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1.  Childhood Obstructive Sleep Apnea Associates with Neuropsychological Deficits and Neuronal Brain Injury 
PLoS Medicine  2006;3(8):e301.
Childhood obstructive sleep apnea (OSA) is associated with neuropsychological deficits of memory, learning, and executive function. There is no evidence of neuronal brain injury in children with OSA. We hypothesized that childhood OSA is associated with neuropsychological performance dysfunction, and with neuronal metabolite alterations in the brain, indicative of neuronal injury in areas corresponding to neuropsychological function.
Methods and Findings
We conducted a cross-sectional study of 31 children (19 with OSA and 12 healthy controls, aged 6–16 y) group-matched by age, ethnicity, gender, and socioeconomic status. Participants underwent polysomnography and neuropsychological assessments. Proton magnetic resonance spectroscopic imaging was performed on a subset of children with OSA and on matched controls. Neuropsychological test scores and mean neuronal metabolite ratios of target brain areas were compared.
Relative to controls, children with severe OSA had significant deficits in IQ and executive functions (verbal working memory and verbal fluency). Children with OSA demonstrated decreases of the mean neuronal metabolite ratio N-acetyl aspartate/choline in the left hippocampus (controls: 1.29, standard deviation [SD] 0.21; OSA: 0.91, SD 0.05; p = 0.001) and right frontal cortex (controls: 2.2, SD 0.4; OSA: 1.6, SD 0.4; p = 0.03).
Childhood OSA is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex. We speculate that untreated childhood OSA could permanently alter a developing child's cognitive potential.
Childhood obstructive sleep apnea is associated with deficits of IQ and executive function and also with possible neuronal injury in the hippocampus and frontal cortex.
Editors' Summary
Sleep is essential for health, and in children it is crucial to normal development. Symptomatic childhood sleep-disordered breathing (SDB) is the name for a range of conditions in which children have difficulties with breathing when they are asleep. The conditions range from simple snoring to the most severe condition, known as obstructive sleep apnea (OSA). Apnea means a temporary absence of breathing, and in OSA this is caused by a temporary but repeated blockage of the flow of air to the lungs. In children, OSA occurs for a number of reasons including enlarged tonsils, long-term allergy, and obesity. About two in every hundred children have OSA. The symptoms of OSA are loud snoring at night, disrupted, restless sleep, undue tiredness, and difficulties in concentration. The main test for it is a sleep study (polysomnography). If untreated, researchers believe that it may lead to a number of long-term problems with health and learning; children with disorders of sleep have been shown to have memory problems, lower general intelligence, and worse executive function (the ability to adapt to new situations), and may have behavioral problems similar to those of attention deficit hyperactivity disorder (ADHD).
Why Was This Study Done?
Adults with sleep apnea have been shown to have abnormalities of parts of their brain, specifically the frontal cortex, cerebellum, and hippocampus, but so far there are no data on whether there are similar changes in children. Children with sleep apnea may have cognitive deficits, but the research on this topic is limited.
What Did the Researchers Do and Find?
The researchers wanted to investigate the brains of children with OSA to see if there was any evidence of changes in the brain and if these changes were associated with any learning problems. They studied 31 children (19 with OSA and 12 healthy controls, aged 6–16 y). Participants underwent polysomnography and neuropsychological assessments, such as IQ tests and tests of their ability to perform tasks involving decision making. Some of the children also had specialized scans of their brains (known as proton magnetic resonance spectroscopic imaging) that can measure the levels of certain metabolites—substances that are produced as a result of brain activity. The researchers then compared the neuropsychological test scores with the levels of the metabolites. They found that relative to controls, children with severe OSA had lower IQ and ability to perform tasks involving decision making. Children with OSA also had changes in metabolites in the brain similar to those seen in diseases in which there is damage to brain cells.
What Do These Findings Mean?
It seems clear that OSA in children is associated with learning problems, and that these learning problems may in turn be associated with changes in brain metabolites. The changes in metabolites are not necessarily permanent—in other diseases where changes have been found they can be reversed with treatment. If these results are confirmed in other children with OSA, it will highlight the importance of treating children for OSA as soon as possible. In addition, the measurement of metabolites may be a way of measuring how well children are responding to treatment.
Additional Information.
Please access these Web sites via the online version of this summary at
MedlinePlus's encyclopedia has an entry on sleep apnea
The American Sleep Apnea Association has information about having a child investigated for sleep apnea
The National Sleep Foundation also provides information about sleep disorders
PMCID: PMC1551912  PMID: 16933960
2.  Sleep Dysfunction and Thalamic Abnormalities in Adolescents at Ultra High-Risk for Psychosis 
Schizophrenia research  2013;151(0):10.1016/j.schres.2013.09.015.
Sleep dysfunction is a pervasive, distressing characteristic of psychosis, yet little is known regarding sleep quality prior to illness onset. At present, it is unclear whether sleep dysfunction precedes the emergence of psychotic symptoms, signifying a core feature of the disorder, or if it represents a consequence of prolonged contact with aspects of schizophrenia and its treatment (e.g., medication use or neurotoxicity) or co-morbid symptoms (e.g., depressive and manic symptomatology). The current study examined sleep dysfunction in adolescents at ultra high-risk (UHR) for psychosis, relationships between sleep disturbances and psychosis symptoms, volume of an integral sleep-structure (thalamus), and associations between thalamic abnormalities and sleep impairment in UHR youth.
Thirty-three UHR youth and 33 healthy controls (HC) participated in a self-assessment of sleep functioning (Pittsburgh Sleep Quality Index; PSQI), self and parent-report clinical interviews, and structural magnetic resonance imaging (MRI).
UHR adolescents displayed increased latency to sleep onset and greater sleep disturbances/disrupted continuity compared to HC youth, over and above concurrent mood symptoms. Among UHR youth, increased sleep dysfunction was associated with greater negative symptom severity but not positive symptoms. Compared to HC adolescents, UHR participants displayed decreased bilateral thalamus volume, which was associated with increased sleep dysfunction.
Sleep dysfunction occurs during the pre-psychotic period, and may play a role in the etiology and pathophysiology of psychosis. In addition, the relationship of disrupted sleep to psychosis symptoms in UHR youth indicates that prevention and intervention strategies may be improved by targeting sleep stabilization in the pre-psychotic period.
PMCID: PMC3855888  PMID: 24094679
Schizophrenia; Premorbid; Psychosis; Ultra High-Risk; Prodromal; Sleep Dysfunction
3.  Increased Cerebral Blood Flow Velocity in Children with Mild Sleep-Disordered Breathing 
Pediatrics  2006;118(4):e1100-e1108.
Sleep-disordered breathing describes a spectrum of upper airway obstruction in sleep from simple primary snoring, estimated to affect 10% of preschool children, to the syndrome of obstructive sleep apnea. Emerging evidence has challenged previous assumptions that primary snoring is benign. A recent report identified reduced attention and higher levels of social problems and anxiety/depressive symptoms in snoring children compared with controls. Uncertainty persists regarding clinical thresholds for medical or surgical intervention in sleep-disordered breathing, underlining the need to better understand the pathophysiology of this condition. Adults with sleep-disordered breathing have an increased risk of cerebrovascular disease independent of atherosclerotic risk factors. There has been little focus on cerebrovascular function in children with sleep-disordered breathing, although this would seem an important line of investigation, because studies have identified abnormalities of the systemic vasculature. Raised cerebral blood flow velocities on transcranial Doppler, compatible with raised blood flow and/or vascular narrowing, are associated with neuropsychological deficits in children with sickle cell disease, a condition in which sleep-disordered breathing is common. We hypothesized that there would be cerebral blood flow velocity differences in sleep-disordered breathing children without sickle cell disease that might contribute to the association with neuropsychological deficits.
Thirty-one snoring children aged 3 to 7 years were recruited from adenotonsillectomy waiting lists, and 17 control children were identified through a local Sunday school or as siblings of cases. Children with craniofacial abnormalities, neuromuscular disorders, moderate or severe learning disabilities, chronic respiratory/cardiac conditions, or allergic rhinitis were excluded. Severity of sleep-disordered breathing in snoring children was categorized by attended polysomnography. Weight, height, and head circumference were measured in all of the children. BMI and occipitofrontal circumference z scores were computed. Resting systolic and diastolic blood pressure were obtained. Both sleep-disordered breathing children and the age- and BMI-similar controls were assessed using the Behavior Rating Inventory of Executive Function (BRIEF), Neuropsychological Test Battery for Children (NEPSY) visual attention and visuomotor integration, and IQ assessment (Wechsler Preschool and Primary Scale of Intelligence Version III). Transcranial Doppler was performed using a TL2-64b 2-MHz pulsed Doppler device between 2 PM and 7 PM in all of the patients and the majority of controls while awake. Time-averaged mean of the maximal cerebral blood flow velocities was measured in the left and right middle cerebral artery and the higher used for analysis.
