Rapid eye movement sleep changes during the adaptation night in combat veterans with posttraumatic stress disorder.

BACKGROUND: Hyperarousal in posttraumatic stress disorder (PTSD) is manifested during sleep as well as waking. Elevated rapid eye movement sleep (REMS) phasic activity, likely signifying central nervous system alerting, has been identified in PTSD. The authors reasoned that PTSD compared to control subjects would show particularly increased REMS phasic activity on the first night of polysomnography, with adaptation to a novel environment. METHODS: First-night polysomnograms of 17 veterans with PTSD were compared with those of 11 control subjects. Sleep was also studied in subsets of both groups over two nights. RESULTS: On the first night, the PTSD subjects had a higher density of rapid eye movements in the first REMS period. This measure was increased on the first compared to the second night, but there was no interaction effect between night and group. CONCLUSIONS: REMS changes are again demonstrated in veterans with PTSD. Introduction to a novel environment activated a REMS phasic process, but not differentially in PTSD compared to control subjects.

REM sleep inhibition by desipramine: evidence for an alpha-1 adrenergic mechanism.

The acute administration of drugs that block norepinephrine (NE) reuptake suppresses rapid eye movement (REM) sleep in cats and other mammals. The mechanism is presumed to involve NE acting on cells in a pontine REM sleep-generator region. Postsynaptic noradrenergic receptor mechanisms have not been identified. In the present experiments, we tested the ability of the alpha-1 antagonist prazosin and the beta antagonist propranolol to reverse the REM sleep suppression produced by the NE reuptake blocker desipramine (DMI) in the cat. DMI reduced the number of REM sleep episodes, the REM percentage (REM sleep time/total sleep time), and the average REM sleep episode duration. The co-administration of prazosin, but not propranolol, increased the REM percentage and the average REM sleep episode duration toward the placebo level. The co-administration of the peripherally-acting, anti-hypertensive agent hydralazine did not reverse the DMI-induced REM sleep suppression. While the identity of the brain region(s) involved in mediating the alpha-1 noradrenergic suppression of REM sleep by DMI remains unclear, there is reason to consider forebrain structures including the amygdala as well as the pontine areas that generally have been implicated in REM sleep control.

Stimulus-elicited behavior in rapid eye movement sleep without atonia.

Alert wakefulness (W) and rapid eye movement sleep (REM) are remarkably similar on several measures of brain activity, but 2 differences in REM are reduced sensory responsiveness and atonia in postural muscles. Pontine tegmental lesions create REM without atonia (REM-A), releasing motor behavior. In 9 cats, we studied the acoustic startle reflex (ASR), orienting (OR), and ponto-geniculo-occipital waves (PGOE) elicited by tones during W, REM, REM-A, and non-REM (NREM). OR occurred in W and REM-A, being most complete in cats with the most elaborate spontaneous behavior. ASR occurred in W, NREM, and REM-A in lesioned cats. In normal cats, ASR rarely appeared in NREM and REM. PGOE had similar characteristics in both groups. The similarity of REM to W is particularly obvious when cats lack motoneuronal inhibition.

Inhibition of the enteroviruses that cause acute hemorrhagic conjunctivitis (AHC) by benzimidazoles; enviroxime (LY 122772) and enviradone (LY 127123).

