Eye movements and abducens motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis

Study Objectives:

The aim of this work was to characterize eye movements and abducens (ABD) motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis (NRPC).

Methods:

Six female adult cats were prepared for chronic recording of eye movements (using the scleral search-coil technique), electroencephalography, electromyography, ponto-geniculo-occipital (PGO) waves in the lateral geniculate nucleus, and ABD motoneuron activities after microinjections of the cholinergic agonist carbachol into the NRPC.

Results:

Unilateral microinjections of carbachol in the NRPC induced tonic and phasic phenomena in the oculomotor system. Tonic effects consisted of ipsiversive rotation to the injected side, convergence, and downward rotation of the eyes. Phasic effects consisted of bursts of rhythmic rapid eye movements directed contralaterally to the injected side along with PGO-like waves in the lateral geniculate and ABD nuclei. Although tonic effects were dependent on the level of drowsiness, phasic effects were always present and appeared along with normal saccades when the animal was vigilant. ABD motoneurons showed phasic activities associated with ABD PGO-like waves during bursts of rapid eye movements, and tonic and phasic activities related to eye position and velocity during alertness.

Conclusion

The cholinergic activation of the NRPC induces oculomotor phenomena that are somewhat similar to those described during REM sleep. A precise comparison of the dynamics and timing of the eye movements further suggests that a temporal organization of both NRPCs is needed to reproduce the complexity of the oculomotor behavior during REM sleep.

Citation:

Márquez-Ruiz J; Escudero M. Eye movements and abducens motoneuron behavior after cholinergic activation of the nucleus reticularis pontis caudalis. SLEEP 2010;33(11):1517-1527.     

Phasic motor activity reduction occurring with horizontal rapid eye movements during active sleep in human

We describe the phasic reduction of motor activity occurring with horizontal rapid eye movements (REMs) during active sleep in 15 children (12 healthy children and 3 patients with severe brain damage). A REM-related decrease in intercostal muscle activity was demonstrated by averaging integrated surface electromyograms. In the healthy subjects, this reduction had a mean latency from the REM onset of 37.1 ms and a duration of 225.9 ms. This phenomenon was also observed in the 3 patients who had lost cerebral function. We hypothesized a brainstem origin for the effect. A REM-related mentalis muscle activity loss, detected by averaging mentalis muscle twitches, was observed in 10 healthy children among the subjects. This loss began at 59.1 ms before the onset of REMs and lasted for 230.2 ms on average. In addition, a transient decrease in integrated REM activity surrounding mentalis muscle twitches (a twitch-related reduction of REMs) was observed. We discuss the similarity between REM-related phasic reduction of muscle activity obtained for intercostal and mentalis muscles and pontogeniculo-occipital (PGO) wave-related inhibitory postsynaptic potentials reported for feline lumbar and trigeminal motoneurons, respectively. We then assume the presence of a phasic event generator, functioning during active sleep in healthy humans, which triggers at least three generators; that is, the generator of PGO waves (or REMs), motor inhibition, and of motor excitation including muscle twitches.     

Tonic and phasic phenomena underlying eye movements during sleep in the cat

Mammalian sleep is not a homogenous state, and different variables have traditionally been used to distinguish different periods during sleep. Of these variables, eye movement is one of the most paradigmatic, and has been used to differentiate between the so-called rapid eye movement (REM) and non-REM (NREM) sleep periods. Despite this, eye movements during sleep are poorly understood, and the behaviour of the oculomotor system remains almost unknown. In the present work, we recorded binocular eye movements during the sleep–wake cycle of adult cats by the scleral search-coil technique. During alertness, eye movements consisted of conjugated saccades and eye fixations. During NREM sleep, eye movements were slow and mostly unconjugated. The two eyes moved upwardly and in the abducting direction, producing a tonic divergence and elevation of the visual axis. During the transition period between NREM and REM sleep, rapid monocular eye movements of low amplitude in the abducting direction occurred in coincidence with ponto-geniculo-occipital waves. Along REM sleep, the eyes tended to maintain a tonic convergence and depression, broken by high-frequency bursts of complex rapid eye movements. In the horizontal plane, each eye movement in the burst comprised two consecutive movements in opposite directions, which were more evident in the eye that performed the abducting movements. In the vertical plane, rapid eye movements were always upward. Comparisons of the characteristics of eye movements during the sleep–wake cycle reveal the uniqueness of eye movements during sleep, and the noteworthy existence of tonic and phasic phenomena in the oculomotor system, not observed until now.     

