Reduction of transcallosal inhibition upon awakening from REM sleep in humans as assessed by transcranial magnetic stimulation

STUDY OBJECTIVES: The aim of the study is to assess, in humans, transcallosal inhibition upon awakening from rapid eye movement (REM) and non-REM sleep, by paired-pulse transcranial magnetic stimulation (TMS). DESIGN: During the daytime, a baseline session of motor evoked potentials (MEPs) was recorded. During the nighttime, the TMS sessions were administered just before sleep onset and upon awakenings from REM and stage 2 sleep, both in the early and final part of night. SETTING: The sleep research laboratory at the University of Rome "La Sapienza." PARTICIPANTS: Ten right-handed subjects participated in the experiment for 4 consecutive sleep-recording nights. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: During the daytime, a robust transcallosal inhibition was found; the MEP amplitude reduction ranged from 35% to 40%. During the nighttime, a decrease of transcallosal inhibition from right-to-left motor cortex, as compared to that from left-to-right motor cortex, was observed. The direct assessment of MEP changes, as a function of sleep stage and of the time of night, pointed to a drop of transcallosal inhibition after awakening from REM sleep. Therefore, the inhibitory activity of transcallosal fibers observed after non-REM awakening almost disappeared after REM sleep awakenings. CONCLUSIONS: The drastic drop of transcallosal inhibition after awakenings from REM sleep represents the first evidence in humans of a change of interhemispheric connectivity mediated by the corpus callosum during this sleep stage and may open new avenues for a better understanding of some aspects of sleep mechanisms (ie, dreaming function and dream mentation).     

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.     

The estimation of sleep quality in different stages and cycles of sleep

Dream content in NREM and REM sleep correlates with the subjective experience of having slept immediately before awakening. The estimation of depth of sleep depends on the quality of the NREM sleep stages. The presence of dreaming in a given sleep stage is more important for the subjective experience of having slept than the duration of the sleep episode before the awakening. Neurotic insomniac patients more often deny mental activity when awoken from NREM and REM sleep, than do healthy subjects. These data suggest that spontaneous awakenings in different sleep stages, especially in the first sleep cycle, correlate with the insomniac's tendency to underestimate sleep duration and quality.     

Inhibitory and excitatory intracortical circuits across the human sleep–wake cycle using paired-pulse transcranial magnetic stimulation

Studies using single-pulse transcranial magnetic stimulation (TMS) have shown that excitability of the corticospinal system is systematically reduced in natural human sleep as compared to wakefulness with significant differences between sleep stages. However, the underlying excitatory and inhibitory interactions on the corticospinal system across the sleep–wake cycle are poorly understood. Here, we specifically asked whether in the motor cortex short intracortical inhibition (SICI) and facilitation (ICF) can be elicited at all in sleep using the paired-pulse TMS protocol, and if so, how SICI and ICF vary across sleep stages. We studied 28 healthy subjects at interstimulus intervals of 3 ms (SICI) and 10 ms (ICF), respectively. Magnetic stimulation was performed over the hand area of the motor cortex using a focal coil and evoked motor potentials were recorded from the contralateral first dorsal interosseus muscle (1DI). Relevant data was obtained from 13 subjects (NREM 2: n = 7; NREM 3/4: n = 7; REM: n = 7). Results show that both SICI and ICF were present in NREM sleep. SICI was significantly enhanced in NREM 3/4 as compared to wakefulness and all other sleep stages whereas in NREM 2 neither SICI nor ICF differed from wakefulness. In REM sleep SICI was in the same range as in wakefulness, but ICF was entirely absent. These results in humans support the hypothesis derived from animal experiments which suggests that intracortical inhibitory mechanisms are involved in the control of neocortical pyramidal cells in NREM and REM sleep, but along different intraneuronal circuits. Further, our findings suggest that cortical mechanisms may additionally contribute to the inhibition of spinal motoneurones in REM sleep.     

