The European Insomnia Guideline: An update on the diagnosis and treatment of insomnia 2023.

Progress in the field of insomnia since 2017 necessitated this update of the European Insomnia Guideline. Recommendations for the diagnostic procedure for insomnia and its comorbidities are: clinical interview (encompassing sleep and medical history); the use of sleep questionnaires and diaries (and physical examination and additional measures where indicated) (A). Actigraphy is not recommended for the routine evaluation of insomnia (C), but may be useful for differential-diagnostic purposes (A). Polysomnography should be used to evaluate other sleep disorders if suspected (i.e. periodic limb movement disorder, sleep-related breathing disorders, etc.), treatment-resistant insomnia (A) and for other indications (B). Cognitive-behavioural therapy for insomnia is recommended as the first-line treatment for chronic insomnia in adults of any age (including patients with comorbidities), either applied in-person or digitally (A). When cognitive-behavioural therapy for insomnia is not sufficiently effective, a pharmacological intervention can be offered (A). Benzodiazepines (A), benzodiazepine receptor agonists (A), daridorexant (A) and low-dose sedating antidepressants (B) can be used for the short-term treatment of insomnia (≤ 4 weeks). Longer-term treatment with these substances may be initiated in some cases, considering advantages and disadvantages (B). Orexin receptor antagonists can be used for periods of up to 3 months or longer in some cases (A). Prolonged-release melatonin can be used for up to 3 months in patients ≥ 55 years (B). Antihistaminergic drugs, antipsychotics, fast-release melatonin, ramelteon and phytotherapeutics are not recommended for insomnia treatment (A). Light therapy and exercise interventions may be useful as adjunct therapies to cognitive-behavioural therapy for insomnia (B).

Light Therapy for Cancer-Related Fatigue in (Non-)Hodgkin Lymphoma Survivors: Results of a Randomized Controlled Trial.

PURPOSE: To evaluate the short- and long-term effects of light therapy on fatigue (primary outcome) and sleep quality, depression, anxiety, quality of life, and circadian rhythms (secondary outcomes) in survivors of (non-)Hodgkin lymphoma presenting with chronic cancer-related fatigue. METHODS: We randomly assigned 166 survivors (mean survival 13 years) to a bright white light intervention (BWL) or dim white light comparison (DWL) group. Measurements were completed at baseline (T0), post-intervention (T1), at three (T2), and nine (T3) months follow-up. A mixed-effect modeling approach was used to compare linear and non-linear effects of time between groups. RESULTS: There were no significant differences between BWL and DWL in the reduction in fatigue over time. Both BWL and DWL significantly (p < 0.001) improved fatigue levels during the intervention followed by a slight reduction in this effect during follow-up (EST0-T1 = -0.71; EST1-T3 = 0.15). Similar results were found for depression, sleep quality, and some aspects of quality of life. Light therapy had no effect on circadian rhythms. CONCLUSIONS: BWL was not superior in reducing fatigue compared to DWL in HL and DLBCL survivors. Remarkably, the total sample showed clinically relevant and persistent improvements on fatigue not commonly seen in longitudinal observational studies in these survivors.

Insulin resistance as a marker for the immune-metabolic subtype of depression.

OBJECTIVE: Insulin resistance (IR), a marker of metabolic dysregulation and pro-inflammatory state, moderates the antidepressant treatment effect in patients with type 2 diabetes (T2D) and is therefore a potential marker for personalized treatment. Based on data from a light therapy trial (NTR4942), we aimed to evaluate whether 1) depression symptoms differ according to the level of IR, and 2) improvement of specific depression symptoms drive the positive effects of light therapy in those with higher IR. METHODS: This secondary analysis in 59 individuals with depression and T2D explored differences in depressive symptom profile (30-item Inventory of Depressive Symptomatology (IDS)) at baseline and in response to light therapy (versus placebo), between lower and higher IR individuals, using Likelihood Ratio tests and Linear-by-linear association. IR was measured using the gold standard, a hyperinsulinemic-euglycaemic clamp. RESULTS: At baseline, higher IR individuals reported more symptoms of irritability (p=0.024) anhedonia (no interest in people and activities: p=0.011; absence of pleasure and enjoyment: p=0.021), fatigue (fatigue: p=0.036; physical fatigue: p=0.035) and hypersomnia (p=0.029) relative to persons with lower IR, who reported more insomnia (nightly awakening: p=0.041; early morning awakening: p=0.012). Light therapy led to an improvement across IDS symptoms in higher IR individuals, while in lower IR individuals, light therapy improved early morning awakening (p=0.005) and interest in people and activities (p=0.015), but worsened mood (feeling sad: p=0.001; feeling irritable: p=0.002; interpersonal sensitivity: p=0.014). CONCLUSIONS: Results add to the hypothesis of an immune-metabolic subtype of depression, and suggest that IR might be a promising focus for precision medicine.

