Facilitation of the acoustic startle reflex by ponto-geniculo-occipital waves: effects of PCPA

The relationship between ponto-geniculo-occipital (PGO) waves and motor activity during waking and non-rapid eye movement (non-REM) sleep stages was studied in cats treated with the serotonin synthesis inhibitor p-chlorophenylalanine (PCPA). PGO waves appeared in waking after daily treatment with PCPA. The magnitude of the acoustic startle elicited in the absence of prior PGO waves was increased (by a mean of 555%) by the PCPA treatment as compared to that of the pre-drug level. When startle-eliciting stimuli were presented shortly after the occurrence of the PGO wave, the response amplitude was further enhanced as compared to that of the baseline startle. The effect was maximal 50 ms following the peak of the PGO wave (average 192% of the baseline level), with return to the baseline startle level within 200 ms. A similar effect could also be seen with waking eye-movement potentials (EMPs) in drug-naive animals. Over half of the spontaneous PGO waves were found to be preceded or followed by discrete head-body movements. After PCPA, the amplitude of auditory-evoked LGN PGO waves increased during quiet waking (QW) while those in non-REM and REM sleep states did not change. It was concluded that serotonergic systems produce a tonic suppression of startle response and PGO amplitude in waking. PGO spikes in waking are associated with a phasic facilitation of the sensorimotor mechanisms involved in startle.     

The effects of varying stimulus intensity on P300 during REM sleep.

Event-related potentials (ERPs) are often used to measure the extent of information processing during sleep. Previous studies have indicated that a late positive wave, P300, can be elicited during REM sleep if stimuli are very rare and/or very loud. The present study examined the role of stimulus intensity in eliciting a P300 during REM sleep. Eight subjects were presented with auditory tone pips with an intensity of either 0, 60, 80 or 100 dB SPL. Stimuli were delivered at random with equal probability. Trials were sorted by stage of sleep, stimulus intensity, and presence or absence of rapid eye movements in REM sleep. During the waking state, when subjects read a book, the loud 100 dB stimulus elicited short (P3a) and long latency (P300) positive waves (peaking at 293 and 373 ms respectively). In stage of 2 non-REM sleep, N1 decreased to baseline level while P2 increased in amplitude compared to the waking state. A P300 could not be observed in stage 2 sleep regardless of the level of stimulus intensity. During REM sleep, a late P300 (latency 363 ms) was elicited by the 100 dB stimulus. The earlier positive peak (i.e. P3a) was not apparent. The P300 was reduced in amplitude compared to the waking state. Its amplitude did not differ between phasic and tonic states of REM sleep. A late parietal negative slow wave (SW) was also apparent during REM. Although the SW was larger during phasic compared to tonic REM, the difference was not significant. These data suggest that stimuli which are sufficiently intrusive to elicit a P300 in the waking state continue to do so in REM sleep.     

Psychophysiological alterations in post-traumatic stress disorder.

Psychophysiological research in trauma-exposed populations has provided objective data supporting the validity of the post-traumatic stress disorder (PTSD) diagnostic concept. Consistent with a conditioning model, PTSD patients show specific increased peripheral physiological responding to audio-visually and imaginally presented stimuli symbolizing or resembling the etiologic traumatic event. PTSD patients respond to startling stimuli with larger autonomic and electromyographic responses, especially under threat conditions. Electroencephalographic event-related potential (ERP) response abnormalities in PTSD include reduced P2 amplitude at high stimulus intensities, impaired P1 habituation, and attenuated P3 amplitude to target auditory stimuli. However, larger P3 and N1 amplitude responses and shorter P3 and N1 latencies have been reported in PTSD subjects in response to trauma-related stimuli. These ERP findings suggest sensory, cognitive, and affective processing abnormalities in PTSD. Polysomnographic sleep studies have revealed increased awakenings, reduced sleep time, and increased motor activity, or in some cases, paradoxical deepening of sleep. There is also evidence for increased phasic eye movement activity during rapid eye movement (REM) sleep and disrupted REM continuity in PTSD. Psychophysiological studies are offering valuable insights into the pathophysiology of this important neuropsychiatric condition.     

