Neurophysiological assessment of brain function and maturation: I. A measure of brain adaptation in high risk infants

ELSEVIER

er, Neurophysiologic assess ographic studies permit the clinician to recognize expected patterns of brain maturation in the healthy neonate. By comparison, one can detect encephalopathic

Scher MS. Neurophysiological assessment of brain function and maturation: I. A measure of brain adaptation in

high risk infants. Pediatr Neurol 1997; 16: I9 I- 198.

vere physiologic expre

Severe brain dysfunction is expressed in only a minority of medically ill neonates [I]. Most hig ternatively express dysfunction as mo tent aberrations in physiologic behaviors. Infants at risk may also respond to either prenatal and/or postnatal stress by demonstrating more subtle expressions of brain dysfunction. As is discussed in the t review, neurobehavioral and neurophysiologic p of neurological organization and maturation arc altered in hcahhy infants as compared with those in a term cohort. ceptional term ages, a dysmature neurological emerges for the asymptomatic preterm infant which reflects ontogenctic brain adaptation [2]. an adaptive response to stress which may be appropriate for the present level of maturity but ultimately affects subsequent developmental stages. Because of the substantially higher risk of neurodevelopmental compromise of the preterm infant, considering physiologic dysmaturity in the spectrum of neurological disorders would greatly aid the clinici prognostic skills for this group of high risk children. limited clinical repertoire of the neonate and young infant requires that the clinician consider neurophysio:ogic expressions of deviant behavior as subclinical expressions of static encephalopathies which will later emerge during infancy.

istence of brain be at risk for lat

From the Department of Pediatrics: University of Pittsburgh School Medicine; Children’s Hospital of Pittsburgh; and Developmental Neurophysiology Laboratory; Magee-Womens Hospital; Pittsburgh. Pennsylvania.

0 1997 by Elsevier Science Inc. All rights reserved. PII SO887-8994(97)00008-8 * 0887-8994/97/$17.00

of

Communications should be addressed to: Dr. Scher; Developmental Neurophysiology Laboratory: Magee-Womens Hospital; 300 Halket Street; Pittsburgh. Received June 7. 1996; accepted August 9. 1996.

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es

Markedly abnormalencephalopathicEFG patterns have traditionally been associatedwith neuropa?lolcgic lesions on postmortem examination in neonates[3], brain lesions evident on neuroimagingstudies in survivors [4], evolving EEG pattern abnormalitiesduring infancy such as hypsarrhymia [5], and major neurodevelopmentalsequelaeduring childhood [6,7]. Severe electrographic abnormalities such as burst suppressionand low voltage invariant patterns are documented for only a minority of high risk newborns. Less severe encephalopathiesoccur more frequently in recovering neonates,but are more difficult to grade (i.e., mild to moderate abnormalities) [5]. As a further confounder in preterminfants, suspectedencephalopathicpatterns are more difficult to distinguish from immature EEG patterns [I]. Few studies have investigated whether neonatesexpress less severe brain dysfunction as sleep disorganization or altered rates of neurophysiologic maturation 18.91.It would be clinically expedient to apply interpretative principles of maturational estimatesto predict neurological outcome for the substantially larger segmentof the population of infants who survive less severe and reversible clinical illnesses. Recent studies demonstratehow physiologic differences in EEG-sleep organization for asymptomatic neonatesat risk predict short and long term developmentalor cognitive deficits: e.g., higher percentagesof quiet sleep on day I of life in asymptomatic term infants were associated with lower developmentalassessmentsat 6 months of age 1101,Lower spectral EEG energiesfor healthy preterm and term neonatescorrelated with poorer neurodevelopment~~l pcrf’ormancesat I2 and 24 months of age 111I. Finally. lower quiet sleep percentagesin neonatesrecovering from medical illnesses predicted poorer intellectual performanceson cognitive testing at 8 years of age when children were rearedin an impoverished socioeconomicenvironment [ 121.These observationssuggestthat altered neonatal EEG-sleep organization correlates with poorer neurological performance in asymptomatic or recovering infants, despite the absenceof severe neonatal brain disorders. Longitudinal studies at older ages needto establish whether persistent changes in EEG sleep for such “vulnerable” children correlate more strongly with compromised neurological outcome, given the later influences of socioeconomic factors. A Needs to Be Identifie

