Arousal responses to olfactory or trigeminal stimulation during sleep

STUDY OBJECTIVES: The interaction of sensory physiology and sleep has been studied for various sensory systems. Nevertheless, the question whether chemosensory (especially olfactory) stimuli may lead to arousals during sleep remains under discussion. Specifically, the central processing of olfactory information shows fundamental differences compared to other sensory systems. DESIGN: Prospective controlled trial. SETTING: Sleep research facility, University Hospital. PARTICIPANTS: Five young healthy, normosmic volunteers. INTERVENTION: Intranasal chemosensory stimulation during sleep was based on air-dilution olfactometry. For olfactory stimulation H2S (smell of rotten eggs) was used in 4 concentrations (1, 2, 4, and 8 ppm). For trigeminal stimulation CO2 (stinging sensation) was also administered in 4 concentrations (10%, 20%, 40%, and 60% v/v) while odorless stimuli were used for control. MEASUREMENTS: Arousal reactions due to chemosensory stimulation were assessed during overnight polysomnography 30 seconds after the presentation of every stimulus during 23 nights of testing. RESULTS: For olfactory testing, an average number of 703 olfactory stimuli and 157 odorless controls were used for analysis per subject. Even the highest stimulus concentration did not produce an increase in arousal frequency. For trigeminal testing, an average number of 405 stimuli and 79 controls were used for analysis per subject, and an increase in arousal frequency was observed following the increase of stimulus concentration. CONCLUSIONS: With the present results we were able to demonstrate that, in contrast to trigeminal stimulation, the presentation of a strong but selective olfactory stimulus does not lead to arousals during nocturnal sleep in humans.     

Information processing during sleep: the effect of olfactory stimuli on dream content and dream emotions

Research has shown that external stimuli presented during sleep can affect dream content, thus reflecting information processing of the sleeping brain. Olfactory stimuli should have a stronger effect on dream emotions because their processing is linked directly to the limbic system. Because selective olfactory stimulation does not increase arousal activity, intense olfactory stimulation is therefore a prime paradigm for studying information processing during sleep. Fifteen healthy, normosmic volunteers were studied by intranasal chemosensory stimulation during rapid eye movement sleep based on air-dilution olfactometry. For olfactory stimulation, hydrogen sulphide (smell of rotten eggs) and phenyl ethyl alcohol (smell of roses) was used and compared with a control condition without stimulation. The olfactory stimuli affected significantly the emotional content of dreams: the positively toned stimulus yielded more positively toned dreams, whereas the negative stimulus was followed by more negatively toned dreams. Direct incorporations, i.e. the dreamer is smelling something, were not found. The findings indicate that information processing of olfactory stimuli is present in sleep and that the emotional tone of dreams can be influenced significantly depending upon the hedonic characteristic of the stimulus used. It would be interesting to conduct learning experiments (associating specific odours with declarative material) to study whether this declarative material is incorporated into subsequent dreams if the corresponding odour cue is presented during sleep. It would also be interesting to study the effect of positively toned olfactory stimuli on nightmares.     

Experimentally induced arousals during sleep: a cross-modality matching paradigm

Micro-arousals occur spontaneously or in response to exogenous and endogenous sensory input during sleep. The function of micro-arousals remains unclear, for example, whether it reflects a disturbance or a preparatory response to environmental changes. The goal of this study was to assess arousal responsiveness when two types of sensory stimulations were used: auditory (AD) alone and the addition of a vibrotactile (VT) sensation. Ten normal sleepers participated in three nights of polygraphic recordings. The first night was for habituation and to rule out sleep disorders, and the second to collect baseline sleep data. During the third night, AD and VT + AD stimuli, with three levels of intensities for auditory and vibratory signals, were randomly given to induce arousal responses in sleep stages 2, 3 and 4 and rapid eye movement (REM). The frequency of the arousal responses increased with stimulus intensity for all sleep stages and was lowest in stages 3 and 4. In non-REM (NREM) sleep, combined VT + AD stimulation induced more frequent and more intense arousal responses than AD alone. In REM sleep, more frequent micro-arousals rather than awakenings were triggered by combined stimulations. In stage 2, the response rate of total induced K-complexes did not differ between both types of stimulations while more K-complexes followed by arousals were evoked by the combined VT + AD stimulation than by the AD alone. The induced arousals were associated with an increase in heart rate in all sleep stages. An increase in suprahyoid muscle tone was observed in NREM sleep only, REM being not associated with a rise in muscle tone following experimental stimulation. Most leg and body movements occurred in response to induced awakenings. These results suggest that the cross-modality sensory stimuli triggered more arousal responses in comparison with single-modality stimuli. In an attempt to wake a sleeping subject, the addition of a tactile stimulation, such as shaking the shoulder, is an effective strategy that increases the arousal probability.     

