Disruption of Circadian Sleep/Wake Rhythms in Infants May Herald Future Development of Autism Spectrum Disorder.

We investigated whether the abnormal rhythms in infants are related to the future development of autism spectrum disorder (ASD), using a questionnaire from September to October 2016. The parents of 160 children with ASD (male, n = 123; female, n = 37) were recruited from two hospitals in K and H cities, and as a control group, 145 children (male, n = 75; female, n = 70) were recruited from four nursery schools in T city. The associations between ASD and bedtime and waking time on weekdays and weekends in infancy (<1 years of age), at 1-3 years, and at 3-5 years of ages were studied using a multivariable logistic regression analysis. In particular, at <3 years of age, the following factors were associated with an increased prevalence of ASD in the future: (1) short sleep periods (<8 h); (2) taking a long time to fall asleep (>60 min); (3) sleep beginning after 22:00; (4) a wake-up time after 08:00; and (5) frequent (>3 times) and long-term awakening periods (>60 min). The misalignment and/or shift of the circadian rhythm in infants may be one of the precursors and/or risk factors for the future development of ASD.

Developmental changes in neonatal hemodynamics during tactile stimulation using whole-head functional near-infrared spectroscopy.

Neural-activity-associated hemodynamic changes have been used to noninvasively measure brain function in the early developmental stages. However, the temporal changes in their hemodynamics are not always consistent with adults. Studies have not evaluated developmental changes for a long period using the same stimuli; therefore, this study examined the normalized relative changes in oxygenated hemoglobin (Δ[oxy-Hb]) in full-term infants and compared them with neonates up to 10 months of age during the administration of tactile vibration stimuli to their limbs using whole-head functional near-infrared spectroscopy. The time to peak of normalized Δ[oxy-Hb] was not affected by age. The amplitude of normalized Δ[oxy-Hb] showed an effect of age in broader areas, including sensorimotor-related but excluding supplementary motor area; the amplitude of normalized Δ[oxy-Hb] decreased the most in the 1-2-month-old group and later increased with development. We hypothesized that these results may reflect developmental changes in neural activity, vasculature, and blood oxygenation.

Maternal Inflammation with Elevated Kynurenine Metabolites Is Related to the Risk of Abnormal Brain Development and Behavioral Changes in Autism Spectrum Disorder.

Several studies show that genetic and environmental factors contribute to the onset and progression of neurodevelopmental disorders. Maternal immune activation (MIA) during gestation is considered one of the major environmental factors driving this process. The kynurenine pathway (KP) is a major route of the essential amino acid L-tryptophan (Trp) catabolism in mammalian cells. Activation of the KP following neuro-inflammation can generate various endogenous neuroactive metabolites that may impact brain functions and behaviors. Additionally, neurotoxic metabolites and excitotoxicity cause long-term changes in the trophic support, glutamatergic system, and synaptic function following KP activation. Therefore, investigating the role of KP metabolites during neurodevelopment will likely promote further understanding of additional pathophysiology of neurodevelopmental disorders, including autism spectrum disorder (ASD). In this review, we describe the changes in KP metabolism in the brain during pregnancy and represent how maternal inflammation and genetic factors influence the KP during development. We overview the patients with ASD clinical data and animal models designed to verify the role of perinatal KP elevation in long-lasting biochemical, neuropathological, and behavioral deficits later in life. Our review will help shed light on new therapeutic strategies and interventions targeting the KP for neurodevelopmental disorders.

The Effects of Maternal Interleukin-17A on Social Behavior, Cognitive Function, and Depression-Like Behavior in Mice with Altered Kynurenine Metabolites.

