Left-Right Locomotor Coordination in Human Neonates.

Terrestrial locomotion requires coordinated bilateral activation of limb muscles, with left-right alternation in walking or running, and synchronous activation in hopping or skipping. The neural mechanisms involved in interlimb coordination at birth are well known in different mammalian species, but less so in humans. Here, 46 neonates (of either sex) performed bilateral and unilateral stepping with one leg blocked in different positions. By recording EMG activities of lower-limb muscles, we observed episodes of left-right alternating or synchronous coordination. In most cases, the frequency of EMG oscillations during sequences of consecutive steps was approximately similar between the two sides, but in some cases it was considerably different, with episodes of 2:1 interlimb coordination and episodes of activity deletions on the blocked side. Hip position of the blocked limb significantly affected ipsilateral, but not contralateral, muscle activities. Thus, hip extension backward engaged hip flexor muscle, and hip flexion engaged hip extensors. Moreover, the sudden release of the blocked limb in the posterior position elicited the immediate initiation of the swing phase of the limb, with hip flexion and a burst of an ankle flexor muscle. Extensor muscles showed load responses at midstance. The variable interlimb coordination and its incomplete sensory modulation suggest that the neonatal locomotor networks do not operate in the same manner as in mature locomotion, also because of the limited cortical control at birth. These neonatal mechanisms share many properties with spinal mammalian preparations (i.e., independent pattern generators for each limb, and for flexor and extensor muscles, load, and hip position feedback).SIGNIFICANCE STATEMENT Bilateral coupling and reciprocal activation of flexor and extensor burst generators represent the fundamental mechanisms used by mammalian limbed locomotion. Considerable progress has been made in deciphering the early development of the spinal networks and left-right coordination in different mammals, but less is known about human newborns. We compared bilateral and unilateral stepping in human neonates, where cortical control is still underdeveloped. We found neonatal mechanisms that share many properties with spinal mammalian preparations (i.e., independent pattern generators for each limb, the independent generators for flexor and extensor muscles, load, and hip-position feedback. The variable interlimb coordination and its incomplete sensory modulation suggest that the human neonatal locomotor networks do not operate in the same manner as in mature locomotion.

Distinct locomotor precursors in newborn babies.

Mature locomotion involves modular spinal drives generating a set of fundamental patterns of motoneuron activation, each timed at a specific phase of locomotor cycles and associated with a stable muscle synergy. How locomotor modules develop and to what extent they depend on prior experience or intrinsic programs remains unclear. To address these issues, we herein leverage the presence at birth of two types of locomotor-like movements, spontaneous kicking and weight-bearing stepping. The former is expressed thousands of times in utero and postnatally, whereas the latter is elicited de novo by placing the newborn on the ground for the first time. We found that the neuromuscular modules of stepping and kicking differ substantially. Neonates kicked with an adult-like number of temporal activation patterns, which lacked a stable association with systematic muscle synergies across movements. However, on the ground neonates stepped with fewer temporal patterns but all structured in stable synergies. Since kicking and ground-stepping coexist at birth, switching between the two behaviors may depend on a dynamic reconfiguration of the underlying neural circuits as a function of sensory feedback from surface contact. We tracked the development of ground-stepping in 4- to 48-mo-old infants and found that, after the age of 6 mo, the number of temporal patterns increased progressively, reaching adult-like conformation only after independent walking was established. We surmise that mature locomotor modules may derive by combining the multiple patterns of repeated kicking, on the one hand, with synergies resulting from fractionation of those revealed by sporadic weight-bearing stepping, on the other hand.

The development of lung biochemical monitoring can play a key role in the early prediction of bronchopulmonary dysplasia.

AIM: Despite advances in perinatal management, there is a flat trend in incidences of respiratory distress syndrome (RDS) and bronchopulmonary dysplasia (BPD) in preterm infants. The main feature of BPD development in preterm infants is an imbalance between increased exposure to free radicals and inadequate antioxidant defences. We investigated the associations between BPD and lipid hydro-peroxide (LOOH) and glutathione (GSH) concentrations in bronchoalveolar lavage fluid (BALF). METHODS: In this prospective study, BALF samples were collected from 44 preterm infants with RDS and oxidative stress markers were measured in 11 with BPD and 33 controls without BPD. RESULTS: LOOH levels were significantly higher (p < 0.01) in the BPD group (median 16.35; 25th-75th centile 13.75-17.05 nmol/mL) than in the no BPD group (median 13.18; 25th-75th centile 12.92-13.63 nmol/mL). Conversely, GSH levels were significantly lower in the BPD group (p < 0.01) (median 11.52; 25th-75th centile 6.95-13.85 µmol/mg) than the no BPD group (median: 18.69; 25th-75th centile: 13.89-23.64 µmol/mg). Multiple regression analysis showed significant correlations between BPD and mechanical ventilation time (p < 0.01) and LOOH levels (p < 0.05). CONCLUSION: Early LOOH level increases in preterm infants developing BPD suggest that lung biochemical monitoring of sick infants might be possible and BPD could be predicted early by evaluating biomarkers.

