Onabotulinumtoxin A (BoNTA) has been reported to be effective in the therapy for migraines. Acupuncture has been used worldwide for the treatment of migraine attacks. Injection of a small amount of drug at acupuncture points is an innovation as compared to traditional acupuncture. The purpose of this study was to evaluate and compare the effectiveness of fixed (muscle)-site and acupoint-site injections of BoNTA for migraine therapy in a randomized, double-blinded, placebo-controlled clinical trial extending over four months. Subjects with both episodic and chronic migraines respectively received a placebo (n = 19) or BoNTA (2.5 U each site, 25 U per subject) injection at fixed-sites (n = 41) including occipitofrontalis, corrugator supercilii, temporalis and trapeziue, or at acupoint-sites (n = 42) including Yintang (EX-HN3), Taiyang (EX-HN5), Baihui (GV20), Shuaigu (GB8), Fengchi (GB20) and Tianzhu (BL10). The variations between baseline and BoNTA post-injection for four months were calculated monthly as outcome measures. BoNTA injections at fixed-sites and acupoint-sites significantly reduced the migraine attack frequency, intensity, duration and associated symptoms for four months compared with placebo (p < 0.01). The efficacy of BoNTA for migraines in the acupoint-site group (93% improvement) was more significant than that in the fixed-site group (85% improvement) (p < 0.01). BoNTA administration for migraines is effective, and at acupoint-sites shows more efficacy than at fixed-sites. Further blinded studies are necessary to establish the efficacy of a low dose toxin (25 U) introduced with this methodology in chronic and episodic migraines.

Our previous studies have demonstrated that neuropeptide S (NPS), via selective activation of the neurons bearing NPS receptor (NPSR) in the olfactory cortex, facilitates olfactory function. High level expression of NPSR mRNA in the subiculum complex of hippocampal formation suggests that NPS-NPSR system might be involved in the regulation of olfactory spatial memory. The present study was undertaken to investigate effects of NPS on the scopolamine- or MK801-induced impairment of olfactory spatial memory using computer-assisted 4-hole-board spatial memory test, and by monitoring Fos expression in the subiculum complex in mice. In addition, dual-immunofluorescence microscopy was employed to identify NPS-induced Fos-immunereactive (-ir) neurons that also bear NPSR. Intracerebroventricular administration of NPS (0.5 nmol) significantly increased the number of visits to switched odorants in recall trial in mice suffering from odor-discriminating inability induced by scopolamine, a selective muscarinic cholinergic receptor antagonist, or MK801, a N-methyl-D-aspartate receptor antagonist, after training trials. The improvement of olfactory spatial memory by NPS was abolished by the NPSR antagonist [D-Val(5)]NPS (40 nmol). Ex vivo c-Fos and NPSR immunohistochemistry revealed that, as compared with vehicle-treated mice, NPS markedly enhanced Fos expression in the subiculum complex encompassing the subiculum (S), presubiculum (PrS) and parasubiculum (PaS). The percentages of Fos-ir neurons that also express NPSR were 91.3, 86.5 and 90.0 % in the S, PrS and PaS, respectively. The present findings demonstrate that NPS, via selective activation of the neurons bearing NPSR in the subiculum complex, ameliorates olfactory spatial memory impairment induced by scopolamine and MK801 in mice.

