Investigating non-inferiority of internet-delivered versus face-to-face cognitive behavioural therapy for insomnia (CBT-I): a randomised controlled trial (iSleep well).

BACKGROUND: Insomnia is a highly prevalent disorder associated with numerous adverse health outcomes. Cognitive behavioural therapy for insomnia (CBT-I) is recommended as first-line treatment by clinical guidelines but is accessible to only a minority of patients suffering from insomnia. Internet-delivered CBT-I (iCBT-I) could contribute to the widespread dissemination of this first-line treatment. As there is insufficient evidence regarding non-inferiority, this study directly aims to compare therapist-guided internet-delivered versus face-to-face CBT-I in terms of insomnia severity post-treatment. Furthermore, a health-economic evaluation will be conducted, and potential benefits and disadvantages of therapist-guided iCBT-I will be examined. METHODS: This study protocol describes a randomised controlled two-arm parallel-group non-inferiority trial comparing therapist-guided iCBT-I with face-to-face CBT-I in routine clinical care. A total of 422 patients with insomnia disorder will be randomised and treated at 16 study centres throughout Germany. Outcomes will be assessed at baseline, 10 weeks after randomisation (post), and 6 months after randomisation (follow-up). The primary outcome is insomnia severity measured using the Insomnia Severity Index. Secondary outcomes include depression-related symptoms, quality of life, fatigue, physical activity, daylight exposure, adverse events related to treatment, and a health-economic evaluation. Finally, potential moderator variables and several descriptive and exploratory outcomes will be assessed (e.g. benefits and disadvantages of internet-delivered treatment). DISCUSSION: The widespread implementation of CBT-I is a significant healthcare challenge. The non-inferiority of therapist-guided iCBT-I versus face-to-face CBT-I will be investigated in an adequately powered sample in routine clinical care, with the same therapeutic content and same level of therapist qualifications provided with both interventions. If this trial demonstrates the non-inferiority of therapist-guided iCBT-I, healthcare providers may be more confident recommending this treatment to their patients, contributing to the wider dissemination of CBT-I. TRIAL REGISTRATION: Trial registration number in the German Clinical Trials Register: DRKS00028153 ( https://drks.de/search/de/trial/DRKS00028153 ). Registered on 16th May 2023.

Long-term effects of environmental dynamic lighting on sleep-wake rhythm, mood and behaviour in older adults with intellectual disabilities.

BACKGROUND: Sleep-wake problems and depressive symptoms are common in people with intellectual disabilities (IDs) and are thought to be related to the unstable sleep-wake rhythm in this population. Previously, we showed that after increasing environmental light exposure, mid-sleep and sleep onset advanced, and mood improved over a period of 14 weeks after installing environmental dynamic light installations in the living room of people with IDs. We invited participants of that short-term study to take part in the current study on sleep-wake rhythm, mood and behaviour in older adults with IDs 1 year after installing environmental dynamic light installations in the common living rooms of six group homes. METHODS: A pre-post study was performed from October 2017 to February 2019. We included 45 participants (63.5 ± 8.5 years, 67% female) from six group home facilities who provided data at baseline (9, 4 and 1 weeks prior to installing light installations), short term (3, 7 and 14 weeks after installing light installations) and 1 year (54 weeks after installing light installations). Wrist activity was measured with actigraphy (GENEActiv) to derive the primary outcome of interdaily stability of sleep-wake rhythms as well as sleep estimates. Mood was measured with the Anxiety, Depression and Mood Scale. Behaviour was measured with the Aberrant Behaviour Checklist. RESULTS: One year after installing dynamic lighting, we did not find a change in interdaily stability. Total sleep time decreased (ß = -25.40 min; confidence interval: -10.99, -39.82), and sleep onset time was delayed (ß = 25.63 min; confidence interval: 11.18, 40.08). No effect on mood or behaviour was found. CONCLUSIONS: We did not find a change in sleep-wake rhythm, mood or behaviour in older persons with IDs living in care facilities 1 year after installing the light. We did find evidence for a long-term effect on sleep duration and sleep timing. The results have to be interpreted with care as the current study had a limited number of participants. The need for more research on the long-term effects of enhancing environmental light in ID settings is evident.

