Tailoring Biomimetic Phosphorylcholine-Containing Block Copolymers as Membrane-Targeting Cellular Rescue Agents.

Some synthetic polymers can block cell death when applied following an injury that would otherwise kill the cell. This cellular rescue occurs through interactions of the polymers with cell membranes. However, general principles for designing synthetic polymers to ensure strong, but nondisruptive, cell membrane targeting are not fully elucidated. Here, we tailored biomimetic phosphorylcholine-containing block copolymers to interact with cell membranes and determined their efficacy in blocking neuronal death following oxygen-glucose deprivation. By adjusting the hydrophilicity and membrane affinity of poly(2-methacryloyloxyethyl phosphorylcholine) (polyMPC)-based triblock copolymers, the surface active regime in which the copolymers function effectively as membrane-targeting cellular rescue agents was determined. We identified nonintrusive interactions between the polymer and the cell membrane that alter the collective dynamics of the membrane by inducing rigidification without disrupting lipid packing or membrane thickness. In general, our results open new avenues for biological applications of polyMPC-based polymers and provide an approach to designing membrane-targeting agents to block cell death after injury.

Poloxamer 188 decreases membrane toxicity of mutant SOD1 and ameliorates pathology observed in SOD1 mouse model for ALS.

Here we report a gain in function for mutant (mt) superoxide dismutase I (SOD1), a cause of familial amyotrophic lateral sclerosis (FALS), wherein small soluble oligomers of mtSOD1 acquire a membrane toxicity. Phosphatidylglycerol (PG) lipid domains are selectively targeted, which could result in membrane damage or "toxic channels" becoming active in the bilayer. This PG-selective SOD1-mediated membrane toxicity is largely reversible in vitro by a widely-available FDA-approved surfactant and membrane-stabilizer P188. Treatment of G93ASOD1 transgenic mice with P188 significantly delayed symptoms onset, extended survival and decreased motoneuron death. The use of P188 or an analogue, which targets mtSOD1 misfolding-induced membrane toxicity, may provide a new direction for ALS treatment.

Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents.

The goal of this work was to define the contributions of intrinsic and synaptic mechanisms toward spontaneous network-wide bursting activity, observed in dissociated rat hippocampal cell cultures. This network behavior is typically characterized by short-duration bursts, separated by order of magnitude longer interburst intervals. We hypothesize that while short-timescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Nap) currents govern burst onset during interburst intervals. To test this, we used synaptic receptor antagonists picrotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP) to selectively block GABAA, AMPA, and NMDA receptors and riluzole to selectively block Nap channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABAA + NMDA + AMPA, NMDA + AMPA, GABAA + AMPA, GABAA + NMDA, AMPA, NMDA, GABAA, and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify the aforementioned independent and interactive synaptic receptor contributions toward spectro-temporal burst properties including intraburst spike rate, burst activity index, burst duration, power in the local field potential, network connectivity, and transmission delays. We found that blocking intrinsic Nap currents completely abolished bursting activity, demonstrating their critical role in burst onset within the network. On the other hand, blocking different combinations of synaptic receptors revealed that spectro-temporal burst properties are uniquely associated with synaptic functionality and that excitatory connectivity is necessary for the presence of network-wide bursting. In addition to confirming the critical contribution of direct excitatory effects, mixed-effects modeling also revealed distinct combined (nonlinear) contributions of excitatory and inhibitory synaptic activity to network bursting properties.

The membrane-active tri-block copolymer pluronic F-68 profoundly rescues rat hippocampal neurons from oxygen-glucose deprivation-induced death through early inhibition of apoptosis.

Pluronic F-68, an 80% hydrophilic member of the Pluronic family of polyethylene-polypropylene-polyethylene tri-block copolymers, protects non-neuronal cells from traumatic injuries and rescues hippocampal neurons from excitotoxic and oxidative insults. F-68 interacts directly with lipid membranes and restores membrane function after direct membrane damage. Here, we demonstrate the efficacy of Pluronic F-68 in rescuing rat hippocampal neurons from apoptosis after oxygen-glucose deprivation (OGD). OGD progressively decreased neuronal survival over 48 h in a severity-dependent manner, the majority of cell death occurring after 12 h after OGD. Administration of F-68 for 48 h after OGD rescued neurons from death in a dose-dependent manner. At its optimal concentration (30 µm), F-68 rescued all neurons that would have died after the first hour after OGD. This level of rescue persisted when F-68 administration was delayed 12 h after OGD. F-68 did not alter electrophysiological parameters controlling excitability, NMDA receptor-activated currents, or NMDA-induced increases in cytosolic calcium concentrations. However, F-68 treatment prevented phosphatidylserine externalization, caspase activation, loss of mitochondrial membrane potential, and BAX translocation to mitochondria, indicating that F-68 alters apoptotic mechanisms early in the intrinsic pathway of apoptosis. The profound neuronal rescue provided by F-68 after OGD and the high level of efficacy with delayed administration indicate that Pluronic copolymers may provide a novel, membrane-targeted approach to rescuing neurons after brain ischemia. The ability of membrane-active agents to block apoptosis suggests that membranes or their lipid components play prominent roles in injury-induced apoptosis.

