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Implications of Brain Development Research

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Resolution 517, introduced by the Mississippi Delegation, and Resolution 520, introduced by the American Association of Public Health Physicians, were referred to the Board of Trustees at the 1998 Annual Meeting. Resolution 517 asked that our American Medical Association (AMA) "undertake a comprehensive review of recent research on brain development and learning in order to provide a uniform body of knowledge summarizing the implications [of] this research on the practice of medicine, the development of public health policy, and the development of comprehensive school health education." Resolution 520 asked our AMA "to undertake a comprehensive review of the recent research on the development of the brain in order to (1) provide a uniform body of knowledge; and (2) consider the implications of the application of the results of this research on (a) the practice of medicine and public health; and (b) the development of public health and social policy on a national level." 

These resolutions asked for a summary of the recent findings in central nervous system neurodevelopment and the factors that may adversely affect it. They requested identification of the consequences of these negative factors that may lead to poor physical or mental health or to behavioral, educational, or social problems later in life as a result of compromised brain development. 

Research on the key aspect of these resolutions, namely the impact of brain development on learning, draws from many scientific disciplines. Principal among these are (1) educational theory and practice; (2) early childhood development; (3) cognitive psychology; (4) cognitive neuroscience; and (5) neurodevelopment. In broad terms, this listing moves sequentially from conclusions based on social science research on groups of children to more detailed analyses of cognitive and neuropsychological data on groups of subjects and controls, and finally to examination of the putative anatomic and physiological underpinnings of learning. The neurodevelopmental findings that have drawn the attention of educators and others incorporate neuropathology, cellular physiology, and functional neuro-imaging as the investigational tools. 

Extensive reviews in each of these areas have been conducted.^{1-7(inter alia)} Therefore, this report will briefly summarize the key neurodevelopmental processes that are thought to be linked to learning; review some of the environmental factors known to adversely affect cognition and/or behavior; discuss the known linkages between these factors and neurodevelopmental steps; and address policy implications based on these linkages. 

Highlights of Neurodevelopmental Findings

Shortly after birth, neonatal brains undergo a period of intense synaptic proliferation to levels far greater than those seen in adult brains. Later in infancy there is a spontaneous, normal period of synaptic pruning or reduction. In rhesus monkeys the synaptic density (i.e., the number of synapses per unit of brain tissue volume) peaks at 2 to 4 months of age and then gradually declines until about age 3 years, where it remains at adult levels. The proliferation and pruning appear to occur uniformly throughout the rhesus cortex.⁸ 

The more limited data on human brains suggest that these programmed fluctuations in synaptic density also occur, but they vary by brain region.  ⁹ Synaptogenesis in the visual cortex, for example, begins its rapid growth at about age 2 months, peaks at 8 to 10 months, and then declines gradually until about age 10 years.¹⁰ By contrast, synaptogenesis in the frontal cortex begins and peaks later, and pruning is not complete until adolescence.¹¹ Interpretation of these findings about synaptic density counts is further complicated because synaptogenesis and pruning may occur at different rates in different structures within the same brain region or even for a particular group of neurons in different parts of their dendritic fields.¹² 

Two phenomena thought to be related to this process of synaptogenesis and pruning are those of so-called "critical periods" and neural plasticity, both of which have been studied extensively over the past 30 years. Deprivation of adequate sensory or motor input during particular times in a specific brain system's development (i.e., the critical period) can lead to impairments in that system's functioning, both at that time and in the future.^13,14 Perhaps the best-studied system has been vision in cats: the original studies of Wiesel and Hubel ¹⁵ showed that ocular deprivation in kittens (by sewing an eyelid shut) during the first 3 months of life led to permanent blindness and marked pathological changes in the lateral geniculate body and some of its cortical connections; by contrast, similar deprivation of visual input in normal adult cats did not cause these changes. Later research showed, however, that even in kittens some recovery of vision was possible, suggesting that critical periods were not absolute.^16,17

It is now thought that the need for appropriate sensory input is greatest during a brain system's period of rapid synaptogenesis and that experiential input helps shape the particular synaptic connections that are formed and also which ones are eliminated. This process corresponds to what Black  ¹⁸ describes as the "experience-expectant" type of neural plasticity that is tied to the brain's developmental timetable; however, this observation has only been described with great confidence in the visual system. By contrast, "experience-dependent" plasticity allows incorporation of useful but idiosyncratic information throughout life.¹⁸ The onset of critical periods and their durations vary widely over the different neural systems in the brain. At present, it is not known whether there are critical periods during which particular types of stimulation are needed and after which plasticity is greatly reduced. Not is it known whether neuronal plasticity responsiveness is present in discreet, sensitive periods versus demonstrating more gradual decrease over time. It is important to note that the nature of the required sensory inputs during critical periods is felt to be quite general and thus generally available in all but the most neglectful or deprived environments. 

