An episode of geniospasm in sleep: Toward new insights into pathophysiology?

Polysomnography and needle electromyography were performed on three members of a family with hereditary geniospasm. Electromyography showed simultaneous bilateral discharges exclusively in the mentalis muscle. In one subject we documented a paroxysm of geniospasm during sleep phase 2. This activity ceased with the onset of REM sleep. In view of the mechanism of REM atonia and the bilateral chin EMG discharges, our findings support a supranuclear origin of the peculiar mentalis muscle paroxysms. © 2007 Movement Disorder Society     

Kv3 potassium channels control the duration of different arousal states by distinct stochastic and clock-like mechanisms

Sleep-wake behavior is tightly controlled in many animal species, suggesting genetically encoded, homeostatic control mechanisms that determine arousal-state dynamics. We reported that two voltage-gated potassium channels, Kv3.1 and Kv3.3, control sleep in wild-type and Kv3-mutant mice. Compared with wild-type (WT), homozygous double mutants (DKO) that lack these channels sleep 40% less in the light and 22% less in the dark. To understand how the lack of these channels affects sleep, we analysed arousal-state changes during the light period where the differences are greatest between WT and DKO. We determined the kinetic complexity of each arousal state from the episode durations of wakefulness, slow-wave sleep and rapid eye movement sleep (REMS). Based on the number of exponential components in episode-duration histograms, WT and DKO mice have several kinetically distinct states of wakefulness, and these states are longer in duration in DKO. For slow-wave sleep, WT mice have a single slow-wave sleep (SWS) state in contrast to DKO mice, which show two distinct SWS states, one that is 60% shorter than that in WT and a second that is similar in duration. Both WT and DKO mice have two kinetically distinct REMS states. DKO mice show an 84% reduction in the frequency of short REMS episodes (<45 s) without any change in the occurrence of long REMS episodes (>60 s). In contrast to the stochastic control of episode durations of wakefulness and SWS, the durations of both REMS states are normally distributed, indicating that the underlying control processes are fundamentally different.     

The rat ponto-medullary network responsible for paradoxical sleep onset and maintenance: a combined microinjection and functional neuroanatomical study

The neuronal network responsible for paradoxical sleep (PS) onset and maintenance has not previously been identified in the rat, unlike the cat. To fill this gap, this study has developed a new technique involving the recording of sleep-wake states in unanaesthetized head-restrained rats whilst locally administering pharmacological agents by microiontophoresis from glass multibarrel micropipettes, into the dorsal pontine tegmentum and combining this with functional neuroanatomy. Pharmacological agents used for iontophoretic administration included carbachol, kainic acid, bicuculline and gabazine. The injection sites and their efferents were then identified by injections of anterograde (phaseolus vulgaris leucoagglutinin) or retrograde (cholera toxin B subunit) tracers through an adjacent barrel of the micropipette assembly and by C-Fos immunostaining. Bicuculline, gabazine and kainic acid ejections specifically into the pontine sublaterodorsal nucleus (SLD) induced within a few minutes a PS-like state characterized by a continuous muscle atonia, low voltage EEG and a lack of reaction to stimuli. In contrast, carbachol ejections into the SLD induced wakefulness. In PHA-L, glycine and C-Fos multiple double-labelling experiments, anterogradely labelled fibres originating from the SLD were seen apposed on glycine and C-Fos positive neurons (labelled after 90 min of pharmacologically induced PS-like state) from the ventral gigantocellular and parvicellular reticular nuclei. Altogether, these data indicate that the SLD nuclei contain a population of neurons playing a crucial role in PS onset and maintenance. Furthermore, they suggest that GABAergic disinhibition and glutamate excitation of these neurons might also play a crucial role in the onset of PS.     

