Executive Function Assessment in 2-Year-Olds Born Preterm.

OBJECTIVE: Our objective was to investigate the executive function and its relationship with gestational age, sex, maternal education, and neurodevelopmental outcome at 2 years corrected age in children born preterm. METHOD: Executive function was assessed by means of the Multisearch Multilocation Task (MSML), Reversed Categorization Task (RevCat), and Snack Delay Task (SDT). Infant and maternal characteristics were gathered from the child's record. The developmental outcome was measured by the Bayley Scales and a multidisciplinary risk evaluation for autism. RESULTS: The executive function battery was completed by 97 children. The majority were able to successfully complete the MSML and SDT but failed RevCat. The lower the gestational age and the maternal education, the lower the executive function scores. Better cognition and motor function, as well as low autism risk, were associated with better executive function scores. Executive function was not related to sex. INTERPRETATION: This cohort study provides evidence that it is feasible to assess executive function in 2-year-olds born preterm. Executive function is related to gestational age and maternal education and is positively correlated with behavioral outcome. Therefore, executive functions can be a valuable target for early intervention, resulting in improvements in neurodevelopmental outcomes in children born preterm.

Prenatal diagnosis of congenital diaphragmatic hernia: Parental counselling and support needs.

OBJECTIVE: To define the dimensions of patient-centeredness of prenatal care for parents who had a fetus with isolated congenital diaphragmatic hernia (CDH) by exploring their values, experiences, needs and preferences. METHODS: In-depth interviews with parents who were faced with the prenatal diagnosis of isolated CDH. RESULTS: Interviews (n = 18) identified seven dimensions of patient-centeredness. Parental preferences are respected by unconditional acceptance of parental choices and needs. After diagnosis access to care should occur by swift referral to a specialised centre to prevent parents receiving contradictory information. Information and education help parents to gain some sense of control and cope with the many uncertainties. A multidisciplinary team with a coordinating professional is perceived supportive (coordination and integration), and seamless referral between local and treatment centres reduces parental distress (continuity and transition). Family-centred emotional support helps parents to cope with emotions and distress. Informal support by involvement of family and friends and trusted peer-support is of added value. CONCLUSION: The impact of the uncertainty of outcome in this condition is tremendous and needs to be considered when providing prenatal care. After initial diagnosis, one should avoid speculation about the severity of the condition and outcome, and provide swift referral to a specialist centre expert in managing CDH. Provision of realistic and comprehensive information helps parents cope. Multidisciplinary and continuous support throughout the full trajectory, but also integrated psychosocial support should become standard-of-care.

The effect of early procedural pain in preterm infants on the maturation of electroencephalogram and heart rate variability.

ABSTRACT: Preterm infants show a higher incidence of cognitive, social, and behavioral problems, even in the absence of major medical complications during their stay in the neonatal intensive care unit (NICU). Several authors suggest that early-life experience of stress and procedural pain could impact cerebral development and maturation resulting in an altered development of cognition, behavior, or motor patterns in later life. However, it remains very difficult to assess this impact of procedural pain on physiological development. This study describes the maturation of electroencephalogram (EEG) signals and heart rate variability in a prospective cohort of 92 preterm infants (<34 weeks gestational age) during their NICU stay. We took into account the number of noxious, ie, skin-breaking, procedures they were subjected in the first 5 days of life, which corresponded to a median age of 31 weeks and 4 days. Using physiological signal modelling, this study shows that a high exposure to early procedural pain, measured as skin-breaking procedures, increased the level of discontinuity in both EEG and heart rate variability in preterm infants. These findings have also been confirmed in a subset of the most vulnerable preterm infants with a gestational age lower than 29 weeks. We conclude that a high level of early pain exposure in the NICU increases the level of functional dysmaturity, which can ultimately impact preterm infants' future developmental outcome.

A Bradycardia-Based Stress Calculator for the Neonatal Intensive Care Unit: A Multisystem Approach.