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Advances in obstetric and neonatal care have dramatically improved the survival rate of high risk infants, particularly for very low birth weight neonates.Low birth weight status is considered one developmental risk, but reports conflict regardingthe nature and magnitude of the

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risks involved [ I3- 1S]. Disparity among different findings may be partially explained by variations in the definition of clinical populations, the inclusion or exclusion of children with varying types and degrees of medical complications, the iength of follow-up, and the assessmentof developmental outcome. Excessive environmental stimulatirjn in a noisy and disruptive neonatal intensive care unit (NICU) also may contribute to decreasedweight gain and prolongation of illnessesassociatedwith prematurity (e.g., respiratory or gastrointestionaldysfunction) [ 191and, ultimately, developmentalcompromise. Socioeconomicfactors continue to be important long term modifiers which may determine the persistenceor degree of neurodevelopmental compromise [ 2i)]. Longterm neurodevelopmentalstudies of neonatesborn with varying types and degreesof medical illnesses have traditionally focused on specific fetal (e.g., intrauterine growth restriction), maternal (e.g., preeclampsia),or neonatal medical complications (e.g., chronic lung disease, seizures, or intracranial hemorrhage). Advances in fetal and neonatal intensive care have certainly altered the morbidity for such groups of neonates,as exemplified by the lowered incidence of respiratory distress syndrome because of artificial surfactant use [21], decreasedneonatal infection rates becauseof prophylactic maternal treatment for vaginal bacterial infections [22], and the lowered incidence of seizures [4] and intraventricular hemorrhage [231. However, greater attention now must be paid to neonatal populations that manifest less severe and more reversible medical conditions, but who nonethelessexperience brain dysfunction and therefore may remain at risk. Because high risk survivors may experience developmental disorders during childhood, particularly those who were prclcrtii at birth, improved diagnostic acumen remains a high priority 124,251.Such children more likely manifest deficits in gross motor, perceptual-motor, and cognitive tasks and perform at a substandardlevel at school ages. Recently, researchershave even documentedincreaseddevelopmental risk in healthy preterm neonates[ 11,26,27]. Others suggest that developmentaldeficits, at least in part, result from excessive sensory stimulation in an “unfriendly” extrauterine environment [ 191 or a suboptimal home environment [28]. New studies need to examine the relations between neonatal medical risk to outcome, as modified by environmental/social factors during the formative years during infancy and early childhood.

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Concomitant with improvements in neonatal survival, an awarenessof two groups of survivors who later manifest developmental problems has increased. One group consists of acutely ill neonateswith severe encephalopathies who require sophisticated intensive care management but survive neonatal diseases. These children re-

main at considerable risk for neurodevelopmental sequelae, particularly if they manifest seizures, intracranial hemorrhage, or central nervous system infection, all of which are easily identified in the newborn period. Longterm follow-up studies of such children indicate that 10 to 50% of such children manifest some degree of sensory and/or cognitive deficits [29]. Once these survivors reach school age, one fifth to one third require special education assistance, despite normal intelligence and no clearly definable neurologic handicap [30,3 11. Yet most NICUs now serve a shrinking subset of infants with severe brain dysfunction or damage. Identification of neonates with specific neurologic disorders such as seizures or intracranial hemorrhage does not accurately predict compromised outcome for most survivors. Severely encephalopathic neonates represent a small proportion of infants at risk for developmental disabilities [32]. A larger group of children constitutes the “silent majority” of neonates [29] who develop neurodevelopmental disorders despite recovery from less severe or more subtle and persistent antepartum, intrapartum, or neonatal complications. Many of these children present clinically only during late infancy or early childhood with developmental delay, cerebral palsy, and/or language delay, without advanced warning signs. Problems range from hearing loss in 3%, visual loss in 5%, to delay in psychomotor development in neurologic damage in as many as 50% [29]. More sensitive diagnostic evaluations of the maturing central nervous system are neededduring the neonatal and infancy periods to complement the clinical examination.