Polysomnographic features of REM sleep behavior disorder: development of a scoring method.

REM sleep behavior disorder (RBD) is characterized by the intermittent absence of REM sleep EMG atonia and the appearance of elaborate motor activity associated with dream mentation. There are no specific diagnostic criteria for RBD based upon polysomnographic findings. We describe a new scoring method and show its sensitivity to treatment with clonazepam. An increased phasic submental EMG density occurs in RBD patients, but REM density is similar to that of controls. Clonazepam selectively decreases REM sleep phasic activity but exerts no effect on REM sleep atonia. Periodic limb movements in sleep (PLMS) occur equally in both REM and NREM sleep in RBD patients, suggesting that normal suppression of PLMS in REM sleep is due to motor inhibition.     

The effect of state on sensory gating: comparison of waking, REM and non-REM sleep.

OBJECTIVES: Auditory sensory gating is an electrophysiological assay that has been employed in clinical and basic research to clarify the neurobiological basis of perceptual and attentional impairments associated with schizophrenia and other diseases. In addition to genetically-linked characteristics, this measure also exhibits potentially confounding sensitivity to behavioral state, most notably acute stress. The goal of the present study is to determine if auditory sensory gating of evoked potential component P50 ('P1') could be measured during rapid eye movement (REM) sleep, as an alternative to the waking state. METHODS: The suppression of vertex-recorded auditory evoked potential components, P30, P50 and N100, was measured as a function of stimulus redundancy using the paired-click paradigm during all-night sleep in 10 control subjects. Average evoked responses were computed separately for 30 min periods of waking, REM sleep, and non-REM (stage 2) sleep. RESULTS: Evoked response component P50 exhibited suppression to the paired-click stimulus during REM sleep, not significantly different than waking. Suppression of wave N100 was significantly poorer during both sleep stages than waking. Component P30 was not suppressed in response to repetitive stimuli under any state of vigilance. CONCLUSIONS: In addition to waking, response suppression of evoked potential component P50 can be measured during REM sleep, thus allowing the separation of trait- and state-dependent effects in future investigations of auditory sensory gating.     

Activity of serotonin-containing neurons in the nucleus raphe pallidus of freely moving cats

Serotonergic neurons within nucleus raphe pallidus (NRP) of freely moving cats initially were distinguished by their slow (< 8 Hz), regular discharge and long duration (mean = 2.3 ms) action potentials. The activity of serotonergic NRP neurons was highest during active waking (mean = 4.85 ± 0.37 spikes/s) and gradually slowed, with little change in firing pattern, during the transition from waking through slow wave sleep (middle of SWS: mean = 3.76 ± 0.36 spikes/s). In REM sleep there was a precipitous decrease in firing rate (mean = 0.92 ± 0.23 spikes/s) and loss of discharge regularity. Although there was no significant difference in firing rate between active and quiet waking, discharge rates were significantly increased during transient elevations of the EMG, but these rate increases usually were associated with specific motor behaviors only. The activity of serotonergic NRP neurons during SWS was not related to the occurrence of either sleep spindles in the cortical EEG or PGO waves recorded from the lateral geniculate nucleus. These neurons also were relatively unresponsive to phasic auditory or visual stimuli, with most of the neurons examined showing weak excitatory responses. Activity of all serotonergic NRP neurons tested was suppressed (mean = −81.3 ± 4.3%) by the serotonergic agonist 5-methoxy-N,N-dimethyltryptamine (250 μg/kg, i.m.). The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus of freely moving cats and the issue of homogeneity in central serotonergic systems is discussed.     

