Neurovascular coupling in the developing neonatal brain at rest.

The neonatal brain is an extremely dynamic organization undergoing essential development in terms of connectivity and function. Several functional imaging investigations of the developing brain have found neurovascular coupling (NVC) patterns that contrast with those observed in adults. These discrepancies are partly due to that NVC is still developing in the neonatal brain. To characterize the vascular response to spontaneous neuronal activations, a multiscale multimodal noninvasive approach combining simultaneous electrical, hemodynamic, and metabolic recordings has been developed for preterm infants. Our results demonstrate that the immature vascular network does not adopt a unique strategy to respond to spontaneous cortical activations. NVC takes on different forms in the same preterm infant during the same recording session in response to very similar types of neural activation. This includes (a) positive stereotyped hemodynamic responses (increases in HbO, decreases in HbR together with increases in rCBF and rCMRO2), (b) negative hemodynamic responses (increases in HbR, decreases in HbO together with decreases in rCBF and rCMRO2), and (c) Increases and decreases in both HbO-HbR and rCMRO2 together with no changes in rCBF. Age-related NVC maturation is demonstrated in preterm infants, which can contribute to a better understanding/prevention of cerebral hemodynamic risks in these infants.

Assessment of cerebrovascular development and intraventricular hemorrhages in preterm infants with optical measures of the brain arterial pulse wave.

Preterm infants (born at 24-34 weeks of gestational age) suffer from a high incidence of neurological complications. Cerebrovascular lesions (intraventricular hemorrhages, IVH, and ischemic injury) due to the immaturity of the vascular system and its inability to adapt to the extra-uterine environment are the major causes of adverse neurological outcomes. We investigated the feasibility of assessing cerebrovascular status in preterm infants using a novel non-invasive optical procedure, pulse-DOT, usable within the incubator. Pulse-DOT, validated in adults, provides estimates of cerebral arterial status based on optical measurements of the pulse wave. These measurements are taken with a high-density optode montage and provide accurate spatial and temporal information. We found that two pulse parameters (pulse relaxation function, PReFx, and pulse rise time, PRT) in the investigated frontotemporal region, correlated with infant's age at recording, indexing cerebrovascular development. Moreover, PRT differentiated infants with and without concurrent IVH (sensitivity = 100%, specificity = 70%). These values are at least as high as those of the resistivity index obtained with transcranial Doppler of the middle cerebral artery, the current clinical method of choice for investigating arterial elasticity in preterm infants. This makes pulse-DOT a promising tool for investigating cerebrovascular risk factors and related pathologies in preterm infants.

Consequence of intraventricular hemorrhage on neurovascular coupling evoked by speech syllables in preterm neonates.

Intraventricular Hemorrhage (IVH) is the leading cause of neurological and cognitive impairment in preterm neonates with an incidence that increases with increasing prematurity. In the present study, we tested how preterm neonates with IVH react to external stimulation (i.e. speech syllables). We compared their neural responses measured by electroencephalography (EEG), and hemodynamic responses measured by functional near-infrared spectroscopy (fNIRS), with those of healthy preterms. A neural response to syllables was observed in these infants, but did not induce a vascular response in contrast with healthy neonates. These results clearly demonstrate that the cerebral vascular network in IVH preterm neonates was unable to compensate for the increased metabolism resulting from neuronal activation in response to external stimulation. Optical imaging is thus a sensitive tool to identify altered cerebral hemodynamic in critically ill preterms before behavioral changes are manifested or when only minor abnormalities on other functional monitoring techniques such as EEG are visible. We propose that a multi-modal approach provides unique opportunities for early monitoring of cognitive functions and opens up new possibilities for clinical care and recommended practices by studying the difficulties of the premature brain to adapt to its environment.

Evaluation of the (1,3)-ß-D-glucan assay for the diagnosis of neonatal invasive yeast infections.

