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CHAPTER 6
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THE DEVELOPING BRAIN
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Draft: 3-14-2000
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My changes are tracked in red or green and marked by an *asterisk
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My comments (red) are enclosed in {curly brackets}--bill
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The brain is the ultimate organ of adaptation. It takes in information and orchestrates
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complex behavioral repertoires that allow us to act in sometimes marvelous, sometimes terrible
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ways. For humans, most of what we think of as the “self” –what we think, what we remember,
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what we can do, how we feel--is acquired by the brain from the experiences we have after birth.
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Some of this information is acquired during critical or sensitive periods of development when the
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brain appears uniquely ready to take in certain kinds of information, while other information can
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be acquired across broad swaths of development that can extend into adulthood. This spectrum
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of possibilities is well captured by coinciding evidence of the remarkably rapid brain
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development that characterizes early development and of the brain’s lifelong capacity for growth
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and change. The balance between the enduring significance of early brain development and the
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impressive plasticity of the brain lies at the heart of the current controversy about the effects on
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the brain of early experience.
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The past 20 years have seen unprecedented progress in our understanding of how the
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brain develops and, in particular, of the phenomenal changes in both the circuitry and
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neurochemistry of the brain that occur during prenatal and early postnatal development. As
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discussed in Chapter 3, our knowledge of the ways in which genes and the environment interact
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to affect the development of the brain has expanded by leaps and bounds. The years ahead will
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bring even more breathtaking progress as, for example, the completion of the human genome
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project provides a map of the genome. This promises an explosion of our ability to understand
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the interweaving of genetic and environmental influences as they affect both brain and
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behavioral development.
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The growth in “brain knowledge” naturally leads to demands to understand what this
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means for how we should raise children and what we can do to improve their development.
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Accordingly, efforts to translate this emerging knowledge for public consumption have
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proliferated in recent years. Some of this information has been well and accurately portrayed;
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but some has also been misportrayed. The challenge of deciphering what this information means
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for what we should do as parents, guardians, and teachers of young children is enormous. There
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are few neuroscience studies of very young children and those that exist have not usually focused
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on the brain regions that affect cognition, emotions, and other complex developmental tasks.
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Much of our fundamental knowledge about brain development is actually based upon
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experimental studies in animals. The translation of this information from basic neuroscience into
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“rules” for application to humans can be quite straightforward when very similar mechanisms are
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involved in humans and animals, as is the case with the developing visual system. But, the
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interpretation of other data from animals, or even some data from humans (such as estimates of
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the density of synapses in various brain regions at various ages), can be extraordinarily complex
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or inappropriate when the brain mechanisms of cognition, language, and social-emotional
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development are addressed. In this context, it is essential to balance excitement about all that we
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are learning with caution about the limits of what we understand today.
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This chapter’s synthesis of what science now tells us about the developing brain focuses
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on the role of experience in early brain development. Following a brief discussion of how we
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study the developing brain, we provide an overview of early brain development from conception
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through the early childhood years. We then turn to a discussion of how early experiences
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contribute to brain development. Four themes run throughout this section:
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1. Developmental neuroscience research tells us a great deal about the conditions that pose
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dangers to the developing brain and from which young children need to be protected. It tells
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us virtually nothing about what we can do to create enhanced or accelerated brain
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development.
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2. The developing brain is open to influential experiences across broad swaths of development.
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The openness to experience is part of what accounts for the remarkable adaptability of the
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developing mind. Although there are a few aspects of brain growth that require particular
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kinds of experience at particular points in development, as far as we know at present, this is
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exceptional rather than typical for human brain growth.
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3.
The kinds of early experiences on which healthy brain development depends are ubiquitous
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in typical early human experience—just as nature intended. This means, however, that our
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greatest concerns should be devoted to children who, for reasons of visual impairments,
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auditory processing deficits, major perceptual-motor delays, and other basic deficits, cannot
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obtain these experiences on which the developing nervous system depends.
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4. Abusive and neglectful care, growing up in a dangerous or toxic environment, and related
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conditions are manifest risks for healthy brain development. Beyond these extremes, the
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nature and boundaries of the environmental conditions necessary for healthy brain growth are
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less well known*, partly owing to the complexity and the cumulative achievements of
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cognitive, language, and socioemotional growth. This is cutting-edge research.
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HOW DO WE STUDY THE DEVELOPING BRAIN?
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Neuroscience techniques have advanced significantly, rendering studies of young
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children's brains more feasible and informative than in the recent past. These techniques have
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enabled scientists to learn more about how babies' brains change with development and how
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vulnerable or resilient they are to environmental insults. The repertoire of techniques that can be
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used with preschool-age and young children is circumscribed because some of the more direct
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methods (i.e., looking from inside the brain) of studying brains are either invasive (e.g., Positron
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Emission Tomopraphy requires the injection of a radioactive substance) or require long periods
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of remaining* still (e.g., functional Magnetic Resonance Imaging). Nevertheless, by tracking the
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brain's activity from the outside with the electroencephalogram, event-related potentials, and
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magnetic encaphalography, researchers can record the electrical and/or magnetic field* activity
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of the brain while the baby or child is presented with different stimuli (e.g., speech sounds) and
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identify which parts of the brain are active and how active they are when children are "doing"
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different things. This approach has been used to reveal that the neural substrate for recognizing
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faces and facial expressions is remarkably similar in the infant and the adult (de Haan and
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Nelson, 1997, 1999), and that babies' brains change as they learn their native language (Neville,
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Bavelier, Corina, Rauschecker, Karni, Lalwani, Braun, Clark, Jezzard, and Turner, 1998). <*
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In addition, children with focal brain damage can be studied using neuropsychological
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tools that involve giving young children behavioral tasks that have been shown to depend on
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specific neural circuits (e.g., working memory, spatial planning) and observing how performance
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varies with the particular part of the brain that is damaged (Luciana and Nelson, 1998). This
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approach has been used in a longitudinal study of language development in children who
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suffered focal brain damage in the first months of life and revealed the extensive capacity for
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recovery of language functioning in these children (Bates and Roe, in press). Finally, among
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children for whom medical reasons have required that their brains be studied, PET has revealed
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the patterns of synaptic growth and pruning that characterize early development (Chugani, 1994).
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(See Appendix B for a fuller discussion of technologies for studying the developing human
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brain.)
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For Chugani’s stuff, could one say “revealed metabolic patterns consonant with synaptic
growth and pruning occurring in early development”*
WHAT “DEVELOPS” IN EARLY BRAIN DEVELOPMENT?
The development of the brain has a long trajectory, beginning within a few days after
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conception and continuing through adolescence. The nervous system undergoes its most
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dramatic development during the first few years of life. Yet the processes that establish the
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structure and functioning of the brain, made possible by the developing networks of synapses
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that interconnect nerve cells and by the progressive fine-tuning of the neurons for the roles they
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will play within their synaptic networks, continue well into adolescence. The milestones of brain
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development from the prenatal period up to school entry involve the development and migration
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of brain cells to where they belong *in the brain, embellishments of nerve cells through the
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sprouting of new axons or by expanding the dendritic surface; the formation of connections, or
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synapses, between nerve cells; and the postnatal addition of other types of cells, notably glia.
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Fascination with the earliest stages of brain development is understandable. During this period,
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the spinal cord is formed, nearly all of the billions of neurons of the mature brain are produced,
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the dual processes of neural differentiation and cell migration establish their functional roles, and
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synaptogenesis proceeds apace. As we discussed in Chapter 3, these processes represent an
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elaborate interplay between gene activity and the surrounding environments within and outside
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of* the child.
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There have been significant changes over time in the parameters of brain development
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that have captivated public attention. Twenty years ago, we were fascinated by our ability to
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measure developmental changes in the degree to which* neurons in different areas of the brain
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became wrapped in the white, fatty matter—myelin—that insulates nerve cells and affects the
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speed with which nerve impulses are transmitted from one cell to another. Myelination is, in fact,
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affected by the young child’s behavioral experiences and nutrition, as we discuss below. Today,
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we are focused on information--not all of it new--about the rate of synapse development,
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particularly studies by Huttenlocher and his colleagues (detailed below) showing that there is a
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tremendous burst of synapse formation early in life followed by a decline in synapse number
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apparently extending into adolescence in some areas of the brain. Combined with evidence that
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synapses that are used are retained and those not used are eliminated, there has been a frenzy of
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concern about “using it or losing it” in the first years of life. In comparison to the brain’s wiring,
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far less attention has been paid to the neurochemistry of early brain development. Yet, the
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neurochemistry of brain development is essential to the brain’s capacity to learn from experience
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and is likely to play an important role in the regulation of behavior. We discuss this critical
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aspect of early brain development, as well.
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Development of the Brain’s Wiring Diagram
Brain development proceeds in overlapping phases: making the brain cell (neurulation and
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neurogenesis), getting the cells to where they need to be (migration), growing axons and
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dendrites—structures they need to link with other nerve cells (neuronal differentiation and
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pathfinding), developing synapses, the* or points of communication with other cells
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(synaptogenesis), refining those synapses (maturation and pruning), and, finally, forming the
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supportive tissue that surrounds the nerve cells and makes for efficient communication among
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them (gliogenesis and myelination*).
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The brain and spinal cord arise from a set of cells on the back (dorsal part) of the
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developing embryo called the neural plate. Two rows of rapidly dividing cells arise from the
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plate on each side along its length and fold over centrally into the neural tube. The anterior or
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head end of the neural tube forms a set of swollen enlargements that give rise to the various parts
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of the brain—the forebrain containing the cerebral hemispheres, the midbrain containing
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important pathways to and from the forebrain, and the hindbrain containing the brainstem and
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cerebellum. The remainder of the neural tube becomes the spinal cord, peripheral nerves, and
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certain endocrine, or hormone, glands in the body. Under the control of regulatory genes, the
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brain cells migrate to where they belong in accord with the functions they will ultimately serve.
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These genes provide developmental directions to particular groups of cells, which tell them what
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to do and where to go in the embryonic brain. Both cell proliferation and migration vary from
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area to area but these processes are generally complete by six prenatal months. The exceptions to
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this rule include the cerebellum, whose development is more prolonged. The preceding two
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sentences are definitely inaccurate. Both the hippocampal formation and the cerebellum
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generate neurons postnatally. I doubt that cerebral cortical neurogenisis and migration are
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complete by the 2nd trimester, but I can check on this. I am not sure how much specificity is
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warranted or whether there might not be a better way to say this.*
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Within the neural tube, the innermost cells divide repeatedly, giving rise first to the cells
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that primarily become nerve cells, or neurons, and later giving rise to both neurons and the
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supportive tissue components called glia. Once the nerve cells are formed and finish migrating,
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they rapidly extend axons and dendrites and begin to form connections with each other, called
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synapses, often over relatively long distances. These connections allow nerve cells to
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communicate with each other. This process starts prenatally and continues well into the
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childhood years. There is evidencein many* parts of the nervous system, that* the stability and
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strength of these synapses is largely determined by the activity, that is the firing, of these
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connections. The speed with which neurons communicate with each other across the synapses is
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determined by the development of myelin, a substance that wraps itself around nerve axons. By
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insulating the nerve cell axon, myelin increases conduction velocity. The development of myelin
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*is a protracted developmental process extending well into the postnatal period. The rate and
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extent of myelination is also affected by experience.* Most myelinated pathways are laid down
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in the first ten years, but in some cases, such as the frontal cortex, myelination continues into the
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third decade of life. The unique “wiring diagram” that this process produces in each individual
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brain guides our thoughts, memories, feelings and behaviors.