Characterization of REM-sleep associated ponto-geniculo-occipital waves in the human pons

STUDY OBJECTIVES: Ponto-geniculo-occipital (PGO) waves are phasic pontine, lateral geniculate, and cortical field potentials occurring during and before REM sleep that are proposed to mediate a wide variety of sleep related neural processes. We sought to identify and characterize human PGO waves. DESIGN: We recorded simultaneously from intrapontine depth electrodes and scalp electrodes in a human subject across sleep states. SETTING: Tertiary care neurological and neurosurgical referral center. PATIENTS OR PARTICIPANTS: We studied a patient involved in a study of the clinical effects of unilateral pedunculopontine nucleus (PPN) stimulation on Parkinson disease (PD). INTERVENTIONS: No interventions. MEASUREMENTS AND RESULTS: We recorded phasic potentials from the human pons occurring during and before REM sleep with a morphology, temporal distribution, and localization similar to those of PGO waves in other mammals. The source of these potentials was localized to a circumscribed region of the pontomesencephalic tegmentum. These potentials were only incompletely associated with eye movements. They were followed by characteristic cortical potentials with a latency of 20-140 msec. CONCLUSIONS: We conclude that PGO waves are a feature of human REM sleep, that they are generated or propagated in the pontomesencephalic tegmentum, that they are only partially associated with eye movements, and that they are associated with characteristic changes in cortical activity.     

Phasic activity of the basolateral amygdala, cingulate gyrus, and hippocampus during REM sleep in the cat

We analyzed the electrical activity of the basolateral amygdala (BLA), anterior and posterior regions of the cingulate gyrus (A-CG and P-CG), the dorsal hippocampus (DH), the anterior ventral thalamic nucleus (AVTN), and the sensory motor cortex during the rapid eye movements and ponto-geniculo-occipital (PGO) activity of REM sleep in cats in chronic preparation. Polygraphic recordings and computational perievent averages using the phasic contractions of the lateral rectus muscle (LR) of the eyeball as the triggering signal of the analysis were performed. We observed biphasic potentials (200-300 ms) of variable amplitude, related to the phasic phenomena of REM sleep, in the BLA, A-CG, P-CG, DH, and AVTN. The latencies of the potentials of these regions were always greater than those of the geniculate PGO activities. We propose that the recorded limbic potentials resulted from propagation of PGO activity and that this phenomenon may reflect the limbic structure of the hallucinatory, vegetative, and emotional components of REM sleep.     

Bulbo-thalamic neurons related to thalamocortical activation processes during paradoxical sleep