Documentation of brain damage or dysfunction may be difficult to detect in infants who are too ill or immature to be assessed by conventional clinical examination protocols [4,5]. In addition, clinical scoring systems do not accurately assessthe degree of gestational immaturity in neonates, particularly under 30 weeks conceptional age (CA). Furthermore, the NICU environment in a confining isolette does not allow easy access to infants for exami0th conventional ain imaging and neurophysive been used to supplement clinical observations in neonates with suspected brain disorders. Serial cranial ultrasound and EEG-sleep studies document the ontogeny of brain structures and neurophysiologic patterns, respectively, for a given conceptional age range and consequently help track the persistence or resolution of brain damage or dysfunction. Such ities of diagnostic tools help document persistent ab period brain structure or function during the conva after clinical recovery of a neonate or in a child who has always remained asymptomatic. Despite recent advances in radiologic procedures that utilize functional imagi principles [i.e., functional or positron emission t ography (PET) scanning], such

images provide detailed but brief combined “snapshots*’ of brain structure and function and are experimental or inaccessible for bedside monitoring [33-351. Serial EEGsleep studies, on the other hand, offer a continuous record of brain function at the bedside, even in the absence ol’ anatomic damage. Knowledge of the interrelations among multiple physiologic measureswhich constitute EEG sleep behavior can help one to detect deviations from expected ontogenetic patterns, and predict compromised neurologic performance, even in asymptomatic survivors after transient illnesses with structurally intact brains by conventional neuroimaging procedures. nata for HOW can the clinician direct serial examinations, imaging, or neurophysiologic testing toward the appropriate high risk groups ? Literature concerning perinatal risk scales, as reviewed by Molfese [36], suggests that such scales are generally valid to predict perinatal outcome and therefore are applicable to selective testing in the neonatal period. Yet most biologic risk scales do not consider subtle and persistent brain disordets beyond seizures or specific brain lesions, such as intraventricular hemorrhage and periventricular leukomalacia. Such indices also become less accurate with respect to prediction of outcome in later childhood. Most neonatal medical complication scores only medical and cognitive development through 1 year of age for the most severely affected group 137,381,with a reliance on the most easily identifiable brain lesions or encephalopathic processes. ore recent indices have be developed by Scott et al. 1391, Korner et al. [40], a Thompson et al. 141J predict neurodevelopmentaloutcome to early childhood for neonates with a wider range of medical complications. These various risk scales were vised to delineate biologic risk or vulnerability; yet as predictive ability of biologic risk wanes over the first years of life, consideration of socioeconomic factors increasingly account for differences in later developmental outcome. Evidence now suggests that the quality of t giving environment serves to minimize or maximize earlier biologic risk [40]. To improve the quality of life for high risk infants, a better understanding is needed concerning biological, psychosocial, and developmental processes which interrelate to influence subsequentdevelopment. Theoretical approaches have applied an ecological symptoms theory perspective [42], in which low bifi weight is viewed as one potential stressor to which the vor to adapt. For inindividual and family oped on the premise that the duration and severity of uries based on the detrimental effects of mia, insufficient substrates for metabolism, or direct damage to tissue.

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highly reliable and strongly predictive of developmental outcome through either 2 years 1411 or 3 years 1401 CA. Contributions of birth weight and gestational age to developmental outcome were subsumed by each scale. Gradations of biologic risk status based on the scales we~c established, and the continuing contribution of these indices to cognitive, motor, and neurodevelopmental functioning was determined [44]. Yet these scores do not incorporate neurobiological or neurophysiologic expressions of dysfunction beyond obvious seizure states or gross injuries to the brain. Assessment of subtle clinical examination abnormalities or alterations in the neurophysiologic patterns are not incorporated in these scales. An accumulating body of evidence also links maternal stress to child behaviors and cognitive outcome. Stress of daily life has been related to maternal distress, less satisfactory parenting, less functional family status, maternalreported behavior problems, and lower social confidence of children at 5 years of age 1451. In turn, maternal distress influences a mother’s perception of and interactions with her children [28]. Maternal depressive mood has been related to perceptions of child maladjustment, to increased levels of vague or interrupting maternal commands to which children cannot reply 1461, and to lower child cognitive functioning at 1 year of age [47]. For longitudinal studies of this type, it remains important to investigate the process of parenting since varying parenting styles may have important influences on controlled intervention programs which serve both the child at risk and stress management for the caregiver.

ent and Adaptation: Genetic Brain maturation generally follows a continuous intrauterine to extrauterine process from embryonic lift into childhood through four major sequential steps [4X I: ( I ) differentiation of primitive neuroblasts into functional neurons: (2) a process in which differentiated neuronal elements follow a predetermined path from their site of origin to the anatomic terminus where appropriate connections will be established: (3) dendritic arborization and synaptogenesis; and (4) evolution of functional transmission sites (i.e., different neurotransmitter pools) and improved conductance properties (i.e., myelination). This orderly maturational sequence is primarily dictated by the genetic substrate. Regressive events. such as programmed cell death, axonal pruning, and synaptic elimination continually modify brain structure during development. Such events occur both during intrauterine and extrauterine time periods and subs-zntiallq r a!ter brain structure and function. Biological responses to environmental factors are generally termed plasticity which modify these regressive processes. Reordering of neuronal connectivity and receptor sensitivity can have profound effects on complex physiological and/ or cognitive potentialities [49].

