parent report of difficulty falling and/or staying asleep and sleep disordered breathing (SDB) as an apnea hypopnea index of ≥ 1.
The prevalence of insomnia symptoms was 19.3% and did not significantly change (20.2%) when children with SDB were excluded. A significant interaction between gender and age revealed that the prevalence of insomnia symptoms was highest in girls age 11–12 (30.6%). This gender difference was not associated with significant differences between girls and boys 11–12 yrs old in terms of anxiety and depressive symptoms. In contrast girls’11–12 years old with insomnia symptoms, but not boys of the same group, demonstrated clinically significant PSG sleep disturbances compared to those without insomnia symptoms.
These data suggest that one out of five young children and preadolescents of the general population have insomnia symptoms. Importantly, the prevalence of insomnia symptoms peaks in girls age 11–12 and is associated with objective sleep disturbances that maybe related to hormonal changes associated with the onset of puberty rather than anxiety and depression per se.
PMCID: PMC3912735  PMID: 24333223
Preadolescent children; epidemiology; insomnia; sociodemographics; puberty; gender
10.  Habitual Sleep Duration Associated with Self-Reported and Objectively-Determined Cardiometabolic Risk Factors 
Sleep medicine  2013;15(1):42-50.
Self-reported short and/or long sleep duration have been associated with adverse cardiometabolic health outcomes in laboratory and epidemiologic studies, but interpretation of such data has been limited by methodological issues.
Adult respondents of the 2007-2008 US National Health and Nutrition Examination Survey (NHANES) were examined in a cross-sectional analysis (N=5,649). Self-reported sleep duration was categorized as very short (<5hrs), short (5-6hrs), normal (7-8hrs) or long (≥9hrs). Obesity, diabetes, hypertension, and hyperlipidemia were assessed by self-reported history and objectively. Statistical analyses included univariate comparisons across sleep duration categories for all variables. Binary logistic regression analyses, cardiometabolic factor as outcome and with sleep duration category as predictor, were assessed with and without covariates. Observed relationships were further assessed for dependence on race/ethnicity.
In adjusted analyses, very short sleep was associated with self-reported hypertension (OR=2.02, 95%CI[1.45, 2.81], p<0.0001), self-reported hyperlipidemia (OR=1.96, 95%CI[1.43, 2.69], p<0.0001), objective hyperlipidemia (OR=1.41, 95%CI[1.04, 1.91], p=0.03), self-reported diabetes (OR=1.76, 95%CI[1.13, 2.74], p=0.01), and objective obesity (OR=1.53, 95%CI[1.13, 2.06], p=0.005). Regarding short sleep (5-6hrs), in adjusted analyses, elevated risk was seen for self-reported hypertension (OR=1.22, 95%CI[1.02, 1.45], p=0.03) self-reported obesity (OR=1.21, 95%CI[1.03, 1.43], p=0.02) and objective obesity (OR=1.17, 95%CI[1.00, 1.38], p<0.05). Regarding long sleep (≥9hrs), no elevated risk was found for any outcomes. Interactions with Race/Ethnicity were significant for all outcomes; race/ethnicity differences in patterns of risk varied by outcome studied. In particular, the relationship between very short sleep and obesity was strongest among Blacks/African-Americans and the relationship between short sleep and hypertension is strongest among non-Hispanic Whites, Blacks/African-Americans, and non-Mexican Hispanics/Latinos.
Short sleep duration is associated with self-reported and objectively-determined adverse cardiometabolic outcomes, even after adjustment for many covariates. Also, these patterns of risk depend on race/ethnicity.
PMCID: PMC3947242  PMID: 24333222
Sleep Duration; Epidemiology; Obesity; Cardiovascular Disease; Hypertension; Cholesterol; Diabetes
11.  Objectively-measured sleep duration and hyperglycemia in pregnancy 
Sleep medicine  2013;15(1):51-55.
Our primary purpose was to assess the impact of objectively-measured nighttime sleep duration on gestational glucose tolerance. We additionally examined associations of objectively-measured daytime sleep duration and nap frequency on maternal glycemic control.
