8

The Developing Brain

The brain is the ultimate organ of adaptation. It takes in information and orchestrates complex behavioral repertoires that allow human beings to act in sometimes marvelous, sometimes terrible ways. Most of what people think of as the “self”—what we think, what we remember, what we can do, how we feel—is acquired by the brain from the experiences that occur after birth. Some of this information is acquired during critical or sensitive periods of development, when the brain appears uniquely ready to take in certain kinds of information, while other information can be acquired across broad swaths of development that can extend into adulthood. This spectrum of possibilities is well captured by coinciding evidence of both the remarkably rapid brain development that characterizes the early childhood period and the brain's lifelong capacity for growth and change. The balance between the enduring significance of early brain development and its impressive continuing plasticity lies at the heart of the current controversy about the effects on the brain of early experience.

The past 20 years have seen unprecedented progress in understanding how the brain develops and, in particular, the phenomenal changes in both its circuitry and neurochemistry that occur during prenatal and early postnatal development. As discussed in Chapter 2, knowledge of the ways in which genes and the environment interact to affect the maturation of the brain has expanded by leaps and bounds. The years ahead will bring even more breathtaking progress as, for example, knowledge of the human genome is increasingly transformed into knowledge about how genes are



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From Neurons to Neighborhoods: The Science of Early Childhood Development 8 The Developing Brain The brain is the ultimate organ of adaptation. It takes in information and orchestrates complex behavioral repertoires that allow human beings to act in sometimes marvelous, sometimes terrible ways. Most of what people think of as the “self”—what we think, what we remember, what we can do, how we feel—is acquired by the brain from the experiences that occur after birth. Some of this information is acquired during critical or sensitive periods of development, when the brain appears uniquely ready to take in certain kinds of information, while other information can be acquired across broad swaths of development that can extend into adulthood. This spectrum of possibilities is well captured by coinciding evidence of both the remarkably rapid brain development that characterizes the early childhood period and the brain's lifelong capacity for growth and change. The balance between the enduring significance of early brain development and its impressive continuing plasticity lies at the heart of the current controversy about the effects on the brain of early experience. The past 20 years have seen unprecedented progress in understanding how the brain develops and, in particular, the phenomenal changes in both its circuitry and neurochemistry that occur during prenatal and early postnatal development. As discussed in Chapter 2, knowledge of the ways in which genes and the environment interact to affect the maturation of the brain has expanded by leaps and bounds. The years ahead will bring even more breathtaking progress as, for example, knowledge of the human genome is increasingly transformed into knowledge about how genes are

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From Neurons to Neighborhoods: The Science of Early Childhood Development expressed in the brain. This promises a dramatic expansion in the ability to understand the interweaving of genetic and environmental influences as they affect both brain and behavioral development (see Nelson and Bloom, 1997). Growth in brain knowledge naturally leads to questions about what it means for raising children and, specifically, for improving their development. Accordingly, efforts to translate this emerging knowledge for public consumption have proliferated in recent years. Some of this information has been portrayed well and accurately, but some has not. The challenge of deciphering what this information means for what parents, guardians, and teachers of young children should do is enormous. There are actually few neuroscience studies of very young children, and those that exist have not usually focused on the brain regions that affect cognition, emotions, and other complex developmental tasks. Much of the fundamental knowledge about brain development is based on experimental studies of animals. The translation of this information from basic neuroscience into rules for application to humans can be quite straightforward when the mechanisms involved are very similar in humans and animals, as is the case with the developing visual system. But the interpretation of other data from animals, or even some data from humans (such as estimates of the density of synapses in various brain regions at various ages), can be extraordinarily complex or inappropriate when the brain mechanisms of cognition, language, and social-emotional development are addressed. In this context, it is essential to balance excitement about all the new learning with caution about the limits of what is understood today. This chapter about the developing brain focuses on the role of experience in early brain development. Following a brief discussion of how to study the developing brain is an overview of early brain development from conception through the early childhood years. We then turn to a discussion of how early experiences contribute to brain development. Four themes run throughout this section: Developmental neuroscience research says a great deal about the conditions that pose dangers to the developing brain and from which young children need to be protected. It says virtually nothing about what to do to create enhanced or accelerated brain development. The developing brain is open to influential experiences across broad periods of development. This openness to experience is part of what accounts for the remarkable adaptability of the developing mind. Although there are a few aspects of brain growth that require particular kinds of experience at particular times, as far as we know at present, this is more the exception than the norm for human brain growth.

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From Neurons to Neighborhoods: The Science of Early Childhood Development The kinds of early experiences on which healthy brain development depends are ubiquitous in typical early human experience—just as nature intended. This means, however, that concern should be devoted to children who, for reasons of visual impairment, auditory processing problems, major perceptual-motor delays, and other basic deficits cannot obtain these experiences on which the developing nervous system depends. Abusive or neglectful care, growing up in a dangerous or toxic environment, and related conditions are manifest risks for healthy brain development. Beyond these extremes, the nature and boundaries of the environmental conditions necessary for healthy brain growth are less well known, partly owing to the complexity and the cumulative achievements of cognitive, language, and socioemotional growth. Exploration in this area is cutting-edge research. STUDYING THE DEVELOPING BRAIN Neuroscience techniques have advanced significantly, rendering studies of young children's brains more feasible and informative than in the recent past. These techniques have enabled scientists to learn more about how babies' brains change with development and how vulnerable or resilient they are to environmental harm. However, the repertoire of techniques that can be used with preschool-age and even younger children is still limited. Some of the more direct methods (i.e., looking into the brain) are either invasive (e.g., positron emission tomography requires the injection of a radioactive substance) or require long periods of remaining still (e.g., functional magnetic resonance imaging). Nevertheless, by tracking the brain's activity from the outside with the electroencephalogram, eventrelated potentials, and magnetic encephalography, researchers can learn about brain functioning in very young children. For instance, scientists can record the electrical or magnetic activity of the brain while the child is presented with different stimuli (e.g., speech sounds) and identify which parts of the brain are active and how active they are when children are doing different things. This approach has been used to reveal that the neural substrate for recognizing faces and facial expressions is remarkably similar in infants and adults (de Haan and Nelson, 1997, 1999), and that babies' brains change as they learn their native language (Neville et al., 1998). In addition, children with localized brain damage can be studied using neuropsychological tools. These entail giving young children behavioral tasks that have been shown to involve specific brain functions (e.g., working memory, spatial planning) and observing how performance varies with the particular part of the brain that is damaged (Luciana and Nelson, 1998). This approach, used in a longitudinal study of language develop-