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Synaptic Overproduction and LossI would skip Rakic below and just cite Huttenlocher.
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Rakic’s monkey work does not support the idea of differential timing across cortical regions and
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was also derivative of a long line of research by others and hardly a landmark. “Over 20 years
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ago, Huttenlocher (e.g., Huttenlocher, 1979; Huttenlocher and Dabholkar, 1997) first showed
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that there is a pattern to synaptogenesis in the human cerebral cortex, characterized by…
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Beginning 20 years ago, the work of Rakic with monkeys (e.g., Rakic, Bourgeois, Eckenhoff,
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Zecevic, and Goldman-Rakic, 1986) and Huttenlocher with humans (e.g., Huttenlocher, 1979;
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Huttenlocher and Dabholkar, 1997) made landmark contributions to our understanding of the
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phenomenon of synapse development. Specifically, there is a pattern to synaptogenesis
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characterized by the rapid proliferation and overproduction of synapses, followed by a phase of
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synapse elimination or pruning that eventually brings the overall number of synapses down to
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their adult levels. This process is most exhuberant during the first few years of life, although it
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can extend well into adolescence. Within this developmental span, however, different brain
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regions with different functions appear to develop on different time courses (see Figure 1 –
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Nelson). Huttenlocher estimated that the peak of synaptic overproduction in the visual cortex
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occurs about midway through the first year of life, followed by a gradual retraction until the
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middle to the end of the preschool period, by which time the number of synapses has reached
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adult levels. In areas of the brain that subserve audition and language, a similar although
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somewhat later time course is observed. However, in the prefrontal cortex (the area of the brain
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where higher-level cognition takes place), a very different picture emerges. Here the peak of
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overproduction occurs at around one year of age, and it is not until middle to late adolescence
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that adult numbers of synapses are obtained1. For some reason the text reversed color below
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Many of the human findings regarding synaptic overproduction and loss were based upon measurements
of the density of synapses, rather than upon measurements of the actual number of synapses. Density measures
reflect both how many synapses are present and how many other things (e.g., nerve cell bodies, dendrites and axons;
glial cells, and blood vessels are present in addition to synapses. The human brain adds lots of cells to the cerebral
cortex postnatally (almost 2/3 of the mass of the cerebral cortex is added after birth), and this makes density
estimates very difficult to interpret. Thus, evidence available to date does not allow us to determine how ubiquitous
synapse overproduction and loss is in brain development generally or in humans specifically.
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Scientists have pondered the purpose of synaptic overproduction and loss for a very long
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time. One of the earliest observations was made by the turn of the century Nobel laureate
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Spanish neuroanatomist Santiago Ramon y Cajal:
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“I noticed that every ramification, dendritic or axonic, in the course of formation, passes
through a chaotic period, so to speak, a period of trials, during which there are sent out at random
experimental conductors most of which are destined to disappear. …What mysterious forces
precede the appearance of the processes, promote their growth and ramification … and finally
establish those protoplasmic kisses, the intercellular articulations, which seem to constitute the
final ecstasy of an epic love story?” [Recollections of My Life, 1917]
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cat visual cortex produced a greater number of synapses during development than it actually
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retained into adulthood. Subsequent work in monkeys and cats by Hubel and Weisel and their
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collaborators (e.g., LeVay, Hubel & Weisel, 1980) demonstrated that as the physiological
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functioning of the visual cortex became more refined and precise, the anatomical synaptic
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connections were also refined. Those that fit the intended pattern were retained, while those that
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did not were eliminated.
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A more modern formulation of the love story began with the Cragg (1975) report that the
The scientists also showed that visual experience played a necessary role in this process.
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If experience was distorted, such that one eye got much more stimulation than the other, its
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connections were pared back less drastically than usual, and the connections with the
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inexperienced eye were pruned more than usual. In short, the development of patterned
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organization in the visual cortex was dependent upon visual experience and involved the
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selective loss of connections that were not appropriate to the pattern. Synapses appear to be
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programmed to be eliminated if they are not functionally confirmed, based upon some not fully
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known aspects of their activity history. In general, frequently active connections, like those of
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the more experienced eye, are more likely to survive.
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While the data are not as complete for other sensory modalities, it is reasonably clear that
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building the organized neural systems that guide sensory and motor development involves the
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production of excess connections followed by some sort of pruning that leaves the system in a
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more precisely organized pattern. Moreover, in both humans and animals, the effects of
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experience on these systems--normal or abnormal--become increasingly irreversible over time.
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In kittens, irreversible deficits in vision will result with deprivation lasting for only 2-3 months
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after birth. In humans, irreversible deficits in vision are present when corrections for optical
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conditions such as strabismus in which, due to muscular weakness, one eye deviates from and
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cannot be brought into alignment with the other normally functioning eye, are not made by the
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time the child reaches elementary school. The deficits become more pronounced with more
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prolonged visual deprivation. Thus, a sensitive period exists for vision, but rather than being
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sharply demarcated, it gradually tapers off.
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A very useful heuristic for considering how experience becomes incorporated into the
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developing synaptic connections of the human brain, discussed briefly in Chapter 3, has been
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offered by Greenough and Black (1986, 1992). They distinguish between experience-expectant
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and experience-dependent mechanisms guiding brain development. Experience-expectant
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synaptogenesis refers to situations in which a species-typical experience (that is, something that
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all members of a species experience barring highly aberrant conditions) plays a necessary role in
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the developmental organization of the nervous system. Normal brain growth relies on these
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forms of environmental exposure. For example, the visual cortex “expects” exposure to light and
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patterned visual information, and is genetically programmed to utilize these inputs for normal
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development. Deprivation of these ubiquitous and essential forms of environmental input can
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permanently compromise behavioral functioning, which is why it is essential to detect and treat
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early sensory deficits (e.g., cataracts, strabismus, auditory deficits) that interfere with the
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detection and registering of expected experiences.
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“Experience-dependent” synaptogenesis, in contrast, refers to encoding* new experiences
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that occur through-out life, foster new brain growth and the refinement of existing brain
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structures, and vary for every individual. This process optimizes the individual’s adaptation to
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specific and possibly unique features of the environment. Whereas in experience-expectant
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development, all brains depend on the same basic experiences to develop normally, in
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experience-dependent development, individual differences in brain development depend upon
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the idiosyncratic experiences that we encounter across the life span. Experience-dependent
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development is also linked to synaptogenesis, but in this case all we know is that experience
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triggers more plentiful connections among neurons. We do not know if this occurs through a
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process of overproduction and pruning, or if a more continuous pattern of growth is involved.
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Whatever the specific mechanism, experience-dependent brain development is a source of
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enduring plasticity and of adaptability to the demands of everyday life. {“our special” conflicts
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with the fact that most of our real information comes from animal studies}** Importantly, there
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appears to be no abrupt transition from the utilization of experience-expectant processes to
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utilization of experience-dependent processes of brain development. In fact, it seems likely that
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the greater potential for recovery that characterizes young animals probably reflects the
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availability of both mechanisms.
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Postnatal Neurogenesis
We now need to add the possibility of postnatal neurogenesis—the postnatal production
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of new nerve cells—to the repertoire of mechanisms by which the human brain continues to
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develop after the early childhood years. Prevailing knowledge about brain development, notably
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that the adult human brain does not produce new neurons has recently been challenged by new
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insights into adult brain development. Specifically, important forebrain regions, such as the
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hippocampal dentate gyrus (which is involved in establishing memory for facts and relationships
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among events and places in one’s experience), continue to receive new nerve cells into adulthood
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in humans (e.g., Eriksson, Perfilieva, Bjork-Eriksson, Alborn, Nordborg, Peterson, & Gage,
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1998). Recent findings in monkeys indicate that new neurons are also being formed each day and
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migrating to areas including the prefrontal cortex, the seat of planning and decision-making
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(Gould et al.*, 1999). Although it remains to be determined how significant this neuronal
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addition is to the functioning of the brain, it certainly lends further support to the argument that
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the brain continuously remodels itself.
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The Neurochemistry of Early Brain Development
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Once the neurons and their* synapses, axons, and dendrites have been established, the sending
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and receiving of messages in the nervous system depends on chemical messengers. A number of
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these chemical messengers affect gene expression in nerve cells in ways that have long-lasting
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effects on how nerves grow, respond to stimulation, and function. They are thus intimately
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involved in the growth and development of the nervous system and in neural plasticity. The past
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two decades have seen an explosion of information about these chemical messengers. In addition
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to the classic neurotransmitters, over 60 other peptide and steroid molecules have been identified
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that have direct effects on the brain. Currently there is little from this field that we can apply
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directly to human development with confidence. However, because the study of neurochemistry
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promises to revolutionize the way we think about the nervous system, a brief overview of some
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core ideas from this work is warranted.
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Chemical messengers that affect the brain operate through receptors, most of which are located
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in the dendrites and synapses of nerve cells. Like locks and keys, the physical structure of the
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messenger (the key) has to fit the physical structure of the receptor (the lock) for the chemical
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messenger to have any effect on the nerve cell. Receptors are specific. They typically recognize
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or bind with only one natural* molecule. For many years, this type of specificity gave rise to the
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hope that science would be able to link specific neurochemicals to specific behaviors, allowing
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highly focused manipulations of behavior through pharmacological intervention (i.e., drug
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therapy). However, despite what filters its way into the popular press (e.g., low serotonin levels
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cause aggression), the way the biochemistry of the brain operates is vastly more complex than
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one chemical-one behavior. For example,It says above that receptors only bind with one
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molecule. Conflict with point below.*** it now appears that many of the chemicals that affect
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brain function are able to unlock several different receptors. This allows the same (or quite
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similar) chemical to have different functions and to play a role in multiple (albeit often related)
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behavioral systems.