Most newborns in the neonatal intensive care unit (NICU) are premature and at risk of invasive fungal infections (IFIs). Invasive yeast infections (IYIs) are the most common fungal infections in this population. These infections are difficult to diagnose because symptoms are nonspecific, and the sensitivity of blood cultures is low. The serum (1,3)-ß-D-glucan (BDG) assay provides a reliable marker for the diagnosis of IFIs in adults with haematological malignancies. We assessed the diagnostic performance of this test in neonatal IYIs and its contribution to the monitoring of antifungal treatment. A retrospective study was performed in the NICU of the French University Hospital of Amiens from February 2012 to February 2014. Forty-seven neonates (33 males, 14 females) with a median gestational age of 30 weeks (IQR: 27-31) and median birth weight of 1200 g (IQR: 968-1700) were included and divided into three groups: 21 control neonates (CTRL), 20 neonates with probable IYI (PB), and six with proven IYI (PV). Median BDG levels were significantly higher in the global IYI group (PB + PV): 149 pg/ml (IQR: 85-364) vs. CTRL group: 39 pg/ml (IQR: 20-94) (P < .001). The optimal cut-off was 106 pg/ml (sensitivity 61.5%; specificity 81%). BDG levels decreased with antifungal treatment. BDG was detectable in cerebrospinal fluid, but the interest of this for diagnostic purposes remains unclear. Our results suggest that the BDG assay may be useful for the early identification of IYIs in neonates and for monitoring antifungal therapy efficacy.

Molecular epidemiology of a Malassezia pachydermatis neonatal unit outbreak.

The non-lipid-dependent yeast Malassezia pachydermatis is predominantly zoophilic but occasionally colonizes the human skin. This yeast caused an outbreak in a neonatal iIntensive care unit (NICU). This study aimed to describe the molecular epidemiology of this M. pachydermatis outbreak. All the M. pachydermatis isolates collected at a French University Hospital from January 2012 to April 2013 were included in the study. M. pachydermatis isolates, sampled from various biological samples sites in 25 patients, were identified via MALDI-TOF mass spectrometry and typed using intergenic-spacer 1 (IGS1) nucleotide sequence polymorphisms analysis. By analyzing 90 IGS1 sequences (including 43 deposited in GenBank), we found that of the 186 M. pachydermatis isolates, 47 were viable for typing and all of them clustered within type 3; 78.7% clustered within the 3D subtype; the remaining clustered within three newly described subtypes: 3E (4.3%), 3F (8.5%) and 3 G (8.5%). No particular subtype was associated with a collection site or a particular time period. This first molecular investigation of a M. pachydermatis outbreak in neonates showed that multiple genotypes can colonize the same neonate patient by. The source of this polyclonal outbreak could not be identified. It stopped after infection control measures, including the prohibition of a lipid-rich moisturizing hand cream used by the health care staff, had been implemented.

Relationship between relative cerebral blood flow, relative cerebral blood volume, and relative cerebral metabolic rate of oxygen in the preterm neonatal brain.

The mechanisms responsible for coupling between relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative cerebral metabolic rate of oxygen ([Formula: see text]), an important function of the microcirculation in preterm infants, remain unclear. Identification of a causal relationship between rCBF-rCBV and [Formula: see text] in preterms may, therefore, help to elucidate the principles of cortical hemodynamics during development. We simultaneously recorded rCBF and rCBV and estimated [Formula: see text] by two independent acquisition systems: diffuse correlation spectroscopy and near-infrared spectroscopy, respectively, in 10 preterms aged between 28 and 35 weeks of gestational age. Transfer entropy was calculated in order to determine the directionality between rCBF-rCBV and [Formula: see text]. The surrogate method was applied to determine statistical significance. The results show that rCBV and [Formula: see text] have a predominant driving influence on rCBF at the resting state in the preterm neonatal brain. Statistical analysis robustly detected the correct directionality of rCBV on rCBF and [Formula: see text] on rCBF. This study helps to clarify the early organization of the rCBV-rCBF and [Formula: see text] inter-relationship in the immature cortex.

Blood product transfusions are associated with an increase in serum (1-3)-beta-d-glucan in infants during the initial hospitalization in neonatal intensive care unit (NICU).

