5
Perspectives from Developmental Neuroscience

Chapter 4 described the multiple risk and protective factors that can play a role in mental, emotional, and behavioral (MEB) disorders and that can inform the design of prevention interventions, placing these contributing factors in the framework of developmental processes. This chapter illustrates research advances in the framework of developmental neuroscience, including the anatomical and functional development of the brain, molecular and behavioral genetics, molecular and cellular neurobiology, and systems-level neuroscience, that relate to the prevention of MEB disorders. Perspectives from developmental neuroscience provide a foundation for understanding the development of cognitive abilities, emotions, and behaviors during childhood and adolescence, and they thereby reveal valuable opportunities for novel advances in future prevention research.

Reducing Risks for Mental Disorders: Frontiers for Preventive Intervention Research, the 1994 Institute of Medicine (IOM) report, emphasized the importance of the relationship between prevention research and a knowledge base that includes both basic and applied research in neurobiology and genetics. This knowledge base contributes to the understanding of the causes, course, and outcomes of MEB disorders, and it continues to be increasingly important for informing how prevention efforts may intervene in causal pathways that lead to disorders.

In the years since the 1994 IOM report, understanding of the biological processes that underlie brain development has grown at an unprecedented rate, and the past several decades have witnessed much greater interest in the neurobiological underpinnings of MEB disorders. These disorders are



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5 Perspectives from Developmental Neuroscience C hapter 4 described the multiple risk and protective factors that can play a role in mental, emotional, and behavioral (MEB) disorders and that can inform the design of prevention interventions, placing these contributing factors in the framework of developmental processes. This chapter illustrates research advances in the framework of develop- mental neuroscience, including the anatomical and functional development of the brain, molecular and behavioral genetics, molecular and cellular neurobiology, and systems-level neuroscience, that relate to the prevention of MEB disorders. Perspectives from developmental neuroscience provide a foundation for understanding the development of cognitive abilities, emo- tions, and behaviors during childhood and adolescence, and they thereby reveal valuable opportunities for novel advances in future prevention research. Reducing Risks for Mental Disorders: Frontiers for Preventive Interven- tion Research, the 1994 Institute of Medicine (IOM) report, emphasized the importance of the relationship between prevention research and a knowl- edge base that includes both basic and applied research in neurobiology and genetics. This knowledge base contributes to the understanding of the causes, course, and outcomes of MEB disorders, and it continues to be increasingly important for informing how prevention efforts may intervene in causal pathways that lead to disorders. In the years since the 1994 IOM report, understanding of the biological processes that underlie brain development has grown at an unprecedented rate, and the past several decades have witnessed much greater interest in the neurobiological underpinnings of MEB disorders. These disorders are 

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4 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS increasingly being understood as dynamic disruptions in key developmental processes that exert their effects throughout the life span. Unraveling the causes and consequences of complex MEB disorders remains an enormous challenge. However, major advances have been made not only in identify- ing genetic and environmental factors that play causal roles in the genesis of disorders, but also in understanding more fully the interaction between genetic and environmental influences in causing or protecting against spe- cific diseases. In addition, advances in the emerging field of epigenetics have begun to provide information about the complex ways in which genetic traits are expressed as disease and the possible mechanisms through which environment and experience can influence gene expression. This chapter begins with the role of genetics and the interplay of genetic and environmental factors in MEB disorders. This is followed by a discus- sion of brain development and its relationship to MEB disorders. Next is an examination of neural systems and their role in complex processes that underlie the cognitive and social competence that is essential to healthy emotional and behavioral development. The third section addresses the relationship between developmental neuroscience and prevention science. The final section presents conclusions and recommendations. GENETICS The importance of understanding genetic influences in brain develop- ment goes well beyond simply explaining the hereditary components of dis- orders. Genes are the basic component from which the brain’s structure and function are determined and regulated. Genes encode proteins, and proteins are the building blocks of cells, interacting with the molecular and physical features of their surroundings to determine cellular structure and function. Individual cells interact functionally with other cells within the neural cir- cuits that make up the structure of the brain, which in turn interact with other neural circuits to determine behaviors. Behaving organisms interact with their environments, which can cause adaptive changes in neural sys- tems, circuits, and cells and ultimately in the expression of genes—which in turn modifies brain structure and function. The complexity of the pathways connecting the genes and the environments of organisms to their behaviors has frustrated most attempts to correlate genes directly with behaviors and with specific diagnostic syndromes in the field of psychiatric genetics (Inoue and Lupski, 2003; Joober, Sengupta, and Boksa, 2005; Sanders, Duan, and Gejman, 2004; van den Bree and Owen, 2003). Inherited or sporadic genetic mutations can profoundly affect the pro- duction, structure, or function of the protein that a gene encodes. This can have a dramatic and highly consistent effect in producing disease. However, more subtle variations in the genetic sequence can also affect protein struc-