Glutamatergic and cholinergic projections to the pontine inhibitory area identified with horseradish peroxidase retrograde transport and immunohistochemistry

Previous studies in our laboratory have shown that microinjection of acetylcholine and non-N-methyl-D-aspartate (NMDA) glutamate agonists into the pontine inhibitory area (PIA) induce muscle atonia. The present experiment was designed to identify the PIA afferents that could be responsible for these effects, by use of retrograde transport of wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP), glutamate immunohistochemistry and NADPH-diaphorase staining techniques. Experiments were performed in both decerebrate and intact cats. Dense retrograde WGA-HRP labelling was found in neurons in the periaqueductal gray (PAG) and mesencephalic reticular formation (MRF) at the red nucleus (RN) level, ventral portion of paralemniscal tegmental field (_VFTP), retrorubral nucleus (RRN), contralateral side of PIA (_CPIA), pontis reticularis centralis caudalis (PoC), and most rostral portion of the nucleus parvicellularis (NPV) and nucleus praepositus hypoglossi (PH) at the level of the pontomedullary junction; moderate labelling was seen in pedunculopontine nucleus, pars compacta (PPNc), laterodorsal tegmental nucleus (LDT), superior colliculus (SC), MRF and PAG at the level caudal to RN, medial and superior vestibular nuclei, and principle sensory trigeminal nucleus (5P); and light labelling was seen in dorsal raphe (DR) and locus coeruleus complex (LCC). The projection neurons were predominantly ipsilateral to the injection site, except for both vFTP and RRN, which had more projection cells on the contralateral side. Double labelled WGA-HRP/NADPH-d neurons could be found in PPNc and LDT. Double labelled WGA-HRP/glutamatergic neurons could be seen at high densities in MRF, RRN, vFTP, and cPIA, moderate densities in SC, LDT, PPNc, PoC, and NPV, and low densities in PH, 5P, DR, LCC, and PAG. No cells in LDT and PPNc were triple labelled with NADPH-d, glutamate antibody and WGA-HRP. The mesopontine efferents identified here may mediate the suppression of muscle tone in REM sleep and coordinate muscle tone during head and neck movements. © 1993 Wiley-Liss, Inc.

1 This article is a US Government work and, as such, is in the public domain in the United States of America.

     

Sleep-wake states and cortical synchronization control by pregnenolone sulfate into the pedunculopontine nucleus

Cholinergic neurons of the pedunculopontine tegmentum nucleus (PPT) are crucial for initiation and maintenance of electroencephalographic (EEG) desynchronization states like paradoxical sleep and wakefulness. These neurons are regulated by classical neurotransmitter systems from the pontomesencephalic reticular formation and basal ganglia. In addition to this regulation, PPT neuron activity could be modulated by endogenous neurosteroids and particularly by pregnenolone sulfate (PREG-S) because synthesis enzymes of this neurosteroid are present in this area and peripheral administrations of PREG-S affect sleep-wakefulness states. To test this hypothesis, we studied the effects of different doses of PREG-S infusion into the PPT on sleep-wakefulness states in rats. Our results show dose-dependent effects of PREG-S on sleep-wakefulness states. Low concentration of PREG-S (5 ng) increased the amount of paradoxical sleep without any modification of slow wave sleep and wakefulness. High level of PREG-S (10 and 20 ng) increased paradoxical sleep and slow wave sleep together with an increase of delta power and a decrease of theta power during wakefulness. Dependent on the doses used, PREG-S thus can promote paradoxical sleep alone or the global propensity to fall asleep, impairing the quality of wakefulness. These results unveil a new regulation pathway for PPT neurons and strengthen the role of PREG-S in sleep-wakefulness regulation.     

