Regional Differences in Gamma-Aminobutyric Acid and Glutamate Concentrations in the Healthy Newborn Brain.

BACKGROUND AND PURPOSE: Gamma-aminobutyric acid and glutamate system disruptions may underlie neonatal brain injury. However, in vivo investigations are challenged by the need for special 1H-MR spectroscopy sequences for the reliable measurement of the neurotransmitters in this population. We used J-edited 1H-MR spectroscopy (Mescher-Garwood point-resolved spectroscopy) to quantify regional in vivo gamma-aminobutyric acid and glutamate concentrations during the early postnatal period in healthy neonates. MATERIALS AND METHODS: We prospectively enrolled healthy neonates and acquired Mescher-Garwood point-resolved spectroscopy spectra on a 3T MR imaging scanner from voxels located in the cerebellum, the right basal ganglia, and the right frontal lobe. CSF-corrected metabolite concentrations were compared for regional variations and cross-sectional temporal trends with advancing age. RESULTS: Fifty-eight neonates with acceptable spectra acquired at postmenstrual age of 39.1 (SD, 1.3) weeks were included for analysis. Gamma-aminobutyric acid (+ macromolecule) (2.56 [SD, 0.1]) i.u., glutamate (3.80 [SD, 0.2]), Cho, and mIns concentrations were highest in the cerebellum, whereas NAA (6.72 [SD, 0.2]), NAA/Cho, Cr/Cho, and Glx/Cho were highest in the basal ganglia. Frontal gamma-aminobutyric acid (1.63 [SD, 0.1]), Glx (4.33 [SD, 0.3]), Cr (3.64 [SD, 0.2]), and Cho concentrations were the lowest among the ROIs. Glx, NAA, and Cr demonstrated a significant adjusted increase with postmenstrual age (ß = 0.2-0.35), whereas gamma-aminobutyric acid and Cho did not. CONCLUSIONS: We report normative regional variations and temporal trends of in vivo gamma-aminobutyric acid and glutamate concentrations reflecting the functional and maturational status of 3 distinct brain regions of the neonate. These measures will serve as important normative values to allow early detection of subtle neurometabolic alterations in high-risk neonates.

Cerebral modulation of the autonomic nervous system in term infants.

OBJECTIVE: Central topography of autonomic nervous system (ANS) function has yet to be fully deciphered. In adults it has been shown to lateralize sympathetic and parasympathetic influence predominantly to the right and left cerebral hemispheres, respectively. We examined functional topography of central ANS in newborn subjects utilizing spectral analysis of heart rate variability (HRV), an established measure of ANS function. STUDY DESIGN: We studied newborns with hypoxic-ischemic encephalopathy participating in a prospective study undergoing a therapeutic hypothermia protocol.We included subjects with continuous heart rate data over the first 3 h of normothermia (post rewarming) and brain magnetic resonance imaging, which was reviewed and scored according to a 4 region scheme. HRV was evaluated by spectral analysis in the low-frequency (0.05 to 0.25 Hz) and high-frequency (0.3 to 1 Hz) ranges. The relationship between injured brain regions and HRV was studied using multiple regressions. RESULTS: Forty eight newborns were included. When examined in isolation, right hemisphere injury had a significant negative effect on HRV (-0.088; 95% CI: -0.225,-0.008). The combination of posterior fossa region injury with right hemispheric injury or left hemispheric injury demonstrated significant positive (0.299; 95% CI: 0.065, 0.518) and negative (-0.475; 95% CI: -0.852, -0.128) influences on HRV, respectively. The association between brain injury location and HRV in the high-frequency range did not reach significance. CONCLUSION: Our data support the notion that lateralized cerebral modulation of the ANS, specifically of its sympathetic component, is present in the term newborn, and suggest complex modulation of these tracts by components of the posterior fossa.

Elucidating Metabolic Maturation in the Healthy Fetal Brain Using 1H-MR Spectroscopy.

