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Wakefulness
Terms modified by Wakefulness Selected AbstractsApproaches to measuring the effects of wake-promoting drugs: a focus on cognitive functionHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2009Christopher J. Edgar Abstract Objectives In clinical drug development, wakefulness and wake-promotion may be assessed by a large number of scales and questionnaires. Objective assessment of wakefulness is most commonly made using sleep latency/maintenance of wakefulness tests, polysomnography and/or behavioral measures. The purpose of the present review is to highlight the degree of overlap in the assessment of wakefulness and cognition, with consideration of assessment techniques and the underlying neurobiology of both concepts. Design Reviews of four key areas were conducted: commonly used techniques in the assessment of wakefulness; neurobiology of sleep/wake and cognition; targets of wake promoting and/or cognition enhancing drugs; and ongoing clinical trials investigating wake promoting effects. Results There is clear overlap between the assessment of wakefulness and cognition. There are common techniques which may be used to assess both concepts; aspects of the neurobiology of both concepts may be closely related; and wake-promoting drugs may have nootropic properties (and vice versa). Clinical trials of wake-promoting drugs often, though not routinely, assess aspects of cognition. Conclusions Routine and broad assessment of cognition in the development of wake-promoting drugs may reveal important nootropic effects, which are not secondary to alertness/wakefulness, whilst existing cognitive enhancers may have underexplored or unknown wake promoting properties. Copyright © 2009 John Wiley & Sons, Ltd. [source] Activation of the basal forebrain by the orexin/hypocretin neuronesACTA PHYSIOLOGICA, Issue 3 2010E. Arrigoni Abstract The orexin neurones play an essential role in driving arousal and in maintaining normal wakefulness. Lack of orexin neurotransmission produces a chronic state of hypoarousal characterized by excessive sleepiness, frequent transitions between wake and sleep, and episodes of cataplexy. A growing body of research now suggests that the basal forebrain (BF) may be a key site through which the orexin-producing neurones promote arousal. Here we review anatomical, pharmacological and electrophysiological studies on how the orexin neurones may promote arousal by exciting cortically projecting neurones of the BF. Orexin fibres synapse on BF cholinergic neurones and orexin-A is released in the BF during waking. Local application of orexins excites BF cholinergic neurones, induces cortical release of acetylcholine and promotes wakefulness. The orexin neurones also contain and probably co-release the inhibitory neuropeptide dynorphin. We found that orexin-A and dynorphin have specific effects on different classes of BF neurones that project to the cortex. Cholinergic neurones were directly excited by orexin-A, but did not respond to dynorphin. Non-cholinergic BF neurones that project to the cortex seem to comprise at least two populations with some directly excited by orexin-A that may represent wake-active, GABAergic neurones, whereas others did not respond to orexin-A but were inhibited by dynorphin and may be sleep-active, GABAergic neurones. This evidence suggests that the BF is a key site through which orexins activate the cortex and promote behavioural arousal. In addition, orexins and dynorphin may act synergistically in the BF to promote arousal and improve cognitive performance. [source] Experience-dependent plasticity in hypocretin/orexin neurones: re-setting arousal thresholdACTA PHYSIOLOGICA, Issue 3 2010X.-B. Gao Abstract The neuropeptide hypocretin is synthesized exclusively in the lateral hypothalamus and participates in many brain functions critical for animal survival, particularly in the promotion and maintenance of arousal in animals , a core process in animal behaviours. Consistent with its arousal-promoting role in animals, the neurones synthesizing hypocretin receive extensive innervations encoding physiological, psychological and environmental cues and send final outputs to key arousal-promoting brain areas. The activity in hypocretin neurones fluctuates and correlates with the behavioural state of animals and intensive activity has been detected in hypocretin neurones during wakefulness, foraging for food and craving for addictive drugs. Therefore, it is likely that hypocretin neurones undergo experience-dependent changes resulting from intensive activations by stimuli encoding changes in the internal and external environments. This review summarizes the most recent evidence supporting experience-dependent plasticity in hypocretin neurones. Current data suggest that nutritional and behavioural factors lead to synaptic plasticity and re-organization of synaptic architecture in hypocretin neurones. This may be the substrate of enhanced levels of arousal resulting from behavioural changes in animals and may help to explain the mechanisms underlying the changes in arousal levels induced by physiological, psychological and environmental factors. [source] Orexins/hypocretins control bistability of hippocampal long-term synaptic plasticity through co-activation of multiple kinasesACTA PHYSIOLOGICA, Issue 3 2010O. Selbach Abstract Aim:, Orexins/hypocretins (OX/Hcrt) are hypothalamic neuropeptides linking sleep,wakefulness, appetite and neuroendocrine control. Their role and mechanisms of action on higher brain functions, such as learning and memory, are not clear. Methods:, We used field recordings of excitatory post-synaptic potentials (fEPSP) in acute mouse brain slice preparations to study the effects of orexins and pharmacological inhibitors of multiple kinases on long-term synaptic plasticity in the hippocampus. Results:, Orexin-A (OX-A) but not orexin-B (OX-B) induces a state-dependent long-term potentiation of synaptic transmission (LTPOX) at Schaffer collateral-CA1 synapses in hippocampal slices from adult (8- to 12-week-old) mice. In contrast, OX-A applied to slices from juvenile (3- to 4-week-old) animals causes a long-term