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Synaptogenesis, for instance, has sharp spurts and sudden decreases across all areas of the cortex at specific ages during infancy [50]. Synaptogenetic-developmental spurts occur in humans at 1, 4, 8, and I3 months of age. Concurrent with these stages in synaptogenesis, rapid changes occur in sensorimotor development [ 5 I]. Evolving neurophysiological patterns during early development reflect some of these developmental readjustments and adaptive changes of the brain. For instance; changes in sleep architecture and continuity [52] up to conceptional term ages, increasing spectral EEG energies [53,54], and greater spectral EEG coherence into infancy and childhood [55-571 are neurophysiologic markers of maturational change during extrauterine brain development. Although the newborn’s brain consists of preprogrammed developmental templates that emerge with or without outside influences, adverse conditions such as prematurity, medical illnesses, or environmental influences significantly reshape the genetic blueprint for brain maturation; e.g., neonatal survivors weighing as little as 500 to 750 gr may sustain brain injury from diverse medical conditions such as intracranial hemorrhage or chronic lung disease. Yet most survivors now escape the most severe forms of these medical conditions. As an example, one level 3 NICU service identifies only l-2% of neonates with seizures [4], 8% with grade III and IV intraventricular hemorrhage, and 6% with periventricular leukomalacia from a total annual NICU admission census of 1,200 infants. Yet more subtle and persistent medical or environmental stresses, such as inadequate nutritional supplementation, insufficient oxygenation delivery due to lung immaturity, and excessive sensory stimulation also altel brain structure and function. Adaptive responses of the neonatal brain to thcsc transient illncsscs and/or environmental stresses consequently effect the postnatal regressivc processes of programmed cell death, intercortical connectivity, and synaptogenesis, which ultimately redirect subsequent brain maturation.

evelo ental Alterations of Stress: ntogenetic Adaptation Adaptation, in general, is a universal modification of structure and/or function of a species to “fit” the environment. Developmental biologists further define this process for immature organisms as ontogenetic adaptation. Incomplete neuronal and glial differentiation exists before and after birth, which constitutes a special scenario pertaining to brain adaptation in an immature organism [2]. Special emphasis is placed on structure and function of the immature organism’s current level of development, which will dictate how it will respond to environmental and biologic conditions. Rather than mimicking the adult form, the immature subject adopts maturational strategies that are unique to that stage of the developmental cycle. Ontogenetic adaptation is a model of plasticity, which implies

that a balance exists between the needs of the present developmental stage with the anticipated needs at subsequent stages of maturation. Modifications in structure and function by the neonate, for instance, occur because of transient medical illnesses and/or environmental influences to maintain physiologic homeostasis in a way that will ensure survival as well as the developmental status quo at that stage of maturation. However, although adaptation at one stage of development may prove successful for the neonate, changes resulting from this earlier strategy may prove maladaptive for the infant at later developmental stages.

