Sleep-related changes in blood pressure in hypocretin-deficient narcoleptic mice

Objectives. Blood pressure (BP) physiologically has higher and lower values during the active and rest period, respectively. Subjects failing to show the appropriate BP decrease (10-20%) on passing form diurnal activity to nocturnal rest and sleep have increased risk of target organ damage at the cardiac, vascular and cerebrovascular levels. Hypocretin (HCRT) releasing neurons, mainly located in the lateral hypothalamus, project widely to the central nervous system. Thus HCRT neurons are involved in several autonomic functions, including BP regulation. HCRT neurons also play a key role in wake-sleep cycle regulation, the lack of which becomes evident in HCRT-deficient narcoleptic patients. I investigated whether chronic lack of HCRT signaling alters BP during sleep in mouse models of narcolepsy. Methods. The main study was performed on HCRT-ataxin3 transgenic mice (TG) with selective post-natal ablation of HCRT neurons, HCRT gene knockout mice (KO) with preserved HCRT neurons, and Wild-Type control mice (WT) with identical genetic background. Experiments where replicated on TG and WT mice with hybrid genetic background (hTG and hWT, respectively). Mice were implanted with a telemetric pressure transducer (TA11PA-C10, DSI) and electrodes for discriminating wakefulness (W), rapid-eye-movement sleep (REMS) and non-REMS (NREMS). Signals were recorded for 3 days. Mean BP values were computed in each wake-sleep state and analyzed by ANOVA and t-test with significance at p<0.05. Results. The decrease in BP between either NREMS or REMS and W was significantly blunted in TG and KO with respect to WT as well as in hTG with respect to hWT. Conclusions. Independently from the genetic background, chronic HCRT deficiency leads to a decreased BP difference between W and sleep potentially adverse in narcoleptic subjects. These data suggest that HCRT play an important role in the sleep-dependent cardiovascular control.

Cyclic alternating pattern in sleep and its relationship to creativity

Background/Objectives: Sleep has been shown to enhance creativity, but the reason for this enhancement is not entirely known. There are several different physiological states associated with sleep. In addition to rapid (REM) and non-rapid eye movement (NREM) sleep, NREM sleep can be broken down into Stages (1-4) that are characterized by the degree of EEG slow wave activity. In addition, during NREM sleep there are transient but cyclic alternating patterns (CAP) of EEG activity and these CAPs can also be divided into three subtypes (A1-A3) according to speed of the EEG waves. Differences in CAP ratios have been previously linked to cognitive performances. The purpose of this study was to learn the relationship CAP activity during sleep and creativity. Methods: The participants were 8 healthy young adults (4 women), who underwent 3 consecutive nights of polysomnographic recording and took the Abbreviated Torrance Test for Adults (ATTA) on the 2 and 3rd mornings after the recordings. Results: There were positive correlations between Stage 1 of NREM sleep and some measures of creativity such as fluency (R= .797; p=.029) and flexibility ( R=.43; p=.002), between Stage 4 of Non-REM sleep and originality (R= .779; p=.034) and a global measure of figural creativity (R= .758; p=.040). There was also a negative correlation between REM sleep and originality (R= -.827; p= .042) . During NREM sleep the CAP rate, which in young people is primarily the A1 subtype, also correlated with originality (R= .765; p =.038). Conclusions: NREM sleep is associated with low levels of cortical arousal and low cortical arousal may enhance the ability of people to access to the remote associations that are critical for creative innovations. In addition, A1 CAP activity reflects frontal activity and the frontal lobes are important for divergent thinking, also a critical aspect of creativity.