depression (LTDOX) in the same pathway. LTPOX is blocked by pharmacological inhibition of orexin receptor-1 (OX1R) and plasticity-related kinases, including serine/threonine- (CaMKII, PKC, PKA, MAPK), lipid- (PI3K), and receptor tyrosine kinases (Trk). Inhibition of OX1R, CaMKII, PKC, PKA and Trk unmasks LTDOX in adult animals. Conclusion:, Orexins control not only the bistability of arousal states and threshold for appetitive behaviours but, in an age- and kinase-dependent manner, also bidirectional long-term synaptic plasticity in the hippocampus, providing a possible link between behavioural state and memory functions. [source] Histamine-1 receptor is not required as a downstream effector of orexin-2 receptor in maintenance of basal sleep/wake statesACTA PHYSIOLOGICA, Issue 3 2010M. Hondo Abstract Aim:, The effect of orexin on wakefulness has been suggested to be largely mediated by activation of histaminergic neurones in the tuberomammillary nucleus (TMN) via orexin receptor-2 (OX2R). However, orexin receptors in other regions of the brain might also play important roles in maintenance of wakefulness. To dissect the role of the histaminergic system as a downstream mediator of the orexin system in the regulation of sleep/wake states without compensation by the orexin receptor-1 (OX1R) mediated pathways, we analysed the phenotype of Histamine-1 receptor (H1R) and OX1R double-deficient (H1R,/,;OX1R,/,) mice. These mice lack OX1R-mediated pathways in addition to deficiency of H1R, which is thought to be the most important system in downstream of OX2R. Methods:, We used H1R deficient (H1R,/,) mice, H1R,/,;OX1R,/, mice, OX1R and OX2R double-deficient (OX1R,/,;OX2R,/,) mice, and wild type controls. Rapid eye movement (REM) sleep, non-REM (NREM) sleep and awake states were determined by polygraphic electroencephalographic/electromyographic recording. Results:, No abnormality in sleep/wake states was observed in H1R,/, mice, consistent with previous studies. H1R,/,;OX1R,/, mice also showed a sleep/wake phenotype comparable to that of wild type mice, while OX1R,/,; OX2R,/, mice showed severe fragmentation of sleep/wake states. Conclusion:, Our observations showed that regulation of the sleep/wake states is completely achieved by OX2R-expressing neurones without involving H1R-mediated pathways. The maintenance of basal physiological sleep/wake states is fully achieved without both H1 and OX1 receptors. Downstream pathways of OX2R other than the histaminergic system might play an important role in the maintenance of sleep/wake states. [source] Role of orexin in the regulation of glucose homeostasisACTA PHYSIOLOGICA, Issue 3 2010H. Tsuneki Abstract Orexin-A (hypocretin-1) and orexin-B (hypocretin-2) are hypothalamic neuropeptides that play key roles in the regulation of wakefulness, feeding, reward, autonomic functions and energy homeostasis. To control these functions indispensable for survival, orexin-expressing neurones integrate peripheral metabolic signals, interact with many types of neurones in the brain and modulate their activities via the activation of orexin-1 receptor or orexin-2 receptor. In addition, a new functional role of orexin is emerging in the regulation of insulin and leptin sensitivities responsible for whole-body glucose metabolism. Recent evidence indicates that orexin efficiently protects against the development of peripheral insulin resistance induced by ageing or high-fat feeding in mice. In particular, the orexin receptor-2 signalling appears to confer resistance to diet-induced obesity and insulin insensitivity by improving leptin sensitivity. In fact, the expression of orexin gene is known to be down-regulated by hyperglycaemia in the rodent model of diabetes, such as ob/ob and db/db mice. Moreover, the levels of orexin receptor-2 mRNA have been shown to decline in the brain of mice along with ageing. These suggest that hyperglycaemia due to insulin insensitivity during ageing or by habitual consumption of a high-fat diet leads to the reduction in orexin expression in the hypothalamus, thereby further exacerbating peripheral insulin resistance. Therefore, orexin receptor controlling hypothalamic insulin/leptin actions may be a new target for possible future treatment of hyperglycaemia in patients with type 2 diabetes. [source] Hypocretin/orexin in fish physiology with emphasis on zebrafishACTA PHYSIOLOGICA, Issue 3 2010P. Panula Abstract One hypocretin/orexin (hcrt) gene has been identified in several fish species. The first pufferfish gene was identified in 2002 and the zebrafish gene was cloned in 2004. Its structure is very similar to that of mammals, and it encodes for two active peptides with C-termini similar to those of mammals. The gene is expressed in the brain in only one hypothalamic nucleus, which sends projections to the telencephalon, diencephalon, mesencephalon and rhombencephalon. The terminal fibres are found in close contact with many aminergic cell groups, including those of raphe serotonergic, locus coeruleus noradrenergic, several dopaminergic cell groups and the sole histaminergic hypothalamic cluster. One receptor corresponding to mammalian hcrt 2 receptor has been identified in fish. Overexpression of hcrt in zebrafish has been reported to consolidate wakefulness and inhibit rest. On the other hand, fish lacking the hcrt receptor show short and fragmented sleep instead of sleepiness and cataplexy. Food deprivation increases hcrt mRNA expression in zebrafish brain, and intracerebroventricular hcrt peptides stimulate food consumption and feeding behaviour in goldfish. Hcrt peptides thus have important roles in fish physiology. Many genetic and functional methods available render fish, especially zebrafish, a suitable organism to study new aspects of hcrt physiology in vertebrates. [source] Physiological functions of glucose-inhibited neuronesACTA PHYSIOLOGICA, Issue 1 2009D. Burdakov Abstract Glucose-inhibited neurones are an integral part of neurocircuits regulating cognitive arousal, body weight and vital adaptive behaviours. Their firing is directly suppressed by extracellular glucose through poorly understood signalling cascades culminating in opening of post-synaptic K+ or possibly