Genetics and epigenetics of rare hypersomnia.

Herein we focus on connections between genetics and some central disorders of hypersomnolence - narcolepsy types 1 and 2 (NT1, NT2), idiopathic hypersomnia (IH), and Kleine-Levin syndrome (KLS) - for a better understanding of their etiopathogenetic mechanisms and a better diagnostic and therapeutic definition. Gene pleiotropism influences neurological and sleep disorders such as hypersomnia; therefore, genetics allows us to uncover common pathways to different pathologies, with potential new therapeutic perspectives. An important body of evidence has accumulated on NT1 and IH, allowing a better understanding of etiopathogenesis, disease biomarkers, and possible new therapeutic approaches. Further studies are needed in the field of epigenetics, which has a potential role in the modulation of biological specific hypersomnia pathways.

The dynamics of cyclic-periodic phenomena during non-rapid and rapid eye movement sleep.

Sleep is a complex physiological state characterized by distinct stages, each exhibiting unique electroencephalographic patterns and physiological phenomena. Sleep research has unveiled the presence of intricate cyclic-periodic phenomena during both non-rapid eye movement and rapid eye movement sleep stages. These phenomena encompass a spectrum of rhythmic oscillations and periodic events, including cyclic alternating pattern, periodic leg movements during sleep, respiratory-related events such as apneas, and heart rate variability. This narrative review synthesizes empirical findings and theoretical frameworks to elucidate the dynamics, interplay and implications of cyclic-periodic phenomena within the context of sleep physiology. Furthermore, it invokes the clinical relevance of these phenomena in the diagnosis and management of sleep disorders.

European expert guidance on management of sleep onset insomnia and melatonin use in typically developing children.

Sleeping problems are prevalent among children and adolescents, often leading to frequent consultations with pediatricians. While cognitive-behavioral therapy has shown effectiveness, especially in the short term, there is a lack of globally endorsed guidelines for the use of pharmaceuticals or over-the-counter remedies in managing sleep onset insomnia. An expert panel of pediatric sleep specialists and chronobiologists met in October 2023 to develop practical recommendations for pediatricians on the management of sleep onset insomnia in typically developing children. When sleep onset insomnia is present in otherwise healthy children, the management should follow a stepwise approach. Practical sleep hygiene indications and adaptive bedtime routine, followed by behavioral therapies, must be the first step. When these measures are not effective, low-dose melatonin, administered 30-60 min before bedtime, might be helpful in children over 2 years old. Melatonin use should be monitored by pediatricians to evaluate the efficacy as well as the presence of adverse effects.    Conclusion: Low-dose melatonin is a useful strategy for managing sleep onset insomnia in healthy children who have not improved or have responded insufficiently to sleep hygiene and behavioral interventions.

The impact of COVID-19 on menstrual cycle's alterations, in relation to depression and sleep disturbances: a prospective observational study in a population of medical students.

BACKGROUND: The sars-Cov-2 pandemic has determined psychological stress, particularly in the young population of medical students. We studied the impact of the pandemic on menstrual cycle alteration in relation to psychological stress, presence of depression, sleep disturbances and post-traumatic stress, on a population of medical students. METHODS: 293 female students at the Faculty of Medicine and Psychology of the Sapienza University of Rome (23.08 years old ± 3.8) were enrolled. In March 2021, one year after quarantine, a personal data sheet on menstrual cycle, examining the quality of the menstrual cycle during the pandemic, compared to the previous period. Concomitantly, the Beck Depression Inventory and the Impact of Event Scale have been administered. A Pearson chi-square test was assessed to evaluate the difference between the characteristics of the menstrual cycle and the scores obtained with the questionnaires. RESULTS: A statistically significant association between menstrual alterations and stress during pandemic had been found. The onset of depressive symptoms and sleep disturbances was observed in 57.1% and in 58.1% of young women with cycle's alterations, respectively. Amenorrhea was three times more common in female students with depressive symptoms, premenstrual syndrome had a significant correlation with both depression and sleep disturbances. The pandemic has been related to menstrual alterations, with depressive symptoms and sleep disorders. Amenorrhea is connected to depression, as observed on the functional hypothalamic amenorrhea. CONCLUSIONS: The pandemic affected the menstrual cycle as well as the depressive symptoms and sleep. Practical implications of the study lead to the development of strategies for psychological intervention during the pandemic experience, in order to help medical trainees, with specific attention to women's needs. Future studies should analyze the impact of other types of social stress events, on sleep, depression and the menstrual cycle beside the pandemic.