BACKGROUND AND PURPOSE: (1)H-MRS provides a noninvasive way to study fetal brain maturation at the biochemical level. The purpose of this study was to characterize in vivo metabolic maturation in the healthy fetal brain during the second and third trimester using (1)H-MRS. MATERIALS AND METHODS: Healthy pregnant volunteers between 18 and 40 weeks gestational age underwent single voxel (1)H-MRS. MR spectra were retrospectively corrected for motion-induced artifacts and quantified using LCModel. Linear regression was used to examine the relationship between absolute metabolite concentrations and ratios of total NAA, Cr, and Cho to total Cho and total Cr and gestational age. RESULTS: Two hundred four spectra were acquired from 129 pregnant women at mean gestational age of 30.63 ± 6 weeks. Total Cho remained relatively stable across the gestational age (r(2) = 0.04, P = .01). Both total Cr (r(2) = 0.60, P < .0001) as well as total NAA and total NAA to total Cho (r(2) = 0.58, P < .0001) increased significantly between 18 and 40 weeks, whereas total NAA to total Cr exhibited a slower increase (r(2) = 0.12, P < .0001). Total Cr to total Cho also increased (r(2) = 0.53, P < .0001), whereas total Cho to total Cr decreased (r(2) = 0.52, P < .0001) with gestational age. The cohort was also stratified into those that underwent MRS in the second and third trimesters and analyzed separately. CONCLUSIONS: We characterized metabolic changes in the normal fetal brain during the second and third trimesters of pregnancy and derived normative metabolic indices. These reference values can be used to study metabolic maturation of the fetal brain in vivo.

Assessment of MRI-Based Automated Fetal Cerebral Cortical Folding Measures in Prediction of Gestational Age in the Third Trimester.

BACKGROUND AND PURPOSE: Traditional methods of dating a pregnancy based on history or sonographic assessment have a large variation in the third trimester. We aimed to assess the ability of various quantitative measures of brain cortical folding on MR imaging in determining fetal gestational age in the third trimester. MATERIALS AND METHODS: We evaluated 8 different quantitative cortical folding measures to predict gestational age in 33 healthy fetuses by using T2-weighted fetal MR imaging. We compared the accuracy of the prediction of gestational age by these cortical folding measures with the accuracy of prediction by brain volume measurement and by a previously reported semiquantitative visual scale of brain maturity. Regression models were constructed, and measurement biases and variances were determined via a cross-validation procedure. RESULTS: The cortical folding measures are accurate in the estimation and prediction of gestational age (mean of the absolute error, 0.43 ± 0.45 weeks) and perform better than (P = .024) brain volume (mean of the absolute error, 0.72 ± 0.61 weeks) or sonography measures (SDs approximately 1.5 weeks, as reported in literature). Prediction accuracy is comparable with that of the semiquantitative visual assessment score (mean, 0.57 ± 0.41 weeks). CONCLUSIONS: Quantitative cortical folding measures such as global average curvedness can be an accurate and reliable estimator of gestational age and brain maturity for healthy fetuses in the third trimester and have the potential to be an indicator of brain-growth delays for at-risk fetuses and preterm neonates.

Heart rate variability in encephalopathic newborns during and after therapeutic hypothermia.

OBJECTIVE: To evaluate whether heart rate variability (HRV) measures are predictive of neurological outcome in babies with hypoxic ischemic encephalopathy (HIE). STUDY DESIGN: This case-control investigation included 20 term encephalopathic newborns treated with systemic hypothermia in a regional neonatal intensive care unit. Electrocardiographic data were collected continuously during hypothermia. Spectral analysis of beat-to-beat heart rate interval was used to quantify HRV. HRV measures were compared between infants with adverse outcome (death or neurodevelopmental impairment at 15 months, n = 10) and those with favorable outcome (survivors without impairment, n = 10). RESULT: HRV differentiated infants by outcome during hypothermia through post-rewarming, with the best distinction between groups at 24 h and after 80 h of life. CONCLUSION: HRV during hypothermia treatment distinguished HIE babies who subsequently died or had neurodevelopmental impairment from intact survivors. This physiological biomarker may identify infants in need of adjuvant neuroprotective interventions. These findings warrant further investigation in a larger population of infants with HIE.