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5 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE ture and function, producing much more subtle effects. For example, many of the genetic variants that have been associated with MEB disorders are single nucleotide polymorphisms, that is, substitutions of single nucleotides, the structural components of the genetic sequence (van Belzen and Heutnik, 2006; Sanders, Duan, and Gejman, 2004). Variability in the number of copies of a specific gene sequence (known as copy number variants), which can be caused by rearrangements, microdeletions, or microduplications of the sequence, has also emerged as an important contributor to MEB dis- orders (Lee and Lupski, 2006), such as schizophrenia (Walsh, McClellan, et al., 2008; Xu, Roos, et al., 2008; International Schizophrenia Consortium, 2008; Stefansson, Rujescu, et al., 2008) and autism (Sebat, Lakshmi, et al., 2007; Marshall, Noor, et al., 2008). These kinds of gene variations can have a more graded influence on molecular and cellular functions than do large deletions or rearrangements of genes. The influences of these gene variants on the structural and functional features of cells, neural circuits, and the behaviors they subserve are correspondingly graded as well. Variations in the genetic sequences that encode proteins are only one level of influence on the expression of those genes in the production of cellular proteins. Variations in the sequence of the nonencoding, regula- tory portions of a gene also have important influences on its expression, as can variations in other genes that encode regulatory proteins. In addition, microRNAs (small sequences of RNA, an intermediate genetic component in the process of making proteins from DNA) can influence the expression of genes and their protein products by altering how the proteins are gener- ated from a gene sequence (Boyd, 2008; Stefani and Slack, 2008). These additional levels of regulation can determine when in the course of devel- opment, where in the brain, and to what degree a gene is expressed—all without changing the DNA sequence of the gene. Many studies, including family studies and gene association studies, have demonstrated a genetic component to MEB disorders (Thapar and Stergiakouli, 2008; van Belzen and Heutnik, 2006). However, genetic studies have not yet found an association of single genes with most MEB disorders. Instead, sequence variants in multiple genes have been shown to be associated with an elevated risk or susceptibility for developing many diseases, such as autism (Muhle, Trentacoste, and Rapin, 2004), depression (Levinson, 2006; Lopez-Leon, Janssens, et al., 2008), schizophrenia (Owen, O’Donovan, and Harrison, 2005), addiction (Goldman, Oroszi, and Ducci, 2005), and bipolar disorder (Serretti and Mandelli, 2008). A review of these many reported associations of specific genes with individual disorders is beyond the scope of this report. In nearly all instances of these reported associations, the influence of individual genes on the risk for developing a disorder is small (Kendler, 2005; Thapar and Stergiakouli, 2008), usually less than the influence of

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6 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS family history and less than that of other nongenetic risk factors. The asso- ciation is also often nonspecific (Kendler, 2005), with single gene variants being associated with multiple disorders. Moreover, genetic profiles vary greatly among affected individuals. Not everyone with the susceptibility variant in any one of the associated genes will develop the disorder, and not everyone with a particular disorder will have the susceptibility variant of any associated gene. Therefore, a single genetic variant will rarely be necessary or sufficient to produce a disorder, a point similar to findings on the association of environmental risk factors with MEB disorders (described later in this chapter and in Chapter 4). One strategy that has emerged to address the complexity of linking genes to disorders is to identify more narrowly defined behaviors, characteristics, or biological markers, termed “endophenotypes,” that correlate with specific disorders or that are com- mon to more than one disorder. These endophenotypes can serve as a sim- pler, more readily identifiable focus of genetic studies (Caspi and Moffitt, 2006; Gottesman and Gould, 2003; van Belzen and Heutink, 2006). Beyond finding associations between genetic variants and MEB dis- orders or endophenotypes, identifying the effects that specific genes have on molecular pathways, cellular organization, functioning of neural networks, and behavior is crucially important to developing effective intervention approaches based on the modifiable components of the pathways from genes to behavior. This level of genetic research requires experimental manipulations in animal models. Most commonly this involves modifica- tion of the genome of mice by inserting, deleting, or mutating specific genes and, in some cases, controlling where in the brain, in what cell types, and when during the course of development a gene is turned off or on. This extraordinary degree of spatial and temporal control over gene expression makes animal models invaluable in identifying the molecular processes of normal and pathological brain development. The disadvantage of animal models, however, is the difficulty of representing the complex cognitive, behavioral, and emotional symptoms experienced by humans. Although the effects of experimental manipulation on certain aspects of cognition and memory can be assessed through the ability of animals to learn and repeat standardized tasks, analogues of emotional experience and thought can be inferred only through behavior that must be correlated with subjective human experience (Cryan and Holmes, 2005; Joel, 2006; McKinney, 2001; Murcia, Gulden, and Herrup, 2005; Powell and Miyakawa, 2006; Sousa, Almeida, and Wotjak, 2006). Animal models are proving to be of central importance in identifying the likely disturbances in molecular and cellular pathways caused by single gene mutations in some neurodevelopmental disorders, including the fragile X, Prader-Willi, Angelman, and Rett syndromes. Knowledge of those molecu- lar pathways already has led to promising treatment approaches in animal