Do better nights lead to better days? Guided internet-based cognitive behavioral therapy for insomnia in people suffering from a range of mental health problems: Protocol of a pragmatic randomized clinical trial.

BACKGROUND: Insomnia is the transdiagnostically shared most common complaint in disorders of anxiety, stress and emotion regulation. Current cognitive behavioral therapies (CBT) for these disorders do not address sleep, while good sleep is essential for regulating emotions and learning new cognitions and behaviours: the core fundaments of CBT. This transdiagnostic randomized control trial (RCT) evaluates whether guided internet-delivered cognitive behavioral therapy for insomnia (iCBT-I) (1) improves sleep, (2) affects the progression of emotional distress and (3) enhances the effectiveness of regular treatment of people with clinically relevant symptoms of emotional disorders across all mental health care (MHC) echelons. METHODS: We aim for 576 completers with clinically relevant symptoms of insomnia as well as at least one of the dimensions of generalized anxiety disorder (GAD), social anxiety disorder (SAD), panic disorder (PD), posttraumatic stress disorder (PTSD) or borderline personality disorder (BPD). Participants are either pre-clinical, unattended, or referred to general- or specialized MHC. Using covariate-adaptive randomization, participants will be assigned to a 5 to 8-week iCBT-I (i-Sleep) or a control condition (sleep diary only) and assessed at baseline, and after two and eight months. The primary outcome is insomnia severity. Secondary outcomes address sleep, severity of mental health symptoms, daytime functioning, mental health protective lifestyles, well-being, and process evaluation measures. Analyses use linear mixed-effect regression models. DISCUSSION: This study can reveal for whom, and at which stage of disease progression, better nights could mean substantially better days. TRIAL REGISTRATION: International Clinical Trial Registry Platform (NL9776). Registered on 2021-10-07.

Light up: an intervention study of the effect of environmental dynamic lighting on sleep-wake rhythm, mood and behaviour in older adults with intellectual disabilities.

BACKGROUND: Evidence-based interventions to improve the sleep-wake rhythm, mood and behaviour in older adults with intellectual disabilities (ID) are limited. Increasing light exposure has been shown to be effective in improving the sleep-wake rhythm, mood, and behaviour in other populations. The current study investigates the effect of installing environmental dynamic lighting in common living rooms of care facilities on sleep-wake rhythm, mood, and behaviour in older adults with ID. METHODS: A non-randomised, non-concurrent, multiple baseline study was performed from October 2017 to May 2018. Fifty-four participants [mean (SD) age of 63.42 (8.6) years, 65% female] in six care facilities were included. All participants had three baseline measurements (Weeks 1, 5 and 9). Dynamic lighting was installed in Week 10, after which three intervention measurements took place (Weeks 12, 17 and 24). Sleep characteristics and the sleep-wake rhythm were assessed using actigraphy (GENEActiv). Mood was measured with the Anxiety, Depression and Mood Scale (ADAMS) and behaviour with the Aberrant Behaviour Checklist (ABC). RESULTS: Mixed-effect regression analysis showed a worsening of the primary outcome interdaily stability (P = 0.001). This could be attributed to one care facility, whereas interdaily stability did not change in the other care facilities (P = 0.74). Dynamic lighting led to earlier mid-sleep (P = 0.003) and sleep onset (P < .0001) and improved mood as indicated by lower scores on the ADAMS depression (-0.64 SD, P < 0.001) and social avoidance (-0.47 SD, P = 0.004) subscales. The prevalence of screening above cut-off for depression decreased from 23 to 9.8% (OR = .16, P = 0.003). For behaviour, a decrease was seen in hyperactivity (-0.43 SD, P < 0.001), lethargy (-0.35 SD, P = 0.008) and irritability (-0.33 SD, P < .001) as measured with the ABC. No adverse effects were reported. CONCLUSION: Installing dynamic lighting in common living areas for older adults with ID improved the mood and behaviour of the residents up to 14 weeks after placement. Integrated dynamic lighting is a promising, undemanding and potentially effective addition to improve mood and behaviour in care organisations for people with ID, but does not seem to do so by improving sleep or sleep-wake rhythms.

