Associations Between Fluctuations in Daytime Sleepiness and Motor and Non-Motor Symptoms in Parkinson's Disease.

BACKGROUND: Non-motor fluctuations are a major concern in Parkinson's disease (PD), and they have been categorized into neuropsychiatric, autonomic and sensory fluctuations. However, this categorization does not include sleep and sleep-related features, and the association between daytime sleepiness and other motor and/or non-motor fluctuations in PD remains to be elucidated. OBJECTIVE: To investigate the relationship between daytime sleepiness and other non-motor and motor fluctuations in people with PD. METHODS: A three-day home diary recording daytime sleepiness, mood, anxiety, and motor symptoms was used along with the Karolinska Sleepiness Scale (KSS) and 6 days of accelerometer (Parkinson's KinetiGraph™; PKG™) registration to detect motor fluctuations among people with a DaTSCAN verified clinical PD diagnosis (32 men; mean PD duration, 8.2 years). Participants were categorized as motor fluctuators or non-fluctuators according to the UPDRS part IV and/or the presence of motor and non-motor fluctuations. RESULTS: Fifty-two people with PD participated. Daytime sleepiness correlated significantly with motor symptoms, mood and anxiety among those classified as motor fluctuators (n = 28). Motor fluctuators showed stronger correlations between the individual mean level of all diary variables (daytime sleepiness, anxiety, mood and motor symptoms) when compared to the non-fluctuators (n = 24). Stronger positive within-individual correlations were found among fluctuators in comparison to non-fluctuators. In general, PKG data did not correlate with diary data. CONCLUSION: Episodes of daytime sleepiness, as reported by home diaries, were associated with other self-reported non-motor and motor fluctuations, but were not supported by PKG data.

A 10-Year Follow-Up of Excessive Daytime Sleepiness in Parkinson's Disease.

INTRODUCTION: The aim of this prospective study was to investigate excessive daytime sleepiness (EDS) over time and in relation to other PD symptoms among people with Parkinson's disease (PD). METHODS: Thirty participants younger than 65 years with PD were randomly selected. At inclusion, mean (SD) disease duration was 6.2 (4.8) years and median (min-max) severity of PD was classified as stage II (stages I-III) according to Hoehn and Yahr. Participants were followed annually for 10 years with clinical assessments of their PD status, medications, comorbidities, and a standardized interview about their sleep habits and occurrence of daytime sleepiness. EDS was assessed by the self-reported Epworth Sleepiness Scale (ESS). Seventeen participants completed the 10-year longitudinal follow-up. RESULTS: Fifteen of 30 persons were classified to suffer from EDS (ESS > 10) at baseline. At the group level, EDS remained stable over 10 years and did not deteriorate in parallel with worsening of motor symptoms. Furthermore, EDS was associated with sleep quality, fatigue, anxiety, depression, and axial/postural/gait impairments. CONCLUSIONS: EDS did not worsen over 10 years, although other PD aspects did. EDS in PD seems to be a complex nonmotor symptom that is unrelated to deterioration of motor symptoms in PD.

Light Therapy With Scheduled Rise Times in Young Adults With Delayed Sleep Phase Disorder: Therapeutic Outcomes and Possible Predictors.

Clinical trials with light therapy (LT) for delayed sleep phase disorder (DSPD) are sparse and little is known about factors that are favorable for improvements. In this study, LT with scheduled rise times was conducted at home for 14 days by 44 participants with DSPD aged 16-26 years. Primary outcomes were sleep onset and sleep offset. Potential predictors were demographic characteristics, chronotype, dim light melatonin onset, the number of days the LT lamp was used, the daily duration of LT, daytime sleepiness, anxiety, depression, worry, and rumination. Significant advances were observed in sleep onset and sleep offset from baseline to the end of treatment. The number of days of LT predicted earlier sleep onset and sleep offset.

Learning performance is linked to procedural memory consolidation across both sleep and wakefulness.

