HUMAN DEVELOPMENT: Biological and Genetic Processes

23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH 10.1146/annurev.psych.56.091103.070208

Irving I. Gottesman Department of Psychiatry and Department of Psychology, University of Minnesota, Minneapolis, Minnesota 55454; email: [email protected] Daniel R. Hanson Departments of Psychiatry and Psychology, University of Minnesota, Minneapolis, and Veterans Administration Hospital, Minneapolis, Minnesota 55417; email: [email protected]

KeyWords adaptive systems, endophenotypes, CNS plasticity, schizophrenia, autism ■ Abstract Adaptation is a central organizing principle throughout biology, whether we are studying species, populations, or individuals. Adaptation in biological systems occurs in response to molar and molecular environments. Thus, we would predict that genetic systems and nervous systems would be dynamic (cybernetic) in contrast to pre- vious conceptualizations with genes and brains fixed in form and function. Questions of nature versus nurture are meaningless, and we must turn to epigenetics—the way in which biology and experience work together to enhance adaptation throughout thick and thin. Defining endophenotypes—road markers that bring us closer to the biological origins of the developmental journey—facilitates our understanding of adaptive or maladaptive processes. For human behavioral disorders such as schizophrenia and autism, the inherent plasticity of the nervous system requires a systems approach to incorporate all of the myriad epigenetic factors that can influence such outcomes.

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. CONTENTS Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org INTRODUCTION ...... 264 COMPLEX ADAPTIVE SYSTEMS IN HUMAN DEVELOPMENT ...... 265 The Meaning of “Gene-Environment Interaction” ...... 265 Epigenesis ...... 266 Endophenotypes ...... 268 Generation and Degeneration as a Continuum of Development ...... 270 BUILDING THE BRAIN FROM THE GENES UP ...... 271 Cellular Differentiation and Migration ...... 271 Angiogenesis ...... 271 PLASTICITY ...... 272 EXAMPLE: AUTISM ...... 274 Epidemiology ...... 274 0066-4308/05/0203-0263$14.00 263 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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Twin Data Paradoxes ...... 275 Phenotypes and Endophenotypes ...... 276 EXAMPLE: OFFSPRING OF SCHIZOPHRENIC PARENTS, CHILDHOOD ONSET CASES, AND COTWINS AS “MEDIA” FOR GROWING ENDOPHENOTYPES ...... 276 Systems Biology ...... 276 Prospective High-Risk Studies ...... 277 Candidate Genes ...... 278 Clues from Childhood Schizophrenia ...... 279 CONCLUSIONS AND A GLIMPSE AT THE FUTURE ...... 279 CONFLICT OF INTEREST STATEMENT ...... 280

INTRODUCTION

Newton’s laws of physics and Einstein’s theories of relativity anchor the physical sciences. Biological sciences have a parallel organizing principle in the concept of adaptation (Holland 1975). Adaptation can be viewed from many perspectives, including adaptation of species, of populations, or of individuals. The time scale for evolutionary adaptation of species occurs over a very long period, measured in multiple generations. During this process, genotypes (DNA) are altered through mutation followed by natural selection to reconﬁgure the architectures of species. Populations adapt on an intermediate time scale that is often within one, or a few, life spans. Genetic diversity reﬂected in population individual differences allows for deployment of different partially heritable skill sets for different challenges. Forexample, human populations have both created and then adapted to the changes from a largely agrarian existence to a complex industrial world within one or two life spans. Individuals adapt over short time frames measured in fractions of a life span. This ability to adapt quickly is an evolutionarily derived trait. We humans, with opposable thumbs, hands freed by upright locomotion, expanded forebrains, and skills with symbolic language, are the most adaptable of all creatures. This chapter is about adaptation and how, in large part, our genetic and biological systems foster adaptation in health and detract from it in illness.

