Soo Hyun Kwon

The Role of Neuroimaging in Predicting Neurodevelopmental Outcomes of Preterm Neonates

Magnetic resonance imaging (MRI) is a safe and high-resolution neuroimaging modality that is increasingly used in the neonatal population to assess brain injury and its consequences on brain development. It is superior to cranial ultrasound for the definition of patterns of both white and gray matter maturation and injury and therefore has the potential to provide prognostic information on the neurodevelopmental outcomes of the preterm population. Furthermore, the development of sophisticated MRI strategies, including diffusion tensor imaging, resting state functional connectivity, and magnetic resonance spectroscopy, may increase the prognostic value, helping to guide parental counseling and allocate early intervention services.

Does prenatal stress alter the developing connectome

Human neurodevelopment requires the organization of neural elements into complex structural and functional networks called the connectome. Emerging data suggest that prenatal exposure to maternal stress plays a role in the wiring, or miswiring, of the developing connectome. Stress-related symptoms are common in women during pregnancy and are risk factors for neurobehavioral disorders ranging from autism spectrum disorder, attention deficit hyperactivity disorder, and addiction, to major depression and schizophrenia. This review focuses on structural and functional connectivity imaging to assess the impact of changes in women’s stress-based physiology on the dynamic development of the human connectome in the fetal brain.

Gene-environment interactions in severe intraventricular hemorrhage of preterm neonates

Intraventricular hemorrhage (IVH) of the preterm neonate is a complex developmental disorder, with contributions from both the environment and the genome. IVH, or hemorrhage into the germinal matrix of the developing brain with secondary periventricular infarction, occurs in that critical period of time before the 32nd to 33rd wk postconception and has been attributed to changes in cerebral blood flow to the immature germinal matrix microvasculature. Emerging data suggest that genes subserving coagulation, inflammatory, and vascular pathways and their interactions with environmental triggers may influence both the incidence and severity of cerebral injury and are the subject of this review. Polymorphisms in the Factor V Leiden gene are associated with the atypical timing of IVH, suggesting an as yet unknown environmental trigger. The methylenetetrahydrofolate reductase (MTHFR) variants render neonates more vulnerable to cerebral injury in the presence of perinatal hypoxia. The present study demonstrates that the MTHFR 677C>T polymorphism and low 5-min Apgar score additively increase the risk of IVH. Finally, review of published preclinical data suggests the stressors of delivery result in hemorrhage in the presence of mutations in collagen 4A1, a major structural protein of the developing cerebral vasculature. Maternal genetics and fetal environment may also play a role.

Preterm birth alters neonatal, functional rich club organization

Alterations in neural networks are associated with the cognitive difficulties of the prematurely born. Using functional magnetic resonance imaging, we analyzed functional connectivity for preterm (PT) and term neonates at term equivalent age. Specifically, we constructed whole-brain networks and examined rich club (RC) organization, a common construct among complex systems where important (or “rich”) nodes connect preferentially to other important nodes. Both PT and term neonates showed RC organization with PT neonates exhibiting significantly reduced connections between these RC nodes. Additionally, PT neonates showed evidence of weaker functional segregation. Our results suggest that PT birth is associated with fundamental changes of functional organization in the developing brain.

Functional magnetic resonance connectivity studies in infants born preterm: suggestions of proximate and long-lasting changes in language organization.

Sophisticated neuroimaging strategies demonstrate alterations in functional connectivity at school age, adolescence, and young adulthood in individuals born preterm. Recent data suggest these alterations are present in the postnatal period prior to term‐equivalent age in neonates born preterm. Likewise, functional organization increases across development, but the influence of preterm birth on this fundamental infrastructure is immediate and unchanging. This article briefly reviews the current methods of measuring functional connectivity throughout development in those born preterm, and the association of functional connectivity with language disorders. Taken together, these data suggest that the effects of preterm birth on the functional organization of language in the developing brain are both proximate and long‐lasting.

Alterations in Anatomical Covariance in the Prematurely Born

Abstract Preterm (PT) birth results in long‐term alterations in functional and structural connectivity, but the related changes in anatomical covariance are just beginning to be explored. To test the hypothesis that PT birth alters patterns of anatomical covariance, we investigated brain volumes of 25 PTs and 22 terms at young adulthood using magnetic resonance imaging. Using regional volumetrics, seed‐based analyses, and whole brain graphs, we show that PT birth is associated with reduced volume in bilateral temporal and inferior frontal lobes, left caudate, left fusiform, and posterior cingulate for prematurely born subjects at young adulthood. Seed‐based analyses demonstrate altered patterns of anatomical covariance for PTs compared with terms. PTs exhibit reduced covariance with R Brodmann area (BA) 47, Brocas area, and L BA 21, Wernickes area, and white matter volume in the left prefrontal lobe, but increased covariance with R BA 47 and left cerebellum. Graph theory analyses demonstrate that measures of network complexity are significantly less robust in PTs compared with term controls. Volumes in regions showing group differences are significantly correlated with phonological awareness, the fundamental basis for reading acquisition, for the PTs. These data suggest both long‐lasting and clinically significant alterations in the covariance in the PTs at young adulthood.