Viral infection and chronic maternal inflammation during pregnancy are correlated with a higher prevalence of autism spectrum disorder (ASD). However, the pathoetiology of ASD is not fully understood; moreover, the key molecules that can cross the placenta following maternal inflammation and contribute to the development of ASD have not been identified. Recently, the pro-inflammatory cytokine, interleukin-17A (IL-17A) was identified as a potential mediator of these effects. To investigate the impact of maternal IL-17A on offspring, C57BL/6J dams were injected with IL-17A-expressing plasmids via the tail vein on embryonic day 12.5 (E12.5), and maternal IL-17A was expressed continuously throughout pregnancy. By adulthood, IL-17A-injected offspring exhibited behavioral abnormalities, including social and cognitive defects. Additionally, maternal IL-17A promoted metabolism of the essential amino acid tryptophan, which produces several neuroactive compounds and may affect fetal neurodevelopment. We observed significantly increased levels of kynurenine in maternal serum and fetal plasma. Thus, we investigated the effects of high maternal concentration of kynurenine on offspring by continuously administering mouse dams with kynurenine from E12.5 during gestation. Obviously, maternal kynurenine administration rapidly increased kynurenine levels in the fetal plasma and brain, pointing to the ability of kynurenine to cross the placenta and change the KP metabolites which are affected as neuroactive compounds in the fetal brain. Notably, the offspring of kynurenine-injected mice exhibited behavioral abnormalities similar to those observed in offspring of IL-17A-conditioned mice. Several tryptophan metabolites were significantly altered in the prefrontal cortex of the IL-17A-conditioned and kynurenine-injected adult mice, but not in the hippocampus. Even though we cannot exclude the possibility or other molecules being related to ASD pathogenesis and the presence of a much lower degree of pathway activation, our results suggest that increased kynurenine following maternal inflammation may be a key factor in changing the balance of KP metabolites in fetal brain during neuronal development and represents a therapeutic target for inflammation-induced ASD-like phenotypes.

Neonatal irritable sleep-wake rhythm as a predictor of autism spectrum disorders.

Recently, it has been suggested that sleep problems in autism spectrum disorder (ASD) not only are associated symptoms, but may be deeply related to ASD pathogenesis. Common clinical practice relating to developmental disorders, has shown that parents of children with ASD have often stated that it is more difficult to raise children in the neonatal period because these children exhibit sleep problems. This study investigated the possibility that abnormal neonatal sleep-wake rhythms are related to future ASD development. We administered questionnaires to assess parent(s) of children with ASD and controls. A retrospective analysis was conducted among 121 children with ASD (94 male and 27 female children) recruited from the K-Development Support Center for Children (K-ASD), 56 children with ASD (40 male and 16 female children) recruited from the H-Children's Sleep and Development Medical Research Center (H-ASD) and 203 children (104 male and 99 female children) recruited from four nursery schools in T-city (control). Irritable/over-reactive types of sleep-wake rhythms that cause difficulty in raising children, such as 1) frequently waking up, 2) difficulty falling asleep, 3) short sleep hours, and 4) continuous crying and grumpiness, were observed more often in ASD groups than in the control group. Additionally, the number of the mothers who went to bed after midnight during pregnancy was higher in the ASD groups than in the control group. Sleep-wake rhythm abnormalities in neonates may be considerable precursors to future development of ASD. Formation of ultradian and postnatal circadian rhythms should be given more attention when considering ASD development. Although this is a retrospective study, the results suggest that a prospective study regarding this issue may be important in understanding and discovering intervention areas that may contribute to preventing and/or properly treating ASD.

Video-based evaluation of infant crawling toward quantitative assessment of motor development.

This study proposes a quantitative evaluation support system for infant motor development and uses the system to analyze hands-and-knees creeping and belly crawling. This system measures movements using two video cameras and extracts movement features via background and inter-frame subtractions of original images. Eight evaluation indices for each crawling cycle are calculated, enabling markerless movement analysis of infants. Cross-sectional analysis of 16 10-month-olds confirmed significant differences between hands-and-knees creeping and belly crawling in five of the eight indices, demonstrating the system capability to quantitatively differentiate between creeping and crawling. Longitudinal analysis of one infant (aged 7-10 months) also suggested that the proposed quantitative indices can follow changes in crawling characteristics and evaluate infants' motor development process. The results from the experiments suggest that the proposed system may enable diagnosis support in clinical practice.

Inadequate sleep as a contributor to impaired glucose tolerance: A cross-sectional study in children, adolescents, and young adults with circadian rhythm sleep-wake disorder.

