Effects of calibrated blue-yellow changes in light on the human circadian clock.

Evening exposure to short-wavelength light can affect the circadian clock, sleep and alertness. Intrinsically photosensitive retinal ganglion cells expressing melanopsin are thought to be the primary drivers of these effects. Whether colour-sensitive cones also contribute is unclear. Here, using calibrated silent-substitution changes in light colour along the blue-yellow axis, we investigated whether mechanisms of colour vision affect the human circadian system and sleep. In a 32.5-h repeated within-subjects protocol, 16 healthy participants were exposed to three different light scenarios for 1 h starting 30 min after habitual bedtime: baseline control condition (93.5 photopic lux), intermittently flickering (1 Hz, 30 s on-off) yellow-bright light (123.5 photopic lux) and intermittently flickering blue-dim light (67.0 photopic lux), all calibrated to have equal melanopsin excitation. We did not find conclusive evidence for differences between the three lighting conditions regarding circadian melatonin phase delays, melatonin suppression, subjective sleepiness, psychomotor vigilance or sleep.The Stage 1 protocol for this Registered Report was accepted in principle on 9 September 2020. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.13050215.v1 .

Melanopic irradiance defines the impact of evening display light on sleep latency, melatonin and alertness.

Evening light-emitting visual displays may disrupt sleep, suppress melatonin and increase alertness. Here, we control melanopic irradiance independent of display luminance and colour, in 72 healthy males 4 h before habitual bedtime and expose each of them to one of four luminance levels (i.e., dim light, smartphone, tablet or computer screen illuminance) at a low and a high melanopic irradiance setting. Low melanopic light shortens the time to fall asleep, attenuates evening melatonin suppression, reduces morning melatonin, advances evening melatonin onset and decreases alertness compared to high melanopic light. In addition, we observe dose-dependent increases in sleep latency, reductions in melatonin concentration and delays in melatonin onset as a function of melanopic irradiance-not so for subjective alertness. We identify melanopic irradiance as an appropriate parameter to mitigate the unwanted effects of screen use at night. Our results may help the many people who sit in front of screens in the evening or at night to fall asleep faster, feel sleepier, and have a more stable melatonin phase by spectrally tuning the visual display light without compromising the visual appearance.

Brain activity during a working memory task after daily caffeine intake and caffeine withdrawal: a randomized double-blind placebo-controlled trial.

Acute caffeine intake has been found to increase working memory (WM)-related brain activity in healthy adults without improving behavioral performances. The impact of daily caffeine intake-a ritual shared by 80% of the population worldwide-and of its discontinuation on working memory and its neural correlates remained unknown. In this double-blind, randomized, crossover study, we examined working memory functions in 20 young healthy non-smokers (age: 26.4 ± 4.0 years; body mass index: 22.7 ± 1.4 kg/m2; and habitual caffeine intake: 474.1 ± 107.5 mg/day) in a 10-day caffeine (150 mg × 3 times/day), a 10-day placebo (3 times/day), and a withdrawal condition (9-day caffeine followed by 1-day placebo). Throughout the 10th day of each condition, participants performed four times a working memory task (N-Back, comprising 3- and 0-back), and task-related blood-oxygen-level-dependent (BOLD) activity was measured in the last session with functional magnetic resonance imaging. Compared to placebo, participants showed a higher error rate and a longer reaction time in 3- against 0-back trials in the caffeine condition; also, in the withdrawal condition we observed a higher error rate compared to placebo. However, task-related BOLD activity, i.e., an increased attention network and decreased default mode network activity in 3- versus 0-back, did not show significant differences among three conditions. Interestingly, irrespective of 3- or 0-back, BOLD activity was reduced in the right hippocampus in the caffeine condition compared to placebo. Adding to the earlier evidence showing increasing cerebral metabolic demands for WM function after acute caffeine intake, our data suggest that such demands might be impeded over daily intake and therefore result in a worse performance. Finally, the reduced hippocampal activity may reflect caffeine-associated hippocampal grey matter plasticity reported in the previous analysis. The findings of this study reveal an adapted neurocognitive response to daily caffeine exposure and highlight the importance of classifying impacts of caffeine on clinical and healthy populations.