Non-pharmacological treatment for insomnia following acquired brain injury: A systematic review.

Insomnia symptoms following acquired brain injury are serious and common, associated with cognitive and emotional complaints. This systematic review aims to summarize and appraise the current knowledge regarding the efficacy of non-pharmacological treatments for insomnia after traumatic brain injury and stroke in adults. A systematic search in the electronic databases of Medline, PsycINFO and Embase was conducted on January 15, 2019. The search strategy included traumatic brain injury or stroke and a combination of keywords and Boolean operators to represent the concept of insomnia. Articles were restricted to those in English and study populations of human adults. A total of 4341 studies were found, of which 16 were included, representing seven different non-pharmacological treatments. While the quality and quantity of the studies does not allow for firm conclusions, the outcomes suggest that cognitive behavioural therapy improves insomnia and sleep quality. The results highlight the need for larger studies of better methodological quality on non-pharmacological interventions for insomnia following brain injury.

Bright light therapy for depression in Parkinson disease: A randomized controlled trial.

OBJECTIVE: To assess the efficacy of bright light therapy (BLT) in reducing depressive symptoms in patients with Parkinson disease (PD) and major depressive disorder (MDD) compared to a control light. METHODS: In this double-blind controlled trial, we randomized patients with PD and MDD to treatment with BLT (±10,000 lux) or a control light (±200 lux). Participants were treated for 3 months, followed by a 6-month naturalistic follow-up. The primary outcome of the study was the Hamilton Depression Rating Scale (HDRS) score. Secondary outcomes were objective and subjective sleep measures and salivary melatonin and cortisol concentrations. Assessments were repeated halfway, at the end of treatment, and 1, 3, and 6 months after treatment. Data were analyzed with a linear mixed-model analysis. RESULTS: We enrolled 83 participants. HDRS scores decreased in both groups without a significant between-group difference at the end of treatment. Subjective sleep quality improved in both groups, with a larger improvement in the BLT group (B [SE] = 0.32 [0.16], p = 0.04). Total salivary cortisol secretion decreased in the BLT group, while it increased in the control group (B [SE] = -8.11 [3.93], p = 0.04). CONCLUSION: BLT was not more effective in reducing depressive symptoms than a control light. Mood and subjective sleep improved in both groups. BLT was more effective in improving subjective sleep quality than control light, possibly through a BLT-induced decrease in cortisol levels. CLINICALTRIALSGOV IDENTIFIER: NCT01604876. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that BLT is not superior to a control light device in reducing depressive symptoms in patients with PD with MDD.

Effects of Light Therapy on Mood and Insulin Sensitivity in Patients With Type 2 Diabetes and Depression: Results From a Randomized Placebo-Controlled Trial.

OBJECTIVE: Depression is common in patients with type 2 diabetes and adversely affects quality of life and diabetes outcomes. We assessed whether light therapy, an antidepressant, improves mood and insulin sensitivity in patients with depression and type 2 diabetes. RESEARCH DESIGN AND METHODS: This randomized, double-blind, placebo-controlled trial included 83 patients with depression and type 2 diabetes. The intervention comprised 4 weeks of light therapy (10,000 lux) or placebo light therapy daily at home. Primary outcomes included depressive symptoms (Inventory of Depressive Symptomatology [IDS]) and insulin sensitivity (M-value derived from the results of a hyperinsulinemic-euglycemic clamp). Secondary outcomes were related psychological and glucometabolic measures. RESULTS: Intention-to-treat analysis showed that light therapy was not superior to placebo in reducing depressive symptoms (-3.9 IDS points [95% CI -9.0 to 1.2]; P = 0.248) and had no effect on insulin sensitivity (0.15 mg/kg*min [95% CI -0.41 to 0.70]; P = 0.608). Analyses incorporating only those participants who accurately adhered to the light therapy protocol (n = 51) provided similar results, but did suggest positive effects of light therapy on depression response rates (≥50% reduction in IDS points) (26% more response; P = 0.031). Prespecified analysis showed effect moderation by baseline insulin sensitivity (P = 0.009) and use of glucose-lowering medication (P = 0.023). Light therapy did not affect depressive symptoms in participants with higher insulin sensitivity or those who use only oral glucose-lowering medication or none at all, but it did produce a relevant effect in participants with lower insulin sensitivity (-12.9 IDS points [95% CI -21.6 to -4.2]; P = 0.017) and a trend toward effectiveness in those using insulin (-12.2 IDS points [95% CI -21.3 to -3.1]; P = 0.094). Light therapy was well tolerated. CONCLUSIONS: Although this trial is essentially inconclusive, secondary analyses indicate that light therapy might be a promising treatment for depression among a subgroup of highly insulin-resistant individuals with type 2 diabetes.