Motoneuron properties during electromyogram pauses in sleep

Electrophysiological antecedents to electromyogram pauses of NREM sleep were studied intracellularly in hindlimb motoneurons. Phasic-event-related hyperpolarizing potentials (PRHP) were 0.2–7.1 mV in amplitude and 9–90 ms in duration, and coincided with dorsal neck EMG pauses and PGO waves. Motoneurons, if spontaneously discharging, were silenced during PRHPs. The discharge rate of spike trains elicited by depolarizing current reduced during PRHPs. Membrane conductance measurements indicated that PRHPs did not arise simply from soma inhibition but from either presynaptic inhibition or conductance changes in electrically-remote dendrites. EMP pauses, which normally occur spontaneously, could be evoked by stimulation of low threshold fibers in peripheral nerves. PRHPs were most prevalent in REM sleep. We concluded that EMG pauses are generated by the same cholinergic brainstem mechanism that generates spino-bulbo-spinal presynaptic inhibition of group Ia afferents. The pauses resemble the inhibitory phase of startle responses, providing evidence for the hypothesis that startle responses are spontaneously elicited in NREM and REM sleep.     

Subcutaneous administration of nicotine changes dorsal raphe serotonergic neurons discharge rate during REM sleep

In the present study nicotine (0.1 mg/kg, s.c.) increased discharge rate of putative dorsal raphe (DRN) serotonergic neurons of behaving rats during REM sleep (362.61%), without any significant change during waking and non-REM sleep. Since serotonergic DRN neurons gate PGO onset, these results suggest that nicotine-induced suppression of PGO spikes during REM sleep previously reported is achieved through stimulation of dorsal raphe serotonergic cells.     

Behavioral correlates of dopaminergic unit activity in freely moving cats

Single unit activity of dopaminergic neurons in the substantia nigra was recorded in freely moving cats under a variety of conditions. These neurons displayed their highest discharge rate during active waking (3.68 ± 0.30 spikes/s), which was 20% greater than their discharge rate during quiet waking (3.07 ± 0.20). Although these cells fired somewhat faster during active waking, their activity displayed no correlation with phasic EMG changes, and, in general, their activity showed little relationship to overt behavioral changes. As the cat progressed from quiet waking through slow-wave sleep and REM sleep there was no significant change in either the rate or pattern of firing of dopaminergic neurons. In addition, no correlation was observed between the activity of these neurons and either sleep spindles or PGO waves. These neurons did respond, however, to the repeated presentation of a click or light flash with excitation followed by inhibition, with no evidence of habituation. One of the most impressive changes in dopaminergic unit acttivity was a large decrease in association with orienting responses. This was seen in over 50% of the cells in which this relationship was examined. As the behavioral orientation habituated with repeated stimulus presentation, so did the associated dopaminergic unit suppression. In conclusion, dopaminergic neurons maintain a remarkably constant rate and pattern of firing across a variety of behaviors and states. However, this stability can be dramatically altered under special circumtances, such as during and following orienting responses.     

New pathways and data on rapid eye movement sleep behaviour disorder in a rat model

ObjectiveAn abnormality in auditory evoked responses localised to the inferior colliculus (IC) has been reported in rapid eye movement (REM) sleep behaviour disorder (RBD) patients. The external cortex of the inferior colliculus (ICX) has been demonstrated not only to be involved in auditory processing, but also to participate in the modulation of motor activity.MethodsRats were surgically implanted with electrodes for electroencephalography (EEG) and electromyography (EMG) recording and guide cannulae aimed at the ICX for drug infusions. Drug infusions were conducted after the animals recovered from surgery. Polysomnographic recordings with video were analysed to detect normal and abnormal sleep states.ResultsBaclofen, a gamma-aminobutyric acid B (GABA_B) receptor agonist, infused into the ICX increased phasic motor activity in slow-wave sleep (SWS) and REM sleep and tonic muscle activity in REM sleep; it also elicited RBD-like activity during the infusion and post-infusion period. In contrast, saclofen, a GABA_B receptor antagonist, did not produce significant changes in motor activities in sleep. Baclofen infusions in ICX also significantly increased REM sleep during the post-infusion period, while saclofen infusions did not change the amount of any sleep–waking states.ConclusionsThis study suggests that GABA_B receptor mechanisms in the ICX may be implicated in the pathology of RBD.     