Periodic leg movements during sleep and iron status in infants with prematurity, Down syndrome and Prader-Willi syndrome.

Sleep disturbances including bedtime problems and night awakenings are common during infancy. Polysomnography during the first years of life is performed mainly to rule out sleep-disordered breathing; however, sleep-related movement disorders can constitute a significant contributor to sleep disruption in this age group. Almost no studies have investigated the presence of periodic limb movements during sleep and underlying iron deficiency in infants, especially in those born preterm or with an underlying genetic syndrome. In this retrospective study we included infants 3-24 months referred for polysomnography for snoring or frequent nocturnal awakenings. All children had bloodwork (ferritin and haemoglobin) conducted within 3 months of the overnight sleep study. We studied 79 infants, including 31 (39.2%) full-term without diagnosis, 10 (12.7%) born premature, 16 (20.3%) with Down syndrome, 15 (19.0%) with Prader-Willi syndrome, and the remaining seven (8.9%) had various disorders. Compared with those with Down syndrome, Prader-Willi syndrome and full-term infants, those with prematurity showed a statistically significant elevated periodic limb movement index and lower ferritin levels than the other groups. Both ferritin (r = -0.18) and haemoglobin (r = -0.30) were negatively correlated with periodic limb movement index; however, this correlation reached statistical significance only for haemoglobin. Iron deficiency is associated with increased periodic leg movements during sleep in infants. Infants with prematurity had higher periodic limb movement index and lower ferritin levels than infants with Down syndrome, Prader-Willi syndrome or without diagnosis.

The Role of Supplements and Over-the-Counter Products to Improve Sleep in Children: A Systematic Review.

The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.

Sleep microstructure in attention deficit hyperactivity disorder according to the underlying sleep phenotypes.

The analysis of sleep microstructure in attention deficit hyperactivity disorder (ADHD) revealed an under-representation of the EEG slow component during NREM sleep. Previous studies either excluded or did not characterize objectively sleep disorders, which notoriously affect sleep architecture. The present study aimed to investigate the cyclic alternating pattern in a real clinical sample of children with ADHD, in whom sleep disorders could be considered. Twenty-seven consecutively enrolled drug-naïve children (mean age, 10.53 years; nine females) and 23 controls (mean age, 10.22 years; 11 females) underwent a full sleep investigation, including attended video-polysomnography. Visual cyclic alternating pattern analysis was performed in a blinded way. Children with ADHD had one or more sleep disorders (a narcolepsy-like phenotype was found in two cases, sleep onset insomnia in three cases, arousal disorder in one case, movement disorder phenotype in six cases and obstructive sleep apnea in 11 cases, and six children had sleep-related epileptiform discharges). Children with ADHD and normal controls showed a similar microstructure with a cyclic alternating pattern rate of about 50%. Children with obstructive sleep apnea had a significantly higher cyclic alternating pattern rate during stage N3. Despite not reaching statistical differences, a lower cyclic alternating pattern rate and A1 index were found in children without epileptic abnormalities/obstructive sleep apnea. Our analysis might allow differentiation of the "primary form" of ADHD associated with a decrease of NREM instability from those forms associated with sleep apnea and epileptic activity.

10-year anniversary of the European Somnologist examination - A historic overview and critical appraisal.

The European Somnologist certification programme was developed by the European Sleep Research Society to improve patient care in sleep medicine by providing an independent evaluation of theoretical and practical knowledge. The examination of eligible experts plays a key role in this procedure. A process was started more than 15 years ago to create the European sleep medicine curriculum, eligibility criteria for certification, and sleep centre accreditation criteria. The process was characterised by interdisciplinary collaboration, consensus, and achieving new solutions. During the past 10 years, experience has been gained by the examination and certification of more than 1000 sleep medicine experts from more than 50 countries. The process has continuously been improved. However, as the programme was designed and administered mainly by medical experts in the field, systematic influence from teaching and pedagogic experts was partially underrepresented. The current critical appraisal pinpoints several missing links in the process - mainly as a missing constructive alignment between learning objectives, learning and teaching activities, and the final assessment. A series of suggestions has been made to further improve the ESRS certification programme.