Light rescues circadian behavior and brain dopamine abnormalities in diurnal rodents exposed to a winter-like photoperiod.

Seasonal affective disorder (SAD), beyond mood changes, is characterized by alterations in daily rhythms of behavior and physiology. The pathophysiological conditions of SAD involve changes in day length and its first-line treatment is bright light therapy. Animal models using nocturnal rodents have been studied to elucidate the neurobiological mechanisms of depression, but might be ill suited to study the therapeutic effects of light in SAD since they exhibit light-aversive responses. Here Arvicanthis ansorgei, a diurnal rodent, was used to determine behavioral, molecular and brain dopamine changes in response to exposure to a winter-like photoperiod consisting of a light-dark cycle with 8 h of light, under diminished light intensity, and 16 h of darkness. Furthermore, we evaluated whether timed-daily bright light exposure has an effect on behavior and brain physiology of winter-like exposed animals. Arvicanthis under a winter-like condition showed alterations in the synchronization of the locomotor activity rhythm to the light-dark cycle. Moreover, alterations in day-night activity of dopaminergic neurotransmission were revealed in the nucleus accumbens and the dorsal striatum, and in the day-night clock gene expression in the suprachiasmatic nucleus. Interestingly, whereas dopamine disturbances were reversed in animals exposed to daily light at early or late day, altered phase of the daily rhythm of locomotion was reverted only in animals exposed to light at the late day. Moreover, Per2 gene expression in the SCN was also affected by light exposure at late day in winter-like exposed animals. These findings suggest that light induces effects on behavior by mechanisms that rely on both circadian and rhythm-independent pathways influencing the dopaminergic circuitry. This last point might be crucial for understanding the mechanisms of non-pharmacological treatment in SAD.

Progression of Dementia Assessed by Temporal Correlations of Physical Activity: Results From a 3.5-Year, Longitudinal Randomized Controlled Trial.

Cross-sectional studies show that activity fluctuations in healthy young adults possess robust temporal correlations that become altered with aging, and in dementia and depression. This study was designed to test whether or not within-subject changes of activity correlations (i) track the clinical progression of dementia, (ii) reflect the alterations of depression symptoms in patients with dementia, and (iii) can be manipulated by clinical interventions aimed at stabilizing circadian rhythmicity and improving sleep in dementia, namely timed bright light therapy and melatonin supplementation. We examined 144 patients with dementia (70-96 years old) who were assigned to daily treatment with bright light, bedtime melatonin, both or placebos only in a 3.5-year double-blinded randomized clinical trial. We found that activity correlations at temporal scales <~2 hours significantly decreased over time and that light treatment attenuated the decrease by ~73%. Moreover, the decrease of temporal activity correlations positively correlated with the degrees of cognitive decline and worsening of mood though the associations were relatively weak. These results suggest a mechanistic link between multiscale activity regulation and circadian/sleep function in dementia patients. Whether temporal activity patterns allow unobtrusive, long-term monitoring of dementia progression and mood changes is worth further investigation.

Resting-State fMRI Functional Connectivity Is Associated with Sleepiness, Imagery, and Discontinuity of Mind.