The human hand motor area is transiently suppressed by an unexpected auditory stimulus.

OBJECTIVE: To study the effect of a loud auditory stimulus on the excitability of the human motor cortex. METHODS: Ten normal volunteers participated in this study. The size of responses to transcranial magnetic or electrical cortical stimulation (TMS or TES) given at different times (ISIs) after a loud sound were compared with those to TMS or TES alone (control response). Different intensities and durations of sound were used at several intertrial intervals (ITIs). In addition, we examined how the presence of a preceding click modulated the effect of a loud sound (prepulse inhibition). The incidence of startle response evoked by various stimuli was also studied. RESULTS: A loud auditory stimulus suppressed EMG responses to TMS when it preceded the magnetic stimulus by 30-60 ms, whereas it did not affect responses to TES. This suggests that the suppression occurred at a cortical level. Significant suppression was evoked only when the sound was louder than 80 dB and longer than 50 ms in duration. Such stimuli frequently elicited a startle response when given alone. The effect was not evoked if the ITI was 5 s, but was evoked when it was longer than 20 s. A preceding click reduced the suppression elicited by loud sounds. CONCLUSIONS: Auditory stimuli that produced the greatest effect on responses to TMS had the same characteristics as those which yielded the most consistent auditory startle. We suggest that modulation of cortical excitability occurs in parallel with the auditory startle and both may arise from the same region of the brain-stem.     

The amplitude of elicited PGO waves: a correlate of orienting

Ponto-geniculo-occipital (PGO) waves spontaneously occur in the pons, lateral geniculate body (LGB), and occipital cortex during rapid eye movement sleep (REM), and PGO-like waves (PGO_E) may be elicited in LGB during sleep and waking. Because REM has been hypothesized to be a state of continual “orienting” or “hyper-alertness,” we tested whether the amplitudes of PGO_E in “alerting” situations (the abrupt onset of a loud sound or presentation of a novel stimulus within a series of stimuli) that evoke orienting responses (OR) would be greater than those following stimuli without OR. We also compared PGO_E accompanying OR to PGO_E during REM and NREM when OR are absent. The amplitudes of PGO_E in W were greatest when OR were observed, and the amplitudes of PGO_E accompanying OR were not significantly different from PGO_E amplitudes in REM. Likewise, the amplitudes of PGO_E during REM were not significantly different from those of the highest amplitude spontaneous PGO waves. We propose that the presence of PGO_E signals registration of stimuli and that stimuli of sufficient significance to induce behavioral OR in waking also elicit PGO_E of significantly greater amplitudes in all behavioral states. These findings support the hypothesis that the presence of high-amplitude PGO waves in REM indicates that the brain is in a state of more-or-less continual orienting.     

Phasic EEG activities associated with rapid eye movements during REM sleep in man

Human cortical potentials associated with rapid eye movements (REMs) during REM sleep were recorded in 6 normal young adults by using the averaging technique. The potentials were compared with those recorded during voluntary saccades in the waking state in a dark or an illuminated room. A positive potential of relatively long duration with peak latency of about 200 msec and a wide spread bilateral distribution and of highest amplitude in the mid-parietal area appeared only during REM sleep. It is suggested that this positive potential is phasic EEG activity appearing in association with REMs during REM sleep in man. Comparison of this positive potential with P300s induced by task-irrelevant visual stimuli disclosed that they resemble each other. The possibility was discussed that this positive potential occurring in association with REMs during REM sleep is indeed a P300 appearing in response to visual images in dream.     