63 urban, low-income, pregnant women wore wrist actigraphs for an average of 6 full days in mid-pregnancy prior to screening for hyperglycemia using the 1-hour oral glucose tolerance test (OGTT). Correlations of nighttime and daytime sleep durations with 1-hour OGTT values were analyzed. Multivariable logistic regression was used to evaluate independent associations between sleep parameters and hyperglycemia, defined as 1-hour OGTT values ≥ 130 mg/dL.
Mean nighttime sleep duration was 6.9 ± 0.9 hours which was inversely correlated with 1-hour OGTT values (r = −0.28, p = 0.03). Shorter nighttime sleep was associated with hyperglycemia, even after controlling for age and body mass index (adjusted OR: 0.2; 95% CI: 0.1, 0.8). There were no associations of daytime sleep duration and nap frequency with 1-hour OGTT values or hyperglycemia.
Using objective measures of maternal sleep time, we found that women with shorter nighttime sleep durations had an increased risk of gestational hyperglycemia. Larger prospective studies are needed to confirm our negative daytime sleep findings.
PMCID: PMC3947268  PMID: 24239498
Sleep duration; Actigraphy; Pregnancy; Hyperglycemia; Gestational diabetes
12.  Sleep and sadness: exploring the relation among sleep, cognitive control, and depressive symptoms in young adults 
Sleep medicine  2013;15(1):144-149.
Sleep disturbance is a common feature of depression. However, recent work has found that individuals who are vulnerable to depression report poorer sleep quality compared to their low-risk counterparts, suggesting that sleep disturbance may precede depression. In addition, both sleep disturbance and depression are related to deficits in cognitive control processes. Thus we examined if poor sleep quality predicts subsequent increases in depressive symptoms and if levels of cognitive control mediated this relation.
Thirty-five undergraduate students participated in 2 experimental sessions separated by 3 weeks. Participants wore an actigraph watch between sessions, which provided an objective measure of sleep patterns. We assessed self-reported sleep quality and depressive symptoms at both sessions. Last, individuals completed an exogenous cuing task, which measured ability to disengage attention from neutral and negative stimuli during the second session.
Using path analyses, we found that both greater self-reported sleep difficulty and more objective sleep stability measures significantly predicted greater difficulty disengaging attention (i.e., less cognitive control) from negative stimuli. Less cognitive control over negative stimuli in turn predicted increased depression symptoms at the second session. Exploratory associations among the circadian locomotor output cycles kaput gene, CLOCK, single nucleotide polymorphism (SNP), rs11932595, as well as sleep assessments and depressive symptoms also are presented.
These preliminary results suggest that sleep disruptions may contribute to increases in depressive symptoms via their impact on cognitive control. Further, variation in the CLOCK gene may be associated with sleep quality.
PMCID: PMC4217155  PMID: 24332565
sleep; circadian rhythm; actigraphy; cognitive control; depression; CLOCK gene
13.  Autonomic complaints in patients with Restless Leg Syndrome 
Sleep medicine  2013;14(12):1413-1416.
Data regarding autonomic function in restless legs syndrome (RLS) is limited to heart rate and blood pressure changes in cases having periodic limb movements (PLMS).
We compared autonomic symptoms of 49 subjects with RLS vs. 291 Controls using the SCOPA-Autonomic questionnaire (23 items in six domains scored 0–3). The total score and domain scores were transformed to 0 to 100 points. Subjects with neurodegenerative disorders (i.e. dementia, parkinsonism) were excluded.
The RLS group was younger (mean±SD 77.9 ± 8.0 vs. 80.5 ± 7.9 yrs, p=.03) and had more women (84% vs. 69%, p=.04). The mean SCOPA-Aut Total score was higher in the RLS group compared with Controls (20 ± 11 vs. 16 ± 9, p= .005). Additionally the RLS group had abnormalities in GI, cardiovascular, and pupillomotor domains. When comparing the percentage of subjects with any complaint on individual questions (score of ≥ 1) the RLS group had a greater number of subjects with sialorrhea, constipation, early abdominal fullness, lightheadedness when standing, and heat intolerance.