Early life stress in the neonatal intensive care unit (NICU) can predispose premature infants to adverse health outcomes and neurodevelopment delays. Hands-on-care and procedural pain might induce apneas, hypoxic events, and sleep-wake disturbances, which can ultimately impact maturation, but a data-driven method based on physiological fingerprints to quantify early-life stress does not exist. This study aims to provide an automatic stress detector by investigating the relationship between bradycardias, hypoxic events and perinatal stress in NICU patients. EEG, ECG, and SpO 2 were recorded from 136 patients for at least 3 h in three different monitoring groups. In these subjects, the stress burden was assessed using the Leuven Pain Scale. Different subspace linear discriminant analysis models were designed to detect the presence or the absence of stress based on information in each bradycardic spell. The classification shows an area under the curve in the range [0.80-0.96] and a kappa score in the range [0.41-0.80]. The results suggest that stress seems to increase SpO 2 desaturations and EEG regularity as well as the interaction between the cardiovascular and neurological system. It might be possible that stress load enhances the reaction to respiratory abnormalities, which could ultimately impact the neurological and behavioral development.

Maturation of the Autonomic Nervous System in Premature Infants: Estimating Development Based on Heart-Rate Variability Analysis.

This study aims at investigating the development of premature infants' autonomic nervous system (ANS) based on a quantitative analysis of the heart-rate variability (HRV) with a variety of novel features. Additionally, the role of heart-rate drops, known as bradycardias, has been studied in relation to both clinical and novel sympathovagal indices. ECG data were measured for at least 3 h in 25 preterm infants (gestational age ≤32 weeks) for a total number of 74 recordings. The post-menstrual age (PMA) of each patient was estimated from the RR interval time-series by means of multivariate linear-mixed effects regression. The tachograms were segmented based on bradycardias in periods after, between and during bradycardias. For each of those epochs, a set of temporal, spectral and fractal indices were included in the regression model. The best performing model has R 2 = 0.75 and mean absolute error MAE = 1.56 weeks. Three main novelties can be reported. First, the obtained maturation models based on HRV have comparable performance to other development models. Second, the selected features for age estimation show a predominance of power and fractal features in the very-low- and low-frequency bands in explaining the infants' sympathovagal development from 27 PMA weeks until 40 PMA weeks. Third, bradycardias might disrupt the relationship between common temporal indices of the tachogram and the age of the infant and the interpretation of sympathovagal indices. This approach might provide a novel overview of post-natal autonomic maturation and an alternative development index to other electrophysiological data analysis.

Corrigendum: Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

[This corrects the article on p. 313 in vol. 6, PMID: 26582992.].

Protective effects of intermittent hypoxia on brain and memory in a mouse model of apnea of prematurity.

Apnea of prematurity (AOP) is considered a risk factor for neurodevelopmental disorders in children based on epidemiological studies. This idea is supported by studies in newborn rodents in which exposure to intermittent hypoxia (IH) as a model of AOP significantly impairs development. However, the severe IH used in these studies may not fully reflect the broad spectrum of AOP severity. Considering that hypoxia appears neuroprotective under various conditions, we hypothesized that moderate IH would protect the neonatal mouse brain against behavioral stressors and brain damage. On P6, each pup in each litter was randomly assigned to one of three groups: a group exposed to IH while separated from the mother (IH group), a control group exposed to normoxia while separated from the mother (AIR group), and a group of untreated unmanipulated pups left continuously with their mother until weaning (UNT group). Exposure to moderate IH (8% O2) consisted of 20 hypoxic events/hour, 6 h per day from postnatal day 6 (P6) to P10. The stress generated by maternal separation in newborn rodents is known to impair brain development, and we expected this effect to be smaller in the IH group compared to the AIR group. In a separate experiment, we combined maternal separation with excitotoxic brain lesions mimicking those seen in preterm infants. We analyzed memory, angiogenesis, neurogenesis and brain lesion size. In non-lesioned mice, IH stimulated hippocampal angiogenesis and neurogenesis and improved short-term memory indices. In brain-lesioned mice, IH decreased lesion size and prevented memory impairments. Contrary to common perception, IH mimicking moderate apnea may offer neuroprotection, at least in part, against brain lesions and cognitive dysfunctions related to prematurity. AOP may therefore have beneficial effects in some preterm infants. These results support the need for stratification based on AOP severity in clinical trials of treatments for AOP, to determine whether in patients with moderate AOP, these treatments are beneficial or deleterious.

