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Physiological stress and brain vulnerability Understanding the Neurobiology of Connectivity in Preterm Infants.

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Physiological Stress and Brain
Vulnerability: Understanding the
Neurobiology of Connectivity
in Preterm Infants
dvances in maternal fetal medicine and neonatology
have resulted in the increased survival of very premature and extremely premature infants. Currently
>90% of infants who are born very preterm (28–
32 weeks gestation) and >75% of infants born extremely
premature (<28 weeks gestation) survive.1 However, surviving children, especially those at the limits of viability,
have high rates of neurodevelopmental disability.2 Much
attention has been focused on understanding the causal
pathways underlying retinopathy of prematurity and
periventricular leukomalacia, the complex antecedents of
visual and neuromotor disability. However, understanding
the mechanisms underlying cognitive disability, whose
sequelae include challenges in perception, executive
function, communication, and learning, have not been
systematically undertaken.3 It is in this respect that the
article by Smith and colleagues can be examined.4
Who Was Studied?
This interdisciplinary team of nurses, neonatologists, and
child neurologists prospectively enrolled infants of
<31 weeks gestation in the first 12 hours of life and
examined how the frequency of procedural stress
(eg, intubation, suctioning, venous, and arterial line
placements) impacted on brain structure and function.
Of the 55 infants who were recruited, there were 8
deaths, reflecting the high risk of mortality in this
cohort, even after excluding infants with sepsis or with
high probability of death during the first day of life.
Infant stress was measured using the Neonatal Infant
Stressor Scale (NISS), a record of 36 common procedures
and interventions that can be sequentially recorded at the
bedside.5 Cumulative stress using the NISS was recorded
over 3 chronological epochs: the first 14 days of life, 14
to 28 days, and from admission to term age equivalent
or discharge (whichever occurred first). Magnetic
resonance imaging (MRI) was performed at term age
equivalent at 36 to 44 weeks post menstrual age without
sedation using protocolized brain regional volumetric calculations as well as diffusion and functional connectivity
scans.6,7 In addition, a neurobehavioral evaluation using
the NICU (neonatal intensive care unit) Network Neurobehavioral Scale (NNNS) and the Dubowitz neurological
exams took place.8,9 The NNNS captures both behavioral and neurological organization and has been validated among infants with prenatal exposures to licit and
illicit drugs as well as infants born to mothers requiring
medications for anxiety, depression, and seizures.
What Was Found?
• Exposure to potential stressors in the NICU varies
with each individual infant.
• After increased procedural stressors, there was
decreased brain size in the frontal and parietal regions
as well as decreased temporal lobe microstructure and
functional connectivity. In addition, both abnormal
neurological examination and neuromotor delays were
more prevalent in those infants at term age equivalent
with higher rates of cumulative procedural stressors.
• By examining brain metrics, diffusion MRIs, and
function connectivity MRIs, a complete picture of
altered brain development was observed that was
not related to degree of prematurity, intraventricular
hemorrhage, or duration of ventilation.
• These findings document observable structural,
functional, and behavioral consequences of procedural stress at term age equivalent among very and
extremely preterm infant survivors.
What Does This Mean?
Despite advances in cardiopulmonary management,
infection control, and nutrition, these infants are exposed
to a wide variety of procedural stressors. The patterns of
brain structural and functional abnormalities would help
explain the high rates of attention, executive function,
coordination, perceptual, communication, and academic
C 2011 American Neurological Association
of Neurology
disorders that the majority of these children experience
in early school years.10,11 Most importantly, the altered
interhemispheric temporal connectivity may reflect the
neurobiological substrate for the spectrum of communicative, reading, and written language disorders that often
occur in these children during their school years. These
early connectivity abnormalities may serve as an imaging
marker and help us to go beyond an emphasis on toddler
sensory–motor development to a better understanding of
the substrates of higher cortical functioning.12
Saigal S, Doyle LW. An overview of mortality and sequelae of
preterm birth from infancy to adulthood [review]. Lancet 2008;
Bauer SC, Msall ME. Optimizing neurodevelopmental outcomes
after prematurity: lessons in neuroprotection and early intervention
[review]. Minerva Pediatr 2010;62:485–497.