Disturbed sleep is a common subjective complaint among individuals with anxiety disorders. Sleep deprivation increases general and specific anxiety symptoms among healthy individuals. The amygdala is critical for regulating anxiety and also involved in mediating the effects of emotions on sleep. Neuropeptide S (NPS) and NPS receptors (NPSR) are reported as a novel endogenous arousal and anxiolytic system, but it is unclear yet whether this system is involved in anxiety-like behavior and sleep caused by sleep deprivation, and how it plays anxiolytic effect underlying the comorbid condition. In the present study, we demonstrate that paradoxical sleep deprivation (PSD) induced by modified multiple platform method (MMPM) for 24 h caused anxiety-like behavior, a prolonged sleep latency and subsequent paradoxical sleep (PS) rebound accompanied by an increase in electroencephalogram (EEG) theta (4.5–8.5 Hz) activities across light and dark phase in rats. The increase of PS after PSD was due to an increase of episode number during light phase and both episode number and duration during dark phase. Central action of NPS (1 nmol) attenuated PSD-induced anxiety-like behavior, and altered PSD-induced sleep-wake disturbances through increasing wakefulness, and suppressing PS and EEG theta activities. The reduction in PS time following NPS administration during light phase was because of a decreased episode number. Furthermore, sleep amount in 24 h in PSD rats given NPS was lesser than that given saline. PSD significantly enhanced NPSR mRNA expression level in the amygdala. NPS remarkably increased the number of Fos-ir neurons in the basolateral amygdala (BLA), the central amygdala (CeA) and medial amygdala (MeA). The majority of Fos-ir neurons induced by NPS also expressed NPSR. These results suggest that NPSR upregulation in the amygdala is presumably related to the PSD-induced anxiety-like behavior and sleep disturbances, and that NPS counteracts PSD-induced anxiety-like behavior and sleep disturbances possibly through activating the neurons bearing NPSR in the amygdala. In addition, the little sleep increase in PSD rats treated with NPS suggests that NPS can function as an anxiolytic without causing a subsequent sleep rebound.

A prominent hypothesis, the "flip-flop switch" model, predicts that histaminergic (HAergic) neurons in the tuberomammillary nucleus (TMN), an important component of the ascending arousal system, are inactivated by GABA mainly from the ventrolateral preoptic nucleus to allow the appearance and maintenance of sleep. However, which sleep state and the band of EEG activity induced by GABAergic inactivation of the TMN are unclear. In this study, alterations of sleep-wake states and cortical EEG power spectral density were investigated following muscimol, a GABA-receptor agonist, microinjected bilaterally into the TMN in freely moving rats and HA pretreated rats, respectively. Muscimol dosed at 0.25 and 0.50 μg/side into the TMN during dark period dose-dependently increased slow wave sleep (SWS) accompanied by an increase in cortical EEG delta (0.5-4 Hz) and spindle (8.2-12 Hz) activities. In the meanwhile, wakefulness and EEG beta (12.2-30 Hz) activity were decreased significantly, while paradoxical sleep and EEG theta (4.2-8 Hz) activity were not changed. The increase of muscimol-induced SWS was because of prolonged SWS bout duration and not to an increased bout number. Muscimol (0.50 μg/side) administration 2 h after HA (0.125 μg/side) treatment during light period reversed the HA-induced wakefulness and EEG beta 2 (20.2-30 Hz) activity into SWS and EEG delta activity. These results demonstrate that the GABAergic inactivation of the TMN in freely moving rats and HA-treated rats promotes SWS and slow activity of cortical EEG, suggesting that the potential function of the GABA receptor in the TMN is to dampen vigilant arousal.

The ontogenetic sleep hypothesis suggested that rapid eye movement (REM) sleep is ontogenetically primitive. Namely, REM sleep plays an imperative role in the maturation of the central nervous system. In coincidence with a rapidly developing brain during the early period of life, a remarkably large amount of REM sleep has been identified in numerous behavioral and polysomnographic studies across species. The abundant REM sleep appears to serve to optimize a cerebral state suitable for homeostasis and inherent neuronal activities favorable to brain maturation, ranging from neuronal differentiation, migration, and myelination to synaptic formation and elimination. Progressively more studies in Mammalia have provided the underlying mechanisms involved in some REM sleep-related disorders (e.g., narcolepsy, autism, attention deficit hyperactivity disorder (ADHD)). We summarize the remarkable alterations of polysomnographic, behavioral, and physiological characteristics in humans and Mammalia. Through a comprehensive review, we offer a hybrid of animal and human findings, demonstrating that early-life REM sleep disturbances constitute a common feature of many neurodevelopmental disorders. Our review may assist and promote investigations of the underlying mechanisms, functions, and neurodevelopmental diseases involved in REM sleep during early life.