Prevalence and spectrum of in utero structural brain abnormalities in fetuses with complex congenital heart disease.

BACKGROUND AND PURPOSE: Brain injury is a major complication in neonates with complex congenital heart disease. Preliminary evidence suggests that fetuses with congenital heart disease are at greater risk for brain abnormalities. However, the nature and frequency of these brain abnormalities detected by conventional fetal MR imaging has not been examined prospectively. Our primary objective was to determine the prevalence and spectrum of brain abnormalities detected on conventional clinical MR imaging in fetuses with complex congenital heart disease and, second, to compare the congenital heart disease cohort with a control group of fetuses from healthy pregnancies. MATERIALS AND METHODS: We prospectively recruited pregnant women with a confirmed fetal congenital heart disease diagnosis and healthy volunteers with normal fetal echocardiogram findings who underwent a fetal MR imaging between 18 and 39 weeks gestational age. RESULTS: A total of 338 fetuses (194 controls; 144 with congenital heart disease) were studied at a mean gestational age of 30.61 ± 4.67 weeks. Brain abnormalities were present in 23% of the congenital heart disease group compared with 1.5% in the control group (P < .001). The most common abnormalities in the congenital heart disease group were mild unilateral ventriculomegaly in 12/33 (36.4%) and increased extra-axial spaces in 10/33 (30.3%). Subgroup analyses comparing the type and frequency of brain abnormalities based on cardiac physiology did not reveal significant associations, suggesting that the brain abnormalities were not limited to those with the most severe congenital heart disease. CONCLUSIONS: This is the first large prospective study reporting conventional MR imaging findings in fetuses with congenital heart disease. Our results suggest that brain abnormalities are prevalent but relatively mild antenatally in fetuses with congenital heart disease. The long-term predictive value of these findings awaits further study.

Brain perfusion in encephalopathic newborns after therapeutic hypothermia.

BACKGROUND AND PURPOSE: Cerebral perfusion patterns in neonates with HIE after therapeutic hypothermia have not been well described. The objectives of this study were to compare global and regional perfusion between infants with HIE and neonate controls and to relate measures of cerebral perfusion to brain injury on conventional MR imaging in neonates with HIE. MATERIALS AND METHODS: Term encephalopathic neonates meeting criteria for hypothermia between June 2011 and January 2012 were enrolled in this prospective observational study. MR imaging-ASL was performed in the second week of life. Comparisons were made with data from neonate controls who underwent the same imaging protocol. NIRS measures of cerebral oxygenation during and immediately after hypothermia were also evaluated in a subset of patients. Secondary analyses were performed to assess cerebral perfusion and oxygenation differences by pattern of injury on qualitative MR imaging interpretation. RESULTS: We enrolled 18 infants with HIE and 18 control infants. Mean global CBF and regional CBF in the basal ganglia, thalamus, and anterior white matter were higher in cases compared with controls. Infants with HIE with injury on MR imaging, however, had lower CBF (significant in the thalamus) compared with those with normal MR imaging. Decreased FTOE by NIRS further differentiated patients with HIE with injury on MR imaging. CONCLUSIONS: Disturbed cerebral perfusion is observed in the second week of life in some babies with HIE despite treatment with hypothermia. Infants with HIE with injury on MR imaging have lower regional CBF in the thalamus compared with those without injury, possibly representing pseudonormalization of CBF and low metabolic demand after progression to irreversible brain injury.

Delayed cortical development in fetuses with complex congenital heart disease.