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7 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE models (Chang, Bray, et al., 2008; Bear, Dolen, et al., 2008; Chahrour and Zoghbi, 2007; Dolen, Osterweil, et al., 2007; Giacometti, Luikenhuis, et al., 2007; Guy, Gan, et al., 2007). Animal models have also successfully linked risk genes with disturbances in particular molecular pathways that may predispose to the development of more complex, polygenic disorders, such as depression (Cryan and Holmes, 2005; Urani, Chourbaji, and Gass, 2005), anxiety disorders (Cryan and Holmes, 2005), obsessive compul- sive disorder (Joel, 2006), autism (Moy and Nadler, 2008), schizophrenia (O’Tuathaigh, Babovic, et al., 2007), and substance abuse (Kalivas, Peters, and Knackstedt, 2006). Despite the challenge of studying the role of genes in the etiology of MEB disorders, advances in technology continue to make large-scale genotyping more feasible and affordable, and the combination of human genetics studies and approaches using animal models has proven to be informative in identifying genes of risk in multifactorial, complex non- psychiatric disorders, such as asthma (Moffatt, 2008) and diabetes (Florez, 2008); they will undoubtedly make important contributions in psychiatric genetics in coming years. Gene–Environment Interactions and Correlations Most complex behaviors and the most common forms of MEB dis- orders are likely to arise from a combination of multiple interacting genetic and environmental influences (Caspi and Moffitt, 2006; Rutter, Moffitt, and Caspi, 2006). The effect of a common genetic variant in altering the risk for a disorder, for example, is likely to be conditioned heavily by the experi- ences of a developing child, just as the effects of experience in producing a disorder are likely to be conditioned by the genetic background that the child inherits from his or her parents (Rutter, Moffitt, and Caspi, 2006; Thapar, Harold, et al., 2007). These so-called gene–environment (GxE) interactions can confer both risk and protective effects on the child relative to the effects of either the genetic or environmental influences in isolation. A number of interactions between specific identified genes and spe- cific environmental risk factors have been demonstrated in MEB disorders (Rutter, Moffitt, and Caspi, 2006). For example, a landmark prospective epi- demiological study found that the number of copies an individual carries of the short variant of a region of the serotonin transporter gene (5-HTTLPR) significantly increases, in a dose-dependent fashion, the risk for developing depressive symptoms, major depressive disorder, and suicidality—but only in the context of adverse or stressful early life experiences (Caspi, Sugden, et al., 2003) (see Figure 5-1). Similarly, a polymorphism in the gene that encodes monoamine oxidase A (MAOA), an enzyme that metabolizes neuro- transmitters, moderates the effect of maltreatment on developing antisocial

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8 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS Probability of Major Depression Episode No Severe Probable Maltreatment Maltreatment Maltreatment FIGURE 5-1 Gene–environment interaction between effects of prior maltreatment and genotype for 5-1 new the 5-HTTLPR allele on developing depression later in life. Maltreatment has the biggest effect for two copies of the short (s/s) allele and the smallest effect for two copies of the long (l/l) allele. There is an intermediate effect for one copy of each allele (s/l). SOURCE: Caspi, Sugden, et al. (2003). problems later in life (Kim-Cohen, Caspi, et al., 2006; Caspi, McClay, et al., 2002): Maltreated children who have the genotype that confers high levels of MAOA expression are less likely to develop conduct disorder, antisocial personality, or adult violent crime. In another domain, a common poly- morphism of the dopamine transporter gene has been reported to interact with the risk conferred by prenatal exposure to tobacco smoke, leading to increased hyperactive-impulsive and oppositional behaviors in later child- hood (Kahn, Khoury, et al., 2003). In contrast to GxE interactions, gene–environment correlations are genetic influences on variations in the likelihood that an individual will expe- rience specific environmental circumstances (Jaffee and Price, 2007; Rutter and Silberg, 2002; Rutter, Moffitt, and Caspi, 2006). Gene–environment correlations can confound cause and effect and hinder measurement of GxE interactions because a genetically determined behavioral trait can produce a systematic variation in environmental exposure, and that environmental variation can be deemed erroneously to be a cause of a behavioral trait under study (Jaffee and Price, 2007; Lau and Eley, 2008). Children with autism, for example, are chronically and consistently withdrawn from their caregivers. This chronic withdrawal might induce in the caregiver a sense of hopelessness about ever making a deep interpersonal connection with the child, prompting a secondary withdrawal on the part of the caregiver. An

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 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE unsuspecting researcher might inadvertently and erroneously attribute the child’s impoverished social relatedness to the caregiver’s withdrawal, when in fact it was caused by a particular genetic variant. Epigenetic Effects Epigenetic effects are potentially heritable alterations of gene expres- sion that do not involve actual modification of the DNA sequence. Instead, alterations in the level of gene expression are induced by changes in the three-dimensional packaging of DNA that in turn make a gene either more or less amenable to production of a protein product. All known mechanisms that produce epigenetic changes in gene expression involve enzymatic processes that add or remove substrates either from the DNA or from histone proteins that are physically associated with DNA and that determine its three-dimensional packing structure (Tsankova, Renthal, et al., 2007). Epigenetic modifications of gene expression are in continual flux, as competing factors modify and unmodify DNA and its associated proteins, as well as their related behavioral phenotypes. Epigenetic determinants are increasingly invoked as possible explana- tions for a multitude of “complex genetic” phenotypes, in which multiple genes are each thought to account for a small amount of variance in the clinical phenotype. Moreover, recent research has shown that epigenetic mechanisms can produce short-term adaptation of the phenotype to a changing environment. For example, abundant naturalistic and experimen- tal evidence in humans and animal models has shown that early experi- ence influences reactivity to stress later in life, even into adulthood, and that epigenetic modification of genes that encode components of the stress response can contribute to these enduring effects (Kaffman and Meaney, 2007; Weaver, 2007). Perhaps most remarkably, a changing environment has been shown to trigger epigenetic effects that can be transmitted across generations, in species as diverse as yeast and humans (Rakyan and Beck, 2006; Richards, 2006; Whitelaw and Whitelaw, 2006). The quality of maternal care given to rat pups, for example, produces epigenetic modifications of gene expression in the brains of the pups that influence the quality of maternal care they provide as adults to their own offspring. This cross-generation transmis- sion has been shown to account for variability in maternal behavior toward offspring that is either nurturing or neglectful (Champagne, 2008). Several examples suggest that epigenetic mechanisms are important in understanding the causes and in improving the prevention and treatment of MEB disorders (Tsankova, Renthal, et al., 2007). One well-known example is the Prader-Willi and the Angelman syndromes, disorders with highly distinct phenotypes that are nevertheless both caused by a mutation