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The brain is also able to alter its sensitivity to a chemical messenger by changing the
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presence, conformation (structure), and availability of the chemical’s receptors. Often receptor
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changes reflect the history of the nerve cell’s experience with its neurochemical. High levels of
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the chemical operating on the receptor frequently result in a decrease in the nerve’s receptors for
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that chemical (a process called down regulation); sometimes a dearth of a chemical important in
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a nerve’s functioning results in an increase in receptor number (i.e., up-regulation). Up- and
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down-regulation take* place over hours and days, partially explaining why some psychoactive
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drugs take time before they begin to influence behavior and why some drugs, with time, need to
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be taken in higher and higher dosages to have the same effects. Some of these shifts in chemical
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messenger/receptor systems appear to be relatively permanent, perhaps especially those that
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occur during periods of rapid development; others are more transient, reflecting the normal
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turnover (production, decline, replacement) of receptors. This complexity is hardly user-friendly
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for those who are trying to decipher the mysteries of the brain, but it does allow the brain to be
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highly plastic, toning its functioning in highly nuanced ways, often quite rapidly, without the
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need to prune or grow dendrites or synapses.
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Neurochemical/receptor systems also lie at the heart of how the brain alters its physical
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structure. A variety of different nerve growth factors (i.e., chemicals that play a role in the
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growth of dendrites and synapses) have been identified. These growth factors are present in
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different quantities and locations at different points in development of the brain, regulated by
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genes involved in normal brain development. They also change in their concentration in response
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to nerve damage, playing a role in the brain’s attempts to adapt to and restore functioning
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following trauma. Receptor systems also play critical roles in both experience-dependent and
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experience-expectant neural plasticity. The NMDA receptor is one receptor, but not the only one,
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which plays a role in neural plasticity. It appears* to support learning by helping to foster what is
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termed “long-term potentiation”. Long-term potentiation, a memory “model” involving increased
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synaptic strength,* is brought about by* sustained rapid* activity in the neural circuits involved
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in newly acquired information, analagous* to repeating a new phone number in order to
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memorize it. It also appears that at critical points in the development of neural systems there is
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sometimes an increase in NMDA receptors. This increase seems to “open the window” for the
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development of that neural system, allowing stimulation to have large effects, with the window
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closing when the number of NMDA receptors decreases.
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Changes in chemical messenger systems and their receptors tend to tone the nervous
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system, altering sensitivity to stimuli and probabilities of responses, rather than necessarily
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causing particular behaviors. The following thought experiment, provides a good example. You
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have been on a low calorie diet (and have stuck to it) for several weeks. Numerous
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neurochemical changes in your brain have been set into motion by this starvation. All of these
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changes do not mean that you will eat that luscious steak the waiter just set in front of you (the
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fact that you are dieting, are a vegetarian, and did not order the steak will hopefully rule the day).
342
But the myriad of neurochemical changes in your brain set into motion by starvation will
343
probably make you more sensitive to how good the steak smells, make you salivate more, make
344
you remember that steak for a long time, and so on-- all changes orchestrated to help increase the
345
probability that you will break down and eat the steak that your body might, in fact, “need”. As
346
this thought experiment indicates, the behavioral impact of changes in neurochemistry are
347
dependent on the context and the individual’s history. Like our temperaments, they tend to
348
orchestrate a bias or propensity to respond in particular ways rather than rigidly determine that a
349
behavior will always be expressed. A number of researchers believe that in order to understand
350
the neural bases of temperament and emotions, we will need to understand the genetic and
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experiential processes that regulate these complex neurochemical systems of the brain
352
throughout development.
353
Characteristically, the neurochemical systems of the brain are open both to input from
354
the environment and to events occurring in the body below the neck. There is increasing animal
355
evidence that the environment plays a role in regulating aspects of brain neurochemistry. For
356
example, the licking and grooming that the mother rat does of her pups (infant rats) appears to
357
enhance the production of serotonin and thyroid hormone, both important in the neurochemistry
358
of brain development. There is also increasing evidence that elements of early caregiving may
359
help modulate the neurochemicals involved in pain and distress. Thus, the fats and sugars in
360
breast milk appear to stimulate taste receptors linked to central opioid (natural pain killer)
361
pathways, stimulating mild analgesia. Similarly, tactile stimulation of the mouth appears to
362
operate through non-opioid pain-killing neurochemistry affecting brain pathways controlling
363
distress. Some of these effects have been demonstrated in human infants. The evidence that the
364
regulation of neuroactive chemical systems extends into basic caregiving activities is exciting,
365
even though much of it still has been demonstrated only in animals. This evidence promises to
366
help explain how alterations in the environment early in life may have wide-ranging effects on
367
brain development and may alter, probabilistically, patterns of behavioral responding for
368
children with different rearing histories.
369
370
HOW IS THE BRAIN AFFECTED BY EARLY EXPERIENCE?
371
Our account of early brain development emphasizes the ways in which the nervous
372
system is designed to recruit and incorporate experience into its developing architecture and
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neurochemistry. Normal experience (e.g., good nutrition, patterned visual information) supports
374
normal brain development and abnormal experience (e.g., prenatal alcohol exposure, occluded
375
vision) can cause abnormal neural and behavioral development (Black, Jones, Nelson, &
376
Greenough, 1998). As such, plasticity is a double-edged sword that leads to both adaptation and
377
vulnerability. We have seen that the process of synaptic overproduction and loss is dependent
378
upon environmental information, although our evidence is largely restricted to sensory systems.
379
Similarly, the brain’s neurochemistry is exquisitely sensitive to behavioral and environmental
380
stimuli. We are, however, far from linking specific types or amounts of experience to the
381
developing structure or neurochemistry of the immature human brain, and, conversely, from
382
understanding how early brain development affects the ways in which young children process
383
the abundance of information and experiences that their environments present to them. Answers
384
to questions about when during development particular experiences must occur and when, in
385
fact, timing is important and when not also lie, to a large extent, beyond the boundaries of
386
current knowledge. Research on the developing brain can, nevertheless, provide a framework for
387
considering the effects of early experience on development more generally. The questions that
388
have been asked by neuroscientists have their parallels in research on behavioral development, as
389
we will discuss in the following chapters.
390
Two issues have played pivotal roles in guiding scientific inquiry about early experience
391
and the brain. The first issue concerns the nature of early experiences. Those who raise and work
392
with young children are deeply concerned about whether they are providing them with the
393
“right” experiences and protecting them from “harmful” ones. What damage is done by exposure
394
to inappropriate experiences, and how reversible is this damage? What degree of enhancement
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395
can be achieved by exposure to enriched experiences, and how long do beneficial effects last?
396
We actually know much more about the negative consequences for brain development of
397
harmful environments than we do about the benefits of advantageous environments. We also
398
know relatively more about the effects of pre- and perinatal environments on the developing
399
nervous system than we do about environmental influences after the first few months of life.
400
The second issue concerns the timing of experience and is often expressed in terms of
401
critical or sensitive periods. Much of the contemporary discussion of the importance of the first
402
three years of life is framed in the terminology of sensitive periods. But, does it really matter
403
when the child is exposed to particular experiences? Do specific experiences need to occur
404
during specific windows of time in order for the brain to develop normally? Can the brain
405
recover or compensate when critical experiences are missed? In addition to the examples
406
regarding the visual system, described above, there are some very dramatic instances of timing
407
effects. For example, an injury to the rat’s cortex on the first day after birth causes more
408
ultimate* damage to brain tissue and greater loss of normal behavioral functioning than a similar
409
injury on day 5 (add cite this is Bryan Kolb* ). The presence of testosterone in the third
410
trimester of human fetal development organizes the physiological characteristics of brain regions
411
such as the hypothalamus in the male direction such that release of hormones that govern sexual
412
and reproductive functions follows the tonic, non-cyclic pattern seen in the post-adolescent male
413
(add cite). Prior to or after this critical period of sensitivity to the hormone, the presence of
414
testosterone does not have the same* organizing effects upon brain structure and physiology. The
415
zebra finch must be exposed to the father’s song between X and Y or it will fail to develop the
416
capacity to produce the full* adult song specific to its species (add cite).
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417
In developmental science, the term “sensitive periods” is preferred to “critical periods”
418
because it implies less rigidity in the nature and timing of formative early experiences
419
(Immelman & Suomi, 1981). Sensitive periods can be defined as unique episodes in
420
development when specific structures or functions become especially susceptible to particular
421
experiences in ways that alter their future structure or function (Bornstein, 1989; Thompson, in
422
press). This susceptibility can operate in two ways: First, certain early experiences uniquely
423
prepare the young children for the future by establishing certain capabilities at a time when
424
development is most plastic and responsive to stimulation. Second, the young child is highly
425
vulnerable to the absence of these essential experiences, and the result may be permanent risk of
426
dysfunction. In fact, it is extraordinarily difficult to study issues of timing in human development
427
given that it is profoundly unethical to deprive children of needed experiences in order to
428
“introduce” them at different developmental stages. We are thus dependent upon animal studies
429
that are generating fascinating evidence of timing effects (see, for example, Bornstein, 1989;
430
Knudsen, 1999) but have dubious translations to humans and on so called “experiments of
431
nature”, such as prenatal exposures that occur at different points in fetal development (which we
432
discuss below) and research on children with sensory deficits, as in the case of deaf children who
433
are not exposed to normal language inputs (which we discuss in Chapter 8).
434
Within these parameters, it is well known that a variety of environmental factors play a
435
significant role in modulating early brain development. Our greatest insights have come from
436
research on the detrimental consequences of stress and of early biologic insults and deprivations.
437
We have also learned a great deal from efforts to trace the neurobiological consequences of
438
prematurity. Following a brief overview of the research that stimulated excitement about the
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439
brain’s receptivity to environmental influence, we turn to the research on biologic insults, stress
440
and prematurity. We close by highlighting several cross-cutting issues, including a brief reprise
441
on timing and comments on the confluence of adverse inputs, individual variability in responses,
442
common pathways of influence, and modifiability and recovery.
443
444
The Contribution of Environmental Variation
Documented differences in the brains and behaviors of animals that have experienced
445
markedly discrepant early environments has emerged from the laboratory of Greenough and his
446
colleagues (Black and Greenough, 1998; Black et al., 1998;* Greenough and Black, 1992; ).
447
Rats, not babies, are the subjects of study. They are either housed from infancy or placed as
448
adults in cages that vary in the degree of stimulation they offer to the rat. The “complex” cages
449
contain play objects and other animals. Animals reared or housed in these cages outperform rats
450
raised alone or placed in typically barren laboratory cages on a variety of learning and problem-
451
solving tasks (e.g., making their way through a maze, finding a hidden platform in a pool of
452
water, learning a relationship between a cue such as a light and a reward, etc.*). The brains
453
of the rats reared in the complex environments also showed more mature synaptic structure,
454
more dendritic spines, larger neuronal dendritic fields, more synapses per neuron, more
455
supportive glial tissue* and increased capillary branching that increases blood volume and
456
oxygen supply to the brain*. Importantly, these effects do not appear to be characterized by a
457
critical period. The indicators of both superior performance and more developed brains
458
characterized the rats exposed to the complex environments as adults, as well as those reared in
459
these environments, although the effects occured more rapidly and to a greater degree in the
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460
younger animals*. Thus, both early and later exposure to greater environmental stimulation had
461
beneficial consequences.