Arousal responses to somatosensory and mild hypoxic stimuli are depressed during quiet sleep in healthy term infants

STUDY OBJECTIVES: To compare arousal responses to somatosensory and hypoxic stimuli in sleeping human infants and to determine whether sleep state and postnatal age exerted similar changes in these arousal responses. DESIGN: We delivered somatosensory (nasal air-jet) stimulation and mild hypoxia (15% oxygen) to 10 healthy term infants aged 2 to 4 weeks, 2 to 3 months, and 5 to 6 months during identified sleep states. Hypoxic challenges were terminated at arousal, when the oxygen saturation fell below 85%, or at 5 minutes (failure to arouse). RESULTS: Infants failed to arouse to a greater percentage of hypoxia tests during quiet sleep (QS) than during active sleep (AS) at 2 to 3 months and 5 to 6 months of age (P < 0.01). Infants failed to arouse to a greater percentage of hypoxic challenges during QS at 2 to 3 months and 5 to 6 months than at 2 to 4 weeks of age. Arousal latency to hypoxia was significantly longer in QS than in AS at each study age; however, arousal latency was not affected by postnatal age. Arousal thresholds to somatosensory stimulation were significantly greater in QS than in AS, except at 2 to 4 weeks of age. In AS, arousability to the air-jet was greater at 2 to 3 months compared to 2 to 4 weeks of age (P < 0.05); in QS it was lower at 5 to 6 months compared to 2 to 4 weeks of age (P < 0.05). Arousal latency to hypoxia and arousal thresholds to air-jet stimulation were not correlated within infants. CONCLUSION: We conclude that arousal responses of infants to somatosensory and respiratory stimuli are similarly affected by sleep state and postnatal age. Infants are less arousable to both stimulus modalities in QS than in AS, and less arousable at 5 to 6 months of age than at 2 to 4 weeks in QS.     

Habituation of the infant arousal response.

STUDY OBJECTIVES: Arousal is considered to be an important protective response in a sleeping infant and its depression could leave an infant vulnerable to a life threatening stimulus. We found previously that arousal to a non-respiratory (tactile) stimulus occurs in a sequence of events that begins with spinal, followed by brainstem responses, and then a cortical electroencephalographic (EEG) arousal response. We hypothesized that repeated stimuli would depress the arousal responses by habituation and that spinal and brainstem responses would be more resistant to habituation than cortical responses. PARTICIPANTS: We studied 22 normal infants. INTERVENTIONS: The infants underwent polysomnographic monitoring during a daytime nap. Tactile stimuli was applied to the infants foot at 5-second intervals. MEASUREMENTS AND RESULTS: We found that spinal, brainstem, and cortical responses occurred on the first trial of each test. Repeated trials during non-rapid eye movement (NREM) and rapid eye movement (REM) sleep resulted in a decrease in the incidence of each individual response and eventually elimination of the arousal responses. Cortical responses were eliminated first, followed by brainstem responses and finally spinal responses. The elimination of each of the responses occurred more rapidly during REM sleep that during NREM sleep. CONCLUSIONS: Habituation of the infant arousal sequence occurs with repeated tactile stimulation. There is a serial habituation of responses from the cortical to the spinal level, which occurs more rapidly during REM sleep. Rapid habituation to innocuous stimuli is probably beneficial in avoiding detrimental sleep disruptions. However, in situations requiring the protective functions of arousal, such habituation could be detrimental to an infant.     