Complexity of modular neuromuscular control increases and variability decreases during human locomotor development.

When does modular control of locomotion emerge during human development? One view is that modularity is not innate, being learnt over several months of experience. Alternatively, the basic motor modules are present at birth, but are subsequently reconfigured due to changing brain-body-environment interactions. One problem in identifying modular structures in stepping infants is the presence of noise. Here, using both simulated and experimental muscle activity data from stepping neonates, infants, preschoolers, and adults, we dissect the influence of noise, and identify modular structures in all individuals, including neonates. Complexity of modularity increases from the neonatal stage to adulthood at multiple levels of the motor infrastructure, from the intrinsic rhythmicity measured at the level of individual muscles activities, to the level of muscle synergies and of bilateral intermuscular network connectivity. Low complexity and high variability of neuromuscular signals attest neonatal immaturity, but they also involve potential benefits for learning locomotor tasks.

Comparing of two different epidemic seasons of bronchiolitis.

Acute bronchiolitis is the most common cause of hospitalizations in infants < 12 months of age and preventive efforts remain the most important strategy to date. Recently prophylaxis with palivizumab (PLV) was limited to preterm infants with < 29 weeks gestational age (wGA).We performed a single center analysis in preterm infants (GA between 30 and 32 weeks) and age < 12 months to compare prophylaxis with PLV and frequency and characteristics of bronchiolitis and bronchiolitis-related hospitalization in two consecutive epidemic seasons (S1 vs S2).We found a rising trend in rate of bronchiolitis and bronchiolitis-related hospitalization in S1 vs S2. Among hospitalization, we found an increased morbidity with an increase in the rate of mechanical ventilation in S2. Additionally, hospitalization occurred in subjects with younger chronological age in S2 compared with S1.Our result cannot be generalized because deriving from a single Center and further evaluation on wider simple size are warranted, but it suggests an increase in the incidence, gravity and precocity of bronchiolitis in 29-32 wGE preterm infants with the change in National guidelines for prophylaxis.

Re-comparing of three different epidemic seasons of bronchiolitis: different prophylaxis approaches.

During the last epidemic season of bronchiolitis (S2, years 2016-2017) we performed a single Centre analysis in inborn infant of 30+ 0-32+ 6 gestational age and age < 12 months who did not receive prophylaxis with palivizumab (PLV), in light of the current AIFA (Italian Drug Agency) guidelines restricting the time of the prophylaxis to those born < 30 weeks of gestational age. During that epidemic season, we observed a rising trend of bronchiolitis-related hospitalization and an increased rate of mechanical ventilation in preterm child compared to the previous one (S1, years 2015-2016) during which infants of this same gestational age received palivizumab (PLV) prophylaxis, according to the 2015 Italian Guidelines.In light of the revised AIFA guidelines (November 2017), allowing once again prophylaxis with PLV in infants of > 30 weeks gestational age, we decided to repeat our observation during the last epidemic season (S3, years 2017-2018), in order to compare ours infants of 30+ 0-32+ 6 gestational age with preterm of the same gestational age born in our unit in the previous seasons (S1 and S2), to evaluate the clinical impact of the different prophylaxis approaches.The new observation confirmed the clinical efficacy of PLV in this delicate group of newborns in preventing almost completely new episodes of bronchiolitis. Of the 6 newborns who developed bronchiolitis, 4 had received only a single dose of PLV, providing suboptimal protection, before the onset of bronchiolitis; furthermore 3 developed a mild form allowing to be treated at home.

Lutein levels in arterial cord blood correlate with neuroprotein activin A in healthy preterm and term newborns: A trophic role for lutein?

BACKGROUND: Lutein (LT) is a naturally occurring xanthophyll carotenoid most predominant in the central nervous system (CNS), but its neurotrophic role is still debated. We therefore investigated whether cord blood concentrations correlated with a well-established neurobiomarker, namely activin A. METHODS: We conducted a prospective study on the distribution of LT and activin A in arterial cord blood of healthy preterm (n=50) and term (n=82) newborns according to weeks of gestational age (wGA) and gender. RESULTS: LT and activin A showed a pattern of concentration characterized by higher levels (P<0.01, for all) at 33-36 wGA followed by a progressive decrease (P<0.01, for all) from 37 onwards with a dip at term. Both LT and activin A were gender-dependent with significantly (P<0.01, for all) higher levels in all recruited females and after sub-grouping for preterm and term births. LT (R=0.33; P<0.001) correlated with wGA at sampling. There were significant positive correlations between lutein and activin A in male (R=0.93; P<0.001) and female (R=0.89; P<0.001) groups. CONCLUSIONS: The present data showing a correlation between LT and activin A support the notion of a neurotrophic role gender-dependent for LT and open the way to further investigations correlating LT with well-established biochemical markers of CNS development/damage.

