Sleep Problems in Preschoolers With Autism Spectrum Disorder Are Associated With Sensory Sensitivities and Thalamocortical Overconnectivity.

BACKGROUND: Projections between the thalamus and sensory cortices are established early in development and play an important role in regulating sleep as well as in relaying sensory information to the cortex. Atypical thalamocortical functional connectivity frequently observed in children with autism spectrum disorder (ASD) might therefore be linked to sensory and sleep problems common in ASD. METHODS: Here, we investigated the relationship between auditory-thalamic functional connectivity measured during natural sleep functional magnetic resonance imaging, sleep problems, and sound sensitivities in 70 toddlers and preschoolers (1.5-5 years old) with ASD compared with a matched group of 46 typically developing children. RESULTS: In children with ASD, sleep problems and sensory sensitivities were positively correlated, and increased sleep latency was associated with overconnectivity between the thalamus and auditory cortex in a subsample with high-quality magnetic resonance imaging data (n = 29). In addition, auditory cortex blood oxygen level-dependent signal amplitude was elevated in children with ASD, potentially reflecting reduced sensory gating or a lack of auditory habituation during natural sleep. CONCLUSIONS: These findings indicate that atypical thalamocortical functional connectivity can be detected early in development and may play a crucial role in sleep problems and sensory sensitivities in ASD.

Network Pharmacology-Based and Molecular Docking-Based Analysis of Suanzaoren Decoction for the Treatment of Parkinson's Disease with Sleep Disorder.

This study is aimed at exploring the possible mechanism of action of the Suanzaoren decoction (SZRD) in the treatment of Parkinson's disease with sleep disorder (PDSD) based on network pharmacology and molecular docking. Traditional Chinese Medicine Systems Pharmacology (TCMSP) was used to screen the bioactive components and targets of SZRD, and their targets were standardized using the UniProt platform. The disease targets of "Parkinson's disease (PD)" and "Sleep disorder (SD)" were collected by OMIM, GeneCards, and DisGeNET databases. Thereafter, the protein-protein interaction (PPI) network was constructed using the STRING platform and visualized by Cytoscape (3.7.2) software. Then, the DAVID platform was used to analyze the Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. Cytoscape (3.7.2) software was also used to construct the network of the "herb-component-target-pathway." The core active ingredients and core action targets of the drug were verified by molecular docking using AutoDock software. A total of 135 Chinese herbal components and 41 corresponding targets were predicted for the treatment of PDSD using SZRD. Fifteen important signaling pathways were screened, such as the cancer pathway, TNF signaling pathway, PI3K-AKT signaling pathway, HIF-1 signaling pathway, and Toll-like receptor signaling pathway. The results of molecular docking showed that the main active compounds could bind to the representative targets and exhibit good affinity. This study revealed that SZRD has the characteristics and advantages of "multicomponent, multitarget, and multipathway" in the treatment of PDSD; among these, the combination of the main active components of quercetin and kaempferol with the key targets of AKT1, IL6, MAPK1, TP53, and VEGFA may be one of the important mechanisms. This study provides a theoretical basis for further study of the material basis and molecular mechanism of SZRD in the treatment of PDSD.

Hippocampal and Reticulo-Thalamic Parvalbumin Interneurons and Synaptic Re-Organization during Sleep Disorders in the Rat Models of Parkinson's Disease Neuropathology.

We investigated the alterations of hippocampal and reticulo-thalamic (RT) GABAergic parvalbumin (PV) interneurons and their synaptic re-organizations underlying the prodromal local sleep disorders in the distinct rat models of Parkinson's disease (PD). We demonstrated for the first time that REM sleep is a predisposing state for the high-voltage sleep spindles (HVS) induction in all experimental models of PD, particularly during hippocampal REM sleep in the hemiparkinsonian models. There were the opposite underlying alterations of the hippocampal and RT GABAergic PV+ interneurons along with the distinct MAP2 and PSD-95 expressions. Whereas the PD cholinopathy enhanced the number of PV+ interneurons and suppressed the MAP2/PSD-95 expression, the hemiparkinsonism with PD cholinopathy reduced the number of PV+ interneurons and enhanced the MAP2/PSD-95 expression in the hippocampus. Whereas the PD cholinopathy did not alter PV+ interneurons but partially enhanced MAP2 and suppressed PSD-95 expression remotely in the RT, the hemiparkinsonism with PD cholinopathy reduced the PV+ interneurons, enhanced MAP2, and did not change PSD-95 expression remotely in the RT. Our study demonstrates for the first time an important regulatory role of the hippocampal and RT GABAergic PV+ interneurons and the synaptic protein dynamic alterations in the distinct rat models of PD neuropathology.