Effects of ambient temperature on cardiovascular regulation during sleep in hypocretin-deficient narcoleptic mice

Hypocretin 1 and 2 (HCRT, also called Orexin A and B) are neuropeptides released by neurons in the lateral hypothalamus. HCRT neurons widely project to the entire neuroaxis. HCRT neurons have been reported to participate in various hypothalamic physiological processes including cardiovascular functions, wake-sleep cycle, and they may also influence metabolic rate and the regulation of body temperature. HCRT neurons are lost in narcolepsy, a rare neurological disorder, characterized by excessive daytime sleepiness, cataplexy, sleep fragmentation and occurrence of sleep-onset rapid-eye-movement episodes. We investigated whether HCRT neurons mediate the sleep-dependent cardiovascular adaptations to changes in ambient temperature (Ta). HCRT-ataxin3 transgenic mice with genetic ablation of HCRT neurons (n = 11) and wild-type controls (n = 12) were instrumented with electrodes for sleep scoring and a telemetric blood pressure (BP) transducer (DSI, Inc.). Simultaneous sleep and BP recordings were performed on mice undisturbed and freely-behaving at 20 °C, 25 °C, and 30 °C for 48 hours at each Ta. Analysis of variance of BP indicated a significance of the main effects of wake-sleep state and Ta, their interaction effect, and the wake-sleep state x mouse strain interaction effect. BP increased with decreasing Ta. This effect of Ta on BP was significantly lower in rapid-eye-movement sleep (REMS) than either in non-rapid-eye-movement sleep (NREMS) or wakefulness regardless of the mouse strain. BP was higher in wakefulness than either in NREMS or REMS. This effect of sleep on BP was significantly reduced in mice lacking HCRT neurons at each Ta, particularly during REMS. These data suggest that HCRT neurons play a critical role in mediating the effects of sleep but not those of Ta on BP in mice. HCRT neurons may thus be part of the central neural pathways which mediate the phenomenon of blood pressure dipping on passing from wakefulness to sleep.

Analysis of cerebral and autonomic response to respiratory events in patients with Sleep Apnea Syndrome

The arousal scoring in Obstructive Sleep Apnea Syndrome (OSAS) is important to clarify the impact of the disease on sleep but the currently applied American Academy of Sleep Medicine (AASM) definition may underestimate the subtle alterations of sleep. The aims of the present study were to evaluate the impact of respiratory events on cortical and autonomic arousal response and to quantify the additional value of cyclic alternating pattern (CAP) and pulse wave amplitude (PWA) for a more accurate detection of respiratory events and sleep alterations in OSAS patients. A retrospective revision of 19 polysomnographic recordings of OSAS patients was carried out. Analysis was focused on quantification of apneas (AP), hypopneas (H) and flow limitation (FL) events, and on investigation of cerebral and autonomic activity. Only 41.1% of FL events analyzed in non rapid eye movement met the AASM rules for the definition of respiratory event-related arousal (RERA), while 75.5% of FL events ended with a CAP A phase. The dual response (EEG-PWA) was the most frequent response for all subtypes of respiratory event with a progressive reduction from AP to H and FL. 87.7% of respiratory events with EEG activation showed also a PWA drop and 53,4% of the respiratory events without EEG activation presented a PWA drop. The relationship between the respiratory events and the arousal response is more complex than that suggested by the international classification. In the estimation of the response to respiratory events, the CAP scoring and PWA analysis can offer more extensive information compared to the AASM rules. Our data confirm also that the application of PWA scoring improves the detection of respiratory events and could reduce the underestimation of OSAS severity compared to AASM arousal.

Anosognosia for cerebral achromatopsia--a longitudinal case study

Cerebral achromatopsia is a rare disorder of colour vision caused by bilateral damage to the occipito-temporal cortex. Patients with cerebral achromatopsia are commonly said to suffer due to their disturbed colour sense. Here, we report the case of a patient with cerebral achromatopsia who was initially unaware of his deficit, although three experiments with eye movement recordings demonstrated his severe inability to use colour information in everyday tasks. During two months, the evolution of his colour vision deficit was followed with repeated standardized colour vision tests and eye movement recordings. While his performance continuously improved, he became more and more aware of the deficit. Only after colour vision had almost normalized, his subjective colour sensation was inconspicuous again. The simultaneous occurrence of achromatopsia and the corresponding anosognosia and their parallel recovery suggest that both deficits were due to dysfunction of the same brain region. Consequently, the subjective experience of colour loss in achromatopsia may depend on the residual function of the damaged colour centre.