Restless Sleep Disorder (RSD): a New Sleep Disorder in Children. A Rapid Review.

PURPOSE OF REVIEW: Restless sleep disorder (RSD) is a recently identified pediatric sleep disorder characterized by frequent movements during sleep associated with daytime symptoms. In this review we summarize the expanding evidence of the clinical presentation of RSD, potential pathophysiology, associated comorbidities, and current treatment options that will help the pediatrician identify children with RSD in a timely manner. RECENT FINDINGS: RSD is diagnosed in 7.7% of children referred evaluated in a pediatric sleep center. Children with RSD present with frequent nightly movements during sleep for at least 3 months, and have daytime symptoms related to poor sleep quality including excessive sleepiness, hyperactivity, irritability among other symptoms. Current evidence shows an increased sympathetic predominance, increased NREM sleep instability, and iron deficiency, as well as increased prevalence in parasomnias and attention deficit hyperactivity disorder. Consensus diagnostic criteria were recently published to diagnose RSD and emergent evidence suggests that iron supplementation improves its nighttime and daytime symptoms.

The Role of Vitamin D in Sleep Disorders of Children and Adolescents: A Systematic Review.

This review investigates the association between vitamin D and sleep disorders. Vitamin D is an essential nutrient known to play an important role in the growth and bone health of the human body, but it also appears to play a role in sleep. The goal of our review is to examine the association between vitamin D and sleep disorders in children and adolescents. We summarize the evidence about the role and the mechanism of action of vitamin D in children and adolescents with sleep disorders such as insomnia, obstructive sleep apnea (OSA), restless legs syndrome (RLS), and other sleep disorders. Systematic electronic database searches were conducted using Pubmed and Cochrane Library. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The studies that met the established inclusion criteria were analyzed and compared. Results suggest a strict relationship between vitamin D deficiency in children and sleep disorders. There is evidence that vitamin D is implicated in the different neurochemical mechanisms involved in sleep regulation and mainly in the serotonergic and dopaminergic pathways. This might be responsible for the association of vitamin D deficiency and restless sleep, sleep hyperhidrosis, OSA, and RLS.

Heart rate changes associated with the different types of leg movements during sleep in children, adolescents and adults with restless legs syndrome.

The objective of this study was to describe in detail the heart rate changes accompanying short-interval leg movements during sleep, periodic leg movements during sleep, and isolated leg movements during sleep in children and adolescents with restless legs syndrome, and to compare them with the same findings in adults with restless legs syndrome. We analysed time series of R-R intervals synchronized to the onset of short-interval leg movements during sleep, periodic leg movements during sleep or isolated leg movements during sleep that entailed an arousal during non-rapid-eye-movement sleep. We assessed cardiac activation based on the heart rate changes with respect to baseline during non-rapid-eye-movement sleep without leg movements. All types of leg movements recorded during sleep were accompanied by important heart rate changes also in children, with an overall impact similar to that observed in adults. In all age groups, heart rate changes accompanying short-interval leg movements during sleep were constituted by a tachycardia, without a subsequent relative bradycardia, that was instead evident for periodic leg movements during sleep and isolated leg movements during sleep. Moreover, an age-related decline of the relative bradycardia following the heart rate increase, in association with periodic leg movements during sleep and isolated leg movements during sleep, was observed. Our findings show that important heart rate changes accompany all leg movements during sleep at all ages in restless legs syndrome, with significant age-related differences. This information represents an important contribution to the ongoing scientific debate on the possibility and opportunity to treat periodic leg movements during sleep.

Causality of cortical and cardiovascular activity during cyclic alternating pattern in non-rapid eye movement sleep.