Neurologic impairment is a major complication of complex congenital heart disease (CHD). A growing body of evidence suggests that neurologic dysfunction may be present in a significant proportion of this high-risk population in the early newborn period prior to surgical interventions. We recently provided the first evidence that brain growth impairment in fetuses with complex CHD has its origins in utero. Here, we extend these observations by characterizing global and regional brain development in fetuses with hypoplastic left heart syndrome (HLHS), one of the most severe forms of CHD. Using advanced magnetic resonance imaging techniques, we compared in vivo brain growth in 18 fetuses with HLHS and 30 control fetuses from 25.4-37.0 weeks of gestation. Our findings demonstrate a progressive third trimester fall-off in cortical gray and white matter volumes (P < 0.001), and subcortical gray matter (P < 0.05) in fetuses with HLHS. Significant delays in cortical gyrification were also evident in HLHS fetuses (P < 0.001). In the HLHS fetus, local cortical folding delays were detected as early as 25 weeks in the frontal, parietal, calcarine, temporal, and collateral regions and appear to precede volumetric brain growth disturbances, which may be an early marker of elevated risk for third trimester brain growth failure.

Cerebellar cleft: confirmation of the neuroimaging pattern.

We recently described the neuroimaging and clinical findings in 6 children with cerebellar clefts and proposed that they result from disruptive changes following prenatal cerebellar hemorrhage. We now report an additional series of 9 patients analyzing the clinical and neuroimaging findings. The clefts were located in the left cerebellar hemisphere in 5 cases, in the right in 3, and bilaterally in one child who had bilateral cerebellar hemorrhages as a preterm infant at 30 weeks gestation. In one patient born at 24 weeks of gestation a unilateral cerebellar hemorrhage has been found at the age of 4 months. Other findings included disordered alignment of the folia and fissures, an irregular gray/white matter junction, and abnormal arborization of the white matter in all cases. Supratentorial abnormalities were found in 4 cases. All but 2 patients were born at term. We confirm the distinct neuroimaging pattern of cerebellar clefts. Considering the documented fetal cerebellar hemorrhage in our first series, we postulate that cerebellar clefts usually represent residual disruptive changes after a prenatal cerebellar hemorrhage. Exceptionally, as now documented in 2 patients, cerebellar clefts can be found after neonatal cerebellar hemorrhages in preterm infants. The short-term outcome in these children was variable.

Time course of changes in diffusion-weighted magnetic resonance imaging in a case of neonatal encephalopathy with defined onset and duration of hypoxic-ischemic insult.

The onset and duration of hypoxic-ischemic (HI) insults rarely can be determined precisely in perinatal asphyxia. The need to establish the timing of HI insults will be critical for the successful application of evolving neuroprotective therapies that may be administered to the asphyxiated newborn. Diffusion-weighted magnetic resonance imaging has emerged as an imaging technique that can be used to identify HI brain injury before the detection of abnormalities by conventional magnetic resonance imaging. This case illustrates the early changes in diffusion-weighted and conventional magnetic resonance imaging studies and in quantitative values of the apparent diffusion coefficient in a unique case of neonatal asphyxia in which the onset and duration of the HI insult were known.hypoxia-ischemia, newborn brain, perinatal asphyxia, diffusion-weighted imaging, proton magnetic resonance spectroscopy.

Developmental and neurologic effects of alpha-stat versus pH-stat strategies for deep hypothermic cardiopulmonary bypass in infants.