Environmental Factors

A number of lines of research have examined the effects of various environmental factors on these neurodevelopmental processes. These factors include prenatal drug exposure, nutrition, sensorimotor and emotional stimulation, and stress. It is often extremely difficult to isolate the effects of any single factor: controlled, laboratory studies in animals may have uncertain applicability to humans, while naturalistic human studies are often complicated by the presence of multiple confounding factors. There is generally an additive or even synergistic effect when multiple factors co-occur. Almost all of the studies of these factors have examined anatomic, physiological, behavioral, or neuropsychological outcomes; they have not examined the impact on the specific neurodevelopmental processes described in the previous section. 

Prenatal Drug Exposure. Alcohol consumption during pregnancy is associated with smaller neonatal head size, neuropathological changes, and electroencephalographic disturbances.¹⁹ Children affected by the fetal alcohol syndrome exhibit developmental delay, hyperactivity, delayed motor development, poor psychomotor performance, and visual, perceptual deficits.^20,21 Early studies of the adverse effects of cocaine exposure were probably exaggerated by co-occurrent risk factors,²² but prenatal cocaine exposure is associated with smaller neonatal head size,²³ brain echolucencies and echodensities,²⁴ and poor habituation to environmental stress.²⁵ Although children exposed to opiates during fetal development appear to have smaller head size, worse cognition, and more behavioral problems than those who were not exposed, these differences appear to be largely explained by non-drug factors.^26,27 Maternal smoking during pregnancy is associated with reduced intelligence and an increase in behavioral problems in the child.²⁸

Nutrition. Concern has been raised about whether certain nutritional deficiencies occurring during critical periods of brain development might impair neural structure modeling, perhaps with permanent sequelae; however, evidence to date is modest. A review of 165 animal studies did not find performance differences between undernourished animals and well-nourished controls.²⁹ Some of the more recent preclinical and clinical data using more sensitive instruments has identified performance differences resulting from malnutrition.³⁰ Malnourished infants with cystic fibrosis  ³¹ or marasmus  ³² later develop normally if nutritional status is restored, although in the latter case only if there is also an improvement in psychomotor stimulation. 

Considerable controversy exists over the significance of differences in IQ between children who as infants received maternal breast milk versus those who received formula. This effect is thought to be mediated by a deficiency in long-chain polyunsaturated fatty acids: formula lacks the n-3 series of docosahexaenoic acid (DHA), and this deficiency has been associated with decreased visual acuity.³³ It is believed that other developing neural systems may be adversely affected by such a deficiency. Iron deficiency, as long as it is serious enough to be accompanied by anemia, has been shown to delay mental and psychomotor development in young children, and replacement therapy is beneficial in correcting these impairments.³⁴

Stress and Buffers. Severe or prolonged physiological or psychological stress has long been implicated in a variety of behavioral and emotional problems, and certain environmental factors appear to help buffer (reduce the impact of) such stress. These effects are thought to be mediated largely by hypothalamic-pituitary-adrenal (HPA) axis hormones, and some recent studies have examined HPA axis effects on the developing brain. Activation of the HPA axis leads to elevated circulating levels of glucocorticoids, which appear to reduce neuronal reserve (resistance to trauma) and to cause dendritic atrophy. This has been most studied in the hippocampus (a structure vital to memory and learning), but these effects may also occur in other brain regions with high levels of glucocorticoid receptors, such as the cingulate gyrus, the amygdala, and parts of the frontal lobe.³⁵

Most of the neuroendocrine studies have been carried out in rats, and to a lesser extent, in pups and rhesus monkeys. No direct data show that glucocorticoids affects brain development and function in humans, but several observations suggest that these same effects may be relevant.³⁶ At around 3 months of age, human infants begin to display a circadian rhythm in cortisol production and a decreased adrenocortical response to ACTH; these effects become more pronounced over the rest of the first year of life. These phenomena correspond to diminished and behavioral responses to stressful events such as vaccination injections or physical examinations.³⁷ Secure maternal attachments lead to less reactivity of the HPA axis in infants exposed to novel or noxious stimuli, and insecure attachment is associated with greater cortisol response.³⁸ Infants who exhibit disorganized/disoriented attachment patterns have higher baseline cortisol levels: these patterns are seen in children with a depressed caregiver or who are abused or neglected.³⁹ Infants with depressed mothers exhibit autonomic and neuroendocrine dysregulation, but provision of nondepressed caregivers or interventions to help the mother appear to diminish this dysregulation.⁴⁰

Environmental Enrichment. Many studies have demonstrated that interventions with children identified as at high risk for intellectual disabilities and poor educational performance can improve outcomes.^41-43 These interventions involve some combination of intensive education, family counseling, provision of health care, nutritional support, special instruction, and other services. Such programs date back over 35 years and have drawn on a large body of educational and developmental research, including numerous outcome studies. 