GABA, Resting State Connectivity and the Developing Brain

Background: Preclinical data demonstrate that gamma-aminobutyric acid (GABA) interneurons initiate connectivity in the developing brain. Objectives: The goal of this study was to compare GABA concentration and its relationship to functional connectivity in the brains of term and preterm infants at term-equivalent age. Methods: Infants received both magnetic resonance spectroscopy (MRS) and functional magnetic resonance imaging (fMRI) scans at term-equivalent age. Whole brain functional connectivity MRI data using intrinsic connectivity distribution maps were compared to identify areas with differences in resting-state functional connectivity between the preterm and term control groups. MRS measured concentrations of GABA, glutamate, N-acetyl-aspartate (NAA) and choline; NAA/choline was then calculated for comparison between the 2 groups. Results: Preterm infants had lower right frontal GABA and glutamate concentrations than term controls and showed a significantly different relationship between connectivity and GABA concentration in the right frontal lobe. Preterm infants had a positive correlation between GABA concentration and connectivity, while term controls demonstrated a negative correlation between these two developmentally regulated parameters. Conclusion: These results suggest that regional GABA concentrations are associated with normal and altered neonatal resting-state connectivity.

Prenatal stress alters amygdala functional connectivity in preterm neonates.

Exposure to prenatal and early-life stress results in alterations in neural connectivity and an increased risk for neuropsychiatric disorders. In particular, alterations in amygdala connectivity have emerged as a common effect across several recent studies. However, the impact of prenatal stress exposure on the functional organization of the amygdala has yet to be explored in the prematurely-born, a population at high risk for neuropsychiatric disorders. We test the hypothesis that preterm birth and prenatal exposure to maternal stress alter functional connectivity of the amygdala using two independent cohorts. The first cohort is used to establish the effects of preterm birth and consists of 12 very preterm neonates and 25 term controls, all without prenatal stress exposure. The second is analyzed to establish the effects of prenatal stress exposure and consists of 16 extremely preterm neonates with prenatal stress exposure and 10 extremely preterm neonates with no known prenatal stress exposure. Standard resting-state functional magnetic resonance imaging and seed connectivity methods are used. When compared to term controls, very preterm neonates show significantly reduced connectivity between the amygdala and the thalamus, the hypothalamus, the brainstem, and the insula (p < 0.05). Similarly, when compared to extremely preterm neonates without exposure to prenatal stress, extremely preterm neonates with exposure to prenatal stress show significantly less connectivity between the left amygdala and the thalamus, the hypothalamus, and the peristriate cortex (p < 0.05). Exploratory analysis of the combined cohorts suggests additive effects of prenatal stress on alterations in amygdala connectivity associated with preterm birth. Functional connectivity from the amygdala to other subcortical regions is decreased in preterm neonates compared to term controls. In addition, these data, for the first time, suggest that prenatal stress exposure amplifies these decreases.

Moving from controversy to consensus: premedication for neonatal intubation

Neonatal tracheal intubation is a high-risk procedure for patients in neonatal intensive care units (NICUs), and can be associated with multiple adverse events, both short term and long term. Premedication for this procedure, including sedation and paralytics, has been shown to improve success rates and potentially mitigate the risk of airway injury. However, despite the awareness of these benefits, there has been significant variability in the adoption of this practice. Neonatal tracheal intubation is a common but potentially high-risk procedure for patients in NICUs [1]. Unsuccessful attempts are frequent [2], as are adverse events such as significant oxygen desaturation [3], bradycardia [4], and potential airway injury [5]. These risks are even more significant for preterm infants, with recent authors reporting increased risk of severe intraventricular hemorrhage (IVH) and adverse neurodevelopmental outcomes in patients requiring multiple intubation attempts [4, 6, 7]. Taken together, these concerns present a major challenge for neonatal care providers, and significant effort is being dedicated towards improving the safety of this critical procedure. The use of sedation and paralytic agents to facilitate nonemergent neonatal tracheal intubation and potentially mitigate the risk of adverse outcomes has been a topic of much discussion for many years. Premedication for intubation is utilized commonly in adult and pediatric populations [8]. Numerous authors have reported improvement in procedural success rates and decreased risk of airway injury in the neonatal population when premedication is utilized for tracheal intubation [9–16]. However, despite the identified benefits of premedication and issuance of an endorsement supporting its use by the American Academy of Pediatrics in 2010 [17], there has been significant variability in the adoption of the use of sedation and paralytic agents for tracheal intubation premedication across NICUs nationally, and many individual providers have not incorporated routine use of premedication into their practice [18, 19]. Institutional and individual provider variation in the routine use of premedication for intubation likely has many contributing factors. Some of the common concerns raised by providers are listed here, along with potential strategies to alleviate concern or decrease potential risk: (1) Personal preference: Providers initially trained to intubate patients without using premedication may feel that, since they are generally able to secure the airway, these additional steps are not necessary and only serve to delay or prolong the procedure. However, as evidence continues to mount that use of premedication may result in both shortterm and long-term benefits to patients in terms of improved physiologic stability, lower risk of adverse events/airway injury, and decreased risk of associated IVH and poor neurodevelopmental outcomes, the importance of using premedication for tracheal intubation becomes more clear. (2) Inability to secure airway in an apneic patient: Intubators may have concern about potentially having difficulty securing the airway in a patient without spontaneous respiratory effort, which would be the case after premedication with sedation and paralytic medications. This can be addressed on several fronts. Proactively identifying risk factors for airway abnormalities, which are often evident in the patient history or physical exam findings, might alter the planning for the procedure (including personnel present, equipment used, and choice of premedication) and could help to mitigate this risk. As noted above, the utilization of premedication often improves procedural success rates, and in the event of adverse medication side effects, reversal agents could be administered. (3) Lack of familiarity with medication regimen or concern about side effects: Providers who are not experienced in the utilization of sedation/paralytic agents for neonatal * Lindsay Johnston Lindsay.johnston@yale.edu