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From Neurons to Neighborhoods: The Science of Early Childhood Development ment in children who suffered focal brain damage in the first months of life, revealed the extensive capacity for recovery of language functioning in these children (Bates and Roe, in press). Finally, among children whose medical conditions have required that their brains be studied, positron emission tomography has revealed metabolic patterns consonant with synaptic growth and pruning occurring in early development (Chugani and Phelps, 1986). (See Appendix B, as well as Nelson and Bloom, 1997, for a fuller discussion of technologies for studying the developing human brain.) WHAT DEVELOPS IN EARLY BRAIN DEVELOPMENT? The development of the brain has a long trajectory, beginning within a few days after conception and continuing through adolescence and beyond. The nervous system undergoes its most dramatic development during the first few years of life. Yet the processes that establish the structure and functioning of the brain, made possible by the developing networks of synapses that interconnect nerve cells and by the progressive fine-tuning of the neurons for the roles they will play within their synaptic networks, continue well into adolescence. The milestones of brain development from the prenatal period until school entry involve the development and migration of brain cells to where they belong in the brain, embellishments of nerve cells through the sprouting of new axons or by expanding the dendritic surface; the formation of connections, or synapses, between nerve cells; and the postnatal addition of other types of cells, notably glia. Fascination with the earliest stages of brain development is understandable. During this period, the spinal cord is formed, nearly all of the billions of neurons of the mature brain are produced, the dual processes of neural differentiation and cell migration establish the neuron's functional roles, and synaptogenesis proceeds apace. These processes represent an elaborate interplay between gene activity and the surrounding environments both inside and outside the child. There have been significant changes over time in the aspects of brain development that have captured public attention. Twenty years ago, people were fascinated by the ability to measure developmental changes in the degree to which neurons in different areas of the brain become wrapped in the white, fatty matter—myelin—that insulates nerve cells and affects the speed with which nerve impulses are transmitted from one cell to another. Myelination is, in fact, affected by the young child's behavioral experiences and nutrition, as discussed below. Today, the public is more focused on information, not all of it new, about the rate of synapse development, particularly on studies showing that there is a tremendous burst of synapse formation early in life, followed by a decline in synapse number, apparently extending into adolescence in some areas of the brain. Combined with

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From Neurons to Neighborhoods: The Science of Early Childhood Development evidence that synapses that are used are retained and those not used are eliminated, there has been a frenzy of concern expressed as “use it or lose it” in the first years of life. It turns out, however, that synapse elimination is a normal part of development. In comparison to the brain's wiring, far less attention has been paid to the neurochemistry of early brain development, which is essential to the brain's capacity to learn from experience and is likely to play an important role in the regulation of behavior. Development of the Brain's Wiring Diagram Brain development proceeds in overlapping phases: making the brain cells (neurulation and neurogenesis), getting the cells to where they need to be (migration), growing axons and dendrites, which are structures needed to link with other nerve cells (neuronal differentiation and pathfinding), developing synapses or points of communication with other cells (synaptogenesis), refining those synapses (maturation and pruning), and, finally, forming the supportive tissue that surrounds the nerve cells and makes for efficient communication among them (gliagenesis or myelination). The brain and spinal cord arise from a set of cells on the back (dorsal part) of the developing embryo called the neural plate. Two rows of rapidly dividing cells arise from the plate on each side along its length and fold over centrally into the neural tube. The anterior or head end of the neural tube forms a set of swollen enlargements that give rise to the various parts of the brain—the forebrain containing the cerebral hemispheres, the midbrain containing important pathways to and from the forebrain, and the hindbrain containing the brainstem and cerebellum. The remainder of the neural tube becomes the spinal cord, peripheral nerves, and certain endocrine, or hormone, glands in the body. Under the control of regulatory genes, the brain cells migrate to where they belong in accord with the functions they will ultimately serve. These genes provide developmental directions to particular groups of cells, which tell them what to do and where to go in the embryonic brain. Within the neural tube, the innermost cells divide repeatedly, giving rise first to the cells that primarily become nerve cells, or neurons, and later giving rise to both neurons and the supportive tissue components called glia. Once the nerve cells are formed and finish migrating, they rapidly extend axons and dendrites and begin to form connections with each other, called synapses, often over relatively long distances. These connections allow nerve cells to communicate with each other. This process starts prenatally and continues well into the childhood years. There is evidence in many parts of the nervous system that the stability and strength of these synapses are largely determined by the activity, that is, the firing, of these connections. The speed with which neurons conduct nerve impulses is