Guided internet-based cognitive behavioral therapy for insomnia in patients with borderline personality disorder: Study protocol for a randomized controlled trial.

Borderline personality disorder (BPD) is a highly disabling psychiatric disorder with emotion dysregulation at its core, resulting in affective instability, impulsivity and sometimes self-harming or suicidal behavior. Sleep is increasingly recognized to play a crucial role in emotion regulation. BPD patients often suffer from (severe) insomnia, potentially aggravating symptoms and preventing recovery from BPD. Yet, the effects of insomnia treatments have not been investigated in context of BPD. Guided internet-based cognitive behavioral therapy for insomnia (iCBT-I; i-Sleep) has been proven effective in improving both insomnia and affective symptoms. In this randomized controlled trial among 96 patients with a DSM-5 diagnosis of BPD (or other personality disorder with ≥4 BPD traits) and insomnia symptoms, we will test the effectiveness of iCBT-I before regular BPD treatment starts, during the waitlist period, on BPD symptoms. Patients in the control group monitor their sleep through a sleep diary during the waitlist period and also receive standard BPD treatment after that. Using linear mixed models we will test the hypothesis that the iCBT-I group improves more than the control group on BPD symptoms (primary outcome), insomnia severity, additional subjective and objective sleep variables, emotion regulation, comorbid anxiety and depression complaints, and quality of life. These effects are thought to arise from a direct effect of improved sleep on emotion regulation and a synergistic effect on the consolidation and internalization of the BPD treatment effect. To our knowledge, this is the first trial assessing effectiveness of CBT-I in patients with BPD (traits). The accessibility of the studied intervention greatly facilitates clinical implication in case of positive results.

Shedding light on light exposure in elderly with intellectual disabilities.

BACKGROUND: Light exposure affects mood and sleep regulation. Sleep problems and mood complaints are common in elderly with intellectual disabilities (ID) living in care facilities. Insufficient light exposure is hypothesised to contribute to the high prevalence of these problems. The current study is the first to describe the personal light exposure pattern during the waking day in elderly with ID. METHODS: The study sample consists of 82 elderly with ID (aged 62.3 ± 9.4 years) living in 16 residential homes of three care organisations in the Netherlands. Personal light exposure was measured continuously for 7-10 days using a HOBO data logger light sensor, measuring illuminance at chest height. Participants wore a wrist-worn accelerometer (Actiwatch or Geneactiv) to indicate the bedtimes to determine the waking day. RESULTS: The variation in illuminance is small during the waking day. Elderly with ID spend most of their waking day (mean duration = 14:32:43 h) in dim light (1-500 lux) environment and spend a median of 32 min in light > 1000 lux. Within participants, the threshold associated with better sleep (>50 min of light > 1000 lux) was reached for 34% of the days, and the threshold associated with less depressive symptoms (>30 min of light > 1000 lux) was reached in 46% of the days. Exposure > 1000 lux was lower during weekends than during weekdays. CONCLUSION: Elderly with ID spend most of their waking day in low light levels and did not meet the proposed values associated with better sleep and mood. Given the importance of adequate light exposure for regulation of sleep and mood, and the prevalence of sleep and mood problems in elderly with ID, the current study suggests that the lit environment for this already frail population should be given more attention.

The impact of maintenance therapy on sleep-wake rhythms and cancer-related fatigue in pediatric acute lymphoblastic leukemia.