INTRODUCTION: Serum (1-3)-beta-d-glucan (BDG) assay has been proposed as an adjunct for the rapid diagnosis of invasive fungal infection (IFI). However, false-positive results have been reported following transfusion of blood products in adults. AIMS: To assess the relationship between blood product transfusion and elevated BDG in neonates. METHOD: Retrospective study including neonates ≤32 weeks, with no fungal colonization or infection, in whom BDG assay was performed for suspicion of IFI. Patients were classified in Transfusion (n = 78) and No Transfusion (n = 55) groups depending on whether or not they were transfused. Clinical, biochemical and microbiological characteristics were recorded. A BDG assay >80 pg/mL was considered as positive. STATISTICAL ANALYSES: bivariate and multivariate logistic regression. Results (median, IQR): One hundred and thirty-three infants were included (gestational age 28.4 weeks, 26.9-30; birth weight 1000 g, 847-1300). BDG was higher in the Transfusion group (170 pg/mL, 65-317) than in the No Transfusion group (57 pg/mL, 34-108; p < 0.001). False-positive BDG assay results were associated with red blood cells (RBC) and fresh frozen plasma (FFP) transfusions. CONCLUSION: BDG is increased after RBC and FFP transfusions in neonates, leading to overdiagnosis of IFI. Fungal colonization status in peripheral sites and central cultures could help to reduce the risk of misdiagnosis.

Functional Maps at the Onset of Auditory Inputs in Very Early Preterm Human Neonates.

During the last trimester of human gestation, neurons reach their final destination and establish long- and short-distance connections. Due to the difficulties obtaining functional data at this age, the characteristics of the functional architecture at the onset of sensory thalamocortical connectivity in humans remain largely unknown. In particular, it is unknown to what extent responses evoked by an external stimulus are general or already sensitive to certain stimuli. In the present study, we recorded high-density event-related potentials (ERPs) in 19 neonates, tested ten weeks before term (28-32 weeks gestational age (wGA), that is, at an average age of 30 wGA) by means of a syllable discrimination task (i.e., a phonetic change: ba vs. ga; and a voice change: male vs. female voice). We first observed that the syllables elicited 4 peaks with distinct topographies implying a progression of the sensory input along a processing hierarchy; second, repetition induced a decrease in the amplitude (repetition suppression) of these peaks, but their latencies and topographies remained stable; and third, a change of stimulus generated mismatch responses, which were more precisely time-locked to event onset in the case of a phonetic change than in the case of a voice change. A hierarchical and parallel functional architecture is therefore able to process environmental sounds in a timely precise fashion, well before term birth. This elaborate functional architecture at the onset of extrinsic neural activity suggests that specialized areas weakly dependent on the environment are present in the perisylvian region as part of the genetic endowment of the human species.

Noninvasive technique for the diagnosis of patent ductus arteriosus in premature infants by analyzing pulse wave phases on photoplethysmography signals measured in the right hand and the left foot.

OBJECTIVE: To evaluate the impact of patent ductus arteriosus (PDA) on the pulse phase difference (PPD) between the left foot (postductal region) and the right hand (preductal region). MATERIALS AND METHODS: PPD was determined from arterial photoplethysmography signals (pulse waves) measured by infrared sensors routinely used for pulse oximetry in 56 premature infants less than 32 weeks gestation. Only infants with significant PDA (sPDA) diagnosed by echocardiography were treated with ibuprofen (for 3 days). Patients were classified according to whether or not they responded (Success/Failure) to this treatment. The Control group was composed of infants in whom ductus had already closed spontaneously at the time of the first echocardiography. The 3 groups were compared in terms of PPD at the beginning (T1) and at the end (T2) of the study. For patients in the Failure (n = 17) and Success groups (n = 18), T1 corresponded to the first day of treatment and T2 to the day after completion of the course of ibuprofen. In the Control group (n = 21), T1 corresponded to 1 to 3 days of life (DOL), and T2 to 4-6 DOL. RESULTS: Compared to the Control group, PPD was higher in the Failure (at T1 and T2) and Success (at T1) groups characterized by sPDA. After ibuprofen therapy, PPD in the Success group decreased to about the level observed in the Control group. The area under the ROC curve of PPD for the diagnosis of sPDA was 0.98 (95% CI 0.96-1); for an optimal cut-off of PPD ≥ 1.65 deg/cm, the sensitivity was 94.2% and the specificity was 98.3%. CONCLUSION: In this study, PPD was correlated with ductus arteriosus status evaluated by echocardiography, indicating involvement of the ductal shunt in the mechanism of redistribution in systemic vascular territories. PPD can be considered for the diagnosis of hemodynamically significant PDA.

Patent ductus arteriosus in preterm infants is associated with cardiac autonomic alteration and predominant parasympathetic stimulation.