Migraine and Sleep-An Unexplained Association?

Migraine and sleep disorders are common chronic diseases in the general population, with significant negative social and economic impacts. The association between both of these phenomena has been observed by clinicians for years and is confirmed by many epidemiological studies. Despite this, the nature of this relationship is still not fully understood. In recent years, there has been rapid progress in understanding the common anatomical structures of and pathogenetic mechanism between sleep and migraine. Based on a literature review, the authors present the current view on this topic as well as ongoing research in this field, with reference to the key points of the biochemical and neurophysiological processes responsible for both these disorders. In the future, a better understanding of these mechanisms will significantly expand the range of treatment options.

5-Hydroxytryptophan (5-HTP): Natural Occurrence, Analysis, Biosynthesis, Biotechnology, Physiology and Toxicology.

L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.

A longitudinal analysis of phenotypic and symptom characteristics associated with inter-individual variability in employment interference in patients with breast cancer.

PURPOSE: A breast cancer diagnosis has a substantial economic impact. Study aims were to evaluate for inter-individual differences in cancer's level of interference with employment and identify phenotypic and symptom characteristics associated with higher levels of interference. METHODS: Patients (n = 387) were enrolled prior to breast cancer surgery and followed for 12 months. Interference with employment was measured using a 0 (no problem) to 10 (severe problem) numeric rating scale. Hierarchical linear modeling (HLM) was used to evaluate for inter-individual differences in trajectories of employment interference and characteristics associated with employment interference at enrollment and over 12 months. RESULTS: Patients' mean age was 55.0 (±11.7) years and the majority underwent breast conservation surgery (80.6%). Mean employment interference score was 3.2 (±3.7). Unconditional model for employment interference demonstrated a decreasing linear trend (-.076/month). Younger age, lower income, higher pain intensity, and having an axillary lymph node dissection were associated with higher pre-surgical interference scores. Having a sentinel lymph node biopsy was associated with ongoing employment interference scores. Higher sleep disturbance scores were associated with both initial and ongoing employment interference scores. Receipt of chemotherapy, use of complementary or alternative therapies, and re-excision or mastectomy following surgery were significant time varying covariates. CONCLUSION: This study is the first to use HLM to describe inter-individual differences in the trajectories of cancer's interference with employment and associated factors prior to and for 12 months following breast cancer surgery. Patients with the identified risk factors warrant ongoing assessments of employment interference and appropriate referrals.

Medical marijuana use for pediatric oncology patients: single institution experience.

Medical marijuana (MM) is widespread in many medical fields, including oncology, with limited use in pediatric oncology where research is scarce and often shows conflicting results. This research focuses on alleviating side effects of anticancer treatment as an integral part of supportive and palliative care of children with cancer. We report our experience with MM treatment in 50 children, adolescents, and young adults with different types of cancer during 2010-2017. The main indications for prescriptions were nausea and vomiting, decreased mood, disturbed sleep, and pain. The medication was supplied to 30 patients via oil drops (60%) and 11 via smoking (22%), followed by vaporization, capsules, or combinations of various routes. Positive effects were reported by verbal children and parents in 80% of cases. MM was generally well tolerated with few patients reporting toxicity, with the most common adverse reactions being burning in the throat and anxiety attacks in subjects who chose to smoke the product. We conclude that MM may serve as a potentially useful complementary therapy to conventional supportive treatment of children suffering from cancer at the end of life. Further research is needed on the safety and efficacy and the consequences of prolonged use in pediatric populations.

ADAM22 and ADAM23 modulate the targeting of the Kv1 channel-associated protein LGI1 to the axon initial segment.