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From Neurons to Neighborhoods: The Science of Early Childhood Development determined by the development of myelin, a substance that wraps itself around nerve axons. By insulating the nerve cell axon, myelin increases conduction velocity. The development of myelin is a protracted process extending well into the postnatal period. The rate and extent of myelination is also affected by experience. Most myelinated pathways are laid down in the early years, but for some, as in the frontal cortex, myelination continues into the third decade of life. The unique wiring diagram that brain development produces in each individual brain guides thoughts, memories, feelings, and behaviors. Synaptic Overproduction and Loss Beginning 20 years ago, Huttenlocher (e.g., Huttenlocher, 1979; Huttenlocher and Dabholkar, 1997) first showed that there is a pattern to synaptogenesis in the human cerebral cortex characterized by the rapid proliferation and overproduction of synapses, followed by a phase of synapse elimination or pruning that eventually brings the overall number of synapses down to their adult levels. This process is most exuberant during the first few years of life, although it can extend well into adolescence. Within this developmental span, however, different brain regions with different functions appear to develop on different time courses (see Figure 8-1). Huttenlocher estimated that the peak of synaptic overproduction in the visual cortex occurs about midway through the first year of life, followed by a gradual retraction until the middle to the end of the preschool period, by which time the number of synapses has reached adult levels. In areas of the brain that subserve audition and language, a similar although somewhat later time course was observed. However, in the prefrontal cortex (the area of the brain where higher-level cognition takes place), a very different picture emerges. Here the peak of overproduction occurs at around one year of age, and it is not until middle to late adolescence that adult numbers of synapses are obtained.1 Scientists have pondered the purpose of synaptic overproduction and loss for a very long time. One of the earliest observations was made by 1   Many of the human findings regarding synaptic overproduction and loss were based on measurements of the density of synapses, rather than on 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 two-thirds 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 enable determination of how ubiquitous synapse overproduction and loss are in brain development generally or in humans specifically.

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From Neurons to Neighborhoods: The Science of Early Childhood Development FIGURE 8-1 Human brain development. SOURCE: Charles A. Nelson, University of Minnesota. Reprinted with permission.

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From Neurons to Neighborhoods: The Science of Early Childhood Development Spanish neuroanatomist and Nobel laureate Santiago Ramon y Cajal (Ramon y Cajal, 1989[1917]): 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? A more modern formulation of the love story began with the Cragg (1975) report that the cat visual cortex produced a greater number of synapses during development than it actually retained into adulthood. Subsequent work in monkeys and cats by Hubel and Wiesel and their collaborators (e.g., LeVay et al., 1980) demonstrated that as the physiological functioning of the visual cortex became more refined and precise, the anatomical synaptic connections were also refined. Those that fit the intended pattern were retained, and those that did not were eliminated. Scientists also showed that visual experience played a necessary role in this process. If experience was distorted, so that one eye got much more stimulation than the other, for example, its connections were pared back less drastically than usual, and the connections with the inexperienced eye were pruned more than usual. In short, the development of patterned organization in the visual cortex was dependent on visual experience and involved the selective loss of connections that were not appropriate to the pattern. Synapses appear to be programmed to be eliminated if they are not functionally confirmed, based on some not fully known aspects of their activity history. In general, frequently active connections, like those of the more experienced eye, are more likely to survive. While the data are not as complete for other senses, it is reasonably clear that building the organized neural systems that guide sensory and motor development involves the production of excess connections followed by some sort of pruning that leaves the system in a more precisely organized pattern. Moreover, in both humans and animals, the effects of experience on these systems—normal or abnormal—become increasingly irreversible over time. In kittens, irreversible deficits in vision will result with deprivation lasting for only 2-3 months after birth. In humans, irreversible deficits in vision are present when corrections for such optical conditions as strabismus (in which, due to muscular weakness, one eye deviates from and cannot be brought into alignment with the other normally functioning eye) are not made by the time the child reaches elementary school. Deficits become more pronounced with more prolonged visual deprivation. Thus, a sensi-

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From Neurons to Neighborhoods: The Science of Early Childhood Development tive period exists for vision, but rather than being sharply demarcated, it gradually tapers off. A useful way to consider how experience becomes incorporated into the developing synaptic connections of the human brain, discussed briefly in Chapter 2, has been offered by Greenough and Black (Black and Greenough, 1986; Greenough and Black, 1992). They distinguish between experience-expectant and experience-dependent mechanisms guiding brain development. Experience-expectant synaptogenesis refers to situations in which a species-typical experience (that is, something that all members of a species experience, barring highly aberrant conditions) plays a necessary role in the developmental organization of the nervous system. Normal brain growth relies on these forms of environmental exposure. For example, the visual cortex “expects” exposure to light and patterned visual information and is genetically programmed to utilize these inputs for normal development. Deprivation of these ubiquitous and essential forms of environmental input can permanently compromise behavioral functioning, which is why it is essential to detect and treat early sensory deficits (e.g., cataracts, strabismus, auditory deficits) that interfere with the detection and registering of expected experiences. Experience-dependent synaptogenesis, in contrast, refers to encoding new experiences that occur throughout life, foster new brain growth and the refinement of existing brain structures, and vary for every individual. This process optimizes the individual's adaptation to specific and possibly unique features of the environment. Whereas in experience-expectant development, all brains depend on the same basic experiences to develop normally, in experience-dependent development, individual differences in brain development depend on the idiosyncratic experiences that are encountered across the life span. Experience-dependent development is also linked to synaptogenesis, but in this case all we know is that experience triggers more plentiful connections among neurons. We do not know if this occurs through a process of overproduction and pruning, or if a more continuous pattern of growth is involved. Whatever the specific mechanism, experience-dependent brain development is a source of enduring plasticity and of adaptability to the demands of everyday life. And it is important to note that there appears to be no abrupt transition from utilization of experience-expectant processes to utilization of experience-dependent processes of brain development. In fact, it seems likely that the greater potential for recovery from deprivation or damage that characterizes young animals probably reflects the availability of both mechanisms. Postnatal Neurogenesis We now need to add the possibility of postnatal neurogenesis—the postnatal production of new nerve cells—to the repertoire of mechanisms