OBJECTIVES: In a randomized single-center trial, we compared developmental and neurologic outcomes at 1 and 2 to 4 years of age in children who underwent reparative cardiac operations at less than 9 months of age after use of the alpha-stat versus pH-stat strategy during deep hypothermic cardiopulmonary bypass. METHODS: Among 168 children eligible for follow-up, 1-year developmental evaluations were carried out on 111, neurologic evaluations on 110, and electroencephalographic evaluations on 102. Parents of 122 children completed questionnaires on behavior and development when children were 2 to 4 years of age. RESULTS: The Psychomotor Development Index scores of the alpha-stat and pH-stat groups did not differ significantly (P =.97). For Mental Development Index scores, the treatment group effect differed according to diagnosis (P =.007). In the D -transposition of the great arteries (n = 59) and tetralogy of Fallot (n = 36) subgroups, the pH-stat group had slightly higher Mental Development Index scores than the alpha-stat group, although these differences were not statistically significant. In the ventricular septal defect subgroup (n = 16), the alpha-stat group had significantly higher scores. Psychomotor Development Index and Mental Development Index scores were significantly higher in the group with D -transposition of the great arteries than in the other 2 groups (P =.03 and P =.01, respectively). Across all diagnoses, Mental Development Index scores were significantly higher than Psychomotor Development Index scores (P <.001). Treatment group assignment was not significantly associated with abnormalities on neurologic examination (P =.70) or electroencephalographic examination (P =.77) at 1 year or with parents' ratings of children's development (P =.99) or behavior (P =.27) at age 2 to 4 years. CONCLUSIONS: Use of alpha-stat versus pH-stat acid-base management strategy during reparative infant cardiac operations with deep hypothermic cardiopulmonary bypass was not consistently related to either improved or impaired early neurodevelopmental outcomes.

Cerebral infarction in Menkes' disease.

Menkes' disease is an X-linked disorder caused by impaired intracellular transport of copper. Currently, no therapy effectively arrests the relentless neurodegeneration of Menkes' disease. Previous neuroimaging reports of patients with Menkes' disease describe a range of abnormalities, including intracranial vessel tortuosity and cerebral white matter changes. We report two infants with Menkes' disease who developed ischemic cerebrovascular disease early in infancy. Magnetic resonance studies, including diffusion-weighted imaging and proton magnetic resonance spectroscopy, demonstrated bilateral infarctions of deep gray matter nuclei, a finding not previously described in Menkes' disease. Potential mechanisms for these cerebrovascular lesions in Menkes' disease include the susceptibility to free radical attack and inadequate energy supply from oxidative phosphorylation. These infarctions may play an unrecognized but important role in the neurodegeneration of children with Menkes' disease. The development of effective therapeutic agents against this disease will require a more detailed understanding of such underlying mechanisms.

Hydrocephalus associated with glycogen storage disease type II (Pompe's disease).

The authors describe a case of hydrocephalus in an 8-month, 2-week-old infant who had been previously diagnosed with glycogen storage disease type II. Cranial imaging revealed no evidence of obstruction within the ventricular system. This case adds to the central nervous system complications associated with this disorder. Several possible mechanisms for the hydrocephalus observed in this infant are discussed.

New technologies in pediatric neurology. Near-infrared spectroscopy.

Near-infrared spectroscopy (NIRS) is a relatively new technology that offers the enormous advantage of making measurements in vivo of changes in cerebral hemodynamics and oxygenation. Because NIRS is noninvasive and portable, it can provide real-time measurements of these changes at the bedside. Thus NIRS is ideally suited to the study of many physiological and pathological processes affecting the brain, particularly in the infant or young child in the intensive care unit or operating room. This review outlines the basic principles, advantages, and limitations of the current state of NIRS technology. An emphasis is placed on the animal and clinical studies that are relevant to the field of child neurology, with an eye to the future evolution and potential applications of this promising technique.

Mechanisms of brain injury during infant cardiac surgery.

Neurological injury is a major and often debilitating complication of congenital heart disease and open-heart surgery. Paradoxically, the full impact of this complication has been underscored by the marked decrease in mortality and the rescue of infants with desperate and previously lethal heart conditions. Although recent focus has been on mechanisms of brain injury originating during open-heart surgery, this article also emphasizes the importance of mechanisms initiated or perpetuated during the preoperative and postoperative periods. In addition to the usually implicated mechanism of hypoxia-ischemia, recent genetic advances suggest an important role for genetic deletion syndromes. Inflammatory cascades have been implicated in the end-organ injury seen after cardiopulmonary bypass and might play a role in neurological dysfunction. These mechanisms are reviewed, with an emphasis on recent developments in our understanding of brain injury in this population.

The pursuit of effective neuroprotection during infant cardiac surgery.

