Locus coeruleus neurons: cessation of activity during cataplexy.

Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, emotionally significant stimuli. We now report that locus coeruleus neurons cease discharge throughout cataplexy periods in canine narcoleptics. Locus coeruleus discharge rates during cataplexy were as low as or lower than those seen during rapid-eye-movement sleep. Prazosin, an alpha1 antagonist, and physostigmine, a cholinesterase inhibitor, both of which precipitate cataplexy, decreased locus coeruleus discharge rate. Our results are consistent with the hypothesis that locus coeruleus activity contributes to the maintenance of muscle tone in waking, and that reduction in locus coeruleus discharge plays a role in the loss of muscle tone in cataplexy and rapid-eye-movement sleep. Our results also show that the complete cessation of locus coeruleus activity is not sufficient to trigger rapid-eye-movement sleep in narcoleptics.     

Sleep-waking discharge patterns of neurons recorded in the rat perifornical lateral hypothalamic area

The perifornical lateral hypothalamic area (PF-LHA) has been implicated in the control of several waking behaviours, including feeding, motor activity and arousal. Several cell types are located in the PF-LHA, including projection neurons that contain the hypocretin peptides (also known as orexins). Recent findings suggest that hypocretin neurons are involved in sleep-wake regulation. Loss of hypocretin neurons in the human disorder narcolepsy is associated with excessive somnolence, cataplexy and increased propensity for rapid eye movement (REM) sleep. However, the relationship of PF-LHA neuronal activity to different arousal states is unknown. We recorded neuronal activity in the PF-LHA of rats during natural sleep and waking. Neuronal discharge rates were calculated during active waking (waking accompanied by movement), quiet waking, non-REM sleep and REM sleep. Fifty-six of 106 neurons (53 %) were classified as wake/REM-related. These neurons exhibited peak discharge rates during waking and REM sleep and reduced discharge rates during non-REM sleep. Wake-related neurons (38 %) exhibited reduced discharge rates during both non-REM and REM sleep when compared to that during waking. Wake-related neurons exhibited significantly higher discharge rates during active waking than during quiet waking. The discharge of wake-related neurons was positively correlated with muscle activity across all sleep-waking states. Recording sites were located within the hypocretin-immunoreactive neuronal field of the PF-LHA. Although the neurotransmitter phenotype of recorded cells was not determined, the prevalence of neurons with wake-related discharge patterns is consistent with the hypothesis that the PF-LHA participates in the regulation of arousal, muscle activity and sleep-waking states.     

Differentiation of presumed serotonergic dorsal raphe neurons in relation to behavior and wake-sleep states.

Using extracellular single unit recording, either alone or in combination with microdialysis application of drugs, we examined the characteristics of presumed serotonergic dorsal raphe neurons during wake-sleep states in the freely moving cat. Recordings were made from a total of 272 neurons in the dorsal raphe nucleus. Of these, 240 (88%) were classified as serotonergic on the basis of their typical long-duration action potential, slow discharge activity, and reduced spontaneous discharge rate during paradoxical sleep compared to during slow-wave sleep. An inhibitory response to serotonergic agonists and a slow conduction velocity were seen in all neurons of this type tested or identified by stimulation of the main ascending serotonergic pathway. These presumed serotonergic dorsal raphe neurons could be subdivided into two typical previously identified groups (types I-A and I-B) and four atypical new groups (types I-C, II-A, II-B, and II-C) according to differences in firing patterns during wake-sleep states. The typical neurons were evenly distributed in the dorsal raphe nucleus and their activity was related to the level of behavioral arousal, since they discharged regularly at a high rate during waking and at progressively slower rates during slow-wave sleep, and ceased firing either during slow-wave sleep with ponto-geniculo-occipital waves and paradoxical sleep (type I-A) or only during paradoxical sleep (type I-B). In contrast, the atypical subgroups were unevenly distributed in the dorsal raphe nucleus and exhibited firing patterns distinct from those of the typical neurons, such as sustained tonic activity during paradoxical sleep (types I-C and II-C) or showing their highest rate of tonic discharge during slow-wave sleep, with suppression of discharge during both waking and paradoxical sleep (type II-B). From these data we suggest that presumed serotonergic dorsal raphe neurons play different roles in behavioral state control and that there is functional topographic organization in the dorsal raphe nucleus.     