Enviradone (EvirD, (E)-1-[(1-methylethyl) sulfonyl]-6-(1-phenyl-1-propenyl)-1 H- benzimidazole-2-amine) and Enviroxime (EvirX, 2-amino-1-(isopropyl-sulfonyl)-6-benzimidazole phenyl ketone oxime) inhibited enterovirus 70 (EV70) and coxsackievirus A24 variant (CA24v) infection of conjunctival and laryngeal cells. On average, the continuous presence of 1-3 micrograms of EvirD or EvirX/ml in cell cultures acutely infected with EV70 or CA24v inhibited virus production (> 2 log10 reduction) and 100% of the viral cytopathogenic effect (CPE). The 50% CPE inhibitory dose (ID50) for EvirD and EvirX against 11 EV70 and 15 CA24v isolates ranged from 0.01 to 0.3 microgram and 0.01-0.65 microgram/ml, respectively. The mean ID50 for EvirD and EvirX against the 26 AHC viruses was 0.17 +/- 0.12 microgram and 0.13 +/- 0.14 microgram/ml, respectively. Pretreatment for 15 min with 3 micrograms EvirX/ml or for 1-2 h with 3 micrograms EvirD/ml protected conjunctival cells against viral CPE. The cells were resistant to infection for 1-2 h at 33 and 37 degrees C after removal of EvirD and EvirX. The addition of 10 micrograms EvirD/ml up to 6 h or 10 micrograms EvirX/ml 1-2 h after low multiplicity infection inhibited viral CPE. Ten-fold less EvirD inhibited EV70 when added to glioma cells 2 h before infection than when added 2 h after infection. Our results indicate that EvirX and EvirD inhibit AHC viruses in vitro at concentrations that are not cytotoxic and suggest that EvirX or EvirD may be prove useful against AHC.

Motor dysfunction during sleep in posttraumatic stress disorder.

A subjective disturbance of sleep, including the occurrence of repetitive, stereotypical anxiety dreams, is characteristic of posttraumatic stress disorder (PTSD). The phenomenology of the PTSD anxiety dream has seemed most consistent with an underlying rapid eye movement (REM) sleep dysfunction. However, motor behavior reportedly can accompany PTSD dreams, and normal REM sleep typically involves a nearly total paralysis of the body musculature. As a means of understanding this discrepancy, anterior tibialis muscle activity during sleep was studied in a group of Vietnam combat veterans with current PTSD and in an age-matched normal control group. The PTSD subjects had a higher percentage of REM sleep epochs with at least one prolonged twitch burst; they also were more likely to have periodic limb movements in sleep, during nonrapid eye movement sleep. Both these forms of muscle activation also have been observed in REM behavior disorder (RBD), a parasomnia characterized by the actual enactment of dream sequences during REM sleep. The identification of RBD-like signs in PTSD adds to the evidence for a fundamental disturbance of REM sleep phasic mechanisms in PTSD.

Central administration of two 5-HT receptor agonists: effect on REM sleep initiation and PGO waves.

Cholinergic neurons in the pedunculopontine tegmental (PPT) and the laterodorsal tegmental (LDT) nuclei are implicated in the generation of rapid eye movement sleep (REM) and ponto-geniculo-occipital (PGO) waves. Serotonin (5-HT) has a role in sleep-wake regulation and appears to inhibit PGO wave generation. We studied the effects of the central infusion of the relatively specific 5-HT1A receptor agonist 8-hydroxy-2-(n-dipropylamino)tetralin (DPAT) and the less specific 5-HT1 receptor agonist 1(3-chlorophenyl)piperazine (mCPP) on the regulation of REM and on PGO wave generation. DPAT (0.0, 0.002, 0.01, 0.08, and 0.8 microgram/0.5 microliter normal saline) and mCPP (0.0, 0.02, 0.2, 2.0, and 20.0 micrograms/0.5 microliter normal saline) were infused unilaterally into the peribrachial region of PPT (PB) in cats. Additionally, DPAT (0.01 microgram/0.5 microliter) was infused bilaterally into PB in a separate experiment. Low dosages of DPAT (unilateral or bilateral) decreased successful entrances into REM (0.01 microgram) and time spent asleep (0.002 microgram and 0.01 microgram) without affecting outward behavior. No dosage of mCPP significantly decreased the number of REM episodes, and neither drug decreased REM episode duration once REM had been entered. Neither drug affected the rate of PGO waves independently of modulating behavioral state. We propose that 5-HT1A receptor mechanisms have an inhibitory role in actual REM initiation, possibly by facilitating endogenously generated excitation of brainstem startle mechanisms at the onset of REM.

Rapid eye movement sleep disturbance in posttraumatic stress disorder.