Twenty-one snoring children had an apnea/hypopnea index <5, consistent with mild sleep-disordered breathing below the conventional threshold for surgical intervention. Compared with 17 nonsnoring controls, these children had significantly raised middle cerebral artery blood flow velocities. There was no correlation between cerebral blood flow velocities and BMI or systolic or diastolic blood pressure indices. Exploratory analyses did not reveal any significant associations with apnea/hypopnea index, apnea index, hypopnea index, mean pulse oxygen saturation, lowest pulse oxygen saturation, accumulated time at pulse oxygen saturation <90%, or respiratory arousals when examined in separate bivariate correlations or in aggregate when entered simultaneously. Similarly, there was no significant association between cerebral blood flow velocities and parental estimation of child’s exposure to sleep-disordered breathing. However, it is important to note that whereas the sleep-disordered breathing group did not exhibit significant hypoxia at the time of study, it was unclear to what extent this may have been a feature of their sleep-disordered breathing in the past. IQ measures were in the average range and comparable between groups. Measures of processing speed and visual attention were significantly lower in sleep-disordered breathing children compared with controls, although within the average range. There were similar group differences in parental-reported executive function behavior. Although there were no direct correlations, adjusting for cerebral blood flow velocities eliminated significant group differences between processing speed and visual attention and decreased the significance of differences in Behavior Rating Inventory of Executive Function scores, suggesting that cerebral hemodynamic factors contribute to the relationship between mild sleep-disordered breathing and these outcome measures.
Cerebral blood flow velocities measured by noninvasive transcranial Doppler provide evidence for increased cerebral blood flow and/or vascular narrowing in childhood sleep-disordered breathing; the relationship with neuropsychological deficits requires further exploration. A number of physiologic changes might alter cerebral blood flow and/or vessel diameter and, therefore, affect cerebral blood flow velocities. We were able to explore potential confounding influences of obesity and hypertension, neither of which explained our findings. Second, although cerebral blood flow velocities increase with increasing partial pressure of carbon dioxide and hypoxia, it is unlikely that the observed differences could be accounted for by arterial blood gas tensions, because all of the children in the study were healthy, with no cardiorespiratory disease, other than sleep-disordered breathing in the snoring group. Although arterial partial pressure of oxygen and partial pressure of carbon dioxide were not monitored during cerebral blood flow velocity measurement, assessment was undertaken during the afternoon/early evening when the child was awake, and all of the sleep-disordered breathing children had normal resting oxyhemoglobin saturation at the outset of their subsequent sleep studies that day. Finally, there is an inverse linear relationship between cerebral blood flow and hematocrit in adults, and it is known that iron-deficient erythropoiesis is associated with chronic infection, such as recurrent tonsillitis, a clinical feature of many of the snoring children in the study. Preoperative full blood counts were not performed routinely in these children, and, therefore, it was not possible to exclude anemia as a cause of increased cerebral blood flow velocity in the sleep-disordered breathing group. However, hemoglobin levels were obtained in 4 children, 2 of whom had borderline low levels (10.9 and 10.2 g/dL). Although there was no apparent relationship with cerebral blood flow velocity in these children (cerebral blood flow velocity values of 131 and 130 cm/second compared with 130 and 137 cm/second in the 2 children with normal hemoglobin levels), this requires verification. It is of particular interest that our data suggest a relationship among snoring, increased cerebral blood flow velocities and indices of cognition (processing speed and visual attention) and perhaps behavioral (Behavior Rating Inventory of Executive Function) function. This finding is preliminary: a causal relationship is not established, and the physiologic mechanisms underlying such a relationship are not clear. Prospective studies that quantify cumulative exposure to the physiologic consequences of sleep-disordered breathing, such as hypoxia, would be informative.
PMCID: PMC1995426  PMID: 17015501
sleep disordered breathing; cerebral blood flow; transcranial Doppler; executive function; neuropsychological function
4.  Sleep deprivation amplifies striatal activation to monetary reward 
Psychological medicine  2013;43(10):2215-2225.
Sleep loss produces abnormal increases in reward-seeking, though the mechanisms underlying this phenomenon are poorly understood. The present study examined the influence of one night of sleep deprivation on neural responses to a monetary reward task in a sample of late adolescents/young adults.
Using a within-subjects crossover design, 27 healthy, right-handed late-adolescents/young adults (16 females, 11 males; mean age 23.1 years) completed functional magnetic resonance imaging following a night of sleep deprivation and following a night of normal sleep. Participants’ recent sleep history was monitored using actigraphy for one week prior to each sleep condition.
Following sleep deprivation, participants exhibited increased activity in the ventral striatum and reduced deactivation in medial prefrontal cortex during the winning of monetary reward, relative to the same task following normal sleep conditions. Shorter total sleep time over the five nights before the sleep deprived testing condition was associated with reduced deactivation in the medial prefrontal cortex during reward.
These findings support the hypothesis that sleep loss produces aberrant functioning in reward neural circuitry, increasing the salience of positively-reinforcing stimuli. Aberrant reward functioning related to insufficient sleep may contribute to the development and maintenance of reward dysfunction-related disorders, such as compulsive gambling, eating, substance abuse, and mood disorders.
PMCID: PMC3742668  PMID: 23286303
sleep; sleep deprivation; reward; functional magnetic resonance imaging
5.  Sleep-Disordered Breathing and Mortality: A Prospective Cohort Study 
PLoS Medicine  2009;6(8):e1000132.
In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.
Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older.
Methods and Findings
We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: <5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: ≥30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80–1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleep-disordered breathing showed a pattern of association similar to all-cause mortality.
Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing.
Please see later in the article for the Editors' Summary
Editors' Summary
About 1 in 10 women and 1 in 4 men have a chronic condition called sleep-disordered breathing although most are unaware of their problem. Sleep-disordered breathing, which is commonest in middle-aged and elderly people, is characterized by numerous, brief (10 second or so) interruptions of breathing during sleep. These interruptions, which usually occur when relaxation of the upper airway muscles decreases airflow, lower the level of oxygen in the blood and, as a result, affected individuals are frequently aroused from deep sleep as they struggle to breathe. Symptoms of sleep-disordered breathing include loud snoring and daytime sleepiness. Treatments include lifestyle changes such as losing weight (excess fat around the neck increases airway collapse) and smoking cessation. Affected people can also use special devices to prevent them sleeping on their backs, but for severe sleep-disordered breathing, doctors often recommend continuous positive airway pressure (CPAP), a machine that pressurizes the upper airway through a face mask to keep it open.
Why Was This Study Done?
Sleep-disordered breathing is a serious condition. It is associated with several adverse health conditions including coronary artery disease (narrowing of the blood vessels that supply the heart, a condition that can cause a heart attack) and daytime sleepiness that can affect an individual's driving ability. In addition, several clinic- and community-based studies suggest that sleep-disordered sleeping may increase a person's risk of dying. However, because these studies have been small and have often failed to allow for other conditions and characteristics that affect an individual's risk of dying (“confounding factors”), they provide inconsistent or incomplete information about the potential association between sleep-disordered breathing and the risk of death. In this prospective cohort study (part of the Sleep Heart Health Study, which is researching the effects of sleep-disordered breathing on cardiovascular health), the researchers examine whether sleep-disordered breathing is associated with all-cause mortality (death from any cause) in a large community sample of adults. A prospective cohort study is one in which a group of participants is enrolled and then followed forward in time (in this case for several years) to see what happens to them.
What Did the Researchers Do and Find?