Cl, channels. In mammalian brains, two groups of glucose-inhibited neurones are best understood at present: neurones of the hypothalamic arcuate nucleus (ARC) that express peptide transmitters NPY and agouti-related peptide (AgRP) and neurones of the lateral hypothalamus (LH) that express peptide transmitters orexins/hypocretins. The activity of ARC NPY/AgRP neurones promotes food intake and suppresses energy expenditure, and their destruction causes a severe reduction in food intake and body weight. The physiological actions of ARC NPY/AgRP cells are mediated by projections to numerous hypothalamic areas, as well as extrahypothalamic sites such as the thalamus and ventral tegmental area. Orexin/hypocretin neurones of the LH are critical for normal wakefulness, energy expenditure and reward-seeking, and their destruction causes narcolepsy. Orexin actions are mediated by highly widespread central projections to virtually all brain areas except the cerebellum, including monosynaptic innervation of the cerebral cortex and autonomic pre-ganglionic neurones. There, orexins act on two specific G-protein-coupled receptors generally linked to neuronal excitation. In addition to sensing physiological changes in sugar levels, the firing of both NPY/AgRP and orexin neurones is inhibited by the ,satiety' hormone leptin and stimulated by the ,hunger' hormone ghrelin. Glucose-inhibited neurones are thus well placed to coordinate diverse brain states and behaviours based on energy levels. [source] Altered interaction between cardiac vagal influence and delta sleep EEG suggests an altered neuroplasticity in patients suffering from major depressive disorderACTA PSYCHIATRICA SCANDINAVICA, Issue 3 2010F. Jurysta Jurysta F, Kempenaers C, Lancini J, Lanquart J-P, van de Borne P, Linkowski P. Altered interaction between cardiac vagal influence and delta sleep EEG suggests an altered neuroplasticity in patients suffering from major depressive disorder. Objective:, Major depressive disorder (MDD), which is associated with altered neuroplasticity and increased relative cardiac sympathic activity, enhances the risk of cardiovascular pathologies. Interaction between cardiac sympatho-vagal indexes and delta sleep power is probably altered in MDD. Method:, Sleep characteristics and cardiac sympatho-vagal indexes of 10 depressive patients were compared to 10 control men across the first three non-rapid eye movement (NREM),REM cycles. Interaction between normalized high frequency (HF) and delta power bands was studied using coherence analysis. Results:, Patients showed increased sleep latency, stage 1 and wake durations. No differences in heart rate variabilities were observed: Total power, HF and RR-interval decreased from NREM to REM sleep and wakefulness in both groups. Gain value was lower in patients while coherence and phase shift were similar between groups. Modifications in HF appear 8 min before modifications in delta. Conclusion:, Major depressive disorder is related to an altered link between cardiac vagal influence and delta sleep, suggesting disorders in cardiovascular controls and an altered neuroplasticity. [source] A succession of anesthetic endpoints in the Drosophila brainDEVELOPMENTAL NEUROBIOLOGY, Issue 11 2006Bruno van Swinderen Abstract General anesthetics abolish behavioral responsiveness in all animals, and in humans this is accompanied by loss of consciousness. Whether similar target mechanisms and behavioral endpoints exist across species remains controversial, although model organisms have been successfully used to study mechanisms of anesthesia. In Drosophila, a number of key mutants have been characterized as hypersensitive or resistant to general anesthetics by behavioral assays. In order to investigate general anesthesia in the Drosophila brain, local field potential (LFP) recordings were made during incremental exposures to isoflurane in wild-type and mutant flies. As in higher animals, general anesthesia in flies was found to involve a succession of distinct endpoints. At low doses, isoflurane uncoupled brain activity from ongoing movement, followed by a sudden attenuation in neural correlates of perception. Average LFP activity in the brain was more gradually attenuated with higher doses, followed by loss of movement behavior. Among mutants, a strong correspondence was found between behavioral and LFP sensitivities, thereby suggesting that LFP phenotypes are proximal to the anesthetic's mechanism of action. Finally, genetic and pharmacological analysis revealed that anesthetic sensitivities in the fly brain are, like other arousal states, influenced by dopaminergic activity. These results suggest that volatile anesthetics such as isoflurane may target the same processes that sustain wakefulness and attention in the brain. LFP correlates of general anesthesia in Drosophila provide a powerful new approach to uncovering the nature of these processes. © 2006 Wiley Periodicals, Inc. J Neurobiol 66: 1195,1211, 2006 [source] The sleep of co-sleeping infants when they are not co-sleeping: Evidence that co-sleeping is stressfulDEVELOPMENTAL PSYCHOBIOLOGY, Issue 1 2002Melissa Hunsley Abstract Co-sleeping proponents consider the practice to be "natural" and a potential protection against sudden infant death syndrome (SIDS); others consider the practice of an infant sleeping in the parents' bed for prolonged periods at night to place an infant at risk for harm or death. For this study, co-sleeping was investigated from a different perspective, that is, as a significant early experience to investigate as it may have implications for the infant's development. The sleep of 101 normal, full-term infants was recorded nonintrusively in the home for 24 hr periods when they were 5 weeks and 6 months old. Infants were assigned to three groups: short-term co-sleepers, long-term co-sleepers, and non-co-sleepers. Their sleep states and wakefulness were compared at the two ages and over age. At 5 weeks and 6 months, the long-term co-sleeping infants differed significantly from the non-co-sleepers on a number of measures: At 5 weeks, they showed more quiet sleep and longer bouts of quiet sleep; and at 6 months, they also showed less active sleep, fewer