We investigated whether learning performance in a procedural finger tapping task before nocturnal sleep would predict performance gains after sleep in 60 young adults. Gains were defined as change in correctly tapped digit sequences between learning (12 trials administered in the evening) and retesting (3 trials administered in the morning after sleep). The same task was also administered to a separate wake group (N = 54 young adults), which learned in the morning and was retested in the evening. Learning performance was determined by either using the average performance on the last three learning trials or the average performance on the best three learning trials. Our results demonstrated an inverse association between learning performance and gains in procedural skill, i.e., good learners exhibited smaller performance gains across both wakefulness and sleep than poor learners. Regardless of learning performance, gains in finger tapping skills were greater after sleep than daytime wakefulness. Importantly, some of our findings were influenced by how learning performance was estimated. Collectively, these results suggest that learning performance and the method through which it is estimated may influence performance gains in finger tapping skills across both sleep and wakefulness.

Sleep patterns in a randomized controlled trial of auricular acupuncture and cognitive behavioral therapy for insomnia.

The aim of the study was to objectively examine how sleep patterns were affected in a short- and long-term perspective after auricular acupuncture (AA) and cognitive behavioral therapy for insomnia (CBT-i). Sixty participants with insomnia disorders (men/women 9/51; mean age of 60.5 years, (SD 9.4)), were randomized to group treatment with AA or CBT-i. Actigraphy recordings were made at baseline, post-treatment and 6-month follow-up. The CBT-i group reduced their time in bed, their actual sleeping time, their sleep latency and their actual time awake. The AA group slept longer, increased their time in bed and decreased their sleep latency post-treatment. The between-groups results differed in wake-up time, rising, time in bed, actual sleep time and actual wake time. The differences were not maintained six months later. In accordance with previous findings the results support the notion that the objective sleep time does not necessarily affect the subjective perception of insomnia.

Sleep restriction alters plasma endocannabinoids concentrations before but not after exercise in humans.

Following binding to cannabinoid receptors, endocannabinoids regulate a variety of central nervous system processes including appetite and mood. Recent evidence suggests that the systemic release of these lipid metabolites can be altered by acute exercise and that their levels also vary across the 24-h sleep-wake cycle. The present study utilized a within-subject design (involving 16 normal-weight men) to determine whether daytime circulating endocannabinoid concentrations differ following three nights of partial sleep deprivation (4.25-h sleep opportunity, 2:45-7a.m. each night) vs. normal sleep (8.5-h sleep opportunity, 10:30p.m.-7a.m. each night), before and after an acute bout of ergometer cycling in the morning. In addition, subjective hunger and stress were measured. Pre-exercise plasma concentrations of 2-arachidonoylglycerol (2AG) were 80% higher 1.5h after awakening (vs. normal sleep, p<0.05) when participants were sleep-deprived. This coincided with increased hunger ratings (+25% vs. normal sleep, p<0.05). Moreover, plasma 2AG was elevated 15min post-exercise (+44%, p<0.05). Sleep duration did not however modulate this exercise-induced rise. Finally, subjective stress was generally lower on the day after three nights of short sleep vs. normal sleep, especially after exercise (p<0.05). Given that activation of the endocannabinoid system has been previously shown to acutely increase appetite and mood, our results could suggest that behavioral effects of acute sleep loss, such as increased hunger and transiently improved psychological state, may partially result from activation of this signaling pathway. In contrast, more pronounced exercise-induced elevations of endocannabinoids appear to be less affected by short sleep duration.

Delayed sleep phase disorder in a Swedish cohort of adolescents and young adults: Prevalence and associated factors.