Selective REM sleep deprivation in narcolepsy

Narcolepsy is characterized by excessive daytime sleepiness and rapid eye movement (REM) sleep abnormalities, including cataplexy. The aim of this study was to assess REM sleep pressure and homeostasis in narcolepsy. Six patients with narcolepsy and six healthy controls underwent a REM sleep deprivation protocol, including one habituation, one baseline, two deprivation nights (D1, D2) and one recovery night. Multiple sleep latency tests (MSLTs) were performed during the day after baseline and after D2. During D1 and D2 REM sleep was prevented by awakening the subjects at the first polysomnographic signs of REM sleep for 2 min. Mean sleep latency and number of sleep-onset REM periods (SOREMs) were determined on all MSLT. More interventions were required to prevent REM sleep in narcoleptics compared with control subjects during D1 (57 ± 16 versus 24 ± 10) and D2 (87 ± 22 versus 35 ± 8, P = 0.004). Interventions increased from D1 to D2 by 46% in controls and by 53% in narcoleptics (P < 0.03). Selective REM sleep deprivation was successful in both controls (mean reduction of REM to 6% of baseline) and narcoleptics (11%). Both groups had a reduction of total sleep time during the deprivation nights (P = 0.03). Neither group had REM sleep rebound in the recovery night. Narcoleptics had, however, an increase in the number of SOREMs on MSLT (P = 0.005). There was no increase in the number of cataplexies after selective REM sleep deprivation. We conclude that: (i) REM sleep pressure is higher in narcoleptics; (ii) REM sleep homeostasis is similar in narcoleptics and controls; (iii) in narcoleptics selective REM sleep deprivation may have an effect on sleep propensity but not on cataplexy.

Visual symptoms in Parkinson's disease and Parkinson's disease dementia

Visual symptoms are common in PD and PD dementia and include difficulty reading, double vision, illusions, feelings of presence and passage, and complex visual hallucinations. Despite the established prognostic implications of complex visual hallucinations, the interaction between cognitive decline, visual impairment, and other visual symptoms remains poorly understood. Our aim was to characterize the spectrum of visual symptomatology in PD and examine clinical predictors for their occurrence. Sixty-four subjects with PD, 26 with PD dementia, and 32 age-matched controls were assessed for visual symptoms, cognitive impairment, and ocular pathology. Complex visual hallucinations were common in PD (17%) and PD dementia (89%). Dementia subjects reported illusions (65%) and presence (62%) more frequently than PD or control subjects, but the frequency of passage hallucinations in PD and PD dementia groups was equivalent (48% versus 69%, respectively; P = 0.102). Visual acuity and contrast sensitivity was impaired in parkinsonian subjects, with disease severity and age emerging as the key predictors. Regression analysis identified a variety of factors independently predictive of complex visual hallucinations (e.g., dementia, visual acuity, and depression), illusions (e.g., excessive daytime somnolence and disease severity), and presence (e.g., rapid eye movement sleep behavior disorder and excessive daytime somnolence). Our results demonstrate that different "hallucinatory" experiences in PD do not necessarily share common disease predictors and may, therefore, be driven by different pathophysiological mechanisms. If confirmed, such a finding will have important implications for future studies of visual symptoms and cognitive decline in PD and PD dementia.

Sleep stage II contributes to the consolidation of declarative memories

Various studies suggest that non-rapid eye movement (NREM) sleep, especially slow-wave sleep (SWS), is vital to the consolidation of declarative memories. However, sleep stage 2 (S2), which is the other NREM sleep stage besides SWS, has gained only little attention. The current study investigated whether S2 during an afternoon nap contributes to the consolidation of declarative memories. Participants learned associations between faces and cities prior to a brief nap. A cued recall test was administered before and following the nap. Spindle, delta and slow oscillation activity was recorded during S2 in the nap following learning and in a control nap. Increases in spindle activity, delta activity, and slow oscillation activity in S2 in the nap following learning compared to the control nap were associated with enhanced retention of face-city associations. Furthermore, spindles tended to occur more frequently during up-states than down-states within slow oscillations during S2 following learning versus S2 of the control nap. These findings suggest that spindles, delta waves, and slow oscillations might promote memory consolidation not only during SWS, as shown earlier, but also during S2.

Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study

The aim of this study was to describe the clinical and PSG characteristics of narcolepsy with cataplexy and their genetic predisposition by using the retrospective patient database of the European Narcolepsy Network (EU-NN). We have analysed retrospective data of 1099 patients with narcolepsy diagnosed according to International Classification of Sleep Disorders-2. Demographic and clinical characteristics, polysomnography and multiple sleep latency test data, hypocretin-1 levels, and genome-wide genotypes were available. We found a significantly lower age at sleepiness onset (men versus women: 23.74 ± 12.43 versus 21.49 ± 11.83, P = 0.003) and longer diagnostic delay in women (men versus women: 13.82 ± 13.79 versus 15.62 ± 14.94, P = 0.044). The mean diagnostic delay was 14.63 ± 14.31 years, and longer delay was associated with higher body mass index. The best predictors of short diagnostic delay were young age at diagnosis, cataplexy as the first symptom and higher frequency of cataplexy attacks. The mean multiple sleep latency negatively correlated with Epworth Sleepiness Scale (ESS) and with the number of sleep-onset rapid eye movement periods (SOREMPs), but none of the polysomnographic variables was associated with subjective or objective measures of sleepiness. Variant rs2859998 in UBXN2B gene showed a strong association (P = 1.28E-07) with the age at onset of excessive daytime sleepiness, and rs12425451 near the transcription factor TEAD4 (P = 1.97E-07) with the age at onset of cataplexy. Altogether, our results indicate that the diagnostic delay remains extremely long, age and gender substantially affect symptoms, and that a genetic predisposition affects the age at onset of symptoms.

Cellular mechanisms of burst firing-mediated long-term depression in rat neocortical pyramidal cells

During wakefulness and sleep, neurons in the neocortex emit action potentials tonically or in rhythmic bursts, respectively. However, the role of synchronized discharge patterns is largely unknown. We have recently shown that pairings of excitatory postsynaptic potentials (EPSPs) and action potential bursts or single spikes lead to long-term depression (burst-LTD) or long-term potentiation, respectively. In this study, we elucidate the cellular mechanisms of burst-LTD and characterize its functional properties. Whole-cell patch-clamp recordings were obtained from layer V pyramidal cells in somatosensory cortex of juvenile rats in vitro and composite EPSPs and EPSCs were evoked extracellularly in layers II/III. Repetitive burst-pairings led to a long-lasting depression of EPSPs and EPSCs that was blocked by inhibitors of metabotropic glutamate group 1 receptors, phospholipase C, protein kinase C (PKC) and calcium release from the endoplasmic reticulum, and that required an intact machinery for endocytosis. Thus, burst-LTD is induced via a Ca2+- and phosphatidylinositol-dependent activation of PKC and expressed through phosphorylation-triggered endocytosis of AMPA receptors. Functionally, burst-LTD is inversely related to EPSP size and bursts dominate single spikes in determining the sign of synaptic plasticity. Thus burst-firing constitutes a signal by which coincident synaptic inputs are proportionally downsized. Overall, our data thus suggest a mechanism by which synaptic weights can be reconfigured during non-rapid eye movement sleep.

Extending lifetime of plastic changes in the human brain

The ability of the brain to adjust to changing environments and to recover from damage rests on its remarkable capacity to adapt through plastic changes of underlying neural networks. We show here with an eye movement paradigm that a lifetime of plastic changes can be extended to several hours by repeated applications of theta burst transcranial magnetic stimulation to the frontal eye field of the human cortex. The results suggest that repeated application of the same stimulation protocol consolidates short-lived plasticity into long-lasting changes.

Effects of sleep fragmentation on the arousability to resistive loading in NREM and REM sleep in normal men