462
Studies of complex environments in rats have also revealed the role that such
463
environments can play in processes of recovery. For example, the detrimental behavioral effects
464
of prenatal exposure to low to moderate levels of alcohol in rats (e.g., ataxia and impairments in
465
learning spatial tasks) can be attenuated by raising the animals in a complex environment
466
(Hannigan et al., 1993). A program of forced motor skill training in alcohol exposed rats nearly
467
eliminated motor dysfunction and it subsequently increased synapse number in their cerebellar
468
cortex (Klintsova et al., 1997, 1998*). Finally, increasing the complexity of the environment
469
before and/or after brain damage in developing and adult rats enhances recovery from the
470
impairments produced by damage to various brain areas, probably through mechanisms that
471
involve the development of alternative strategies rather than the direct recovery of lost functions
472
(see Jones et al., 1998*).
473
Two additional facets of this research are important to highlight, in part because they
474
have been the subject of serious misinterpretation. First, these findings bear more directly on
475
issues of deprivation than of enrichment. In fact, the complex cages in Greenough’s research
476
presented the rats with fewer challenges and learning opportunities than rats would typically*
477
confront in their natural wild habitats.. {The preceding statement is untrue or at least not
478
demonstrated. While we have not looked at long intervals, we see very little decline of the effects
479
on synapses over periods equivalent to the length of the exposure. Glial effects diminish over
480
that same time period. The following sentence is OK.} Second, while long-term neuron and
481
synapse studies have not been conducted, the effects of exposure to a complex environment on
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482
learning ability diminish over time if the rats are removed from the environment.* The
483
intervention provided by the complex cages thus functioned more like a tetanus shot that requires
484
boosters than the small*pox vaccine that provides a permanent inoculation against disease. As
485
we shall see later, most of the risks for which we design early interventions for humans act more
486
like tetanus than small pox.
487
Most of the research that we can turn to for evidence of experience-brain connections
488
does not concern improvements upon deprivation, as with the complex environment* rats, but
489
rather explores the detrimental consequences of harmful influences. We now turn to the research
490
on biologic insults and the developing brain.
491
{I still think something is missing here and that we have thrown out the baby with the
492
bashing (of zero to 3). The foregoing sections bend over backwards to say that bad things can
493
happen but that we know nothing about positive environmental qualities beyond the sub-neutral.
494
I disagree, as I have at several points in our meetings. I believe that, despite falling short of the
495
real environment, the complex environment studies point to a continuum that implies positive
496
effects of a better than average environment. I believe that the studies of verbal interactions in
497
the home and subsequent child performance similarly imply the existence of a multidimensional
498
continuum with anchor points that could be described as “impoverished” and “enriched” with
499
meaningful implications for cognitive, linguistic and social development. And I think it is a
500
mistake to imply that, as long as some minimal threshold exceeded by most kids is reached, we
501
“don’t have to worry.” Maybe it’s just that I like to take some credit for my outstanding
502
daughter…. So erase this and say whatever you wish, but remember that I objected.}
503
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504
505
Early Biologic Insults and the Developing Brain
Research on early biologic insults provides fundamental insights into the vulnerability
506
and resilience of the developing central nervous system. This area of research also offers a
507
compelling illustration that plasticity cuts both ways, leaving the developing fetus and young
508
child simultaneously vulnerable to harm and receptive to positive influences. Finally, this
509
research suggests that the current emphasis on the birth-to-three years may have unwittingly
510
bypassed the stage of development, namely the prenatal period, when damaging environmental
511
conditions may have among the most devastating effects on development and, consequently,
512
when preventive efforts may have the greatest benefits.
513
Environmental factors that play a significant role in modulating prenatal and early
514
postnatal brain development include substances and circumstances that are necessary for normal
515
brain development, as well as exposures to chemicals, diseases, and stressors that are toxic or
516
disruptive. Tables 1 and 2 note some that are beneficial or detrimental, respectively. The factors
517
listed are by no means exhaustive. They are examples selected on the basis of clinical
518
importance, availability of basic research on brain effects, and/or existence of relevant clinical
519
studies of human infants. In this section, we consider a few of these biologic insults in more
520
detail: and an infectious disease (rubella); a developmental neurotoxin (alcohol), and a nutrient
521
deficiency (iron).
522
Infectious Diseases
523
Rubella is a classic example of an infectious disease that causes harm in utero. Exposure to
524
rubella early in prenatal development affects the organs (e.g., eyes, ears) that are developing at the
525
time if the virus crosses the placental barrier. Because the development of organs is largely
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526
compete by the end of the first trimester, fetal development during the second and third trimesters
527
of pregnancy is largely protected from the negative effects of the rubella virus.
528
The rubella story demonstrates how long it has often taken to recognize that a particular
529
condition or exposure can put the fetus or child at risk. It was widely believed that few diseases
530
were as benign as rubella, or German measles, until 1942 when the first report of the devastating
531
effects of maternal rubella during pregnancy was published {1998}. One of the puzzles is why the
532
medical community did not figure out the connection between maternal rubella and congenital
533
malformations earlier. Some qualities of rubella which exist in other conditions as well, made it
534
difficult to make the connection {1981}. It is not always clear that a fetus has been exposed to a
535
particular infectious illness or toxic agent during pregnancy. In the case of rubella, there are many
536
causes of fever, rash, and other symptoms that are variably seen. To complicate matters further,
537
effects on the developing fetus or child may also be quite variable. For instance, rubella may affect
538
the fetus’ eyes, ears, brain, and/or heart, among other organs. Furthermore, the very idea that the
539
fetus could be vulnerable to harm was novel before the rubella syndrome was accepted. We now
540
know this to be true for many conditions, including BETSY – PLZ Add a couple of examples.
541
The rubella story also illustrates a triumph in prevention. As better methods of diagnosing
542
rubella became available in the 1960s {1983}, there was more certainty about which rashes and
543
nonspecific symptoms in early pregnancy were due to rubella and which were not. Parents then
544
had the option of terminating the pregnancy to prevent the birth of a devastated child. With the
545
advent of vaccination, however, a far better solution is now available. Public health policy
546
requiring universal immunization against rubella has virtually eliminated the problem of the
547
congenital rubella babies in the US.
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548
Developmental Neurotoxins
549
Substances such as drugs and chemicals that are damaging to the developing nervous
550
system are known as developmental neurotoxins. Table 2 indicates a number of these agents.
551
Their effects on brain and behavior have been summarized in several comprehensive volumes
552
{1616,1597}, as well as in hundreds of original research reports. We use prenatal alcohol
553
exposure as an example of this class of early biologic insult. The effects of prenatal alcohol have
554
been studied extensively, and the current state of knowledge was recently considered in depth in
555
another Institute of Medicine report {1967}. Major points related to questions of early
556
brain/behavior development are highlighted here.
557
The adverse effects of prenatal alcohol exposure are now so widely known and accepted,
558
that it is hard to believe that the first report was issued only 30 years ago. Fetal Alcohol
559
Syndrome was first described in the English-language medical literature in 1973 {2000}.
560
Maternal alcohol consumption during pregnancy can lead to facial deformities, loss of neurons,
561
and severe neurobehavioral impairment, among other problems. It is the most common cause of
562
mental retardation and its consequences appear to persist throughout life
563
{1967,1958,1959,1963,1474,1426} [Connor & Streissguth, 1996]. Survey data collected by
564
the Centers for Disease Control show that the incidence of drinking at levels that put the fetus at
565
risk for neurobehavioral impairment was 3.5% in 1995 (the most recent year for which data are
566
available), with binge drinking the predominant pattern (87% of the cases) {1960}. The
567
proportion of women who consume alcohol during pregnancy has decreased since the mid
568
1980’s (Serudula et. al., 1991), although much of the decline is due to changed habits of light
569
drinkers. Women who drink heavily, who pose the greatest risk to the fetus, appear to be more
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570
resistant to prevention efforts. Heavy drinking, and thus the incidence of FAS, is much higher
571
among African-Americans than among European-Americans (Abel, 1995; Faden et al., 1997),
572
and also appears to be high among American Indian populations ( Duimstra et al., 1993).
573
Fetal Alcohol Syndrome (FAS) is the most severe form of prenatal alcohol effects.
574
Defined by a specific pattern of facial and other physical deformities accompanied by growth
575
retardation, FAS identifies a relatively small proportion of children prenatally affected by
576
alcohol. The Institute of Medicine (1996) recently suggested that the term “alcohol-related
577
neurodevelopmental disorder” (ARND) be used to focus specifically on brain dysfunctions in the
578
presence of significant prenatal alcohol exposure but without physical deformities. FAS is
579
estimated to occur at a rate of 1-3 per thousand live births; ARND is likely to be at least ten
580
times more prevalent. Brain dysfunctions in alcohol-exposed children without FAS are often as
581
severe as those in children with FAS.
582
A variety of neurobehavioral changes have been observed in children exposed to alcohol
583
prenatally. These effects range from problems with attention and memory to poor motor
584
coordination to problems with problem-solving and abstract thinking. Infants and toddlers may
585
be delayed in reaching important milestones, have difficulty “tuning out” excess sensory stimuli,
586
and often are hyperactive. About half of all individuals with FAS are mentally retarded (IQ <
587
70). Both severely and more mildly affected children demonstrate slower information processing
588
and longer reaction times, and appear to have specific problems with performance in arithmetic
589
{1833,1874}. These effects have been documented through the early adolescent years and into
590
adulthood. Such results demonstrate the importance of assessing functions other than IQ. In fact,
591
these more sensitive measures often detect effects of early biologic insults in the absence of IQ
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592
differences, and behavioral disturbances may create more functional impairment than a lower IQ.
593
In addition, the more specific and sensitive measures may indicate specific and differing effects
594
of various developmental neurotoxins {1875}.
595
The importance of considering timing (when a condition occurs during development),
596
severity (degree or dose), and chronicity (how long it lasts) in attempting to understand the
597
effects of early biologic insults is well illustrated by prenatal alcohol exposure. In general, the
598
prenatal period appears to be distinguished by its sensitivity to a large array of harmful
599
conditions. But, even within the prenatal period, timing matters. For instance, alcohol exposure
600
early in gestation has different effects on the developing brain from similar exposure later on.