The dynamic interplay between central and autonomic nervous system activities plays a pivotal role in orchestrating sleep. Macrostructural changes such as sleep-stage transitions or phasic, brief cortical events elicit fluctuations in neural outflow to the cardiovascular system, but the causal relationships between cortical and cardiovascular activities underpinning the microstructure of sleep are largely unknown. Here, we investigate cortical-cardiovascular interactions during the cyclic alternating pattern (CAP) of non-rapid eye movement sleep in a diverse set of overnight polysomnograms. We determine the Granger causality in both 507 CAP and 507 matched non-CAP sequences to assess the causal relationships between electroencephalography (EEG) frequency bands and respiratory and cardiovascular variables (heart period, respiratory period, pulse arrival time and pulse wave amplitude) during CAP. We observe a significantly stronger influence of delta activity on vascular variables during CAP sequences where slow, low-amplitude EEG activation phases (A1) dominate than during non-CAP sequences. We also show that rapid, high-amplitude EEG activation phases (A3) provoke a more pronounced change in autonomic activity than A1 and A2 phases. Our analysis provides the first evidence on the causal interplay between cortical and cardiovascular activities during CAP. Granger causality analysis may also be useful for probing the level of decoupling in sleep disorders. This article is part of the theme issue 'Advanced computation in cardiovascular physiology: new challenges and opportunities'.

Peculiar lifespan changes of periodic leg movements during sleep in restless legs syndrome.

The objective of this observational cohort study was to analyse the age-related changes of periodic leg movements during sleep using the newest international scoring rules, to expand past analyses, including patients in the paediatric age range, and also to analyse the changes of short-interval and isolated leg movements during sleep throughout the lifespan. One hundred and sixty-five patients (84 women) with restless legs syndrome were recruited in the following age groups: 16 preschoolers (≤5 years of age), 29 school-age children (6-12 years), 19 adolescents (13-17 years), 17 young adults (19-40 years), 47 adults (41-60 years) and 37 seniors (>60 years). Total, periodic, short-interval and isolated leg movements during sleep and periodicity indexes were obtained by polysomnography. The total index showed (quartic polynomial interpolation) a decrease before 10 years, followed by a steady increase up to 30 years, a relatively stable period until 60 years, and a final increase up to 80 years. This course was almost entirely due to changes in periodic movements. Isolated movements did not change significantly and short-interval movements showed only an increase in seniors. Our study indicates that, in restless legs syndrome, the total index shows a peculiar and unique course throughout the lifespan, mainly due to periodic movements. These age-related changes may mirror developmental changes in network complexity known to occur in dopaminergic circuits. These data further confirm the need to better assess the periodicity of leg movements in sleep during the human development period, in order to obtain clinically useful information.

Sleep-related risk and worrying behaviours: a retrospective review of a tertiary centre's experience.

This retrospective study aims at helping physicians select babies considered at risk for fatal events during sleep. It does so by describing the clinical features and outcome of worrying infants' behaviour during sleep, with the activation of an emergency medical service and/or emergency department, subsequently referred to the Centre for Paediatric Sleep Medicine and sudden infant death syndrome, Regina Margherita Children's Hospital, Turin, Italy. We analysed the medical records of infants < 12 months whose parents reported they had worrying behaviour during sleep in the period 1 January 2009- 31 December 2015. Regional guidelines suggest performing anamnesis and capillary blood gas analysis in case of apparent life-threatening events. There were 33 males, average age 55 ± 54.37 days. On arrival at the emergency medical service/emergency department 97 % infants were asymptomatic; 61 % patients had a capillary blood gas analysis as suggested by the regional guidelines. A clear acid-base disorder was observed in two infants, asymptomatic at medical evaluation, that had assumed an unsafe sleeping position. Two patients presented recurrence of the episode at 3 months.Conclusions: Most worrying infant behaviour during sleep can be related to paraphysiological phenomena; capillary blood gas analysis and anamnesis are pivotal to identify the cases at risk of fatal events.What is Known:• Events that happen during sleep often frighten the parents of newborns. This fear may be induced by the fact that Sudden Infant Death Syndrome typically occurs during sleep.• This tragic event is unpredictable by any clinical features or findings in instrumental examinations and cannot be prevented with an early resuscitation.What is New:• In our retrospective study, most worrying infant behaviour during sleep can be related to paraphysiological phenomena.• Capillary blood gas analysis and anamnesis collection were crucial to identify the only two life-threatening events.