Cataplexy-related neurons in the amygdala of the narcoleptic dog

The amygdala plays an important role in the interpretation of emotionally significant stimuli and has strong projections to brainstem regions regulating muscle tone and sleep. Cataplexy, a symptom of narcolepsy, is a loss of muscle tone usually triggered by sudden, strong emotions. Extracellular single-unit recordings were carried out in the amygdala of narcoleptic dogs to test the hypothesis that abnormal activity of a subpopulation of amygdala neurons is linked to cataplexy.Of the 218 cells recorded, 31 were sleep active, 78 were active in both waking and rapid-eye-movement sleep, 88 were maximally active during waking, and 21 were state independent. Two populations of cells showed a significant change in activity with cataplexy. A population of sleep active cells localized to central and basal nucleus increased discharges prior to and during cataplexy. A population of wake active cells localized to the cortical nucleus decreased activity prior to and during cataplexy. We hypothesize that these cell populations have a role in mediation or modulation of cataplexy through interactions with meso-pontine regions controlling atonia. The anticholinesterase physostigmine, at doses which increased cataplexy, did not alter the activity of the cataplexy-related cells or of other amygdala cells, suggesting that its effect on cataplexy is mediated 'downstream' of the amygdala. The alpha-1 blocker prazosin, at doses which increased cataplexy, increased discharge in a subgroup of the cataplexy active cells and in a number of other amygdala cells, indicating that prazosin may modulate cataplexy by its action on amygdala cells or their afferents.     

Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil

Adrenergic signaling regulates the timing of sleep states and sleep state-dependent changes in muscle tone. Recent studies indicate a possible role for noradrenergic transmission in the wake-promoting action of modafinil, a widely used agent for the treatment of excessive sleepiness. We now report that noradrenergic projections from the locus coeruleus to the forebrain are not necessary for the wake-promoting action of modafinil. The efficacy of modafinil was maintained after treatment of C57BL/6 mice with N-(2-chloroethyl)-N-ethyl 2-bromobenzylamine (DSP-4), which eliminates all noradrenaline transporter-bearing forebrain noradrenergic projections. However, the necessity for adrenergic receptors in the wake-promoting action of modafinil was demonstrated by the observation that the adrenergic antagonist terazosin suppressed the response to modafinil in DSP-4 treated mice. The wake-promoting efficacy of modafinil was also blunted by the dopamine autoreceptor agonist quinpirole. These findings implicate non-noradrenergic, dopamine-dependent adrenergic signaling in the wake-promoting mechanism of modafinil. The anatomical specificity of these dopaminergic-adrenergic interactions, which are present in forebrain areas that regulate sleep timing but not in brain stem areas that regulate sleep state-dependent changes in muscle tone, may explain why modafinil effectively treats excessive daytime sleepiness in narcolepsy but fails to prevent the loss of muscle tone that occurs in narcoleptic patients during cataplexy.     

Rapid-eye-movement sleep involves the memory-conversion circuits in a brain model

People can remember the content of a dream in rapid eye movement (REM) sleep but cannot do so in slow-wave sleep. According to a brain model, memory is stored in encoding synapses as presynaptic axonal 'on-off' patterns and modulating synapses help encoding synapses convert short-term memory into long-term memory. These lead to the hypothesis that REM sleep involves modulating synapses of the memory-conversion circuits including the anterior nuclei and dorsomedial nuclei of the thalamus. Cortical neurons get more rest in slow-wave sleep than in REM sleep. The locus coeruleus, raphe nuclei, and tuberomammillary nuclei get more rest during REM sleep when these nuclei cease to fire. The paralyses of peripheral muscles during REM sleep and cataplexy, and cessation of chorea, athetosis, hemiballismus, and parkinsonism tremor during sleep may result from spinal cord inhibition by the gigantocellular nuclei and raphe nuclei at the reticular formation. Sleep and wake relate to the light-dark cycle on the Earth. Were the light-dark cycle 50 hours a day, the human circadian clock might be around 50 hours. With increasing use of artificial light to keep people awake at night, it may affect the circadian rhythm and firing rate of neurons, the presynaptic axonal 'on-off' patterns as content of consciousness, and the mood.     

Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat

It is well known that noradrenergic locus coeruleus neurons decrease their activity during slow wave sleep and are quiescent during paradoxical sleep. It was recently proposed that their inactivation during paradoxical sleep is due to a tonic GABAergic inhibition arising from neurons located into the dorsal paragigantocellular reticular nucleus (DPGi). However, the discharge profile of DPGi neurons across the sleep-waking cycle as well as their connections with brain areas involved in paradoxical sleep regulation remain to be described. Here we show, for the first time in the unanesthetized rat that the DPGi contained a subtype of neurons with a tonic and sustained firing activation specifically during paradoxical sleep (PS-on neurons). Noteworthy, their firing rate increase anticipated for few seconds the beginning of the paradoxical sleep bout. By using anterograde tract-tracing, we further showed that the DPGi, in addition to locus coeruleus, directly projected to other areas containing wake-promoting neurons such as the serotonergic neurons of the dorsal raphe nucleus and hypocretinergic neurons of the posterior hypothalamus. Finally, the DPGi sent efferents to the ventrolateral part of the periaqueductal gray matter known to contain paradoxical sleep-suppressing neurons. Taken together, our original results suggest that the PS-on neurons of the DPGi may have their major role in simultaneous inhibitory control over the wake-promoting neurons and the permissive ventrolateral part of the periaqueductal gray matter as a means of influencing vigilance states and especially PS generation.     

Carbachol injections into the ventral pontine reticular formation activate locus coeruleus cells in urethane-anesthetized rats

STUDY OBJECTIVES: Two pontine reticular regions are implicated in cholinergic triggering of rapid eye movement (REM) sleep: the dorsomedial tegmental region and the ventral nucleus pontis oralis. We previously determined that, in urethane-anesthetized rats, microinjections of a cholinergic agonist, carbachol, into the dorsal region produce REM sleep-like effects comprising cortical activation, hippocampal theta rhythm, suppression of hypoglossal (XII) nerve activity, and silencing of pontine noradrenergic neurons. Our goal was to determine whether carbachol injections into the ventral nucleus pontis oralis elicits comparable effects. DESIGN: Recording of cortical electroencephalogram, hippocampal activity, XII nerve activity, and discharge of noradrenergic cells of the locus coeruleus. SETTING: Basic neurophysiologic research laboratory. PARTICIPANTS AND INTERVENTIONS: Urethane-anesthetized, paralyzed, and artificially ventilated or nonparalyzed and spontaneously breathing rats with microinjections of carbachol (10 nL, 10 mM) into the ventral nucleus pontis oralis. MEASUREMENTS AND RESULTS: In artificially ventilated rats, carbachol injections repeatedly elicited cortical activation and hippocampal theta rhythm. Concomitantly, the activity of locus coeruleus neurons increased from 2.0 per second +/- 0.4 (SE) to 2.6 per second +/- 0.4 (P < .05, n = 8), as did XII nerve activity (by 42.5% +/- 8.8%; P < .01). In spontaneously breathing animals, carbachol similarly activated the cortical electroencephalogram and hippocampal activity, whereas XII nerve activity was reduced by 6.7% +/- 2.5% (P < .05) together with increased ventilation, as indicated by reduced end-expiratory CO2. CONCLUSION: Carbachol injections into the ventral nucleus pontis oralis activate, rather than silence, noradrenergic locus coeruleus neurons. This is not compatible with the state of REM sleep.     

Noradrenaline involvement in basic and higher integrated REM sleep processes

There has been an abundance of literature devoted to the involvement of noradrenaline in basic rapid eye movement (REM) sleep processes since the subject was first investigated in 1964. Nowadays, the great majority of studies highlight the need for silence in the locus coeruleus noradrenergic neurons as a condition for the occurrence and maintenance of REM sleep. However, throughout the successive years of work on this topic, few researchers have consistently claimed that some amount of noradrenaline is essential for the appearance of this sleep stage. In the first part of this review, each of the papers published in this field is analyzed. Then, in the discussion, arguments supporting the requirement for a given level of noradrenaline for REM sleep occurrence are presented. This second part also examines, based on waking noradrenergic influences on higher integrated brain processes, the major consequences of noradrenergic neuron silence during REM sleep for mental functioning.     