Melatonin suppression does not automatically alter sleepiness, vigilance, sensory processing, or sleep.

Presleep exposure to short-wavelength light suppresses melatonin and decreases sleepiness with activating effects extending to sleep. This has mainly been attributed to melanopic effects, but mechanistic insights are missing. Thus, we investigated whether two light conditions only differing in the melanopic effects (123 vs. 59 lx melanopic EDI) differentially affect sleep besides melatonin. Additionally, we studied whether the light differentially modulates sensory processing during wakefulness and sleep. Twenty-nine healthy volunteers (18-30 years, 15 women) were exposed to two metameric light conditions (high- vs. low-melanopic, ≈60 photopic lx) for 1 h ending 50 min prior to habitual bed time. This was followed by an 8-h sleep opportunity with polysomnography. Objective sleep measurements were complemented by self-report. Salivary melatonin, subjective sleepiness, and behavioral vigilance were sampled at regular intervals. Sensory processing was evaluated during light exposure and sleep on the basis of neural responses related to violations of expectations in an oddball paradigm. We observed suppression of melatonin by ≈14% in the high- compared to the low-melanopic condition. However, conditions did not differentially affect sleep, sleep quality, sleepiness, or vigilance. A neural mismatch response was evident during all sleep stages, but not differentially modulated by light. Suppression of melatonin by light targeting the melanopic system does not automatically translate to acutely altered levels of vigilance or sleepiness or to changes in sleep, sleep quality, or basic sensory processing. Given contradicting earlier findings and the retinal anatomy, this may suggest that an interaction between melanopsin and cone-rod signals needs to be considered. Clinical Trial Registry: German Clinical Trials Register, DRKS00023602, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023602.

The impact of daily caffeine intake on nighttime sleep in young adult men.

Acute caffeine intake can delay sleep initiation and reduce sleep intensity, particularly when consumed in the evening. However, it is not clear whether these sleep disturbances disappear when caffeine is continuously consumed during daytime, which is common for most coffee drinkers. To address this question, we investigated the sleep of twenty male young habitual caffeine consumers during a double-blind, randomized, crossover study including three 10-day conditions: caffeine (3 × 150 mg caffeine daily), withdrawal (3 × 150 mg caffeine for 8 days, then switch to placebo), and placebo (3 × placebo daily). After 9 days of continuous treatment, electroencephalographically (EEG)-derived sleep structure and intensity were recorded during a scheduled 8-h nighttime sleep episode starting 8 (caffeine condition) and 15 h (withdrawal condition) after the last caffeine intake. Upon scheduled wake-up time, subjective sleep quality and caffeine withdrawal symptoms were assessed. Unexpectedly, neither polysomnography-derived total sleep time, sleep latency, sleep architecture nor subjective sleep quality differed among placebo, caffeine, and withdrawal conditions. Nevertheless, EEG power density in the sigma frequencies (12-16 Hz) during non-rapid eye movement sleep was reduced in both caffeine and withdrawal conditions when compared to placebo. These results indicate that daily caffeine intake in the morning and afternoon hours does not strongly impair nighttime sleep structure nor subjective sleep quality in healthy good sleepers who regularly consume caffeine. The reduced EEG power density in the sigma range might represent early signs of overnight withdrawal from the continuous presence of the stimulant during the day.

Wide awake at bedtime? Effects of caffeine on sleep and circadian timing in male adolescents - A randomized crossover trial.