At enrollment, the study participants—more than 6,000 people aged 40 years or older, none of whom were being treated for sleep-disordered breathing—had a health examination. Their night-time breathing, sleep patterns, and blood oxygen levels were also assessed and these data used to calculate each participant's apnea-hypopnea index (AHI)—the number of apneas and hypopneas per hour. During the study follow-up period, 1,047 participants died. Compared to participants without sleep-disordered sleeping, participants with severe sleep-disordered breathing (an AHI of ≥30) were about one and a half times as likely to die from any cause after adjustment for potential confounding factors. People with milder sleep-disordered breathing did not have a statistically significant increased risk of dying. After dividing the participants into subgroups according to their age and sex, men aged 40–70 years with severe sleep-disordered breathing had a statistically increased risk of dying from any cause (twice the risk of men of a similar age without sleep-disordered breathing). Finally, death from coronary artery disease was also associated with sleep-disordered breathing in men but not in women.
What Do These Findings Mean?
These findings indicate that sleep-disordered breathing is associated with an increased risk of all-cause mortality, particularly in men aged 40–70 years, even after allowing for known confounding factors. They also suggest that the increased risk of death is specifically associated with coronary artery disease although further studies are needed to confirm this finding because it was based on the analysis of a small subgroup of study participants. Although this study is much larger than previous investigations into the association between sleep-disordered breathing and all-cause mortality, it has several limitations including its reliance on a single night's measurements for the diagnosis of sleep-disordered breathing. Nevertheless, these findings suggest that clinical trials should now be started to assess whether treatment can reduce the increased risk of death that seems to be associated with this common disorder.
Additional Information
Please access these Web sites via the online version of this summary at
The US National Heart Lung and Blood Institute has information (including a video) about sleep-disordered breathing (sleep apnea) (in English and Spanish)
The UK National Heath Service also provides information for patients about sleep apnea
MedlinePlus provides links to further information and advice about sleep-disordered breathing (in English and Spanish)
More information on the Sleep Heart Health Study is available
PMCID: PMC2722083  PMID: 19688045
6.  Sleep Measured by Polysomnography in Patients Receiving High-Dose Chemotherapy for Multiple Myeloma Prior to Stem Cell Transplantation 
Oncology nursing forum  2013;40(1):73-81.
To describe the objective sleep of patients receiving chemotherapy for multiple myeloma (MM) prior to stem cell transplantation.
A descriptive study with repeated measures.
An international referral center in an urban area of the southern United States.
A convenience sample of a subset of 12 patients with MM, recruited from a randomized, controlled trial.
Objective sleep was assessed using two nights of polysomnography, one obtained before and one after a second cycle of high-dose chemotherapy prior to stem cell transplantation. Demographic and clinical data were obtained through a retrospective chart review.
Main Research Variables
Objective sleep including sleep characteristics, sleep-related respiratory events, and periodic limb movements (PLMs) of sleep.
Sleep was characterized by a relatively short sleep time, excessive time spent awake after the onset of sleep, and poor sleep efficiency (objective sleep quality). Patients spent more than the expected percent of time in non–rapid eye movement sleep and less in rapid eye movement sleep. Arterial oxyhemoglobin saturation nadirs reflected episodes of low arterial oxygen saturation. PLMs during sleep were in the mildly elevated range.
Findings suggest that patients had poor sleep efficiency (objective sleep quality) and were slightly better sleepers after receiving a second cycle of high-dose chemotherapy. A number of patients also demonstrated obstructive sleep apnea and frequent PLMs.
Implications for Nursing
Findings support the need for additional investigation of sleep in patients with MM, particularly poor sleep efficiency and PLMs. Improving sleep may improve quality of life by decreasing associated symptoms such as pain, fatigue, and depression.
Knowledge Translation
Oncology nurses should consider assessing patients with MM for insomnia symptoms, excessive daytime sleepiness, obstructive sleep apnea, and a history of jerking or kicking their legs when asleep. Those symptoms may suggest the need for additional investigation of a possible sleep disorder, which may negatively influence mood and function.
PMCID: PMC4324461  PMID: 23269772
7.  Polysomnography in Patients With Obstructive Sleep Apnea 
Executive Summary
The objective of this health technology policy assessment was to evaluate the clinical utility and cost-effectiveness of sleep studies in Ontario.
Clinical Need: Target Population and Condition
Sleep disorders are common and obstructive sleep apnea (OSA) is the predominant type. Obstructive sleep apnea is the repetitive complete obstruction (apnea) or partial obstruction (hypopnea) of the collapsible part of the upper airway during sleep. The syndrome is associated with excessive daytime sleepiness or chronic fatigue. Several studies have shown that OSA is associated with hypertension, stroke, and other cardiovascular disorders; many researchers believe that these cardiovascular disorders are consequences of OSA. This has generated increasing interest in recent years in sleep studies.
The Technology Being Reviewed
There is no ‘gold standard’ for the diagnosis of OSA, which makes it difficult to calibrate any test for diagnosis. Traditionally, polysomnography (PSG) in an attended setting (sleep laboratory) has been used as a reference standard for the diagnosis of OSA. Polysomnography measures several sleep variables, one of which is the apnea-hypopnea index (AHI) or respiratory disturbance index (RDI). The AHI is defined as the sum of apneas and hypopneas per hour of sleep; apnea is defined as the absence of airflow for ≥ 10 seconds; and hypopnea is defined as reduction in respiratory effort with ≥ 4% oxygen desaturation. The RDI is defined as the sum of apneas, hypopneas, and abnormal respiratory events per hour of sleep. Often the two terms are used interchangeably. The AHI has been widely used to diagnose OSA, although with different cut-off levels, the basis for which are often unclear or arbitrarily determined. Generally, an AHI of more than five events per hour of sleep is considered abnormal and the patient is considered to have a sleep disorder. An abnormal AHI accompanied by excessive daytime sleepiness is the hallmark for OSA diagnosis. For patients diagnosed with OSA, continuous positive airway pressure (CPAP) therapy is the treatment of choice. Polysomnography may also used for titrating CPAP to individual needs.
In January 2005, the College of Physicians and Surgeons of Ontario published the second edition of Independent Health Facilities: Clinical Practice Parameters and Facility Standards: Sleep Medicine, commonly known as “The Sleep Book.” The Sleep Book states that OSA is the most common primary respiratory sleep disorder and a full overnight sleep study is considered the current standard test for individuals in whom OSA is suspected (based on clinical signs and symptoms), particularly if CPAP or surgical therapy is being considered.
Polysomnography in a sleep laboratory is time-consuming and expensive. With the evolution of technology, portable devices have emerged that measure more or less the same sleep variables in sleep laboratories as in the home. Newer CPAP devices also have auto-titration features and can record sleep variables including AHI. These devices, if equally accurate, may reduce the dependency on sleep laboratories for the diagnosis of OSA and the titration of CPAP, and thus may be more cost-effective.
Difficulties arise, however, when trying to assess and compare the diagnostic efficacy of in-home PSG versus in-lab. The AHI measured from portable devices in-home is the sum of apneas and hypopneas per hour of time in bed, rather than of sleep, and the absolute diagnostic efficacy of in-lab PSG is unknown. To compare in-home PSG with in-lab PSG, several researchers have used correlation coefficients or sensitivity and specificity, while others have used Bland-Altman plots or receiver operating characteristics (ROC) curves. All these approaches, however, have potential pitfalls. Correlation coefficients do not measure agreement; sensitivity and specificity are not helpful when the true disease status is unknown; and Bland-Altman plots measure agreement (but are helpful when the range of clinical equivalence is known). Lastly, receiver operating characteristics curves are generated using logistic regression with the true disease status as the dependent variable and test values as the independent variable. Thus, each value of the test is used as a cut-point to measure sensitivity and specificity, which are then plotted on an x-y plane. The cut-point that maximizes both sensitivity and specificity is chosen as the cut-off level to discriminate between disease and no-disease states. In the absence of a gold standard to determine the true disease status, ROC curves are of minimal value.
At the request of the Ontario Health Technology Advisory Committee (OHTAC), MAS has thus reviewed the literature on PSG published over the last two years to examine new developments.
Review Strategy
There is a large body of literature on sleep studies and several reviews have been conducted. Two large cohort studies, the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study, are the main sources of evidence on sleep literature.
To examine new developments on PSG published in the past two years, MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Database of Systematic Reviews and Cochrane CENTRAL, INAHTA, and websites of other health technology assessment agencies were searched. Any study that reported results of in-home or in-lab PSG was included. All articles that reported findings from the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study were also reviewed.
Diffusion of Sleep Laboratories
To estimate the diffusion of sleep laboratories, a list of sleep laboratories licensed under the Independent Health Facility Act was obtained. The annual number of sleep studies per 100,000 individuals in Ontario from 2000 to 2004 was also estimated using administrative databases.