arousals in active sleep, and less wakefulness. Each of these differences indicates a markedly lower arousal level in the long-term co-sleeping infants. This sleep pattern has been repeatedly found to be an indicator of stress. We infer that a major source of stress for these infants is the experience of sleep disturbance documented for infants when they were co-sleeping. Based on extensive evidence for long-term effects of early stress, we conclude that co-sleeping should have significant implications for infants' neurobehavioral development. © 2002 John Wiley & Sons, Inc. Dev Psychobiol 40: 14,22, 2002 [source] Neuroanatomical basis for therapeutic applications of cannabinoid receptor 1 antagonistsDRUG DEVELOPMENT RESEARCH, Issue 8 2009Brian F. Thomas Abstract The CB1 receptor is a Class A G-protein coupled receptor that has a high density and widespread distribution within the central nervous system. Because of its neuroanatomical distribution, the endocannabinoid system can modulate a wide variety of psychological and physiological functions. For example, CB1 receptors are found in brain regions regulating motor activity, cognitive processes, pain, satiety, appetitive behaviors and reward. In correspondence with this distribution, modulation of the endocannabinoid system has been shown to produce changes in coordination, executive function, memory, mood, perception, wakefulness, nociception and appetite. Administration of cannabinoid agonists has also been therapeutically used to reduce nausea, and is also known to decrease body temperature and neuronal excitability, pointing to additional roles for endocannabinoids in these and other physiological/neurological processes. The ongoing elucidation and characterization of the neuroanatomical circuitry within which the CB1 cannabinoid receptor and endocannabinoids are localized to modulate these psychological and physiological processes continues to suggest therapeutic applications for cannabinoid antagonists and inverse agonists. Drug Dev Res 70:527,554, 2009. © 2009 Wiley-Liss, Inc. [source] EEG Characteristics Related to Educational Impairments in Children with Benign Childhood Epilepsy with Centrotemporal SpikesEPILEPSIA, Issue 11 2007Joost Nicolai Summary Purpose: Learning and behavioral difficulties often occur in benign childhood epilepsy with centrotemporal spikes (BCECTS). In recent years, several electroencephalogram (EEG) characteristics have been related to the occurrence of learning and behavioral problems. Methods: From 28 children medical, school and psychological reports were present and children were rated according to a 4-point scale for educational and behavioral impairment (Part 1). Thirty 24-h EEG recordings were reanalyzed for spike frequency, the presence of atypical EEG criteria, and the presence of a nondipole spike. EEGs were scored during wakefulness, first hour of sleep and whole night sleep (minus the first hour of sleep) separately (Part 2). Results: The presence of I: an intermittent slow-wave focus during wakefulness, II: a high number of spikes in the first hour of sleep (and during whole night sleep), and III: multiple asynchronous bilateral spike-wave foci in the first hour of sleep correlates significantly with a sum score , 3 which indicates a complicated course with educational or behavioral impairment. It is sufficient to analyze an EEG during wakefulness and a sleep EEG for only the first hour of sleep instead of a whole night recording to demonstrate those EEG criteria. Conclusions: On basis of our reanalysis we can possibly conclude that the aforementioned EEG characteristics correlate with educational impairments, and that analysing an EEG recording during wake and the first hour of sleep is sufficient to look adequately for those EEG criteria in children with BCECTS. [source] A Study of 43 Patients with Panayiotopoulos Syndrome, a Common and Benign Childhood Seizure SusceptibilityEPILEPSIA, Issue 1 2003Christina Lada Summary: ,Purpose: To determine prevalence, clinical, EEG features, and prognosis of Panayiotopoulos syndrome and to examine the proposition that clinical manifestations are more important than EEG findings. Methods: We analyzed retrospectively the clinical and EEG records of 1,340 children with one or more focal seizures seen in the last 18 years, supplemented with a prospective study from 1998. Panayiotopoulos syndrome was defined by clinical criteria, mainly ictal emesis, irrespective of EEG findings. Results: We analyzed 43 of 90 patients with Panayiotopoulos syndrome who were seizure free >2 years. Girls predominated. Mean age at first seizure was 5 years. Seizures consisted mainly of autonomic manifestations; ictal emesis was often the first symptom, culminating in vomiting in 86%. Of nonautonomic manifestations, lateral eye deviation was the most common; visual symptoms were exceptional. Impairment of consciousness ensued in all seizures, half of which ended with hemi or generalized convulsions. Nearly 46.5% of cases had at least one seizure >30 min, constituting autonomic status epilepticus. Seizures during sleep (84%) were more common than those in wakefulness. EEG showed occipital spikes in 29 patients. Of the other 14 cases, five had extraoccipital abnormalities or brief generalized discharges, and nine had normal awake and sleep EEG. Prognosis was excellent. All 43 children have been free of seizures for ,2 years, 53% having a single seizure, and 47%, an average two to three seizures. Conclusions: Panayiotopoulos syndrome is common and needs wider recognition. EEG shows occipital or extraoccipital abnormalities, is normal in one third of patients, and does not determine clinical manifestations or prognosis, which is excellent despite the high prevalence of lengthy seizures. [source] Effects of Vigabatrin on Sleep,Wakefulness Cycle in Amygdala-Kindled RatsEPILEPSIA, Issue 2 2000Y. H. Raol Summary: Purpose: Our aim was to study the effect of prolonged administration of vigabatrin (VGB) on sleep-wakefulness cycle in kindled seizure-induced rats. Methods: Adult male Wistar rats were implanted stereotaxically with electrodes for kindling and polysomnography. The rats were divided into two groups, kindled