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From Neurons to Neighborhoods: The Science of Early Childhood Development by which the human brain continues to develop after the early childhood years. Prevailing knowledge about brain development, notably that the adult human brain does not produce new neurons, has recently been challenged by new insights into adult brain development. Specifically, important forebrain regions, such as the hippocampal dentate gyrus (which is involved in establishing memory for facts and relationships among events and places in one's experience), continue to receive new nerve cells into adulthood in humans (e.g., Eriksson et al., 1998). Recent findings in monkeys indicate that new neurons are also being formed each day and migrating to areas that include the prefrontal cortex, the seat of planning and decision making (Gould et al., 1999). Although it remains to be determined how significant neuronal additions in adulthood are to the functioning of the brain, it certainly lends further support to the argument that the brain continuously remodels itself. Neurochemistry of Early Brain Development The sending and receiving of messages in the nervous system depends on chemical messengers. A number of these chemical messengers affect gene expression in nerve cells in ways that have long-lasting effects on how nerves grow, respond to stimulation, and function. They are thus intimately involved in the growth and development of the nervous system and in neural plasticity. The past two decades have seen an explosion of information about these chemical messengers. In addition to the classic neurotransmitters, over 60 other peptide and steroid molecules have been identified that have direct effects on the brain. Currently, what can be confidently applied from this field directly to human development is limited. However, the study of neurochemistry is already revolutionizing the way people think about the nervous system, and a brief overview of some basic ideas from this work is warranted. Chemical messengers that affect the brain operate through receptors, most of which are located in the dendrites and synapses of nerve cells. Like locks and keys, the physical structure of the messenger (the key) has to fit the physical structure of the receptor (the lock) for the chemical messenger to have any effect on the nerve cell. Receptors are specific. They typically recognize or bind with only one natural molecule. For many years, this type of specificity gave rise to the hope that science would be able to link specific neurochemicals to specific behaviors, allowing highly focused manipulations of behavior through drug therapy. However, despite what filters its way into the popular press (e.g., low serotonin levels cause aggression), the way the biochemistry of the brain operates is vastly more complex than a match of one chemical with one behavior. For example, it now appears that many of the chemicals that affect brain function are able to unlock several different receptors. This allows the same (or quite similar)

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From Neurons to Neighborhoods: The Science of Early Childhood Development chemical to have different functions and to play a role in multiple (often related) behavioral systems. The brain is also able to alter its sensitivity to a chemical messenger by changing the presence, conformation (structure), and availability of the chemical's receptors. Receptor changes often reflect the history of the nerve cell's experience with its neurochemical. High levels of the chemical operating on the receptor frequently result in a decrease in the nerve's receptors for that chemical (a process called down-regulation); sometimes a dearth of a chemical important in a nerve's functioning results in an increase in receptor number (i.e., up-regulation). Up- and down-regulation takes place over hours and days, partially explaining why some psychoactive drugs take time before they begin to influence behavior and why some drugs, with time, need to be taken in higher and higher dosages to have the same effects. Some of these shifts in chemical messenger-receptor systems appear to be relatively permanent, perhaps especially those that occur during periods of rapid development; others are more transient, reflecting the normal turnover (production, decline, replacement) of receptors. This complexity may complicate things for those who are trying to decipher the mysteries of the brain, but it does allow the brain to be highly plastic, toning its functioning in highly nuanced ways, often quite rapidly. Neurochemical-receptor systems also lie at the heart of how the brain alters its physical structure. A variety of different nerve growth factors (i.e., chemicals that play a role in the growth of dendrites and synapses) have been identified. These growth factors are present in different quantities and locations at different points in development of the brain, regulated by genes involved in normal brain development. They also change in their concentration in response to nerve damage, playing a role in the brain's attempts to adapt to and restore functioning following trauma. Receptor systems play critical roles in both experience-dependent and experience-expectant neural plasticity. The NMDA (N-methyl-D-aspartate) receptor is one receptor, but not the only one, that plays a role in neural plasticity. It appears to support learning by helping to foster what is termed “long-term potentiation.” Long-term potentiation, a memory “model” involving increased synaptic strength, is brought about by sustained, rapid activity in the neural circuits involved in newly acquired information, analogous to repeating a new phone number in order to memorize it. It also appears that at critical points in the development of neural systems, there is sometimes an increase in NMDA receptors. This increase seems to open the window for the development of that neural system, allowing stimulation to have large effects, with the window closing when the number of NMDA receptors decreases. Changes in chemical messenger systems and their receptors tend to tone