The subjective sleep disturbance in posttraumatic stress disorder (PTSD), including the repetitive, stereotypical anxiety dream, suggests dysfunctional rapid eye movement (REM) sleep mechanisms. The polysomnograms of a group of physically healthy combat veterans with current PTSD were compared with those of an age-appropriate normal control group. Tonic and phasic REM sleep measures in the PTSD subjects were elevated on the second night of recorded sleep. Increased phasic REM sleep activity persisted in the PTSD group on the subsequent night. During the study, an anxiety dream occurred in a PTSD subject in REM sleep. The results are consistent with the view that a dysregulation of the REM sleep control system, particularly phasic event generation, may be involved in the pathogenesis of PTSD. The finding of a specific disturbance of sleep unique to PTSD may have significant implications for the design of effective treatments for PTSD.

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 (PGOE) 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 PGOE 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 PGOE accompanying OR to PGOE during REM and NREM when OR are absent. The amplitudes of PGOE in W were greatest when OR were observed, and the amplitudes of PGOE accompanying OR were not significantly different from PGOE amplitudes in REM. Likewise, the amplitudes of PGOE during REM were not significantly different from those of the highest amplitude spontaneous PGO waves. We propose that the presence of PGOE signals registration of stimuli and that stimuli of sufficient significance to induce behavioral OR in waking also elicit PGOE 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.

Varying expressions of alerting mechanisms in wakefulness and across sleep states.

Alerting stimuli, such as intense tones, presented to cats in wakefulness (W) elicit the orienting response (OR) and/or the acoustic startle reflex (ASR) in conjunction with elicited ponto-geniculo-occipital waves (PGOE) from the lateral geniculate body (LGB) and elicited waves from the thalamic central lateral nucleus (CLE). Alerting stimuli presented during rapid eye movement sleep (REM) and non-rapid eye movement sleep (NREM) also elicit PGOE. We presented tones in W, REM and NREM to determine whether CLE could be obtained in sleep and to examine the patterns of responsiveness of PGOE and CLE across behavioral states. Also, we recorded ASR and OR and compared the response patterns of behavioral and central correlates of alerting. The subjects were 7 cats; all exhibited spontaneously occurring waves in LGB and CL. All cats exhibited PGOE and 5 cats exhibited CLE in W, REM and NREM. PGOE and CLE showed less evidence of habituation than did ASR and OR. The pattern of responsiveness of CLE across behavioral states was different from that found for PGOE, and spontaneous CL waves were much rarer than the LGB waves. ASR was elicited in 5 cats during W trials, and in 3 cats during REM trials. OR habituated rapidly in W and did not occur in REM and NREM. The data indicate that central mechanisms of alerting function in sleep states as well as in W and suggest that CLE and PGOE reflect activity in mechanisms underlying cortical desynchronization and visual processes which may act in concert during alerting.

Peripheral and central components of alerting: habituation of acoustic startle, orienting responses, and elicited waveforms.

Behavioral orienting (OR), the acoustic startle reflex (ASR), pontogeniculooccipital (PGO) waves in the lateral geniculate body, and midlatency auditory evoked responses (MLR) represent components of alerting. The habituation rate for each was examined to test the hypothesis that OR, ASR, and PGO waves have related underlying neural mechanisms and determine the similarity in responsiveness between elicited PGO waves (PGOE) and elicited waves in the thalamic central lateral nucleus (CLE), a site that yields MLR. PGOE and CLE waves did not habituate in amplitude after 120 tones; however, the pattern of responses for each waveform was different. OR and ASR significantly decreased amplitude across trials with OR exhibiting a faster, more pronounced decrement. Some separation exists between the peripheral (OR and ASR) and central (PGOE and CLE) components of alerting. PGO and CL waves may have common underlying neural mechanisms.

The effects of changing state on elicited ponto-geniculo-occipital (PGO) waves.