and VGB-treated kindled rats. VGB was administered intraperitonially every day for 21 days, and polysomnographic recordings were taken after doses 1, 7, 14, and 21. The drug effects were evaluated by comparing the records of kindled and drug-treated kindled rats. Results: The VGB-administered kindled rats showed an increase in total sleep time (TST) due to an increase in total non-rapid eye movement (NREM) and light slow-wave sleep stage I (SI) with a decrease in wakefulness. The number of episodes and REM onset latencies were found to be decreased after drug treatment. Conclusions: It can therefore be concluded that VGB has a somnolence-inducing effect and that it might mediate its anti-convulsant effect by altering sleep architecture through sleep-regulating areas. [source] Cerebral autoregulation impairment during wakefulness in obstructive sleep apnea syndrome is a potential mechanism increasing stroke riskEUROPEAN JOURNAL OF NEUROLOGY, Issue 3 2009G. Tsivgoulis No abstract is available for this article. [source] Imaging of acetylcholine esterase activity in brainstem nuclei involved in regulation of sleep and wakefulnessEUROPEAN JOURNAL OF NEUROLOGY, Issue 6 2007C. Eggers Positron emission tomography with 11C- N -methyl-4-piperidyl-acetate (MP4A) was applied in eight healthy volunteers and two patients with mild Alzheimer's disease (AD) to assess acetylcholine esterase (AChE) activity in magnetic resonance imaging-identified brainstem nuclei. Uptake ratios in lateral dorsal tegmental and pedunculopontine nuclei relative to cerebellum yielded reproducible values for the AChE activity in controls and reduced values in AD, more marked in a patient with complaints of disturbed sleep. Cortical AChE activity was related to the extent of cognitive impairment which was more severe in the AD patient without sleep disturbance. This preliminary observational study demonstrates the feasibility to image and assess AChE activity in small nuclei of the brain stem. This approach may be helpful to investigate the interaction of various nuclei in the complex network regulating sleep and wakefulness in representative patient groups with documented sleep disturbance. [source] GluR3 subunit regulates sleep, breathing and seizure generationEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2008Hendrik W. Steenland Abstract The functional role of GluR3 AMPA (,-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptor subunits has remained elusive. In vitro studies of genetic knockout mice have not yielded significant alterations in synaptic communication. However, behavioural approaches utilizing knockout mice have shown that the subunit may be involved in exploration and motor coordination, suggesting that in vivo methodologies may be more forthcoming. We tested the hypothesis that GluR3 subunits are involved in the modulation of neural network activity. We used a freely behaving mouse model to examine the effect of GluR3,/, on field potential recordings of electroencephalogram, vital functions (i.e. breathing and heart rate) and muscle tone across natural sleep and wakefulness states. We found that GluR3,/, mice virtually lack electroencephalographic signatures of NREM sleep (n = 9) as demonstrated by reduction in electroencephalogram power in the low-frequency bands (,1, ,2 and ,). In addition, three of nine GluR3,/, mice expressed seizure activity during wakefulness and sleep, suggesting that deletion of the GluR3 gene may predispose to seizure. GluR3 gene knockout also produced state-dependent respiratory modulation, with a selective reduction in breathing rate during behavioural inactivity. These findings show that GluR3 subunits have diverse neurophysiological impact, modulating oscillatory networks for sleep, breathing and seizure generation. Finally, this is the first study to demonstrate the feasibility of direct diaphragm electromyogram recordings in freely behaving mice. [source] Intracortical inhibition and facilitation upon awakening from different sleep stages: a transcranial magnetic stimulation studyEUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2004Luigi De Gennaro Abstract Intracortical facilitation and inhibition, as assessed by the paired-pulse transcranial magnetic stimulation technique with a subthreshold conditioning pulse followed by a suprathreshold test pulse, was studied upon awakening from REM and slow-wave sleep (SWS). Ten normal subjects were studied for four consecutive nights. Intracortical facilitation and inhibition were assessed upon awakening from SWS and REM sleep, and during a presleep baseline. Independently of sleep stage at awakening, intracortical inhibition was found at 1,3-ms interstimulus intervals and facilitation at 7,15-ms interstimulus intervals. Motor thresholds were higher in SWS awakenings, with no differences between REM awakenings and wakefulness, while motor evoked potential amplitude to unconditioned stimuli decreased upon REM awakening as compared to the other conditions. REM sleep awakenings showed a significant increase of intracortical facilitation at 10 and 15 ms, while intracortical inhibition was not affected by sleep stage at awakening. While the dissociation between motor thresholds and motor evoked potential amplitudes could be explained by the different excitability of the corticospinal system during SWS and REM sleep, the heightened cortical facilitation upon awakening from REM sleep points to a cortical motor activation during this stage. [source] Late-life insomnia: A reviewGERIATRICS & GERONTOLOGY INTERNATIONAL, Issue 3 2009Arne Fetveit Aging is associated with substantial changes in sleep patterns, which are almost always negative in nature. Typical findings in the elderly include a reduction in the deeper stages of sleep and a profound increase in the fragmentation of nighttime sleep by periods of wakefulness. The prevalence of specific sleep disorders increases with age, such as a phase advance in the normal circadian sleep cycle, restless legs syndrome, and obstructive sleep apnea, which is increasingly seen among older individuals and is significantly associated with cardio- and cerebrovascular disease as well as cognitive impairment. Elderly patients with