Music impacts brain cortical microstructural maturation in very preterm infants: A longitudinal diffusion MR imaging study.

Preterm birth disrupts important neurodevelopmental processes occurring from mid-fetal to term-age. Musicotherapy, by enriching infants' sensory input, might enhance brain maturation during this critical period of activity-dependent plasticity. To study the impact of music on preterm infants' brain structural changes, we recruited 54 very preterm infants randomized to receive or not a daily music intervention, that have undergone a longitudinal multi-shell diffusion MRI acquisition, before the intervention (at 33 weeks' gestational age) and after it (at term-equivalent-age). Using whole-brain fixel-based (FBA) and NODDI analysis (n = 40), we showed a longitudinal increase of fiber cross-section (FC) and fiber density (FD) in all major cerebral white matter fibers. Regarding cortical grey matter, FD decreased while FC and orientation dispersion index (ODI) increased, reflecting intracortical multidirectional complexification and intracortical myelination. The music intervention resulted in a significantly higher longitudinal increase of FC and ODI in cortical paralimbic regions, namely the insulo-orbito-temporopolar complex, precuneus/posterior cingulate gyrus, as well as the auditory association cortex. Our results support a longitudinal early brain macro and microstructural maturation of white and cortical grey matter in preterm infants. The music intervention led to an increased intracortical complexity in regions important for socio-emotional development, known to be impaired in preterm infants.

Heated Humidifiers for Noninvasive Respiratory Support and the Risk of Burns in Neonates: A Bench Evaluation.

BACKGROUND: User errors in managing heated humidifiers (HHs) have been suggested to be a source of nasal burns in newborns treated with nasal CPAP. This study evaluated the risk of burns by reproducing 3 typical errors concerning the use of HHs. METHODS: Six HHs were tested on a bench in a traditional nasal CPAP setup: PMH5000, Aircon (Wilamed); MR730, MR850, MR950 (Fisher & Paykel); and H900 (Hamilton). Temperature was measured at the end of the inspiratory tubing limb. Errors tested were (1) misconnection of the HH thermal probes (NoProbe), (2) absence of gas flow while the HH is on (NoFlow), and (3) unsuitable repeated acknowledgment of the HH alarm (NoAlarm). These errors were combined in 3 standardized scenarios: (1) NoProbe + NoFlow + NoAlarm; (2) NoProbe + NoAlarm, and (3) NoFlow + NoAlarm. The NoProbe + NoFlow + NoAlarm and NoProbe + NoAlarm scenarios were not tested in the H900 and MR950 because the proprietary circuits of these HHs are equipped with embedded probes. RESULTS: For each HH, the highest inspiratory gas temperature (HIGT) and the rating on a self-designed risk-of-burn scale (ie, no risk, moderate risk, or severe risk) were reported. In the NoProbe + NoFlow + NoAlarm scenario, the risk was severe for the MR730, PMH5000, MR850, and Aircon, with HIGTs of > 65°C, 58°C, 56°C, and > 65°C, respectively. In the NoProbe + NoAlarm scenario, the risk was also severe for the same 4 HHs, with HIGTs of 56°C, 47°C, 56°C, and 48°C, respectively. In the NoFlow + NoAlarm scenario, the risk was severe for the PMH5000, Aircon, and H900, with HIGTs of 52°C, > 65°C, and 49°C, respectively, and moderate for the MR730, MR850, and MR950, with HIGTs of 45°C, 47°C, and 44°C, respectively). CONCLUSIONS: In case of misuse, 5 of the 6 tested devices presented a severe risk of inducing skin burns, whereas the MR950 presented a moderate risk.

Safety of Red Blood Cell Transfusion Using Small Central Lines in Neonates: An in vitro Non-inferiority Study.