Searching for a marker of REM sleep behavior disorder: submentalis muscle EMG amplitude analysis during sleep in patients with narcolepsy/cataplexy

STUDY OBJECTIVES: To evaluate the amplitude of submentalis muscle EMG activity during sleep in patients with narcolepsy/cataplexy with or without REM sleep behavior disorder (RBD). DESIGN: Observational study with consecutive recruitment. SETTINGS: Sleep laboratory. PATIENTS: Thirty-four patients with narcolepsy/cataplexy and 35 age-matched normal controls. MEASUREMENTS AND RESULTS: Half the patients (17 subjects) had a clinical and video polysomnographic diagnosis of RBD. The average amplitude of the rectified submentalis muscle EMG signal was used to assess muscle atonia, and the new REM sleep Atonia Index was computed. Chin muscle activations were detected and their duration and interval analyzed. REM sleep Atonia Index was lower in both patient groups (with narcolepsy patients with RBD showing the lowest values) with respect to controls, and it did not correlate with age as it did in controls. The total number of chin EMG activations was significantly higher in both patient groups than controls. No significant differences were found between the two groups of patients, although more chin EMG activations were noted in narcolepsy patients with RBD than those without. CONCLUSIONS: Elevated muscle activity during REM sleep is the only polysomnographic marker of RBD. This study shows that polysomnographically evident RBD is present in many patients with narcolepsy/ cataplexy. This condition might be specific to narcolepsy/cataplexy, reflecting a peculiar form of REM sleep related motor dyscontrol (i.e., status dissociatus), paving the way to enacting dream behaviors, and correlated with the specific neurochemical and neuropathological substrate of narcolepsy/cataplexy.     

Distribution of the messenger RNA for the small conductance calcium-activated potassium channel SK3 in the adult rat brain and correlation with immunoreactivity

Small conductance calcium-activated potassium channels are voltage independent potassium channels which modulate the firing patterns of neurons by activating the slow component of the afterhyperpolarization. The genes encoding a family of small conductance calcium-activated potassium channels have been cloned and up to now three known members have been described and named small conductance calcium-activated potassium channel type 1, small conductance calcium-activated potassium channel type 2 and small conductance calcium-activated potassium channel type 3; the distribution of their messenger RNA in the rat CNS has already been performed but only in a limited detail. The present study represents the first detailed analysis of small conductance calcium-activated potassium channel type 3 mRNA distribution in the adult rat brain and resulted in a strong to moderate expression of signal in medial habenular nucleus, substantia nigra compact part, suprachiasmatic nucleus, ventral tegmental area, lateral septum, dorsal raphe and locus coeruleus. Immunohistological experiments were also performed and confirmed the presence of small conductance calcium-activated potassium channel type 3 protein in medial habenular nucleus, locus coeruleus and dorsal raphe. Given the importance of dorsal raphe, locus coeruleus and substantia nigra/ventral tegmental area for serotonergic, noradrenergic and dopaminergic transmission respectively, our results pose the morphological basis for further studies on the action of small conductance calcium-activated potassium channel type 3 in serotonergic, noradrenergic and dopaminergic transmission.     

Restoration of decaying long-term potentiation in the hippocampal formation by stimulation of neuromodulatory nuclei in freely moving rats.