Adolescents often suffer from short and mistimed sleep. To counteract the resulting daytime sleepiness they frequently consume caffeine. However, caffeine intake may exaggerate sleep problems by disturbing sleep and circadian timing. In a 28-hour double-blind randomized crossover study, we investigated to what extent caffeine disturbs slow-wave sleep (SWS) and delays circadian timing in teenagers. Following a 6-day ambulatory phase of caffeine abstinence and fixed sleep-wake cycles, 18 male teenagers (14-17 years old) ingested 80 mg caffeine vs. placebo in the laboratory four hours prior to an electro-encephalographically (EEG) recorded nighttime sleep episode. Data were analyzed using both frequentist and Bayesian statistics. The analyses suggest that subjective sleepiness is reduced after caffeine compared to placebo. However, we did not observe a strong caffeine-induced reduction in subjective sleep quality or SWS, but rather a high inter-individual variability in caffeine-induced SWS changes. Exploratory analyses suggest that particularly those individuals with a higher level of SWS during placebo reduced SWS in response to caffeine. Regarding salivary melatonin onsets, caffeine-induced delays were not evident at group level, and only observed in participants exposed to a higher caffeine dose relative to individual bodyweight (i.e., a dose > 1.3 mg/kg). Together, the results suggest that 80 mg caffeine are sufficient to induce alertness at a subjective level. However, particularly teenagers with a strong need for deep sleep might pay for these subjective benefits by a loss of SWS during the night. Thus, caffeine-induced sleep-disruptions might change along with the maturation of sleep need.

Prospective Study on Salivary Evening Melatonin and Sleep before and after Pinealectomy in Humans.

Melatonin is secreted systemically from the pineal gland maximally at night but is also produced locally in many tissues. Its chronobiological function is mainly exerted by pineal melatonin. It is a feedback regulator of the main circadian pacemaker in the hypothalamic suprachiasmatic nuclei and of many peripheral oscillators. Although exogenous melatonin is approved for circadian rhythm sleep disorders and old-age insomnia, research on endogenous melatonin in humans is hindered by the great interindividual variability of its amount and circadian rhythm. Single case studies on pinealectomized patients report on disrupted but also hypersomnic sleep. This is the first systematic prospective report on sleep with respect to pinealectomy due to pinealocytoma World Health Organization grade I without chemo- or radiotherapy. Before and after pinealectomy, 8 patients completed questionnaires on sleep quality and circadian rhythm (Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, and Morningness-Eveningness Questionnaire), 2 nights of polysomnography, salivary evening melatonin profiles, and qualitative assessment of 2 weeks of actigraphy and sleep logs. Six patients were assessed retrospectively up to 4 years after pinealectomy. Before pinealectomy, all but 1 patient showed an evening melatonin rise typical for indifferent chronotypes. After pinealectomy, evening saliva melatonin was markedly diminished, mostly below the detection limit of the assay (0.09 pg/mL). No systematic change in subjective sleep quality or standard measures of polysomnography was found. Mean pre- and postoperative sleep efficiency was 94% and 95%, and mean sleep-onset latency was 21 and 17 min, respectively. Sleep-wake rhythm during normal daily life did not change. Retrospective patients had a reduced sleep efficiency (90%) and more stage changes, although this was not significantly different from prospective patients. In conclusion, melatonin does seem to have a modulatory, not a regulatory, effect on standard measures of sleep. Study output is limited by small sample size and because only evening melatonin profiles were assessed.

When restless legs syndrome turns malignant.

Usually symptoms of restless legs syndrome (RLS) respond well to treatment with dopaminergic drugs, opiates, or anticonvulsant medications. Yet sometimes symptoms can be severe and become refractory, even to high-dose combination therapy. Here we present two cases of familial RLS with rigorous and unusual motor and sensory symptoms in the form of episodes of myoclonic hyperkinesias and painful sensations in addition to more characteristic features of RLS. Stepwise reduction of all RLS-and antidepressant medication down to opiate monotherapy-and subsequent opiate rotation led to an improvement of symptoms. Yet in both cases, reintroduction of low-dose dopaminergic drugs was necessary to achieve satisfactory treatment effect. We have termed this form of RLS refractory to multiple combinations of all classes of commonly used drugs malignant RLS. Therapeutically simplification and reduction of the drug scheme and opiate rotation should be considered in malignant RLS.

Sleep disturbance after pinealectomy in patients with pineocytoma WHO°I.