Auditory arousal thresholds of good sleepers and poor sleepers with and without flurazepam.

Auditory arousal thresholds of good (N = 12) and poor (N = 12) sleepers (sleep onset insomniacs) were obtained during stage 2, stage 4, and REM sleep at various times of the night. Despite claims of being "light" sleepers who are easily awakened by noise, poor sleeper auditory arousal thresholds were the same as those of good sleepers. Flurazepam (30 mg) increased the auditory arousal thresholds of poor sleepers (N = 6), but the increase was statistically significant only during the period of peak effect which occurred 1--2 hr after ingestion. Consistent with poor sleeper complaints of trouble falling asleep, the return to sleep (i.e., sleep latency) was significantly longer for poor than for good sleepers following stimulus arousals during the first stage 2 and first stage 4 periods of the night. Sleep latencies for good and poor sleepers did not differ significantly following subsequent arousals. The sleep latency following the first stage 2 stimulus arousal was significantly reduced in poor sleepers during flurazepam-induced sleep.     

The relationship between frequency of rapid eye movements in REM sleep and SWS rebound

Previous studies have shown a decrease in rapid eye movement (REM) frequency during desynchronized sleep in recovery nights following total or partial sleep deprivation. This effect has been ascribed to an increase in sleep need or sleep depth consequent to sleep length manipulations. The aims of this study were to assess REM frequency variations in the recovery night after two consecutive nights of selective slow-wave sleep (SWS) deprivation, and to evaluate the relationships between REM frequency and SWS amount and auditory arousal thresholds (AAT), as an independent index of sleep depth. Ten normal males slept for six consecutive nights in the laboratory: one adaptation, two baseline, two selective SWS deprivation and one recovery night. SWS deprivation allowed us to set the SWS amount during both deprivation nights close to zero, without any shortening of total sleep time. In the ensuing recovery night a significant SWS rebound was found, accompanied by an increase in AAT. In addition, REM frequency decreased significantly compared with baseline. This effect cannot be attributed to a variation in prior sleep duration, since there was no sleep loss during the selective SWS deprivation nights. Stepwise regression also showed that the decrease in REM frequency is not correlated with the increase in AAT, the traditional index of sleep depth, but is correlated with SWS rebound.     

Ontogenetic variations in auditory arousal threshold during sleep

Developmental variations in auditory arousal thresholds during sleep were investigated in four groups of normal male subjects - children, preadolescents, adolescents, and young adults. Arousal thresholds were determined during NREM and REM sleep for tones presented via earphone insert on a single night following two adaptation nights of undisturbed sleep. Age-related relationships were observed for both awakening frequency and stimulus intensity required to effect awakening, with awakenings occurring more frequently in response to lower stimulus intensities with increasing age. Although stimulus intensities required for awakening were high and statistically equivalent across sleep stages in nonadults, higher intensity stimuli were required in Stage 4 relative to Stage 2 and REM sleep in adults. These results confirm previous observations of marked resistance to awakening during sleep in preadolescent children and suggest that processes underlying awakening from sleep undergo systematic modification during ontogenetic development.     

Nociceptive responsiveness during slow-wave sleep and waking in the rat

Brainstem neurons that are thought to modulate pain are reported to have state-dependent discharge rates. Yet, the effect of behavioral state upon nociceptive transmission has not been well studied. Therefore, we examined responses to noxious thermal stimulation of the rat hindpaw presented during different behavioral states. Noxious thermal stimuli were applied to rats as they spontaneously cycled through waking and sleeping states. Two different methods of heating the paw - a focused light bulb ("radiant heat") and a CO2 laser ("laser heat")-were employed. Regardless of the heating method used, rats withdrew from noxious thermal stimulation when it was applied in each behavioral state tested. When rats were tested with radiant heat, the withdrawal latency from noxious heat was shorter during slow-wave sleep than during waking. In contrast, when tested with laser heat, there was no difference in either the response latency or magnitude evoked by noxious heat across sleep/wake states. Despite the fact that rats withdrew from noxious heat (using either method of application) applied during sleep, the rats quickly returned to sleep afterwards. The latency to sleep after noxious stimulation was significantly greater during waking than during sleeping. The behavioral response to noxious thermal stimulation includes both an initial motor withdrawal which is enhanced during sleep and arousal or alerting which is suppressed during sleep. Therefore, pain evokes at least two distinct reactions that are differentially modulated across sleep/wake cycles.     