Enhanced synchronization of gamma activity between frontal lobes during REM sleep as a function of REM sleep deprivation in man

Studies have shown that synchrony or temporal coupling of gamma activity is involved in processing and integrating information in the brain. Comparing rapid eye movement (REM) sleep to waking and non-REM (NREM) sleep, interhemispheric temporal coupling is higher, but lower between the frontal and posterior association areas of the same hemisphere. However, the homeostatic response of REM sleep temporal coupling after selective REM sleep deprivation (REMD) has not been studied. This study proposed exploring the effect of one night of selective REMD on the temporal coupling of cortical gamma activity during recovery REM sleep. Two groups of healthy subjects were subjected to either REMD by awakening them at each REM sleep onset, or to NREM sleep interruptions. Subjects slept four consecutive nights in the laboratory: first for adaptation, second as baseline, third for sleep manipulation, and fourth for recovery. Interhemispheric and intrahemispheric EEG correlations were analyzed during tonic REM (no eye movements) for the first three REM sleep episodes during baseline sleep, and recovery sleep after one night of selective REMD. Temporal coupling between frontal lobes showed a significant homeostatic rebound that increased during recovery REM sleep relative to baseline and controls. Results showed a rebound in temporal coupling between the two frontal lobes after REM sleep deprivation, indicating that the enhanced gamma temporal coupling that occurs normally during REM sleep has functional consequences. Conclusion: results suggest that synchronized activity during REM sleep may play an important role in integrating and reprocessing information.     

Spontaneous eyelid movements (ELMS) during sleep are related to dream recall on awakening

The present study aimed to test whether spontaneous eyelid movements (ELMs) during stage 2 and rapid eye movement (REM) sleep are related to more frequent and vivid reports of visual mentation on awakening. Participants were awakened 15 s after an ELM was observed during ongoing REM and stage 2 sleep and immediately asked for a mentation report and to rate the visual vividness of any imagery they could remember. These reports were compared with control reports collected after a period of ELM quiescence before awakening (noELM). Significantly greater frequencies of imagery reports were collected after ELM awakenings compared with noELM awakenings from stage 2, but not REM sleep. When imagery was reported, imagery ratings were not significantly different between ELM and noELM conditions, regardless of sleep stage. The average amount of electroencephalogram (EEG) arousal 15 s after stage 2 awakenings was significantly higher in the ELM compared with noELM conditions. In addition, within the stage 2 ELM condition, EEG arousal was significantly higher when visual imagery was reported compared with reports without imagery; suggesting that the observed increase in imagery reporting from the stage 2 ELM condition could have been mediated by the level of brain arousal. Such arousal possibly provides better conditions to attend and recall previous mental activity from NREM sleep. However, there was no ELM/arousal effect within REM sleep, possibly because this state is already at maximum sleeping levels of arousal, attention and resulting dream recall.     

From physiological neck myoclonus to sleep related head jerk

Neck myoclonus (NM) is a frequent recently described sleep‐related motor phenomenon occurring mainly during REM sleep with uncertain effect on sleep continuity. To better describe this phenomenon we studied 11 consecutive drug‐free patients undergoing a video‐polysomnographic (V‐PSG) study who present at least 5 NM events in one single night of recording. All events were measured and checked for their association with rapid eye and leg movements, EEG arousals, awakenings and Bereitschaftspotential. One hundred and eighty‐two motor events from 11 subjects were analyzed. Motor events were approximately 0.5 s in duration and occurred during REM sleep in 79.7% of the cases. Only 14.8% of the events were associated with rapid eye movements, 52.2% with leg movements, while approximately 80% of them were accompanied by an arousal or awakening. No EEG abnormalities and Bereitschaftspotential were observed. For its duration and its segregation in sleep, NM could be more appropriately named “sleep‐related head jerks” (SRHJ). SRHJ should be recognized and its effect on sleep stability should be re‐considered.     