Summary Neurons histologically localized in the gigantocellular (Gc) and magnocellular (Mc) fields of the bulbar reticular formation were tested for antidromic invasion by stimulating the ventromedial (VM) and intralaminar (centralis lateralis, CL, and centrum medianum, CM) thalamic nuclei, midbrain reticular formation (MRF), and reticulospinal tract. An overwhelming majority (94%) of antidromically identified cells projected either to rostral structures (MRF, medial and intralaminar thalamic nuclei) or to the spinal cord, while only 6% had bifurcating axons.Rostrally projecting bulbar reticular neurons were investigated during various wake-sleep behavioral states, (a) Phasic neurons were related to PGO waves, eye and head movements, and were localized in both Gc and Mc fields, (b) The majority of tonic neurons projected to MRF and VM and they were localized within Mc in a proportion of 85%. In order to test their possible role in activation of thalamocortical processes (as betrayed by EEG desynchronization), the activity of tonically discharging cells was separately evaluated in periods with and without phasic motor events. Half of the tonically discharging neurons had a high selectivity of discharge during paradoxical sleep without REM bursts (PS-); the ratio of their mean discharge rate during PS- to that in quiet wakefulness (QW) or slow-wave sleep (SWS) was 8 and 6, respectively. The other half of the tonic neurons equally increased firing rates from SWS to either QW or PS.The firing rate of rostrally projecting bulbar reticular neurons with tonic discharge patterns was analyzed during transitions from SWS to PS. An increase in discharge rate was found about 30 to 60 s prior to the first sign of EEG desynchronization in PS, during fully synchronized sleep with PGO waves (S-PGO). Statistical testing showed that the increased firing rate was not associated to PGO waves, but was temporally related to the appearance of EEG desynchronization at PS onset. We conclude, on the basis of these and other recent data, that tonically discharging bulbar reticular neurons with identified projections to the midbrain and thalamic nuclei act synergically with rostrally projecting MRF neurons as sources of thalamocortical activation.Supported by grant MT-3689 from Medical Research Council of CanadaSupported by INSERM (U 52), CNRS (LA 162) and DRET (grant 81-205)     

The relationship between cortical recruiting responses and ponto-geniculo-occipital waves during paradoxical sleep in the cat.

In an earlier study it was found that during paradoxical sleep (PS) thalamo-cortical recruiting responses (RRs) and rapid eye movements usually did not appear simultaneously. As shown elsewhere, ponto-geniculo-occipital (PGO) wave activity and rapid eye movements are during PS closely related to each other in time. Similarly, in the present study it was observed that during paradoxical sleep in cats in which the center median nucleus of the thalamus was being stimulated at a rate of 7--9 Hz PGO waves in the geniculate nuclei did not in the rule occur in the presence of RRs recorded from the motor cortex. This effect was most pronounced with respect to series of PGO waves which usually occur at a rate of 4--7 Hz. On the basis of these experiments it was concluded that PGO waves and RRs are reciprocal events and mutually exclusive. Considering to the well-known fact that RRs represent synchronization, this negative correlation between RRs and PGO waves indicates that the desynchronizing tendency typical to paradoxical sleep is most pronounced during the occurrence of PGO waves.     

The relationship between cortical recruiting responses and ponto-geniculo-occipital waves during paradoxical sleep in the cat

In an earlier study it was found that during paradoxical sleep (PS) thalamo-cortical recruiting responses (RRs) and rapid eye movements usually did not appear simultaneously. As shown elsewhere, ponto-geniculo-occipital (PGO) wave activity and rapid eye movements are during PS closely related to each other in time. Similarly, in the present study it was observed that during paradoxical sleep in cats in which the center median nucleus of the thalamus was being stimulated at a rate of 7–9 Hz PGO waves in the geniculate nuclei did not in the rule occur in the presence of RRs recorded from the motor cortex. This effect was most pronounced with respect to series of PGO waves which usually occur at a rate of 4–7 Hz. On the basis of these experiments it was concluded that PGO waves and RRs are reciprocal events and mutually exclusive. Considering the well-known fact that RRs represent synchronization. this negative correlation between RRs and PGO waves indicates that the desynchronizing tendency typical to paradoxical sleep is most pronounced during the occurrence of PGO waves.     

Spectral features of EEG alpha activity in human REM sleep: two variants with different functional roles?

Evidence suggests that an important contribution of spectral power in the alpha range is characteristic of human REM sleep. This contribution is, in part, due to the appearance of well-defined bursts of alpha activity not associated with arousals during both tonic and phasic REM fragments. The present study aims at determining if the REM-alpha bursts constitute a different alpha variant from the REM background alpha activity. Since previous findings showed a selective suppression of background alpha activity over occipital regions during phasic REM fragments and, on the other hand, the density of alpha bursts seem to be independent of the presence or absence of rapid eye movements, one expects to find the same spectral power contribution of alpha bursts in tonic and phasic REM fragments. The results indicated that REM-alpha bursts showed a similar power contribution and topographic distribution (maximum energy over occipital regions) both in tonic and phasic REM fragments. This suggests that two variants of alpha activity with different functional roles are present during the human REM sleep: i) background alpha activity, modulated over occipital regions by the presence of rapid eye movements, which may be an electrophysiological correlate of the visual dream contents; and ii) REM-alpha bursts, independent of the presence of rapid eye movements, which could be facilitating the connection between the dreaming brain and the external world, working as a micro-arousal in this brain state.     