Clinically Oriented Subtyping of Chronic Insomnia of Childhood.

OBJECTIVES: To identify different profiles of pediatric insomnia, based on the most frequent clinical presentations (nocturnal awakenings, difficulty in falling asleep, nocturnal restlessness, early morning awakenings). STUDY DESIGN: A structured parent interview was conducted in 338 children (mean age 21.29 months, SD 10.56) referred by pediatricians because of insomnia resistant to behavioral approaches and common drug treatments. The aim was to assess the characteristics of insomnia in children, together with family sleep-related history. A latent class analysis was run to identify profiles of insomnia. ANOVA and the χ2 test were used to examine differences between profiles. RESULTS: A 3-class model was built by latent class analysis: 17% (n = 58) of children constituted the first class, characterized by difficulties in falling asleep, with restlessness, nocturnal restlessness, and awakenings during the night; the second class, characterized by early morning awakenings, comprised 21% (n = 71) of children; 62% (n = 209) of children fell within the third class because of their high frequency of nocturnal awakenings and difficulties in falling asleep. The first class reported longer sleep latency and the presence of restless legs syndrome and anemia in the family history; depression and/or mood disorders were more frequent in class 2 and allergies and/or food intolerance were more frequent in class 3. CONCLUSIONS: Our study suggests the existence of 3 different phenotypes of insomnia in children, based on clinical, personal, and familial data. The identification of these different phenotypes might help to optimize the assessment and treatment of insomnia in young children.

Practitioner Review: Treatment of chronic insomnia in children and adolescents with neurodevelopmental disabilities.

BACKGROUND: Sleep disturbances, in particular insomnia, represent a common problem in children with neurodevelopmental disabilities (NDDs). Currently, there are no approved medications for insomnia in children by the US Food and Drug Administration or European Medicines Agency and therefore they are prescribed off-label. We critically reviewed pediatric literature on drugs as well as nonpharmacological (behavioral) interventions used for sleep disturbances in children with NDDs. METHODS: PubMed, Ovid (including PsycINFO, Ovid MEDLINE® , and Embase), and Web of Knowledge databases were searched through February 12, 2017, with no language restrictions. Two authors independently and blindly performed the screening. RESULTS: Good sleep practices and behavioral interventions, supported by moderate-to-low level evidence, are the first recommended treatments for pediatric insomnia but they are often challenging to implement. Antihistamine agents, such as hydroxyzine or diphenhydramine, are the most widely prescribed sedatives in the pediatric practice but evidence supporting their use is still limited. An increasing body of evidence supports melatonin as the safest choice for children with NDDs. Benzodiazepines are not recommended in children and should only be used for transient insomnia, especially if daytime anxiety is present. Only few studies have been carried out in children's and adolescents' zolpidem, zaleplon, and eszopiclone, with contrasting results. Limited evidence supports the use of alpha-agonists such as clonidine to improve sleep onset latency, especially in attention deficit/hyperactivity disorder subjects. Tricyclic antidepressants, used in adults with insomnia, are not recommended in children because of their safety profile. Trazodone and mirtazapine hold promise but require further studies. CONCLUSIONS: Here, we provided a tentative guide for the use of drugs for insomnia in children with NDDs. Well-controlled studies employing both objective polysomnography and subjective sleep measures are needed to determine the efficacy, effectiveness, and safety of the currently prescribed pediatric sleep medicines in children with NDDs.

The spectrum of REM sleep-related episodes in children with type 1 narcolepsy.