BACKGROUND: Sleep deprivation and circadian disruption are associated with decreased insulin sensitivity and hyperglycemia. It is uncertain whether circadian sleep-wake disorder (CRSWD), which relates to both the homeostatic sleep system and the circadian timing system, affects glycemic regulation and insulin secretion. We aimed to examine the associations among sleep duration, sleep architecture or circadian rhythm of the sleep-wake cycle, and glucose metabolism in children, adolescents, and young adults with CRSWD. METHODS: This cross-sectional observational study of 124 patients with CRSWD took place at Hyogo Children's Sleep and Development Medical Research Center in Hyogo, Japan. The patients underwent a 3-hour oral glucose tolerance test, anthropometric measurements, sleep-log analyses, and polysomnography. Analysis of covariance models were used to assess the association between sleep architecture or circadian rhythm of sleep-wake cycle and glucose/insulin homeostasis, adjusted for confounding variables such as age, gender, standardized body mass index, and sleep apnea index. RESULTS: Impaired glucose tolerance was detected in 25.8% of all patients with CRSWD. After adjustment for confounding variables, we found a negative association between total sleep time (TST) and the 2-hour plasma glucose level. Stage N1 (%TST) was also a significant predictor of 3-hour glucose level. However, we did not detect an association between circadian rhythm of the sleep-wake cycle and glucose/insulin measures. CONCLUSIONS: Decreased sleep duration and increased stage N1 (%TST) were associated with hyperglycemia in patients with CRSWD. Further research should elucidate how circadian misalignment in patients with CRSWD is associated with glucose and insulin homeostasis.

High frequency of vitamin D deficiency in current pregnant Japanese women associated with UV avoidance and hypo-vitamin D diet.

BACKGROUND: As a consequence of indoor occupations and reduced exposure to sunlight, concerns have been raised that vitamin D deficiency is widespread in developed countries. Vitamin D is known to be associated with increased risks of morbidity and mortality in various diseases. OBJECTIVE: To investigate the serum vitamin D status and its relation with life-style factors in pregnant Japanese women. METHODS: Among a cohort for 3,327 pregnant women who participated in an the adjunct study of the Japan Environment and Children's Study during 2011-2013, in which data were obtained on various life-style factors, including both dietary intake of vitamin D and frequency of UV exposure, this study consisted of 1,592 pregnant women, from whom 2,030 serum samples were drawn in Jan, Apr, Jul, and Oct, and the association between serum 25(OH)D level and life-style factors were analyzed using linear mixed models. RESULTS: Serum 25(OH)D levels were less than 20ng/mL in 1,486 of 2,030 samples (73.2%). There was an obvious seasonal change, with serum 25(OH)D levels of less than 20 ng/mL in 89.8% and 47.8% of samples in spring (April) and autumn (October), respectively. Both the frequency spent under sunlight and dietary intake of vitamin D were significantly associated with serum 25(OH)D level. An increase in sunlight exposure of more than 15 min for 1 to 2 days per week in non-winter, or dietary intake of 2 µg/day of vitamin D resulted in an elevation of 1 ng/mL in serum 25(OH)D levels. CONCLUSION: These findings indicate that vitamin D deficiency is very severe in Japanese pregnant women, especially those rarely exposed to sunlight. The benefits of UV rays should also be informed of when its risk is alerted, and clinicians should propose the adequate UV exposure level.

Task Difficulty Makes 'No' Response Different From 'Yes' Response in Detection of Fragmented Object Contours.

Two-alternative forced choice tasks are often used in object detection, which regards detecting an object as a 'yes' response and detecting no object as a 'no' response. Previous studies have suggested that the processing of yes/no responses arises from identical or similar processing. In this study, we investigated the difference of processing between detecting an object ('yes' response) and not detecting any object ('no' response) by controlling the task difficulty in terms of fragment length and stimulus duration. The results indicated that a 'yes' response depends on accurate and stable decisions through grouping processing, and a 'no' response might involve two distinct processing, including accurate decisions and intuitive decisions. Accurate decisions of 'no' may arise after the rejection of a 'yes' response with grouping processing, which is an accurate but slow response in an easy task. Intuitive decisions of 'no' arise as the result of breaking down the decision process when the received information was insufficient for grouping processing in a difficult task. Therefore, intuitive decisions of 'no' arise quickly but are inaccurate. The different processes associated with yes/no responses were discussed in terms of the hierarchal structure of object recognition, especially with respect to receiving information and grouping.