Tectal activity and eye movements during paradoxical sleep in cats

Phasic negative waves, similar to ponto-geniculo-occipital (PGO) waves, simultaneous with eye movements occurred in the superior colliculus in cats during the desynchronised EEG of paradoxical sleep. The frequency of PGO-like waves in the superior colliculus was about 25% lower than in the lateral geniculate body during the period of eye movements due to absence of 8/sec bursts common in the lateral geniculate body. Eye movements were evoked by stimulating the superior colliculus by rectangular pulse trains, and were accompanied by PGO-like waves in the lateral geniculate body and in the contralateral superior colliculus. During periods of paradoxical sleep, when no spontaneous rapid eye movements and PGO waves occurred, the effect of superior colliculus stimulation decreased. The phasic waves in the superior colliculus are associated apparently with the mechanism of rapid eye movements during paradoxical sleep. They resemble, but are not identical with, the phasic waves recorded under similar conditions in the lateral geniculate body.     

Magnetic stimulation of the human brain during phasic and tonic REM sleep: recordings from distal and proximal muscles

SUMMARY  During REM sleep, a powerful postsynaptic inhibition of spinal motoneurons induces a generalized muscle hypotonia. Despite this inhibition, it has been shown that by transcranial magnetic stimulation of the brain (TMS), muscle responses of normal amplitude can be evoked in small hand muscles of humans. Tonic innervation during sleep is different in postural vs. limb muscles, and the spinal inhibition differs during tonic vs. phasic REM episodes. Both phenomena may affect muscle responses to TMS. In this study, muscle responses of 14 healthy subjects were compared to TMS in abductor digiti minimi, lumbar erector spinae, trapezius, and diaphragm during phasic and tonic REM sleep. In all four muscles, the amplitudes of the muscle responses were extremely variable, ranging for example in trapezius from -100% to +473% as compared to wakefulness. There was no systematic difference between the muscles. Moreover, no differences were found for TMS during phasic REM events compared to tonic REM sleep. Thus, responses to TMS during REM sleep may be preserved, with a decreased or increased amplitude. As a likely explanation, the cortical excitability and/or the spinal inhibition fluctuates during REM sleep in humans.     

Spontaneous eyelid movements during human sleep: a possible ponto‐geniculo‐occipital analogue?

The aim of the present study was to investigate whether eye lid movements (ELMs) were temporally related to the activity of other skeletal musculature and to proposed analogues of ponto-geniculo-occipital (PGO) waves during human sleep. Electroencephalogram (EEG), laryngeal-masseter electromyogram (EMG), electrooculgram (EOG), peri-orbital integrated potentials (PIPs), middle ear muscle activity (MEMA), ankle flexion (AF) and respiration (RESP) were monitored with ELMs during one night's sleep. Results showed that ELMs always occurred during full arousal and movement time. The ELMs that occurred during sleep were most prominent during rapid eye movement (REM) sleep, occurred at higher frequency just before REM, and were observed synchronously with other PGO analogues, supporting the notion that ELMs may be an indicator of PGO activity in humans. Of the ELMs observed during sleep, 16% showed changes in EOG, PIP, MEMA, AF and RESP simultaneously, suggesting generalized muscle activation. This coactivation of muscle activity suggested that the relationship between the muscular measures and PGO activity might be an indirect one, possibly mediated by alerting mechanisms, previously shown to be related to PGO waves in animals. Such an interpretation is consistent with the use of ELM as a widely accepted measure of the eye-blink startle response in awake human subjects.     