PURPOSE: To assess the impact of maintenance therapy and the additional impact of dexamethasone treatment on cancer-related fatigue and sleep-wake rhythms in pediatric acute lymphoblastic leukemia (ALL) patients and to determine the association between these outcomes. METHODS: A national cohort of pediatric ALL patients (≥ 2 years) was included (± 1 year post-diagnosis). Patients receiving dexamethasone were assessed twice (assessment with and without dexamethasone). Actigraphy assessments were used to calculate sleep-wake outcomes with nonparametric methods. Cancer-related fatigue was assessed with the PedsQL Multidimensional Fatigue Scale. Sleep-wake rhythms and cancer-related fatigue were compared between patients participating in the assessment without dexamethasone and healthy children (linear regression) and between assessments with and without dexamethasone (mixed models). Using linear regression, associations between sleep-wake outcomes and cancer-related fatigue were determined during assessments with and without dexamethasone. RESULTS: Responses were collected for 125 patients (113 assessments with and 81 without dexamethasone). The sleep-wake rhythm was less stable (p = 0.03) and less robust (p = 0.01), with lower physical activity levels (p < 0.001) and higher cancer-related fatigue levels (p < 0.001) in ALL patients compared to healthy children. Physical activity was lower (p = 0.001) and cancer-related fatigue more severe (p ≤ 0.001) during assessments with dexamethasone compared to without dexamethasone. Sleep-wake outcomes were significantly associated with cancer-related fatigue during periods without dexamethasone, but not during periods with dexamethasone. CONCLUSION: Sleep-wake rhythms are disturbed, physical activity levels lower, and cancer-related fatigue levels higher during maintenance therapy. Interventions aimed to enhance sleep-wake rhythms during maintenance therapy could improve cancer-related fatigue. Families should be supported in coping with the additional burden of dexamethasone treatment to improve well-being of ALL patients.

Discovery of key whole-brain transitions and dynamics during human wakefulness and non-REM sleep.

The modern understanding of sleep is based on the classification of sleep into stages defined by their electroencephalography (EEG) signatures, but the underlying brain dynamics remain unclear. Here we aimed to move significantly beyond the current state-of-the-art description of sleep, and in particular to characterise the spatiotemporal complexity of whole-brain networks and state transitions during sleep. In order to obtain the most unbiased estimate of how whole-brain network states evolve through the human sleep cycle, we used a Markovian data-driven analysis of continuous neuroimaging data from 57 healthy participants falling asleep during simultaneous functional magnetic resonance imaging (fMRI) and EEG. This Hidden Markov Model (HMM) facilitated discovery of the dynamic choreography between different whole-brain networks across the wake-non-REM sleep cycle. Notably, our results reveal key trajectories to switch within and between EEG-based sleep stages, while highlighting the heterogeneities of stage N1 sleep and wakefulness before and after sleep.

Restless legs syndrome in migraine patients: prevalence and severity.

BACKGROUND AND PURPOSE: Our aim was to study not only the prevalence but more importantly the severity and the correlation between sleep quality and restless legs syndrome (RLS) in a large population of well-defined migraine patients as poor sleep presumably triggers migraine attacks. METHODS: In a large cross-sectional and observational study, data on migraine and RLS were collected from 2385 migraine patients (according to the International Classification of Headache Disorders ICHD-IIIb) and 332 non-headache controls. RLS severity (International RLS Study Group severity scale) and sleep quality (Pittsburgh Sleep Quality Index) were assessed. Risk factors for RLS and RLS severity were calculated using multivariable-adjusted regression models. RESULTS: Restless legs syndrome prevalence in migraine was higher than in controls (16.9% vs. 8.7%; multivariable-adjusted odds ratio 1.83; 95% confidence interval 1.18-2.86; P = 0.008) and more severe (adjusted severity score 14.5 ± 0.5 vs. 12.0 ± 1.1; P = 0.036). Poor sleepers were overrepresented amongst migraineurs (50.1% vs. 25.6%; P < 0.001). Poorer sleep quality was independently associated with RLS occurrence (odds ratio 1.08; P < 0.001) and RLS severity (P < 0.001) in migraine patients. CONCLUSION: Restless legs syndrome is not only twice as prevalent but also more severe in migraine patients, and associated with decreased sleep quality.