sleep disturbances are often considered difficult to treat; yet, they are among the groups with the greatest need of treatment. Management of sleep disturbances begins with recognition and adequate assessment. Hypnotic drugs have clearly been shown to improve subjective and objective sleep measures in short-term situations, but their role in chronic insomnia still remains to be further defined by research evidence. Non-pharmacological treatments, particularly stimulus control and sleep restriction, are effective for conditioned aspects of insomnia and are associated with a stable, long-term improvement in sleep. This review delineates the common causes of disordered sleep in older individuals, and effective diagnostic approaches and treatments for these conditions. [source] Single neuron burst firing in the human hippocampus during sleepHIPPOCAMPUS, Issue 6 2002Richard J. Staba Abstract Although there are numerous non-primate studies of the single neuron correlates of sleep-related hippocampal EEG patterns, very limited hippocampal neuronal data are available for correlation with human sleep. We recorded human hippocampal single neuron activity in subjects implanted with depth electrodes required for medical diagnosis and quantitatively evaluated discharge activity from each neuron during episodes of wakefulness (Aw), combined stage 3 and 4 slow-wave sleep (SWS), and rapid eye movement (REM) sleep. The mean firing rate of the population of single neurons was significantly higher during SWS and Aw compared with REM sleep (p = 0.002; p < 0.0001). In addition, burst firing was significantly greater during SWS compared with Aw (p = 0.001) and REM sleep (p < 0.0001). The synchronized state of SWS and associated high-frequency burst discharge found in human hippocampus may subserve functions similar to those reported in non-primate hippocampus that require burst firing to induce synaptic modifications in hippocampal circuitry and in hippocampal projections to neocortical targets that participate in memory consolidation. Hippocampus 2002;12:724,734. © 2002 Wiley-Liss, Inc. [source] Drug effect on EEG connectivity assessed by linear and nonlinear couplingsHUMAN BRAIN MAPPING, Issue 3 2010Joan F. Alonso Abstract Quantitative analysis of human electroencephalogram (EEG) is a valuable method for evaluating psychopharmacological agents. Although the effects of different drug classes on EEG spectra are already known, interactions between brain locations remain unclear. In this work, cross mutual information function and appropriate surrogate data were applied to assess linear and nonlinear couplings between EEG signals. The main goal was to evaluate the pharmacological effects of alprazolam on brain connectivity during wakefulness in healthy volunteers using a cross-over, placebo-controlled design. Eighty-five pairs of EEG leads were selected for the analysis, and connectivity was evaluated inside anterior, central, and posterior zones of the scalp. Connectivity between these zones and interhemispheric connectivity were also measured. Results showed that alprazolam induced significant changes in EEG connectivity in terms of information transfer in comparison with placebo. Trends were opposite depending on the statistical characteristics: decreases in linear connectivity and increases in nonlinear couplings. These effects were generally spread over the entire scalp. Linear changes were negatively correlated, and nonlinear changes were positively correlated with drug plasma concentrations; the latter showed higher correlation coefficients. The use of both linear and nonlinear approaches revealed the importance of assessing changes in EEG connectivity as this can provide interesting information about psychopharmacological effects. Hum Brain Mapp, 2010. © 2009 Wiley-Liss, Inc. [source] Approaches to measuring the effects of wake-promoting drugs: a focus on cognitive functionHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 5 2009Christopher J. Edgar Abstract Objectives In clinical drug development, wakefulness and wake-promotion may be assessed by a large number of scales and questionnaires. Objective assessment of wakefulness is most commonly made using sleep latency/maintenance of wakefulness tests, polysomnography and/or behavioral measures. The purpose of the present review is to highlight the degree of overlap in the assessment of wakefulness and cognition, with consideration of assessment techniques and the underlying neurobiology of both concepts. Design Reviews of four key areas were conducted: commonly used techniques in the assessment of wakefulness; neurobiology of sleep/wake and cognition; targets of wake promoting and/or cognition enhancing drugs; and ongoing clinical trials investigating wake promoting effects. Results There is clear overlap between the assessment of wakefulness and cognition. There are common techniques which may be used to assess both concepts; aspects of the neurobiology of both concepts may be closely related; and wake-promoting drugs may have nootropic properties (and vice versa). Clinical trials of wake-promoting drugs often, though not routinely, assess aspects of cognition. Conclusions Routine and broad assessment of cognition in the development of wake-promoting drugs may reveal important nootropic effects, which are not secondary to alertness/wakefulness, whilst existing cognitive enhancers may have underexplored or unknown wake promoting properties. Copyright © 2009 John Wiley & Sons, Ltd. [source] Cross-cultural validation of the Leeds sleep evaluation questionnaire (LSEQ) in insomnia patientsHUMAN PSYCHOPHARMACOLOGY: CLINICAL AND EXPERIMENTAL, Issue 8 2003Ricardo Tarrasch Abstract The Leeds sleep evaluation questionnaire (LSEQ) is a standardized self-reporting instrument comprising ten 100,mm visual analogue scales that pertain to the ease of getting to sleep (GTS), quality of sleep (QOS), ease of awakening from sleep (AFS) and alertness and behaviour following wakefulness (BFW). Although the LSEQ has been used in a variety of populations, published psychometric data on insomnia patients are limited. The LSEQ reliability and construct validity was evaluated in 396 French insomnia patients aged 