Superoxide generated at mitochondrial complex III triggers acute responses to hypoxia in the pulmonary circulation.

RATIONALE: The role of reactive oxygen species (ROS) signaling in the O(2) sensing mechanism underlying acute hypoxic pulmonary vasoconstriction (HPV) has been controversial. Although mitochondria are important sources of ROS, studies using chemical inhibitors have yielded conflicting results, whereas cellular models using genetic suppression have precluded in vivo confirmation. Hence, genetic animal models are required to test mechanistic hypotheses. OBJECTIVES: We tested whether mitochondrial Complex III is required for the ROS signaling and vasoconstriction responses to acute hypoxia in pulmonary arteries (PA). METHODS: A mouse permitting Cre-mediated conditional deletion of the Rieske iron-sulfur protein (RISP) of Complex III was generated. Adenoviral Cre recombinase was used to delete RISP from isolated PA vessels or smooth muscle cells (PASMC). MEASUREMENTS AND MAIN RESULTS: In PASMC, RISP depletion abolished hypoxia-induced increases in ROS signaling in the mitochondrial intermembrane space and cytosol, and it abrogated hypoxia-induced increases in [Ca(2+)](i). In isolated PA vessels, RISP depletion abolished hypoxia-induced ROS signaling in the cytosol. Breeding the RISP mice with transgenic mice expressing tamoxifen-activated Cre in smooth muscle permitted the depletion of RISP in PASMC in vivo. Precision-cut lung slices from those mice revealed that RISP depletion abolished hypoxia-induced increases in [Ca(2+)](i) of the PA. In vivo RISP depletion in smooth muscle attenuated the acute hypoxia-induced increase in right ventricular systolic pressure in anesthetized mice. CONCLUSIONS: Acute hypoxia induces superoxide release from Complex III of smooth muscle cells. These oxidant signals diffuse into the cytosol and trigger increases in [Ca(2+)](i) that cause acute hypoxic pulmonary vasoconstriction.

Peroxiredoxin-5 targeted to the mitochondrial intermembrane space attenuates hypoxia-induced reactive oxygen species signalling.

The ability to adapt to acute and chronic hypoxia is critical for cellular survival. Two established functional responses to hypoxia include the regulation of gene transcription by HIF (hypoxia-inducible factor), and the constriction of pulmonary arteries in response to alveolar hypoxia. The mechanism of O2 sensing in these responses is not established, but some studies implicate hypoxia-induced mitochondrial ROS (reactive oxygen species) signalling. To further test this hypothesis, we expressed PRDX5 (peroxiredoxin-5), a H2O2 scavenger, in the IMS (mitochondrial intermembrane space), reasoning that the scavenging of ROS in that compartment should abrogate cellular responses triggered by the release of mitochondrial oxidants to the cytosol. Using adenoviral expression of IMS-PRDX5 (IMS-targeted PRDX5) in PASMCs (pulmonary artery smooth muscle cells) we show that IMS-PRDX5 inhibits hypoxia-induced oxidant signalling in the IMS and cytosol. It also inhibits HIF-1α stabilization and HIF activity in a dose-dependent manner without disrupting cellular oxygen consumption. IMS-PRDX5 expression also attenuates the increase in cytosolic [Ca(2+)] in PASMCs during hypoxia. These results extend previous work by demonstrating the importance of IMS-derived ROS signalling in both the HIF and lung vascular responses to hypoxia.

Sirtuin 3 deficiency does not augment hypoxia-induced pulmonary hypertension.