A delayed sleep-wake and circadian rhythm often occurs during puberty. While some individuals only develop a delayed sleep phase (DSP), others will fulfill the criteria for the diagnosis of delayed sleep phase disorder (DSPD). All previous studies have however not separated DSP from DSPD, and, as a result, the prevalence and associated factors are largely unknown for the two conditions individually. We estimated the prevalence of DSP and DSPD in a Swedish cohort of adolescents and young adults. We also investigated associated factors in the two conditions relative to each other and individuals with no DSP. A questionnaire regarding sleep patterns, demographics, substance use/abuse and symptoms of depression, anxiety, worry and rumination was sent to 1000 randomly selected participants (16-26 years of age) in Uppsala, Sweden (response rate = 68%). DSP was defined as a late sleep onset and a preferred late wake-up time. The DSPD diagnosis was further operationalized according to the Diagnostic and Statistical Manual of Mental Disorders, Edition 5 (DSM-5) criteria including insomnia or excessive sleepiness, distress or dysfunction caused by the DSP and that the sleep problem had been evident for 3 months. DSP occurred at a frequency of 4.6% and DSPD at a frequency of 4% in the investigated cohort. DSP was more common in males and was associated with not attending educational activity or work, having shift work, nicotine and alcohol use and less rumination. DSPD was equally common in males and females and was associated with not attending educational activity or work and with elevated levels of anxiety. Both DSP and DSPD appear to be common in adolescents and young adults in this Swedish cohort. No educational activity or work was associated with both DSP and DSPD. However, there were also apparent differences between the two groups in shift work, substance use and mental health, relative to persons with no DSP. Thus, it seems reasonable to assess DSP and DSPD as distinct entities in future studies.

Two hours of evening reading on a self-luminous tablet vs. reading a physical book does not alter sleep after daytime bright light exposure.

BACKGROUND: The use of electronic devices emitting blue light during evening hours has been associated with sleep disturbances in humans, possibly due to the blue light-mediated suppression of the sleep-promoting hormone melatonin. However, experimental results have been mixed. The present study therefore sought to investigate if reading on a self-luminous tablet during evening hours would alter sleepiness, melatonin secretion, nocturnal sleep, as well as electroencephalographic power spectral density during early slow-wave sleep. METHODS: Following a constant bright light exposure over 6.5 hours (~569 lux), 14 participants (six females) read a novel either on a tablet or as physical book for two hours (21:00-23:00). Evening concentrations of saliva melatonin were repeatedly measured. Sleep (23:15-07:15) was recorded by polysomnography. Sleepiness was assessed before and after nocturnal sleep. About one week later, experiments were repeated; participants who had read the novel on a tablet in the first experimental session continued reading the same novel in the physical book, and vice versa. RESULTS: There were no differences in sleep parameters and pre-sleep saliva melatonin levels between the tablet reading and physical book reading conditions. CONCLUSIONS: Bright light exposure during daytime has previously been shown to abolish the inhibitory effects of evening light stimulus on melatonin secretion. Our results could therefore suggest that exposure to bright light during the day - as in the present study - may help combat sleep disturbances associated with the evening use of electronic devices emitting blue light. However, this needs to be validated by future studies with larger sample populations.

Developing a cognitive behavioral therapy manual for delayed sleep-wake phase disorder.

This article reports the development of a treatment protocol, based on cognitive behavioral therapy (CBT) principles, for delayed sleep-wake phase disorder (DSWPD). The protocol consists of psycho-education, presenting a CBT model for DSWPD, case formulation, motivational interviewing, registering sleep in a diary, strategies to improve the rhythm of sleep and wakefulness, relaxation training, cognitive restructuring, strategies to cope with daytime symptoms, constructing an individualized CBT program, and learning how to deal with relapses. Qualitative data, focusing on how the patients perceived the protocol, were collected within the realm of a trial exploring the efficacy of the protocol. These findings highlighted several advantages but also disadvantages of the therapy. It is our hope that this paper might act as a platform for further clinical work and future research efforts in patients with DSWPD.

Learning and sleep-dependent consolidation of spatial and procedural memories are unaltered in young men under a fixed short sleep schedule.

