The immature autonomic nervous system, hemodynamic regulation, and brain injury in the early developing brain

Introduction

Regulation of brain perfusion and oxygen/substrate delivery is, broadly speaking, dependent upon two partially overlapping systems. These are cardiovascular-respiratory regulation by the brainstem, autonomic nervous system (ANS) centers, and intrinsic cerebral autoregulatory systems. The period of transition from the relatively protected intrauterine environment to the complexities of the external world requires the coordination of the newborn’s cardiovascular and respiratory systems.

The ANS plays a central role in maintaining homeostasis for the infant under fluctuating external conditions. ANS maturation begins in the fetal period and continues after birth. Therefore intrauterine conditions that do not provide a supportive environment for ANS development, including certain maternal medical conditions or illnesses, placental insufficiency, and intrinsic fetal conditions (e.g., congenital heart disease [CHD]), and preterm birth, may significantly affect ANS development and function. ANS immaturity or abnormal maturation may leave vulnerable infants unprepared for ex utero respiratory and hemodynamic demands, exposing the infant to the risks of respiratory, cardiovascular, and hemodynamic instability. Importantly, immature ANS regulation and impaired hemodynamics may not only lead to brain injury but also result in a spectrum of more subtle neurodevelopmental changes whose effects may not become evident until later in childhood.

Significant advances in obstetrical, neonatal, and cardiovascular intensive care, ventilation strategies, and management of neonatal hemodynamics have led to a decline in the earlier, often devastating, forms of brain injury seen in the preterm newborn, for example, cystic periventricular leukomalacia (PVL) and periventricular hemorrhagic infarction (grade IV intraventricular hemorrhage, [P/IVH]) and improved survival for other at-risk newborns, including those with CHD. Although survival of at-risk newborns has greatly improved and, in certain groups, there is a reduced prevalence of severe neuromotor disability and epilepsy among survivors, neuropsychologic disorders continue to manifest in ex-preterm children, former fetal growth-restricted children, and survivors of CHD. Thus neurologic morbidity remains prevalent in survivors of premature birth, high-risk near-term and term births, and cases of complicated fetal-neonatal transition. In this chapter we explore the immature ANS and its relation to brain injury and seek to understand the influence of the developing ANS on brainstem responses and higher cortical functions and outcome.

Why focus on the developing ANS?

There is a complex, potentially bidirectional relationship between immaturity and dysfunction at the brainstem level ANS centers and injury/developmental dysfunction in higher cerebral structures. The link between ANS maturation and brain injury has been most widely studied in the preterm population. Preterm infants with poor neurologic outcomes often have abnormal ANS maturation. ANS dysfunction and brain injury are also prevalent in other at-risk neonatal populations. For example, in infants with CHD, certain forms of which are known to cause delayed brain development, lower ANS function is associated with higher preoperative brain injury scores. In term neonates with neonatal encephalopathy from hypoxia-ischemia (hypoxic ischemic encephalopathy [HIE]) specific patterns of cortical injury were associated with ANS dysfunction. Similarly, neonatal stroke severity is inversely correlated with sympathetic tone. ^{, ,} The causal pathway is not always clear in these cases, and further studies are needed to clarify these relationships. Whether ANS dysfunction causes brain injury or whether brain injury leads to ANS dysfunction remains debatable, and the interaction is likely reciprocal.

The ANS regulates functions of the respiratory, cerebrovascular, and cardiovascular systems, and any abnormal function in these inter-related systems puts the immature brain at risk for injury or maldevelopment. Immature ANS responses likely contribute to hemodynamic and cardiovascular instability in at-risk infants, with impact on the cerebrovascular system. ^, The prevailing paradigm for hemodynamically mediated brain injury in the premature infant is centered on a confluence of insults emanating from the unstable immature cardiovascular system and dysfunctional intrinsic cerebral autoregulation in the context of fragile cerebral vasculature. The brain’s cellular elements are also vulnerable to hypoxemia and inflammation, in particular, the immature oligodendrocytes, enhancing risk for brain injury from periods of hemodynamic instability.