Localization of the GABAergic and non-GABAergic neurons projecting to the sublaterodorsal nucleus and potentially gating paradoxical sleep onset

We recently determined in rats that iontophoretic application of bicuculline or gabazine [two GABAa antagonists] and kainic acid (a glutamate agonist) in the sublaterodorsal nucleus (SLD) induces with a very short latency a paradoxical sleep-like state. From these results, we proposed that GABAergic and glutamatergic inputs to the SLD paradoxical sleep (PS)-executive neurons gate the onset of PS [R. Boissard et al. (2002) Eur. J. Neurosci., 16, 1959-1973]. We therefore decided to determine the origin of the GABAergic and non-GABAergic inputs to the SLD combining ejection of a retrograde tracer [cholera-toxin B subunit (CTb)] with glutamate decarboxylase (GAD) immunohistochemistry. The presence of GAD-immunoreactive neurons in the SLD was confirmed. Then, following CTb ejections centred on the SLD, combined with GAD and CTb immunohistochemistry, double-labelled cells were observed in the mesencephalic and pontine reticular nuclei and to a lesser extent the parvicellular reticular nucleus. A large number of GAD-negative retrogradely labelled cells was also seen in these structures as well as in the primary motor area of the frontal cortex, the central nucleus of the amygdala, the ventral and lateral bed nucleus of the stria terminalis, the lateral hypothalamic area, the lateral and ventrolateral periaqueductal grey and the lateral paragigantocellular reticular nucleus. From these results, we propose that the activation of PS-executive neurons from the SLD is due to the removal of a tonic inhibition from GABAergic neurons localized in the SLD, and the mesencephalic and pontine reticular nuclei. Strong non-GABAergic inputs to the SLD could be excitatory and responsible for the tonic glutamatergic input on the PS-on neurons we have previously described. They could also terminate on SLD GABAergic interneurons and be indirectly responsible for the inhibition of the PS-on neurons during waking and slow-wave sleep.     

Stages 1–2 non–rapid eye movement sleep behavior disorder associated with dementia: A new parasomnia?

A 55-year-old woman with a progressive dementia and frontal syndrome was hospitalized because she was agitated every night after falling asleep (spoke, laughed, cried, tapped, kicked, walked, and fell down). She slept 5.5 hours during video polysomnography, but the theta rhythm electroencephalograph recording typical of sleep stages 1 to 2 and the spindles and K-complexes typical of sleep stage 2 contrasted with continuous muscular twitching, prominent rapid eye movements, vocalizations, and continuous, complex, purposeful movements typical of rapid eye movement (REM) sleep behavior disorder. This newly described stages 1--2 non-REM sleep behavior disorder suggests that central motor pattern generators were disinhibited during non-REM sleep.     

Effects of hypocretin (orexin) neuronal loss on sleep and extracellular adenosine levels in the rat basal forebrain

Neurons containing the neuropeptide hypocretin (HCRT, orexin) are localized only in the lateral hypothalamus, from where they innervate multiple regions implicated in arousal, including the basal forebrain. HCRT activation of downstream arousal neurons is likely to stimulate release of endogenous factors. One such factor is adenosine, which in the basal forebrain increases in level with wakefulness and decreases with sleep, and is hypothesized to regulate the waxing and waning of sleep drive. Does loss of HCRT neurons affect adenosine levels in the basal forebrain? Is the increased sleep that accompanies HCRT loss a consequence of higher adenosine levels in the basal forebrain? In the present study, we investigated these questions by lesioning the HCRT neurons with HCRT‐2–saporin (HCRT‐2–SAP) and measuring sleep and extracellular levels of adenosine in the basal forebrain. In separate groups of rats, the neurotoxin HCRT‐2–SAP or saline was administered locally to the lateral hypothalamus, and 80 days later adenosine and sleep were assessed. Rats given the neurotoxin had a 94% loss of HCRT neurons. These rats woke less at night, and had more rapid eye movement sleep, which is consistent with HCRT hypofunction. These rats also had more sleep after brief periods of sleep deprivation. However, in the lesioned rats, adenosine levels did not increase with 6 h of sleep deprivation, whereas an increase in adenosine levels occurred in rats without lesion of the HCRT neurons. These findings indicate that adenosine levels do not increase with wakefulness in rats with a HCRT lesion, and that the increased sleep in these rats occurs independently of adenosine levels in the basal forebrain.     