Spontaneous phasic activity in the brain: differences between waves in lateral geniculate and central lateral nuclei across sleep states

SUMMARY  Ponto-geniculo-occipital (PGO) waves are spontaneously-occurring macropotential waveforms recorded in the pons, lateral geniculate body (LGB) and occipital cortex. PGO waves mark the onset and course of rapid eye movement sleep (REM). PGO-like waves can be recorded in several brain areas including the thalamic central lateral nucleus (CL). Alerting stimuli elicit PGO waves (PGO_E) from LGB and waves from CL (CL_E) in all behavioural states. We compared spontaneous activity in LGB and CL across behavioral states to examine the relationship of CL waves to PGO waves. Spontaneous waves in LGB and CL may occur concurrently or separately in all states. Although REM is marked by a high level of LGB PGO activity, CL waves are rare. Frequencies of CL and LGB waves are similar in non-REM (NREM) although the waves do not necessarily occur at the same time. These findings suggest that the widespread phasic activity recorded throughout the brain in sleep cannot be assumed to be a non-specific unitary phenomenon propagated from a single brainstem generator.     

Suppression of interictal spikes during phasic rapid eye movement sleep: a quantitative stereo‐electroencephalography study

Tonic and phasic rapid eye movement (REM) sleep seem to represent two different brain states exerting different effects on epileptic activity. In particular, interictal spikes are suppressed strongly during phasic REM sleep. The reason for this effect is not understood completely. A different level of synchronization in phasic and tonic REM sleep has been postulated, yet never measured directly. Here we assessed the interictal spike rate across non‐REM (NREM) sleep, phasic and tonic REM sleep in nine patients affected by drug resistant focal epilepsy: five with type II focal cortical dysplasia and four with hippocampal sclerosis. Moreover, we applied different quantitative measures to evaluate the level of synchronization at the local and global scale during phasic and tonic REM sleep. We found a lower spike rate in phasic REM sleep, both within and outside the seizure onset zone. This effect seems to be independent from the histopathological substrate and from the brain region, where epileptic activity is produced (temporal versus extra‐temporal). A higher level of synchronization was observed during tonic REM sleep both on a large (global) and small (local) spatial scale. Phasic REM sleep appears to be an interesting model for understanding the mechanisms of suppression of epileptic activity.     

PGO-related potentials in lumbar motoneurons during active sleep.

1. The present report describes the relationship that occurs during active sleep between ponto-geniculo-occipital (PGO) waves and changes in spinal cord motoneuron membrane potential. 2. These changes were characterized by the appearance of a complex pattern of motoneuron hyperpolarizing potentials, with a duration of approximately 300 ms, that were centered around the PGO wave. The first hyperpolarizing potential began before the onset of the PGO wave. Emerging from this hyperpolarizing potential was a second, larger-amplitude hyperpolarizing potential; it was followed by a succession of smaller-amplitude hyperpolarizations. 3. All potentials were present in conjunction with PGO waves during active sleep, but they were observed only in some motoneurons when PGO waves occurred during the transition period from quiet sleep to active sleep. 4. The potentials were reversed by chloride, demonstrating that they were inhibitory postsynaptic potentials (IPSPs). 5. These data, combined with the fact that these PGO-related IPSPs are blocked by strychnine, support the hypothesis that they are the result of the phasic enhancement of the activity of the same system that inhibits motoneurons during active sleep.     