Arterial cord blood lutein levels in preterm and term healthy newborns are sex and gestational age dependent.

OBJECTIVE: Lutein is an antioxidant carotenoid exerting a key role in eye health, but no reference curve in the perinatal period is available. DESIGN AND METHODS: We conducted a prospective study on the distribution of lutein and its metabolite 3'-oxolutein in arterial cord blood of preterm (n=40) and term (n=76) newborns according to gestational age, sex and delivery modalities. RESULTS: Lutein and 3'-oxolutein concentrations peaked at the beginning of third trimester (P<0.01, for both) being higher in the preterm than in term group. From 36 weeks onwards, lutein and 3'-oxolutein levels progressively decreased reaching the lowest levels at term between 41 and 42 weeks (P<0.01, for both). Lutein and 3'-oxolutein significantly (P<0.01, for all) correlated with each other (R=0.33) and with gestational age at sampling (R=0.31 and R=0.38 for lutein and 3-oxolutein, respectively) (P<0.001, for all). Indeed, lutein and 3'-oxolutein concentrations were significantly higher (P<0.05, for all) in female than in male and significantly lower (P<0.01, for both) in newborns delivered by caesarean section when compared to vaginal delivery. CONCLUSIONS: Since macula densa and retina are sites of lutein accumulation, the present findings open-up a new cue on the potential role of lutein in the prevention of the retinopathy of prematurity.

Metabolomic analysis of bronchoalveolar lavage fluid in preterm infants complicated by respiratory distress syndrome: preliminary results.

OBJECTIVE: Metabolomics is a technique used to non-invasively determine a snapshot of the current metabolic status of an organism by analyzing intact tissue or bio-fluids. The aim of the present preliminary study was to analyze metabolic profiles in preterm infants complicated by respiratory distress syndrome (RDS) trough bronchoalveolar lavage fluid (BALF) measurement. METHODS: Twelve BALF samples collected at birth prior surfactant, post-surfactant during mechanical ventilation and at extubation time-points, were analyzed by proton nuclear magnetic resonance spectroscopy and Gas chromatography-Mass Spectrometry (GC-MS). RESULTS: GC-MS analysis identified 25 metabolites of whom 10 had a known molecular structure. They were: undecane, decanoic acid, dodecanoic acid, hexadecanoic acid, octadecanoic acid, hexadecanoic acid methyl ester, 9-octadecanoic acid, tetracosanoic acid, myristic acid, phosphate. These metabolites were over-expressed in BALF collected during mechanical ventilation after surfactant administration. CONCLUSIONS: The present preliminary data suggest that metabolic profile in BALF of RDS infants is becoming possible opening a new cue of metabolomics as promising tool in management of sick premature infants.

Locomotor primitives in newborn babies and their development.

How rudimentary movements evolve into sophisticated ones during development remains unclear. It is often assumed that the primitive patterns of neural control are suppressed during development, replaced by entirely new patterns. Here we identified the basic patterns of lumbosacral motoneuron activity from multimuscle recordings in stepping neonates, toddlers, preschoolers, and adults. Surprisingly, we found that the two basic patterns of stepping neonates are retained through development, augmented by two new patterns first revealed in toddlers. Markedly similar patterns were observed also in the rat, cat, macaque, and guineafowl, consistent with the hypothesis that, despite substantial phylogenetic distances and morphological differences, locomotion in several animal species is built starting from common primitives, perhaps related to a common ancestral neural network.

Italia-Netherland PhD Program: the I.O. PhD Research Program.

In the framework of long-term scientific collaboration among the founder members coming from Holland and Italy there was a growing consensus to activate a philosophical doctorate (PhD) program, involving young Italian researchers in the field of perinatal medicine, neonatology and pediatrics. The aims were to promote excellence in research, offering to young Italian physicians the opportunity to maturate an International research experience leading to PhD degree, and to promote human and technological improvement energies in perinatal, neonatal and pediatrics research. Thus, an official collaboration among the Dutch Universities from Maastricht and Utrecht and the Italian Children's Hospital from Alessandria, has been activated on March 1st 2010, finalized to the PhD program. The experimental phase included the selection of projects and relative candidates after an interview-selection focusing on their scientific attitudes and the availability on their research projects. Candidates' selection started on May 2010 and on September 29th ten projects and candidates have been approved by the scientific commission. Research topics included: perinatal asphyxia, aging and the origin of adulthood neurodegenerative disease, neuroprotective strategies, biochemical pulmonology, intrauterine growth retardation and perinatal teratology. To date, all projects have been approved by local Ethics Committee from the University/Hospital of origin of the candidates. Five manuscripts have been published and/or submitted to international Journals regarding pneumology, perinatal asphyxia and teratology, whilst about 60-70% of data regarding clinical studies have already been collected.