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20 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS in the same chromosomal region. Although the locus of the mutation is the same, its effects on the behavioral phenotype of the child differ depending on which parent is the origin of the mutation (Goldstone, 2004; Lalande and Calciano, 2007; Nicholls and Knepper, 2001). Another example of the importance of epigenetic influences in the cause of a disorder is Rett syndrome, a progressive neurodevelopmental disorder characterized by motor, speech, and social behavioral abnormali- ties (Chahrour and Zoghbi, 2007). Mutations in the MeCP2 gene cause Rett syndrome and, less commonly, other neurodevelopmental disorders, including classic autism, mental retardation, early-onset bipolar disorder, and early-onset schizophrenia. This gene encodes a protein that epige- netically alters the expression of other genes (Chahrour and Zoghbi, 2007; Zlatanova, 2005). In other words, this specific genetic mutation causes disease through epigenetic mechanisms, underscoring how complex, inti- mate, and interactive genetic and epigenetic factors are in influencing the development of disorders. Epigenetic modifications of the genome are also necessary for vari- ous learning and memory processes in the brain (Levenson and Sweatt, 2005, 2006; Levenson, Roth, et al., 2006; Reul and Chandramohan, 2007; Fischer, Sananbenesi, et al., 2007), suggesting that these processes may be important in the etiology of various mental retardation syndromes. Epigenetic influences play a prominent role as well in changes in the brain and in behavior related to establishing preferences for drugs of abuse in animal models of addiction (Kumar, Choi, et al., 2005). Finally, epigenetic modifications of the genome have been shown to be necessary to produce the behavioral response to antidepressant medications in a mouse model of depression (Newton and Duman, 2006; Tsankova, Berton, et al., 2006). BRAIN DEVELOPMENT MEB disorders in children involve disturbances in the most complex, highly integrated functions of the human brain. Understanding from a bio- logical perspective how these functional capacities develop and how they are disrupted is an immense challenge. This section offers a brief overview of current knowledge about the complex processes that contribute to the normal development of the human brain, along with examples of their relationship to the causes of MEB disorders. Sources of Knowledge of Human Brain Development Knowledge of normal human brain development and of the abnor- malities that produce disorders is limited by the difficulty of studying the human brain at the level of molecules and cells. The human data on brain

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2 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE development thus far come from a small number of postmortem studies and a larger number of in vivo, or live, brain imaging studies. The scientific value of postmortem studies is limited by the quality and number of tissue samples that are usually available and by the capability to study only a small number of brain regions (Lewis, 2002). In contrast, in vivo imaging has proved to be an important tool for studying postnatal brain develop- ment in humans across the life span (Marsh, Gerber, and Peterson, 2008), although thus far it has provided information about brain structure and function mainly at a macroscopic level of brain organization, revealing little molecular or cellular information (Peterson, 2003b). Understanding of the molecular and cellular development of the human brain is therefore gleaned largely from studies of animal models, extrapo- lated to the maturational timeline of humans. Although a great deal has been learned from those animal models across a wide range of species, how well those findings relate to the development and function of the human brain is not fully known. Moreover, as noted earlier, the molecular bases of the highest-order functions of the human brain cannot be studied easily in animals. Despite limited data from human and nonhuman primates, the consis- tency in findings across species suggests that the general features of brain development in animal models are likely to apply to humans as well. Those findings indicate that the wiring of neural architecture is neither fixed nor static. Instead, it is a dynamic entity that is shaped and reshaped continu- ally throughout development by processes that have their own maturational timetables within and across brain regions. These processes are described briefly here and summarized in Figure 5-2. Overview: Complexities of Brain Development At the visible anatomical level, the human brain develops during gesta- tion into a complex structure having distinct anatomical regions and a highly convoluted surface. Similarly, at the level of cellular architecture, the human brain is a highly complex, layered structure made up of many distinct kinds of cells that have highly specific interconnections. During fetal brain devel- opment, undifferentiated precursor cells need to divide and multiply. The resulting cells must then differentiate into the correct cell types, migrate to the correct place in the brain, and connect properly with other cells. These links among cells must then be organized into functional circuits that sup- port sensation, perception, cognition, emotion, learning, and behavior. In a healthy intrauterine environment, this series of complex and interrelated neurodevelopmental events is initially under the predetermined control of regulatory genes (Rhinn, Picker, and Brand, 2006). In contrast, much of the fine detail of brain organization—how the brain is “wired”—develops

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22 Developmental Phase Early Early Emerging Prenatal Birth Infancy Childhood Childhood Adolescence Adolescence Adulthood Gestation (weeks) 4 8 12 16 20 24 28 32 Neurulation Neuronal Proliferation Neuronal Differentiation Neuronal Migration Synapse Formatio n Programmed Cell D eath Synaptic Pruning Myelination FIGURE 5-2 Timeline of major events in brain development. Fig5-2.eps broadside