At this time, however, none of this work can properly utilize basic neurodevelopmental research because it has not evolved enough to address these educational and other early intervention issues. The most commonly cited (and over-interpreted) study in this regard is that of Greenough et al,  ¹³ who raised rats in a "complex environment" designed to simulate the wild (natural) murine environment in comparison to the research laboratory experience of minimally equipped individual or small group cages. The authors found that rats raised in the experimental environment had an increase of up to 25% in synaptic connections per neuron in the visual cortex when compared with control animals and a somewhat smaller effect in other brain regions studied. It is important to differentiate this modest restitution to a natural murine environment from the far more elaborate concept of an intellectually enriched world that has been proposed as desirable for human infants.⁴⁴

Although these neurodevelopmental findings and their environmental contributions are exciting, the implications for education, medicine, and public health currently remain more speculative than proven. As previously noted, few of these studies were done in humans, and the generalization of animal brain processes to humans is not always reasonable. Secondly, the regions of the brain that have been studied have more often involved sensorimotor regions, with cognition (peri-hippocampal), affect (limbic), or executive functional regions (frontal) less well-studied. Thirdly, knowledge of the ways by which processes such as synaptogenesis, pruning, and critical periods are influenced by environmental input is rudimentary. On evolutionary grounds, the presumption would be that these processes are stable, fairly resistant to adverse environmental factors, and require only a minimal, expectable environment to offer the necessary shaping: in other words, deprivation would need to be particularly severe to derail such development. On the other hand, little is known about the influence of highly enriched or intellectually stimulating environments: it is far from clear whether this leads to performance improvements or simply represents a waste of environmental resources. 

Current Research Efforts

A major effort is underway under the joint direction of three of the National Institutes of Health (NIH) to support research activities designed to elucidate the biological bases of a broad range of cognitive and behavioral disorders in infants and children. The work is being sponsored jointly by the Division of Fundamental Neuroscience and Developmental Disorders of the National Institute of Neurological Disorders and Stroke, the Developmental Psychopathology Research Branch of the National Institute of Mental Health, and the Child Development and Behavior Branch of the National Institute of Child Health and Human Development (NICHD).⁴⁵

This research effort seeks to utilize anatomic and functional magnetic resonance imaging to better characterize normal growth patterns of various brain structures and to compare them with findings in children with known psychiatric, developmental, and brain disorders. In addition, the imaging will be integrated with physiological measures and other imaging modalities, such as magnetic resonance spectroscopy, diffusion tensor imaging, positron emission tomography, single photon emission computerized tomography, electroencephalography/event-related potentials, and magnetoencephalography. Finally, the imaging results will be examined in relation to research conducted at the cellular level. The work will be carried out by Pediatric Study Centers that can conduct longitudinal studies that include neuro-imaging and brain-behavior correlations. 

The NICHD has also developed a portfolio of research program projects to better understand learning disabilities (LD) and their neurodevelopmental underpinnings. NICHD programs at the Beth Israel Harvard Hospital, Johns Hopkins University, and Yale University are examining children with LD and searching for neuroanatomical and neurophysiological correlates. The NICHD is also supporting research on neurodevelopmental outcomes related to long-chain polyunsaturated fatty acids in infant diets. 

The National Institute on Drug Abuse (NIDA) is continuing to conduct and to support research examining the outcomes of perinatal exposure to addictive drugs. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) is conducting and supporting similar research, examining behavioral and neurodevelopmental outcomes of maternal alcohol ingestion during pregnancy. 

Finally, the US Departments of Education and Health and Human Services will soon issue a report entitled, "Young Children's Education, Health, and Development: Profile and Synthesis." This will review many early intervention programs designed to counter effects of poverty and other risk factors associated with impaired educational achievement. 

Summary

There are many environmental risk factors for adverse cognitive and behavioral health outcomes in children, adolescents, and adults. These have been delineated in a variety of epidemiological and clinical studies over the past several decades, and their specific impacts have been studied in educational, developmental, cognitive psychology, and cognitive neuroscience investigations. Recent findings on brain development involving synaptic connections, neural plasticity, and critical periods offer great promise in explaining the neuropathological and neurophysiological mechanisms underlying these adverse outcomes, with eventual understanding at the cellular and neurochemical levels. A great deal of work in these areas is already underway and has been planned for the near future. 

At this time, the scientific findings in human neurodevelopment remain too preliminary to offer clinical or policy recommendations beyond those that already follow from other research. The Council on Scientific Affairs will continue to follow this important field of study and make additional recommendations as data to support them become available. 

RECOMMENDATIONS 

The following statements, recommended by the Council on Scientific Affairs, were adopted by the AMA House of Delegates as AMA policy at the 1999 AMA Annual Meeting. 

1. The AMA supports the efforts of the National Institutes of Health (NIH) and others to encourage and fund research into basic human brain development processes and the relationship of these processes to cognitive development  
2. The AMA supports the efforts of the NIH and others to encourage and fund research exploring the relationships among brain development, environmental factors, and cognitive and behavioral disorders and to seek effective mechanisms to prevent and treat these disorders.

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