Summary of Findings
Literature Review
A total of 315 articles were identified that were published in the past two years; 227 were excluded after reviewing titles and abstracts. A total of 59 articles were identified that reported findings of the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study.
Based on cross-sectional data from the Wisconsin Sleep Cohort Study of 602 men and women aged 30 to 60 years, it is estimated that the prevalence of sleep-disordered breathing is 9% in women and 24% in men, on the basis of more than five AHI events per hour of sleep. Among the women with sleep disorder breathing, 22.6% had daytime sleepiness and among the men, 15.5% had daytime sleepiness. Based on this, the prevalence of OSA in the middle-aged adult population is estimated to be 2% in women and 4% in men.
Snoring is present in 94% of OSA patients, but not all snorers have OSA. Women report daytime sleepiness less often compared with their male counterparts (of similar age, body mass index [BMI], and AHI). Prevalence of OSA tends to be higher in older age groups compared with younger age groups.
Diagnostic Value of Polysomnography
It is believed that PSG in the sleep laboratory is more accurate than in-home PSG. In the absence of a gold standard, however, claims of accuracy cannot be substantiated. In general, there is poor correlation between PSG variables and clinical variables. A variety of cut-off points of AHI (> 5, > 10, and > 15) are arbitrarily used to diagnose and categorize severity of OSA, though the clinical importance of these cut-off points has not been determined.
Recently, a study of the use of a therapeutic trial of CPAP to diagnose OSA was reported. The authors studied habitual snorers with daytime sleepiness in the absence of other medical or psychiatric disorders. Using PSG as the reference standard, the authors calculated the sensitivity of this test to be 80% and its specificity to be 97%. Further, they concluded that PSG could be avoided in 46% of this population.
Obstructive Sleep Apnea and Obesity
Obstructive sleep apnea is strongly associated with obesity. Obese individuals (BMI >30 kg/m2) are at higher risk for OSA compared with non-obese individuals and up to 75% of OSA patients are obese. It is hypothesized that obese individuals have large deposits of fat in the neck that cause the upper airway to collapse in the supine position during sleep. The observations reported from several studies support the hypothesis that AHIs (or RDIs) are significantly reduced with weight loss in obese individuals.
Obstructive Sleep Apnea and Cardiovascular Diseases
Associations have been shown between OSA and comorbidities such as diabetes mellitus and hypertension, which are known risk factors for myocardial infarction and stroke. Patients with more severe forms of OSA (based on AHI) report poorer quality of life and increased health care utilization compared with patients with milder forms of OSA. From animal models, it is hypothesized that sleep fragmentation results in glucose intolerance and hypertension. There is, however, no evidence from prospective studies in humans to establish a causal link between OSA and hypertension or diabetes mellitus. It is also not clear that the associations between OSA and other diseases are independent of obesity; in most of these studies, patients with higher values of AHI had higher values of BMI compared with patients with lower AHI values.
A recent meta-analysis of bariatric surgery has shown that weight loss in obese individuals (mean BMI = 46.8 kg/m2; range = 32.30–68.80) significantly improved their health profile. Diabetes was resolved in 76.8% of patients, hypertension was resolved in 61.7% of patients, hyperlipidemia improved in 70% of patients, and OSA resolved in 85.7% of patients. This suggests that obesity leads to OSA, diabetes, and hypertension, rather than OSA independently causing diabetes and hypertension.
Health Technology Assessments, Guidelines, and Recommendations
In April 2005, the Centers for Medicare and Medicaid Services (CMS) in the United States published its decision and review regarding in-home and in-lab sleep studies for the diagnosis and treatment of OSA with CPAP. In order to cover CPAP, CMS requires that a diagnosis of OSA be established using PSG in a sleep laboratory. After reviewing the literature, CMS concluded that the evidence was not adequate to determine that unattended portable sleep study was reasonable and necessary in the diagnosis of OSA.
In May 2005, the Canadian Coordinating Office of Health Technology Assessment (CCOHTA) published a review of guidelines for referral of patients to sleep laboratories. The review included 37 guidelines and associated reviews that covered 18 applications of sleep laboratory studies. The CCOHTA reported that the level of evidence for many applications was of limited quality, that some cited studies were not relevant to the recommendations made, that many recommendations reflect consensus positions only, and that there was a need for more good quality studies of many sleep laboratory applications.
As of the time of writing, there are 97 licensed sleep laboratories in Ontario. In 2000, the number of sleep studies performed in Ontario was 376/100,000 people. There was a steady rise in sleep studies in the following years such that in 2004, 769 sleep studies per 100,000 people were performed, for a total of 96,134 sleep studies. Based on prevalence estimates of the Wisconsin Sleep Cohort Study, it was estimated that 927,105 people aged 30 to 60 years have sleep-disordered breathing. Thus, there may be a 10-fold rise in the rate of sleep tests in the next few years.
Economic Analysis
In 2004, approximately 96,000 sleep studies were conducted in Ontario at a total cost of ~$47 million (Cdn). Since obesity is associated with sleep disordered breathing, MAS compared the costs of sleep studies to the cost of bariatric surgery. The cost of bariatric surgery is $17,350 per patient. In 2004, Ontario spent $4.7 million per year for 270 patients to undergo bariatric surgery in the province, and $8.2 million for 225 patients to seek out-of-country treatment. Using a Markov model, it was concluded that shifting costs from sleep studies to bariatric surgery would benefit more patients with OSA and may also prevent health consequences related to diabetes, hypertension, and hyperlipidemia. It is estimated that the annual cost of treating comorbid conditions in morbidly obese patients often exceeds $10,000 per patient. Thus, the downstream cost savings could be substantial.
Considerations for Policy Development
Weight loss is associated with a decrease in OSA severity. Treating and preventing obesity would also substantially reduce the economic burden associated with diabetes, hypertension, hyperlipidemia, and OSA. Promotion of healthy weights may be achieved by a multisectorial approach as recommended by the Chief Medical Officer of Health for Ontario. Bariatric surgery has the potential to help morbidly obese individuals (BMI > 35 kg/m2 with an accompanying comorbid condition, or BMI > 40 kg/m2) lose weight. In January 2005, MAS completed an assessment of bariatric surgery, based on which OHTAC recommended an improvement in access to these surgeries for morbidly obese patients in Ontario.
Habitual snorers with excessive daytime sleepiness have a high pretest probability of having OSA. These patients could be offered a therapeutic trial of CPAP to diagnose OSA, rather than a PSG. A majority of these patients are also obese and may benefit from weight loss. Individualized weight loss programs should, therefore, be offered and patients who are morbidly obese should be offered bariatric surgery.
That said, and in view of the still evolving understanding of the causes, consequences and optimal treatment of OSA, further research is warranted to identify which patients should be screened for OSA.
PMCID: PMC3379160  PMID: 23074483
8.  Effects of exercise and diet interventions on obesity-related sleep disorders in men: study protocol for a randomized controlled trial 
Trials  2013;14:235.
Sleep is essential for normal and healthy living. Lack of good quality sleep affects physical, mental and emotional functions. Currently, the treatments of obesity-related sleep disorders focus more on suppressing sleep-related symptoms pharmaceutically and are often accompanied by side effects. Thus, there is urgent need for alternative ways to combat chronic sleep disorders. This study will investigate underlying mechanisms of the effects of exercise and diet intervention on obesity-related sleep disorders, the role of gut microbiota in relation to poor quality of sleep and day-time sleepiness, as well as the levels of hormones responsible for sleep-wake cycle regulation.
Participants consist of 330 (target sample) Finnish men aged 30 to 65 years. Among them, we attempt to randomize 180 (target sample) with sleep disorders into exercise and diet intervention. After screening and physician examination, 101 men with sleep disorders are included and are randomly assigned into three groups: exercise (n = 33), diet (n = 35), and control (n = 33). In addition, we attempt to recruit a target number of 150 healthy men without sleep disorders as the reference group. The exercise group undergoes a six-month individualized progressive aerobic exercise program based on initial fitness level. The diet group follows a six month specific individualized diet program. The control group and reference group are asked to maintain their normal activity and diet during intervention. Measurements are taken before and after the intervention. Primary outcomes include objective sleep measurements by polysomnography and a home-based non-contact sleep monitoring system, and subjective sleep evaluation by questionnaires. Secondary outcome measures include anthropometry, body composition, fitness, sleep disorder-related lifestyle risk factors, composition of gut microbiota and adipose tissue metabolism, as well as specific hormone and neurotranmitter levels and inflammatory biomarkers from venous blood samples.