Induction of long-term potentiation within the hippocampal formation can be modulated by afferent influences from a number of subcortical structures known to be involved in hippocampal-dependent learning and memory. This study performed on freely moving rats investigated the effects of stimulation of the noradrenergic locus coeruleus nucleus and the serotonergic dorsal raphe nucleus on spontaneously decaying posttetanic long-term potentiation in the dentate gyrus and the hippocampal CA1 area, respectively. High-frequency electrical stimulation of the locus coeruleus or the dorsal raphe elicited a well-expressed behavioural reaction of exploratory or defensive type, respectively, but did not significantly alter transmission at perforant path-dentate gyrus or Schaffer collateral-CA synapses, when delivered either before tetanic stimulation of the perforant path or the Schaffer collaterals or long (hours and days) after previously induced long-term potentiation had completely decayed. However, when locus coeruleus or dorsal raphe stimulation was delivered with the same parameters during a limited time (minutes and hours) after marked or even complete decay of tetanus-induced long-term potentiation at perforant path-dentate gyrus or Schaffer collateral-CA1 synapses, the potentiation was partially or entirely restored but never increased beyond the initial level of potentiation. In CA1, stimulation of ipsilateral and contralateral Schaffer collaterals demonstrated that the restoration of previously existing long-term potentiation by dorsal raphe stimulation was input-specific, occurring, like tetanus-induced potentiation, only in the pathway which had previously been tetanized. These findings suggest that the noradrenergic locus coeruleus and the serotonergic dorsal raphe can influence not only induction, but also spontaneous decay of long-term potentiation in the hippocampal formation. Since hippocampal long-term potentiation is thought to play a role in certain kinds of learning and memory, and association of tetanic stimulation with activation of ascending neuromodulatory systems is required for full expression of long-term potentiation, the restoration of hippocampal long-term potentiation by activation of a neuromodulatory system alone may serve as a mechanism of associative reminder which may underlie facilitation of memory retrieval after a period of forgetting, as has been observed in trained rats under similar conditions.     

Is narcolepsy a REM sleep disorder? Analysis of sleep abnormalities in narcoleptic Dobermans

Narcolepsy is a chronic sleep disorder marked by excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Since the discovery of sleep onset REM periods (SOREMPs) in narcoleptic patients, narcolepsy has often been regarded as a disorder of REM sleep generation: REM sleep intrudes in active wake or at sleep onset, resulting in cataplexy, sleep paralysis, or hypnagogic hallucinations. However, this hypothesis has not been experimentally verified. In the current study, we characterized the sleep abnormalities of genetically narcoleptic-cataplectic Dobermans, a naturally occurring animal model of narcolepsy, in order to verify this concept. Multiple sleep latency tests during the daytime revealed that narcoleptic Dobermans exhibit a shorter sleep latency and a higher frequency of SOREMPs, compared to control Dobermans. The total amount of time spent in wake and sleep during the daytime is not altered in narcoleptic dogs, but their wake and sleep patterns are fragmented, and state transitions into and from wake and other sleep stages are altered. A clear 30 min REM sleep cyclicity exists in both narcoleptic and control dogs, suggesting that generation of the ultradian rhythm of REM sleep is not altered in narcoleptics. In contrast, cataplexy displays no cyclicity and can be elicited in narcoleptic animals anytime with emotional stimulation and displays no cyclicity. Stimulation of a cholinoceptive site in the basal forebrain induces a long-lasting attack of cataplexy in narcoleptic dogs; however, bursts of rapid eye movements during this state still occur with a 30 min cyclicity. Sites and mechanisms for triggering cataplexy may therefore be different from those for REM sleep. Cataplexy and a dysfunction in the maintenance of vigilance states, but not abnormal REM sleep generation, may therefore be central to narcolepsy.     

Potential noradrenergic regulation of serotonergic neurons in the median raphe nucleus

Summary Pharmacological and morphological evidence suggests that the functional activity of serotonergic neurons may be regulated by catecholamines. We have attempted to reveal a potential pathway by which this interaction might occur. Rats received bilateral knife cut lesions of the ventral noradrenergic bundle which severed the A-1 and A-2 cell body contributions to this projection. Controls received a sham lesion into the cerebellum. Two weeks later all animals were sacrificed, and norepinephrine and serotonin levels were measured in discrete nuclei of the brain. Lesion placement was confirmed histofluorometrically. Serotonin levels in the median raphe nucleus were significantly reduced by 40%, but levels of serotonin were unaffected in the dorsal raphe nucleus and 8 serotonergic terminal regions. The lesions did not affect levels of norepinephrine in the locus coeruleus, cingulate cortex, or habenula. This study suggests that a noradrenergic projection to the median raphe nucleus from the A-1 and A-2 cell body groups may modulate serotonergic neuronal function.This work was presented, in part, at the Society for Neuroscience Annual Meeting, Anaheim, California, 1977     

Sleep-related neurons in the central nucleus of the amygdala of rats and their modulation by the dorsal raphe nucleus