Autonomic complaints, especially GI, cardiovascular, and oversensitivity to light, are significantly increased in subjects with RLS. Causes for autonomic dysfunction in RLS require further investigation.
PMCID: PMC4105217  PMID: 24152795
Restless Leg Syndrome; Autonomic symptoms
14.  Psychosocial correlates of sleep quality and architecture in women with metastatic breast cancer 
Sleep medicine  2013;14(11):10.1016/j.sleep.2013.07.012.
Sleep disturbance is prevalent among women with metastatic breast cancer (MBC). Our study examined the relationship of depression and marital status to sleep assessed over 3 nights of polysomnography (PSG).
Women with MBC (N=103) were recruited; they were predominately white (88.2%) and 57.8±7.7 years of age. Linear regression analyses assessed relationships among depression, marital status, and sleep parameters.
Women with MBC who reported more depressive symptoms had lighter sleep (e.g., stage 1 sleep; P<.05), less slow-wave sleep (SWS) (P<.05), and less rapid eye movement (REM) sleep (P<.05). Single women had less total sleep time (TST) (P<.01), more wake after sleep onset (WASO) (P<.05), worse sleep efficiency (SE) (P<.05), lighter sleep (e.g., stage 1; P<.05), and less REM sleep (P<.05) than married women. Significant interactions indicated that depressed and single women had worse sleep quality than partnered women or those who were not depressed.
Women with MBC and greater symptoms of depression had increased light sleep and reduced SWS and REM, and single women had worse sleep quality and greater light sleep than married counterparts. Marriage was related to improved sleep for women with more depressive symptoms.
PMCID: PMC3886805  PMID: 24074694
Metastatic Breast Cancer; Polysomnography; Sleep Quality; Sleep Architecture; Depression; Women
15.  Auditory aura in nocturnal frontal lobe epilepsy: a red flag to suspect an extra-frontal epileptogenic zone 
Sleep Medicine  2014;15(11):1417-1423.
•Eleven out of 165 nocturnal frontal lobe epilepsy (NFLE) patients reported an auditory aura as initial ictal symptom.•Extra-frontal origin was documented in 55% of NFLE patients with auditory aura.•Six patients with defined epileptogenic zone had a left temporal origin of seizures.•Auditory aura may be a symptom suggesting an extra-frontal epileptogenic zone.
To describe the anatomo-electro-clinical findings of patients with nocturnal hypermotor seizures (NHS) preceded by auditory symptoms, to evaluate the localizing value of auditory aura.
Our database of 165 patients with nocturnal frontal lobe epilepsy (NFLE) diagnosis confirmed by videopolysomnography (VPSG) was reviewed, selecting those who reported an auditory aura as the initial ictal symptom in at least two NHS during their lifetime.
Eleven patients were selected (seven males, four females). According to the anatomo-electro-clinical data, three groups were identified. Group 1 [defined epileptogenic zone (EZ)]: three subjects were studied with stereo-EEG. The EZ lay in the left superior temporal gyrus in two cases, whereas in the third case seizures arose from a dysplastic lesion located in the left temporal lobe. One of these three patients underwent left Heschl's gyrus resection, and is currently seizure-free. Group 2 (presumed EZ): three cases in which a presumed EZ was identified; in the left temporal lobe in two cases and in the left temporal lobe extending to the insula in one subject. Group 3 (uncertain EZ): five cases had anatomo-electro-clinical correlations discordant.
This work suggests that auditory aura may be a helpful anamnestic feature suggesting an extra-frontal seizure origin. This finding could guide secondary investigations to improve diagnostic definition and selection of candidates for surgical treatment.
PMCID: PMC4247377  PMID: 25224073
Epilepsy; Nocturnal frontal lobe epilepsy; Auditory aura; Epileptogenic zone; Localizing value; Hypermotor seizures
16.  Behavioral parent training to address sleep disturbances in young children with autism spectrum disorder: a pilot trial 
Sleep medicine  2013;14(10):995-1004.