It is expected that the improvement of sleep quality after exercise and diet intervention will be evident both in subjective and objective measures of quality of sleep. Additionally, the change of sleep quality induced by exercise and diet intervention is expected to be related to the changes in specific hormones and inflammatory biomarkers, and in the composition of gut microbiota.
Trial registration
Current Controlled Trials ISRCTN77172005
PMCID: PMC3750567  PMID: 23886347
Lifestyle intervention; Sleep disorders; Quality of sleep; Obstructive sleep apnea; Insomnia; Sleep measurement; Obesity; Gut microbiota; Neurotransmitters
9.  Prevalence of Sleep Deficiency in Early Gestation and its Associations with Stress and Depressive Symptoms 
Journal of Women's Health  2013;22(12):1028-1037.
Sleep deficiency is an emerging concept denoting a deficit in the quantity or quality of sleep. This may be particularly salient for pregnant women since they report considerable sleep complaints. Sleep deficiency is linked with morbidity, including degradations in psychosocial functioning, (e.g., depression and stress), which are recognized risk factors for adverse pregnancy outcomes. We sought to describe the frequency of sleep deficiency across early gestation (10–20 weeks) and whether sleep deficiency is associated with reports of more depressive symptoms and stress.
Pregnant women (N=160) with no self-reported sleep or psychological disorder provided sleep data collected via diary and actigraphy during early pregnancy: 10–12, 14–16, and 18–20 weeks' gestation. Sleep deficiency was defined as short sleep duration, insufficient sleep, or insomnia. Symptoms of depression and stress were collected at the same three time points. Linear mixed effects models were used to analyze the data.
Approximately 28%–38% met criteria for sleep deficiency for at least one time point in early gestation. Women who were sleep deficient across all time points reported more perceived stress than those who were not sleep deficient (p<0.01). Depressive symptoms were higher among women with diary-defined sleep deficiency across all time points (p=0.02).
Sleep deficiency is a useful concept to describe sleep recognized to be disturbed in pregnancy. Women with persistent sleep deficiency appear to be at greater risk for impairments in psychosocial functioning during early gestation. These associations are important since psychosocial functioning is a recognized correlate of adverse pregnancy outcomes. Sleep deficiency may be another important risk factor for adverse pregnancy outcomes.
PMCID: PMC3852611  PMID: 24117003
10.  Chronic Sleep Disturbances and Borderline Personality Disorder Symptoms 
Few studies have examined the experience of chronic sleep disturbances in those with borderline personality disorder (BPD), and further establishing this association may be pertinent to enhancing current treatments, given the relevance of sleep on emotion regulation and stress management.
Data were analyzed (N=5,692) from the National Comorbidity Survey – Replication Part II sample (NCS-R; Kessler & Merikangas, 2004), which assessed personality disorders and sleep problems. Rates of chronic sleep disturbances (difficulty initiating sleep, difficulty maintaining sleep, and waking earlier than desired), as well as the consequences of poor sleep, were examined. Indices for BPD diagnosis and symptoms were used in logistic and linear regression analyses to predict sleep and associated problems after accounting for chronic health problems, Axis I comorbidity, suicidal ideation over the last year, and key sociodemographic variables.
BPD was significantly associated with all three chronic sleep problems assessed, as well as with the consequences of poor sleep. The magnitude of the association between BPD and sleep problems was comparable to Axis I disorders traditionally associated with sleep problems. BPD symptoms interacted with chronic sleep problems to predict elevated social/emotional, cognitive, and self-care impairment.
Sleep disturbances are consistently associated with BPD symptoms, as are the daytime consequences of poor sleep. There may also be a synergistic effect where BPD symptoms are aggravated by poor sleep and lead to higher levels of functional impairment. Sleep in patients with BPD should be routinely assessed, and ameliorating chronic sleep problems may enhance treatment by improving emotion regulation and implementation of therapeutic skills.
PMCID: PMC4129646  PMID: 23731205
borderline personality disorder; insomnia; fatigue; sleep; emotion dysregulation
11.  New neurons in the adult brain: The role of sleep and consequences of sleep loss 
Sleep medicine reviews  2008;13(3):187-194.
Research over the last few decades has firmly established that new neurons are generated in selected areas of the adult mammalian brain, particularly the dentate gyrus of the hippocampal formation and the subventricular zone of the lateral ventricles. The function of adult-born neurons is still a matter of debate. In the case of the hippocampus, integration of new cells in to the existing neuronal circuitry may be involved in memory processes and the regulation of emotionality. In recent years, various studies have examined how the production of new cells and their development into neurons is affected by sleep and sleep loss. While disruption of sleep for a period shorter than one day appears to have little effect on the basal rate of cell proliferation, prolonged restriction or disruption of sleep may have cumulative effects leading to a major decrease in hippocampal cell proliferation, cell survival and neurogenesis. Importantly, while short sleep deprivation may not affect the basal rate of cell proliferation, one study in rats shows that even mild sleep restriction may interfere with the increase in neurogenesis that normally occurs with hippocampus-dependent learning. Since sleep deprivation also disturbs memory formation, these data suggest that promoting survival, maturation and integration of new cells may be an unexplored mechanism by which sleep supports learning and memory processes. Most methods of sleep deprivation that have been employed affect both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Available data favor the hypothesis that decreases in cell proliferation are related to a reduction in REM sleep, whereas decreases in the number of cells that subsequently develop into adult neurons may be related to reductions in both NREM and REM sleep. The mechanisms by which sleep loss affects different aspects of adult neurogenesis are unknown. It has been proposed that adverse effects of sleep disruption may be mediated by stress and glucocorticoids. However, a number of studies clearly show that prolonged sleep loss can inhibit hippocampal neurogenesis independent of adrenal stress hormones. In conclusion, while modest sleep restriction may interfere with the enhancement of neurogenesis associated with learning processes, prolonged sleep disruption may even affect the basal rates of cell proliferation and neurogenesis. These effects of sleep loss may endanger hippocampal integrity, thereby leading to cognitive dysfunction and contributing to the development of mood disorders.
PMCID: PMC2771197  PMID: 18848476
Adult neurogenesis; Cell proliferation; Circadian rhythms; Sleep deprivation; Sleep restriction; Sleep disturbance; Insomnia; Stress; Glucocorticoids; Depression; Learning and memory; Hippocampus
12.  A further evaluation of the cognitive deficits associated with restless legs syndrome (RLS) 
Sleep medicine  2007;9(5):500-505.
Background and purpose
Restless legs syndrome (RLS) is a common sensorimotor disorder that peaks in severity during the night and comes on with rest. As a result, this condition often results in significant chronic sleep loss, especially for those with severe disease. Chronic partial sleep restriction has been associated with conditions such as depression, anxiety, chronic pain, and decline in cognitive function. Furthermore, studies have found that RLS patients suffer from these conditions more than their unaffected peers. Thus, the morbidity rate associated with RLS has often been attributed to the chronic sleep loss that frequently accompanies this condition. However, no study has specifically compared RLS sufferers to otherwise normal sleep-restricted controls in order to assess disease morbidity independent of its sleep deprivation effects. In this study, we compared the cognitive function of RLS patients who were off treatment to sleep-restricted control subjects.
Subjects and Methods
A novel chronic partial sleep-restriction protocol that utilized a 14-day combined inpatient and outpatient design was implemented in order to test the differences in cognitive functioning between RLS patients and sleep-restricted controls. The brief cognitive battery included instruments assessing general intelligence and global executive function in order to control for baseline cognitive function between the groups, and then the effects of sleep loss were assessed using prefrontal lobe–specific tasks. The final sample consisted of 16 RLS (11 male and 5 female) and 13 sleep-restricted control subjects (7 male and 6 female).
In order to examine the differences in cognitive functioning between sleep-restricted controls and RLS subjects, independent samples t-tests were conducted. RLS subjects performed significantly better on both the Letter Fluency (t = 2.13, p < .05) and Category Fluency (t = 2.42, p < .05) than sleep-restricted controls.
RLS subjects performed better than the sleep-restricted controls on two tasks that are particularly sensitive to sleep loss. Although previous studies suggest that sleep deprivation may impact the cognitive function of those with RLS, our data suggests that RLS subjects may show a relative degree of sleep loss adaptation. Future investigations that more closely match the sleep loss pattern of RLS subjects to controls are warranted in order to explore these potential traits further.