BACKGROUND: Hemodynamic disorders in patent ductus arteriosus (PDA) may alter the stimulation of the autonomic nervous system. AIM: The objective of this study was to analyze the orthosympathetic-parasympathetic balance in preterm infants with PDA. STUDY DESIGN AND SUBJECTS: Patients were included from consecutive admissions to Amiens University Hospital from 2009 to 2011. We defined a PDA group and a Control group (echographic criteria). For each patient, three 4-minutes segments of ECG were recorded during quiet sleep and the RR chronologic series were extracted, and spectral (Fourier Transform) and time-domain analyses were performed. For each parameter of heart rate variability (HRV), average of three measures was determined and analysed. RESULTS: Forty-four patients were included for analysis. The total HRV power, LF/HF ratio and SDNN were lower in the PDA group (n = 22, gestational age 28.2 w ± 1.9) than in the Control group (n = 22, gestational age 28.8 w ± 2). The decrease in LF power destabilized the autonomic balance in favour of parasympathetic stimulation. After adjustment for postconceptional age, PDA was still associated with parameters of autonomic neural stimulation. CONCLUSION: These results suggest association of PDA with predominance of parasympathetic stimulation in preterm infants. The mechanisms of homeostasis in patients with PDA are very complex and involve both circulatory adaptations and control by autonomic pathway. If confirmed, our results could be interesting for future researches aiming to verify the interest of new targeted therapies for the management of PDA.

'Leptotrichia amnionii', a newly reported cause of early onset neonatal meningitis.

'Leptotrichia amnionii' is an underestimated fastidious inhabitant of the vaginal flora that can cause upper genital tract infections when predisposing factors are present. We describe here what is believed to be the first reported case of early onset meningitis due to 'L. amnionii' in a neonate with intrauterine growth retardation. The outcome was favourable after cefotaxime treatment.

Syllabic discrimination in premature human infants prior to complete formation of cortical layers.

The ontogeny of linguistic functions in the human brain remains elusive. Although some auditory capacities are described before term, whether and how such immature cortical circuits might process speech are unknown. Here we used functional optical imaging to evaluate the cerebral responses to syllables at the earliest age at which cortical responses to external stimuli can be recorded in humans (28- to 32-wk gestational age). At this age, the cortical organization in layers is not completed. Many neurons are still located in the subplate and in the process of migrating to their final location. Nevertheless, we observed several points of similarity with the adult linguistic network. First, whereas syllables elicited larger right than left responses, the posterior temporal region escaped this general pattern, showing faster and more sustained responses over the left than over the right hemisphere. Second, discrimination responses to a change of phoneme (ba vs. ga) and a change of human voice (male vs. female) were already present and involved inferior frontal areas, even in the youngest infants (29-wk gestational age). Third, whereas both types of changes elicited responses in the right frontal region, the left frontal region only reacted to a change of phoneme. These results demonstrate a sophisticated organization of perisylvian areas at the very onset of cortical circuitry, 3 mo before term. They emphasize the influence of innate factors on regions involved in linguistic processing and social communication in humans.

(1-3)-ß-D-glucan levels in candidiasis infections in the critically ill neonate.

INTRODUCTION: The diagnosis of neonatal invasive Candida infections (ICIs) is problematic because the clinical signs are not specific and blood cultures are rarely positive. Hence, new diagnostic markers are needed. OBJECTIVE: To assess the contribution of serum (1-3)-ß-d-glucan (BDG) levels to the diagnosis of neonatal ICIs and to analyse the change in this parameter during antifungal therapy. METHODS: This retrospective study (December 2010-March 2012) was performed at Amiens University Medical Center (Amiens, France). We included newborns in whom a BDG assay was performed for a suspected ICI and classified as infected (n = 18) or non-infected (n = 43). RESULTS: Sixty-one patients (median (IQR) gestational age: 28.5 weeks (26.7-30.6); birth weight: 1000 g (910-1440)) were included. The BDG level was higher in the infected group (364 pg/ml (131-976) vs. 89 pg/ml (30-127); p < 0.001). The optimal BDG cut-off for distinguishing between non-infected and infected patients was 125 pg/ml (Se = 84%, Sp = 75%). The BDG level fell over the course of antifungal therapy. CONCLUSION: Our study results suggest that BDG levels were increased in neonatal invasive Candida infections (cut-off for BDG positivity > 125 pg/ml). The change in the serum BDG levels may be of value in evaluating the efficacy of antifungal therapy.