Waves similar to ponto-geniculo-occipital (PGO) waves occurring spontaneously in the lateral geniculate body (LGB), pons, and occipital cortex during rapid eye movement (REM) sleep can be elicited in the LGB and the cortex by tones in waking (W), non-rapid eye movement sleep (NREM), and REM. In W, the elicited waves (PGOE) sometimes accompany orienting responses (OR). We have hypothesized that REM is a state resembling exaggerated "orienting" in part because spontaneous PGO waves similar to PGOE accompanying OR are constantly observed in REM. The present experiment tested whether: (1) PGOE and OR were strongly correlated in W across a large number of tone presentations as might be predicted if PGOE were central wave form markers for a state of orienting; and (2) recovery of responsiveness of PGOE to tones would then be greater in REM than NREM, as might be expected if REM but not NREM were a state in which central mechanisms of orienting were highly active. Tones were presented in W and then in REM and NREM to six cats in order to measure the degree of habituation of OR and PGOE simultaneously. PGOE and OR exhibited a degree of independence: the former were readily produced in W despite the rapid decline in OR across trials. Recovery in the amplitude of PGOE occurred in both NREM and REM. The recovery tended to be greater in REM than NREM, although this was not statistically significant. Refinements of the theory that REM represents a state of exaggerated internal orienting are discussed.

Independent assessment of manic and depressive symptoms by self-rating. Scale characteristics and implications for the study of mania.

We report the reliability and validity of the Internal State Scale, a self-report instrument for the simultaneous assessment of severity of manic and depressive symptoms. The Internal State Scale consists of four empirically derived subscales: Activation, Well-Being, Perceived Conflict, and the Depression Index. All subscales had good internal consistency reliability. Activation subscale scores were significantly higher in manic patients than in depressed patients or control subjects, while Well-Being subscale scores were significantly lower and the Depression Index subscale scores were significantly higher in depressed patients than in the other two groups. Activation subscale scores were correlated specifically with clinician ratings of mania. Depression Index subscale scores were correlated specifically with clinician ratings of depression. Further evidence for the validity of the subscales of the Internal State Scale in reflecting manic or depressive symptoms came from discriminant function analysis in which these subscales assigned 88% of subjects to the correct diagnostic groups. In affectively ill patients who were studied in two or more mood states, Activation, Depression Index, and Well-Being subscale scores changed significantly in the predicted directions, while the same discriminant algorithm assigned 79% of mood states to the correct diagnostic category. Bimodal distribution of scores of manic patients on the Well-Being and Depression Index subscales substantiated earlier findings that euphoric mood is not an essential feature of mania. Based on findings from this and previous studies, the hypothesis is proposed that variables related to activation level, and not to mood state, constitute the core characteristics of the manic syndrome.

Effects of stimulus intensity on elicited ponto-geniculo-occipital waves.

Waves similar to spontaneous ponto-geniculo-occipital (PGO) waves of paradoxical sleep (PS) in cats are elicited by tones and can be considered a form of evoked potential termed PGOE. The aims of the present experiment were to determine: (1) the effects of tone intensity on the probability of producing PGOE; (2) the effects of intensity on the amplitude and latency of PGOE across slow-wave sleep (SWS) and PS; (3) whether the effects of intensity on PGOE are similar to those on a particular form of auditory evoked potential known as the mid-latency response (MLR). Increasing the intensity of the stimulus from 60 to 100 in 10 dB increments resulted in increased probability, increased amplitude, and decreased latency of PGOE in both SWS and PS. This pattern was similar to published findings with MLR, and latencies of PGOE (roughly 60-100 msec) fell within the range of 'C wave' type of MLR recorded in intralaminar nuclei of the thalamus of cats. The possibility that PGOE and MLR share underlying mechanisms and represent the same phenomenon is discussed with particular attention to the function of the mechanisms during alerting and orienting.

Effects of monoamine reuptake blockade on ponto-geniculo-occipital wave activity.