Neurology and psychiatry: waking up to opportunities of sleep. : State of the art and clinical/research priorities for the next decade.

In recent years, evidence has emerged for a bidirectional relationship between sleep and neurological and psychiatric disorders. First, sleep-wake disorders (SWDs) are very common and may be the first/main manifestation of underlying neurological and psychiatric disorders. Secondly, SWDs may represent an independent risk factor for neuropsychiatric morbidities. Thirdly, sleep-wake function (SWF) may influence the course and outcome of neurological and psychiatric disorders. This review summarizes the most important research and clinical findings in the fields of neuropsychiatric sleep and circadian research and medicine, and discusses the promise they bear for the next decade. The findings herein summarize discussions conducted in a workshop with 26 European experts in these fields, and formulate specific future priorities for clinical practice and translational research. More generally, the conclusion emerging from this workshop is the recognition of a tremendous opportunity offered by our knowledge of SWF and SWDs that has unfortunately not yet entered as an important key factor in clinical practice, particularly in Europe. Strengthening pre-graduate and postgraduate teaching, creating academic multidisciplinary sleep-wake centres and simplifying diagnostic approaches of SWDs coupled with targeted treatment strategies yield enormous clinical benefits for these diseases.

Cerebral small vessel disease is related to disturbed 24-h activity rhythms: a population-based study.

BACKGROUND AND PURPOSE: Cerebral small vessel disease is common in elderly persons. Patients with dementia or stroke frequently have cerebral small vessel disease and often experience disturbances in the sleep-wake rhythm. It is unknown whether cerebral small vessel disease is related to disturbances in sleep and 24-h activity rhythms. METHODS: This study was conducted in the Rotterdam Study. A total of 970 community-dwelling persons (mean age 59.2 years) underwent brain magnetic resonance imaging and actigraphy. Cerebral small vessel disease was defined as white matter lesions (total volume in millilitres) and the presence of cerebral microbleeds and lacunar infarcts. Twenty-four hour activity rhythms and sleep were measured with actigraphy by estimating the instability and fragmentation of the activity rhythm and total sleep time. Sleep quality was assessed with the Pittsburgh Sleep Quality Index. White matter lesions, instability, fragmentation and sleep quality were standardized for analyses. RESULTS: Higher white matter lesion volume (B = 0.09 per SD, 95% confidence interval 0.02; 0.15) and cerebral microbleeds (B = 0.19 per SD, 95% confidence interval 0.02; 0.37) were significantly related to more fragmented 24-h activity rhythms. None of the small vessel disease markers was related to total sleep time or sleep quality. CONCLUSIONS: White matter lesion volume and the presence of cerebral microbleeds are related to disturbed activity rhythms. This suggests that subclinical brain damage affects the 24-h activity rhythm.

Detection of the mechanism of immunotoxicity of cyclosporine A in murine in vitro and in vivo models.

Transcriptomics in combination with in vitro cell systems is a powerful approach to unravel modes of action of toxicants. An important question is to which extent the modes of action as revealed by transcriptomics depend on cell type, species and study type (in vitro or in vivo). To acquire more insight into this, we assessed the transcriptomic effects of the immunosuppressive drug cyclosporine A (CsA) upon 6 h of exposure of the mouse cytotoxic T cell line CTLL-2, the thymoma EL-4 and primary splenocytes and compared these to the effects in spleens of mice orally treated with CsA for 7 days. EL-4 and CTLL-2 cells showed the highest similarities in response. CsA affected many genes in primary splenocytes that were not affected in EL-4 or CTLL-2. Pathway analysis demonstrated that CsA upregulated the unfolded protein response, endoplasmic reticulum stress and NRF2 activation in EL-4 cells, CTLL-2 cells and primary mouse splenocytes but not in mouse spleen in vivo. As expected, CsA downregulated cell cycle and immune response in splenocytes in vitro, spleens in vivo as well as CTLL-2 in vitro. Genes up- and downregulated in human Jurkat, HepG2 and renal proximal tubular cells were similarly affected in CTLL-2, EL-4 and primary splenocytes in vitro. In conclusion, of the models tested in this study, the known mechanism of immunotoxicity of CsA is best represented in the mouse cytotoxic T cell line CTLL-2. This is likely due to the fact that this cell line is cultured in the presence of a T cell activation stimulant (IL-2) making it more suitable to detect inhibitory effects on T cell activation.