A large percentage of children with autism spectrum disorders (ASD) have bedtime and sleep disturbances. However, the treatment of these disturbances has been understudied. The purpose of our study was to develop a manualized behavioral parent training (BPT) program for parents of young children with ASD and sleep disturbances and to test the feasibility, fidelity, and initial efficacy of the treatment in a small randomized controlled trial (RCT).
Participants and methods
Parents of a sample of 40 young children diagnosed with ASD with an average age of 3.5 years were enrolled in our study. Participants were randomized to either the BPT program group or a comparison group who were given nonsleep-related parent education. Each was individually administered a 5-session program delivered over the 8-week study. Outcome measures of feasibility, fidelity, and efficacy were collected at weeks 4 and 8 after the baseline time point. Children’s sleep was assessed by parent report and objectively by actigraphy.
Of the 20 participants in each group, data were available for 15 participants randomized to BPT and 18 participants randomized to the comparison condition. Results supported the feasibility of the manualized parent training program and the comparison program. Treatment fidelity was high for both groups. The BPT program group significantly improved more than the comparison group based on the primary sleep outcome of parent report. There were no objective changes in sleep detected by actigraphy.
Our study is one of few RCTs of a BPT program to specifically target sleep disturbances in a well-characterized sample of young children with ASD and to demonstrate the feasibility of the approach. Initial efficacy favored the BPT program over the comparison group and suggested that this manualized parent training approach is worthy of further examination of the efficacy within a larger RCT.
PMCID: PMC3775974  PMID: 23993773
Sleep; sleep disturbances; sleep problems; bedtime problems; autism; autism spectrum disorders; parent training; Modified Simonds and Parraga Sleep Questionnaire; actigraphy; randomized controlled trial
17.  Genetic polymorphisms in the aryl hydrocarbon receptor–signaling pathway and sleep disturbances in middle-aged women 
Sleep medicine  2013;14(9):883-887.
We aimed to determine if selected genetic polymorphisms in the aryl hydrocarbon receptor (AHR)–signaling pathway and circadian locomotor output cycles kaput (CLOCK) are associated with insomnia and early awakening in middle-aged women.
Women aged 45 to 54 years (n=639) were recruited into a middle-aged health study and agreed to complete questionnaires and donate blood samples. Questionnaires were used to assess sleep outcomes. Blood samples were processed for genotyping the selected polymorphisms: AHR (rs2066853), AHR repressor (AHRR) (rs2292596), aryl hydrocarbon nuclear translocator (ARNT) (rs2228099), and circadian locomotor output cycles kaput (CLOCK) (rs1801260). Data were analyzed using multivariable logistic regression.
Women heterozygous for the AHRR alleles (GC) had decreased odds of insomnia compared to women homozygous for the AHRR_C allele (adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.49–0.96). Women with at least one of the AHRR_G or CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.64; 95% CI, 0.43–0.96). Additionally, women homozygous for the AHRR_G and CLOCK_C alleles had significantly decreased odds of insomnia compared to women homozygous for the AHRR_C and CLOCK_T alleles (aOR, 0.56; 95% CI, 0.35–0.89). None of the selected single nucleotide polymorphisms (SNPs) or combinations of SNPs were significantly associated with early awakening.
Selected genetic polymorphisms in the AHR-signaling pathway (i.e., AHRR) and CLOCK may play a role in decreasing the risk for experiencing insomnia during the menopausal transition.
PMCID: PMC3750063  PMID: 23768840
polymorphism; CLOCK; AHR; insomnia; early awakening; middle-aged women
18.  Do periodic arm movements during sleep exist in healthy subjects? A polysomnographic study 
Sleep Medicine  2014;15(9):1150-1154.
Despite several polysomnographic studies on periodic leg movements (PLM) in healthy sleep, data on the prevalence and characteristics of periodic arm movements (PAM) in normal subjects are lacking. We aimed to investigate PAM and their association with PLM during wakefulness and sleep in healthy subjects.
Ninety-one participants underwent video-polysomnography according to American Academy of Sleep Medicine 2007 criteria. In addition to standard electromyographic registration, data for both flexor digitorum superficialis muscles were recorded.