BACKGROUND: Because the pineal gland produces melatonin, it is suggested to be involved in the regulation of sleep and circadian rhythm, though there is scant proof of this. Tumors of the pineal gland are rare and various in terms of histological and biological malignancy. We evaluated the occurrence of subjective sleep disturbances in nine patients who underwent a pinealectomy due to pineocytoma WHO°I without additional therapy. METHODS: Patients with intracranial low-grade lesions and patients without a craniotomy who underwent a microscopic lumbar discectomy were matched to our study group by gender, age, and date of surgery. We used standardized sleep questionnaires on sleepiness during the daytime, sleep disturbances, and general pathologic sleep patterns. RESULTS: Patients who underwent a craniotomy either without a pinealectomy (7.2 ± 2.0 points) or with a pinealectomy experienced increased sleep disturbances (6.6 ± 1.3 points) compared to patients who had a lumbar discectomy (2.8 ± 0.4 points), according to the Pittsburgh Sleep Quality Index (PSQI) (p < 0.05). Moreover, sleep disturbances as measured by the insomnia severity index (ISI) were most pronounced in patients who underwent a craniotomy without a pinealectomy (10.4 ± 3.1 points) compared to patients who underwent a pinealectomy or discectomy (5.9 ± 1.9 and 3.3 ± 1.3 points). CONCLUSIONS: Pinealectomy itself did not cause specific sleep impairment, but craniotomy in general did. This interesting and clinically relevant finding needs further investigation.

Frontal cerebral vulnerability and executive deficits from raised intracranial pressure in child traumatic brain injury.

In severe pediatric traumatic brain injury (TBI), a common focus of treatment is raised intracranial pressure (ICP). The aim of this investigation was to test whether raised ICP is associated with later prefrontal executive deficits and regional brain tissue loss, consistent with an anterior vascular compartment syndrome. Thirty-three participants were assigned to one of two severe TBI groups based on whether or not they had increased ICP complicating their critical illness. At follow-up (average 3.9 years), the participants underwent magnetic resonance imaging and a battery of neuropsychological testing focused on prefrontal function. The ICP group had white matter loss that was diffuse as well as regional in the corpus callosum, periventricular tissue, and frontal region. Loss of gray matter in the ICP group was more regionally specific, with bilateral loss in the caudate nuclei and frontal regions, including the right dorsolateral region, right supplementary motor area, and the left orbitofrontal cortex. Both groups had normal intelligence quotients (IQs), but the ICP group showed long-term deficits on various measures of attention and executive function such as working memory, decision-making, and impulsivity. These findings suggest that raised ICP leads to diffuse brain injury and a predilection to hypoperfusion in, at least, the distribution of the anterior cerebral artery. Furthermore, since voxel-based morphometry (VBM) and measures of attention and executive function are sensitive to the phenomenon of raised ICP, we consider that these techniques warrant inclusion in trials assessing ICP-directed therapy.

Alterations in excitotoxicity and prostaglandin metabolism in a transgenic mouse model of Alzheimer's disease.

To address the potential impact of presenilin mutations on the prostaglandin metabolism in a neurodegenerative model of glutamatergic excitotoxicity, we injected kainic acid intraperitoneally (30mg/kg body weight) into mice over-expressing the human N141I mutation of presenilin-2, which is known to cause an early-onset form of Alzheimer's disease. We compared the seizure activity as well as seizure lethality in 2- and 6-month-old mice, transgenic for the above-mentioned point mutation, and their wildtype littermates and found that mice harboring the hN141I mutation showed a relative resistance to excitotoxic treatment. This was associated with a constituitively reduced expression of the cyclooxygenases COX-1 and COX-2 in the hippocampus of N141I presenilin-2 mice and a reduced induction of COX-2 expression post-kainate injection. In the past, clinical trials have suggested that both non-steroidal anti-inflammatory drugs, which impact upon a cell's prostaglandin metabolism, and glutamatergic antagonists might be of benefit to patients suffering from Alzheimer's-type dementias. Yet, the exact mechanism by which these drugs are beneficial remains unclear, although it seems possible that presenilins might be implicated in the process, at least in the case of early-onset forms. The data presented here strongly support the notion of an implication of presenilins in the alterations in the prostaglandin system, which have been observed in Alzheimer's disease and may contribute to the underlying pathogenesis of the disease.