55 years and over, who were treated with placebo (2 weeks) and melatonin (3 weeks). The results supported LSEQ internal consistency, reliability and construct validity with minor differences from those of the original English version. Then the internal consistency of the LSEQ was evaluated in 257 insomnia patients (age 20,80 years) in France and Israel who, following a 1 week placebo baseline, were randomized to placebo or melatonin treatment for 3 weeks. Cronbach's , and Pearson's r correlation coefficients for placebo and drug treatment conditions (p<0.001 for all) supported LSEQ internal consistency in different treatment and age groups and in different languages. It is concluded that the consistency, reliability and validity of the four LSEQ domains allows them to be singled out as independent outcome variables in cross cultural sleep research and clinical practice in adult and elderly patients with insomnia. Copyright © 2003 John Wiley & Sons, Ltd. [source] Effect of epidural dexmedetomidine on intraoperative awareness and post-operative pain after one-lung ventilationACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 6 2010M. ELHAKIM Background: During combined general and regional anaesthesia, it is difficult to use autonomic signs to assess whether wakefulness is suppressed adequately. We compared the effects of a dexmedetomidine,bupivacaine mixture with plain bupivacaine for thoracic epidural anaesthesia on intraoperative awareness and analgesic benefits, when combined with superficial isoflurane anaesthesia (<0.05 maximum alveolar concentration) in patients undergoing thoracic surgery with one-lung ventilation (OLV). Methods: Fifty adult male patients were randomly assigned to receive either epidural dexmedetomidine 1 ,g/kg with bupivacaine 0.5% (group D) or bupivacaine 0.5% alone (group B) after induction of general anaesthesia. Gasometric, haemodynamic and bispectral index values were recorded. Post-operative verbal rating score for pain and observer's assessment of alertness/sedation scale were determined by a blinded observer. Results: Dexmedetomidine reduced the use of supplementary fentanyl during surgery. Patients in group B consumed more analgesics and had higher pain scores after operation than patients of group D. The level of sedation was similar between the two groups in the ICU. Two patients (8%) in group B reported possible intraoperative awareness. There was a limited decrease in PaO2 at OLV in group D compared with group B (P<0.05). Conclusion: In thoracic surgery with OLV, the use of epidural dexmedetomidine decreases the anaesthetic requirements significantly, prevents awareness during anaesthesia and improves intraoperative oxygenation and post-operative analgesia. [source] Inhibition of neural activity depletes orexin from rat hypothalamic slice cultureJOURNAL OF NEUROSCIENCE RESEARCH, Issue 1 2010Shotaro Michinaga Abstract Orexins (hypocretins) are neuropeptides produced by a small population of hypothalamic neurons whose dysregulation may lead to narcolepsy, a neurological disorder characterized by disorganization of sleep and wakefulness. Excessive stimulation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors causes preferential loss of orexin neurons in the hypothalamus, whereas an adequate level of neuronal excitatory activities is generally known to be important for the maintenance of central neurons. By examining the effect of manipulation of neural activity, we found that 24,72 hr application of tetrodotoxin (TTX) caused a substantial decrease in the number of orexin-immunoreactive neurons, but not of melanin-concentrating hormone-immunoreactive neurons, in hypothalamic slice culture. Similar results were obtained when neural activity was arrested by added extracellular Mg2+. Reduction of orexin expression by TTX and Mg2+ was also observed at mRNA level. The decrease of orexin-immunoreactive neurons was attributable to depletion of orexin, because it was reversible after washout of TTX or elevated extracellular Mg2+ and was not associated with induction of cell death. Blockers of voltage-dependent Ca2+ channels as well as of NMDA receptors also induced a significant and selective decrease of orexin-immunoreactive neurons. Moreover, TTX-induced decrease of orexin immunoreactivity was largely abrogated by concurrent application of a moderate concentration of NMDA. These results suggest that Ca2+ entry associated with nontoxic levels of spontaneous activity of glutamatergic inputs plays an important role in the maintenance of orexin neurons in a tissue culture model. © 2009 Wiley-Liss, Inc. [source] Specific increase in non-functional masseter bursts in subjects aware of tooth-clenching during wakefulnessJOURNAL OF ORAL REHABILITATION, Issue 2 2009S. KATASE-AKIYAMA Summary, Previous studies have reported that subjective awareness of a tooth-clenching habit is associated with increased jaw motor activity (Rao SM, Glaros AG, J Dent Res. 1979;58:1872). The aim of this study was to test the hypothesis that subjects with clenching awareness exhibit different motor expressions specific to non-functional oromotor activity under laboratory conditions without psychological or sensory effects. Polygraphic and audio,video recordings were made for a 30-min period of silent reading by 33 subjects without oro-facial pain. Oro-facial behaviours (e.g. swallowing, lip movements) were scored according to the polygraphic and audio,video records and masseter bursts were quantitatively analysed. Subjective psychological/sensory measures were also recorded before and/or after the polygraphic recording using a visual analogue scale. The subjects were classified into two groups one with 15 subjects who were aware of having a tooth-clenching habit and another with 18 who were not aware of any such habit. There were no differences between the groups with respect to the number of functional oro-facial behaviours or subjective psychological/sensory measures. Masseter bursts unrelated to functional oro-facial behaviours occurred more frequently in subjects with awareness [median (range) = 23 (2,187) bursts] than in those without [9·0 (0,36); P = 0·01], while neither burst activity [12·3 (1·8,34·5) % of maximum