Alveolar hypoxia elicits increases in mitochondrial reactive oxygen species (ROS) signaling in pulmonary arterial (PA) smooth muscle cells (PASMCs), triggering hypoxic pulmonary vasoconstriction. Mice deficient in sirtuin (Sirt) 3, a nicotinamide adenine dinucleotide-dependent mitochondrial deacetylase, demonstrate enhanced left ventricular hypertrophy after aortic banding, whereas cells from these mice reportedly exhibit augmented hypoxia-induced ROS signaling and hypoxia-inducible factor (HIF)-1 activation. We therefore tested whether deletion of Sirt3 would augment hypoxia-induced ROS signaling in PASMCs, thereby exacerbating the development of pulmonary hypertension (PH) and right ventricular hypertrophy. In PASMCs from Sirt3 knockout (Sirt3(-/-)) mice in the C57BL/6 background, we observed that acute hypoxia (1.5% O2; 30 min)-induced changes in ROS signaling, detected using targeted redox-sensitive, ratiometric fluorescent protein sensors (roGFP) in the mitochondrial matrix, intermembrane space, and the cytosol, were indistinguishable from Sirt3(+/+) cells. Acute hypoxia-induced cytosolic calcium signaling in Sirt3(-/-) PASMCs was also indistinguishable from Sirt3(+/+) cells. During sustained hypoxia (1.5% O2; 16 h), Sirt3 deletion augmented mitochondrial matrix oxidant stress, but this did not correspond to an augmentation of intermembrane space or cytosolic oxidant signaling. Sirt3 deletion did not affect HIF-1α stabilization under normoxia, nor did it augment HIF-1α stabilization during sustained hypoxia (1.5% O2; 4 h). Sirt3(-/-) mice housed in chronic hypoxia (10% O2; 30 d) developed PH, PA wall remodeling, and right ventricular hypertrophy that was indistinguishable from Sirt3(+/+) littermates. Thus, Sirt3 deletion does not augment hypoxia-induced ROS signaling or its consequences in the cytosol of PASMCs, or the development of PH. These findings suggest that Sirt3 responses may be cell type specific, or restricted to certain genetic backgrounds.

One SUMO is sufficient to silence the dimeric potassium channel K2P1.

Small ubiquitin modifier 1 (SUMO1) is shown to regulate K2P1 background channels in the plasma membrane (PM) of live mammalian cells. Confocal microscopy reveals native SUMO1, SAE1, and Ubc9 (the enzymes that activate and conjugate SUMO1) at PM where SUMO1 and expressed human K2P1 are demonstrated to colocalize. Silent K2P1 channels in excised PM patches are activated by SUMO isopeptidase (SENP1) and resilenced by SUMO1. K2P1-Lys274 is crucial: when mutated to Gln, Arg, Glu, Asp, Cys, or Ala, the channels are constitutively active and insensitive to SUMO1 and SENP1. Tandem mass spectrometry confirms conjugation of SUMO1 to the epsilon-amino group of Lys274 in vitro. FRET microscopy shows that assembly of K2P1 and SUMO1 requires Lys274. Single-particle TIRF microscopy shows that wild-type channels in PM have two K2P1 subunits and assemble with two SUMO1 monomers. Although channels engineered with one Lys274 site carry just one SUMO1 they are activated and silenced by SENP1 and SUMO1 like wild-type channels.

A Randomized Clinical Trial of Inhaled Nitric Oxide Treatment in Premature Infants Reveals the Effect of Maternal Racial Identity on Efficacy.

Respiratory distress syndrome increases the risk of death and bronchopulmonary dysplasia (BPD) in premature infants. Inhaled nitric oxide (iNO) may reduce these risks. Recent meta-analyses have suggested that iNO is effective only at doses higher than 5 ppm and in infants born to Black mothers. In a randomized, double-blinded, controlled trial, infants born before 32 0/7 weeks gestation, weighing <1500 g, and requiring respiratory support were assigned to receive iNO for either seven days (short iNO), or until 33 0/7 weeks PMA (long iNO). The primary outcome was death or BPD. A total of 273 patients were enrolled, of whom 83 receiving long iNO (61.5%) experienced the primary outcome, compared with 65 (47.1%) receiving short iNO (relative risk (RR) 1.37; 95% confidence interval (CI), 1.06-1.79; p = 0.017). This increase was due solely to increased BPD in infants weighing 750-999 g (RR 1.33, 95% CI 1.07-1.66, p = 0.009). However, there was no difference in the numbers of infants requiring supplemental oxygen at 40 weeks PMA. Among infants < 750 g, long-iNO-treated infants had a lower cumulative probability of death (χ2 5.12, p = 0.02). Long iNO increased the primary outcome in non-Black infants (RR 1.93, 95% CI 1.20-3.24) but not in Black infants. Understanding how maternal racial identity determines responses of premature infants to iNO may help narrow the gap in health outcomes between Black and non-Black infants.