OBJECTIVE: To investigate if a fixed short sleep schedule impairs one of the main functions of sleep, which is to consolidate newly learned memories. METHODS: Sixteen young men participated in two experimental conditions, each of which lasted for 3 consecutive days and nights in our laboratory: a short sleep schedule (4.25-h sleep opportunity per night) versus a normal sleep schedule (8.5h per night). In the evening after two experimental nights, participants learned locations of 15 card pairs (spatial memory task) and a procedural finger tapping sequence task. Post-sleep retrieval of both memory tasks was tested the next morning. RESULTS: The short sleep schedule, compared with the normal sleep schedule, considerably altered sleep characteristics, e.g. the proportion of time in slow-wave sleep increased across the three experimental nights. In contrast, neither learning in the evening of day 2, nor subsequent overnight memory consolidation (i.e. concerning the change in memory performance between pre-sleep learning on day 2 and post-sleep retrieval on day 3) differed between the normal and short sleep schedule conditions. CONCLUSIONS: Our findings suggest that learning in the evening and subsequent sleep-dependent consolidation of procedural and spatial memories are unaltered in young men living under a fixed short sleep schedule. Future studies are warranted to validate our findings in other groups (e.g. adolescents and older subjects) and after more prolonged chronic sleep loss paradigms.

Cognitive Behavioral Therapy as an Adjunct Treatment to Light Therapy for Delayed Sleep Phase Disorder in Young Adults: A Randomized Controlled Feasibility Study.

Delayed sleep phase disorder (DSPD) is common among young people, but there is still no evidence-based treatment available. In the present study, the feasibility of cognitive behavioral therapy (CBT) was evaluated as an additive treatment to light therapy (LT) in DSPD. A randomized controlled trial with participants aged 16 to 26 years received LT for two weeks followed by either four weeks of CBT or no treatment (NT). LT advanced sleep-wake rhythm in both groups. Comparing LT+CBT with LT+NT, no significant group differences were observed in the primary endpoints. Although anxiety and depression scores were low at pretreatment, they decreased significantly more in LT+CBT compared to LT+NT. The results are discussed and some suggestions are given for further studies.

A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men.

The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food-related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate-limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects' oral cavities were rinsed with a 1-molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (-3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.

Initial Sleep Time Predicts Success in Manual-Guided Cognitive Behavioral Therapy for Insomnia.

Cognitive behavioral therapy produces significant and long-lasting improvement for individuals with insomnia, but treatment resources are scarce. A "stepped care" approach has therefore been proposed, but knowledge is limited on how to best allocate patients to different treatment steps. In this study, 66 primary-care patients with insomnia attended a low-end treatment step: manual-guided cognitive behavioral therapy (CBT) for insomnia delivered by ordinary primary-care personnel. Based on clinically significant treatment effects, subjects were grouped into treatment responders or nonresponders. Baseline data were analyzed to identify predictors for treatment success. Long total sleep time at baseline assessment was the only statistically significant predictor for becoming a responder, and sleep time may thus be important to consider before enrolling patients in low-end treatments.

Acute Sleep Loss Induces Tissue-Specific Epigenetic and Transcriptional Alterations to Circadian Clock Genes in Men.

CONTEXT: Shift workers are at increased risk of metabolic morbidities. Clock genes are known to regulate metabolic processes in peripheral tissues, eg, glucose oxidation. OBJECTIVE: This study aimed to investigate how clock genes are affected at the epigenetic and transcriptional level in peripheral human tissues following acute total sleep deprivation (TSD), mimicking shift work with extended wakefulness. INTERVENTION: In a randomized, two-period, two-condition, crossover clinical study, 15 healthy men underwent two experimental sessions: x sleep (2230-0700 h) and overnight wakefulness. On the subsequent morning, serum cortisol was measured, followed by skeletal muscle and subcutaneous adipose tissue biopsies for DNA methylation and gene expression analyses of core clock genes (BMAL1, CLOCK, CRY1, PER1). Finally, baseline and 2-h post-oral glucose load plasma glucose concentrations were determined. MAIN OUTCOME MEASURES: In adipose tissue, acute sleep deprivation vs sleep increased methylation in the promoter of CRY1 (+4%; P = .026) and in two promoter-interacting enhancer regions of PER1 (+15%; P = .036; +9%; P = .026). In skeletal muscle, TSD vs sleep decreased gene expression of BMAL1 (-18%; P = .033) and CRY1 (-22%; P = .047). Concentrations of serum cortisol, which can reset peripheral tissue clocks, were decreased (2449 ± 932 vs 3178 ± 723 nmol/L; P = .039), whereas postprandial plasma glucose concentrations were elevated after TSD (7.77 ± 1.63 vs 6.59 ± 1.32 mmol/L; P = .011). CONCLUSIONS: Our findings demonstrate that a single night of wakefulness can alter the epigenetic and transcriptional profile of core circadian clock genes in key metabolic tissues. Tissue-specific clock alterations could explain why shift work may disrupt metabolic integrity as observed herein.