Resting-state functional magnetic resonance imaging (rs-fMRI) is widely used to investigate the functional architecture of the healthy human brain and how it is affected by learning, lifelong development, brain disorders or pharmacological intervention. Non-sensory experiences are prevalent during rest and must arise from ongoing brain activity, yet little is known about this relationship. Here, we used two runs of rs-fMRI both immediately followed by the Amsterdam Resting-State Questionnaire (ARSQ) to investigate the relationship between functional connectivity within ten large-scale functional brain networks and ten dimensions of thoughts and feelings experienced during the scan in 106 healthy participants. We identified 11 positive associations between brain-network functional connectivity and ARSQ dimensions. 'Sleepiness' exhibited significant associations with functional connectivity within Visual, Sensorimotor and Default Mode networks. Similar associations were observed for 'Visual Thought' and 'Discontinuity of Mind', which may relate to variation in imagery and thought control mediated by arousal fluctuations. Our findings show that self-reports of thoughts and feelings experienced during a rs-fMRI scan help understand the functional significance of variations in functional connectivity, which should be of special relevance to clinical studies.

Light therapy for better mood and insulin sensitivity in patients with major depression and type 2 diabetes: a randomised, double-blind, parallel-arm trial.

BACKGROUND: Major depression and type 2 diabetes often co-occur. Novel treatment strategies for depression in type 2 diabetes patients are warranted, as depression in type 2 diabetes patients is associated with poor prognosis and treatment results. Major depression and concurrent sleep disorders have been related to disturbances of the biological clock. The biological clock is also involved in regulation of glucose metabolism by modulating peripheral insulin sensitivity. Light therapy has been shown to be an effective antidepressant that 'resets' the biological clock. We here describe the protocol of a study that evaluates the hypothesis that light therapy improves mood as well as insulin sensitivity in patients with a major depressive episode and type 2 diabetes. METHODS/DESIGN: This study is a randomised, double-blind, parallel-arm trial in 98 participants with type 2 diabetes and a major depressive episode, according to DSM-IV criteria. We will assess whether light therapy improves depressive symptoms and insulin sensitivity, our primary outcome measures, and additionally investigate whether these effects are mediated by restoration of the circadian rhythmicity, as measured by sleep and hypothalamic-pituitary-adrenal axis activity. Participants will be randomly allocated to a bright white-yellowish light condition or dim green light condition. Participants will undergo light therapy for half an hour every morning for 4 weeks at home. At several time points, namely before the start of light therapy, during light therapy, after completion of 4 weeks of light therapy and after 4 weeks follow-up, several psychometrical, psychophysiological and glucometabolic measures will be performed. DISCUSSION: If light therapy effectively improves mood and insulin sensitivity in type 2 diabetes patients with a major depressive episode, light therapy may be a valuable patient friendly addition to the currently available treatment strategies. Additionally, if our data support the role of restoration of circadian rhythmicity, such an observation may guide further development of chronobiological treatment strategies in this patient population. TRIAL REGISTRATION: The Netherlands Trial Register (NTR) NTR4942 . Registered 13 January 2015.

Effectiveness of internet-supported cognitive behavioral and chronobiological interventions and effect moderation by insomnia subtype: study protocol of a randomized controlled trial.

BACKGROUND: DSM-V criteria for insomnia disorder are met by 6 to 10% of the adult population. Insomnia has severe consequences for health and society. One of the most common treatments provided by primary caregivers is pharmacological treatment, which is far from optimal and has not been recommended since a 2005 consensus report of the National Institutes of Health. The recommended treatment is Cognitive Behavioral Therapy for Insomnia. Effectiveness, however, is still limited. Only a few studies have evaluated the effectiveness of chronobiological treatments, including the timed application of bright light, physical activity and body warming. Another opportunity for optimization of treatment is based on the idea that the people suffering from insomnia most likely represent a heterogeneous mix of subtypes, with different underlying causes and expected treatment responses. The present study aims to evaluate the possibility for optimizing insomnia treatment along the principles of personalized and stratified medicine. It evaluates the following: 1. The relative effectiveness of internet-supported cognitive behavioral therapy, bright light, physical activity and body warming; 2. Whether the effectiveness of internet-supported cognitive behavioral therapy for insomnia can be augmented by simultaneous or prior application of bright light, physical activity and body warming; and 3. Whether the effectiveness of the interventions and their combination are moderated by the insomnia subtype. METHODS/DESIGN: In a repeated measures, placebo-controlled, randomized clinical trial that included 160 people diagnosed with insomnia disorder, we are evaluating the relative effectiveness of 4 intervention weeks. Primary outcome is subjective sleep efficiency, quantified using a sleep diary. Secondary outcomes include other complaints of sleep and daytime functioning, health-related cost estimates and actigraphic objective sleep estimates. Compliance will be monitored both subjectively and objectively using activity, light and temperature sensors. Insomnia subtypes will be assessed using questionnaires. Mixed effect models will be used to evaluate intervention effects and moderation by insomnia subtype ratings. DISCUSSION: The current study addresses multiple opportunities to optimize and personalize treatment of insomnia disorder. TRIAL REGISTRATION: Netherlands National Trial Register NTR4010, 4 June 2013.