Emerging Activity Patterns and Synaptogenesis in Dissociated Hippocampal Cultures.

Cultures of dissociated hippocampal neurons display a stereotypical development of network activity patterns within the first three weeks of maturation. During this process, network connections develop and the associated spiking patterns range from increasing levels of activity in the first two weeks to regular bursting activity in the third week of maturation. Characterization of network structure is important to examine the mechanisms underlying the emergent functional organization of neural circuits. To accomplish this, confocal microscopy techniques have been used and several automated synapse quantification algorithms based on (co)localization of synaptic structures have been proposed recently. However, these approaches suffer from the arbitrary nature of intensity thresholding and the lack of correction for random-chance colocalization. To address this problem, we developed and validated an automated synapse quantification algorithm that requires minimal operator intervention. Next, we applied our approach to quantify excitatory and inhibitory synaptogenesis using confocal images of dissociated hippocampal neuronal cultures captured at 5, 8, 14 and 20 days in vitro, the time period associated with the development of distinct neuronal activity patterns. As expected, we found that synaptic density increased with maturation, coinciding with increasing spiking activity in the network. Interestingly, the third week of the maturation exhibited a reduction in excitatory synaptic density suggestive of synaptic pruning that coincided with the emergence of regular bursting activity in the network.

Hypoxia triggers subcellular compartmental redox signaling in vascular smooth muscle cells.

RATIONALE: Recent studies have implicated mitochondrial reactive oxygen species (ROS) in regulating hypoxic pulmonary vasoconstriction (HPV), but controversy exists regarding whether hypoxia increases or decreases ROS generation. OBJECTIVE: This study tested the hypothesis that hypoxia induces redox changes that differ among subcellular compartments in pulmonary (PASMCs) and systemic (SASMCs) smooth muscle cells. METHODS AND RESULTS: We used a novel, redox-sensitive, ratiometric fluorescent protein sensor (RoGFP) to assess the effects of hypoxia on redox signaling in cultured PASMCs and SASMCs. Using genetic targeting sequences, RoGFP was expressed in the cytosol (Cyto-RoGFP), the mitochondrial matrix (Mito-RoGFP), or the mitochondrial intermembrane space (IMS-RoGFP), allowing assessment of oxidant signaling in distinct intracellular compartments. Superfusion of PASMCs or SASMCs with hypoxic media increased oxidation of both Cyto-RoGFP and IMS-RoGFP. However, hypoxia decreased oxidation of Mito-RoGFP in both cell types. The hypoxia-induced oxidation of Cyto-RoGFP was attenuated through the overexpression of cytosolic catalase in PASMCs. CONCLUSIONS: These results indicate that hypoxia causes a decrease in nonspecific ROS generation in the matrix compartment, whereas it increases regulated ROS production in the IMS, which diffuses to the cytosol of both PASMCs and SASMCs.

Nature of interactions between PEO-PPO-PEO triblock copolymers and lipid membranes: (I) effect of polymer hydrophobicity on its ability to protect liposomes from peroxidation.

PEO-PPO-PEO triblock copolymers have opposing effects on lipid membrane integrity: they can behave either as membrane sealants or as membrane permeabilizers. To gain insights into their biomembrane activities, the fundamental interactions between a series of PEO-based polymers and phospholipid vesicles were investigated. Specifically, the effect of copolymer hydrophobicity on its ability to prevent liposomes from peroxidation was evaluated, and partitioning free energy and coefficient involved in the interactions were derived. Our results show that the high degree of hydrophilicity is a key feature of the copolymers that can effectively protect liposomes from peroxidation and the protective effect of the copolymers stems from their adsorption at the membrane surface without penetrating into the bilayer core. The origin of this protective effect induced by polymer absorption is attributed to the retardation of membrane hydration dynamics, which is further illustrated in the accompanying study on dynamic nuclear polarization (DNP)-derived hydration dynamics (Cheng, C.-Y.; Wang, J.-Y.; Kausik, R.; Lee, K. Y. C.; Han S. Biomacromolecules, 2012, DOI: 10.1021/bm300848c).

Etomidate and propofol inhibit the neurotransmitter release machinery at different sites.