ANS development and metrics

The ANS consists of the sympathetic and parasympathetic divisions and has integral control functions on many physiologic aspects of the human body. In addition, the ANS might also provide key inputs to the development of higher cortical and limbic structures involved in emotion, behavior, and thought processing. This important component of our nervous system matures during fetal development and into infancy. ^, Key ANS centers within the brainstem, namely the nucleus tractus solitarius, receive sensory input from peripheral receptors and respond through ANS efferent systems, including the dorsal motor nucleus of the vagus. In addition, supratentorial ANS centers including the anterior thalamus, anterior cingulate gyrus, and the amygdala integrate the more primitive functions of the ANS with higher cortical processes, a major evolutionary advantage for humans. The influence of the impaired developmental ANS on these higher-order cortical structures may contribute to the high rate of psycho-affective disorders in survivors of an abnormal third-trimester environment in utero or ex utero.

The central ANS develops in a “bottom-up” manner, beginning with brainstem and hypothalamic centers early in gestation. Cerebral ANS structures develop later in gestation and during early infancy. Functional maturation of the ANS begins with the sympathetic system, which develops structurally and functionally early in gestation and continues to develop progressively throughout the fetal period. While the unmyelinated vagal (parasympathetic) system is earliest to develop, it remains functionally quiescent until the third trimester when its function becomes integrated with higher cortical centers. The remainder of the parasympathetic system begins to develop after the sympathetic system and does not begin to exert functional influence until the third trimester, when parasympathetic tone increases significantly. ^,

Development in an unsupportive intrauterine or extrauterine environment (as may occur in preterm infants) can have significant effects on ANS function, resulting in alterations in hemodynamic control and risk for brain injury. Early delivery, even late preterm or early term, may be associated with ANS dysfunction. The premature engagement of the ANS in responding to postnatal cardiorespiratory changes may result in “ dysmaturation ”, or a shift in the temporal program of ANS maturation, and aberrant programming of the ANS. Prematurity and ANS development ex utero has been associated with impaired ANS function in several studies, and preterm infants with higher levels of prematurity-related complications appear to have more impaired autonomic function than preterm infants with low levels of complications. This association holds true for neurologic outcomes as well, as preterm infants with adverse neurologic outcomes have lower autonomic tone (measured by heart rate variability [HRV]) compared to age-matched infants with favorable neurologic outcomes.

Measurement of ANS function is challenging in the fetus and fragile newborn. HRV, the fluctuation in the length of time between heart beats (R-R intervals), can be analyzed noninvasively to assess sympathetic and parasympathetic tone, providing a window on the developing ANS. ^, High-frequency variability reflects parasympathetic function and is influenced by the respiratory rate (respiratory sinus arrhythmia), while low-frequency variability results from a combination of sympathetic and parasympathetic inputs and reflects baroreflex-induced changes in HR. HRV is also influenced by the newborns’ sleep state, with active sleep having higher sympathetic tone (low-frequency variability) compared to quiet sleep.

For premature or critically ill term newborns, there are a multitude of “unexpected” stimuli in the ex utero environment, which the immature ANS may be unprepared to experience and process. The neonatal intensive care unit (NICU) or cardiovascular intensive care unit (CICU) environments are harsher than the muted intrauterine milieu for the developing neurosensory systems. Depending on the gestational age (GA) and morbidity of the infant, the extraordinary experiences may include oxygenation disturbances and positive pressure ventilation forces on the lungs, hemodynamic instability increased by a patent ductus arteriosus, infections, painful procedures, light, and air and temperature changes on the delicate skin, among others. These stimuli can create a challenging environment for maturation of the ANS, resulting in delayed or abnormal maturation. ANS dysmaturation may then increase the risk for certain adverse events, including IVH, sudden infant death syndrome, and brief resolved unexplained events (BRUEs, formerly “apparent life-threatening events” [ALTEs]), among others.

In addition to prematurity, development in an unsupportive intrauterine environment, whether secondary to placental insufficiency or intrinsic fetal factors, may have consequences for ANS function. Growth-restricted fetuses (FGR) exhibit delayed/immature ANS function, as evidenced by depressed HRV and suppressed baroreflex and chemoreflex responses. Similarly, fetuses with specific types of critical CHD, including hypoplastic left heart syndrome (HLHS) and transposition of the great arteries (TGA), also have abnormal ANS function. ^, Mechanisms underlying aberrant ANS development under the aforementioned conditions are not well understood. However, both FGR and critical CHD fetuses exhibit delayed brain growth and development. Poor growth and development of the fetus overall and of the central nervous system, specifically, likely contribute.