Aim: This study aimed to investigate the safety of transfusing red blood cell concentrates (RBCCs) through small [24 gauge (24G)] and extra-small [28 gauge [28G)] peripherally inserted central catheters (PICCs), according to guidelines of transfusion practice in Switzerland. Methods: We performed a non-inferiority in vitro study to assess the safety of transfusing RBCC for 4 h at a 4 ml/h speed through 24G silicone and 28G polyurethane PICC lines, compared with a peripheral 24G short catheter. The primary endpoint was hemolysis percentage. Secondary endpoints were catheter occlusion, inline pressure, and potassium and lactate values. Results: For the primary outcome, hemolysis values were not statistically different among catheter groups (0.06% variation, p = 0.95) or over time (2.75% variation, p = 0.72). The highest hemolysis values in both 24G and 28G PICCs were below the non-inferiority predefined margin. We did not observe catheter occlusion. Inline pressure varied between catheters but followed the same pattern of rapid increase followed by stabilization. Potassium and lactate measurements were not statistically different among tested catheters (0.139% variation, p = 0.98 for potassium and 0.062%, p = 0.96 for lactates). Conclusions: This study shows that RBCC transfusion performed in vitro through 24G silicone and 28G polyurethane PICC lines is feasible without detectable hemolysis or pressure concerns. Also, it adds that, concerning hemolysis, transfusion of RBCC in small and extra-small PICC lines is non-inferior to peripheral short 24G catheters. Clinical prospective assessment in preterm infants is needed to confirm these data further.

Tracheal agenesis: optimization of computed tomography diagnosis by airway ventilation.

Tracheal agenesis is a rare and often lethal congenital defect that leads to airway emergency at birth. Computed tomography (CT) is the modality of choice to evaluate anomalous tracheal anatomy. The absence of spontaneous aeration of the tracheobronchial tree in children with tracheal agenesis makes CT interpretation difficult. We describe a procedure of airway management applied in two newborns with suspected tracheal agenesis. Correct airway management was performed immediately prior to CT examination by airway ventilation, with bag-valve mask alone in one case, and attached to an endotracheal tube placed into the esophagus in the other case. The images allowed for classification of tracheal agenesis. Computed tomography with appropriate airway ventilation is fundamental for the diagnosis of tracheal agenesis.

Dynamic spatio-temporal imaging of early reflow in a neonatal rat stroke model.

The aim of the study was to better understand blood-flow changes in large arteries and microvessels during the first 15 minutes of reflow in a P7 rat model of arterial occlusion. Blood-flow changes were monitored by using ultrasound imaging with sequential Doppler recordings in internal carotid arteries (ICAs) and basilar trunk. Relative cerebral blood flow (rCBF) changes were obtained by using laser speckle Doppler monitoring. Tissue perfusion was measured with [(14)C]-iodoantipyrine autoradiography. Cerebral energy metabolism was evaluated by mitochondrial oxygen consumption. Gradual increase in mean blood-flow velocities illustrated a gradual perfusion during early reflow in both ICAs. On ischemia, the middle cerebral artery (MCA) territory presented a residual perfusion, whereas the caudal territory remained normally perfused. On reflow, speckle images showed a caudorostral propagation of reperfusion through anastomotic connections, and a reduced perfusion in the MCA territory. Autoradiography highlighted the caudorostral gradient, and persistent perfusion in ventral and medial regions. These blood-flow changes were accompanied by mitochondrial respiration impairment in the ipsilateral cortex. Collectively, these data indicate the presence of a primary collateral pathway through the circle of Willis, providing an immediate diversion of blood flow toward ischemic regions, and secondary efficient cortical anastomoses in the immature rat brain.

Impact of intracranial blood-flow redistribution on stroke size during ischemia-reperfusion in 7-day-old rats.

We evaluated color-coded pulsed Doppler ultrasound imaging for the assessment of intracranial blood flow in two models of cerebral ischemia in 7-day-old (P7) rats. Blood-flow velocities (BFVs) were measured in the internal carotid arteries and basilar trunk upstream from the circle of Willis, and in the posterior cerebral arteries downstream (1) before, (2) during left middle cerebral artery electrocoagulation and 50 min-transient either one (I/R-1) or both (I/R-2) common carotid (CCA) arteries occlusion, and (3) after release of CCA(s) occlusion. At 48 h after ischemia 41-48% (I/R-1 model) and 24% (I/R-2 model) of rats did not present a lesion. Those rats displayed increased mean BFV in both right internal carotid artery and basilar trunk in I/R-1 model, and increased mean BFV in the basilar trunk (BT) in I/R-2 model. In contrast, no significant changes in mean BFV were observed in lesioned rats. Furthermore, mean BFV in the BT was inversely correlated to the size of the lesion (r² = 0.75, p<0.0001) in the I/R-2 model. Thus, we demonstrated the protective role of collateral support in P7 rodents. Ultrasound imaging can evidence the establishment or not of the cerebral collateral recruitment, leading to the presence or absence of a lesion. This novel approach should greatly help preclinical studies to reduce animal variability.