PMCID: PMC2532669  PMID: 17869573
Restless legs syndrome; Cognition; Sleep deprivation; Chronic sleep restriction; Polysomnogram; Pre-frontal cortex; Verbal fluency test; Trail-making test
13.  Marital quality and the marital bed: Examining the covariation between relationship quality and sleep 
Sleep medicine reviews  2007;11(5):389-404.
The majority of adults sleep with a partner, and for a significant proportion of couples, sleep problems and relationship problems co-occur, yet there has been little systematic study of the association between close relationships and sleep. The association between sleep and relationships is likely to be bi-directional and reciprocal—the quality of close relationships influences sleep and sleep disturbances or sleep disorders influence close relationship quality. Therefore, the purpose of the present review is to summarize the extant research on 1) the impact of co-sleeping on bed partner's sleep; 2) the impact of sleep disturbance or sleep disorders on relationship functioning; and 3) the impact of close personal relationship quality on sleep. In addition, we provide a conceptual model of biopsychosocial pathways to account for the covariation between relationship functioning and sleep. Recognizing the dyadic nature of sleep and incorporating such knowledge into both clinical practice and research in sleep medicine may elucidate key mechanisms in the etiology and maintenance of both sleep disorders and relationship problems and may ultimately inform novel treatments.
PMCID: PMC2644899  PMID: 17854738
Marital quality; close relationships; sleep; sleep disorders
14.  Sleep and cognitive problems in patients with attention-deficit hyperactivity disorder 
Attention-deficit hyperactivity disorder (ADHD) is characterized by inattentive and impulsive behavior. Many ADHD patients reportedly have cognitive dysfunction and sleep problems, including longer sleep latency, lower sleep efficiency, and shorter total sleep time. The purpose of this study was to examine neurocognitive functions and nocturnal sleep parameters in patients with ADHD, using a cognitive function test and actigraphy.
Subjects included 37 male patients with ADHD and 32 controls (7–12 years of age). For each participant, we determined intelligence quotient (IQ) and administered the Matching Familiar Figures Test (MFFT) and 72-hour actigraphy. The relationships between sleep parameters and cognitive functions were assessed.
ADHD patients significantly differed from controls in several cognitive functions and sleep variables. In the MFFT, response error rate (P<0.001) and error counts (P=0.003) were significantly increased in ADHD patients compared with control children. MFFT response latency was significantly shorter in ADHD patients than in controls (P<0.001). In addition, sleep latency (P=0.01), wake after sleep onset (WASO) (P<0.001), and fragmentation index (P<0.001) were evaluated by actigraphy and found to be significantly increased in patients with ADHD compared with controls. However, no significant differences in total sleep time or sleep efficiency were observed. WASO and response error rates were positively correlated in patients with ADHD (rho =0.52, P=0.012). Furthermore, fragmentation index sleep variables were significantly positively correlated with response error (rho =0.44, P=0.008) and response latency rates (rho =0.4, P=0.018) in the MFFT. Reaction error rate was significantly associated with the fragmentation index (beta =0.94, P=0.024).
Patients with ADHD had more sleep problems, including significantly increased sleep latency, WASO, and fragmentation index, and poorer cognitive function, compared with controls. Some of these sleep problems, including WASO and the fragmentation index, were positively correlated with impulsivity, illustrated by the cognitive function tests in patients with ADHD. However, further studies with large sample sizes and the addition of polysomnography and determination of ADHD subtypes should be performed to confirm our results regarding sleep and cognitive problems in patients with ADHD.
PMCID: PMC4172104  PMID: 25258537
ADHD; sleep problems; actigraphy; MFFT
15.  The Underlying Interactome of Childhood Obesity: The Potential Role of Sleep 
Childhood Obesity  2012;8(1):38-42.
Fine-tuning and integration between social rhythms and biological rhythms should be a priority for all, especially for children. As such, the opportunity to sleep should fit the evolving needs for sleep in a child. Unfortunately, children today are highly unlikely to obtain sufficient sleep or live under stable and regular schedules. Poor or dysregulated sleep affects the regulation of homeostatic and hormonal systems underlying somatic and intellectual growth, maturation, and bioenergetics. Therefore, in the prevention and management of childhood obesity, assessments of the “obesogenic” lifestyle, such as dietary and physical activity patterns, need to be coupled with accurate evaluation of the quality and quantity of sleep and with the potential co-existence of sleep-disordered breathing or other sleep disorders. Incorporation of sleep as an integral component of many childhood research studies on obesity should be done a priori rather than as an afterthought. Although parents and health professionals have meticulously delineated, observed, and quantified normal patterns of activities such as eating or playing, the absence of reliable sleep health data in children is all the more puzzling considering that young children engage in sleeping activities more than in any other activity during the 24-hour cycle. Therefore, the most forgotten, overlooked, or even actively ignored behavior of this century is undoubtedly childhood sleep. Trends aiming to reduce sleep in children have emerged, and regrettably continue to gain momentum. In parallel with such undesirable consequences, leading to the blatant disregard of sleep as a vital function rather than a commodity, a reciprocal increase in obesity rates has emerged. The mechanistic links between sleep and metabolism are now emerging, and should prompt incorporation of measures aiming to align sleep with any other antiobesity campaign. To paraphrase a well-known dictum “Somni sano in corpore sano” (healthy sleep in healthy bodies).
PMCID: PMC3647589  PMID: 22799478
16.  The effects of deep brain stimulation on sleep in Parkinson’s disease 
Sleep dysfunction is a common nonmotor symptom experienced by patients with Parkinson’s disease (PD). Symptoms, including excessive daytime sleepiness, sleep fragmentation, rapid eye movement (REM) sleep behavior disorder and others, can significantly affect quality of life and daytime functioning in these patients. Recent studies have evaluated the effects of deep brain stimulation (DBS) at various targets on sleep in patients with advanced PD. Several of these studies have provided evidence that subthalamic nucleus DBS improves subjective and objective measures of sleep, including sleep efficiency, nocturnal mobility, and wake after sleep onset (minutes spent awake after initial sleep onset). Although fewer studies have investigated the effects of bilateral internal globus pallidus and thalamic ventral intermedius DBS on sleep, pallidal stimulation does appear to improve subjective sleep quality. Stimulation of the pedunculopontine nucleus has recently been proposed for selected patients with advanced PD to treat severe gait and postural dysfunction. Owing to the role of the pedunculopontine nucleus in modulating behavioral state, the impact of stimulation at this target on sleep has also been evaluated in a small number of patients, showing that pedunculopontine nucleus DBS increases REM sleep. In this review, we discuss the effects of stimulation at these various targets on sleep in patients with PD. Studying the effects of DBS on sleep can enhance our understanding of the pathophysiology of sleep disorders, provide strategies for optimizing clinical benefit from DBS, and may eventually guide novel therapies for sleep dysfunction.
PMCID: PMC3036959  PMID: 21339905
deep brain stimulation; globus pallidus; Parkinson’s disease; pedunculopontine nucleus; sleep; subthalamic nucleus; ventral intermediate nucleus of the thalamus
17.  Modifiable Factors Associated with Sleep Dysfunction in Adults with Heart Failure 
Sleep dysfunction contributes to poor quality of life in adults with heart failure (HF). The purpose of this study was to identify factors associated with sleep dysfunction that may be modifiable.
Data were collected from 266 subjects enrolled from three sites in the U.S. Sleep dysfunction was measured over the past month with the Pittsburgh Sleep Quality Index, using a score >10 to indicate sleep dysfunction. Potentially modifiable clinical, behavioral, and psychological factors thought to be associated with sleep dysfunction were analyzed with hierarchical logistic regression analysis.
When covariates of age, gender, race, data collection site, and New York Heart Association (NYHA) functional class were entered on the first step, only NYHA was a significant correlate of sleep dysfunction. When the clinical, behavioral, and psychological factors were entered, correlates of sleep dysfunction were the number of drugs known to cause daytime somnolence (OR = 2.08), depression (OR = 1.83), worse overall perceived health (OR = 1.64), and better sleep hygiene (OR = 1.40). Although most (54%) subjects had sleep disordered breathing (SDB), SDB was not a significant predictor of sleep dysfunction.
