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Premature infants who experience cerebrovascular injury frequently have acute and long-term neurologic complications. In this article, we explore the relationship between systemic hemodynamic insults and brain injury in this patient population and the mechanisms that might be at play.

Cerebrovascular insults are a leading cause of brain injury in premature infants, contributing to the high prevalence of motor, cognitive, and behavioral deficits. Understanding the complex pathways linking circulatory immaturity to brain injury in premature infants remains incomplete. These mechanisms are significantly different from those causing injury in the mature brain. The gaps in knowledge of normal and disturbed cerebral vasoregulation need to be addressed. This article reviews current understanding of cerebral perfusion, in the sick premature infant in particular, and discusses challenges that lie ahead.

Background: Infants born very and extremely premature (V/EPT) are at a significantly elevated risk for neurodevelopmental disorders and delays even in the absence of structural brain injuries. These risks may be due to earlier-than-typical exposure to the extrauterine environment, and its bright lights, loud noises, and exposures to painful procedures. Given the relative underdeveloped pain modulatory responses in these infants, frequent pain exposures may confer risk for later deficits. Methods: Resting-state fMRI scans were collected at term equivalent age from 148 (45% male) infants born V/EPT and 99 infants (56% male) born at term age. Functional connectivity analyses were performed between functional regions correlating connectivity to the number of painful skin break procedures in the NICU, including heel lances, venipunctures, and IV placements. Subsequently, preterm infants returned at 18 months, for neurodevelopmental follow-up and completed assessments for autism risk and general neurodevelopment. Results: We observed that V/EPT infants exhibit pronounced hyperconnectivity within the cerebellum and between the cerebellum and both limbic and paralimbic regions correlating with the number of skin break procedures. Moreover, skin breaks were strongly associated with autism risk, motor, and language scores at 18 months. Subsample analyses revealed that the same cerebellar connections strongly correlating with breaks at term age were associated with language dysfunction at 18 months. Conclusions: These results have significant implications for the clinical care of preterm infants undergoing painful exposures during routine NICU care, which typically occurs without anesthesia. Repeated pain exposures appear to have an increasingly detrimental effect on brain development during a critical period, and effects continue to be seen even 18 months later. [ABSTRACT FROM AUTHOR]

Objective: Perioperative stroke and periventricular leukomalacia have been reported to occur commonly in infants with congenital heart disease. We aimed to determine the incidence and type of brain injury in infants undergoing 2-ventricle repair in infancy and to determine risk factors associated with such injury. Methods: Forty-eight infants enrolled in a trial comparing 2 different hematocrits during surgical repair of congenital heart disease underwent brain magnetic resonance imaging scans and neurodevelopmental testing at 1 year of age. Results: Eighteen (38%) of our subjects had tiny foci of hemosiderin by susceptibility imaging, without evidence of abnormalities in corresponding regions on conventional magnetic resonance imaging sequences. Subjects with foci of hemosiderin had a significantly lower Psychomotor Developmental Index at 1 year of age (79.6 ± 16.5, mean ± standard deviation) compared with subjects without these foci (89.5 ± 15.3; P = .04). Older age at surgery and diagnostic group were significantly associated with the presence of hemosiderin foci. Only 1 subject had a small stroke (2%), and 2 subjects had periventricular leukomalacia (4%). Conclusion: Foci of hemosiderin without radiologic evidence of ischemic brain injury are an abnormality associated with adverse neurodevelopmental outcome not previously described in magnetic resonance imaging studies of children with surgically repaired congenital heart disease. The association of hemosiderin foci with older age at surgery and cardiac diagnosis, and not with risk factors associated with brain injury, in previous studies suggests that the cause and pathogenesis of this abnormality are different from ischemic brain lesions reported previously. [Copyright &y& Elsevier]