Serotonergic antidepressants are associated with REM sleep without atonia

STUDY OBJECTIVES: Rapid eye movement (REM) sleep behavior disorder (RBD) is generally observed in older men and in individuals with specific neurologic diseases. There are case reports of RBD in individuals taking serotonergic antidepressants. Our objective was to assess electromyogram (EMG) activity during REM sleep in individuals taking serotonergic antidepressants and in a matched control group not on such medication. DESIGN: Chart review of clinical and polysomnographic data. SETTING: Sleep laboratory affiliated with a general hospital. PARTICIPANTS: 15 subjects taking a serotonergic antidepressant and 15 age-matched individuals not on such medication. MEASUREMENTS: Submental and anterior tibialis tonic and phasic EMG activity during REM sleep, REM latency, time in REM, apnea-hypopnea index, periodic leg movements of sleep index, and sleep-architecture measures. RESULTS: Tonic, but not phasic, submental EMG activity during REM sleep was significantly more common in the antidepressant-treated group than in the control group (P < .02). Tonic REM submental EMG activity correlated with REM latency (r = .42, P = .02) and inversely with REM time (r = -.36, P = .05). Subject age correlated with tonic REM submental EMG activity (r = .58, P = .02) in the antidepressant group There were also trends for more phasic activity in the anterior tibialis (P = .09) and submental (P = .07) EMG in REM sleep in the antidepressant group than in the control group. CONCLUSIONS: Subjects taking serotonergic antidepressants had more EMG activity in the submental lead during REM sleep than did controls. This correlated with measures of REM suppression and age. Individuals taking such medications may be at increased risk of developing REM sleep behavior disorder, particularly with increasing age.     

A complementary relationship between wake and REM sleep in the auditory system: a pre-sleep increase of middle-ear muscle activity (MEMA) causes a decrease of MEMA during sleep

Since some evidence has supported a complementary relationship between waking and REM-sleep eye movement (variations in frequency, amplitude, or direction of waking saccades have been found to inversely affect the corresponding parameters of rapid eye movements), the present study assessed whether this relationship can also be shown for other phasic components of REM sleep, such as middle-ear muscle activity (MEMA), as a consequence of an increase of middle-ear reflex frequency during pre-sleep wake. Ten subjects were studied in three consecutive nights (one adaptation, one baseline, one experimental). In the experimental night, subjects underwent a 2-h pure-tone (1000 Hz, 90 dB SPL) auditory stimulation and MEMA was monitored every 15 min; noise exposure during daytime was also controlled. Results show that MEMA frequency during REM sleep significantly decreased during the experimental nights compared with baseline nights, while each sleep variable as well as mean daily auditory input did not present any significant difference between baseline and experimental nights. Results suggest that the complementary relationship between wake and REM sleep is not bounded to oculomotor activity, but it may also be extended at least to middle-ear muscle phasic activity. Received: 30 April 1999 / Accepted: 14 September 1999     

Are the Eye Movements of Dreaming Sleep Related to the Visual Images of the Dreams?

As a result of recording eye movements during Stage REM sleep by AC electrooculography (EOG) previous investigators concluded that each eye movement is the response to the visual action in each dream. When we repeated the study using DC EOG it was discovered that only a minority of eye movements during Stage REM are in the direction of the visual action in the dream. If only single, large amplitude, prominent eye movements are considered then most such movements are related to colorful, compelling visual action occurring as a prominent single visual action against a quiet background. The AC recording method used in past studies emphasizes these isolated movements; perhaps this explains the disparity in results. At any rate, most eye movements during REM sleep are unrelated to the action in the dream. When these eye movements were analyzed in regard to the direction of movements, sequential order of movements, and randomness in time, we found that similar patterns of oculomotor output were found in all subjects. Thus, the nervous system executes a patterned output of oculomotor activity during dreaming sleep which is fairly consistent in all subjects. At times, however, a link is established between the visual and oculomotor systems and the eyes respond to visual action.     

Distinct features of fast oscillations in phasic and tonic rapid eye movement sleep

Spatiotemporal activity patterns of neurones are organized by different types of coherent network oscillations. Frequency content and cross‐frequency coupling of cortical oscillations are strongly state‐dependent, indicating that different patterns of wakefulness or sleep, respectively, support different cognitive or mnestic processes. It is therefore crucial to analyse specific sleep patterns with respect to their oscillations, including interaction between fast and slow rhythms. Here we report the oscillation profile of phasic rapid eye movement (REM), a form of REM sleep which has been implicated in hippocampus‐dependent memory processing. In all analysed frequency bands (theta, gamma and fast gamma, respectively) we find higher frequencies and higher power in phasic REM compared to tonic REM or wakefulness. Theta‐phase coupling of fast oscillations, however, was highest in tonic REM, followed by phasic REM and wakefulness. Our data suggest different roles of phasic and tonic REM for information processing or memory formation during sleep.     

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.