Melatonin promotes myelination by decreasing white matter inflammation after neonatal stroke.

Melatonin demonstrates neuroprotective properties in adult models of cerebral ischemia, acting as a potent antioxidant and anti-inflammatory agent. We investigated the effect of melatonin in a 7-d-old rat model of ischemia-reperfusion, leading to both cortical infarct and injury in the underlying white matter observed using MRI and immunohistochemistry. Melatonin was given i.p. as either a single dose before ischemia or a double-dose regimen, combining one before ischemia and one 24 h after reperfusion. At 48 h after injury, neither a significant reduction in cortical infarct volume nor a variation in the number of TUNEL- and nitrotyrosine-positive cells within the ipsilateral lesion was observed in melatonin-treated animals compared with controls. However, a decrease in the density of tomato lectin-positive cells after melatonin treatment was found in the white matter underlying cortical lesion. Furthermore, we showed a marked increase in the myelin basic protein-immunoreactivity in the cingulum and in the density of mature oligodendrocytes (APC-immunoreactive) in both the ipsilateral cingulum and external capsule. These results suggest that melatonin is not able to reduce cortical infarct volume in a neonatal stroke model but strongly reduces inflammation and promotes subsequent myelination in the white matter.

Unilateral blood flow decrease induces bilateral and symmetric responses in the immature brain.

The effects of hemodynamic changes in the developing brain have yet to be fully understood. The aim of this study was to explore the relationship between perturbations of the cerebral blood flow in the developing brain via unilateral hypoperfusion in P7 rats. As expected, nuclear caspase-3 (casp3) cleavage and DNA fragmentation were detected at 48 hours after stroke in the injured cortex. Surprisingly, casp3 was also cleaved in the contralateral cortex, although without cell death markers. Delayed (48 hours) casp3 cleavage without DNA fragmentation was also identified after unilateral common carotid artery occlusion, both in the hypoperfused cortex and the unaffected cortex, producing mirror images. Upstream calpain activation, caspase-2 cleavage, and mitochondrial cytochrome c release initiated casp3 cleavage, but did not produce preconditioning. The neuronal marker NeuN co-localized with cleaved casp3 in cortical layers II-III and VI and with gaba-amino butyric acid in layer III. Indeed, collateral supply was provided from the opposite side during carotid artery occlusion but not after reperfusion, and the number of cleaved casp3-positive cells significantly negatively correlated with the common carotid artery immediate reperfusion percentage. In summary, unilateral hypoperfusion, while insufficient to induce cell death, may active bilateral and symmetric casp3 in the P7 rat brain. Additionally, the opposite healthy hemisphere is altered due to the injury and thus should not be used as an internal control.

Gender-related differences in apoptotic pathways after neonatal cerebral ischemia.

Many central nervous system (CNS) diseases display sexual dimorphism, specifically a predilection for one gender or a gender-dependent response to treatment. Exposure to circulating sex steroids is felt to be a chief contributor to this phenomenon. However, CNS diseases of childhood and of the elderly also demonstrate gender predominance and/or sexual dimorphism response to therapies. In this short update, we provide information concerning one of the most interesting new emerging concepts related to the influence of the sex in the pathogenesis of developmental brain injuries leading to different levels of neuroprotection between genders after cerebral hypoxia-ischemia or ischemia.

Effect of the reperfusion after cerebral ischemia in neonatal rats using MRI monitoring.