Factors associated with sleep dysfunction in HF include medications with sleepiness as a side-effect, depression, poorer health perceptions, and better sleep hygiene. Sleep dysfunction may motivate HF patients to address sleep hygiene. Eliminating medications with sleepiness as a side-effect, treating depression and perceptions of poor health may improve sleep quality in HF patients.
PMCID: PMC3106140  PMID: 21353642
heart failure; sleep; sleep dysfunction; perceived health; medications; sleep hygiene; depression
18.  Associations between Circadian Activity Rhythms and Functional Brain Abnormalities among Euthymic Bipolar Patients: A Preliminary Study 
Journal of affective disorders  2014;164:101-106.
Working memory and underlying functional brain deficits have been observed in euthymic bipolar disorder (BD) patients, though there is heterogeneity in the degree of deficits. Sleep/circadian rhythm abnormalities are thought to be a core component of BD and may explain some of the heterogeneity in functional abnormalities. This preliminary study examined associations between sleep/circadian rhythm abnormalities and functional magnetic resonance imaging (fMRI) brain response on a working memory task among BD patients.
Fourteen euthymic medicated BD patients wore an actigraph for seven days before undergoing fMRI with a working memory task. Two matched healthy comparison (HC) groups were used (14 in each sample). One group completed the actigraphy portion and one completed the fMRI portion of the study. Circadian activity rhythm and sleep variables were calculated and compared between BD and HC participants. Variables that significantly differed were used to examine the association between activity rhythms/sleep abnormalities and fMRI working memory brain response in anatomically defined regions.
Sleep efficiency and the rhythm robustness, mesor, and amplitude-to-width ratio were significantly abnormal in BD patients. Individual variability in all the sleep/circadian variables was significantly associated with the degree of abnormality of brain response in the dorsolateral prefrontal cortex and supramarginal gyri.
Small sample size and multiple comparison groups limit the interpretability of these findings.
BD patients have abnormal activity rhythms and sleep efficiency, which are associated with abnormal working memory brain response. These preliminary findings support the notion that the sleep/circadian system is important in the functional brain deficits among BD patients.
PMCID: PMC4079506  PMID: 24856561
Bipolar Disorder; Euthymic; Sleep; Circadian Rhythms; Working Memory; Functional Magnetic Resonance Imaging
19.  Melatonin for sleep problems in children with neurodevelopmental disorders: randomised double masked placebo controlled trial 
Objective To assess the effectiveness and safety of melatonin in treating severe sleep problems in children with neurodevelopmental disorders.
Design 12 week double masked randomised placebo controlled phase III trial.
Setting 19 hospitals across England and Wales.
Participants 146 children aged 3 years to 15 years 8 months were randomised. They had a range of neurological and developmental disorders and a severe sleep problem that had not responded to a standardised sleep behaviour advice booklet provided to parents four to six weeks before randomisation. A sleep problem was defined as the child not falling asleep within one hour of lights out or having less than six hours’ continuous sleep.
Interventions Immediate release melatonin or matching placebo capsules administered 45 minutes before the child’s bedtime for a period of 12 weeks. All children started with a 0.5 mg capsule, which was increased through 2 mg, 6 mg, and 12 mg depending on their response to treatment.
Main outcome measures Total sleep time at night after 12 weeks adjusted for baseline recorded in sleep diaries completed by the parent. Secondary outcomes included sleep onset latency, assessments of child behaviour, family functioning, and adverse events. Sleep was measured with diaries and actigraphy.
Results Melatonin increased total sleep time by 22.4 minutes (95% confidence interval 0.5 to 44.3 minutes) measured by sleep diaries (n=110) and 13.3 (−15.5 to 42.2) measured by actigraphy (n=59). Melatonin reduced sleep onset latency measured by sleep diaries (−37.5 minutes, −55.3 to −19.7 minutes) and actigraphy (−45.3 minutes, −68.8 to −21.9 minutes) and was most effective for children with the longest sleep latency (P=0.009). Melatonin was associated with earlier waking times than placebo (29.9 minutes, 13.6 to 46.3 minutes). Child behaviour and family functioning outcomes showed some improvement and favoured use of melatonin. Adverse events were mild and similar between the two groups.
Conclusions Children gained little additional sleep on melatonin; though they fell asleep significantly faster, waking times became earlier. Child behaviour and family functioning outcomes did not significantly improve. Melatonin was tolerable over this three month period. Comparisons with slow release melatonin preparations or melatonin analogues are required.
Trial registration ISRCT No 05534585.
PMCID: PMC3489506  PMID: 23129488
20.  Sleep problems and functional disability in children with functional gastrointestinal disorders: An examination of the potential mediating effects of physical and emotional symptoms 
BMC Gastroenterology  2012;12:142.
Sleep disturbances are increasingly recognized as a common problem for children and adolescents with chronic pain conditions, but little is known about the prevalence, type, and impact of sleep problems in pediatric functional gastrointestinal disorders (FGIDs). The objectives of the current study were two-fold: 1) to describe the pattern of sleep disturbances reported in a large sample of children and adolescents with FGIDs; and, 2) to explore the impact of sleep by examining the inter-relationships between sleep disturbance, physical symptoms, emotional problems, and functional disability in this population.
Over a 3-year period, 283 children aged 8–17 years who were diagnosed with an FGID and a primary caretaker independently completed questionnaires regarding sleep, emotional functioning, physical symptoms, and functional disability during an initial evaluation for chronic abdominal pain at a pediatric tertiary care center. A verbal review of systems also was collected at that time. Descriptive statistics were used to characterize the pattern of sleep disturbances reported, while structural equation modeling (SEM) was employed to test theorized meditational relationships between sleep and functional disability through physical and emotional symptoms.
Clinically significant elevations in sleep problems were found in 45% of the sample, with difficulties related to sleep onset and maintenance being most common. No difference was seen by specific FGID or by sex, although adolescents were more likely to have sleep onset issues than younger children. Sleep problems were positively associated with functional disability and physical symptoms fully mediated this relationship. Emotional symptoms, while associated with sleep problems, evidenced no direct link to functional disability.
Sleep problems are common in pediatric FGIDs and are associated with functional disability through their impact on physical symptoms. Treatments targeting sleep are likely to be beneficial in improving physical symptoms and, ultimately, daily function in pediatric FGIDs.
PMCID: PMC3527282  PMID: 23067390
Sleep; Functional disability; Functional gastrointestinal disorders; Pediatrics
21.  Intrinsic connectivity network mapping in young children during natural sleep 
NeuroImage  2013;83:10.1016/j.neuroimage.2013.05.020.
Structural and functional neuroimaging have substantively informed the pathophysiology of numerous adult neurological and psychiatric disorders. While structural neuroimaging is readily acquired in sedated young children, pediatric application of functional neuroimaging has been limited by the behavioral demands of in-scanner task performance. Here, we investigated whether functional magnetic resonance imaging (fMRI) acquired during natural sleep and without experimental stimulation offers a viable strategy for studying young children. We targeted the lengthy epoch of non-Rapid Eye Movement, stage 3 (NREM3) sleep typically observed at sleep onset in sleep-deprived children. Seven healthy, preschool-aged children (24-58 months) were studied, acquiring fMRI measurements of cerebral blood flow (CBF) and of intrinsic connectivity networks (ICNs), with concurrent sleep-stage monitoring. ICN data (T2* fMRI) were reliably obtained during NREM3 sleep; CBF data (arterial spin labeled fMRI) were not reliably obtained, as scanner noises disrupted sleep. Applying independent components analysis (ICA) to T2* data, distinct ICNs were observed which corresponded closely with those reported in the adult literature. Notably, a network associated with orthography in adults was not observed, suggesting that ICNs exhibit a developmental trajectory. We conclude that resting-state fMRI obtained in sleep is a promising paradigm for neurophysiological investigations of young children.
PMCID: PMC3815484  PMID: 23727317
Magnetic Resonance Imaging; Intrinsic Connectivity Network; Sleep; pediatric; biomarker
22.  Diversity and Noise Effects in a Model of Homeostatic Regulation of the Sleep-Wake Cycle 
PLoS Computational Biology  2012;8(8):e1002650.