Modulation of γ and spindle-range power by slow oscillations in scalp sleep EEG of children.

Deep sleep is characterized by slow waves of electrical activity in the cerebral cortex. They represent alternating down states and up states of, respectively, hyperpolarization with accompanying neuronal silence and depolarization during which neuronal firing resumes. The up states give rise to faster oscillations, notably spindles and gamma activity which appear to be of major importance to the role of sleep in brain function and cognition. Unfortunately, while spindles are easily detectable, gamma oscillations are of very small amplitude. No previous sleep study has succeeded in demonstrating modulations of gamma power along the time course of slow waves in human scalp EEG. As a consequence, progress in our understanding of the functional role of gamma modulation during sleep has been limited to animal studies and exceptional human studies, notably those of intracranial recordings in epileptic patients. Because high synaptic density, which peaks some time before puberty depending on the brain region (Huttenlocher and Dabholkar, 1997), generates oscillations of larger amplitude, we considered that the best chance to demonstrate a modulation of gamma power by slow wave phase in regular scalp sleep EEG would be in school-aged children. Sleep EEG was recorded in 30 healthy children (aged 10.7 ± 0.8 years; mean ± s.d.). Time-frequency analysis was applied to evaluate the time course of spectral power along the development of a slow wave. Moreover, we attempted to modify sleep architecture and sleep characteristics through automated acoustic stimulation coupled to the occurrence of slow waves in one subset of the children. Gamma power increased on the rising slope and positive peak of the slow wave. Gamma and spindle activity is strongly suppressed during the negative peak. There were no differences between the groups who received and did not receive acoustic stimulation in the sleep parameters and slow wave-locked time-frequency analysis. Our findings show, for the first time in scalp EEG in humans, that gamma activity is associated with the up-going slope and peak of the slow wave. We propose that studies in children provide a uniquely feasible opportunity to conduct investigations into the role of gamma during sleep.

Reduction of nocturnal slow-wave activity affects daytime vigilance lapses and memory encoding but not reaction time or implicit learning.

Total sleep deprivation in healthy subjects has a profound effect on the performance on tasks measuring sustained attention or vigilance. We here report how a selective disruption of deep sleep only, that is, selective slow-wave activity (SWA) reduction, affects the performance of healthy well-sleeping subjects on several tasks: a "simple" and a "complex" vigilance task, a declarative learning task, and an implicit learning task despite unchanged duration of sleep. We used automated electroencephalogram (EEG) dependent acoustic feedback aimed at selective interference with-and reduction of-SWA. In a within-subject repeated measures crossover design, performance on the tasks was assessed in 13 elderly adults without sleep complaints after either SWA-reduction or after normal sleep. The number of vigilance lapses increased as a result of SWA reduction, irrespective of the type of vigilance task. Recognition on the declarative memory task was also affected by SWA reduction, associated with a decreased activation of the right hippocampus on encoding (measured with fMRI) suggesting a weaker memory trace. SWA reduction, however, did not affect reaction time on either of the vigilance tasks or implicit memory task performance. These findings suggest a specific role of slow oscillations in the subsequent daytime ability to maintain sustained attention and to encode novel declarative information but not to maintain response speed or to build implicit memories. Of particular interest is that selective SWA reduction can mimic some of the effects of total sleep deprivation, while not affecting sleep duration.

Bright light treatment in elderly patients with nonseasonal major depressive disorder: a randomized placebo-controlled trial.