The distribution of the voltage-gated Kv1 K+ channels at the axon initial segment (AIS) influences neuronal intrinsic excitability. The Kv1.1 and Kv1.2 (also known as KCNA1 and KCNA2, respectively) subunits are associated with cell adhesion molecules (CAMs), including Caspr2 (also known as CNTNAP2) and LGI1, which are implicated in autoimmune and genetic neurological diseases with seizures. In particular, mutations in the LGI1 gene cause autosomal dominant lateral temporal lobe epilepsy (ADLTE). Here, by using rat hippocampal neurons in culture, we showed that LGI1 is recruited to the AIS where it colocalizes with ADAM22 and Kv1 channels. Strikingly, the missense mutations S473L and R474Q of LGI1 identified in ADLTE prevent its association with ADAM22 and enrichment at the AIS. Moreover, we observed that ADAM22 and ADAM23 modulate the trafficking of LGI1, and promote its ER export and expression at the overall neuronal cell surface. Live-cell imaging indicated that LGI1 is co-transported in axonal vesicles with ADAM22 and ADAM23. Finally, we showed that ADAM22 and ADAM23 also associate with Caspr2 and TAG-1 (also known as CNTN2) to be selectively targeted to different axonal sub-regions. Hence, the combinatorial expression of Kv1-associated CAMs may be critical to tune intrinsic excitability in physiological and epileptogenic contexts.

Frontal Cortex Myo-Inositol Is Associated with Sleep and Depression in Adolescents: A Proton Magnetic Resonance Spectroscopy Study.

AIM: This study used proton magnetic resonance spectroscopy (1H MRS) to evaluate the neurochemistry of the frontal cortex in adolescents with symptoms of sleep and depression. METHODS: Nineteen non-medicated adolescent boys (mean age 16.0 years; 9 clinical cases with depression/sleep symptoms and 10 healthy controls) underwent 1H MRS at 3 T. MR spectra were acquired from the anterior cingulate cortex (ACC), the dorsolateral prefrontal cortex, and frontal white matter. Concentrations of N-acetyl aspartate, total creatine, choline-containing compounds, total glutamine plus glutamate, and myo-inositol (mI) were compared in the 2 subgroups, and correlated with sleep and clinical measures in the total sample. Sleep was assessed with self-report questionnaires and ambulatory polysomnography recordings. RESULTS: Concentrations of mI were lower in both frontal cortical regions among the depressed adolescents than in controls. No statistically significant differences in other metabolite concentrations were observed between the subgroups. Frontal cortex mI concentrations correlated negatively with depression severity, subjective daytime sleepiness, insomnia symptoms, and the level of anxiety, and correlated positively with total sleep time and overall psychosocial functioning. The correlations between mI in the ACC and total sleep time as well as daytime sleepiness remained statistically significant when depression severity was controlled in the analyses. CONCLUSION: Lower frontal cortex mI may indicate a disturbed second messenger system. Frontal cortical mI may thus be linked to the pathophysiology of depression and concomitant sleep symptoms among maturing adolescents. Short sleep and daytime sleepiness may be associated with frontal cortex mI independently from depression.

Thalamic abnormalities in children with continuous spike-wave during slow-wave sleep: An F-18-fluorodeoxyglucose positron emission tomography perspective.

OBJECTIVE: Thalamic injury has been implicated in the development of continuous spike-wave during slow-wave sleep (CSWS) in children with epilepsy. We studied thalamic abnormalities in children with CSWS using F-18-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging. METHODS: Twenty-three patients (12 male; mean age 9 years) with CSWS and normal thalami on brain magnetic resonance imaging (MRI) underwent FDG-PET. Thalamic glucose metabolism, represented by standardized uptake value normalized to whole brain (nSUV, RT for right thalamus and LT for left thalamus), and its asymmetry--absolute asymmetry index (AAI): ¦(RT-LT)¦*100/[(RT+LT)/2]--was calculated. These values were compared with those from 10 normal healthy controls (five female; mean age 11.1 years). RESULTS: Thalamic glucose metabolism was abnormal in 18 patients (78.3%). Thalamic nSUV was decreased (n = 6) or increased (n = 1) bilaterally in seven children without any asymmetry. Abnormal thalamic symmetry [AAI = 3.7-31.5% (0.8-3.3% in controls)] was seen in 11 children. Of these, six children had a unilateral thalamic metabolic abnormality (increased metabolism, n = 3 and decreased metabolism, n = 3), whereas 5 of 14 children had abnormal asymmetry index with bilaterally normal (n = 4) or increased (n = 1) thalamic metabolism. No clear association of thalamic metabolic abnormalities was seen with the stage of evolution of CSWS (prodromal, acute, or residual) or with the cortical FDG abnormalities. SIGNIFICANCE: Functional thalamic abnormalities, both unilateral and bilateral, are frequently seen in patients with CSWS. FDG-PET is a sensitive and quantifiable modality to detect these changes.