Cerebral hypoxia-ischemia is an important cause of brain injury in the newborn infant. Our purpose was to study magnetic resonance (MR) imaging changes in P7 rat brains submitted to permanent or reversible ischemia. Ischemia was induced by permanent electro-cauterization of the middle cerebral artery combined with a permanent or a transient (50 min) common carotid artery occlusion. The early events during ischemia and reperfusion were investigated by T2-weighted images (T2WI) at 1 and 3 h and by serial diffusion-weighted images (DWI) during 3 h in a 7 T magnet with a standard weighted diffusion sequence (b=1282.04 s mm(-2)) and a SEMS sequence. Within the first hour after MCA occlusion, the T2WI areas of contrast enhancement increased to a mean volume of 12.9+/-6.4%, a steady state still detected at 3 h after the ischemic onset (10.5+/-2.5%). Contrast enhancement in DWI increased as soon as 15 min of ischemia in all animals up to 50 min after CCA occlusion. In permanent ischemia, DWI abnormalities volume then increased more slowly from 50 min to 3 h after CCA occlusion (+25%, n=5). In reversible ischemia, the DWI abnormalities volume either moderately decreased and reached a plateau (-8.4%, n=4) or dramatically decreased (-53.0%, n=3). Both T2WI and DWI evidenced a "patchy" pattern of recovery as also shown on cresyl violet-stained sections. In contrast to the adult, early ischemic injury in P7 rat brains is detected as an increase in hyper-intensities both in T2WI and DWI. Our data indicate that reperfusion is able to block edema evolution after neonatal stroke and that early T2WI and more accurately DWI allow to distinguish between different patterns of injury in reversible ischemia.

Perinatal asphyxia may present with features of neonatal atypical hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is the consequence of platelet consumption at sites of endothelial injury. Perinatal asphyxia (PA) may cause renal failure after birth and can be associated with disseminated intravascular coagulopathy (DIC) with platelet consumption. No biological investigation permits us to distinguish clearly between neonatal HUS and DIC. We report on three neonates with renal failure due to different degrees of PA. They presented biological features compatible with HUS, such as fragmentocytes ( approximately 2%), thrombopenia (<50,000/mm(3)), and anemia (<8 g/dl). One patient required peritoneal dialysis. Haptoglobin was undetectable for all three patients. Factor H and factor I, as well as components of the complement system (C3 and C4) and ADAMTS13 activity, were decreased. Two patients received daily fresh frozen plasma infusions over the first 4 weeks. Renal function improved in two patients; one patient had chronic renal failure. No neurological sequelae were noted. All blood parameters suggestive of thrombotic microangiopathy (TMA) were normal on days 12, 30, and 60. We hypothesize that endothelial cell damage concomitant with PA may lead to a vicious circle that results in consumption of platelets and plasma factors involved in hemostasis and/or fibrinolysis. In conclusion, PA, DIC and HUS are difficult to distinguish, and endothelial cell damage may be their common pathophysiological pathway.

Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender.

Hypoxia-ischaemia in the developing brain results in brain injury with prominent features of apoptosis. In the present study, a third generation dipeptidyl broad-spectrum caspase inhibitor, quinoline-Val-Asp(Ome)-CH2-O-phenoxy (Q-VD-OPh), was tested in a model of unilateral focal ischaemia with reperfusion in 7-day-old rats. Q-VD-OPh (1 mg/kg, i.p.) reduced cell death, resulting in significant neuroprotection at 48 h of recovery (infarct volume of 12.6 +/- 2.8 vs. 24.3 +/- 2.2%, p = 0.006). The neuroprotective effects observed at 48 h post-ischaemia hold up at 21 days of survival time and attenuate neurological dysfunction. Analysis by gender revealed that females were strongly protected (6.7 +/- 3.3%, p = 0.006), in contrast to males in which there was no significant effect, when Q-VD-OPh was given after clip removal on the left common carotid artery. Immunoblot analysis demonstrated that Q-VD-OPh inhibits caspase 3 cleavage into its p17 active form and caspase 1 up-regulation and cleavage in vivo. Following ischaemia in P7 rats, males and females displayed different time course and pattern of cytochrome c release and active p17 caspase 3 during the first 24 h of recovery. In contrast, no significant difference was observed for caspase 1 expression between genders. These results indicate that ischaemia activates caspases shortly after reperfusion and that the sex of the animal may strongly influences apoptotic pathways in the pathogenesis of neonatal brain injury. The specificity, effectiveness, and reduced toxicity of Q-VD-OPh may determine the potential use of peptide-derived irreversible caspase inhibitors as promising therapeutics.