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2 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE through a combination of genetic influences, experience and other external influences, and the interaction of genes and experience. Setting Up the Nervous System The nervous system begins to develop in the human fetus 2 to 3 weeks after conception in a process called neurulation, starting as a layer of undifferentiated precursor cells called the neural plate. These cells eventu- ally give rise to all components of the nervous system. As the initial cells divide to create more cells, the neural plate expands, folds, and fuses to form the neural tube (Detrait, George, et al., 2005; Kibar, Capra, and Gros, 2007). The neural tube continues to enlarge while cells in different parts of the tube become specialized, following a spatial pattern established by predetermined molecular mechanisms. From front to back, the neural tube becomes the forebrain (the cerebral cortices), the midbrain (containing neural pathways to and from the forebrain), the hindbrain (the brainstem and cerebellum), and the spinal cord and peripheral nervous system (Rhinn, Picker, and Brand, 2006). Various physiological and environmental factors can affect prenatal brain development in ways that are either lethal or seriously debilitating (Detrait, George, et al., 2005; Kibar, Capra, and Gros, 2007). Low levels of the vitamin folic acid, for example, produce anencephaly and spina bifida, disorders of formation of the neural tube. Other prenatal environmental exposures can predispose a developing fetus to the development of MEB disorders later in life. For example, common prenatal infections, such as influenza, and less common ones, such as rubella, toxoplasmosis, and cyto- megalovirus, can increase the risk of developing mental retardation, schizo- phrenia, and autism (Fruntes and Limosin, 2008; Jones, Lopez, and Wilson, 2003; Meyer, Yee, and Feldon, 2007; Pearce, 2001; Penner and Brown, 2007). Prenatal exposure to various environmental toxins, including certain insecticides used in homes and for agricultural purposes (Rauh, Garfinkel, et al., 2006), tobacco smoke (Herrmann, King, and Weitzman, 2008), and alcohol (Alcohol Research and Health, 2000), can impair behavior and cognition later in childhood (Williams and Ross, 2007). Premature birth and low birth weight can also predispose to a wide variety of disorders (Peterson, 2003a), including schizophrenia (Kunugi, Nanko, and Murray, 2001), autism (Kolevzon, Gross, and Reichenberg, 2007), and learning dis- abilities and educational difficulties (Peterson, 2003a). The Right Cells in the Right Place Between weeks 5 and 25 of human fetal gestation, undifferentiated precursor cells divide repeatedly, rapidly giving rise to large numbers of

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40 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS Hormonal Influences on Brain Development and Behavior Differences between the sexes have been observed across multiple domains of cognitive, emotional, and behavioral development. Boys, for example, appear on average to be predisposed to more physical activity; less tolerance for frustration; and more aggression, impulsivity, and dys- regulated emotions (Eaton and Enns, 1986; Else-Quest, Hyde, et al., 2006; Zahn-Waxler, Shirtcliff, and Marceau, 2008). Girls on average exhibit more rapid language acquisition, greater empathy and social skills, and more fearfulness and anxiety (Else-Quest, Hyde, et al., 2006; Zahn- Waxler, Shirtcliff, and Marceau, 2008). Several processes, ranging from differences in environmental exposures to innate differences in the biological processes that underlie either emo- tion and behavior or responses to the environment, could produce these gender differences (Zahn-Waxler, Shirtcliff, and Marceau, 2008). The dif- ferences are thought to have their basis at least in part in differences in brain structure and function, which are determined largely by the effects on brain development of both sex hormones and genes encoded on sex chromosomes (Arnold, 2004; Davies and Wilkinson, 2006; Hines, 2003). Hormone-dependent sexual differentiation of the brain is thought to be driven primarily by differences in androgen levels in fetal and early post- natal life. Production of testicular androgen in the human male fetus begins during the sixth week of gestation, producing higher testosterone levels in males than in females between weeks 8 and 24 of gestation (Knickmeyer and Baron-Cohen, 2006; Warne and Zajac, 1998). Studies in animal models demonstrate that differences between the sexes in the levels of various ste- roid hormones in the brain during fetal life produce sex-specific differences in neuronal proliferation, cell migration, apoptosis, dendritic branching, and the density of dendritic spines (Cooke, Hegstrom, et al., 1998). These differences between the sexes in fetal brain development in turn produce gender differences in brain form and structure that endure throughout postnatal life (Knickmeyer and Baron-Cohen, 2006; Hines, 2003). Changes in levels of steroidal hormones during puberty are then thought to lead to further modification of brain structure and function across both sexes (Romeo, 2003). Differences between the sexes in brain structure and function are thought to underlie the well-documented gender differences in the diag- nostic and age specificity of MEB disorders. For example, females over- all are more likely than males to develop major depression and anxiety disorders (Pigott, 1999; Rutter, Caspi, and Moffitt, 2003; Zahn-Waxler, Shirtcliff, and Marceau, 2008), while males are more likely to develop ADHD, conduct disorder, substance abuse, tic disorders, and learning disorders (Rutter, Caspi, and Moffitt, 2003; Zahn-Waxler, Shirtcliff, and