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From Neurons to Neighborhoods: The Science of Early Childhood Development has two main negative effects on brain development. First, premature birth predisposes the infant to pathological events that directly injure the brain. These events can be thought of as damage committed by factors that the human at this gestational age would not normally encounter. These can be as seemingly benign as the wrong mixture of nutrients to more obvious neuropathologies such as intracranial hemorrhage. Second, premature birth interrupts the normal process of intrauterine brain development by denying it expected intrauterine stimuli and factors important for growth (e.g., nutrients such as docosohexaenoic acid). One can consider this to be disruption due to omission of factors that are critical for normal development. Ultimately, the morbidity seen at any gestational age is the result of the combination of the number and severity of exposure to both types of influence. The first principle of assessing the effect of prematurity on neurological outcome is to note that the child's general developmental status and intelligence scores decrease with reductions in gestational age (Saigal et al., 1991). Thus, an infant born at 24 weeks is at greater risk than an infant born at 26 weeks, who in turn is at higher risk than an infant born at 28 weeks. Infants born at 24 weeks not only have a less complete brain than those born at 26 weeks, but they also are far more prone to intracranial hemorrhage, hypoglycemia, and postnatal malnutrition, all of which adversely affect the more primitive parts of the brain. Once one moves out of the high-risk groups, however, outcomes become highly variable. Insults Due to Prematurity The literature on neonatal outcomes is replete with studies assessing the effects of intracranial hemorrhage (Papile et al., 1983), periventricular leucomalacia (Feldman et al., 1990; Lowe and Papile, 1990), hypoglyecmia (Duvanel et al., 1999), and malnutrition (Georgieff et al., 1985, 1989; Hack and Breslau, 1986) on head growth and developmental outcome. Besides gestational age and socioeconomic status, the next most important factor in assessing risk of adverse neurological outcomes is the degree of illness of the infant during the newborn period. Infants whose overall physiology is more compromised are more developmentally delayed at 2 years and appear to be at greater risk of prefrontal deficits at age 8 (Brazy et al., 1991; Luciana et al., 1999). Intracranial hemorrhage (also known as intraventricular hemorrhage) is the most extensively studied noxious event that affects the premature infant's brain. This is probably due to the fact that it is easily visualized by cranial ultrasonography and quantifiable into Grades I (least severe) to IV (most severe). Approximately 20 percent of infants between 28 and 34 weeks gestation have intraventricular hemorrhage, with the vast majority

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From Neurons to Neighborhoods: The Science of Early Childhood Development (> 60 percent) rated as Grade I or II. In contrast, 60 percent of infants born between 24 to 28 weeks have intraventricular hemorrhage, and their hemorrhages tend to be the more severe Grade III and IV varieties. Accordingly, the risk of major handicaps, both motor and cognitive, is increased. Infants with lower-grade hemorrhages do not appear to be at any greater risk of major handicap (cerebral palsy, mental retardation) than infants who did not bleed (Papile et al., 1983), although they are at higher risk of minor handicaps (e.g., behavior problems, attention problems, memory deficits) (Lowe and Papile, 1990; Ross et al., 1996). Omission of Factors Important for Normal Brain Development A premature infant with a benign neonatal course nevertheless remains at increased risk of neurological morbidity. Although one can never be assured that all noxious events (both prenatal and postnatal) have been accounted for in any given study, there is mounting evidence that transferring brain growth and development from an intrauterine to an extrauterine environment prematurely is less than optimal even in the absence of other definable neurological risk factors (Chapieski and Evankovich, 1997; Cherkes-Julkowski, 1998; Huppi et al., 1996). Recent research, for example, has demonstrated poorer performance on elicited imitation tasks (a medial temporal lobe function) at age 18 months in 27- to 34-week gestational age preterm infants with completely benign neonatal courses compared with term infants tested at the same post-conceptional age (de Haan et al., 2000). These emerging data strongly suggest that the human brain continues to develop in a unique way in utero until the end of gestation and that early termination of pregnancy disrupts that development with subsequent behavioral consequences. A more pernicious effect of extrauterine life on brain development in small preterm infants is the general problem of malnutrition. Neonatal illness not only predisposes preterm infants to definable adverse events (e.g., intraventricular hemorrhage, hypoxia) but also blocks provision of adequate nutritional substrates to promote normal brain growth and development. Studies have estimated that greater than 50 percent of very low-birthweight infants fall below the 5th percentile for head growth sometime during their hospitalization (rendering them, by definition, microcephalic) (Georgieff et al., 1985). Fortunately, one of the most amazing aspects of early human life is the ability of the head (and brain) to demonstrate catch-up growth. After a period of no growth, the head exhibits a remarkable increase in growth velocity to double or triple normal rates, given adequate protein-energy intakes (Georgieff et al., 1985; Sher and Brown, 1975). There is, however, a point of diminishing return. If the infant has had no growth for more than a month, the subsequent catch-up rate is markedly

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From Neurons to Neighborhoods: The Science of Early Childhood Development reduced, almost as if the potential for catch-up has been lost (Georgieff et al., 1985; Hack and Breslau, 1986; Sher and Brown, 1975). Premature infants with more striking postnatally acquired microcephaly due to malnutrition indeed have smaller head circumferences and poorer scores on the Bayley Scales of Infant Development at age 12 months (Georgieff et al., 1985). Reduced head circumference at 8 months postnatally bodes poorly for developmental outcomes measured at age 3 and 8 years (Hack and Breslau, 1986). These studies suggest that although catch-up head growth is a marvelous compensatory response, it is better to have never experienced the growth deficit in the first place. Extrapolating further, it argues for important windows of opportunity for brain growth late in the third trimester that, if interrupted by premature birth and lack of head growth, may result in the brain being “constructed” in an alternative manner (de Haan et al., 2000). In sum, prematurity confers a significant risk to the developing brain. The risk emanates from both insults that arise during the course of illness in the premature infant and from interruptions of the provision of the expected substrates and environment apparently necessary for normal brain development. We have used examples for which there is a substantial literature (e.g., intraventricular hemorrhage), but hasten to add that other potentially neuropathological factors that are more difficult to isolate and quantify (e.g., hypoxia-ischemia, hypoglycemia, neurotoxic medications such as steroids) are likely to play important roles as well. The ultimate risk to any single premature infant is likely to be a composite of all the known and unknown risk and protective factors that characterize that infant, and on the infant's general extent of biological and environmental vulnerability. Thus the premature infant born to a lower-income mother with few resources who received poor prenatal care is likely to have a much more difficult neonatal course, and therefore be at higher neurodevelop-mental risk, than an infant of the same gestational age born to a mother who received better prenatal care and has more resources. Perhaps this helps explain the overall down-shifting of developmental scores in premature infants from families of lower socioeconomic status (Saigal et al., 1991). Growing awareness of environmentally based differences in the outcomes of premature infants has fueled multiple intervention efforts ranging from dramatic changes in the care these infants receive in neonatal intensive care units (see reviews by Als, 1997; Hernandez-Reif and Field, 2000) to comprehensive initiatives that provide a range of services to the infants and their families from the time they leave the hospital to several months or years after discharge. The best known of the comprehensive approaches is the Infant Health and Development Program (see Box 8-2) (Gross et al., 1997), which included a randomized trial and extensive follow-ups of the participating families.