Sleep deprivation and phasic activity of REM sleep: independence of middle-ear muscle activity from rapid eye movements

In the recovery nights after total and partial sleep deprivation there is a reduction of rapid eye movements during REM sleep as compared to baseline nights; recent evidence provided by a selective SWS deprivation study also shows that the highest percentage of variance of this reduction is explained by SWS rebound. The present study assesses whether the reduction of rapid eye movements (REMs) during the recovery night after total sleep deprivation is paralleled by a decrease of middle-ear muscle activity (MEMA), another phasic muscle activity of REM sleep. Standard polysomnography, MEMA and REMs of nine subjects were recorded for three nights (one adaptation, one baseline, one recovery); baseline and recovery night were separated by a period of 40 hours of continuous wake. Results show that, in the recovery night, sleep deprivation was effective in determining an increase of SWS amount and of the sleep efficiency index, and a decrease of stage 1, stage 2, intra-sleep wake, and NREM latencies, without affecting REM duration and latency. However, MEMA frequency during REM sleep did not diminish during these nights as compared to baseline ones, while there was a clear effect of REM frequency reduction. Results indicate an independence of phasic events of REM sleep, suggesting that the inverse relation between recovery sleep after sleep deprivation and REM frequency is not paralleled by a concomitant variation in MEMA frequency.     

The initial orienting response during human REM sleep as revealed by the N1 component of auditory event-related potentials.

The large N1 wave of the auditory event-related potentials (ERPs) typically occurring to the first stimulus after a long silent interval seems to be associated with the involuntary initial-orienting response. Since the mechanisms involved in the generation of this brain response are assumed to be activated automatically, the present study aims at determining whether this electrophysiological response can also be elicited during human REM sleep, the sleep stage considered most sensitive to external stimuli. To achieve this goal, the auditory N1 wave was analyzed in wakefulness and REM sleep for frequency deviant tones delivered in several positions (1, 2, 4 and 6) within homogenous stimulus trains separated by different intervals of silence (3, 6 and 9 s), the intra-train stimulus interval being 600 ms. A significant increment in the amplitude of the N1 component for the first deviant tone, as compared with deviants delivered in remaining positions, was observed in both brain states, independently of the inter-train interval length. This result cannot be explained by a release-from-refractoriness effect, since only one deviant was presented in each train and the inter-deviant interval hardly changed from one train to another. The increase in N1 to the first stimulus of the train, probably due to the contribution of the neuronal elements responsible for the supratemporal and non-specific components, may be explained by changes in the silent interval, rather than by variations in the stimulus frequency. The enhanced N1 could be reflecting a general increase in sensory sensitivity associated with the arousal factor of the orienting response. These findings suggest that the brain maintains the potential ability to trigger the brain events responsible for the OR elicitation, even during REM sleep.     

Neural coding of stimulus concentration in the human olfactory and intranasal trigeminal systems

Nasal chemical sensations are mediated principally by the olfactory and the trigeminal systems. Over the last few years brain structures involved in processing of trigeminal stimuli have been more and more documented. However, the exact role of individual regions in stimulus intensity processing is unclear. The present study set out to examine the neural network involved in encoding stimulus intensity in the trigeminal system and the olfactory system of humans. Participants were presented with two concentrations of relatively specific trigeminal stimuli (CO2) and olfactory (H2S), respectively. Responses were assessed by functional magnetic resonance imaging (fMRI). Whereas brain responses to stimulus intensity in the olfactory modality involved a wide neural network including cerebellum, entorhinal cortex, visual areas, and frontal regions, contrasting high and low CO2 concentrations revealed activation in a less complex network including various sub-regions of the cingulate cortex. Taken together, these results suggest separate but overlapping neural networks involved in encoding stimulus intensity in the two chemosensory systems.     