The mechanism of general anaesthetic action is only partially understood. Facilitation of inhibitory GABAA receptors plays an important role in the action of most anaesthetics, but is thought to be especially relevant in the case of intravenous anaesthetics, like etomidate and propofol. Recent evidence suggests that anaesthetics also inhibit excitatory synaptic transmission via a presynaptic mechanism(s), but it has been difficult to determine whether these agents act on the neurotransmitter release machinery itself. In the present study we sought to determine whether the intravenous anaesthetics propofol and etomidate inhibit the release machinery. For these studies we used an experimental approach that directly regulated [Ca2+]i at neurotransmitter release sites, thereby bypassing anaesthetic effects on channels and receptors in order to allow anaesthetic effects on the neurotransmitter release machinery to be examined in isolation. The data show that clinically relevant concentrations of propofol and etomidate inhibited the neurotransmitter release machinery in neurosecretory cells and in cultured hippocampal neurons. md130A is a mutant form of syntaxin with a truncated C-terminus. Overexpressing md130A in PC12 cells completely eliminated the reduction in neurotransmitter release produced by propofol, without affecting release itself. In contrast, overexpressing md130A in PC12 cells had little or no effect on the response to etomidate. These results suggest that both propofol and etomidate inhibit neurotransmitter release by a direct interaction with SNAREs and/or SNARE-associated proteins but they do so at different sites.

Safety and efficacy of inhaled nitric oxide treatment for premature infants with respiratory distress syndrome: follow-up evaluation at early school age.

AIMS: The aims of the study were to assess the long-term safety and compare neurodevelopmental outcomes in school-age children born prematurely who received inhaled nitric oxide or placebo during the first week of life in a randomized, double-blinded study. Children treated with inhaled nitric oxide had previously been shown to have decreased intraventricular haemorrhage and periventricular leukomalacia as newborns and decreased cognitive impairment at 2 years (L.W. Doyle and P.J. Anderson. (2005) Arch Dis Child Fetal Neonatal Ed, 90, F484-F8). METHODS: It is follow-up study of medical outcomes, neurodevelopmental assessment and school readiness in 135 of 167 (81%) surviving premature infants seen at 5.7±1.0 years. RESULTS: Compared to placebo-treated children (n=65), iNO-treated children (n=70) demonstrated no difference in growth parameters, school readiness or need for subsequent hospitalization. However, iNO-treated children were less likely to have multiple chronic morbidities or technology dependence (p=0.05). They also had less functional disability (p=0.05). CONCLUSION: These results demonstrate the long-term safety of iNO in premature infants. Furthermore, iNO treatment may improve health status by decreasing the incidence of severe ongoing morbidities and technology dependence and may also decrease the incidence of educational and community functional disability of premature infants at early school age.

CLC-3 channels modulate excitatory synaptic transmission in hippocampal neurons.

It is well established that ligand-gated chloride flux across the plasma membrane modulates neuronal excitability. We find that a voltage-dependent Cl(-) conductance increases neuronal excitability in immature rodents as well, enhancing the time course of NMDA receptor-mediated miniature excitatory postsynaptic potentials (mEPSPs). This Cl(-) conductance is activated by CaMKII, is electrophysiologically identical to the CaMKII-activated CLC-3 conductance in nonneuronal cells, and is absent in clc-3(-/-) mice. Systematically decreasing [Cl(-)](i) to mimic postnatal [Cl(-)](i) regulation progressively decreases the amplitude and decay time constant of spontaneous mEPSPs. This Cl(-)-dependent change in synaptic strength is absent in clc-3(-/-) mice. Using surface biotinylation, immunohistochemistry, electron microscopy, and coimmunoprecipitation studies, we find that CLC-3 channels are localized on the plasma membrane, at postsynaptic sites, and in association with NMDA receptors. This is the first demonstration that a voltage-dependent chloride conductance modulates neuronal excitability. By increasing postsynaptic potentials in a Cl(-) dependent fashion, CLC-3 channels regulate neuronal excitability postsynaptically in immature neurons.

Effects of PEO-PPO-PEO triblock copolymers on phospholipid membrane integrity under osmotic stress.

The effects of PEO-PPO-PEO triblock copolymers, mainly Poloxamer 188, on phospholipid membrane integrity under osmotic gradients were explored using giant unilamellar vesicles (GUVs). Fluorescence leakage assays showed two opposing effects of P188 on the structural integrity of GUVs depending on the duration of their incubation time. A two-state transition mechanism of interaction between the triblock copolymers and the phospholipid membrane is proposed: an adsorption (I) and an insertion (II) state. While the triblock copolymer in state I acts to moderately retard the leakage, their insertion in state II perturbs the lipid packing, thus increasing the membrane permeability. Our results suggest that the biomedical application of PEO-PPO-PEO triblock copolymers, either as cell membrane resealing agents or as accelerators for drug delivery, is directed by the delicate balance between these two states.