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From Neurons to Neighborhoods: The Science of Early Childhood Development BOX 8-2 Infant Health and Development Program Premature babies with low birthweight are more likely than babies with normal birthweight to have a range of health and developmental problems, including lower IQ, cerebral palsy, less emotional maturity, less social competence, and attentional difficulties. Many low-birthweight, premature infants are also considered doubly vulnerable because they are also more likely to experience environmental risks such as living in poverty, having a single parent, or being the child of a teenage mother. The Infant Health and Development Program was a large, randomized clinical trial to determine the efficacy of an intervention designed to promote the physical health, and cognitive and socioemotional development of low-birthweight, premature children. The program provided services for 985 children from birth through age 3 at 8 different sites throughout the United States. All of the children received pediatric surveillance and community referral services. The families of one-third of the children also received family support through home visits throughout the program. Beginning at age 1, the children from these families participated in full-day educational child care in eight child development centers, and their parents participated in regular group meetings. Data on the health, behavior, and cognitive development of all of the children were collected during the 3 years of the program, as well as at ages 5 and 8. Infants participating in the intervention demonstrated improved behavioral functioning (e.g., higher IQ scores, vocabulary gains, and fewer behavioral problems) at the conclusion of the intervention, when they were 3 years old (Infant Health and Development Program, 1990). At age 5, only the heavier low-birthweight infants (i.e., 2,000-2,500 grams) continued to show gains that distinguished them from the children that did not receive the intervention (Brooks-Gunn et al., 1994). By age 8, even the gains of the heavier infants had been substantially diminished (McCarton et al., 1997). The authors have speculated about the outcomes that might have emerged if they had continued the program up to school entry. SOURCES: Brooks-Gunn et al. (1994); Gross et al.(1997); McCartonet al. (1997). The evaluation literature on these interventions offers good news about the capacity of early childhood programs, which emphasize individualized developmental care, as well as initiatives focused on parental coping and training in optimal parenting skills, to improve health outcomes and decrease developmental delays in premature infants. It thus appears that the developmental problems associated with prematurity and low birthweight can be mitigated by intervention. However, this is such a complex biological phenomenon that relatively nonspecific interventions may not be the

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From Neurons to Neighborhoods: The Science of Early Childhood Development most productive approach. Moreover, virtually all experts in this area agree that efforts focused on preventing low birthweight need to be the top priority. Stress and the Developing Brain Research on premature infants has provided substantial evidence of the importance of the caregiving environment for the baby's later progress. This theme emerges, as well, from research on animals regarding how stress affects the developing brain. This research provides preliminary insights into how alterations of the early caregiving environment affect neurochemical aspects of early brain development. Extending this evidence to the human species is not yet warranted, however. There is, for example, only one scientifically reviewed study that has imaged the brains of maltreated children (De Bellis et al., 1999a) (discussed in Chapter 9). The animal evidence, however, is suggestive of the physiological processes that may underlie associations found between highly dysfunctional caregiving and problematic child outcomes, particularly those that lie in the realm of self-regulatory behaviors. This, in turn, points to promising directions for future collaborative research among behavioral and brain scientists. The term “stress” is used by psychologists, physiologists, and the lay public and means different things to each (Engle, 1985). In this report, stress refers to the set of changes in the body and the brain that are set into motion when there are overwhelming threats to physical or psychological well-being (Selye, 1973, 1975). Stress can have dramatic effects on health and development (Johnson et al., 1992). This happens because the physiology of stress produces a shift in the body's priorities. When threats begin to overwhelm one's immediate resources to manage them, a cascade of neurochemical changes that begin in the brain temporarily puts on hold the processes in the body that can be thought of as future-oriented: finding, digesting, and storing food; fighting off colds and viruses; learning things that don't matter right now but may be important sometime in the future; reproducing and rearing offspring. Many of these neurochemical changes take place in the very same brain structures (e.g., hypothalamus and brainstem) that function to regulate heart rate, respiration, food intake and digestion, reproduction, growth, and the building up versus breaking down of energy stores (Stratakis and Chrousos, 1995). These brain regions also play a role in regulating the production of stress responses in the rest of the body. Specifically, the adrenal glands, located on the top of the kidneys, produce adrenaline and cortisol (Axelrod and Reisine, 1984). Adrenaline is part of the sympathetic nervous system. Increases in sympathetic nervous system activity support vigilance, focus attention, increase heart rate, shunt blood to muscles and away from the