Short Sleep Makes Declarative Memories Vulnerable to Stress in Humans.

STUDY OBJECTIVE: This study sought to investigate the role of nocturnal sleep duration for the retrieval of oversleep consolidated memories, both prior to and after being cognitively stressed for ∼30 minutes the next morning. DESIGN: Participants learned object locations (declarative memory task comprising 15 card pairs) and a finger tapping sequence (procedural memory task comprising 5 digits) in the evening. After learning, participants either had a sleep opportunity of 8 hours (between ∼23:00 and ∼07:00, full sleep condition) or they could sleep between ∼03:00 and ∼07:00 (short sleep condition). Retrieval of both memory tasks was tested in the morning after each sleep condition, both before (∼08:30) and after being stressed (∼09:50). SETTING: Sleep laboratory. PARTICIPANTS: 15 healthy young men. RESULTS: The analyses demonstrated that oversleep memory changes did not differ between sleep conditions. However, in their short sleep condition, following stress hallmarked by increased subjective stress feelings, the men were unable to maintain their pre-stress performance on the declarative memory task, whereas their performance on the procedural memory task remained unchanged. While men felt comparably subjectively stressed by the stress intervention, overall no differences between pre- and post-stress recalls were observed following a full night of sleep. CONCLUSIONS: The findings suggest that 8-h sleep duration, within the range recommended by the US National Sleep Foundation, may not only help consolidate newly learned procedural and declarative memories, but also ensure full access to both during periods of subjective stress.

Measurement properties of the minimal insomnia symptom scale as an insomnia screening tool for adults and the elderly.

BACKGROUND: The psychometric properties of the three-item Minimal Insomnia Symptom Scale (MISS) were evaluated using the classical test theory. Different cut-offs for identifying insomnia were suggested in two age groups (≥6 and ≥7 among adult and elderly people, respectively). The aim of the present study was to test the measurement properties of the MISS using the Rasch measurement model, with special emphasis on differential item functioning by gender and age. METHODS: Cross-sectional MISS data from adult (age 20-64 years, n = 1075) and elderly (age 65+, n = 548) populations were analysed using the Rasch measurement model. RESULTS: Data generally met Rasch model requirements and the scale could separate between two distinct groups of people. Differential item functioning was found by age but not gender. The difference between the adult and elderly samples was lower for the originally recommended ≥6 points cut-off (0.09 logits) than for the ≥7 points cut-off (0.23 logits), but greater at the lower and higher ends of the scale. CONCLUSIONS: This study provides general support for the measurement properties of the MISS. Caution should be exercised in comparing raw MISS scores between age groups, but applying a ≥6 cut-off appears to allow for valid comparisons between adults and the elderly regarding the presence of insomnia. Nevertheless, additional studies are needed to determine the clinically optimal cut-score for identification of insomnia.

Insomnia in sweden: a population-based survey.

Aims. Estimate the prevalence of insomnia and examine effects of sex, age, health problems, sleep duration, need for treatment, and usage of sleep medication. Methods. A sample of 1,550 subjects aged 18-84 years was selected for a telephone interview. The interview was completed by 1,128 subjects (72.8%). Results. 24.6% reported insomnia symptoms. Insomnia disorder, that is, insomnia symptoms and daytime consequences, was reported by 10.5%. The prevalence was similar among all age groups, with the exception of women aged 40-49 years who demonstrated a significantly higher prevalence, 21.6%. Having at least one physical or psychiatric disorder was reported by 82.8% of subjects with insomnia disorder. Mean sleep duration for subjects with insomnia disorder was 5.77 hours on weeknights and 7.03 hours on days off/weekends. The corresponding figures for subjects without insomnia disorder were 7.04 hours and 7.86 hours, respectively. Among those with insomnia disorder 62.5% expressed a need for treatment, and 20.0% used prescribed sleep medication regularly. Conclusions. Insomnia disorder is highly prevalent in the population. There are significant associations between insomnia disorder and physical and psychiatric disorders. A majority of subjects with insomnia disorder expressed a need for treatment, indicating a public health problem.