Survival analysis indicates that age-related decline in sleep continuity occurs exclusively during NREM sleep

A common complaint of older persons is disturbed sleep, typically characterized as an inability to return to sleep after waking. As every sleep episode (i.e., time in bed) includes multiple transitions between wakefulness and sleep (which can be subdivided into rapid eye movement [REM] sleep and non-REM [NREM] sleep), we applied survival analysis to sleep data to determine whether changes in the “hazard” (duration-dependent probability) of awakening from sleep and/or returning to sleep underlie age-related sleep disturbances. The hazard of awakening from sleep—specifically NREM sleep—was much greater in older than in young adults. We found, however, that when an individual had spontaneously awakened, the probability of falling back asleep was not greater in young persons. Independent of bout length, the number of transitions between NREM and REM sleep stages relative to number of transitions to wake was approximately 6 times higher in young than older persons, highlighting the difficulty in maintaining sleep in older persons. Interventions to improve age-related sleep complaints should thus target this change in awakenings.     

SLEEP MENTATION AND AUDITORY AWAKENING THRESHOLDS

Auditory awakening thresholds (AATs) were assessed in 53 Ss during all stages of sleep and at various times of night. Sixteen of these Ss met previously devised criteria for an AAT light-sleep group (LSG) and 16 for an AAT deep-sleep group (DSG). Reports of mental activity were collected during awakenings from REM and NREM sleep and rated on a standard questionnaire by Ss and independent judges. The REM mentation of the LSG and DSG did not differ. However, LSG Ss reported dreaming after 71% of their NREM awakenings, while DSG Ss claimed to have been dreaming after only 21% of their NREM awakenings. This difference was supported by other rating scales and by the independent judges. An hypothesis was offered which suggests that dreaming is a function of the level of cerebral arousal in the absence of reality contact, regardless of the stage of sleep, and that LSG Ss, as evidenced by several criteria, were more cerebrally aroused during NREM sleep than DSG Ss.     

Night-time right hemisphere superiority and daytime left hemisphere superiority: a repatterning of laterality across wake-sleep-wake states

During the sleep onset period (SOP), there is a state-specific relative advantage of the right hemisphere (RH). This superiority could either be due to the ability of the RH when operating at levels of reduced arousal, as suggested by its superiority in sustaining vigilance, or it could depend on a more pronounced homeostatic deactivation of the left hemisphere (LH). To evaluate whether variations of lateralization from wake to sleep are consistent with one of these two hypotheses, we considered a finger tapping task (FTT) bimanually performed during two wakeful conditions, during the SOP, upon experimental awakenings from stage 2 and REM sleep in the first and in the second part of the night, and upon morning awakening. The RH advantage in sustaining vigilance would be supported if the relative RH advantage was present throughout the sleep period. Finding that the repatterning of hemispheric asymmetry is present and/or prominent in the first part of the night would support the homeostatic hypothesis, i.e. when the homeostatic process is more pronounced. Results from 16 subjects revealed a significant superiority of the LH during the two wakeful conditions. At sleep onset, a clear reversal of dominance was observed and it was followed by a steady RH superiority upon both REM and NREM sleep awakenings, and upon the morning sleep-wake transition. Therefore, performance in a FTT reveals a repatterning of laterality across wake-sleep-wake states. These results are interpreted as consistent with the hypothesis concerning an advantage of the RH in sustaining vigilance.     

ELECTROMYOGRAM SUPPRESSION DURING SLEEP, DREAM RECALL, AND ORIENTATION TIME

Five subjects had their nocturnal sleep monitored (EEG, EOG, submental EMG) for a total of 42 nights. A total of 196 awakenings to retrieve sleep mentation was distributed among three awakening categories: Non-Rapid Eye Movement (NREM) sleep before the EMG suppression heralding REM-sleep onset; NREM sleep immediately following the EMG suppression heralding REM-sleep onset; and early moments of REM sleep accompanied by EMG suppression. Suppressed-EMG NREM awakenings tended to be associated with lower dream recall frequency and lower Dreamlike Fantasy Scale ratings than did high-EMG NREM awakenings. Orientation times upon experimental awakenings were longer on suppressed-EMG pre-REM awakenings than on high-EMG pre-REM awakenings. A momentary “deepening” of sleep (in terms of less memorable and vivid mental content and of decreased reactivity to the awakening stimulus) thus appears to accompany the pre-REM suppression of neck and chin EMG potentials.     