CONTEXT: Major depressive disorder (MDD) in elderly individuals is prevalent and debilitating. It is accompanied by circadian rhythm disturbances associated with impaired functioning of the suprachiasmatic nucleus, the biological clock of the brain. Circadian rhythm disturbances are common in the elderly. Suprachiasmatic nucleus stimulation using bright light treatment (BLT) may, therefore, improve mood, sleep, and hormonal rhythms in elderly patients with MDD. OBJECTIVE: To determine the efficacy of BLT in elderly patients with MDD. DESIGN: Double-blind, placebo-controlled randomized clinical trial. SETTING: Home-based treatment in patients recruited from outpatient clinics and from case-finding using general practitioners' offices in the Amsterdam region. PARTICIPANTS: Eighty-nine outpatients 60 years or older who had MDD underwent assessment at baseline (T0), after 3 weeks of treatment (T1), and 3 weeks after the end of treatment (T2). Intervention Three weeks of 1-hour early-morning BLT (pale blue, approximately 7500 lux) vs placebo (dim red light, approximately 50 lux). MAIN OUTCOME MEASURES: Mean improvement in Hamilton Scale for Depression scores at T1 and T2 using parameters of sleep and cortisol and melatonin levels. RESULTS: Intention-to-treat analysis showed Hamilton Scale for Depression scores to improve with BLT more than placebo from T0 to T1 (7%; 95% confidence interval, 4%-23%; P = .03) and from T0 to T2 (21%; 7%-31%; P = .001). At T1 relative to T0, get-up time after final awakening in the BLT group advanced by 7% (P < .001), sleep efficiency increased by 2% (P = .01), and the steepness of the rise in evening melatonin levels increased by 81% (P = .03) compared with the placebo group. At T2 relative to T0, get-up time was still advanced by 3% (P = .001) and the 24-hour urinary free cortisol level was 37% lower (P = .003) compared with the placebo group. The evening salivary cortisol level had decreased by 34% in the BLT group compared with an increase of 7% in the placebo group (P = .02). CONCLUSIONS: In elderly patients with MDD, BLT improved mood, enhanced sleep efficiency, and increased the upslope melatonin level gradient. In addition, BLT produced continuing improvement in mood and an attenuation of cortisol hyperexcretion after discontinuation of treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier NCT00332670.

Prevention of depression and sleep disturbances in elderly with memory-problems by activation of the biological clock with light--a randomized clinical trial.

BACKGROUND: Depression frequently occurs in the elderly and in patients suffering from dementia. Its cause is largely unknown, but several studies point to a possible contribution of circadian rhythm disturbances. Post-mortem studies on aging, dementia and depression show impaired functioning of the suprachiasmatic nucleus (SCN) which is thought to be involved in the increased prevalence of day-night rhythm perturbations in these conditions. Bright light enhances neuronal activity in the SCN. Bright light therapy has beneficial effects on rhythms and mood in institutionalized moderate to advanced demented elderly. In spite of the fact that this is a potentially safe and inexpensive treatment option, no previous clinical trial evaluated the use of long-term daily light therapy to prevent worsening of sleep-wake rhythms and depressive symptoms in early to moderately demented home-dwelling elderly. METHODS/DESIGN: This study investigates whether long-term daily bright light prevents worsening of sleep-wake rhythms and depressive symptoms in elderly people with memory complaints. Patients with early Alzheimer's Disease (AD), Mild Cognitive Impairment (MCI) and Subjective Memory Complaints (SMC), between the ages of 50 and 75, are included in a randomized double-blind placebo-controlled trial. For the duration of two years, patients are exposed to approximately 10,000 lux in the active condition or approximately 300 lux in the placebo condition, daily, for two half-hour sessions at fixed times in the morning and evening. Neuropsychological, behavioral, physiological and endocrine measures are assessed at baseline and follow-up every five to six months. DISCUSSION: If bright light therapy attenuates the worsening of sleep-wake rhythms and depressive symptoms, it will provide a measure that is easy to implement in the homes of elderly people with memory complaints, to complement treatments with cholinesterase inhibitors, sleep medication or anti-depressants or as a stand-alone treatment. TRIAL REGISTRATION: ISRCTN29863753.

Sleep loss affects vigilance: effects of chronic insomnia and sleep therapy.

Although complaints of impaired daytime functioning are essential to the diagnosis of primary insomnia, objective evidence for cognitive dysfunction has been hard to establish. A prerequisite for understanding the neurocognitive consequences of primary insomnia is to establish task paradigms that robustly differentiate insomniacs from well-sleeping subjects. We hypothesized that the decline in performance that typically occurs with an increasing cognitive demand would provide a more sensitive measure than performance on a single task version. The hypothesis was tested, first, by assessing the performance on two vigilance tasks with different cognitive demands in 25 elderly patients with primary insomnia and 13 healthy well-sleeping age-matched subjects. Secondly, we investigated the performance response to sleep therapy using a waiting-list controlled design. Sleep therapy consisted of a multi-component intervention including sleep restriction, cognitive behavioral therapy, bright-light therapy, structured physical activity and body temperature manipulations. The results show that insomniacs differed markedly from controls in their reaction times across tasks with different cognitive demands: patients responded faster on the 'simple' vigilance task, yet slower on the 'complex' vigilance task. Sleep therapy effectively restored normal performance: patients became significantly slower on the 'simple' task and faster on the 'complex' task, returning to the performance levels of control subjects. These findings indicate that the performance decline associated with increasing cognitive demands is possibly the first sensitive and robust measure of the neurocognitive sequelae of insomnia. We suggest that future studies on cognition in primary insomnia should apply a design that varies task demands.