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4 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE Marceau, 2008; Apter, Pauls, et al., 1993; Tallal, 1991). The age of onset of MEB disorders is generally earlier in boys than in girls, producing a male predominance of these disorders in prepubertal children. This sex-specific difference in rates of illness reverses following puberty, when the prevalence of disorders is higher in girls. RELEVANCE OF DEVELOPMENTAL NEUROSCIENCE TO PREVENTION Relationship to Prevention Interventions Developmental neuroscience provides a great deal of knowledge that will increasingly support preventive intervention approaches for MEB dis- orders. Knowledge is growing about the determinants of mental health in the prenatal and early postnatal periods of brain development; the impor- tance of consistent and nurturing parental care on development of the brain; and the neural systems that support healthy attachment, socializa- tion, adaptive learning, and self-regulation throughout infancy, childhood, and adolescence. All of this knowledge has important implications for interventions that can not only prevent MEB disorders but also actively promote positive, adaptive, prosocial behaviors and well-being. Specific opportunities to support healthy brain and behavioral development and to protect against environmental factors present themselves at distinct devel- opmental stages, when they are most likely to have a beneficial effect. During the prenatal period and the early years of a child’s life, neuro- biological processes establish the potential for healthy development or, in the presence of various risk factors, the potential for the development of significant cognitive, emotional, and behavioral difficulties. Knowledge of these processes informs preventive approaches in a number of ways. First, as discussed throughout this report, mental and physical health are inseparable, as are brain and physical development. Programs and inter- ventions that support healthy pregnancy are therefore crucial. These can include efforts to ensure adequate and proper nutrition, such as requiring the fortification of foods with folic acid, a universal preventive interven- tion that has reduced the rates of neural tube defects in the United States by 25-30 percent (Pitkin, 2007). Similarly, reducing exposure to environ- mental toxins and infections during pregnancy and minimizing obstetrical complications during childbirth can have powerful effects on preventing MEB disorders (see Chapter 6). Second, this chapter has emphasized the importance of nurturing care for healthy brain development and the lifelong adverse effects that disrup- tions in this care and exposure to harmful experiences early in life can have on both the development and functioning of the brain. Considerable

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42 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS evidence now suggests that these effects can be prevented or reduced by appropriately designed interventions if they are delivered at the proper time. Thus, for example, interventions focused on fostering the bonding and attachment of caregiver and child should begin at birth and be supported for the first several years of a child’s life. This is the aim of such approaches as home visitation and high-quality preschool, which are discussed in the following chapters. On the other hand, the brain continues to develop and retains a large capacity for plasticity throughout infancy, childhood, adolescence, and early adulthood as the neural systems that support such behaviors as attachment, socialization, learning, and self-regulation are refined to achieve healthy cognitive, emotional, and behavioral functioning. Evidence from both traditional models of learned behavior and more novel fields of investigation, such as epigenetics, suggests that environmental improvements can produce long-term changes in brain structure and func- tion, and thus interventions applied even after the optimal sensitive periods of development can attenuate the effects of early adverse experiences. Later developmental stages also bring developmentally specific oppor- tunities to promote protective factors related to more mature behaviors— for example, building social relationships. Difficulties in developing and maintaining healthy relationships are an important aspect of many MEB disorders. Therefore, influencing social relationships positively and build- ing networks of support in families, schools, and communities are among the primary aims of a wide array of prevention programs, as described in Chapters 6 and 7. The development of the neural systems that support self-regulatory functions is important for acquiring developmentally appropriate neuro- cognitive skills that affect mental health and risk for MEB disorders (Blair, 2002; Fishbein, 2000; Greenberg, 2006; Pennington and Ozonoff, 1996; Rothbart and Posner, 2006; Riggs and Greenberg, 2004). Numerous studies have shown that appropriately designed and implemented interventions can improve self-regulatory control of thoughts, emotions, and behavior in people of all ages, even young children (Dowsett and Livesey, 2000; Rueda, Posner, and Rothbart, 2005), and several curricula and training programs have been designed to promote self-regulation in prevention frameworks. For example, the Promoting Alternative Thinking Strategies (PATHS) pro- gram (described in Box 6-7 in Chapter 6) has been shown to increase inhibitory control and working memory (Greenberg, 2006). Likewise, the preschool curriculum Tools of the Mind, designed to build inhibitory con- trol, working memory, and cognitive flexibility, has been shown to improve these functions in an at-risk population (Diamond, Barnett, et al., 2007). Another area in which research in developmental neuroscience has implications for prevention of MEB disorders is targeting the appropriate individuals for the delivery of interventions. The identification of children

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4 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE who are at either increased or diminished risk for developing an MEB disorder based on phenotypic characteristics, genotype, or other biologi- cal markers (such as physiological or brain imaging measures), or who have a history of environmental exposure offers the prospect for applying indicated prevention strategies. The possibility of targeting interventions based on evidence from developmental neuroscience is genuine and valid if the following criteria are met: (1) the evidence for the association between a marker or exposure and a disorder is sufficient to identify children at risk reliably, (2) a sufficiently powerful strategy for preventive intervention is identified that is relevant for the disorder and the risk factors in ques- tion, and (3) the magnitude of the risk or protection that the marker or exposure confers is sufficiently large to justify screening for the marker or exposure. The potential use of individually identified biological information to determine risk raises important ethical concerns (Institute of Medicine, 2006a; Evans, 2007). These concerns frequently arise in the context of acquiring genetic information, and the rapid increase in genetic research related to MEB disorders has coincided with an increase in public inter- est and also in private-sector endeavors to provide commercially available access to individual genetic information (Couzin, 2008; Hill and Sahhar, 2006). One concern is appropriate interpretation of the available evidence to determine whether the above criteria have been met before a marker is implemented as a basis for determining individual risk. Genetic and other biological markers are often perceived to be more deterministic than other risk factors in their potential to predict future disease (Austin and Honer, 2005; Hill and Sahhar, 2006; Kendler, 2005; Institute of Medicine, 2006a). However, given the complex, multifactorial etiology of MEB disorders, single genetic variants have very limited predictive power. This is also likely to be true for physiological or brain imaging measures that are being studied in relationship to MEB disorders. Clearly and accurately communi- cating research findings, including both their promise and limitations, to the public, policy makers, practitioners, and researchers in related disciplines is of paramount importance. If the evidence does support gathering individual genetic and other bio- logical information for research studies, and especially if testing for MEB disorders becomes available outside the research environment as it has for other health conditions, important decisions must be made. These include who determines whether to test an individual, who can gain access to the test results, who counsels the individual about those results, and who can act on the information (Institute of Medicine, 2006a). On the one hand, limiting access to information about individual risk raises concerns about withholding health information. On the other hand, the availability of individualized information leads to concerns about privacy, stigmatization,