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From Neurons to Neighborhoods: The Science of Early Childhood Development digestive system, break down fat stores making energy available to cells, and dampen activity of the immune system. Cortisol is a steroid hormone that plays a myriad of roles in stress physiology. It helps to break down protein stores, liberating energy for use by the body. It suppresses the immune system, suppresses physical growth, inhibits reproductive hormones, and affects many aspects of brain functioning, including emotions and memory. Current understanding of how psychological stimuli, such as experiences of fear and anxiety, set in motion stress physiology is centered on an area of the brain called the amygdala (Miller and Davis, 1997; Rolls, 1992; Schulkin et al., 1994), which has close back-and-forth communication with areas of the brain involved in attention, memory, planning, and behavior control. In animals, experimentally causing a hyperstimulation of the amygdala (a process termed “kindling”) seems to create a hypersensitization of the fear-stress circuits of the brain and changes in behavior that look like an animal version of posttraumatic stress disorder (Rosen et al., 1996). It is as if the fear circuits get locked in the “on” mode and have trouble shutting off. These circuits course through the amygdala and an area called the bed nucleus of the stria terminalis. They appear to be pathways through which circumstances outside the body set in motion the cascade of events inside the body and the brain that undergird fear-stress responses. These events involve the elevation of cortisol and stimulation of the sympathetic arm of the stress response. In animals, flooding the brain with cortisol for prolonged periods of time produces changes in this process that may lower the threshold for activating the fear-stress system (Makino et al., 1994). The result is an animal that more readily experiences fear, anxiety, and stress and may have a harder time dampening or regulating these responses. The amygdala is a fairly mature brain area at birth in humans and seems to be fully mature at least as early as a child's first birthday. All anatomical evidence suggests that by the end of the first year, young children should be capable of experiencing psychologically driven fear, anxiety, and stress. Indeed, fear reactions to strangers (Bronson, 1971; Schaffer, 1966; Waters et al., 1975) and anxiety reactions to separation from familiar caregivers (Ainsworth and Bell, 1970; Bowlby, 1973; Sroufe, 1979) are hallmarks of emotional development in late infancy. Brief periods of stress are not expected to be problematic. Indeed, survival requires the capacity to mount a stress response. However, because the stress system functions to put growth-oriented processes on hold, frequent or prolonged periods of stress may negatively affect development. Evidence from research on rodents and primates suggests that experiences of neglect early in life constitute the kinds of stressful experiences to which young offspring are especially sensitive and may result in a more reactive stress system. In studies of rats, for example, when experimenters

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From Neurons to Neighborhoods: The Science of Early Childhood Development do things to the nest that affect maternal behavior (such as handle the pups), they can affect the development of the rat's stress system (Denenberg, 1999; Levine and Thoman, 1970). Doing things to the nest that result in better organized maternal behavior results in infant rats that develop into less fearful, less stress-reactive adults, whereas doing things that disrupt maternal behavior results in more fearful and stress-reactive adult rats. Researchers have also shown that strains of rodents that are known to be more stress-reactive are characterized by maternal care that involves less licking and grooming (Liu et al., 1997; Meaney et al., 1996; Plotsky and Meaney, 1993). Cross-fostering genetically high stress-reactive infants to mothers from low stress-reactive strains results in the development of a more stress-resilient animal. These effects of early experience in the rat appear to operate through the development of the receptor system in the brain that influences the reactivity of the fear-anxiety circuits. Plenty of input early in life that keeps the stress system dampened down results in the development of a stress-modulating receptor system that can quickly turn off stress reactions. Without this input, the fear-stress system appears to get “shaped” so that the rat pup becomes a more highly reactive adult who has difficulty modulating these responses. In short, the development of a less stress-reactive rat seems to revolve around enhancing and supporting qualities of the caregiving environment. There are monkey analogues of these rat studies, although details of the biobehavioral mechanisms have not been worked out as thoroughly. Infant monkeys deprived of normal social stimulation grow into socially incompetent, fearful adults (Harlow et al., 1971; Young et al., 1973). More recent studies have documented that monkeys reared on cloth surrogates, but exposed every day to several hours of play with other infant monkeys, are not as socially incompetent as monkeys raised in isolation, but they show numerous physiological signs of being very anxious and fearful (Suomi, 1991). They produce higher levels of stress hormones when threatened and they have high levels of anxiety-related brain neurochemicals in the cerebrospinal fluid, which bathes and nourishes the brain and spinal cord. Monkeys reared only with other infant monkeys (i.e., no cloth surrogates to call their own), show similar patterns of high reactivity to stress (Champoux et al., 1989, 1992). A high stress-reactive adult monkey can also be produced by procedures that cause stress to its mother (Coplan et al., 1995, 1996; Rosenblum and Andrews, 1994; Rosenblum et al., 1994; Schneider, 1992a, 1992b; Schneider et al., 1992, 1998). One technique for stressing the mother is to make her food resources unpredictable. This has the effect of deeply disturbing the mother's social relationships with other adult monkeys in her group. The infant monkeys in these unpredictable food studies (who are