601
Case reports from autopsies and more recently, neuroimaging studies {1992,1904,1906} give an
602
indication of central nervous system effects in the human. However, animal models—with
603
experimental manipulation of alcohol exposure and direct examination of brain tissue—continue
604
to provide crucial information. In the mouse, for example, exposure to alcohol on days 7 and 8 of
605
gestation not only results in the typical facial deformities of FAS but also brain anomalies, such
606
as small size overall and deficiencies in cerebral hemispheres, striatum, olfactory bulbs, limbic
607
structures, the corpus callosum, and lateral ventricles. Exposure later in gestation generally does
608
not produce such gross structural malformations but nonetheless kills nerve cells, interferes with
609
synaptogenesis, formation of myelin, and other biochemical processes, including reduction of
610
NMDA receptor binding in the hippocampus.
611
Research with humans also shows that the timing of prenatal alcohol exposure has
612
differential effects {1967, 1958,1959,1963,1426,1474} [same problem with Connor &
613
Streissguth]. The unusual facial features of fetal alcohol syndrome in the human infant (e.g., lowEarly Childhood Development
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614
set ears, short philtrum, cleft palate, cleft lip) appear to be due to heavy exposure early on, in the
615
first trimester, when the structures that come together to form the face are developing. Fetal
616
exposure to alcohol during the second and especially the third trimester of pregnancy appears to
617
be a time of particular vulnerability for the impaired neurobehavioral development discussed
618
above, although some data suggest that these effects extend throughout pregnancy. Dividing cells
619
appear to be particularly sensitive to the toxic effects of alcohol, and hence a period during
620
which extensive neurogenesis occurs would be a time of acute sensitivity to alcohol insult. The
621
cognitive effects associated with exposure to alcohol later in pregnancy, for example, may be
622
associated with the high level of neuronal cell division in pertinent parts of the brain that occurs
623
during the third trimester.
624
The severity of exposure is another important factor in understanding ill effects, perhaps
625
as important as the timing. For prenatal alcohol exposure, greater exposures are associated with
626
worse effects. In addition, episodic binge drinking appears to be more harmful to the developing
627
brain than equivalent levels of alcohol consumed gradually. Experimental animal studies indicate
628
that ingestion of a given dose of alcohol over a short period of time generates a greater peak
629
blood alcohol concentration than the same dose ingested over several days {1961}. Thus, the
630
developing fetus is actually exposed to a higher level of alcohol in binge drinking, and has been
631
found in animal research to experience greater neuronal {1961} and behavioral impairment
632
{1962). In humans, binge drinking is more of a problem than usually recognized, because
633
“moderate” drinkers, who consume 1-2 drinks per week on average, in fact, tend to concentrate
634
their drinking on 1-2 days per week, thus drinking 4-6 drinks {numbers don’t add}* per occasion
635
{1834}. When juxtaposed with evidence on the timing of alcohol exposure, the detrimental
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636
effects of binge drinking suggest that any bouts of drinking during pregnancy run the risk of
637
damaging some aspect of the developing brain.
638
Chronicity is another important factor in understanding the effects of early biologic
639
insults. In the case of prenatal alcohol exposure, it appears that the effects on the fetus worsen
640
with successive pregnancies. Specifically, older mothers who are moderate-to-heavy drinkers are
641
at higher risk for having an affected offspring (1413). This may be due to reduced ability to
642
metabolize alcohol by women who have been drinking heavily for several years {1959,1874}. In
643
the case of alcohol exposure, chronicity should thus be thought of as both a within- and between-
644
pregnancy dimension of risk.
645
Research on early biologic insults has also yielded information on modifiability or brain
646
plasticity. Environmental interventions to reduce the effects of alcohol exposure (other than
647
specific treatment of a toxin or deficiency, e.g. iron replacement for iron deficiency) have been
648
studied in only a few conditions. Prenatal alcohol exposure is perhaps the best-researched in
649
recent years. In animal models, a variety of interventions has been shown to ameliorate some of
650
the central nervous system effects of alcohol {690,1612,1987}. Effective interventions include
651
motor training, procedures that enhance maternal caregiving behaviors, and a postweaning
652
environment that is physically and socially stimulating. However, one should not conclude that
653
the process is trivial. For instance, getting a rat to do motor training may require quite heroic
654
efforts on the part of the investigator, and it is not clear that the intervention brings the brain and
655
behavior of exposed animals fully back to the levels of animals who never experienced the
656
biologic insult. As common sense would suggest, protecting the developing brain from early
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657
biologic insults is a more desirable and effective strategy than trying to correct the deficits once
658
they have occurred.
659
Malnutrition \
660
Prenatally and postnatally, nutritional adequacy is essential for optimal brain
661
development and function (see Georgieff and Rao {1985}, Morgan & Gibson, 1991; for recent
662
reviews) because of the growing brain’s reliance on folic acid, iron, vitamins, and other nutrients.
663
The effects of generalized undernutrition (lack of sufficient protein, energy, and other nutrients)
664
on the developing brain have been studied extensively over several decades
665
{1598,1975,509,1980}. Although adequate nutrient intake is important throughout life, certain
666
nutrients have a more profound effect on the developing brain than others. The timing of nutrient
667
supplementation or deficiency is also important. For example, nutritional deprivation in the
668
second trimester of pregnancy has been shown to result in deficient numbers of neurons, whereas
669
deprivation in the third trimester affects numbers of glial cells and the maturation of neurons
670
(e.g., Dickerson, 1981). Postnatal nutrition also appears to show timing effects, with the first
671
two to three years of life being an especially vulnerable time for sustaining serious impairments
672
in brain growth and experiencing related behavioral consequences. The earlier the malnutrition
673
occurs, the greater the reduction in brain size, and the longer the malnutrition continues, the
674
greater the effect on the brain (Moran & Winick, 1985; Winick, 1976). Moreover, a nutrient that
675
is essential for normal development at one time of life may be superfluous or even toxic at
676
another time.
677
678
Iron deficiency is our nutritional example of how early insults affect brain development,
as there has been a recent burst of relevant research. Iron deficiency is probably the world's most
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679
common single nutrient disorder. Approximately 20-25% of babies worldwide has iron-
680
deficiency anemia, and a much higher proportion has iron deficiency without anemia
681
{402,1997}. The latter is common even in countries where public health interventions have
682
reduced anemia. In the U.S., for instance, the prevalence of iron-deficiency anemia has decreased
683
dramatically {1547}, due to fortification of infant formula and cereal and increased breast
684
feeding, among other factors. However, poor and minority children are still at considerable risk
685
for iron deficiency with or without anemia {1425}. Non-poor white toddlers had the lowest
686
prevalence of iron deficiency (about 3%) in a recent U.S. national survey, while Mexican-
687
American toddlers were at highest risk regardless of economic status, affecting approximately
688
18% and 12% of poor and non-poor Mexican-American children, respectively {1425}.
689
Altered behavior and development are among the most worrisome concerns about iron
690
deficiency in infancy. Iron-deficient anemic infants generally test lower in mental and motor
691
development {183,184,185,186,89,164,526,1078}. Other behavioral differences, such as
692
increased fearfulness, fatigue, and wariness have also been noted {184,89,1078,168,92,218,805}.
693
Although one study reported that test scores improved with a full course of iron treatment {164},
694
the other available studies found that a majority of infants with iron deficiency anemia continued
695
to have lower developmental test scores {89,1078,186,400} despite iron therapy for 2-6 months
696
and correction of anemia. Other behavioral differences were also still observed {805}.
697
Differences thus appear to persist.
698
At early school age, children who were anemic as infants continue to have lower test
699
scores than their peers who did not experience anemia {165,182,191,192,193}. A comprehensive
700
follow-up at the transition to adolescence {1544} found that children who had been treated for
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701
severe, chronic iron deficiency in infancy still scored lower on measures of mental and motor
702
functioning, specifically in arithmetic achievement and written expression, motor functioning,
703
and some specific cognitive processes such as spatial memory and selective recall. They were
704
also more likely to have repeated a grade. Parents and teachers rated the formerly anemic
705
children as showing more anxiety/depression, social problems, and attention problems. In a
706
different, population-based study {1354}, children who were anemic in infancy (presumably due
707
to iron deficiency) were at increased risk for mild/moderate mental retardation at 10 years of age.
708
Thus, severe, chronic iron deficiency in infancy identifies children who continue to be at
709
developmental and behavioral risk more than 10 years later.
710
Basic science research and animal studies indicate some possible mechanisms for such
711
behavioral and developmental differences. Iron is required for enzymes that regulate central
712
nervous system cell division, neurotransmitter synthesis (especially dopamine), myelination, and
713
oxidative metabolism (reviewed in {1985}). Maximal transport of iron into the brain corresponds
714
with the brain growth spurt, and iron deficiency during this period results in a deficit of brain
715
iron in animal models. These observations suggest that the developing brain may be particularly
716
vulnerable to the effects of this nutrient deficiency. Conversely, free or excess iron is toxic to
717
cell membranes and may contribute to neuronal damage following a brain injury.
718
New studies that utilize neurophysiologic and electrophysiologic methods are now providing data
719
on iron-deficient human infants and demonstrating close links to results in animal models. In one
720
such study {1039}, 6-month-old infants with iron deficiency anemia had slower nerve
721
conduction in the auditory pathway. Differences in nerve conduction velocity between anemic
722
and nonanemic infants increased over the following year despite iron therapy. A disruption or
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723
defect in myelination was considered to be a promising explanation given that brain iron is
724
required for myelination, young iron-deficient animals have been noted to be hypomyelinated,
725
and the auditory system is rapidly myelinating in the first two years after birth in the human
726
infant (reviewed in {1039}).
727
The hippocampus, which controls recognition memory among other functions, also
728
appears to be vulnerable to early iron deficiency {1912,1451}. In animal models, iron deficiency
729
results in markedly reduced neuronal metabolism (as indicated by cytochrome coxidase activity)
730
in all subareas of the hippocampus and other regions involved in higher cognitive functions
731
{1912}. Preliminary evidence from a study of infants of diabetic mothers (who are at risk for
732
lower levels of iron in the liver, heart, and brain), using electrophysiologic techniques, has
733
revealed seriously impaired recognition memory despite normal iron status at 6-8 months of age
734
{1986}. These findings are consistent with a hippocampally-based memory deficit tied to iron
735
deficiency. Disruptions in recognition memory, in turn, may be a subtle early effect that could
736
contribute to the later learning disabilities observed in iron-deficient children.