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.     

Corticospinal excitability in human subjects during nonrapid eye movement sleep: single and paired-pulse transcranial magnetic stimulation study

The mechanisms responsible for changes in brain function during normal sleep are poorly understood. In this study, we aimed to investigate the effects of sleep on human corticospinal excitability by estimating resting motor threshold (RMT), and latency and amplitude of motor-evoked potentials (MEPs) after delivering transcranial magnetic stimulation (TMS) in ten healthy subjects. We also aimed to study short-interval intracortical inhibition (SICI) during sleep with paired-pulse TMS (pp-TMS). Ten healthy volunteers were studied. They were monitored immediately before, during and after a 3-h sleep (from 1 p.m. to 4 p.m., immediately after the mid-day meal). EEG was continuously recorded during sleep and the various sleep stages were identified off line. Every 10 min, subjects received ten single stimuli (to estimate RMT, MEP latency and amplitude) and six paired stimuli (to estimate SICI). MEP amplitude decreased and latency and RMT increased during the various sleep stages and returned to baseline values on awakening. Post hoc comparisons showed a significant difference in pp-TMS MEP amplitudes between the sleep and all the other conditions. The changes in TMS evoked variables during the different sleep stages indicate that during nonrapid eye movement sleep, cortical pyramidal neuron excitability (as measured by RMT, MEP latency and amplitude) progressively diminishes and the efficiency of the intracortical GABA-ergic network (as assessed by three pp-TMS) increases. On awakening, these sleep-induced changes in corticospinal excitability return rapidly to values observed during wakefulness.     

Renin as a biological marker of the NREM-REM sleep cycle: effect of REM sleep suppression

SUMMARY  We have previously described that, in normal man, the nocturnal oscillations of plasma renin activity (PRA) exactly reflect the rapid eye movement (REM)–non(N)REM sleep cycles, with increasing PRA levels during NREM sleep and decreasing levels during REM sleep. This study was carried out to determine whether REM sleep suppression affects nocturnal renin profiles and to define which sleep stage is essential for renin release.
In a first experimental series, REM sleep was suppressed by using clomipramine, a tricyclic antidepressant. Seven healthy young men were studied once during a night when a placebo was given and once during a night following a single dose of 50 mg clomipramine. Blood was collected every 10 min from 23.00 hours to 07.00 hours. PRA was measured by radio-immunoassay and the nocturnal profiles were analysed using the pulse detection program ULTRA. Clomipramine suppressed REM sleep in all subjects but one, but did not affect the number of SWS episodes nor their duration. Similar PRA profiles were observed in both experimental conditions. Neither the mean levels, nor the number and the amplitude of the oscillations were modified and the normal relationship between slow wave sleep and increasing PRA levels was preserved.
In a second experimental series, REM sleep was prevented by rapidly awakening the subjects as soon as they fell into REM sleep. The four subjects studied attempted several times to go into REM sleep, but only when PRA levels were decreasing. The interruption of REM sleep by short waking periods did not disturb PRA for which the oscillations remained unaffected. Again, the relationship between SWS and increasing PRA levels was preserved.
These results provide evidence that mechanisms increasing slow-wave activity are principally involved in increasing PRA levels and that replacing REM sleep by waking periods and light sleep does not modify nocturnal PRA oscillations.     

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.     