Taylor HG, Filipek PA, Juranek J, et al. Brain volumes in adolescents
with very low birth weight: effects on brain structure and associations with neuropsychological outcomes. Dev Neuropsychol 2011;
Smith G, Gutovich J, Smyser C, et al. NICU stress associated with
brain development in preterm infants. Ann Neurol 2011;70:
Newnham CA, Inter TE, Milgrom J. Measuring preterm cumulative
stressors within the NICU: the Neonatal Infant Stressor Scale. Early
Hum Dev 2009;85:549–555.
Mathur AM, Neil JJ, McKinstry RC, Inder TE. Transport, monitoring, and successful brain MR imaging in unsedated neonates.
Pediatr Radiol 2008;38:260–264.
Woodward LJ, Anderson PJ, Austin NC, et al. Neonatal MRI to
predict neurodevelopmental outcomes in preterm infants. N Engl
J Med 2006;355:685–694.
Salisbury AL, Fallone MD, Lester B. Neurobehavioral assessment
from fetus to infant: the NICU Network Neurobehavioral Scale
and the Fetal Neurobehavior Coding Scale. Ment Retard Dev
Disabil Res Rev 2005;11:14–20.
Dubowitz L, Ricciw D, Mercuri E. The Dubowitz neurological
examination of the fullterm newborn. Ment Retard Dev Disabil Res
Rev 2005;113:52–60.
Anderson PJ, Doyle LW. Executive functioning in school-aged
children who were born very preterm or with extremely low birth
weight in the 1990s. Pediatrics 2004;114:50–57.
Holsti L, Grunau RV, Whitfield MF. Developmental coordination
disorder in extremely low birth weight chidren at nine years.
J Dev Behav Pediatr 2002;23:9–15.
Anderson PJ, Doyle LW. Cognitive and educational deficits in
children born extremely preterm [review]. Semin Perinatol 2008;
Als H, Duffy FH, McAnulty GB, et al. Early experience alters brain
function and structure. Pediatrics 2004;113:846–857.
Msall ME, Park JJ. The spectrum of behavioral outcomes after
extreme prematurity: regulatory, attention, social, and adaptive
dimensions [review]. Semin Perinatol 2008;32:42–50.
Markham JA, Greenough WT. Experience-driven brain
plasticity: beyond the synapse. Neuron Glia Biol 2004;1:
Nothing to report.
Holtmaat A, Svoboda K. Experience-dependent structural synaptic
plasticity in the mammalian brain. Nat Rev Neurosci 2009;10:
Michael E. Msall, MD
University of Chicago Comer Children’s Hospital and J.P. Kennedy
Research Center on Intellectual and Developmental Disabilities
Chicago, IL
Peterson BS, Vohr B, Staib LH, et al. Regional brain volume
abnormalities and long-term cognitive outcome in preterm infants.
JAMA 2000;284:1939–1947.
DOI: 10.1002/ana.22614
Where Do We Go Next?
We are in an exciting area of relating risk and vulnerability
of the developing brain to brain structure and function.
Importantly, attention to both positive and stressful inputs
are involved in the experience-based plasticity underlying
early childhood learning.13,14 Although these studies are
among the first in humans to take advantage of quantitative
neurometrics, there is extensive animal literature documenting the importance of handling and stress reduction in recovery from biological and neurological injury.15,16 Our
overall goal as both neuroscientists and developmental neurologists is to continue the complicated journey of understanding primary, secondary, and tertiary interventions
underlying brain structure, function, and developmental
outcomes in these vulnerable infants.17 This is the beginning of our journey of developing a comprehensive science
of neuroprotection for these most vulnerable of infants.
Supported in part by the NIH/National Institute of Child
Health and Human Development (grant P30 HD054275),
J.P. Kennedy Intellectual and Developmental Disabilities
Research Center, and Health Resources and Services
Administration/Department of Health and Human Services Leadership Education in Neurodevelopmental and
Related Disorders Training Program (T73 MC11047).
Potential Conflicts of Interest
Volume 70, No. 4
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infant, vulnerability, physiological, preterm, understanding, connectivity, neurobiologie, brain, stress
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