737
Prematurity and Early Brain Development
738
One of the true marvels of human brain development is that an infant can be born
739
prematurely in the early part of the third trimester and not only survive, but achieve something
740
resembling his or her genetic {???????!!!}* potential in mental and motor behavior. Highly
741
sophisticated intensive care techniques have improved survival rates of premature infants,
742
although the borders of viability (approximately 24 weeks gestation) have not changed since
743
1980 (Richardson, et al. 1998). Greater than 95% of infants born after 28 weeks gestation and
744
greater than 50% of infants born at 24-28 weeks survive (Hack, et al. 1991). At the very borders
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745
of viability (22-24 weeks gestation), mortality remains high and of the infants that survive, a
746
high percentage have sustained damage to developing neurologic structures and have significant
747
neurologic morbidity (Allen, et al. 1993). Nevertheless, it is safe to say that over the past decade
748
neonatology has begun to concern itself less with survival (mortality) and more with outcome
749
(morbidity) (Richardson, et al. 1998).
750
It is useful to consider preterm infants as fetuses who develop in extrauterine settings at
751
the time when their brains are growing more rapidly than at any other time in their life (Als,
752
1997; McClellan, 1972). Prematurity has two main negative effects on brain development. First,
753
premature birth predisposes the infant to pathologic events that directly injure the brain. These
754
events can be thought of as damage committed by factors that the human at this gestation would
755
not normally be exposed to. These can be as seemingly benign as the wrong mixture of nutrients
756
to more obvious neuropathologies such as intracranial hemorrhage. Second, premature birth
757
interrupts the normal process of intrauterine brain development by denying it of expected
758
intrauterine stimuli and factors important for growth (e.g. nutrients such as docosohexaenoic
759
acid). One can consider this to be damage due to omission of factors which are critical for normal
760
development. Ultimately, the morbidity seen at any gestational age will be the result of the
761
combination of the number and severity of exposure to both types of factors.
762
The first principle* of assessing the effect of prematurity on neurologic outcome is to
763
note that the child’s general developmental status and intelligence scores decrease with
764
reductions in gestational age (Saigal, et al. 1991). Thus the 24 weeker is at greater risk than the
765
26 weeker who in turn is at higher risk than the 28 weeker. The 24 weeker not only has a less
766
“complete” brain than the 26 weeker, he is also far more prone to intracranial hemorrhage,
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767
hypoglycemia, and postnatal malnutrition, all of which adversely affect his more “primitive”
768
brain. The superimposition of lower socio-economic status on prematurity causes a further
769
decrement in developmental status and intelligence at each successively lower gestational age
770
(Saigal, et al. 1991).
771
Insults Due to Prematurity
772
The neonatal outcome literature is replete with studies assessing the effects of intracranial
773
hemorrhage (Papile, et al. 1983), periventricular leucomalacia (Feldman, et al. 1990, Lowe and
774
Papile 1990), hypoglyecmia (Duvanel, et al. 1999), and malnutrition (Georgieff, et al. 1985,
775
Georgieff, et al. 1989, Hack and Breslau 1986) on head growth and developmental outcome.
776
Besides gestational age and SES, the next most important factor in assessing risk of adverse
777
neurologic outcomes is the degree of illness of the infant during the newborn period. Infants
778
whose overall physiology is more compromised are more developmentally delayed at 2 years
779
and appear to be at greater risk of prefrontal deficits at 8 years of age (Brazy, et al., 1991;
780
Luciana, et al., 1999).
781
Intracranial hemorrhage (also known as intraventricular hemorrhage or IVH) is the most
782
extensively studied noxious event that affects the premature infant’s brain. This is likely due to
783
the fact that IVH is easily visualized by cranial ultrasonography and quantifiable into Grades I
784
(least severe) to IV (most severe). Approximately 20% of infants between 28 and 34 weeks
785
gestation have IVH, with the ???*majority (>60%) rated as Grade I or II. In contrast, 60% of 24
786
to 28 week infants have IVH and their hemorrhages tend to be the more severe Grade III and
787
Grade IV varieties. Accordingly, the risk of major handicaps, both motor and cognitive, is
788
increased. Infants with lower grade hemorrhages do not appear to be at any greater risk of major
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789
handicap (cerebral palsy or mental retardation) than infants who did not bleed (Papile, et al.
790
1983), although they are at higher risk of minor handicaps (e.g., behavior problems, attention
791
problems, memory deficits) (Lowe and Papile 1990, Ross, et al. 1996).
792
Omission of Factors Important for Normal Brain Development
793
A premature infant with a benign neonatal course nevertheless remains at increased risk
794
of neurologic morbidity. Although one can never be assured that all noxious events (both pre-
795
and postnatal) have been accounted for in any given study, there is mounting evidence that
796
transferring brain growth and development from an intrauterine to an extrauterine environment
797
before 38 weeks gestation is less than optimal even in the absence of other definable neurologic
798
risk factors (Chapieski and Evankovich 1997, Cherkes-Julkowski 1998, Huppi, et al. 1996).
799
Recent research, for example, has demonstrated poorer performance on elicited imitation tasks (a
800
medial temporal lobe function) at 18 months of age in 27- to 34- week gestational age preterm
801
infants with completely benign neonatal courses compared with term infants tested at the same
802
post-conceptional age (deHaan et al, 2000). These emerging data strongly suggest that the human
803
brain continues to develop in a unique way in utero until the end of gestation and that early
804
termination of pregnancy disrupts that development with subsequent behavioral consequences.
805
A more pernicious effect of extrauterine life on brain development in small preterm
806
infants is the general problem of malnutrition. Neonatal illness not only predisposes preterm
807
infants to definable neurotoxic events (e.g. IVH, hypoxia) but at the same time does not allow
808
the provision of adequate nutritional substrates to promote normal brain growth and
809
development. Studies have estimated that greater than 50% of very low birth weight infants fall
810
below the 5th percentile for head growth sometime during their hospitalization (rendering them,
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811
by definition, microcephalic) (Georgieff, et al., 1985). Fortunately, one of the most amazing
812
aspects of early human life is the ability of the head (and brain) to demonstrate catch-up growth.
813
After a period of no growth, the head exhibits a remarkable increase in growth velocity to double
814
or triple normal rates, given adequate protein-energy intakes (Georgieff, et al. 1985, Sher and
815
Brown 1975). There is, however, a point of diminishing return. If the infant has had no growth
816
for more than a month, the subsequent catch-up rate is markedly reduced, almost as if the
817
potential for catch-up has been lost (Georgieff, et al. 1985, Hack and Breslau 1986, Sher and
818
Brown 1975). The premature infants with more striking postnatally acquired microcephally due
819
to malnutrition indeed have smaller head circumferences and poorer scores on the Bayley Scales
820
of Infant Development at 12 months of age (Georgieff, et al. 1985). Reduced head circumference
821
at 8 months postnatally bodes poorly for developmental outcomes measured at 3 and 8 years of
822
age (Hack and Breslau 1986). These studies suggest that although catch-up head growth is a
823
marvelous compensatory response, it is better to have never accrued the growth deficit in the first
824
place. Extrapolating further, it argues for important windows of opportunity for brain growth in
825
the late third trimester that, if interrupted by premature birth and lack of head growth, may result
826
in the brain being “constructed” in an alternative manner (deHaan, et al., 2000).
827
In sum, prematurity confers a significant risk to the developing brain. The risk emanates
828
from both insults to the brain that arise during the course of illness in the premature infant and
829
from interruptions of the provision of the expected substrates and environment apparently
830
necessary for normal brain development. We have used examples for which there is a substantial
831
literature (e.g. IVH), but hasten to add that multiple other potentially neuropathologic factors that
832
are more difficult to isolate and quantify (e.g. hypoxia-ischemia, hypoglycemia, neurotoxic
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833
medications such as steroids) likely play important roles as well. The ultimate risk to any one
834
premature infant is likely to be a composite of all the known and unknown risk and protective
835
factors that characterize that infant, and on the infant’s general extent of biological vulnerability.
836
Thus the premature infant born to a lower SES mother who received poor prenatal care is likely
837
to have a much more difficult neonatal course and therefore be at higher neurodevelopmental
838
risk than an infant of the same gestation born to a mother who received better prenatal care and
839
has more resources. Perhaps this helps explain the overall down-shifting of developmental scores
840
in lower SES premature infants (Saigal, et al. 1991).
841
Growing awareness of environmentally-based differences in the outcomes of premature
842
infants has fueled multiple intervention efforts ranging from dramatic changes in the care these
843
infants receive in neonatal intensive care units (NICU’s) (see reviews by Als, 1997; Hernandez-
844
Reif & Field, 2000) to comprehensive initiatives that provide a range of services to the infants
845
and their families from the time they leave the hospital to several months or years post-discharge.
846
The best known of the comprehensive approaches is the Infant Health and Development Program
847
(see box) (Gross, Spiker, & Haynes, 1997), which included a randomized trial and extensive
848
follow-ups of the participating families. The evaluation literature on these interventions offers
849
good news about the capacity of NICU-based stimulation programs, approaches that emphasize
850
individualized developmental care, and initiatives focused on parental coping and training in
851
optimal parenting skills to improve health outcomes and decrease developmental delays in
852
premature infants. Infants participating in the IDHP intervention demonstrated improved
853
behavioral functioning (e.g., higher IQ scores, vocabulary gains, and fewer behavioral problems)
854
at the conclusion of the intervention (when they were 3 years old) (IHDP, 1990), however, at 5
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855
years of age, only the heavier low birthweight infants (i.e., < 2000 grams) continued to show
856
gains that distinguished them from the children that did not receive the intervention (Brooks-
857
Gunn et al., 1994). By 8 years of age, even the gains of the heavier infants had been substantially
858
diminished (McCarton et al., 1997). The authors have speculated about the outcomes that might
859
have emerged if they had continued the program up to school entry. While it appears, therefore,
860
that the developmental problems associated with prematurity and low birthweight can be
861
mitigated by intervention, because this is such a complex, multifaceted biological phenomenon,
862
relatively nonspecific interventions may not be the most productive approach. Moreover,
863
virtually all experts in this area agree that efforts focused on preventing the birth of low
864
birthweight babies need to be the top priority.
865
866
Stress and the Developing Brain
Research on premature infants has provided substantial evidence of the importance of the
867
baby’s caregiving environment for later prognosis. This theme emerges, as well, from research
868
on animals regarding how stress affects the developing brain. This research provides preliminary
869
insights into how alterations of the early caregiving environment affect neurochemical aspects of
870
early brain development. It is premature to extend this evidence to our own species. There is, for
871
example, only one scientifically-reviewed study that has imaged the brains of maltreated children
872
(DeBellis, Keshavan et al., 1999b), which we discuss in Chapter 10. The animal evidence,
873
however, is suggestive of the physiological processes that may underlie associations found
874
between highly dysfunction caregiving and problematic child outcomes and thus points to
875
promising directions for future collaborative research among behavioral and brain scientists.