Neuropathology of sleep disorders: a review.

Sleep disorders are important manifestations of neurodegenerativediseases and sometimes are clinically evident well before the onset of other neurological manifestations. This review addresses theneuroanatomical basis and the mechanisms of sleep regulation in humans in relation to the neuropathology of entities associated with sleep disturbances in selected diseases, including Alzheimer disease, progressive supranuclear palsy, Lewy body disorders, multiple-system atrophy, and fatal familial insomnia. This includes abnormalities of circadian rhythm, insomnia, narcolepsy, rapid eye movements sleep behavior disorders, and excessive daytime sleepiness.

Effects of three Kampo formulae: Tokishakuyakusan (TJ-23), Kamishoyosan (TJ-24), and Keishibukuryogan (TJ-25) on Japanese peri- and postmenopausal women with sleep disturbances.

PURPOSE: To assess the effects of Kampo, a traditional Japanese adaptation of Chinese herbal medicine, on peri- and postmenopausal women with sleep disturbances. METHODS: Among the records of 1,523 peri- and postmenopausal women who are enrolled in the Health and Nutrition Education Program at the Tokyo Medical and Dental University, Menopause Clinic, during 1995-2009, about 151 women suffering from moderate to severe sleep disturbances were retrospectively analyzed. These women had received only health/nutrition education (control; n = 77) or received treatment with one of the three major Kampo formulae: Tokishakuyakusan (TJ-23; n = 42), Kamishoyosan (TJ-24; n = 16), or Keishibukuryogan (TJ-25; n = 16) according to their "Sho" or symptom patterns. Subjective sleep parameters, menopausal symptoms, health-related quality of life, body composition, blood pressure, and pulse rate were compared before and after the intervention. RESULTS: The TJ-25 group had significantly higher body weight, body mass index, body fat, lean body mass, resting energy expenditure, and relatively high blood pressure and heart rate at baseline than the other groups. After ~5-month follow up, TJ-23 reduced the sleep disruption frequency, increased lean body mass, and decreased diastolic pressure. TJ-24 alleviated subjective sleep disturbances; improved difficulties in initiating sleep, disrupted sleep, and non-restorative sleep; and relieved headache/dizziness. TJ-25 improved subjective sleep disturbances, alleviated perspiration, and reduced systolic/diastolic pressure and heart rate. CONCLUSIONS: Each of the Kampo formulae effectively alleviated sleep disturbances in Japanese peri- and postmenopausal women. Middle-aged female patients having sleeping disorder could successfully be treated using Kampo medicines.

Characterization of the spontaneous and gripping-induced immobility episodes on taiep rats.

In 1989, we described a new autosomic-recessive myelin-mutant rat that develops a progressive motor syndrome characterized by tremor, ataxia, immobility episodes (IEs), epilepsy, and paralysis. taiep is the acronym of these symptoms. The rat developed a hypomyelination, followed by demyelination. At an age of 7-8 months, taiep rats developed IEs, characterized electroencephalographically by REM sleep-like cortical activity. In our study, we analyzed the ontogeny of gripping-induced IEs between 5 and 18 months, their dependence to light-dark changes, sexual dimorphism, and susceptibility to mild stress. Our results showed that IEs start at an age of 6.5 months, with a peak frequency between 8.5 and 9.5 months. IEs have two peaks, one in the morning (0800-1000 h) and a second peak in the middle of the night (2300-0100 h). Spontaneous IEs showed an even distribution with a mean of 3 IEs every 2 h. IEs are sexually dimorphic being more common in male rats. The IEs can be induced by gripping the rat by the tail or the thorax, but most of the IEs were produced by gripping the tail. Mild stress produced by i.p. injection of physiological saline significantly decreased IEs. These results suggested that IEs are dependent on several biological variables, which are caused by hypomyelination, followed by demyelization, which causes alterations in the brainstem and hypothalamic mechanisms responsible for the sleep-wake cycle regulation, producing emergence of REM sleep-like behavior during awake periods.