Patterns of regional brain hypometabolism associated with knowledge of semantic features and categories in Alzheimer's disease.

The study of semantic memory in patients with Alzheimer's disease (AD) has raised important questions about the representation of conceptual knowledge in the human brain. It is still unknown whether semantic memory impairments are caused by localized damage to specialized regions or by diffuse damage to distributed representations within nonspecialized brain areas. To our knowledge, there have been no direct correlations of neuroimaging of in vivo brain function in AD with performance on tasks differentially addressing visual and functional knowledge of living and nonliving concepts. We used a semantic verification task and resting 18-fluorodeoxyglucose positron emission tomography in a group of mild to moderate AD patients to investigate this issue. The four task conditions required semantic knowledge of (1) visual, (2) functional properties of living objects, and (3) visual or (4) functional properties of nonliving objects. Visual property verification of living objects was significantly correlated with left posterior fusiform gyrus metabolism (Brodmann's area [BA] 37/19). Effects of visual and functional property verification for non-living objects largely overlapped in the left anterior temporal (BA 38/20) and bilateral premotor areas (BA 6), with the visual condition extending more into left lateral precentral areas. There were no associations with functional property verification for living concepts. Our results provide strong support for anatomically separable representations of living and nonliving concepts, as well as visual feature knowledge of living objects, and against distributed accounts of semantic memory that view visual and functional features of living and nonliving objects as distributed across a common set of brain areas.

Interleukin-1 beta-induced expression of the prostaglandin E-receptor subtype EP3 in U373 astrocytoma cells depends on protein kinase C and nuclear factor-kappaB.

Both interleukin-1beta (IL-1beta) and prostaglandins (PGs) are important mediators of physiological and pathophysiological processes in the brain. PGE2 exerts its effects by binding to four different types of PGE2 receptors named EP1-EP4. EP3 has found to be expressed in neurons, whereas expression of EP3 in glial cells has not been reported in the brain yet. Here we describe IL-1beta-induced EP3 receptor expression in human astrocytoma cells, primary astrocytes of rat and human origin and in rat brain. Using western blot, we found a marked up-regulation of EP3 receptor synthesis in human and rat primary glial cells. Intracerebroventricular administration of IL-1beta stimulated EP3 receptor synthesis in rat hippocampus. The analysis of involved signal transduction pathways by pathway-specific inhibitors revealed an essential role of protein kinase C and nuclear factor-kappaB in astrocytic IL-1beta-induced EP3 synthesis. Our data suggest that PGE2 signaling in the brain may be altered after IL-1beta release due to up-regulation of EP3 receptors. This might play an important role in acute and chronic conditions such as cerebral ischemia, traumatic brain injury, HIV-encephalitis, Alzheimer's disease and prion diseases in which a marked up-regulation of IL-1beta is followed by a prolonged increase of PGE2 levels in the brain.

Regional distribution of the prostaglandin E2 receptor EP1 in the rat brain: accumulation in Purkinje cells of the cerebellum.

Prostaglandin E2 (PGE2), is a major prostanoid produced by the activity of cyclooxygenases (COX) in response to various physiological and pathological stimuli. PGE2 exerts its effects by activating four specific E-type prostanoid receptors (EP1, EP2, EP3, and EP4). In the present study, we analyzed the expression of the PGE2 receptor EP1 (mRNA and protein) in different regions of the adult rat brain (hippocampus, hypothalamus, striatum, prefrontal cerebral cortex, parietal cortex, brain stem, and cerebellum) using reverse transcription- polymerase chain reaction, Western blotting, and immunohistochemical methods. On a regional basis, levels of EP1 mRNA were the highest in parietal cortex and cerebellum. At the protein level, we found very strong expression of EP1 in cerebellum, as revealed by Western blotting experiments. Furthermore, the present study provides for the first time evidence that the EP1 receptor is highly expressed in the cerebellum, where the Purkinje cells displayed very high immunolabeling of their perikaryon and dendrites, as observed in the immunohistochemical analysis. Results from the present study indicate that the EP1 prostanoid receptor is expressed in specific neuronal populations, which possibly determine the region-specific response to PGE2.