Alterations in diurnal rhythmicity in patients treated for nonfunctioning pituitary macroadenoma: a controlled study and literature review.

OBJECTIVE: Patients treated for nonfunctioning pituitary macroadenomas (NFMAs) have fatigue and alterations in sleep characteristics and sleep-wake rhythmicity frequently. As NFMAs often compress the optic chiasm, these complaints might be related to dysfunction of the adjacent suprachiasmatic nucleus (SCN). We aimed to explore whether indirect indices of SCN functioning are altered in the long term after surgery for NFMAs. METHODS: We studied 17 NFMA patients in long-term remission after transsphenoidal surgery, receiving adequate and stable hormone replacement for hypopituitarism, and 17 control subjects matched for age, gender, and BMI. Indirect indices of SCN function were assessed from 24-h ambulatory recordings of skin and core body temperatures, blood pressure, and salivary melatonin levels. Altered melatonin secretion was defined as an absence of evening rise, considerable irregularity, or daytime values >3 pg/ml. We additionally studied eight patients treated for craniopharyngioma. RESULTS: Distal-proximal skin temperature gradient did not differ between NFMAs and control subjects, but proximal skin temperature was decreased during daytime (P=0.006). Core body temperature and non-dipping of blood pressure did not differ, whereas melatonin secretion was often altered in NFMAs (OR 5.3, 95% CI 0.9-30.6). One or more abnormal parameters (≥2.0 SDS of control subjects) were observed during nighttime in 12 NFMA patients and during daytime in seven NFMA patients. Similar patterns were observed in craniopharyngioma patients. CONCLUSION: Heterogeneous patterns of altered diurnal rhythmicity in skin temperature and melatonin secretion parameters were observed in the majority of patients treated for NFMAs. On a group level, both NFMA and craniopharyngioma patients showed a lower daytime proximal skin temperature than control subjects, but other group averages were not significantly different. The observations suggest altered function of central (or peripheral) clock machinery, possibly by disturbed entrainment or damage of the hypothalamic SCN by the suprasellar macroadenoma or its treatment.

Guided Internet-delivered cognitive behavioural treatment for insomnia: a randomized trial.

BACKGROUND: Insomnia is a prevalent problem with a high burden of disease (e.g. reduced quality of life, reduced work capacity) and a high co-morbidity with other mental and somatic disorders. Cognitive behavioural therapy (CBT) is effective in the treatment of insomnia but is seldom offered. CBT delivered through the Internet might be a more accessible alternative. In this study we examined the effectiveness of a guided Internet-delivered CBT for adults with insomnia using a randomized controlled trial (RCT). METHOD: A total of 118 patients, recruited from the general population, were randomized to the 6-week guided Internet intervention (n = 59) or to a wait-list control group (n = 59). Patients filled out an online questionnaire and a 7-day sleep diary before (T0) and after (T1) the 6-week period. The intervention group received a follow-up questionnaire 3 months after baseline (T2). RESULTS: Almost three-quarters (72.9%) of the patients completed the whole intervention. Intention-to-treat (ITT) analysis showed that the treatment had statistically significant medium to large effects (p < 0.05; Cohen's d between 0.40 and 1.06), and resulted more often in clinically relevant changes, on all sleep and secondary outcomes with the exception of sleep onset latency (SOL) and number of awakenings (NA). There was a non-significant difference in the reduction in sleep medication between the intervention (a decrease of 6.8%) and control (an increase of 1.8%) groups (p = 0.20). Data on longer-term effects were inconclusive. CONCLUSIONS: This study adds to the growing body of literature that indicates that guided CBT for insomnia can be delivered through the Internet. Patients accept the format and their sleep improves.