Recent advances in sleep neurobiology have allowed development of physiologically based mathematical models of sleep regulation that account for the neuronal dynamics responsible for the regulation of sleep-wake cycles and allow detailed examination of the underlying mechanisms. Neuronal systems in general, and those involved in sleep regulation in particular, are noisy and heterogeneous by their nature. It has been shown in various systems that certain levels of noise and diversity can significantly improve signal encoding. However, these phenomena, especially the effects of diversity, are rarely considered in the models of sleep regulation. The present paper is focused on a neuron-based physiologically motivated model of sleep-wake cycles that proposes a novel mechanism of the homeostatic regulation of sleep based on the dynamics of a wake-promoting neuropeptide orexin. Here this model is generalized by the introduction of intrinsic diversity and noise in the orexin-producing neurons, in order to study the effect of their presence on the sleep-wake cycle. A simple quantitative measure of the quality of a sleep-wake cycle is introduced and used to systematically study the generalized model for different levels of noise and diversity. The model is shown to exhibit a clear diversity-induced resonance: that is, the best wake-sleep cycle turns out to correspond to an intermediate level of diversity at the synapses of the orexin-producing neurons. On the other hand, only a mild evidence of stochastic resonance is found, when the level of noise is varied. These results show that disorder, especially in the form of quenched diversity, can be a key-element for an efficient or optimal functioning of the homeostatic regulation of the sleep-wake cycle. Furthermore, this study provides an example of a constructive role of diversity in a neuronal system that can be extended beyond the system studied here.
Author Summary
All biological systems are inherently noisy and heterogeneous. Disorder is mostly expected to disturb proper functioning of a system, like it can be the case with noise in a radio signal. However, it has been demonstrated by numerous studies that noise can actually improve signal encoding – the so-called stochastic resonance phenomenon. Recently, it was discovered that quenched diversity (heterogeneity) can also enhance the response of a system to an external perturbation (diversity-induced resonance). In this study we investigate the role of noise and diversity in a neuronal model of sleep-wake cycles based on the dynamics of the wake-promoting orexin neurons that is crucial for stability of wake and sleep states. We demonstrate that suitable levels of diversity introduced in the orexin neurons can significantly improve the quality of the sleep-wake cycle, and may be essential for proper sleep-wake periodicity. Noise, on the other hand, provides only a mild improvement.
PMCID: PMC3426568  PMID: 22927806
23.  Effect of lisdexamfetamine dimesylate on sleep in adults with attention-deficit/hyperactivity disorder 
Sleep problems are common in adults with attention-deficit/hyperactivity disorder (ADHD). This analysis aimed to evaluate the impact of lisdexamfetamine dimesylate (LDX) on sleep quality in adults with ADHD.
This 4-week, phase 3, double-blind, forced-dose escalation study of adults aged 18 to 55 years with ADHD randomized participants to receive placebo (n = 62), or 30 (n = 119), 50 (n = 117), or 70 (n = 122) mg/d LDX, taken once a day in the morning. The self-rated Pittsburgh Sleep Quality Index (PSQI) was administered at baseline and at week 4 to assess sleep quality. The PSQI global score assesses 7 sleep components (subjective sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbances, use of sleeping medications, and daytime dysfunction) each scored from 0 (no difficulty) to 3 (severe difficulty).
The mean baseline PSQI global score was 5.8 for LDX and 6.3 for placebo (P = .19) indicating poor overall sleep quality. At endpoint, least squares (LS) mean change from baseline was -0.8 for LDX vs -0.5 for placebo (P = .33). The daytime functioning component showed significant improvement in LS mean change at endpoint for LDX compared with placebo (LDX -0.4 vs placebo 0.0, P = .0001). LS mean changes for the other 6 PSQI components did not significantly differ from placebo. Sleep-related treatment-emergent adverse events with an incidence ≥2% in the active treatment and placebo groups, respectively, were insomnia (19.3% and 4.8%), initial insomnia (5.0% and 3.2%), middle insomnia (3.6% and 0%), sleep disorder (0.6% and 3.2%), somnolence (0.3% and 3.2%), and fatigue (4.7% and 4.8%), and were generally mild or moderate in severity.
For most subjects, LDX was not associated with an overall worsening of sleep quality and significantly improved daytime functioning in adults with ADHD.
Trial Registration Identifier: NCT00334880
PMCID: PMC2732626  PMID: 19650932
24.  Electrophysiological correlates of behavioural changes in vigilance in vegetative state and minimally conscious state 
Brain  2011;134(8):2222-2232.
The existence of normal sleep in patients in a vegetative state is still a matter of debate. Previous electrophysiological sleep studies in patients with disorders of consciousness did not differentiate patients in a vegetative state from patients in a minimally conscious state. Using high-density electroencephalographic sleep recordings, 11 patients with disorders of consciousness (six in a minimally conscious state, five in a vegetative state) were studied to correlate the electrophysiological changes associated with sleep to behavioural changes in vigilance (sustained eye closure and muscle inactivity). All minimally conscious patients showed clear electroencephalographic changes associated with decreases in behavioural vigilance. In the five minimally conscious patients showing sustained behavioural sleep periods, we identified several electrophysiological characteristics typical of normal sleep. In particular, all minimally conscious patients showed an alternating non-rapid eye movement/rapid eye movement sleep pattern and a homoeostatic decline of electroencephalographic slow wave activity through the night. In contrast, for most patients in a vegetative state, while preserved behavioural sleep was observed, the electroencephalographic patterns remained virtually unchanged during periods with the eyes closed compared to periods of behavioural wakefulness (eyes open and muscle activity). No slow wave sleep or rapid eye movement sleep stages could be identified and no homoeostatic regulation of sleep-related slow wave activity was observed over the night-time period. In conclusion, we observed behavioural, but no electrophysiological, sleep wake patterns in patients in a vegetative state, while there were near-to-normal patterns of sleep in patients in a minimally conscious state. These results shed light on the relationship between sleep electrophysiology and the level of consciousness in severely brain-damaged patients. We suggest that the study of sleep and homoeostatic regulation of slow wave activity may provide a complementary tool for the assessment of brain function in minimally conscious state and vegetative state patients.
PMCID: PMC3155704  PMID: 21841201
sleep; vegetative state; minimally conscious state; consciousness; EEG
25.  A single pair of neurons links sleep to memory consolidation in Drosophila melanogaster 
eLife  null;4:e03868.
Sleep promotes memory consolidation in humans and many other species, but the physiological and anatomical relationships between sleep and memory remain unclear. Here, we show the dorsal paired medial (DPM) neurons, which are required for memory consolidation in Drosophila, are sleep-promoting inhibitory neurons. DPMs increase sleep via release of GABA onto wake-promoting mushroom body (MB) α'/β' neurons. Functional imaging demonstrates that DPM activation evokes robust increases in chloride in MB neurons, but is unable to cause detectable increases in calcium or cAMP. Downregulation of α'/β' GABAA and GABABR3 receptors results in sleep loss, suggesting these receptors are the sleep-relevant targets of DPM-mediated inhibition. Regulation of sleep by neurons necessary for consolidation suggests that these brain processes may be functionally interrelated via their shared anatomy. These findings have important implications for the mechanistic relationship between sleep and memory consolidation, arguing for a significant role of inhibitory neurotransmission in regulating these processes.
eLife digest
Sleep affects memory: if you do not sleep well after a learning task, chances are you will not be able to recall whatever you tried to learn earlier. This is seen in almost all animals ranging from the fruit fly Drosophila, to mice and humans. However, the precise details of how memory and sleep are connected remain unclear.
Drosophila is an excellent model for teasing out the connections between memory and sleep. This is because its brain has a simple and well-studied memory region that contains a pair of nerve cells called the dorsal paired medial neurons. These neurons enable memories to be stored for the long term. Here, Haynes et al. asked whether these neurons can also affect sleep, and if so, how.
The experiments show that the dorsal paired medial neurons promote sleep in fruit flies. The neurons release a signaling molecule called GABA, which is detected by a type of neighboring ‘mushroom body’ neuron that usually promotes wakefulness. This leads to increases in the levels of chloride ions in the mushroom body neurons, but no change in the levels of calcium ions and a molecule called cAMP, which indicates that GABA inhibits these cells. Flies that have lower levels of two receptor proteins that detect GABA sleep less than normal flies.
Haynes et al.'s findings suggest that dorsal paired medial neurons deactivate their neighbors to promote sleep in fruit flies. This result was unexpected because current models of memory formation propose that dorsal paired medial neurons can activate the mushroom body neurons. Understanding how inhibiting mushroom body neurons influences memory will require researchers to reassess these models.
PMCID: PMC4305081  PMID: 25564731
learning and memory; circuits; sleep; D. melanogaster

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