The amygdala (AMY) plays an important role in initiating appropriate neurobehavioral responses to emotionally arousing events. Its major efferents from the central nucleus (Ace) to the basal forebrain, hypothalamus and brainstem permit it to influence sleep mechanisms. To characterize further the neuronal activity of AMY during sleep and wakefulness, we recorded single neuronal activity in Ace across behavioral states in freely moving, normally behaving rats. Of the 49 neurons recorded from Ace, 24 neurons had firing patterns related to sleep-wakefulness (S-W). Of these, 50% (n = 12) had a high firing frequency during wakefulness (W) or both W and REM sleep (REM), 12% (n = 3) were non-REM (NREM)-related, 17% (n = 4) had a high firing rate in REM (REM-ON), and 20% (n = 5) fired at a low rate during REM. Because serotonin introduced into AMY during REM induces short-latency changes of state, we also studied the effects of low frequency (1 Hz) electrical stimulation of the dorsal raphe nucleus (DRN) on Ace neurons. All REM-ON neurons recorded from Ace were inhibited by DRN stimulation, and other cell types were unaffected. Thus, we found that the majority of cells in Ace related to S-W fired slowly during NREM and increased their discharge during W and/or REM, and that the DRN has the potential for modulating the spontaneous activity of REM-ON cells in rats.     

Disinhibition of perifornical hypothalamic neurones activates noradrenergic neurones and blocks pontine carbachol-induced REM sleep-like episodes in rats

Studies in behaving animals suggest that neurones located in the perifornical (PF) region of the posterior hypothalamus promote wakefulness and suppress sleep. Among such cells are those that synthesize the excitatory peptides, orexins (ORX). Lack of ORX, or their receptors, is associated with narcolepsy/cataplexy, a disorder characterized by an increased pressure for rapid eye movement (REM) sleep. We used anaesthetized rats in which pontine microinjections of a cholinergic agonist, carbachol, can repeatedly elicit REM sleep-like episodes to test whether activation of PF cells induced by antagonism of endogenous, GABA_A receptor-mediated, inhibition suppresses the ability of the brainstem to generate REM sleep-like state. Microinjections of the GABA_A receptor antagonist, bicuculline (20 nl, 1 m m ), into the PF region elicited cortical and hippocampal activation, increased the respiratory rate and hypoglossal nerve activity, induced c-fos expression in ORX and other PF neurones, and increased c-fos expression in pontine A7 and other noradrenergic neurones. The ability of pontine carbachol to elicit any cortical, hippocampal or brainstem component of the REM sleep-like response was abolished during the period of bicuculline-induced activation. The activating and REM sleep-suppressing effect of PF bicuculline was not attenuated by systemic administration of the ORX type 1 receptor antagonist, SB334867. Thus, activation of PF neurones that are endogenously inhibited by GABA_A receptors is sufficient to turn off the brainstem REM sleep-generating network; the effect is, at least in part, due to activation of pontine noradrenergic neurones, but is not mediated by ORX type 1 receptors. A malfunction of the pathway that originates in GABA_A receptor-expressing PF neurones may cause narcolepsy/cataplexy.     

REM sleep characteristics in narcolepsy and REM sleep behavior disorder

STUDY OBJECTIVES: To assess the presence of polysomnographic characteristics of REM sleep behavior disorder (RBD) in narcolepsy; and to quantify REM sleep parameters in patients with narcolepsy, in patients with "idiopathic" RBD, and in normal controls. DESIGN: Sleep laboratory study PARTICIPANTS: Sixteen patients with narcolepsy and cataplexy matched for age and sex with 16 patients with "idiopathic" RBD and with 16 normal controls were studied. MEASUREMENTS AND RESULTS: Higher percentages of REM sleep without atonia, phasic electromyographic (EMG) activity, and REM density were found in patients with narcolepsy than normal controls. In contrast, RBD patients had a higher percentage of REM sleep without atonia but a lower REM density than patients with narcolepsy and normal controls. Based on a threshold of 80% for percentage of REM sleep with atonia, 50% of narcoleptics and 87.5% of RBD patients had abnormal REM sleep muscle activity. No significant behavioral manifestation in REM sleep was noted in either narcoleptics or controls. We also found a higher frequency of periodic leg movements during wake (PLMW) and during sleep (PLMS) in narcoleptic patients compared to controls. CONCLUSIONS: The present study demonstrates abnormalities in REM sleep motor regulation with an increased frequency of REM sleep without atonia, phasic EMG events and PLMS in narcoleptic patients when compared to controls. These abnormalities were seen more prominently in patients with RBD than in narcoleptics, with the exception of the PLMS index. We proposed that dysfunctions in hypocretin/dopaminergic system may lead to motor dyscontrol in REM sleep that results in dissociated sleep/wake states.     