Cholinergic reduction of REM sleep duration is reverted by auditory stimulation

It was previously shown that an auditory stimulus given prior to and throughout a rapid eye movement (REM) sleep period was capable of inducing a significant increase in REM sleep duration and pontogeniculo-occipital (PGO) spike density. The purpose of this study was to determine whether the increase in REM duration is dependent on PGO spike density. We administered atropine to cats at doses of 0.1–0.6 mg/kg and the effects on REM duration and PGO spikes was determined. The doses of 0.2 and 0.3 mg/kg of atropine were then utilized to compare REM sleep periods with and without auditory stimulation. The results showed that both REM duration and PGO spikes were decreased by atropine, but could be dissociated from each other depending on the doses. In addition, it was shown that the auditory stimulus protected the animals from the effects of atropine but only in relation to REM sleep duration. The results indicate that both REM sleep duration and PGO spikes have a cholinergic component and that the auditory stimulus exerts its REM enhancing properties in a manner which seems to be independent of the PGO spike density. The results are discussed in terms of receptor availability and/or excitability levels of medial reticular neurons.     

Ponto-geniculo-occipital-wave suppression amplifies lateral geniculate nucleus cell-size changes in monocularly deprived kittens

We have previously shown that during the post-natal critical period of development of the cat visual system, 1 week of instrumental rapid eye movement (REM) sleep deprivation (IRSD) during 2 weeks of monocular deprivation (MD) results in significant amplification of the effects of solely the 2-week MD on cell-size in the binocular segment of the lateral geniculate nucleus (LGN) [36,40]. In this study, we examined whether elimination of ponto-geniculo-occipital (PGO)-wave phasic activity in the LGN during REM sleep (REMS), rather than suppression of all REMS state-related activity, would similarly yield enhanced plasticity effects on cell-size in LGN. PGO-activity was eliminated in LGN by bilateral pontomesencephalic lesions [8,32]. This method of removing phasic activation at the level of the LGN preserved sleep and wake proportions as well as the tonic activities (low voltage, fast frequency ECoG and low amplitude EMG) that characterize REM sleep. The lesions were performed in kittens on post-natal day 42, at the end of the first week of the 2-week period of MD, the same age when IRSD was started in the earlier study. LGN interlaminar cell-size disparity increased in the PGO-wave-suppressed animals as it had in behaviorally REM sleep-deprived animals. Smaller A1/A-interlaminar ratios reflect the increased disparity effect in both the REM sleep- and PGO-suppressed groups compared to animals subjected to MD-alone. With IRSD, the effect was achieved because the occluded eye-related, LGN A1-lamina cells tended to be smaller relative to their size after MD-alone, whereas after PGO-suppressing lesions, the A1-lamina cells retained their size and the non-occluded eye-related, A-lamina cells tended to be larger than after MD-alone. Despite this difference, for which several possible explanations are offered, these A1/A-interlaminar ratio data indicate that in conjunction either with suppression of the whole of the REMS state or selective removal of REM sleep phasic activity at the LGN, altered visual input evokes more LGN cell plasticity during the developmental period than it would otherwise. These data further support involvement of the REM sleep state in reducing susceptibility to plasticity changes and undesirable variability in the course of normative CNS growth and maturation.     

Activity of serotonin-containing neurons in nucleus raphe magnus in freely moving cats

Serotonergic neurons were recorded in the nucleus raphe magnus in freely moving cats and were initially identified on-line by their characteristic slow and regular spontaneous activity during quiet waking (3.42 +/- 0.33 spikes/s; mean +/- SE). Discharge rates of these serotonergic neurons were highest during active waking (4.49 +/- 0.40 spikes/s), intermediate during slow-wave sleep (middle: 2.14 +/- 0.23 spikes/s), and lowest during REM sleep (0.20 +/- 0.03 spikes/s). Although these cells fired at a rate 31.3% higher during active waking than during quiet waking, their activity displayed no correlation with phasic elevations of the nuchal EMG or overt body movements. In addition, no relationship was observed between the activity of these neurons during slow-wave sleep and the occurrence of sleep spindles in the cortical EEG or pontogeniculooccipital waves recorded from the lateral geniculate nucleus. Serotonergic neurons of nucleus raphe magnus were also relatively unresponsive to phasic auditory and visual stimuli, with about half of the cells examined showing weak excitatory responses. These neurons did respond, however, to the administration of a small dose of the serotonin specific agonist, 5-methoxy-N,N-dimethyltryptamine (250 micrograms/kg, i.m.) with a mean decrease in unit activity of 73.6 +/- 4.5%. The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus, nucleus centralis superior, and nucleus raphe pallidus of freely moving cats.     