Altered Brain Maturation in Preterm Infants eflects Ontogenetic Adaptation: ow Much is due llnesses or to Prematurity Itself? Ontogenetic adaptation has been documented in high risk preterm infants. Neurobehavioral and neurophysiological differences between preterm and fullterm neonates reflect alterations in functional brain maturation because of conditions of prematurity [58,59]. Conventional wisdom suggests that low birth weight infants are largely comparable in brain development to term infants at matched postconceptional ages (i.e., CA = gestational age + postnatal age after birth). Neurological development of the infant is generally assumed to follow a similar sequence with respect to brain maturation. independent of intrauterine or extrauterine experiences 1601. This ~~i:i reaffirmed by St. Anne Dargassies [61] with respect to neurological maturation of muscle tone and developmental reflexes. However, such assumptions do not universally apply to all aspects of neurological function in preterm infants. Very low birthweight infants at cotlccpti0nal tcm ages differ from term infants f0r specific neurobehavioral items ranging from activity Icvels. motor development, tcnipcrament, autonomic behavior, and sleep organization. They are less interactive 1621, exhibit fewer flexion responses, and have delayed neurohehavioral development [ 63-7 II; they manifest weaker motor responses such as neck extension in prone and supported sitting positions, have decreased flexion of limb traction and recoil or decreased popliteal angle and diminished reflex response such as rooting, sucking, and grasping [63,66,68,69,72]. Als et al. [68] and Gorga, et al. [69] described smoother, more consistent motor control in term infants as compared with preterm infants. Preterms are less consolable [63,66,613], with poorer organization of state, attention, and autonomic regulation than term infants. Variable orienting responses to auditory and visual stimulation were also noted in the preterm groups [68,69,73 1. These altered neurological functions reflect brain adaptation to conditions of prematurity as expressed by altered waking and sleep behaviors. Functional brain maturation in preterm neonates can also be documented on serial EEG-sleep studies as evolving neurophysiological behaviors which are associated

with infants at successively older CA (4,741. Electragraphic patterns of preterm neonates at any given CA are generally assumed to be largely iden borns who are born at that same age. wever, differences in EEG-sleep between preterm and term groups at matched CA have been documented and suggest alterations in neurophysiological development because of prematurity; longer bursts during trace altemant, early sleep spindle appearance. more immature EEG patterns, and poor phase stability for specific EEG frequency bands were initially observed [75-781. More recently, differences between groups in architectural, phasic, continuity 1521. spectral [79-8 I], and autonomic measures [82-851 suggest that functional brain maturation in the preterm neonate, as expressed by EEG-sleep patterns, is not equivalent to that of term infants at conceptional term ages. These differences persisted for preterm infants even if they remained healthy throughout the study period [52,80-831. Comparing structural/biochemical maturation of the brain with behavioral maturation, Hiippi et al. demonstrated anatomic and neurobehavioral delays in healthy preterm infants at conceptional term age.; ,‘353. What are the later developmental and cognitive consequences of these early behavioral, neurophysiological, and structural adaptive strategies?

Less severe encephalopathies are difficult to quantify and may consist only of changes in the rate of brain maturation rather than the expressions of spcci abnormalities such as burst suppression. postnatal stresses may accelerate or delay tion for specific groups of high risk neonates. with intrauterine growth restriction. for instanc spond by an acceleration of brain and iung function at’tcl birth [ 861 documented >2 weeks after the expected clinical neurologic examination or neurophysiologi ies [87-901. The mechanisms that may be responsible fat such developmental acceleration include positive glucocorticoid effects on brain development [ 9 I,92 J. altered levels of catecholamines which affect neurotransmission [93.94]. and even direct stimulation of the central nervous system which enhances neural activity 195,961. Other newborns respond to stress from transient medical illnesses by delays in brain maturation, as re immature EEG-sleep patterns (i.e., defined as m weeks younger than the reported postconc Delayed EEG patterns may be only tr intidnts who manifest, but recover from. disease [97]. On the other hand, dela which persist to conceptional term ages in neonates with b delayed neurodevel chronic lung disease correlate ment at 3 years of age 19,981. layed sleep organizat in neonates with chronic lung disease 1991 and prenatal

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substance exposure [S] are also associated with compromised outcome with or without clinical signs of neurologic dysfunction. Finally, delayed latencies on sensory evoked responsesin infants with hyperbilirubinemia, asphyxia, or Lain malformation may also correlate with delayed neurologic outcome [ 1001. Therefore, acceleratedor delayed functional brain maturation, based on neurophysiologic monitoring, each reflects dysmaturity of brain function, despite the absenceof severe encephalopathicpatterns. The cumulative impact of medical illnesses and environmental/social influences on these two processesof brain dysmaturity have not been fully addressed,either in terms of neurobehavioralor neurophysiologic markers. The second part of this review will examine the process of brain adaptation in preterm neonates, which represent one group of high risk neonates with both medical as well as environmental stressors that potentially affect brain development. This work was supported in part by grants NSOll 10. NS26793. and RR00084 to MSS. Scaife Family Foundation, the Twenty-five Club of Magee-Womens Hospital, the Cradle Roll Auxiliary, and the MageeWomens Hospital Research Fund. Ms. Margie Phillips provided secretarial assistance.

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