Pneumotaxic area neuronal discharge during sleep-waking states in the cat

We examined the spontaneous activity of single neurons within the nucleus parabrachialis medialis (NPBM; pneumotaxic center) of unanesthetized, unrestrained cats in relation to the respiratory cycle during different sleep-waking states. State-related changes were found in the mean discharge rate of NPBM neurons and in the relationship of their activity to the respiratory cycle. These changes in pneumotaxic center neuronal activity paralleled the variations in respiratory patterns associated with different sleep-waking states. State-related changes in NPBM neuronal activity could partially account for the different respiratory patterns of each sleep-waking state by modulating inspiratory-expiratory phase transitions.     

Modification of REM sleep and associated phasic activities by protein synthesis inhibitors

The sleep-wake cycle and multiple-unit activity following the administration of various doses of protein synthesis inhibitors was studied in unrestrained cats. Special care was taken to analyze the effects of those drugs on phasic and tonic rapid eye movement (REM) sleep periods. It was observed that protein synthesis inhibitors decreased specifically total REM sleep time, at the expense of wakefulness, without altering slow-wave sleep time. It was further noted that the reduction in REM sleep was the result of a decrease in the frequency of REM periods, rather than in the duration of each individual period. In addition, protein synthesis inhibitors decreased phasic REM sleep and notably prolonged tonic REM periods. Moreover the phasic bursts of multiple-unit activity normally seen during REM sleep in control recordings were practically absent during REM sleep after the administration of protein synthesis inhibitors. It is suggested that protein molecules may participate in the mechanisms which trigger REM sleep.     

Sleep and kindling: I. Effects of initial afterdischarge threshold determination

Recent work indicated a significant correlation between seizure latencies following exposure to the convulsant drug monomethylhydrazine (MMH) and afterdischarge (AD) thresholds obtained at the beginning of basolateral amygdala kindling in cats. A profound alteration in state physiology is an early and sustained feature of the prodrome with MMH but has not been shown in relation to initial AD thresholds. The present experiment examined state variables during the earliest phase of kindling in an effort to determine if other similarities exist between these two experimental models of epilepsy. Eighteen cats (experimental, N = 12; control, N = 6) were surgically prepared for basolateral amygdala stimulation and for the evaluation of standard state variables. Postoperatively, two baseline, 12-h, polygraphic recordings were obtained in the experimental group. AD thresholds were then established using a method of limits procedure, after which a third 12-h polygraphic recording was obtained as long as 48 h later. Control animals underwent the same polygraphic recording sequence but never received amygdala stimulation. AD thresholds in experimental animals varied considerably. Threshold values were not systematically related either to histologically verified electrode sites throughout the basolateral amygdala or to changes in the sleep-waking cycle. State evaluation indicated that the experimental animals showed a sustained facilitation of waking and a suppression of slow-wave sleep during the poststimulation recording compared with their own baseline and with controls. These findings indicate a further resemblance between the MMH and kindling models of epilepsy, which, in conjunction with other similarities, could be indicative of a common pathological mechanism.     

Sleep and kindling: II. Effects of generalized seizure induction

Recent work indicated a significant correlation between seizure latencies following exposure to the convulsant drug monomethylhydrazine (MMH) and afterdischarge (AD) thresholds obtained at the beginning of basolateral amygdala kindling in cats. A profound alteration in state physiology is an early and sustained feature of the prodrome with MMH but has not been shown in relation to initial AD thresholds. The present experiment examined state variables during the earliest phase of kindling in an effort to determine if other similarities exist between these two experimental models of epilepsy. Eighteen cats (experimental, N = 12; control, N = 6) were surgically prepared for basolateral amygdala stimulation and for the evaluation of standard state variables. Postoperatively, two baseline, 12-h, polygraphic recordings were obtained in the experimental group. AD thresholds were then established using a method of limits procedure, after which a third 12-h polygraphic recording was obtained as long as 48 h later. Control animals underwent the same polygraphic recording sequence but never received amygdala stimulation. AD thresholds in experimental animals varied considerably. Threshold values were not systematically related either to histologically verified electrode sites throughout the basolateral amygdala or to changes in the sleep-waking cycle. State evaluation indicated that the experimental animals showed a sustained facilitation of waking and a suppression of slow-wave sleep during the poststimulation recording compared with their own baseline and with controls. These findings indicate a further resemblance between the MMH and kindling models of epilepsy, which, in conjunction with other similarities, could be indicative of a common pathological mechanism.     