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876
The term stress is used by psychologists, physiologists, and the lay public. It means
877
different things to each (Engle, 1985). We adopt the convention of using stress to refer to the set
878
of changes in the body and brain that are set into motion when there are overwhelming threats to
879
our physical or psychological wellbeing (Selye, 1973; Selye, 1975). Stress can have dramatic
880
effects on health and development (Johnson, Kamilaris, Chrousos, & Gold, 1992b). This happens
881
because the physiology of stress produces a shift in the body’s priorities. When threats begin to
882
overwhelm our immediate resources to manage them, a cascade of neurochemical changes that
883
begin in the brain temporarily puts the processes in the body that can be thought of as future-
884
oriented--finding, digesting and storing food; fighting off colds and viruses; learning things that
885
don’t matter right now but may be important sometime in the future; reproducing and rearing
886
offspring--on hold. Many of these neurochemical changes take place in the very same brain
887
structures (e.g. hypothalamus and brainstem) that function to regulate heart rate, respiration, food
888
intake and digestion, reproduction, growth, and the building up versus breaking down of energy
889
stores (Stratakis & Chrousos, 1995).
890
These brain regions also play a role in regulating the production of stress hormones “
891
below the neck”. Specifically, the adrenal glands, located on the top of the kidneys, produce
892
adrenaline and cortisol (Axelrod and Reisine, 1984). Adrenaline is part of the sympathetic
893
nervous system (SNS). Increases in SNS activity support vigilance, narrow attention, increase
894
heart rate, shunt blood to muscles and away from the digestive system, break down fat stores
895
making energy available to cells, and dampen activity of the immune system. Cortisol is a steroid
896
hormone that plays a myriad of roles in stress physiology. It helps to break down protein stores,
897
liberating energy for use by the body. It suppresses the immune system, suppresses physical
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898
growth, inhibits reproductive hormones, and affects many aspects of brain functioning, including
899
emotions and memory.
900
Our understanding of how psychological stimuli, such as experiences of fear and anxiety,
901
recruit stress physiology is currently centered on an area of the brain called the amygdala (Davis,
902
1997; Rolls, 1992; Schulkin et. al., 1994) which has close back and forth communication with
903
areas of the brain involved in attention, memory, planning, and behavior control. In animals,
904
experimentally causing a hyper-stimulation of the amygdala (a process termed ‘kindling’) seems
905
to create a hyper-sensitization of the fear-stress circuits of the brain and changes in behavior that
906
look like an animal version of post-traumatic stress disorder (PTSD) (Rosen, Sitcoske, & Glowa,
907
1996). It is as if the fear circuits get locked in the “on” mode and have trouble shutting off. These
908
circuits course through the amygdala and an area called the bed nucleus of the stria terminalis.
909
They appear to be pathways through which circumstances outside the body set in motion the
910
cascade of events inside the body and the brain that undergird fear-stress responses. These events
911
involve the elevation of cortisol and stimulation of the sympathetic arm of the stress response. In
912
animals, flooding the brain with cortisol for prolonged periods of time produce changes in this
913
process that may lower the threshold for activating the fear-stress system (Makino, Gold, &
914
Schulkin, 1994). The result is an animal that more readily experiences fear, anxiety, and the
915
stress that accompanies these emotions and may have a harder time dampening or regulating
916
these responses.
917
The amygdala is a fairly mature brain area at birth in humans and seems to be fully
918
mature at least as early as a child’s first birthday. All anatomical evidence suggests that by the
919
end of the first year, young children should be capable of experiencing psychologically-driven
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920
fear, anxiety, and stress. Indeed, fear reactions to strangers (Bronson, 1971; Schaffer, 1966;
921
Waters, Matas, & Sroufe, 1975) and anxiety reactions to separation from familiar caregivers
922
(Ainsworth & Bell, 1970; Bowlby, 1973; Sroufe, 1979) are hallmarks of emotional development
923
in late infancy. Brief periods of stress are not expected to be problematic. Indeed, survival
924
requires the capacity to mount a stress response. However, because the stress system functions to
925
put growth-oriented processes on hold, frequent or prolonged periods of stress may negatively
926
affect development.
927
Evidence from research on rodents and primates suggests that experiences of neglect
928
early in life constitute the kinds of stressful experiences to which young offspring are especially
929
sensitive and may result in a more reactive stress system. In studies of rats, for example, when
930
experimenters do things to the nest (such as handle the pups ) that affect maternal behavior, they
931
can affect the development of the rat’s stress system (Denenberg, 1999; Levine & Thoman,
932
1970). Doing things to the nest that result in better organized maternal behavior results in infant
933
rats that develop into less fearful, less stress-reactive adults, whereas doing things that disrupt
934
maternal behavior results in more fearful and stress-reactive adult rats. Researchers have also
935
shown that strains of rodents that are known to be more stress reactive are characterized by
936
maternal care that involves less licking and grooming (Liu et al., 1997; Meaney, 1996; Plotsky &
937
Meaney, 1993). Cross-fostering genetically high stress-reactive infants to mothers from low
938
stress-reactive strains results in the development of a more stress resilient animal. These early
939
experience effects in the rat appear to operate through the development of the receptor system in
940
the brain that influences the reactivity of the fear-anxiety circuits. Plenty of input early in life
941
that keeps the stress system dampened down results in the development of a stress-modulating
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942
receptor system that can quickly turn off stress reactions. Absent this input, the fear-stress system
943
appears to get “shaped*” so that the rat pup becomes a more highly reactive adult who has
944
difficulty modulating these responses. In short, the development of a less stress-reactive rat
945
seems to revolve around enhancing and supporting qualities of the caregiving environment.
946
There are monkey analogues of these rat studies, although details of the bio-behavioral
947
mechanisms have not been worked out as elegantly. Infant monkeys deprived of normal social
948
stimulation grow into socially incompetent, fearful adults (Harlow, Harlow, & Suomi, 1971;
949
Laurens, Suomi, Harlow, & McKinney, 1973). More recent studies have documented that
950
monkeys reared on cloth surrogates, but exposed every day to several hours of play with other
951
infant monkeys, are not as socially incompetent as monkeys raised in isolation, but they show
952
numerous physiological signs of being very anxious and fearful (Suomi, 1991). They produce
953
higher levels of stress hormones when threatened and they have high levels of anxiety-related
954
brain neurochemicals in the cerebrospinal fluid which flows from the brain into the spinal cord.
955
Monkeys reared only with other infant monkeys (i.e., no cloth surrogates to call their own), show
956
similar patterns of high stress reactivity (Champoux, 1989; Champoux, Byrne, DeLizio, &
957
Suomi, 1992). A high stress-reactive adult monkey can also be produced by procedures that
958
cause stress to its mother (Schneider, 1992a; Schneider, 1992b; Schneider et al., 1998;
959
Schneider, Coe, & Lubach, 1992 Coplan et al., 1996; Coplan, Rosenblum, & Gorman, 1995;
960
Rosenblum & Andrews, 1994; Rosenblum et al., 1994). One technique for stressing the mother is
961
to make her food resources unpredictable. This has the effect of deeply disturbing the mother’s
962
social relationships with other adult monkeys in her group. The infant monkeys in these
963
unpredictable food studies (who are roughly equivalent in developmental age to 1- to 2-year old
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964
human children) experience high levels of stress hormones (like their mothers) and grow up into
965
highly fearful, socially less competent adult animals (Rosenblum & Andrews, 1994; Rosenblum
966
et al., 1994). These effects were obtained even though food was never uncertain for the young
967
monkeys themselves, and thus seem to be mediated by what this uncertainty and disturbance in
968
the social environment does to their mothers.
969
We have a great deal to learn about how the social environment connects with the
970
biology of growth and the regulation of stress physiology in human infants and children.
971
Intriguing research is emerging, however, which suggests that the development of stress
972
regulation in young children may be a very promising place to look for brain-experience
973
dynamics. For example, both failure to thrive and psychosocial dwarfism (Gohlke, Khadilkar,
974
Skuse, & Stanhope, 1998; Skuse, 1985), in which children’s pituitary glands fail to secrete
975
sufficient growth hormone (Skuse, Albanese, Stanhope, Gilmour, & Voss, 1996), are associated
976
with failures in the social environment (Alanese et al., 1994). Removing the child from the
977
problematic social system reverses the disorder and growth increases rapidly. A significant
978
implication of this research, as well as that on orphanage-reared infants discussed in Chapter 10,
979
is that the human brain may be capable of greater plasticity and self-righting tendencies than
980
have been observed in the animal studies. In general, we have much to learn about the extent to
981
which the neurological pathways between caregiving environments and dysfunctional behavior
982
that are emerging in the animal literature apply to human offspring and about the effects of
983
remedial experiences that attempt to enhance the development of children from early abusive and
984
neglectful environments.
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985
In sum, neuroscience evidence from animal research is increasingly pointing to
986
experiences of neglect, stress and trauma within the caregiving environment as a source of
987
compromised brain development. Research on rodents and primates indicates that the ways in
988
which the brain learns to respond to stressful and fear-inducing circumstances are profoundly
989
affected by the capacity of the infant’s caregivers to regulate the developing stress system.
990
Disruptions to the caregiving environment that produce stress in the mother appear to alter the
991
offspring’s developing stress reactivity, as seen behaviorally in high levels of fearfulness and
992
neurologically in how the brain releases and modulates stress hormones. Alternatively,
993
supportive and nurturant caregiving can protect offspring from these consequences. Although
994
this evidence is compelling with regard to the significance of early rearing environments as they
995
affect the developing brain, we are at the frontier of exploring these issues in human babies. In
996
the future, research that blends neuroscience and behavioral research promises to help explain
997
how alterations in the environment early in life may have effects on brain development and may
998
alter, probabilistically, patterns of behavioral responding for children with different rearing
999
histories. The capacity of the developing human brain to reorganize itself when beneficial
1000
caregiving environments are substituted for highly depriving circumstances also warrants
1001
expanded research attention.
1002
1003
Cross-Cutting Issues
We have reviewed a range of evidence regarding the influence of early environments on
1004
brain development. When examined topic by topic, however, issues that are common to or cut
1005
across specific areas of research do not necessarily surface. We close this section, therefore, with
1006
a brief discussion of several such issues.
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1007
Timing, Severity, and Chronicity
1008
The effects of early biologic insults vary depending on when the insult or stressor occurs,
1009
how severe it is, and how long it lasts, even within the prenatal period. We know less about these
1010
issues with regard to exposure to stress, although the brain systems that are affected are
1011
developing rapidly during the early childhood years. Issues of timing, severity, and chronicity are
1012
critical to understanding what aspects of brain development are particularly vulnerable, when
1013
they are vulnerable, which functions recover spontaneously, and which can be corrected or
1014
improved with intervention. Few conditions have been studied systematically enough to provide
1015
information on each of these issues, despite the tremendous clinical importance for the many
1016
infants exposed to early biologic insults. There is however, little doubt that timing, severity, and
1017
chronicity matter. We also saw that severity and chronicity can be different paths to similar
1018
outcomes. Episodic binge drinking early in pregnancy may be as bad for the developing brain as
1019
lower levels of alcohol consumption throughout gestation. Despite the urgent questions involved,
1020
separating the effects of timing, severity, and chronicity is often impossible in human studies and
1021
requires ingenuity and elaborate experiments even in animal models.