Narcolepsy and depression and the neurobiology of gammahydroxybutyrate

A voluminous literature describes the relationship between disturbed sleep and depression. The breakdown of sleep is one of the cardinal features of depression and often also heralds its onset. Frequent arousals, periods of wakefulness and a short sleep onset REM latency are typical polysomnographic features of depression. The short latency to REM sleep has been attributed to the combination of a monoaminergic deficiency and cholinergic supersensitivity and these irregularities have been proposed to form the biological basis of the disorder. A similar imbalance between monoaminergic and cholinergic neurotransmission has been found in narcolepsy, a condition in which frequent awakenings, periods of wakefulness and short sleep onset REM latencies are also characteristic findings during sleep. In many cases of narcolepsy, this imbalance appears to result from a deficiency of hypocretin but once established, whether in depression or narcolepsy, this disequilibrium sets the stage for the dissociation or premature appearance of REM sleep and for the dissociation of the motor inhibitory component of REM sleep or cataplexy. In the presence of this monoaminergic/cholinergic imbalance, gammahydroxybutyrate (GHB) may acutely further reduce the latency of REM sleep and induce cataplexy, in both patients with narcolepsy or depression. On the other hand, the repeated nocturnal application of GHB in patients with narcolepsy improves the continuity of sleep, prolongs the latency to REM sleep and prevents cataplexy. Evidence to date suggests that GHB may restore the normal balance between monoaminergic and cholinergic neurotransmission. As such, the repeated use of GHB at night and the stabilization of sleep over time makes GHB an effective treatment for narcolepsy and a potentially effective treatment for depression.     

Demonstration of monoamine oxidase-A and -B in the human brainstem by a histochemical technique

The distribution of both monoamine oxidase subtypes, monoamine oxidase-A and -B, is demonstrated in brainstems from 16 humans by use of a histochemical technique. The results presented here, focus primarily upon the aminergic areas of the substantia nigra, the locus coeruleus and the raphe nuclei. While dopaminergic neurons of the substantia nigra revealed no staining for monoamine oxidase, noradrenergic neurons of the locus coeruleus stained positively with the monoamine oxidase-A substrate serotonin, and serotonergic neurons of the raphe nuclei were stained by the monoamine oxidase-B substrate beta-phenylethylamine. In addition, data are presented showing that glial cells stain predominantly for monoamine oxidase-B.     

Expert-system classification of sleep/waking states in infants

This work is part of a project to develop an expert system for automated classification of the sleep/waking states in human infants; i.e. active or rapid-eye-movement sleep (REM), quiet or non-REM sleep (NREM), including its four stages, indeterminate sleep (IS) and wakefulness (WA). A model to identify these states, introducing an objective formalisation in terms of the state variables characterising the recorded patterns, is presented. The following digitally recorded physiological events are taken into account to classify the sleep/waking states: predominant background activity and the existence of sleep spindles in the electro-encephalogram; existence of rapid eye movements in the electro-oculogram; and chin muscle tone in the electromyogram. Methods to detect several of these parameters are described. An expert system based on artificial ganglionar lattices is used to classify the sleep/waking states, on an off-line minute-by-minute basis. Algorithms to detect patterns automatically and an expert system to recognise sleep/waking states are introduced, and several adjustments and tests using various real patients are carried out. Results show an overall performance of 96.4% agreement with the expert on validation data without artefacts, and 84.9% agreement on validation data with artefacts. Moreover, results show a significant improvement in the classification agreement due to the application of the expert system, and a discussion is carried out to justify the difficulties of matching the expert's criteria for the interpretation of characterising patterns.