Transcranial magnetic stimulation and sleep disorders: pathophysiologic insights

The neural mechanisms underlying the development of the most common intrinsic sleep disorders are not completely known. Therefore, there is a great need for noninvasive tools which can be used to better understand the pathophysiology of these diseases. Transcranial magnetic stimulation (TMS) offers a method to noninvasively investigate the functional integrity of the motor cortex and its corticospinal projections in neurologic and psychiatric diseases.     

Relationship between CSF hypocretin levels and hypocretin neuronal loss

The sleep disorder narcolepsy may now be considered a neurodegenerative disease, as there is a massive reduction in the number of neurons containing the neuropeptide, hypocretin (HCRT). Most narcoleptic patients have low to negligible levels of HCRT in the cerebrospinal fluid (CSF), and such measurements serve as an important diagnostic tool. However, the relationship between HCRT neurons and HCRT levels in CSF in human narcoleptics is not known and cannot be directly assessed. To identify this relationship in the present study, the neurotoxin, hypocretin-2-saporin (HCRT2-SAP), was administered to the lateral hypothalamus (LH) to lesion HCRT neurons. CSF was extracted at circadian times (ZT) 0 (time of lights-on) or ZT8 at various intervals (2, 4, 6, 12, 21, 36, 60 days) after neurotoxin administration. Compared to animals given saline in the LH, rats with an average loss of 73% of HCRT neurons had a 50% decline in CSF HCRT levels on day 60. The decline in HCRT levels was evident by day 6 and there was no recovery or further decrease. The decline in HCRT was correlated with increased REM sleep. Lesioned rats that were kept awake for 6 h were not able to release HCRT to match the output of saline rats. As most human narcoleptics have more than 80% reduction of CSF HCRT, the results from this study lead us to conclude that in these patients, virtually all of the HCRT neurons might be lost. In those narcoleptics where CSF levels are within the normal range, it is possible that not all of the HCRT neurons are lost and that the surviving HCRT neurons might be increasing output of CSF HCRT.     

Sleep in depression: the influence of age,gender and diagnostic subtype on baseline sleep and the cholinergic REM induction test with RS 86

Summary One hundred and eight healthy controls and 178 patients with a major depressive disorder according to DSM-III were investigated in the sleep laboratory after a 7-day drug wash-out period. Subsamples of 36 healthy controls and 56 patients additionally took part in the cholinergic rapid eye movement (REM) sleep induction test with RS 86. Data analysis revealed that age exerted powerful influences on sleep in control subjects and depressed patients. Sleep efficiency and amount of slow wave sleep (SWS) decreased with age, whereas the number of awakenings, early morning awakening, and amounts of wake time and stage 1 increased with age. REM latency was negatively correlated with age only in the group of patients with a major depression. Statistical analysis revealed group differences for almost all parameters of sleep continuity with disturbed indices in the depressed group. Differences in SWS were not detected. REM latency and REM density were altered in depression compared to healthy subjects. Sex differences existed for the amounts of stage 1 and SWS. The cholinergic REM induction test resulted in a significantly more pronounced induction of REM sleep in depressed patients compared with healthy controls, provoking sleep onset REM periods as well in those depressed patients showing baseline REM latencies in the normal range. Depressed patients with or without melancholia (according to DSM-III) did not differ from each other, either concerning baseline sleep or with respect to the results of the cholinergic REM induction test. The results stress the importance of age when comparing sleep patterns of healthy controls with those of depressed patients. Furthermore they underline the usefulness of the cholinergic REM induction test for differentiating depressed patients from healthy controls and support the reciprocal interaction model of nonREM-REM regulation and the cholinergic-aminergic imbalance hypothesis of affective disorders.     