Responsiveness of human nasal mucosa to trigeminal stimuli depends on the site of stimulation

There is evidence that functionally different areas can be distinguished within the nasal mucosa with regard to stimulation site and stimulus properties. The aim of the present study was the comparison of electrophysiological and psychophysical measures obtained in response to mechanical and chemosomatosensory stimulation of two different regions of the nasal mucosa. A total of 40 volunteers participated in this study (age range 21-36 years). Chemosomatosensory event-related potentials (ERPs) were recorded using gaseous CO2 as stimulant, while somatosensory ERPs were recorded in response to intranasal mechanical stimuli (air puffs). Stimuli were released to the anterior portion and to the posterior portion of the nasal cavity. A significant interaction between stimulus properties and site of stimulation could be detected after analysis of ERP parameters and intensity ratings. Thus, the chemosensory stimulus was perceived as stronger in the anterior portion of the nasal cavity whereas this was not the case for mechanosensory stimuli. In addition, mechanosensory stimuli were found to evoke ERPs with shorter latencies. These results underline the idea that the respiratory mucosa should not be seen as a homogeneous tissue. It exhibits varying sensitivities to trigeminal stimulation depending on stimulus quality and site of stimulation. Hence, perception of chemosensory stimuli seems to be most accurate in the anterior portion of the nasal cavity, while sensitivity to mechanical stimuli appears to be highest in the posterior portion. In addition, these differences within the respiratory mucosa may contribute to differences in the perception of orthonasal and retronasal odorous stimulation.     

Minimal olfactory perception during sleep: why odor alarms will not work for humans

STUDY OBJECTIVES: To examine olfactory arousal threshold during sleep in comparison to an auditory tone. DESIGN: On night 1, participants rated odor intensity when awake and experienced olfactory stimuli during stage 1 sleep. Night 2 involved stage 2, stage 4, and rapid-eye-movement (REM) sleep trials using the "staircase" threshold-detection method. Electroencephalogram, electrooculogram, electromyogram, electrocardiogram, and respiration were recorded along with behavioral response. An 800-Hz tone was given on trials when odors failed to arouse. SETTING: Participants slept in individual rooms. Stimulus-delivery systems were operated from a separate room, where an experimenter observed physiologic recordings and behavioral responses. PARTICIPANTS: Three healthy men and 3 women aged 20 to 25 years (mean, 22 years). INTERVENTIONS: Two odorants, peppermint and pyridine, at 4 concentrations were presented through nasal cannulas using an air-dilution olfactometer. Tones were played over a speaker. MEASUREMENTS: Behavioral (button press and oral) responses, electroencephalographic activation, and changes in breathing and heart rate were assessed. RESULTS: Participants responded to odors on 92% of stage 1 sleep trials. Peppermint was ineffective in stages 2, 4, and REM sleep. Pyridine produced behavioral threshold on 45% of stage 2 trials, none in stage 4, and one third of REM sleep trials. Tones were effective on at least 75% of trials. Heart rate increased significantly only following behavioral responses to odors or tones across sleep stages. CONCLUSIONS: The data indicate that human olfaction is not reliably capable of alerting a sleeper.     

Awakening Latency From Sleep For Meaningful and Non-Meaningful Stimuli

Personally significant and non-significant low intensity sound stimuli were used to determine awakening latencies from sleep stages REM and 2. Latency was measured from stimulus onset to a) the sleeper's own acknowledgement of waking, and b) alpha rhythm onset. Both stimuli were presented twice, once in each sleep stage, to 8 Ss. Voluntary response latencies in REM were shorter than in stage 2 (p <.025) but no difference was found for the latency of alpha rhythm onset. The personally significant stimulus, however, caused a significantly shorter awakening latency using both criteria. The results suggest that perceptual thresholds are low in both sleep stages 2 and REM but that the ability or willingness to organize a response is greater in REM sleep.     