Sixty-two subjects (68.1%) had a PAM index during wakefulness >5/h (median PAM index during wakefulness, 8.8/h; range, 0–77). Seven subjects (7.7%) had a PAM index >5/h during sleep (median PAM index during sleep, 0.7/h; range, 0–47.4). In 14% of cases, PAM during wakefulness were coincident with PLM during wakefulness. During sleep, this coincidence was not evident. The correlation between PAM and PLM was weak to moderate (during wakefulness: Spearman's ρ = 0.576, P < 0.001; during sleep: Spearman's ρ = 0.222, P = 0.036).
In healthy subjects, PAM occur predominantly during wakefulness with no apparent true periodicity. In contrast to classical PLM, some PAM may not present a true periodic phenomenon, but rather random voluntary movements meeting the wide range of periodicity criteria for PLM.
PMCID: PMC4175008  PMID: 25037838
Periodic arm movements; Sleep; Healthy subjects; Polysomnography; AASM 2.0
19.  New Pathways and Data on REM sleep behavior disorder in a rat model 
Sleep medicine  2012;14(8):719-728.
An abnormality in auditory evoked responses localized to the inferior colliculus (IC) has been reported in RBD patients. The external cortex of the inferior colliculus (ICX) has been demonstrated not only to be involved in auditory processing but also participate in the modulation of motor activity.
Rats were surgically implanted with electrodes for EEG and EMG recording and guide cannulae aimed at the ICX for drug infusions. Drug infusions were conducted after the animals recovered from surgery. Polysomnographic recordings with video were analyzed to detect normal and abnormal sleep states.
Baclofen, a GABAB receptor agonist, infused into the ICX increased phasic motor activity in SWS and REM sleep and tonic muscle activity in REM sleep; it also elicited RBD-like activity during the infusion and post-infusion period. In contrast, saclofen, a GABAB receptor antagonist, did not produce significant changes in motor activities in sleep. Baclofen infusions in ICX also significantly increased REM sleep during the post-infusion period, while saclofen infusions did not change the amount of any sleep-waking states.
This study suggests that GABAB receptor mechanisms in the ICX may be implicated in the pathology of RBD.
PMCID: PMC3546264  PMID: 23058690
20.  Perspectives on the rapid eye movement sleep switch in rapid eye movement sleep behavior disorder 
Sleep medicine  2013;14(8):707-713.
Rapid eye movement (REM) sleep in mammals is associated with wakelike cortical and hippocampal activation and concurrent postural muscle atonia. Research during the past 5 decades has revealed the details of the neural circuitry regulating REM sleep and muscle atonia during this state. REM-active glutamatergic neurons in the sublaterodorsal nucleus (SLD) of the dorsal pons are critical for generation for REM sleep atonia. Descending projections from SLD glutamatergic neurons activate inhibitory premotor neurons in the ventromedial medulla (VMM) and in the spinal cord to antagonize the glutamatergic supraspinal inputs on the motor neurons during REM sleep. REM sleep behavior disorder (RBD) consists of simple behaviors (i.e., twitching, jerking) and complex behaviors (i.e., defensive behavior, talking). Animal research has lead to the hypothesis that complex behaviors in RBD are due to SLD pathology, while simple behaviors of RBD may be due to less severe SLD pathology or dysfunction of the VMM, ventral pons, or spinal cord.
PMCID: PMC3776319  PMID: 23768838
Neural circuitry; Brainstem; Atonia; Phasic regulation; Tonic regulation
21.  Morbidities in Rapid Eye Movement Sleep Behaviour Disorders 
Sleep medicine  2013;14(8):782-787.