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44 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS and bias and could potentially have negative effects on employment and the ability to obtain adequate health, life, and disability insurance (Institute of Medicine, 2006a). To address these concerns, a broad array of social, ethical, and legal factors should ultimately contribute to decisions about how research findings are applied and how tests to gather information about individual risk are implemented. Such decisions need to incorporate a research-informed, evidence-based understanding of how practitioners, policy makers, and the public will interpret the information and how sys- tems and individuals will make use of the information. These concerns are also important in considering how to use individually identified psychologi- cal, social, and other environmental risk factors to screen for the risk of developing MEB disorders (see also Chapter 8). Relationship to Prevention Research Defining the neural substrates of healthy cognitive, behavioral, and emotional development and, in particular, understanding the plasticity of such substrates in the face of environmental interventions can provide an important basis for prevention research and for identifying many promising avenues for future study. Rich theories of the pathogenesis of MEB disorders in young people can be developed using animal models and other methods of basic science research, as well as neurobiological studies in humans. Accordingly, theo- ries derived from developmental neuroscience should have a prominent role in informing the design of such interventions. Research that further identi- fies how environmental factors affect basic neurodevelopmental processes, such as neuronal migration, synaptogenesis, synaptic pruning, and myelina- tion, may reveal potential new targets for preventive interventions. These targets might range from more specific reduction of exposures to potential pharmacological approaches that can enhance neurobiological processes or attenuate some of the deleterious effects of adverse environmental expo- sures. Similarly, a greater understanding of the functional activity in neu- ral systems that subserve emotion and behavior might aid in developing improved cognitive training strategies that can protect against the develop- ment of disorder by enhancing regulatory or compensatory systems capable of reducing the risk for psychopathology. Strategies to alter the genome are not a near-term prospect. How- ever, identifying genetic variants that are associated with disorders and understanding the underlying molecular mechanisms may lead to preven- tion strategies based on correcting molecular disturbances in the pathways that lead from genes to behavior, including the molecular pathways that underlie the effects of known risk factors for disorders. Identifying gene– environment interactions can also suggest ways of correcting pathogenic

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45 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE mechanisms that can be used in new prevention strategies designed to target molecular mechanisms and bolster resilience to the effects of adverse environmental exposures. In addition to uncovering causal mechanisms, an improved understand- ing of the genetic determinants of MEB disorders can provide a powerful tool for the study of environmental influences on the development of dis- orders. Accounting experimentally or statistically for genetic determinants allows for a much more powerful and experimentally controllable assess- ment of environmental determinants. Thus, genetic approaches should ulti- mately help to clarify which are the most potent environmental influences in the development of disorders and to prioritize possible biological targets for prevention interventions. Epigenetics research not only provides support for preventive interven- tion approaches, as described in this chapter, but also can lead to novel ways of thinking about the design of new and more effective prevention strategies. For example, although the epigenetic causes of disorders are dif- ficult to disentangle from the more traditional effects of learned behavior, growing knowledge of the epigenetically based, transgenerational transmis- sion of maternal care and other behavioral adaptations to the environment raises the possibility that future prevention approaches targeting epigenetic mechanisms may be able to help break cross-generational cycles of such behaviors as violence and substance abuse. In designing these new interventions, however, it is important to remem- ber that epigenetically transmitted behavioral and emotional dispositions, including stress responsivity, are adaptive for different environmental cir- cumstances (Fish, Shahrokh, et al., 2004). One must therefore take care to ensure that the interventions do not unwittingly produce a mismatch between the newly modified environment and the epigenetically transmitted behavior that was optimized for enhanced survival in the previous, unmodi- fied environment. Such a mismatch could conceivably serve as a risk for pathology, adding a level of complexity to the optimal design of preventive interventions despite the best of intentions in the design and implementa- tion of an intervention. While theories from developmental neuroscience can inform prevention approaches, findings from prevention trials that suggest causal mechanisms should generate hypotheses that can be tested and further elaborated by basic and clinical neuroscientists using animal models and other neuroscience- based approaches. Therapeutic interventions for already-established human disorders generally offer little insight into the causes of disorders. The fact that penicillin treats pneumonia, for example, does not indicate that the pneumonia is caused by a deficiency of penicillin. As discussed in Chapters 4 and 10, prevention trials permit rigorous testing of causal mechanisms, as well as mediating and moderating effects. If designed in