Activity of serotonin-containing neurons in nucleus centralis superior of freely moving cats

Serotonergic neurons were recorded in the nucleus centralis superior (NCS) in freely moving cats and were initially identified on-line by their slow and regular spontaneous activity (mean 2.55 +/- 0.21 spikes/s). Discharge rates of NCS serotonergic neurons were highest during active waking (AW) (mean 2.94 +/- 0.28 spikes/s), decreased during slow-wave sleep (middle of SWS: mean 1.38 +/- 0.18 spikes/s), and were lowest during REM sleep (mean 0.46 +/- 0.13 spikes/s). The activity of serotonergic NCS neurons did not significantly increase during transient elevations of the EMG during AW but did significantly decrease immediately preceding, and during the occurrence of, SWS spindles. These neurons were responsive to phasic auditory and visual stimuli, with most neurons showing excitatory responses. In response to a small dose of the serotonin-specific agonist 5-methoxy-N,N-dimethyltryptamine (50 micrograms/kg, i.m.), NCS serotonergic neurons responded with a mean decrease in unit activity of 43.9 +/- 6.1%. Among the NCS serotonergic neurons a subpopulation differed from the remaining serotonergic neurons in that they showed a much smaller decrease in unit activity across the sleep-wake cycle and responded with an inhibition of activity to phasic auditory and visual stimuli. The results of this study are compared with those previously reported for serotonergic neurons in the dorsal raphe nucleus, nucleus raphe pallidus, and nucleus raphe magnus of freely moving cats.     

Comparison of the event-related potentials between tonic and phasic periods of rapid eye movement sleep

The event-related potentials (ERP) of eight young healthy volunteers were recorded during wakefulness and rapid eye movement (REM) sleep using an auditory discrimination task. REM sleep was classified into phasic and tonic periods according to the presence or absence of REM. In wakefulness, deviant stimuli elicited a P300 that was maximal over parieto-central areas. During the tonic period of REM sleep, deviant stimuli elicited a P200 and a P400. The P200 was distributed more anteriorly and the P400 was distributed more posteriorly than the P300; however, no prominent ERP components were observed during the phasic period. The study's findings suggest that the brain is less sensitive to external stimuli during the phasic period than during the tonic period of REM sleep.     

The effects of pramipexole in REM sleep behavior disorder

The authors evaluated the effects of pramipexole, a dopaminergic D2-D3 receptor agonist, on eight patients with idiopathic REM sleep behavior disorder. Five patients reported a sustained reduction in the frequency or intensity of sleep motor behaviors, which was confirmed by video recording, although no change was observed for the percentage of phasic EMG activity during REM sleep. Surprisingly, a decrease in the percentage of time spent with REM sleep muscle atonia was observed with treatment. The treatment did not modify the indexes of periodic leg movements.     

Elicited ponto-geniculo-occipital waves by auditory stimuli are synchronized with hippocampal theta-waves

The study demonstrated that ponto-geniculo-occipital (PGO) waves are phase-locked with hippocampal theta-waves during rapid eye movement (REM) sleep. A possible mechanism for influencing a PGO wave generator by hippocampal theta-waves was hypothesized. The generator is known to receive afferent inputs such as auditory input. To test this hypothesis, the temporal relationship between hippocampal theta-waves and elicited PGO waves (PGO(E)) by auditory stimuli was analysed. The analysis showed that PGO(E) were synchronized with theta-waves, but did not reset the phase of a theta-wave. Because the occurrence of PGO(E) and spontaneous PGO waves shared the same phase-dependency on theta-waves, the results strongly suggest that the PGO wave generator was driven by theta-waves, as originally hypothesized.