OBJECTIVES: Cerebral pressure passivity is common in sick premature infants and may predispose to germinal matrix/intraventricular hemorrhage (GM/IVH), a lesion with potentially serious consequences. We studied the association between the magnitude of cerebral pressure passivity and GM/IVH. PATIENTS AND METHODS: We enrolled infants <32 weeks' gestational age with indwelling mean arterial pressure (MAP) monitoring and excluded infants with known congenital syndromes or antenatal brain injury. We recorded continuous MAP and cerebral near-infrared spectroscopy hemoglobin difference (HbD) signals at 2 Hz for up to 12 hours/day and up to 5 days. Coherence and transfer function analysis between MAP and HbD signals was performed in 3 frequency bands (0.05-0.25, 0.25-0.5, and 0.5-1.0 Hz). Using MAP-HbD gain and clinical variables (including chorloamnionitis, Apgar scores, gestational age, birth weight, neonatal sepsis, and Score for Neonatal Acute Physiology II), we built a logistic regression model that best predicts cranial ultrasound abnormalities. RESULTS: In 88 infants (median gestational age: 26 weeks [range 23-30 weeks]), early cranial ultrasound showed GM/IVH in 31(37%) and parenchymal echodensities in 10 (12%) infants; late cranial ultrasound showed parenchymal abnormalities in 19 (30%) infants. Low-frequency MAP-HbD gain (highest quartile mean) was significantly associated with early GM/ lVH but not other ultrasound findings. The most parsimonious model associated with early GM/IVH included only gestational age and MAP-HbD gain. CONCLUSIONS: This novel cerebrovascular monitoring technique allows quantification of cerebral pressure passivity as MAP-HbD gain in premature infants. High MAP-HbD gain is significantly associated with GM/IVH. Precise temporal and causal relationship between MAP-HbD gain and GM/IVH awaits further study. [ABSTRACT FROM AUTHOR]

OBJECTIVE. Hypotension is a commonly treated complication of prematurity, although definitions and management guidelines vary widely. Our goal was to examine the relationship between current definitions of hypotension and early abnormal cranial ultrasound findings. METHODS. We prospectively measured mean arterial pressure in 84 infants who were ≤30 weeks' gestational age and had umbilical arterial catheters in the first 3 days of life. Sequential 5-minute epochs of continuous mean arterial pressure recordings were assigned a mean value and a coefficient of variation. We applied to our data 3 definitions of hypotension in current clinical use and derived a hypotensive index for each definition. We examined the association between these definitions of hypotension and abnormal cranial ultrasound findings between days 5 and 10. In addition, we evaluated the effect of illness severity (Score for Neonatal Acute Physiology II) on cranial ultrasound findings. RESULTS. Acquired lesions as shown on cranial ultrasound, present in 34 (40%) infants, were not predicted by any of the standard definitions of hypotension or by mean arterial pressure variability. With hypotension defined as mean arterial pressure < 10th percentile (<33 mm Hg) for our overall cohort, mean value for mean arterial pressure and hypotensive index predicted abnormal ultrasound findings but only in infants who were ≥27 weeks' gestational age and those with lower illness severity scores. CONCLUSIONS. Hypotension as diagnosed by currently applied thresholds for preterm infants is not associated with brain injury on early cranial ultrasounds. Blood pressure management directed at these population-based thresholds alone may not prevent brain injury in this vulnerable population. [ABSTRACT FROM AUTHOR]

Background. Advanced neuroimaging techniques have brought increasing recognition of cerebellar injury among premature infants. The developmental relationship between early brain injury and effects on the cerebrum and cerebellum remains unclear. Objectives. To examine whether cerebral parenchymal brain lesions among preterm infants are associated with subsequent decreases in cerebellar volume and, conversely, whether primary cerebellar injury is associated with decreased cerebral brain volumes, with advanced, 3-dimensional, volumetric MRI at term gestational age equivalent. Methods. Total cerebellar volumes and cerebellar gray and myelinated white matter volumes were determined through manual outlining for 74 preterm infants with unilateral periventricular hemorrhagic infarction (14 infants), bilateral diffuse periventricular leukomalacia (20 infants), cerebellar hemorrhage (10 infants), or normal term gestational age equivalent MRI findings (30 infants). Total brain and right/left cerebral and cerebellar hemispheric volumes were calculated. Results. Unilateral cerebral brain injury was associated with significantly decreased volume of the contralateral cerebellar hemisphere. Conversely, unilateral primary cerebellar injury was associated with a contralateral decrease in supratentorial brain volume. Cerebellar gray matter and myelinated white matter volumes were reduced significantly not only among preterm infants with primary cerebellar hemorrhage but also among infants with cerebral parenchymal brain injury. Conclusions. These data suggest strongly that both reduction in contralateral cerebellar volume with unilateral cerebral parenchymal injury and reduction in total cerebellar volume with bilateral cerebral lesions are related to trophic transsynaptic effects. Early-life cerebellar injury may contribute importantly to the high rates of cognitive, behavioral, and motor deficits reported for premature infants. [ABSTRACT FROM AUTHOR]