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46 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS partnership with developmental neuroscientists, such trials therefore offer an unprecedented opportunity to evaluate the neurobiological correlates of preventive interventions by identifying and measuring the anatomical, functional, and neural systems–level effects of those interventions. Because longitudinal studies can identify environmental influences on intervention outcomes and phenotypes over the course of disorders, preventive trials also offer a context for evaluating the hypothesized mechanisms and effects of genetic factors by examining how genetic predispositions may inhibit or enhance the effects of an intervention (an example is the study described in Chapter 4 on serotonin transporter genotype in a prevention intervention trial by Brody, Kogan, et al., 2008). Because the effect sizes of interven- tions are often small, this kind of information should help in tailoring an intervention to specific individuals, thereby enhancing the magnitude of its beneficial effects. CONCLUSIONS AND RECOMMENDATIONS Advances in neuroscience since 1994 have contributed to the grow- ing knowledge of the determinants of mental health, the pathogenesis of disorders, and the ways in which the determinants of those disorders can be influenced through intervention strategies. Much evidence points to the central importance of brain development during the prenatal and early postnatal periods and of nurturing care for the development of the neural systems that support healthy attachment, socialization, adaptive learning, and self-regulation throughout infancy, childhood, and adolescence. The growing knowledge base in these areas has important implications in sup- port of strategies to promote healthy cognitive, emotional, and behavioral development and to prevent MEB disorders. Conclusion: Environment and experience have powerful effects on modifying brain structure and function at all stages of development in young people. Intervention strategies that modify environment and experience have great potential to promote healthy development of the brain and to prevent MEB disorders. The growth of knowledge in developmental neuroscience has been particularly rapid in the defining of the roles of genetic, epigenetics, and gene–environment interactions on brain development. First, in the field of genetics, a great deal has been learned about the specific genes and molecular pathways that cause specific but fairly rare neurodevelopmental disorders. These advances have made realistic the previously remote hope that these devastating conditions might one day be treated or prevented. These advances have helped to point the way toward similar progress in

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47 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE understanding more common MEB disorders in children. Technological advances in large-scale, rapid-throughput genotyping have made feasible the study of the genetic vulnerabilities and underpinnings of more common disorders. Second, advances in understanding and identifying gene–environment interactions have illuminated the ways in which specific genetic variants and life experiences both confer risk for and protect against developing MEB disorders. Third, much has been learned about the mechanisms of epigenetic modification of the genome that can confer enduring changes in gene expression and behavior. These epigenetic modifications have provided a much greater appreciation of the importance of biological adaptation of the developing organism to its environment. Bringing together knowledge in these three areas has important implications for the prospects of influenc- ing causal biological pathways through modifications of the environment in new prevention intervention strategies (see Figure 5-3). FIGURE 5-3 Intervention opportunities. Fig5-3.eps bitmap

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48 PREVENTING MENTAL, EMOTIONAL, AND BEHAVIORAL DISORDERS Conclusion: Genetic and other neurobiological factors contribute to the development of MEB disorders in young people, but their relative con- tribution is influenced by environmental factors. Similarly, the effects of environmental manipulations are constrained by genetic and other neurobiological factors. Thus, efforts to understand the neurological basis of cognitive, emo- tional, and behavioral development, and especially to understand how these neural substrates can be modified through environmental intervention, are clearly an important basis for prevention research. Although research efforts are justified for intervention strategies at all stages of development in young people, developmental neuroscience has provided overwhelming evidence for the particular importance of fetal and early postnatal develop- ment for establishing the fundamental anatomical and functional architec- ture of the human brain that will endure throughout life, as well as evidence for the existence of sensitive periods for environmental influences in infancy. Therefore, the prenatal period and early infancy warrant a relatively high level of focus in research efforts. Recommendation 5-1: Research funders, led by the National Institutes of Health, should dedicate more resources to formulating and testing hypotheses of the effects of genetic, environmental, and epigenetic influences on brain development across the developmental span of childhood, with a special focus on pregnancy, infancy, and early childhood. Greater collaboration between prevention researchers and develop- mental neuroscientists could provide a powerful scientific synergy. Theories of pathogenesis derived from developmental neuroscience should inform the design of preventive interventions, and prevention trials should be used to inform and evaluate hypotheses of causal mechanisms derived from devel- opmental neuroscience. Likewise, prevention trials should be designed to identify, measure, and evaluate neurobiological effects as possible mediators in preventive interventions. Hypotheses about causal mechanisms generated from prevention research should be tested and expanded using basic and clinical neuroscience approaches. Conclusion: Collaborations among prevention scientists and basic and clinical developmental neuroscientists could strengthen understand- ing of disease mechanisms and improve preventive interventions by mutually informing and testing hypotheses of causal mechanisms and theories of pathogenesis.

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4 PERSPECTIVES FROM DEVELOPMENTAL NEUROSCIENCE In order to take greatest advantage of the potential for progress through collaboration, more detailed strategies to link prevention science with clini- cal and basic neuroscience are needed. This link needs to be supported both at the level of funding for individual investigators and also at the level of institutional infrastructure and support through funding for multi- disciplinary research consortia. Recommendation 5-2: Research funders, led by the National Insti- tutes of Health, should dedicate resources to support collaborations between prevention scientists and basic and clinical developmental neuroscientists. Such collaborations should include both basic science approaches and evaluations of the effects of prevention trials on neuro- biological outcomes, as well as the use of animal models to identify and test causal mechanisms and theories of pathogenesis. Recommendation 5-3: Research funders, led by the National Institutes of Health, should fund research consortia to develop multidisciplinary teams with expertise in developmental neuroscience, developmental psychopathology, and preventive intervention science to foster transla- tional research studies leading to more effective prevention efforts. A well-supported collaborative research approach of this kind would provide an opportunity to investigate the potential use of genotyping and other biological markers as a basis for indicated prevention strategies. This opportunity needs to be approached with appropriate attention to social, ethical, and legal issues related to the use of individually identified biologi- cal information. Conclusion: The prospect of using genetic and other neurobiological markers to identify young people at risk of MEB disorders raises impor- tant concerns, such as potential stigma, bias, and denial of insurance coverage. However, knowingly withholding scientific knowledge from populations who can benefit from them also raises ethical issues. Recommendation 5-4: The National Institutes of Health should lead efforts to study the feasibility and ethics of using individually identi- fied genetic and other neurobiological risk factors to target preventive interventions for MEB disorders.

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