1022
Confluence of Risks
1023
Early biologic risks and insults often do not occur in isolation [Figure in Child Dev.
1024
paper]. In fact, they typically are increased among infants who also grow up in disadvantaged
1025
environments. Low birth weight, elevated lead levels, and iron deficiency, for example, are all
1026
more prevalent among poor and/or minority infants in the U.S.{Lozoff, NRC race paper. The co-
1027
occurrence of environmental and biologic risks requires cautious interpretation of research
1028
findings given how difficult it is to disentangle poorer developmental and behavioral outcomes
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1029
that are due to the biologic exposure, rather than to the problematic environment. The confluence
1030
of risks is not confined to the overlap of environmental disadvantage and early biologic factors.
1031
The early biologic insults themselves are often intertwined or induce other risks: women who
1032
drink heavily during pregnancy are also more likely to smoke, take other drugs, and have poor
1033
diets; iron deficiency exacerbates lead absorption, and so on. The confluence of risks is the
1034
reality of many babies' lives, and the overlap raises important questions. If a baby is exposed to
1035
alcohol and nicotine prenatally, is that worse than either chemical by itself? Does it make a
1036
difference if a baby born prematurely then experiences a nutritional deficiency postnatally?
1037
When biologic and environmental risks co-occur, are the effects on child development additive
1038
(e.g., 2 + 2 = 4) or synergistic (2+2=6)? Answering these questions in humans is difficult, and
1039
even in animal models there has been relatively little research on co-occurring risks.
1040
Nonetheless, such studies promise to provide fundamental information about the developing
1041
brain.
1042
Individual Variability
1043
There is a great deal of variability in the response to early biologic risks. For example,
1044
low birth weight babies are a heterogeneous group consisting of those born prematurely and term
1045
babies who did not grow optimally in utero. They are frequently categorized as low birthweight
1046
(2500 grams or less), very low birthweight (1500 grams or less), or extremely low birthweight
1047
(1000 grams or less). Neurocognitive differences, observed at all levels of low birth weight, are
1048
greater the lower the birth weight.{1411} Research showing clear differences, on average,
1049
between infants who experienced a early biologic insult and normal controls tells us little about
1050
the effect on an individual child. Even though an exposed group may generally do less well than
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1051
a non-exposed group, some children may show no ill effects. As we understand more about
1052
environmental factors and genetic influences on brain development, some of this variation may
1053
be explained. In the meantime, it is important to be cautious in applying research findings of
1054
average differences between groups to the clinical care of an individual child.
1055
Common Pathways
1056
Investigators understandably seek to identify specific central nervous system effects of
1057
the particular biologic insult they study. Yet, the search for specific effects, while undeniably
1058
important, may be misguided in some respects. Many of the biologic risks in Tables 1 and 2 are
1059
involved in numerous central nervous system processes.{Morgane; Neurotox issue} Thus,
1060
diffuse, subtle, or multiple effects would be expected for many of these factors, and their
1061
characterization may be as important as the search for specific effects. Certain brain functions
1062
may be particularly vulnerable, regardless of the specific biologic insult or stressor. For example,
1063
animal research indicates that the hippocampus is affected by a number of conditions, including
1064
hypoxia-ischemia (common in premature infants), lead, iron deficiency, and exposure to stress in
1065
the form of maternal separation. Similarly, human studies suggest that certain behavior patterns
1066
are frequently observed in infants exposed to a variety of early biologic insults. For instance,
1067
longitudinal studies of children born with low birth weight, exposed to alcohol prenatally, with
1068
elevated lead levels, or who experienced iron deficiency in infancy all show increased attention
1069
problems. Memory functions and behavioral wariness are additional candidates. More
1070
coordinated choices of outcome measures in studies of developmental and behavioral outcome in
1071
human infants who experience different early biologic insults and stressors might identify more
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1072
outcomes in common and suggest testable hypotheses about basic mechanisms underlying the
1073
observed ill effects.
1074
Modifiability and Recovery
1075
Both observational and experimental studies provide crucial information about whether
1076
the ill effects of early biologic insults are modifiable by specific treatment or spontaneous
1077
recovery. Results from these studies address fundamental questions about both sensitive periods
1078
that constrain modifiability and the ongoing plasticity of the developing brain that keeps it open
1079
to influence by the environment, as well as about the extent of adaptation that is possible
1080
following damage. Research on animals clearly indicates that brain structure and behavioral
1081
functioning can be modified even in the face of clear biologic insult.
1082
The research on stress further suggests that more than adequate caregiving may be required
1083
following detrimental early experiences to return the young animal to a normal developmental
1084
pathway.
1085
Because there is minimal neuroscience data on young children who experience conditions
1086
of early psychosocial adversity, we know little about the capacity of the human brain to
1087
reorganize itself following conditions of disrupted caregiving, biologic insults, privation of
1088
stimulation, and so on early in life. We noted that a variety of interventions have been shown to
1089
ameliorate some of the central nervous system effects of prenatal alcohol exposure, and the
1090
behavioral effects of prematurity, but that sometimes extensive if not heroic efforts are required
1091
and that functioning is seldom fully restored. Other insults appear to leave even more lasting
1092
damage, as appears to be the case with iron deficiency anemia. There is an urgent need for
1093
continued basic science and clinical studies of the effects of specific environmental interventions
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1094
in the whole array of early biologic insults and stressors. It may turn out that the brain is
1095
considerably more plastic than is often assumed. Alternatively, it may provide even more
1096
compelling evidence that preventing early biologic insults is the best avenue for ensuring healthy
1097
development.
1098
1099
1100
SUMMARY AND CONCLUSIONS
Basic research on the development of the brain is a rapidly moving frontier. Abundant
1101
evidence indicates that brain development begins well before birth, extends far into the adult
1102
years, and is specifically designed to recruit and incorporate experience into its emerging
1103
architecture and functioning. For some systems, environmental inputs need to occur prenatally or
1104
relatively early in life after which time the brain becomes decreasingly capable of developing
1105
normally. But, available evidence indicates that such critical periods are more exceptional than
1106
normative in human development. For the vast majority of brain development, including areas of
1107
the brain involved in cognitive, emotional, and social development, we either have not explored
1108
questions regarding critical or sensitive periods or it appears that the brain remains open to
1109
experiences across broad swaths of development. This makes sense. Adaptation depends upon
1110
the rapid consolidation of capabilities essential to survival and the life-long flexibility to adjust to
1111
changing circumstances and learn new skills. As a result, assertions that the “die has been cast”
1112
by the time the child enters school are not supported by neuroscience evidence and can create
1113
unwarranted pessimism about the potential efficacy of interventions that are initiated after the
1114
preschool years. On the other hand, what happens early matters.
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1115
Concerns about protecting the developing brain need to begin well before birth. During
1116
the prenatal months, the developing brain is highly vulnerable to intrinsic hazards (such as neural
1117
migration{??????!!!!!*** how is migration a hazard?}) and external insults resulting from drug
1118
or alcohol exposure, viral infection, malnutrition (including deprivation of iron, folic acid, and
1119
other essential nutrients), and environmental and other teratogens. This directs attention to efforts
1120
to protect brain development during pregnancy and the earliest months of life, including the
1121
importance of prenatal and postnatal care, as well as expanded health and public health efforts to
1122
improve nutritional quality and reduce drug and viral exposure. It also argues for continued
1123
efforts to reduce the incidence of premature births and to ameliorate the adverse consequences of
1124
prematurity. Neuroscience evidence may, in fact, provide a stronger scientific basis for
1125
preventive efforts and interventions aimed at the prenatal and perinatal periods than for
1126
initiatives designed to enrich the environments of older children. In general, existing evidence
1127
about the developing brain has much more to tell us about the conditions that deprive the brain of
1128
what it needs than about those that enhance development beyond what might otherwise be
1129
expected.
1130
For some fundamental aspects of development, the contemporary concern with early
1131
environments may actually be misplaced insofar as the vast majority of children receive the
1132
kinds of experiences that they need. {This lack of appreciation of Parents Do Matter is, in my
1133
opinion, inappropriate and incorrect. Not that it does not apply to sensory systems, but where do
1134
you say that it might apply to cognitive, language and other complex facets of development?}*
1135
This appears to be the case, for example, for the development of sensory systems. For most
1136
children, the question regarding sensory development is less whether the environment is
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1137
providing the necessary experience and more whether the child can detect or register the
1138
experience and process it adequately. This shifts our focus to early detection, identification, and
1139
treatment of problems such as visual impairments, auditory processing deficits, and major
1140
perceptual-motor delays that have profound effects upon the child’s capacity to access and
1141
incorporate the stimulation needed to organize the developing nervous system. For these aspects
1142
of development, there is solid evidence that the timing of corrective efforts matters a great deal.
1143
A final implication of research on early brain development concerns the detrimental
1144
effects of early and sustained stressful experiences, particularly those that derive from aberrant or
1145
disrupted caregiving environments. Evidence from research on animals suggests that such
1146
experiences over-activate neural pathways that regulate fear-stress responses in the immature
1147
brain, perhaps placing them on a “high alert” setting that may alter, probabilistically, patterns of
1148
behavioral responding in adult animals with different rearing histories. Translations to human
1149
development are purely speculative, however, emerging evidence (reviewed in chapter 10)
1150
regarding the physiology of children subjected to serious deprivation and trauma early in life are
1151
consistent with the animal studies, as is the richer body of behavioral data on young children
1152
exposed to such early adverse experiences. This is an especially promising arena for research
1153
that integrates animal and human studies using both neuroscience and behavioral approaches,
1154
and explores not only the negative consequences of early stress and trauma but also the capacity
1155
of the brain to reorganize itself following highly depriving circumstances early in life.
1156
What, in sum, does neuroscientific research on early brain development tell us about
1157
caring for children? It reminds us that the young children warranting the greatest concern are
1158
those growing up in environments, starting prenatally, that fail to provide them with adequate
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1159
nutrition and other growth-fostering inputs, expose them to biologic insults, and subject them to
1160
abusive and highly neglectful care. Children with undetected sensorimotor difficulties (whose
1161
developing brains may not receive the stimulation they need) also warrant great concern. The
1162
brain research also, however, reassures us that brain development is probably on course for the
1163
vast majority of young children who are protected from these conditions, and, in many instances,
1164
can be affected positively by timely corrective interventions focused on early insults and deficits.
1165
{see comment above}*
1166
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