Objective. Cognitive impairments and academic failure are commonly reported in survivors of preterm birth. Recent studies suggest an important role for the cerebellum in the development of cognitive and social functions. The objective of this study was to examine the impact of prematurity itself, as well as prematurity-related brain injuries, on early postnatal cerebellar growth with quantitative MRI. Methods. Advanced 3-dimensional volumetric MRI was performed and cerebellar volumes were obtained by manual outlining in preterm (<37 weeks) and healthy term-born infants. Intracranial and total brain volumes were also calculated. Results. A total of 169 preterm and 20 healthy fullterm infants were studied; 145 had preterm MRI (pMRI), 75 had term MRI (tMRI), and 51 underwent both pMRI and tMRI. From 28 weeks' postconceptional age to term, mean cerebellar volume (177%) in preterm infants increased at a much faster rate than did mean intracranial (110%) or mean brain (107%) volumes. Smaller cerebellar volume was significantly related to lower gestational age at birth and to intracranial and total brain volumes. Mean cerebellar volume of preterm infants at tMRI was significantly smaller than the volumes of term-born infants. Cerebellar growth impairment was correlated strongly with associated brain injuries, even in the absence of direct cerebellar injury. Conclusions. Our data suggest that the growth of the immature cerebellum is particularly rapid during late gestation. However, this accelerated growth seems to be impeded by premature birth and associated brain injury. The long-term neurodevelopmental disabilities seen in survivors of premature birth may be attributable in part to impaired cerebellar development. [ABSTRACT FROM AUTHOR]

Premature birth is associated with high prevalence of neurodevelopmental impairments in surviving infants. The putative role of cerebellar and brainstem dysfunction remains poorly understood, particularly in the absence of overt structural injury. We compared in-utero versus ex-utero global, regional and local cerebellar and brainstem development in healthy fetuses (n ​= ​38) and prematurely born infants without evidence of structural brain injury on conventional MRI studies (n ​= ​74) that were performed at two time points: the first corresponding to the third trimester, either in utero or ex utero in the early postnatal period following preterm birth (30–40 weeks of gestation; 38 control fetuses; 52 premature infants) and the second at term equivalent age (37–46 weeks; 38 control infants; 58 premature infants). We compared 1) volumetric growth of 7 regions in the cerebellum (left and right hemispheres, left and right dentate nuclei, and the anterior, neo, and posterior vermis); 2) volumetric growth of 3 brainstem regions (midbrain, pons, and medulla); and 3) shape development in the cerebellum and brainstem using spherical harmonic description between the two groups. Both premature and control groups showed regional cerebellar differences in growth rates, with the left and right cerebellar hemispheres showing faster growth compared to the vermis. In the brainstem, the pons grew faster than the midbrain and medulla in both prematurely born infants and controls. Using shape analyses, premature infants had smaller left and right cerebellar hemispheres but larger regional vermis and paravermis compared to in-utero control fetuses. For the brainstem, premature infants showed impaired growth of the superior surface of the midbrain, anterior surface of the pons, and inferior aspects of the medulla compared to the control fetuses. At term-equivalent age, premature infants had smaller cerebellar hemispheres bilaterally, extending to the superior aspect of the left cerebellar hemisphere, and larger anterior vermis and posteroinferior cerebellar lobes than healthy newborns. For the brainstem, large differences between premature infants and healthy newborns were found in the anterior surface of the pons. This study analyzed both volumetric growth and shape development of the cerebellum and brainstem in premature infants compared to healthy fetuses using longitudinal MRI measurements. The findings in the present study suggested that preterm birth may alter global, regional and local development of the cerebellum and brainstem even in the absence of structural brain injury evident on conventional MRI. • Differential regional cerebellar and brainstem growths in premature infants versus healthy fetuses. • Altered cerebellar and brainstem shape in premature infants versus healthy fetuses. • Alterations in cerebellar and brainstem development in premature infants persist at term equivalent age. [ABSTRACT FROM AUTHOR]