voluntary clenching and 10·1 (6·5,25·1) %, respectively] nor duration [1·17 (0·2,2·2) s and 1·28 (0·3,4·1) s, respectively] differed between the groups. The occurrence of functional oro-facial behaviours or other body behaviours (e.g. limb and body movements) did not differ between the two groups. These findings suggest that the increased masseter activity in subjects with tooth-clenching awareness is characterized by a specific increase in non-functional masseter bursts. [source] Quantitative EEG in Patients With Alcohol-Related SeizuresALCOHOLISM, Issue 10 2010Trond Sand Background:, To investigate whether quantitative electroencephalography (QEEG) recorded within a few days after a generalized seizure can improve the discrimination between alcohol-related seizures (ARSs), seizures in epilepsy and other seizures. In addition, we wanted to evaluate the influence of various external factors on QEEG, e.g., drug use, time from seizure occurrence, and alcohol intake. Methods:, An ARS was defined by (i) scores ,8 in the Alcohol Use Disorders Identification Test (AUDIT) and (ii) no history of epilepsy. Twenty-two ARS patients, 21 epileptic patients with seizures (ES), 30 AUDIT-negative patients with seizures (OS), and 37 well-controlled epileptic outpatients (EPO) were included. EEG from 79 sciatica patients (SC) served as an additional control group. EEG was recorded in relaxed wakefulness with eyes closed. Spectral analysis of ongoing resting EEG activity was performed. For the main analysis, spectral band amplitudes were averaged across 14 electrodes. Results:, Major quantitative EEG abnormalities were mainly seen in the ES group. AUDIT score correlated negatively with QEEG band amplitudes in patients with seizures unrelated to alcohol, but not in the ARS group. Recent alcohol intake correlated negatively with delta and theta amplitude. We could not confirm that beta activity is increased in ARS subjects. Conclusions:, A QEEG with slightly reduced alpha amplitude supports a clinical diagnosis of ARS. An abnormally slow QEEG profile and asymmetry in the temporal regions indicates ES. QEEG predicted the clinical diagnosis better than standard EEG. [source] Role of Wake-Promoting Basal Forebrain and Adenosinergic Mechanisms in Sleep-Promoting Effects of EthanolALCOHOLISM, Issue 6 2010Mahesh M. Thakkar Background:, Ethanol intake has significant impact on sleep. However, the cellular substrates responsible for sleep promotion following ethanol intake are unknown. The purine nucleoside, adenosine, is responsible for mediating many neuronal and behavioral responses to ethanol. Studies performed in cell cultures suggest that ethanol inhibits equilibrative nucleoside transporter 1 to block the reuptake of adenosine resulting in increased extracellular adenosine. Adenosine also has a pivotal role in sleep regulation. Adenosine acts via A1 receptor to inhibit the wake-promoting neurons of the basal forebrain (BF) resulting in the promotion of sleep. Is ethanol-induced sleep associated with the inhibition of the BF wake-promoting neurons? Do adenosinergic mechanisms in the BF have a role in sleep-promoting effects of ethanol? Methods:, To address these questions, we performed 3 experiments in Sprague,Dawley rats. First, we verified the effect of ethanol on sleep promotion. Second, we evaluated the effect of ethanol on c-Fos expression (a marker of neuronal activation) in the BF wake-promoting neurons and third we monitored the effects of A1 receptor blockade in the BF on ethanol-induced sleep. Results:, Significant increase in non-rapid eye movement (NREM) sleep with a concomitant decrease in wakefulness was observed during the first 12 hours postethanol. REM sleep remained unaffected. Ethanol administration caused a significant decrease in the number of BF wake-promoting neurons with c-Fos immunoreactivity. Bilateral microinjections of a selective A1R receptor antagonist 8-cyclopentyl-1, 3-dipropylxanthine into the BF significantly attenuated sleep-promoting effects of ethanol. Conclusion:, These results suggest that the inhibition of BF wake-promoting neurons by adenosinergic mechanism may be responsible for the sleep promoting effects of ethanol. We believe our study is the first to investigate the cellular mechanisms responsible for the somnogenic effects of ethanol. [source] Performance monitoring during sleep inertia after a 1-h daytime napJOURNAL OF SLEEP RESEARCH, Issue 3 2010SHOICHI ASAOKA Summary Performance monitoring is an essential function involved in the correction of errors. Deterioration of this function may result in serious accidents. This function is reflected in two event-related potential (ERP) components that occur after erroneous responses, specifically the error-related negativity/error negativity (ERN/Ne) and error positivity (Pe). The ERN/Ne is thought to be associated with error detection, while the Pe is thought to reflect motivational significance or recognition of errors. Using these ERP components, some studies have shown that sleepiness resulting from extended wakefulness may cause a decline in error-monitoring function. However, the effects of sleep inertia have not yet been explored. In this study, we examined the effects of sleep inertia immediately after a 1-h daytime nap on error-monitoring function as expressed through the ERN/Ne and Pe. Nine healthy young adults participated in two different experimental conditions (nap and rest). Participants performed the arrow-orientation task before and immediately after a 1-h nap or rest period. Immediately after the nap, participants reported an increased effort to perform the task and tended to estimate their performance as better, despite no objective difference in actual performance between the two conditions. ERN/Ne amplitude showed no difference between the conditions; however, the amplitude of the Pe was reduced following the nap. These results suggest that individuals can detect their own error responses, but the motivational significance ascribed to these errors might be diminished during the sleep inertia experienced after a 1-h nap. This decline might lead to overestimation of their performance. 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