Advances in infant cardiac surgery have resulted in a dramatic decline in mortality rates; however, neurological morbidity remains an important concern. The effectiveness of a number of interventional strategies to prevent or minimize brain injury during open heart surgery are currently being investigated. This article provides an overview of two approaches: (1) interventions to enhance intraoperative cerebral oxygenation so as to prevent hypoxic-ischemic insults, and (2) the application of cerebral rescue therapies to attenuate the cascade of brain injury. Infant cardiac surgery provides a controlled environment in which to apply these neuroprotective approaches, so as to optimize the quality of life of these vulnerable children.

Posthemorrhagic hydrocephalus and brain injury in the preterm infant: dilemmas in diagnosis and management.

Advances in neonatal critical care have reduced the incidence of intraventricular hemorrhage (IVH) in the newborn. Paradoxically, however, the prevalence of the complications of IVH including posthemorrhagic hydrocephalus (PHHC) has increased. By virtue of its association with long-term neurodevelopmental disability, posthemorrhagic hydrocephalus is an ominous diagnosis in the premature infant. Animal models have demonstrated that ventricular distention may cause direct cerebral parenchymal injury. Evidence for secondary parenchymal injury in the premature infant with PHHC is by necessity indirect. The precise impact of secondary parenchymal injury on the overall neurological outcome of premature infants with PHHC remains unclear in large part because of the vulnerability of the immature brain to other forms of injury (e.g., periventricular leukomalacia) that may be difficult to distinguish from injury due to distention. Furthermore, parenchymal injury due to PVL may cause ventricular enlargement that does not benefit from CSF diversion. Because these primary and secondary mechanisms of injury may operate concurrently, the precise or dominant cause of ventricular enlargement is often difficult to establish with certainty in the neonatal period. These diagnostic dilemmas have in turn impeded the development and evaluation of therapies specifically aimed at reversing ventricular distention and preventing secondary parenchymal injury. This article focuses on the current dilemmas in diagnosis and management of this potentially reversible form of injury as well as on potential future strategies for its prevention.

Hypoxic-ischemic brain injury in the newborn. Cellular mechanisms and potential strategies for neuroprotection.

Recent advances have delineated many of the complex cellular mechanisms of cerebral hypoxic-ischemic injury. These developments have created opportunities for the design of rational "mechanism-based" strategies that target specific injurious processes. A number of neuroprotective agents have entered adult clinical trial and practice. For the newborn infant, progress in this areas has been judiciously delayed by toxicity concerns. Central to those safety concerns is the close relationship between mechanisms of hypoxic-ischemic cellular injury and normal developmental processes. These cellular mechanisms and the dilemmas facing the advance of this field are discussed. The likelihood of an effective single "magic bullet" neuroprotective strategy emerging in the near future appears remote. Rather more likely is the development of "cocktail" therapies that seek to exploit synergistic antagonism at multiple levels in the complex concentration of cellular events mediating hypoxic-ischemic cellular injury. However, such combination therapies will require elucidation of the complex inter-relationships between mechanisms of cellular injury, brain development, and the combination of therapies envisioned.

Neurologic complications of cardiac disease in the newborn.

Advances in the management of infants with congenital heart disease have lead to a striking decrease in mortality. The most dramatic impact has been in the newborn infant with complex and previously lethal heart disease. These heart lesions have become amenable to corrective procedures in the newborn period because of the development of support techniques such as low-flow cardiopulmonary bypass and deep hypothermic circulatory arrest. However, these techniques have demonstrated their own inherit risk for neurologic injury. Consequently, in recent years there has emerged a growing population of infants surviving congenital heart disease only to manifest subsequent neurologic complications originating from injury in the hemodynamically unstable preoperative period or periods of intraoperative hypoperfusion. The preservation of neurology function has emerged as the next frontier in the management of congenital heart disease. Finally, neurologic dysfunction in the newborn with cardiac disease may reflect associated brain malformations or the combined cardiac and brain manifestations of inherited metabolic disease. The clinical features and mechanisms of brain injury are discussed for these structural and metabolic cardiac diseases presenting in the newborn infant.