Idiopathic Rapid Eye Movement (REM) Sleep Behaviour Disorder (iRBD, RBD without any obvious comorbid major neurological disease), is strongly associated with numerous comorbid conditions. The most prominent is that with neurodegenerative disorders, especially synuclein-mediated disorders, above all Parkinson Disease (PD). Idiopathic RBD is an important risk factor for the development of synucleinopathies. Comorbidity studies suggest that iRBD is associated with a number of other potential pre-motor manifestations of synucleinopathies such as, cognitive and olfactory impairment, reduced autonomic function, neuropsychiatric manifestations and sleep complaints. Furthermore, patients with PD and RBD may have worse prognosis in terms of impaired cognitive function and overall morbidity/mortality; in dementia, the presence of RBD is strongly associated with clinical hallmarks and pathological findings of dementia with Lewy bodies. These findings underline the progressive disease process, suggesting involvement of more brain regions in patients with a more advanced disease stage. RBD is also associated with narcolepsy, and it is likely that RBD associated with narcolepsy is a distinct subtype associated with different comorbidities. RBD is also associated with antidepressant medications, autoimmune conditions, and, in rare cases, brainstem lesions.
PMCID: PMC3979349  PMID: 23375425
REM Sleep Behavior Disorder; morbidity; narcolepsy; parkinsonism; comorbidity
22.  Rapid eye movement sleep behavior disorder in adults younger than 50 years of age 
Sleep medicine  2013;14(8):768-774.
Rapid eye movement (REM) sleep behavior disorder (RBD) occurring prior to age 50 is termed early-onset RBD. Early-onset RBD comprises a substantial minority of cases, and demonstrates the differences in demographics, comorbidities, and clinical considerations from previously described typical RBD with onset >50 years. The world literature on RBD is reviewed with specific focus on features that distinguish early-onset RBD, including more gender parity, increased proportion of idiopathic cases, increased proportion of cases associated with narcolepsy, parasomnia overlap disorder, antidepressants, and possibly autoimmune disorders, and clinical presentation.
PMCID: PMC3979350  PMID: 23347910
REM sleep behavior disorder (RBD); Narcolepsy; Antidepressant; Parasomnia; Parasomnia overlap disorder (POD); Autoimmune
23.  Clinicopathologic correlations in 172 cases of rapid eye movement sleep behavior disorder with or without a coexisting neurologic disorder 
Sleep medicine  2013;14(8):754-762.
To determine the pathologic substrates in patients with rapid eye movement (REM) sleep behavior disorder (RBD) with or without a coexisting neurologic disorder.
The clinical and neuropathologic findings were analyzed on all autopsied cases from one of the collaborating sites in North America and Europe, were evaluated from January 1990 to March 2012, and were diagnosed with polysomnogram (PSG)-proven or probable RBD with or without a coexisting neurologic disorder. The clinical and neuropathologic diagnoses were based on published criteria.
172 cases were identified, of whom 143 (83%) were men. The mean ± SD age of onset in years for the core features were as follows – RBD, 62 ± 14 (range, 20–93), cognitive impairment (n = 147); 69 ± 10 (range, 22–90), parkinsonism (n = 151); 68 ± 9 (range, 20–92), and autonomic dysfunction (n = 42); 62 ± 12 (range, 23–81). Death age was 75 ± 9 years (range, 24–96). Eighty-two (48%) had RBD confirmed by PSG, 64 (37%) had a classic history of recurrent dream enactment behavior, and 26 (15%) screened positive for RBD by questionnaire. RBD preceded the onset of cognitive impairment, parkinsonism, or autonomic dysfunction in 87 (51%) patients by 10 ± 12 (range, 1–61) years. The primary clinical diagnoses among those with a coexisting neurologic disorder were dementia with Lewy bodies (n = 97), Parkinson’s disease with or without mild cognitive impairment or dementia (n = 32), multiple system atrophy (MSA) (n = 19), Alzheimer’s disease (AD)(n = 9) and other various disorders including secondary narcolepsy (n = 2) and neurodegeneration with brain iron accumulation-type 1 (NBAI-1) (n = 1). The neuropathologic diagnoses were Lewy body disease (LBD)(n = 77, including 1 case with a duplication in the gene encoding α-synuclein), combined LBD and AD (n = 59), MSA (n = 19), AD (n = 6), progressive supranulear palsy (PSP) (n = 2), other mixed neurodegenerative pathologies (n = 6), NBIA-1/LBD/tauopathy (n = 1), and hypothalamic structural lesions (n = 2). Among the neurodegenerative disorders associated with RBD (n = 170), 160 (94%) were synucleinopathies. The RBD-synucleinopathy association was particularly high when RBD preceded the onset of other neurodegenerative syndrome features.