Early motor signs of autism spectrum disorder in spontaneous position and movement of the head.

We examined the characteristics of spontaneous movements at 9-20 weeks postterm age in very low birth-weight infants who later developed autism spectrum disorder (ASD). We analyzed video recordings of spontaneous movements of 39 children who had no clinical issues [typically developing (TD) group], 21 children who showed developmental delay, and 14 children who were diagnosed with ASD (ASD group) at 6 years of age. Head position in each video frame was classified by visual inspection. The percentage of midline head position (PMHP) and number of changes in head position were calculated. Spontaneous limb movements were quantified using six indices. The values of PMHP were significantly lower in the ASD group than in the TD group. The lower PMHP during early infancy is associated with later development of ASD. Poorer performance in maintaining midline position of the head at this period may distinguish infants who later develop ASD from those who show TD.

Eye movement activity in normal human fetuses between 24 and 39 weeks of gestation.

Rapid eye movement (REM) sleep occurs throughout a relatively large proportion of early development, and normal REM activity appears to be required for healthy brain development. The eye movements (EMs) observed during REM sleep are the most distinctive characteristics of this state. EMs are used as an index of neurological function postnatally, but no specific indices of EM activity exist for fetuses. We aimed to identify and characterize EM activity, particularly EM bursts suggestive of REM periods, in fetuses with a gestational age between 24 and 39 weeks. This cross-sectional study included 84 normal singleton pregnancies. Fetal EMs were monitored using real-time ultrasonography for 60 min and recorded as videos. The videos were manually converted into a time series of EM events, which were then analyzed by piecewise linear regression for various EM characteristics, including EM density, EM burst density, density of EMs in EM bursts, and continuous EM burst time. Two critical points for EM density, EM burst density, and density of EMs in EM bursts were evident at gestation weeks 28-29 and 36-37. Overall EM activity in human fetuses increased until 28-29 weeks of gestation, then again from 36-37 to 38-39 weeks of gestation. These findings may be useful for creating indices of fetal neurological function for prognostic purposes.

Frontier studies on fatigue, autonomic nerve dysfunction, and sleep-rhythm disorder.

Fatigue is defined as a condition or phenomenon of decreased ability and efficiency of mental and/or physical activities, caused by excessive mental or physical activities, diseases, or syndromes. It is often accompanied by a peculiar sense of discomfort, a desire to rest, and reduced motivation, referred to as fatigue sensation. Acute fatigue is a normal condition or phenomenon that disappears after a period of rest; in contrast, chronic fatigue, lasting at least 6 months, does not disappear after ordinary rest. Chronic fatigue impairs activities and contributes to various medical conditions, such as cardiovascular disease, epileptic seizures, and death. In addition, many people complain of chronic fatigue. For example, in Japan, more than one third of the general adult population complains of chronic fatigue. It would thus be of great value to clarify the mechanisms underlying chronic fatigue and to develop efficient treatment methods to overcome it. Here, we review data primarily from behavioral, electrophysiological, and neuroimaging experiments related to neural dysfunction as well as autonomic nervous system, sleep, and circadian rhythm disorders in fatigue. These data provide new perspectives on the mechanisms underlying chronic fatigue and on overcoming it.

Probability distributions of the electroencephalogram envelope of preterm infants.