The effects of selective interruption and deprivation of sleep in the human newborn

In two separate studies, newborn infants' responses to sleep stage deprivation were investigated. In the first study, neonates were selectively awakened from either REM or NREM sleep during 1 interfeeding sleep period and allowed to recover in an undistrubed second. In the 2nd study, infants were kept totally awake for 1 interfeeding period and allowed to sleep undisturbed during the next. The results indicate that selective sleep stage deprivation by manual awakenings was impossible to achieve during the newborn period. Rather, the infants were partially sleep deprived (both stages of sleep were reduced) with increased amounts of wakefulness. During the disturbance the interrupted sleep stage demonstrated considerable “tenacity.” During undisturbed recovery sleep, in both studies, total sleep time was markedly increased. NREM sleep demonstrated a greater tendency for preferential recovery than REM sleep.     

The thematic continuity of mental experiences in REM and NREM sleep

In this study the characteristics of interrelated contents in paired reports of mental sleep experience (MSE) were analyzed to obtain insight as to the functioning of processes by which contents previously stored in memory are retrieved and inserted into MSE in rapid eye movements (REM) and non-REM (NREM) sleep. Ten subjects were awakened 3 times on each of 4 nights after 3 min of NREM sleep (in stage II or III before the first REM), of the first phase of REM sleep, and again of NREM sleep (in stage II or III after the first REM). The contents of all the possible pairings of reports were scored by using Clark's (1970) feature-matching model and compared with respect to the factors 'night' (same/different), 'type of report pairs' (1stNREM-REM/REM-2ndNREM/1stNREM-2ndNREM), 'unit interrelated' (lexical/propositional), 'interrelationship' (paradigmatic/syntagmatic). The occurrences of interrelations were greater for same night pairs than for different night pairs, but without significant differences between types of report pairs: these data provide support for the thematic continuity of MSE in both NREM and REM sleep. The units interrelated in pairs of reports were more frequent at a lexical than a propositional level, showing more paradigmatic than syntagmatic interrelationships: these data suggest that the re-elaboration of contents of previous MSEs occurs mainly at a lower level, and that the modality of processing previous contents by insertion into current MSE is similar in NREM and REM sleep.(ABSTRACT TRUNCATED AT 250 WORDS)     

Sleep inertia varies with circadian phase and sleep stage in older adults

The purpose of our analysis was to determine if older adults show sleep inertia effects on performance at scheduled wake time, and whether these effects depend on circadian phase or sleep stage at awakening. Using the Digit Symbol Substitution Test, effects of sleep inertia on performance were assessed over the first 30 min after wake time on baseline days and when sleep was scheduled at different circadian phases. Mixed model analyses revealed that performance improved as time awake increased; that beginning levels of performance were poorest when wake time was scheduled to occur during the biological night; and that effects of sleep inertia on performance during the biological night were greater when awaking from non-REM (NREM) sleep than from REM sleep. Based on our current understanding of sleep inertia effects in young subjects, and previous reports that older subjects awaken at an earlier circadian phase and are more likely to have their final awakening from NREM sleep than younger adults, our findings suggest older adults may be more vulnerable to sleep inertia effects than young adults.     

Rapid eye movement activity before spontaneous awakening in elderly subjects

Previous research in young subjects found that rapid eye movement (REM) density is higher in those REM phases which are followed by an awakening (REM-W) than in those preceding NREM (REM-N), suggesting a 'gating role' of REM sleep toward the awakening. It is not yet known whether this evidence is maintained in elderly subjects, who display, relative to young subjects, more awakenings, different sleep states from which the awakenings come (NREM in a high proportion of cases) and a general impairment of rapid eye movement activity (REMA). To investigate this issue, we have compared in three different age groups (young, old and 'old old' subjects) the features of REMA, including REM density and the amount and duration of REM bursts, between REM-W and REM-N. Whereas in the young REM density is higher in REM-W than in REM-N, this difference is already reduced in the old group and fully cancelled in the old old subjects. The evidence that old individuals spontaneously wake up despite the absence of an increase of REMA could imply that in the aged awakening is not preceded by an increase of the arousal level (expressed in REM sleep by the REMA). The similar duration of REM bursts for REM-W and REM-N in both groups of old subjects suggests that with age a marked impairment occurs in the organizational aspects of REMs, independently from the following state.