Rapid eye movement sleep patterns of brain activation and deactivation occur within unique functional networks

Rapid eye movement (REM) sleep is a paradoxical state where the individual appears asleep while the electroencephalogram pattern resembles that of wakefulness. Regional differences in brain metabolism have been observed during REM sleep compared to wakefulness, but it is not known whether the spatial distribution of metabolic differences corresponds to known functional networks in the brain. Here, we use a combination of techniques to evaluate the networks associated with sites of REM sleep activation and deactivation from previously published positron emission tomography studies. We use seed‐based functional connectivity from healthy adults acquired during quiet rest to show that REM‐activation regions are functionally connected in a network that includes retrosplenial cingulate cortex, parahippocampal gyrus, and extrastriate visual cortices, corresponding to components of the default mode network and visual networks. Regions deactivated during REM sleep localize to right‐lateralized fronto‐parietal and salience networks. A negatively correlated relationship was observed between REM‐activation and deactivation networks. Together, these findings show that regional activation and deactivation patterns of REM sleep tend to occur in distinct functional connectivity networks that are present during wakefulness, providing insights regarding the differential contributions of brain regions to the distinct subjective experiences that occur during REM sleep (dreaming) relative to wakefulness.     

The mammalian sympathetic prevertebral ganglia: Models for the study of neuronal networks and basic neuronal properties

The mammalian sympathetic prevertebral ganglia regulate various visceral functions and in particular the digestive tract motility. Several integrative properties of these ganglia have been described: convergence of central inputs, projection of visceral inputs at the pre- and post synaptic level and pacemaker activity of the neurones. This review presents the results obtained on another integrative property which has been widely studied over the last 10 years: the modulation of the fast central inputs by neuromodulators such as nitric oxide, ceramide and GABA. These substances facilitate or inhibit the fast central inputs through complex interrelated actions. We also present striking results recently obtained during the study of a regulatory reflex of the digestive tract motility organized by the prevertebral ganglia: the gastro-duodenal inhibitory reflex. During this reflex, the neurotransmitter released by the visceral afferent fibres to activate the ganglionic neurones is gaseous: nitric oxide. Moreover, the mechanism conducting the excitation along the afferent and efferent fibres is independent of action potentials. This mechanism requires the integrity of the membrane lipid rafts and the activation in cascade of the following second messenger sequence: ceramide, calcium, nitric oxide and guanosine 3′, 5′-cyclic monophosphate. The existence of this mechanism gives grounds for rethinking one of the central dogmas in neuroscience according to which excitation is only conducted along nerves by an electrical phenomenon, the action potential. All these results strengthen the role of the prevertebral ganglia as a model for the study of neuronal networks and basic neuronal properties.     

Immunological approach to the study of neurohumoral sleep factors: Effects on REM sleep of antibodies to brain stem proteins

Proteins were collected for several months from the reticular formation of some 40 cats. The sodium dodecyl sulfate electrophoretic profile showed eight visible bands. Rabbits were inoculated with these proteins four times at weekly intervals in order to produce antibodies. Antibodies were also produced against cat serum proteins and cat serum albumin. These antibodies were tested for their effects on the sleep-wake cycle of another group of cats. The results of these experiments showed that the anti-reticular formation (MRF) antibodies and not antiserum or antialbumin antibodies, produced a specific decrease in rapid eye movement (REM) sleep without altering slow-wave sleep. It was also observed that when the anti-MRF antibodies were incubated with MRF proteins, the effect was lost, but that it persisted when they were incubated with serum protein only. It was also noted that the reduction in REM sleep was the result of an increase in the latency and a decrease in the frequency of REM periods, rather than in the duration of individual periods. In addition, the antibodies decreased some of the phasic elements of REM sleep such as multiple-unit and eye movement bursts. These experiments present the first direct evidence suggesting that specific protein molecules play an important role in triggering REM sleep.