STUDY OBJECTIVE: In healthy subjects, arousability to inspiratory resistive loading is greater during rapid eye movement (REM) sleep compared with non-REM (NREM) sleep but is poorest in REM sleep in patients with sleep apnea. We therefore examined the hypothesis that sleep fragmentation impairs arousability, especially from REM sleep. DESIGN: Two blocks of 3 polysomnographies (separated by at least 1 week) were performed randomly. An inspiratory-loaded night followed either 2 undisturbed control nights (LN(C)) or 2 acoustically fragmented nights (LN(F)) SETTING: Sleep laboratory. PARTICIPANTS: Sixteen healthy men aged 20 to 29 years. INTERVENTIONS: In both loaded nights, an inspiratory resistive load was added via a valved facemask every 2 minutes during sleep and turned off either when arousal occurred or after 2 minutes. MEASUREMENTS AND RESULTS: During LN(F), arousability remained significantly greater in REM sleep (71% aroused within 2 minutes) compared with stage 2 (29%) or stage 3/4 (16%) sleep. After sleep fragmentation, arousability was decreased in stage 2 sleep (LN(F): 29%; LN(C): 38%; p < .05) and low in early REM sleep, increasing across the night (p < .01). In stage 3/4 sleep, neither an attenuation nor a change across the night was seen after sleep fragmentation. CONCLUSIONS: Mild sleep fragmentation is already sufficient to attenuate arousability in stage 2 sleep and to decrease arousability in early, compared with late, REM sleep. This means that sleep fragmentation affects the arousal response to increasing resistance and that the effects are different in stage 2 and REM sleep. The biologic reason for this increase in the arousal response in REM sleep across the night is not clear.

To look or not to look at threat? Scanpath differences within a group of spider phobics

Predicting the behavior of phobic patients in a confrontational situation is challenging. While avoidance as a major clinical component of phobias suggests that patients orient away from threat, findings based on cognitive paradigms indicate an attentional bias towards threat. Here we present eye movement data from 21 spider phobics and 21 control subjects, based on 3 basic oculomotor tasks and a visual exploration task that included close-up views of spiders. Relative to the control group, patients showed accelerated reflexive saccades in one of the basic oculomotor tasks, while the fear-relevant exploration task evoked a general slowing in their scanning behavior and pronounced oculomotor avoidance. However, this avoidance strongly varied within the patient group and was not associated with the scores from spider avoidance-sensitive questionnaire scales. We suggest that variation of oculomotor avoidance between phobics reflects different strategies of how they cope with threat in confrontational situations.

Cortical reorganization after brain damage: the oculomotor model

Recovery from eye movement deficits after cortical lesions is amazingly rapid and almost complete, which is in sharp contrast to most other neurological deficits of cerebral lesions. The underlying mechanisms of this successful recovery remain uncertain. We had the rare opportunity to examine two patients with recovery from saccade deficits after a lesion restricted to the frontal eye field (FEF) by means of transcranial magnetic stimulation (TMS). The results provide direct evidence that recovery depended on the integrity of the oculomotor regions of the nonlesioned contralesional hemisphere, and that the compensatory network is task-specific.

Lung aeration during sleep

BACKGROUND: During sleep, ventilation and functional residual capacity (FRC) decrease slightly. This study addresses regional lung aeration during wakefulness and sleep. METHODS: Ten healthy subjects underwent spirometry awake and with polysomnography, including pulse oximetry, and also CT when awake and during sleep. Lung aeration in different lung regions was analyzed. Another three subjects were studied awake to develop a protocol for dynamic CT scanning during breathing. RESULTS: Aeration in the dorsal, dependent lung region decreased from a mean of 1.14 +/- 0.34 mL (+/- SD) of gas per gram of lung tissue during wakefulness to 1.04 +/- 0.29 mL/g during non-rapid eye movement (NREM) sleep (- 9%) [p = 0.034]. In contrast, aeration increased in the most ventral, nondependent lung region, from 3.52 +/- 0.77 to 3.73 +/- 0.83 mL/g (+ 6%) [p = 0.007]. In one subject studied during rapid eye movement (REM) sleep, aeration decreased from 0.84 to 0.65 mL/g (- 23%). The fall in dorsal lung aeration during sleep correlated to awake FRC (R(2) = 0.60; p = 0.008). Airway closure, measured awake, occurred near and sometimes above the FRC level. Ventilation tended to be larger in dependent, dorsal lung regions, both awake and during sleep (upper region vs lower region, 3.8% vs 4.9% awake, p = 0.16, and 4.5% vs 5.5% asleep, p = 0.09, respectively). CONCLUSIONS: Aeration is reduced in dependent lung regions and increased in ventral regions during NREM and REM sleep. Ventilation was more uniformly distributed between upper and lower lung regions than has previously been reported in awake, upright subjects. Reduced respiratory muscle tone and airway closure are likely causative factors.