Prefrontal hypoactivation and recovery in insomnia.

STUDY OBJECTIVES: Although subjective complaints about daytime cognitive functioning are an essential symptom of chronic insomnia, abnormalities in functional brain activation have not previously been investigated. This study was designed to investigate functional brain activation differences as a possible result of chronic insomnia, and the reversibility of these differences after nonmedicated sleep therapy. DESIGN: Insomniacs and carefully matched controls underwent functional magnetic resonance imaging (fMRI) scanning during the performance of a category and a letter fluency task. Insomniacs were randomly assigned to either a 6-week period of nonpharmacological sleep therapy or a wait list period, after which fMRI scanning was repeated using parallel tasks. Task-related brain activation and number of generated words were considered as outcome measures. SETTING: The outpatient sleep clinic of the VU University Medical Center, Department of Clinical Neurophysiology; fMRI was performed at the Department of Radiology. PARTICIPANTS: Twenty-one patients suffering from chronic insomnia and 12 matched controls. INTERVENTIONS: Nonpharmacological sleep therapy for 6 weeks, consisting of cognitive behavioral therapy, body temperature and bright light interventions, sleep hygiene, and physical activity counseling. MEASUREMENT AND RESULTS: Compared to controls, insomnia patients showed hypoactivation of the medial and inferior prefrontal cortical areas (Brodmann Area 9, 44-45), which recovered after sleep therapy but not after a wait list period. CONCLUSIONS: Insomnia interferes in a reversible fashion with activation of the prefrontal cortical system during daytime task performance.

Bright light in elderly subjects with nonseasonal major depressive disorder: a double blind randomised clinical trial using early morning bright blue light comparing dim red light treatment.

BACKGROUND: Depression frequently occurs in the elderly. Its cause is largely unknown, but several studies point to disturbances of biological rhythmicity. In both normal aging, and depression, the functioning of the suprachiasmatic nucleus (SCN) is impaired, as evidenced by an increased prevalence of day-night rhythm perturbations, such as sleeping disorders. Moreover, the inhibitory SCN neurons on the hypothalamus-pituitary adrenocortical axis (HPA-axis) have decreased activity and HPA-activity is enhanced, when compared to non-depressed elderly. Using bright light therapy (BLT) the SCN can be stimulated. In addition, the beneficial effects of BLT on seasonal depression are well accepted. BLT is a potentially safe, nonexpensive and well accepted treatment option. But the current literature on BLT for depression is inconclusive. METHODS/DESIGN: This study aims to show whether BLT can reduce non-seasonal major depression in elderly patients. Randomized double blind placebo controlled trial in 126 subjects of 60 years and older with a diagnosis of major depressive disorder (MDD, DSM-IV/SCID-I). Subjects are recruited through referrals of psychiatric outpatient clinics and from case finding from databases of general practitioners and old-people homes in the Amsterdam region. After inclusion subjects are randomly allocated to the active (bright blue light) vs. placebo (dim red light) condition using two Philips Bright Light Energy boxes type HF 3304 per subject, from which the light bulbs have been covered with bright blue- or dim red light- permitting filters. Patients will be stratified by use of antidepressants. Prior to treatment a one-week period without light treatment will be used. At three time points several endocrinological, psychophysiological, psychometrically, neuropsychological measures are performed: just before the start of light therapy, after completion of three weeks therapy period, and three weeks thereafter. DISCUSSION: If BLT reduces nonseasonal depression in elderly patients, then additional lighting may easily be implemented in the homes of patients to serve as add-on treatment to antidepressants or as a stand-alone treatment in elderly depressed patients. In addition, if our data support the role of a dysfunctional biological clock in depressed elderly subjects, such a finding may guide further development of novel chronobiological oriented treatment strategies. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00332670.