Type 1 narcolepsy is a central hypersomnia due to the loss of hypocretin-producing neurons and characterized by cataplexy, excessive daytime sleepiness, sleep paralysis, hypnagogic hallucinations and disturbed nocturnal sleep. In children, close to the disease onset, type 1 narcolepsy has peculiar clinical features with severe cataplexy and a complex admixture of movement disorders occurring while awake. Motor dyscontrol during sleep has never been systematically investigated. Suspecting that abnormal motor control might affect also sleep, we systematically analysed motor events recorded by means of video polysomnography in 40 children with type 1 narcolepsy (20 females; mean age 11.8 ± 2.6 years) and compared these data with those recorded in 22 age- and sex-matched healthy controls. Motor events were classified as elementary movements, if brief and non-purposeful and complex behaviours, if simulating purposeful behaviours. Complex behaviours occurring during REM sleep were further classified as 'classically-defined' and 'pantomime-like' REM sleep behaviour disorder episodes, based on their duration and on their pattern (i.e. brief and vivid-energetic in the first case, longer and with subcontinuous gesturing mimicking daily life activity in the second case). Elementary movements emerging either from non-REM or REM sleep were present in both groups, even if those emerging from REM sleep were more numerous in the group of patients. Conversely, complex behaviours could be detected only in children with type 1 narcolepsy and were observed in 13 patients, with six having 'classically-defined' REM sleep behaviour disorder episodes and seven having 'pantomime-like' REM sleep behaviour disorder episodes. Complex behaviours during REM sleep tended to recur in a stereotyped fashion for several times during the night, up to be almost continuous. Patients displaying a more severe motor dyscontrol during REM sleep had also more severe motor disorder during daytime (i.e. status cataplecticus) and more complaints of disrupted nocturnal sleep and of excessive daytime sleepiness. The neurophysiological hallmark of this severe motor dyscontrol during REM sleep was a decreased atonia index. The present study reports for the first time the occurrence of a severe and peculiar motor disorder during REM sleep in paediatric type 1 narcolepsy and confirms the presence of a severe motor dyscontrol in these patients, emerging not only from wakefulness (i.e. status cataplecticus), but also from sleep (i.e. complex behaviours during REM sleep). This is probably related to the acute imbalance of the hypocretinergic system, which physiologically acts by promoting movements during wakefulness and suppressing them during sleep.

Short-interval leg movements during sleep entail greater cardiac activation than periodic leg movements during sleep in restless legs syndrome patients.

Periodic leg movements during sleep (PLMS) are sequences of ≥4 motor events with intermovement intervals (IMI) of 10-90 s. PLMS are a supportive diagnostic criterion for restless legs syndrome (RLS) and entail cardiac activation, particularly when associated with arousal. RLS patients also over-express short-interval leg movements during sleep (SILMS), which have IMI <10 s and are organized mainly in sequences of two movements (doublets). We tested whether the cardiac activation associated with SILMS doublets differs from that associated with PLMS in a sample of 25 RLS patients. We analysed time-series of R-R intervals synchronized to the onset of SILMS doublets or PLMS that entailed an arousal during non-rapid eye movement (NREM) sleep. We assessed cardiac activation based on the R-R interval decrease with respect to baseline during NREM sleep without leg movements. We found that the duration of the R-R interval decrease with SILMS doublets was significantly longer than that with PLMS, whereas the maximal decrease in R-R interval was similar. Scoring SILMS in RLS patients may therefore be relevant from a cardiac autonomic perspective.

Sequence analysis of leg movements during sleep with different intervals (<10, 10-90 and >90 s) in restless legs syndrome.

The aim of this study was to define the time structure of leg movements during sleep occurring with an intermovement interval (onset-to-onset) shorter than 10 s in patients with restless legs syndrome and controls, and to compare it to the structure of movements with intervals of 10-90 s or >90 s. Polysomnographic recordings of 141 untreated patients and 68 age-matched normal controls were analysed. All movements were detected and classified into three categories, separated by intervals of <10, 10-90 or >90 s. The number of movements included in each category was significantly higher in patients than in controls. The movements with an interval of >90 s occurred steadily during the night, whereas the hourly distribution of movements with intervals of <10 or 10-90 s was decreasing or bell-shaped in patients or controls, respectively. Movements with an interval of <10 s tended to have a shorter duration and constituted shorter sequences than movements with intervals of 10-90 or >90 s. The time structure features of the three categories of movements considered in this study were found to be clearly different. This, together with previous observations on the differential effects of dopamine agonists on movements with different intervals, suggests that movements with intervals of <10 and >90 s are regulated by neurotransmitter mechanisms different from those modulating movements with an interval of 10-90 s.