Impact of inhaled nitric oxide on white matter damage in growth-restricted neonatal rats.

BACKGROUND: Fetal growth restriction is the second leading cause of perinatal morbidity and mortality, and neonates with intrauterine growth retardation (IUGR) have increased neurocognitive and neuropsychiatric morbidity. These neurocognitive impairments are mainly related to injury of the developing brain associated with IUGR. Growing evidence from preclinical models of brain injury in both adult and neonatal rodents supports the view that nitric oxide can promote neuroprotection. METHODS: In a model of IUGR induced by protracted gestational hypoxia leading to diffuse white matter injury, we subjected neonatal rats to low dose (5 ppm) but long-lasting (7 d) exposure to inhaled NO (iNO). We used a combination of techniques, including immunohistochemistry, quantitative PCR, and cognitive assessment, to assess neuroprotection. RESULTS: Antenatal hypoxia-induced IUGR was associated with severe neuroinflammation and delayed myelination. iNO exposure during the first postnatal week significantly attenuated cell death and microglial activation, enhanced oligodendroglial proliferation and finally improved myelination. Remarkably, iNO was associated with the specific upregulation of P27kip1, which initiates oligodendrocytic differentiation. Finally, iNO counteracted the deleterious effects of hypoxia on learning abilities. CONCLUSION: This study provides new evidence that iNO could be effective in preventing brain damage and/or enhancing repair of the developing brain.

Emotional disorders in adult mice heterozygous for the transcription factor Phox2b.

Phox2b is an essential transcription factor for the development of the autonomic nervous system. Mice carrying one invalidated Phox2b allele (Phox2b(+/-)) show mild autonomic disorders including sleep apneas, and impairments in chemosensitivity and thermoregulation that recover within 10days of postnatal age. Because Phox2b is not expressed above the pons nor in the cerebellum, this mutation is not expected to affect brain development and cognitive functioning directly. However, the transient physiological disorders in Phox2b(+/-) mice might impair neurodevelopment. To examine this possibility, we conducted a behavioral test battery of emotional, motor, and cognitive functioning in adult Phox2b(+/-) mice and their wildtype littermates (Phox2b(+/+)). Adult Phox2b(+/-) mice showed altered exploratory behavior in the open field and in the elevated plus maze, both indicative of anxiety. Phox2b(+/-) mice did not show cognitive or motor impairments. These results suggest that also mild autonomic control deficits may disturb long-term emotional development.

Inhaled NO prevents hyperoxia-induced white matter damage in neonatal rats.

White matter damage (WMD) and bronchopulmonary dysplasia (BPD) are the two main complications occurring in very preterm infants. Inhaled nitric oxide (iNO) has been proposed to promote alveolarization in the developing lung, and we have reported that iNO promotes myelination and induces neuroprotection in neonatal rats with excitotoxic brain damage. Our hypothesis is that, in addition to its pulmonary effects, iNO may be neuroprotective in rat pups exposed to hyperoxia. To test this hypothesis, we exposed rat pups to hyperoxia, and we assessed the impact of iNO on WMD and BPD. Rat pups were exposed to either hyperoxia (80% FiO2) or to normoxia for 8 days. Both groups received iNO (5 ppm) or air. We assessed the neurological and pulmonary effects of iNO in hyperoxia-injured rat pups using histological, molecular and behavioral approaches. iNO significantly attenuated the severity of hyperoxia-induced WMD induced in neonatal rats. Specifically, iNO decreased white matter inflammation, cell death, and enhanced the density of proliferating oligodendrocytes and oligodendroglial maturation. Furthermore, iNO triggered an early upregulation of P27kip1 and brain-derived growth factor (BDNF). Whereas hyperoxia disrupted early associative abilities, iNO treatment maintained learning scores to a level similar to that of control pups. In contrast to its marked neuroprotective effects, iNO induced only small and transient improvements of BPD. These findings suggest that iNO exposure at low doses is specifically neuroprotective in an animal model combining injuries of the developing lung and brain that mimicked BPD and WMD in preterm infants.