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From Neurons to Neighborhoods: The Science of Early Childhood Development roughly equivalent in developmental age to 1- to 2-year-old human children) experience high levels of stress hormones (like their mothers) and grow up into highly fearful, socially less competent adult animals (Rosenblum and Andrews, 1994; Rosenblum et al., 1994). These effects were obtained even though food was never uncertain for the young monkeys themselves, and thus seem to be influenced by what this uncertainty and disturbance in the social environment does to their mothers. There is a great deal to learn about how the social environment connects with the biology of growth and the regulation of stress physiology in human infants and children. Intriguing research is emerging, however, to suggest that the development of stress regulation in young children may be a very promising place to look for brain-experience dynamics. For example, both failure to thrive and psychosocial dwarfism (Gohlke et al., 1998; Skuse, 1985), in which children's pituitary glands fail to secrete sufficient growth hormone (Skuse et al., 1996), are associated with failures in the social environment (Alanese et al., 1994). Removing the child from the problematic social system reverses the disorder and growth increases rapidly. This research, as well as that on orphanage-reared infants discussed in Chapter 9, raises extremely important questions about the plasticity and self-righting tendencies inherent in the human (as well as the animal) brain. In general, there is much to learn about the extent to which the neurological pathways between caregiving environments and dysfunctional behavior that are emerging in the animal literature apply to human offspring and about the effects of remedial experiences that attempt to enhance the development of children from early abusive and neglectful environments. In sum, neuroscience evidence from animal research is increasingly pointing to experiences of neglect, stress, and trauma within the caregiving environment as a source of compromised brain development. Research on rodents and primates indicates that the ways in which the brain learns to respond to stressful and fear-inducing circumstances are profoundly affected by the capacity of the infant's caregivers to regulate the developing stress system. Disruptions to the caregiving environment that produce stress in the mother appear to alter the offspring's developing reactivity to stress, as seen behaviorally in high levels of fearfulness and neurologically in how the brain releases and modulates stress hormones. Alternatively, supportive and nurturant caregiving can protect offspring from these consequences. Although this evidence is compelling with regard to the significance of early rearing environments as they affect the developing brain, we are barely at the beginning of exploring these issues in human babies (Kimmel et al., 1990; McLoyd and Lozoff, 2000; Morgane et al., 1993).

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From Neurons to Neighborhoods: The Science of Early Childhood Development SUMMARY AND CONCLUSIONS Basic research on the development of the brain is a rapidly moving frontier. Abundant evidence indicates that brain development begins well before birth, extends into the adult years, and is specifically designed to recruit and incorporate experience into its emerging architecture and functioning. For some systems, environmental inputs need to occur prenatally or relatively early in life, after which time the brain becomes decreasingly capable of developing normally. But available evidence indicates that such critical periods are more exceptional than typical in human development. For the vast majority of brain development, including areas of the brain involved in cognitive, emotional, and social development, either questions regarding critical or sensitive periods have not been explored or it appears that the brain remains open to experiences across broad swaths of development. This makes sense. Adaptation depends on the rapid consolidation of capabilities essential to survival and the life-long flexibility to adjust to changing circumstances and learn new skills. As a result, assertions that the die has been cast by the time the child enters school are not supported by neuroscience evidence and can create unwarranted pessimism about the potential efficacy of interventions that are initiated after the preschool years. Nevertheless, what happens early matters. Concerns about protecting the developing brain need to begin well before birth. During the prenatal months, the developing brain is highly vulnerable to intrinsic hazards (such as errors of neural migration) and external insults resulting from drug or alcohol exposure, viral infection, malnutrition, and other environmental harms. This directs attention to efforts to protect brain development during pregnancy and the earliest months of life, including the importance of prenatal and postnatal medical care, as well as expanded public health efforts to improve nutritional quality and reduce drug and viral exposure. It also argues for continued efforts to reduce the incidence of premature births and to ameliorate the adverse consequences of prematurity. Neuroscience evidence also directs attention to the early detection, identification, and treatment of problems such as visual impairments, auditory deficits, and major perceptual-motor delays that have profound effects on children's capacity to access and incorporate the stimulation needed to organize the developing nervous system. For these aspects of development, there is solid evidence that the timing of corrective efforts matters a great deal. Beyond this evidence regarding detrimental influences on brain development, neuroscience offers few insights into how early environments can function to enhance development beyond what might otherwise be expected. The experiments with complex environments conducted on rats reveal the benefits of more enriched environments, indicate that younger

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From Neurons to Neighborhoods: The Science of Early Childhood Development brains react more rapidly and to a greater degree to environmental variation, and suggest that removal from complex environments results in decreasing benefits over time. Nevertheless, we do not yet have the evidence on infant brains to translate these findings from animal research into tangible recommendations for early interventions aimed at children's cognitive or social-emotional development. For these insights, additional behavioral evidence from human development is needed. A final implication of research on early brain development concerns the detrimental effects of early and sustained stressful experiences, particularly those that derive from aberrant or disrupted caregiving environments. Evidence from research on animals suggests that such experiences overactivate neural pathways that regulate fear-stress responses in the immature brain, perhaps placing them on a “high alert” setting that may alter patterns of behavioral responding in adult animals with different rearing histories. Translations of these findings to human development are largely speculative. However, emerging evidence regarding the physiology of children subjected to serious deprivation and trauma early in life are consistent with the animal studies, as is the richer body of behavioral data on young children exposed to such early adverse experiences. This is an especially promising area for research that integrates animal and human studies, using both neuroscience and behavioral approaches, and explores not only the negative consequences of early stress and trauma but also the capacity of the brain to reorganize itself following highly depriving circumstances early in life. In sum, the neuroscientific research on early brain development says that the young children warranting the greatest concern are those growing up in environments, starting before birth, that fail to provide them with adequate nutrition and other growth-fostering inputs, expose them to biological insults, and subject them to abusive and neglectful care. Children with undetected sensorimotor difficulties (whose developing brains may not receive the stimulation they need) also warrant concern. The brain research also reassures that brain development is probably on course for the vast majority of young children who are protected from these conditions and, in many instances, can be affected positively by timely corrective interventions focused on early insults and deficits.

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