Acute sleep deprivation in healthy young men: impact on population diversity and function of circulating neutrophils.

Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0 ± 0.2 × 10(9)/l vs. 2.6 ± 0.2 × 10(9)/l, sleep vs. TSD, respectively) and the population contained more immature CD16(dim)/CD62L(bright) cells (0.11 ± 0.040 × 10(9)/l [5.5 ± 1.1%] vs. 0.26 ± 0.020 × 10(9)/l [9.9 ± 1.4%]). As the rise in numbers of circulating mature CD16(bright)/CD62L(bright) neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8 ± 0.15 × 10(9)/l [88 ± 1.8%] vs. 2.1 ± 0.12 × 10(9)/l [82 ± 2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.

Increased impulsivity in response to food cues after sleep loss in healthy young men.

OBJECTIVE: To investigate whether acute total sleep deprivation (TSD) leads to decreased cognitive control when food cues are presented during a task requiring active attention, by assessing the ability to cognitively inhibit prepotent responses. METHODS: Fourteen males participated in the study on two separate occasions in a randomized, crossover within-subject design: one night of TSD versus normal sleep (8.5 hours). Following each nighttime intervention, hunger ratings and morning fasting plasma glucose concentrations were assessed before performing a go/no-go task. RESULTS: Following TSD, participants made significantly more commission errors when they were presented "no-go" food words in the go/no-go task, as compared with their performance following sleep (+56%; P<0.05). In contrast, response time and omission errors to "go" non-food words did not differ between the conditions. Self-reported hunger after TSD was increased without changes in fasting plasma glucose. The increase in hunger did not correlate with the TSD-induced commission errors. CONCLUSIONS: Our results suggest that TSD impairs cognitive control also in response to food stimuli in healthy young men. Whether such loss of inhibition or impulsiveness is food cue-specific as seen in obesity-thus providing a mechanism through which sleep disturbances may promote obesity development-warrants further investigation.

Continuous subcutaneous hydrocortisone infusion versus oral hydrocortisone replacement for treatment of addison's disease: a randomized clinical trial.

CONTEXT: Conventional glucocorticoid replacement therapy fails to mimic the physiological cortisol rhythm, which may have implications for morbidity and mortality in patients with Addison's disease. OBJECTIVE: The objective of the study was to compare the effects of continuous sc hydrocortisone infusion (CSHI) with conventional oral hydrocortisone (OHC) replacement therapy. DESIGN, PATIENTS, AND INTERVENTIONS: This was a prospective crossover, randomized, multicenter clinical trial comparing 3 months of treatment with thrice-daily OHC vs CSHI. From Norway and Sweden, 33 patients were enrolled from registries and clinics. All patients were assessed at baseline and after 8 and 12 weeks in each treatment arm. MAIN OUTCOME MEASURES: The morning ACTH level was the primary outcome measure. Secondary outcome measures were effects on metabolism, health-related quality of life (HRQoL), sleep, and safety. RESULTS: CSHI yielded normalization of morning ACTH and cortisol levels, and 24-hour salivary cortisol curves resembled the normal circadian variation. Urinary concentrations of glucocorticoid metabolites displayed a normal pattern with CSHI but were clearly altered with OHC. Several HRQoL indices in the vitality domain improved over time with CSHI. No benefit was found for either treatments for any subjective (Pittsburgh Sleep Quality Index questionnaire) or objective (actigraphy) sleep parameters. CONCLUSION: CSHI safely brought ACTH and cortisol toward normal circadian levels without adversely affecting glucocorticoid metabolism in the way that OHC did. Positive effects on HRQoL were noted with CSHI, indicating that physiological glucocorticoid replacement therapy may be beneficial and that CSHI might become a treatment option for patients poorly controlled on conventional therapy.