In this large series of PSG-confirmed and probable RBD cases that underwent autopsy, the strong association of RBD with the synucleinopathies was further substantiated and a wider spectrum of disorders which can underlie RBD now are more apparent.
PMCID: PMC3745815  PMID: 23474058
REM sleep behavior disorder; Parasomnia; Lewy body disease; Dementia with Lewy bodies; Parkinson’s disease; Multiple system atrophy; Synuclein; Synucleinopathy
24.  Relationship between delta power and the electrocardiogram-derived cardiopulmonary spectrogram: possible implications for assessing the effectiveness of sleep 
Sleep medicine  2013;15(1):125-131.
The physiologic relationship between slow-wave activity (SWA) (0–4 Hz) on the electroencephalogram (EEG) and high-frequency (0.1–0.4 Hz) cardiopulmonary coupling (CPC) derived from electrocardiogram (ECG) sleep spectrograms is not known. Because high-frequency CPC appears to be a biomarker of stable sleep, we tested the hypothesis that that slow-wave EEG power would show a relatively fixed-time relationship to periods of high-frequency CPC. Furthermore, we speculated that this correlation would be independent of conventional nonrapid eye movement (NREM) sleep stages.
We analyzed selected datasets from an archived polysomnography (PSG) database, the Sleep Heart Health Study I (SHHS-I). We employed the cross-correlation technique to measure the degree of which 2 signals are correlated as a function of a time lag between them. Correlation analyses between high-frequency CPC and delta power (computed both as absolute and normalized values) from 3150 subjects with an apnea-hypopnea index (AHI) of ≤5 events per hour of sleep were performed.
The overall correlation (r) between delta power and high-frequency coupling (HFC) power was 0.40 ± 0.18 (P = .001). Normalized delta power provided improved correlation relative to absolute delta power. Correlations were somewhat reduced in the second half relative to the first half of the night (r = 0.45 ± 0.20 vs r = 0.34 ± 0.23). Correlations were only affected by age in the eighth decade. There were no sex differences and only small racial or ethnic differences were noted.
These results support a tight temporal relationship between slow wave power, both within and outside conventional slow wave sleep periods, and high frequency cardiopulmonary coupling, an ECG-derived biomarker of “stable” sleep. These findings raise mechanistic questions regarding the cross-system integration of neural and cardiopulmonary control during sleep.
PMCID: PMC4114218  PMID: 24269134
Delta power; Sleep spectrogram; High frequency coupling; Correlation; Sleep effectiveness; NREM slow oscillation
25.  Clinical Significance of night-to-night sleep variability in insomnia 
Sleep medicine  2012;13(5):469-475.
Study Objectives
To evaluate the clinical relevance of night-to-night variability of sleep schedules and insomnia symptoms.
The sample consisted of 455 patients (193 men, mean age=48) seeking treatment for insomnia in a sleep medicine clinic. All participants received group cognitive behavioral therapy for insomnia (CBTI). Variability in sleep parameters was assessed using sleep diary data. Two composite scores were computed, a behavioral schedule composite score (BCS) and insomnia symptom composite score (ICS). The Insomnia Severity Index, the Beck Depression Inventory, and the Morningness-Eveningness Composite Scale were administered at baseline and post-treatment.
Results revealed that greater BCS scores were significantly associated with younger age, eveningness chronotype, and greater depression severity (p<.001). Both depression severity and eveningness chronotype independently predicted variability in sleep schedules (p<.001). Finally, CBTI resulted in reduced sleep variability for all sleep diary variables, except bedtime. Post-treatment symptom reductions in depression severity were greater among those with high versus low baseline BCS scores (p<.001).
Results suggest that variability in sleep schedules predict reduction in insomnia and depressive severity following group CBTI. Schedule variability may be particularly important to assess and address among patients with high depression symptoms and those with evening chronotype.
PMCID: PMC4086618  PMID: 22357064
insomnia; sleep variability; depression; chronotype; CBTI; circadian rhythm

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