Olfactory classical conditioning in neonatal mouse pups using thermal stimuli.

Mouse models are increasingly used to investigate genetic contributions to developmental disorders in children, especially newborns. In particular, early cognitive assessment in newborn mice is critical to evaluate pediatric drug efficacy and toxicity. Unfortunately, methods for behavioral tests in newborn mice are scarce. Therefore, developing such tests for newborn mice is a priority challenge for neurogenetics and pharmacological research. The aim of the present study was to develop a conditioning method well suited to high-throughput cognitive screening in newborn mice. To this end, we developed an odor-preference conditioning test using ambient temperature as an unconditioned stimulus (US) and artificial odors as conditioned stimuli (CS). First, we showed that mouse pups move toward the thermoneutral temperature when offered a choice between a thermoneutral and cold environment, thus showing thermotaxis. Second, we conducted a classical conditioning paradigm in pups aged six to ten days. In terms of central nervous system development, this period corresponds to extreme prematurity to early post-term period in humans. During acquisition, the pups were alternatively exposed to odor CS paired with either cold or warm temperatures. Immediately after acquisition, the pups underwent a two-odor choice test, which showed preference for the odor previously paired with the warm temperature, thus showing conditioning. The proposed paradigm is easy to conduct, and requires modest experimenter interference. The method is well suited for high-throughput screening of early associative disorders in newborn mice.

Cold stimulates the behavioral response to hypoxia in newborn mice.

In newborns, hypoxia elicits increased ventilation, arousal followed by defensive movements, and cries. Cold is known to affect the ventilatory response to hypoxia, but whether it affects the arousal response remains unknown. The aim of the present study was to assess the effects of cold on the ventilatory and arousal responses to hypoxia in newborn mice. We designed an original platform measuring noninvasively and simultaneously the breathing pattern by whole body plethysmography, body temperature by infrared thermography, as well as motor and ultrasonic vocal (USV) responses. Six-day-old mice were exposed twice to 10% O(2) for 3 min at either cold temperature (26 degrees C) or thermoneutrality (33 degrees C). At 33 degrees C, hypoxia elicited a marked increase in ventilation followed by a small ventilatory decline, small motor response, and almost no USVs. Body temperature was not influenced by hypoxia, and oxygen consumption (Vo(2)) displayed minimal changes. At 26 degrees C, hypoxia elicited a slight increase in ventilation with a large ventilatory decline and a large drop of Vo(2). This response was accompanied by marked USV and motor responses. Hypoxia elicited a small decrease in temperature after the return to normoxia, thus precluding any causal influence on the motor and USV responses to hypoxia. In conclusion, cold stimulated arousal and stress responses to hypoxia, while depressing hypoxic hyperpnea. Arousal is an important defense mechanism against sleep-disordered breathing. The dissociation between ventilatory and behavioral responses to hypoxia suggests that deficits in the arousal response associated with sleep breathing disorders cannot be attributed to a depressed hypoxic response.

Learned defense response to hypoxia in newborn mice.

In newborns, hypoxia elicits defensive behaviors including awakening from sleep, body movements and crying. An inability to produce this defense response is a risk factor for sudden infant death syndrome and other respiratory control disorders. In this study, we examined the possibility that the defense response to hypoxia in newborns is partly determined by early exposure to hypoxia. We explored this possibility in 6-day-old mice, which resemble human preterm infants of approximately 25-30 weeks' gestational age. Ultrasonic vocalizations (USVs) were recorded as a marker for the defense response to hypoxia. In a conditioning experiment, newborn mice were exposed to two artificial odors (conditioned stimuli, CS). For acquisition (two trials), pups were exposed to one odor (CS+) in a hypoxic gas mixture (10% O2, which was the unconditioned stimulus, US) and to another odor (CS-) in air. Then, the pups were exposed to each odor while breathing air. Newborn mice produced significantly more USVs when exposed to the odor previously paired with hypoxia than to the control odor. Thus, associative learning may shape the defense response to hypoxia in newborns.