OBJECTIVE: To determine the stationary characteristics of electroencephalogram (EEG) envelopes for prematurely born (preterm) infants and investigate the intrinsic characteristics of early brain development in preterm infants. METHODS: Twenty neurologically normal sets of EEGs recorded in infants with a post-conceptional age (PCA) range of 26-44 weeks (mean 37.5 ± 5.0 weeks) were analyzed. Hilbert transform was applied to extract the envelope. We determined the suitable probability distribution of the envelope and performed a statistical analysis. RESULTS: It was found that (i) the probability distributions for preterm EEG envelopes were best fitted by lognormal distributions at 38 weeks PCA or less, and by gamma distributions at 44 weeks PCA; (ii) the scale parameter of the lognormal distribution had positive correlations with PCA as well as a strong negative correlation with the percentage of low-voltage activity; (iii) the shape parameter of the lognormal distribution had significant positive correlations with PCA; (iv) the statistics of mode showed significant linear relationships with PCA, and, therefore, it was considered a useful index in PCA prediction. CONCLUSION: These statistics, including the scale parameter of the lognormal distribution and the skewness and mode derived from a suitable probability distribution, may be good indexes for estimating stationary nature in developing brain activity in preterm infants. SIGNIFICANCE: The stationary characteristics, such as discontinuity, asymmetry, and unimodality, of preterm EEGs are well indicated by the statistics estimated from the probability distribution of the preterm EEG envelopes.

Auditory observation of infant-directed speech by mothers: experience-dependent interaction between language and emotion in the basal ganglia.

Adults address infants with a special speech register known as infant-directed speech (IDS), which conveys both linguistic and emotional information through its characteristic lexicon and exaggerated prosody (e.g., higher pitched, slower, and hyperarticulated). Although caregivers are known to regulate the usage of IDS (linguistic and emotional components) depending on their child's development, the underlying neural substrates of this flexible modification are largely unknown. Here, using an auditory observation method and functional magnetic resonance imaging (fMRI) of four different groups of females, we revealed the experience-dependent influence of the emotional component on linguistic processing in the right caudate nucleus when mothers process IDS: (1) non-mothers, who do not use IDS regularly, showed no significant difference between IDS and adult-directed speech (ADS); (2) mothers with preverbal infants, who primarily use the emotional component of IDS, showed the main effect of the emotional component of IDS; (3) mothers with toddlers at the two-word stage, who use both linguistic and emotional components of IDS, showed an interaction between the linguistic and emotional components of IDS; and (4) mothers with school-age children, who use ADS rather than IDS toward their children, showed a tendency toward the main effect of ADS. The task that was most comparable to the naturalistic categories of IDS (i.e., explicit-language and implicit-emotion processing) recruited the right caudate nucleus, but it was not recruited in the control, less naturalistic condition (explicit-emotion and implicit-language processing). Our results indicate that the right caudate nucleus processes experience-and task-dependent interactions between language and emotion in mothers' IDS.

Jerky spontaneous movements at term age in preterm infants who later developed cerebral palsy.

BACKGROUND: Assessment of spontaneous movements in infants has been a powerful predictor of cerebral palsy (CP). Recent advancements on computer-based video analysis can provide detailed information about the properties of spontaneous movements. AIMS: The aim of this study was to investigate the relationship between spontaneous movements of the 4 limbs at term age and the development of CP at 3 years of age by using a computer-based video analysis system. STUDY DESIGN AND SUBJECTS: We analyzed video recordings of spontaneous movements at 36-44 weeks postmenstrual age (PMA) for 145 preterm infants who were born preterm (22-36 weeks PMA with birthweights of 460-1498g). Sixteen of the infants developed CP by 3 years of age, while 129 developed normally. We compared 6 movement indices calculated from 2-dimensional trajectories of all limbs between the 2 groups. RESULTS: We found that the indices of jerkiness were higher in the CP group than in the normal group (p<0.1 for arms and p<0.01 for legs). No decline was observed in the average velocity and number of movement units in the CP group compared with to the normal group. CONCLUSIONS: Jerkiness of spontaneous movements at term age provides additional information for predicting CP in infants born preterm.

Effects of preterm birth on intrinsic fluctuations in neonatal cerebral activity examined using optical imaging.