Unaltered instrumental learning and attenuated body-weight gain in rats during non-rotating simulated shiftwork.

Exposure to shiftwork has been associated with multiple health disorders and cognitive impairments in humans. We tested if we could replicate metabolic and cognitive consequences of shiftwork, as reported in humans, in a rat model comparable to 5 wks of non-rotating night shifts. The following hypotheses were addressed: (i) shiftwork enhances body-weight gain, which would indicate metabolic effects; and (ii) shiftwork negatively affects learning of a simple goal-directed behavior, i.e., the association of lever pressing with food reward (instrumental learning), which would indicate cognitive effects. We used a novel method of forced locomotion to model work during the animals' normal resting period. We first show that Wistar rats, indeed, are active throughout a shiftwork protocol. In contrast with previous findings, the shiftwork protocol attenuated the normal weight gain to 76 ± 8 g in 5 wks as compared to 123 ± 15 g in the control group. The discrepancy with previous work may be explained by the concurrent observation that with our shiftwork protocol rats did not adjust their between-work circadian activity pattern. They maintained a normal level of activity during the "off-work" periods. In the control experiment, rats were kept active during the dark period, normally dominated by activity. This demonstrated that forced activity, per se, did not affect body-weight gain (mean ± SEM: 85 ± 11 g over 5 wks as compared to 84 ± 11 g in the control group). Rats were trained on an instrumental learning paradigm during the fifth week of the protocol. All groups showed equivalent increases in lever pressing from the first (3.8 ± .7) to the sixth (21.3 ± 2.4) session, and needed a similar amount of sessions (5.1 ± .3) to reach a learning criterion (≥ 27 out of 30 lever presses). These results suggest that while on prolonged non-rotating shiftwork, not fully reversing the circadian rhythm might actually be beneficial to prevent body-weight gain and cognitive impairments.

Slow brain oscillations of sleep, resting state, and vigilance.

The most important quest of cognitive neuroscience may be to unravel the mechanisms by which the brain selects, links, consolidates, and integrates new information into its neuronal network, while preventing saturation to occur. During the past decade, neuroscientists working within several disciplines have observed an important involvement of the specific types of brain oscillations that occur during sleep--the cortical slow oscillations; during the resting state--the fMRI resting state networks including the default-mode network (DMN); and during task performance--the performance modulations that link as well to modulations in electroencephalography or magnetoencephalography frequency content. Understanding the role of these slow oscillations thus appears to be essential for our fundamental understanding of brain function. Brain activity is characterized by oscillations occurring in spike frequency, field potentials or blood oxygen level-dependent functional magnetic resonance imaging signals. Environmental stimuli, reaching the brain through our senses, activate or inactivate neuronal populations and modulate ongoing activity. The effect they sort is to a large extent determined by the momentary state of the slow endogenous oscillations of the brain. In the absence of sensory input, as is the case during rest or sleep, brain activity does not cease. Rather, its oscillations continue and change with respect to their dominant frequencies and coupling topography. This chapter briefly introduces the topics that will be addressed in this dedicated volume of Progress in Brain Research on slow oscillations and sets the stage for excellent papers discussing their molecular, cellular, network physiological and cognitive performance aspects. Getting to know about slow oscillations is essential for our understanding of plasticity, memory, brain structure from synapse to DMN, cognition, consciousness, and ultimately for our understanding of the mechanisms and functions of sleep and vigilance.

Increases in extracellular serotonin and dopamine metabolite levels in the basal forebrain during sleep deprivation.