Norepinephrine (NE) and serotonin (5HT) likely inhibit the generation of ponto-geniculo-occipital (PGO) waves. Either desipramine (DMI) or sertraline (SER:1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1-naphthyl amine) was administered in the cat for 2.5 weeks to probe noradrenergic and serotonergic mechanisms, respectively. Placebo days were compared with the first day of drug and with days that followed 2.5 weeks of drug (chronic). PGO rates during REM sleep and the preceding transition period were significantly decreased by either chronic DMI or SER. Cat PGO waves resemble waves that accompany alerting to intense or novel stimuli in wakefulness. Depressive disorders in humans have features of hyperarousal; PGO wave suppression by antidepressant drugs may relate to clinical antidepressant actions.

REM sleep suppression by monoamine reuptake blockade: development of tolerance with repeated drug administration.

Drugs that block monoamine reuptake initially suppress rapid eye movement (REM) sleep in the cat and other species. Less is known about the effects of repeated drugs administration. Desipramine (DMI) and sertraline [1S,4S-N-methyl-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-1 -naphthylamine] (SER), which are relatively specific in blocking norepinephrine and serotonin reuptake, respectively, were each given to cats for approximately two and a half weeks. Six-hour sleep polygraphic records were obtained under the placebo condition, after acute drug administration, and again during chronic drug administration. DMI and SER both reduced REM sleep percentage acutely and in each case. Significant tolerance then developed. These actions of DMI and SER reflected changes in mean REM sleep episode duration as well as REM sleep episode number. Such differential effects of acute and chronic monoamine reuptake blockade on REM sleep behavior in the cat may ultimately be correlated with pharmacological changes at the receptor level.

Sleep disturbance as the hallmark of posttraumatic stress disorder.

The reexperiencing of a traumatic event in the form of repetitive dreams, memories, or flashbacks is one of the cardinal manifestations of posttraumatic stress disorder (PTSD). The dream disturbance associated with PTSD may be relatively specific for this disorder, and dysfunctional REM sleep mechanisms may be involved in the pathogenesis of the posttraumatic anxiety dream. Furthermore, the results of neurophysiological studies in animals suggest that CNS processes generating REM sleep may participate in the control of the classical startle response, which may be akin to the startle behavior commonly described in PTSD patients. Speculating that PTSD may be fundamentally a disorder of REM sleep mechanisms, the authors suggest several strategies for future research.

The effects of tones on PGO waves in slow wave sleep and paradoxical sleep.

Ponto-geniculo-occipital (PGO) waves are macropotential waveforms occurring spontaneously during paradoxical sleep (PS) in the pons, the lateral geniculate body (LGB), and the occipital cortex of the cat. In our earlier work (6, 20) tones elicited waves in the LGB and the occipital cortex during both slow wave sleep (SWS) and PS that resembled PGO waves in form and amplitude. Using a limited and variable number of trials, we observed that these elicited waveforms, which we term elicited PGO waves (PGOE), seemed to decline rapidly in amplitude and probability during SWS but not during PS. The present two experiments served as a more rigorous test of the hypothesis that the rate of habituation of PGOE would be more rapid in SWS. In a first experiment seven cats were studied in up to four sessions in PS and four in SWS; each session consisted of 32 1000-Hz, 90-dB SPL tones lasting 90 ms. We found that (i) the number of PGOE was significantly greater in PS; (ii) the mean amplitude of the waves was greater in PS; (iii) the probability of eliciting a wave tended to decline faster in SWS, but some decline also occurred in PS; and (iv) on the first trial, PGOE were more easily produced in SWS. Results of a second experiment with five cats suggested that the decline in the probability of PGOE in PS was not accounted for by differences in the ease of eliciting them at different times into a PS episode. The role of the dorsal raphe nucleus (DRN) in modulating state-dependent differences in PGOE is discussed.

Habituation of the startle reflex in posttraumatic stress disorder.

The authors investigated habituation of the eye-blink component of the startle reflex to repeated affectively neutral tactile and auditory stimuli in nine subjects with posttraumatic stress disorder and nine controls. Each group showed rapid habituation in both tactile and auditory modalities.