A double-blind, placebo-controlled investigation of the effects of two doses of a valerian preparation on the sleep, cognitive and psychomotor function of sleep-disturbed older adults.

One of the most popular herbal remedies for the alleviation of sleep problems is valerian. However, research into valerian is sparse, and studies differ greatly with respect to design, measures, and preparations used. This clinical study used standardized sleep EEG and psychometric tests to evaluate the clinical efficacy of a valerian preparation (Li 156). A placebo-controlled three way crossover clinical trial was completed using 16 (5 male and 11 female) sleep-disturbed participants (aged 50 to 64 years, mean age 55.9, SD 4.68). Participants slept overnight in a sleep laboratory, following a 21:00 hours dose of valerian 300 mg, valerian 600 mg, or placebo (double-blind). EEG sleep was recorded for each participant at 23:00 hours until 07:00 hours, when a psychometric evaluation was performed the morning after dose. Test periods were separated by six days washout period. Results showed no significant effect between valerian 300 mg, valerian 600 mg or placebo on any EEG parameter or psychometric measure. This suggests valerian at these doses is ineffective as an acute dose for sleep problems. However, valerian is widely used, and is traditionally sedative. Therefore, more research is required into therapeutic dose, types of valerian preparation, and the optimum period of use for therapeutic effect.

Stereological analysis of the hypothalamic hypocretin/orexin neurons in an animal model of depression.

Affective disorders often occur in combination with disrupted sleep-wake cycles and abnormal fluctuations in hypothalamic neurotransmitters. Hypocretin (orexin) is a hypothalamic neuropeptide linked to narcolepsy, a sleep-related disorder characterized by profound disturbances in the normal sleeping pattern and variable degrees of depression. Wistar-Kyoto (WKY) rats exhibit depressive characteristics and patterns of sleep disruption similar to that observed in depressed human patients. In this study we sought to determine whether the total number or the size of hypothalamic hypocretin neurons in WKY rats differ from their control, Wistar (WIS) rats. Immunocytochemical and stereological methods were applied to quantify hypocretin-1 containing neurons in the hypothalamus. The study revealed 18% fewer hypocretin-1 positive neurons as well as a 15% decrease in average neuronal soma size of hypocretin-1 producing cells in the hypothalamus of WKY rats compared to WIS rats. These findings support the view that reduced number or size of hypothalamic hypocretinergic neurons may underlie the disrupted sleep pattern associated with depressive characteristics in WKY rats.

The neuroanatomy of sleep. Considerations on the role of the thalamus in sleep and a proposal for a caudorostral organization

This review synthetizes the most important historical contributions in sleep anatomy and the pioneer discoveries in sleep medicine in the light of our clinical observations in Fatal Familial Insomnia FFI, a genetic prion disease. Together with Morvan's chorea and Delirium Tremens, FFI is characterized by inability to sleep with severe loss of sleep spindles and delta sleep, with preserved presleep behaviour and abnormal REM sleep, associated with motor and autonomic overactivation. We labelled this pattern as Agrypnia Excitata AE. AE is due to dysfunction in thalamolimbic circuits, which emphasizes the key role of the thalamus in sleep physiology and indicates that the anatomo-functional substrate of stage 1 non-REM sleep differs from that generating slow-wave-sleep SWS, spindle and delta activity. Accordingly, the sleep-wake cycle in man should be conceptualized as consisting of 5 different behavioural and electrophysiological distinct states: active wakefulness, quiet wakefulness, drowsiness or stage 1 non-REM, SWS which incorporates spindle and delta sleep and REM sleep. An intricate neuronal network extending from the caudal brainstem to the forebrain controls these different wake and sleep behaviours with several, at least three distinct generators (AU)

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