Medical advancements in neonatology have significantly increased the number of high-risk preterm survivors. However, recent long-term follow-up studies have suggested that preterm infants are at risk for behavioral, educational, and emotional problems. Although clear relationships have been demonstrated between preterm infants and developmental problems during childhood and adolescence, less is known about the early indications of these problems. Recently, numerous studies on resting-state functional connectivity (RSFC) have demonstrated temporal correlations of activity between spatially remote cortical regions not only in healthy adults but also in neuropathological disorders and early childhood development. In order to compare RSFC of the cerebral cortex between preterm infants at term-equivalent ages and full-term neonates without any anatomical abnormality risk during natural sleep, we used an optical topography system, which is a recently developed extension of near-infrared spectroscopy. We clarified the presence of RSFC in both preterm infants and full-term neonates and showed differences between these groups. The principal differences were that on comparison of RSFC between the bilateral temporal regions, and bilateral parietal regions, RSFC was enhanced in preterm infants compared with full-term neonates; whereas on comparison of RSFC between the left temporal and left parietal regions, RSFC was enhanced in full-term neonates compared with preterm infants. We also demonstrated a difference between the groups in developmental changes of RSFC related to postmenstrual age. Most importantly, these findings suggested that preterm infants and full-term neonates follow different developmental trajectories during the perinatal period because of differences in perinatal experiences and physiological and structural development.

Specific characteristics of spontaneous movements in preterm infants at term age are associated with developmental delays at age 3 years.

AIM: The aim of this study was to investigate the relationship between the characteristics of spontaneous movements in preterm infants at term age and developmental delay at 3 years of age. METHOD: We analysed video recordings of the spontaneous movements in the supine position of 124 preterm infants (44 males, 80 females) at 36 to 44 weeks postmenstrual age (PMA). The infants were born preterm (22-36wks PMA; birthweight 489-1696g) and had not received a diagnosis of a neurological or developmental disorder by the age of 3 years. The recorded spontaneous movements were quantified using six movement indices, which were calculated from two-dimensional trajectories of all limbs. The infants were divided into three developmental groups, normal, borderline, or delayed, based on their developmental quotient as calculated using the Kyoto Scale of Psychological Development 2001 (Kyoto Scale) at 3 years of age. Group differences in the movement indices were analysed. RESULTS: In the delayed group, average velocity of arms and legs were significantly lower (p<0.05 and p<0.01 respectively), the numbers of movement units of arms and legs were significantly lower (p<0.05 and p<0.01 respectively), kurtosis of acceleration of arms and legs was significantly higher (p<0.05 in each case), and correlation between limb velocities was higher (p<0.05) than in the normal group. INTERPRETATION: In children who exhibited developmental delay at 3 years of age, the spontaneous movements at term age can be described as less active with intermittent occurrences of abrupt and synchronized movements of the limbs. Recognition of these characteristics of spontaneous movements at term age may be used as a predictor for subsequent cognitive and behavioural development in preterm infants.

Decreased right temporal activation and increased interhemispheric connectivity in response to speech in preterm infants at term-equivalent age.

Preterm infants are at increased risk of language-related problems later in life; however, few studies have examined the effects of preterm birth on cerebral responses to speech at very early developmental stages. This study examined cerebral activation and functional connectivity in response to infant-directed speech (IDS) and adult-directed speech (ADS) in full-term neonates and preterm infants at term-equivalent age using 94-channel near-infrared spectroscopy. The results showed that compared with ADS, IDS increased activity in larger brain areas such as the bilateral frontotemporal, temporal, and temporoparietal regions, both in full-term and preterm infants. Preterm infants exhibited decreased activity in response to speech stimuli in the right temporal region compared with full-term infants, although the significance was low. Moreover, preterm infants exhibited increased interhemispheric connectivity compared with full-term controls, especially in the temporal and temporoparietal regions. These differences suggest that preterm infants may follow different developmental trajectories from those born at term owing to differences in intrauterine and extrauterine development.

Where and how infants look: the development of scan paths and fixations in face perception.

It is well known that infants prefer faces but relatively little is known about how infants look at face. The present work examined the development of face perception by using the scan paths. Infants (aged 6-13.5 months) and adults were presented with images of upright and inverted faces, and looking times and scan paths were compared. Similarity between participants' scan paths demonstrated that infants collect facial information more efficiently from upright faces than from inverted faces, and this ability gradually develops with age. Analyses of looking times also revealed that preferences for upright faces were gradually replaced by preferences for inverted faces by approximately 10 months of age. The results indicate that the processing of configural information gradually develops throughout infancy.