Hypercapnia alters sleep state pattern

Mild hypercapnia in the adult animal does not affect sleep pattern but more severe hypercapnia in the fetus increases the duration of REM sleep. Adult male rats were exposed daily for 2-3 h sessions at random to 6, 7, and 8% CO2 or room air. Breathing CO2 caused a 60% increase in sleep onset latency, a 28% decrease in sleep duration, but no change in percent time spent in REM. However, the duration of REM sleep episodes increased by 30%. Thus, in both fetal and adult animals severe hypercapnia appears to have a similar effect on sleep pattern.     

Lead stimulus modality change and the attentional modulation of the acoustic and electrical blink reflex

Two experiments investigated the effects of the sensory modality of the lead and of the blink-eliciting stimulus during lead stimulus modality change on blink modulation at lead intervals of 2500 and 3500 ms. Participants were presented with acoustic, visual, or tactile change stimuli after habituation training with lead stimuli from the same or a different sensory modality. In Experiment 1, latency and magnitude of the acoustic blink were facilitated during a change to acoustic or visual lead stimuli, but not during a change to tactile lead stimuli. After habituation to acoustic lead stimuli, blink magnitude was smaller during tactile change stimuli than during habituation stimuli. The latter finding was replicated in Experiment 2 in which blink was elicited by electrical stimulation of the trigeminal nerve. The consistency of the findings across different combinations of lead stimulus and blink-eliciting stimulus modalities does not support a modality-specific account of attentional blink modulation. Rather, blink modulation during generalized orienting reflects modality non-specific processes, although modulation may not always be found during tactile lead stimuli.     

Arousal thresholds during human tonic and phasic REM sleep

The goal of the present study was to investigate arousal thresholds (ATs) in tonic and phasic episodes of rapid eye movement (REM) sleep, and to compare the frequency spectrum of these sub‐states of REM to non‐REM (NREM) stages of sleep. We found the two REM stages to differ with regard to behavioural responses to external acoustic stimuli. The AT in tonic REM was indifferent from that in sleep stage 2, and ATs in phasic REM were similar to those in slow‐wave sleep (stage 4). NREM and REM stages of similar behavioural thresholds were distinctly different with regard to their frequency pattern. These data provide further evidence that REM sleep should not be regarded a uniform state. Regarding electroencephalogram frequency spectra, we found that the two REM stages were more similar to each other than to NREM stages with similar responsivity. Ocular activity such as ponto‐geniculo‐occipital‐like waves and microsaccades are discussed as likely modulators of behavioural responsiveness and cortical processing of auditory information in the two REM sub‐states.     

Changes in emotional responses to aversive pictures across periods rich in slow-wave sleep versus rapid eye movement sleep

OBJECTIVE: Since Freud's "Interpretation of Dreams," sleep has been related to emotional functions, where dreams were assumed to play a cathartic role. In psychophysiological research, this role was attributed mainly to rapid eye movement (REM) sleep. The present study compared processing pictures with negative emotional impact over intervals covering either early sleep dominated by slow-wave sleep (SWS) or late REM sleep-dominated sleep. METHOD: Emotional reactions were assessed by a nonverbal rating procedure along the two emotional dimensions valence (positive vs. negative) and arousal (low vs. high). Two groups of healthy men were tested across 3-hour periods of early and late nocturnal sleep (sleep group) or corresponding intervals filled with wakefulness (wake group). After the intervals, subjects rated new pictures together with old pictures already presented before the interval. Sleep was recorded polysomnographically. RESULTS: As expected, the amount of REM sleep was about three times greater during late than early nocturnal sleep, whereas a reversed distribution was observed for SWS (p<.001). Valence ratings indicated a shift toward enhanced negative ratings after late sleep (p<.05), contrasting with a trend toward more positive ratings after early sleep (p<.10). Arousal habituated slightly to repeated presentation of the same stimuli, but sleep generally enhanced subsequent arousal ratings (p<.05). Effects of sleep did not depend on whether pictures had low or high emotional impact. CONCLUSIONS: Indicating a priming-like enhancement of emotional reactivity after periods rich in REM sleep, results do not confirm a cathartic function of REM sleep or sleep in general.