Predicting school readiness from neurodevelopmental assessments at age 2 years after respiratory distress syndrome in infants born preterm.

AIM: To determine whether neurodevelopmental outcomes at the age of 2 years accurately predict school readiness in children who survived respiratory distress syndrome after preterm birth. METHOD: Our cohort included 121 preterm infants who received surfactant and ventilation and were enrolled in a randomized controlled study of inhaled nitric oxide for respiratory distress syndrome. Abnormal outcomes at the age of 2 years were defined as neurosensory disability (cerebral palsy, blindness, or bilateral hearing loss) or delay (no neurosensory disability but Bayley Scales of Infant Development mental or performance developmental index scores <70). School readiness (assessed at a mean age of 5y 6mo, SD 1y) was determined using neurodevelopmental assessments of motor, sensory, receptive vocabulary, perceptual, conceptual, and adaptive skills. RESULTS: The mean birthweight of the cohort (57 males, 64 females) was 987g (SD 374), and the mean gestational age was 27.3 weeks (SD 2.6). At the age of 2 years, the neurodevelopmental classification was 'disabled' in 11% and 'delayed' in 23%. At the age of 5 years 6 months, intensive special education was required for 11% and some special education for 21%. Disability and delay at the age of 2 years were 92% and 50% predictive of lack of school readiness respectively, whereas only 15% of children who were normal at the age of 2 years were not school ready at the later assessment. Children with delay at 2 years were more likely to need special education if they were socially disadvantaged. INTERPRETATION: Without preschool developmental supports, preterm survivors living in poverty will require more special education services.

Correlates of Normal and Abnormal General Movements in Infancy and Long-Term Neurodevelopment of Preterm Infants: Insights from Functional Connectivity Studies at Term Equivalence.

Preterm infants born before 32 weeks gestation have increased risks for neurodevelopmental impairment at two years of age. How brain function differs between preterm infants with normal or impaired development is unknown. However, abnormal spontaneous motor behavior at 12-15 weeks post-term age is associated with neurodevelopmental impairment. We imaged brain blood oxygen level-dependent signals at term-equivalent age in 62 infants born at <32 weeks gestation and explored whether resting state functional connectivity (rsFC) differed with performances on the General Movement Assessment (GMA) at 12-15 weeks, and Bayley III scores at two years of corrected age. Infants with aberrant general movements exhibited decreased rsFC between the basal ganglia and regions in parietal and frontotemporal lobes. Infants with normal Bayley III cognitive scores exhibited increased rsFC between the basal ganglia and association cortices in parietal and occipital lobes compared with cognitively impaired children. Infants with normal motor scores exhibited increased rsFC between the basal ganglia and visual cortices, compared with children with motor impairment. Thus, the presence of abnormal general movements is associated with region-specific differences in rsFC at term. The association of abnormal long-term neurodevelopmental outcomes with decreased rsFC between basal ganglia and sub-score specific cortical regions may provide biomarkers of neurodevelopmental trajectory and outcome.

Approaches to Noninvasive Respiratory Support in Preterm Infants: From CPAP to NAVA.

Endotracheal intubation and invasive mechanical ventilation have been mainstays in respiratory care of neonates with respiratory distress syndrome. Together with antenatal steroids and surfactant, this approach has accounted for significant reductions in neonatal mortality. However, with the increased survival of very low birthweight infants, the incidence of bronchopulmonary dysplasia (BPD), the primary respiratory morbidity of prematurity, has also increased. Arrest of alveolar growth and development and the abnormal development of the pulmonary vasculature after birth are the primary causes of BPD. However, invasive ventilation-associated lung inflammation and airway injury have long been believed to be important contributors. In fact, discontinuing invasive ventilation in favor of noninvasive respiratory support has been considered the single best approach that neonatologists can implement to reduce BPD. In this review, we present and discuss the mechanisms, efficacy, and long-term outcomes of the four main approaches to noninvasive respiratory support of the preterm infant currently in use: nasal continuous positive airway pressure, high-flow nasal cannula, nasal intermittent mandatory ventilation, and neurally adjusted ventilatory assist. We show that noninvasive ventilation can decrease rates of intubation and the need for invasive ventilation in preterm infants with respiratory distress syndrome. However, none of these noninvasive approaches decrease rates of BPD. Accordingly, noninvasive respiratory support should be considered for clinical goals other than the reduction of BPD.