The basal forebrain (BF) is an important mediator of cortical arousal, which is innervated by all ascending arousal systems. During sleep deprivation (SD) a site-specific accumulation of sleep factors in the BF results in increased sleep pressure (Kalinchuk et al., 2006; Porkka-Heiskanen et al., 1997; Porkka-Heiskanen et al., 2000). However, animals are able to stay awake and even increase their neuronal activity in the BF and cortex during SD, suggesting increased activity of the ascending arousal systems to counteract the effect of sleep pressure. This study used in vivo microdialysis to measure the effect of a 6h SD, by "gentle handling" in freely moving rats, on the extracellular levels of serotonin and dopamine metabolites (5-HIAA, and DOPAC and HVA respectively) in the BF. Additionally, because glucocorticoids can interact with monoaminergic neurotransmission, and SD could be stressful, corticosterone levels were measured. We found an increase in extracellular serotonin and dopamine metabolite levels (n=8, p≤0.05). No interaction between corticosterone and the monoaminergic systems was apparent. Extracellular corticosterone levels showed no increase during the first 3h of SD, and the subsequent increase (n=8, p≤0.05) did not result in values exceeding the normal diurnal maximum, indicating that no substantial stress was induced. The results demonstrate that SD increases extracellular dopamine and serotonin metabolites in the BF, suggesting increased activity of the ascending arousal systems. It remains to be investigated what the specific roles of the dopaminergic and serotonergic ascending arousal systems are in BF-mediated cortical arousal.

Dynamics underlying spontaneous human alpha oscillations: a data-driven approach.

Although the cognitive and clinical correlates of spontaneous human alpha oscillations as recorded with electroencephalography (EEG) or magnetoencephalography (MEG) are well documented, the dynamics underlying these oscillations is still a matter of debate. This study proposes a data-driven method to reveal the dynamics of these oscillations. It demonstrates that spontaneous human alpha oscillations as recorded with MEG can be viewed as noise-perturbed damped harmonic oscillations. This provides evidence for the hypothesis that these oscillations reflect filtered noise and hence do not possess limit-cycle dynamics. To illustrate the use of the model, we apply it to two data-sets in which a decrease in alpha power can be observed across conditions. The associated differences in the estimated model parameters show that observed decreases in alpha power are associated with different kinds of changes in the dynamics. Thus, the model parameters are useful dynamical biomarkers for spontaneous human alpha oscillations.

Chronic insomnia: clinical and research challenges--an agenda.

Chronic insomnia afflicts up to 10% of the population in Western industrialized countries. It is characterized by delayed sleep onset, problems in maintaining sleep, early morning awakening or the feeling of non-restorative sleep coupled with significant daytime impairments on an emotional, social or professional level. It can occur as a co-morbid condition in any other medical or mental disorder, but also as a primary condition. Within the last decade new diagnostic and differential diagnostic approaches have been suggested that enhance diagnostic precision. Epidemiological data and data relating to the health care and cost situation of chronic insomnia suggest a huge burden for society. Chronic insomnia leads to a clear-cut increased risk for psychopathology (i. e., affective disorders) and probably also for cardiovascular and metabolic dysfunction. The pathophysiology of the condition is still poorly understood and will profit from integrating modern neuroscientific approaches (animal studies, molecular biology, neuroimaging, neurophysiology, etc.). Current treatment strategies are mainly based on cognitive behavioural interventions (CBT-I) and hypnotic treatment with benzodiazepine receptor agonists and sedating antidepressants. Although the effectiveness of these treatments has been clearly demonstrated, a substantial proportion of patients proves to be treatment-resistant or profits only poorly. The question of long-term pharmaceutical treatment of chronic insomnia, at least in Europe, is unresolved and urgently needs answers. Novel rational treatment avenues require clues on causes and mechanisms from integrated neuroscientific approaches. The important issues concerning insomnia treatment in the future especially in Europe will be reviewed and discussed critically.