The relationship between insomnia and body temperatures.

Sleepiness and sleep propensity are strongly influenced by our circadian clock as indicated by many circadian rhythms, most commonly by that of core body temperature. Sleep is most conducive in the temperature minimum phase, but is inhibited in a "wake maintenance zone" before the minimum phase, and is disrupted in a zone following that phase. Different types of insomnia symptoms have been associated with abnormalities of the body temperature rhythm. Sleep onset insomnia is associated with a delayed temperature rhythm presumably, at least partly, because sleep is attempted during a delayed evening wake maintenance zone. Morning bright light has been used to phase advance circadian rhythms and successfully treat sleep onset insomnia. Conversely, early morning awakening insomnia has been associated with a phase advanced temperature rhythm and has been successfully treated with the phase delaying effects of evening bright light. Sleep maintenance insomnia has been associated not with a circadian rhythm timing abnormality, but with nocturnally elevated core body temperature. Combination of sleep onset and maintenance insomnia has been associated with a 24-h elevation of core body temperature supporting the chronic hyper-arousal model of insomnia. The possibility that these last two types of insomnia may be related to impaired thermoregulation, particularly a reduced ability to dissipate body heat from distal skin areas, has not been consistently supported in laboratory studies. Further studies of thermoregulation are needed in the typical home environment in which the insomnia is most evident.

Effect of bright light and melatonin on cognitive and noncognitive function in elderly residents of group care facilities: a randomized controlled trial.

CONTEXT: Cognitive decline, mood, behavioral and sleep disturbances, and limitations of activities of daily living commonly burden elderly patients with dementia and their caregivers. Circadian rhythm disturbances have been associated with these symptoms. OBJECTIVE: To determine whether the progression of cognitive and noncognitive symptoms may be ameliorated by individual or combined long-term application of the 2 major synchronizers of the circadian timing system: bright light and melatonin. DESIGN, SETTING, AND PARTICIPANTS: A long-term, double-blind, placebo-controlled, 2 x 2 factorial randomized trial performed from 1999 to 2004 with 189 residents of 12 group care facilities in the Netherlands; mean (SD) age, 85.8 (5.5) years; 90% were female and 87% had dementia. INTERVENTIONS: Random assignment by facility to long-term daily treatment with whole-day bright (+/- 1000 lux) or dim (+/- 300 lux) light and by participant to evening melatonin (2.5 mg) or placebo for a mean (SD) of 15 (12) months (maximum period of 3.5 years). MAIN OUTCOME MEASURES: Standardized scales for cognitive and noncognitive symptoms, limitations of activities of daily living, and adverse effects assessed every 6 months. RESULTS: Light attenuated cognitive deterioration by a mean of 0.9 points (95% confidence interval [CI], 0.04-1.71) on the Mini-Mental State Examination or a relative 5%. Light also ameliorated depressive symptoms by 1.5 points (95% CI, 0.24-2.70) on the Cornell Scale for Depression in Dementia or a relative 19%, and attenuated the increase in functional limitations over time by 1.8 points per year (95% CI, 0.61-2.92) on the nurse-informant activities of daily living scale or a relative 53% difference. Melatonin shortened sleep onset latency by 8.2 minutes (95% CI, 1.08-15.38) or 19% and increased sleep duration by 27 minutes (95% CI, 9-46) or 6%. However, melatonin adversely affected scores on the Philadelphia Geriatric Centre Affect Rating Scale, both for positive affect (-0.5 points; 95% CI, -0.10 to -1.00) and negative affect (0.8 points; 95% CI, 0.20-1.44). Melatonin also increased withdrawn behavior by 1.02 points (95% CI, 0.18-1.86) on the Multi Observational Scale for Elderly Subjects scale, although this effect was not seen if given in combination with light. Combined treatment also attenuated aggressive behavior by 3.9 points (95% CI, 0.88-6.92) on the Cohen-Mansfield Agitation Index or 9%, increased sleep efficiency by 3.5% (95% CI, 0.8%-6.1%), and improved nocturnal restlessness by 1.00 minute per hour each year (95% CI, 0.26-1.78) or 9% (treatment x time effect). CONCLUSIONS: Light has a modest benefit in improving some cognitive and noncognitive symptoms of dementia. To counteract the adverse effect of melatonin on mood, it is recommended only in combination with light. TRIAL REGISTRATION: controlled-trials.com/isrctn Identifier: ISRCTN93133646.