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. By understanding the ramifications of the concept of adaptation in biological systems, most of the details of biological development and behavioral function Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org can be derived (Turkheimer 1998, 2004). In so doing, we quickly confront two old dogmas and hope to teach them new tricks. First, if we accept the idea that our genomes have been “designed” by evolution to maximize adaptability, we could not conclude that genetically mediated traits are fixed and immutable. On the contrary, if our genomes are tuned to maximize adaptability, we would expect genetic factors to play an important role in change even within the individual and over short time frames. The idea that genetic factors influencing behavior are fixed stems mostly from the study of human genetic diseases such as the inborn errors of metabolism and chromosomal anomalies. However, these are examples of broken genes, which cannot be generalized to genes functioning via “rheostatic” control. For example, phenylketonuria (PKU), a recessive disorder producing one kind of mental retardation, is due to a dysfunctional genotype for phenylalanine 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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hydroxylase. In the absence of normal function, people cannot metabolize ubiqui- tous dietary phenylalanine, leading to high concentrations that damage the brain. However, the normal or even half-normal genotype allows the individual to adapt to widely varying amounts of phenylalanine, thus preventing toxic levels even with massive ingestion. The expression of any one gene is embedded within a biological system influenced by a multitude of other genetic and environmental influences; concepts of gene regulation (expression) and epigenesis are now essential for understanding development (Carey 2003, Petronis 2004). The classic Mendelian disorders involve genes that are so broken as to overshadow ancillary modifiers. Such dramatic errors of nature divert us from appreciating the subtle, complex, and dynamic nature of biological systems (Dipple & McCabe 2000) that allows them to be adaptive and self-regulating. Second, it has been a long-held belief that the central nervous system is hard- wired and cannot be changed easily by the time we reach adulthood. From the perspective of adaptability, this would make no sense because we continue to learn, change, and adapt throughout the life span. The brain does change with experience and the underlying physiology is guided by genetic factors (Grossman et al. 2003, Insel & Fernald 2004, Kennedy et al. 2003, Weaver et al. 2002). Just as observations of broken genes lead to the erroneous conclusion that genetic effects are unmodifiable, the observations that broken brains (e.g., stroke, trauma) do not heal has led to the belief that the central nervous system (CNS) is a fixed structure. However, in the intact brain, synaptic connections and neuronal circuits are shaped continuously to enhance adaptation. Everything that is genetic is biological, but not all things biological are genetic. Having stated that our genomes and CNS are designed to promote adaptation, we must then consider to what are the adaptations responding. The obvious answer is the environment. However, a global concept such as environment is not helpful. In the PKU example, environmental factors could mean the difference between normal IQ and mental retardation. But, by “environment,” we are not referring to air quality, climate, economic class, amount of parental affection, or hours spent watching Sesame Street. All of these factors may have an impact on a child with PKU, but the trait-relevant environment is the amount of phenylalanine in the diet by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. (Meehl 1977). Thus, the outcomes for a person with the PKU mutation (genotype)

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org are determined to a large degree by diet (trait-relevant environment), mediated through the biology of phenylalanine blood levels (endophenotype) that affect the eventual IQ (phenotype).

COMPLEX ADAPTIVE SYSTEMS IN HUMAN DEVELOPMENT

The Meaning of “Gene-Environment Interaction” The phrase “gene-environment interaction” is used in a variety of ways and with avariety of meanings (Carey 2003, pp. 291–297; Rutter & Silberg 2002). A few words of clariﬁcation are offered as a prelude to the discussion following about 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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epigenesis. The G × E interaction concept originated from early quantitative genetics (Falconer 1960), especially agricultural genetics, and represents, in a strict sense, an interaction effect in an analysis of variance. As such, G × E interaction means that different genotypes respond differently to different environments. As a quick example, suppose you took some rice seeds and wheat seeds (the different genotypes) and planted some of each in wet conditions and some in dry conditions (the different environments). In the wet conditions, the rice grew vigorously but the wheat drowned and failed. In the dry condition, the wheat thrived but the rice withered. Another way to phrase the gene environment interaction concept is to indicate that both genes and environment make a difference for the development of some trait. Height is a simple example: A person’s height depends on genes promoting height as well as on good nutrition. No matter what your genotype, good nutrition will help individuals grow to their full potential. However, no matter what the genotype, good nutrition always works in the same direction to enhance height. This may be thought of as coaction, but it is not G × E interaction in the strict analysis-of-variance sense. The study of human development does not allow the easy quantification and manipulation of genetic and environmental variables in the same manner as agricultural genetics, thus limiting our abilities to assess G × E interaction in the analysis-of-variance sense. Simple additive models that suggest the phenotype is the sum of environmental and genetic effects do not conform to biological realities (cf. Meaney 2001). The additive model reduces human development to a simple recipe, but there is more to it than adding two parts genes to three parts environment plus a pinch of luck. Turkheimer and colleagues (Turkheimer et al. 2003) demonstrate that socioeconomic status modified the heritability of IQ in a nonlinear fashion such that, in impoverished families, 60% of the variance in IQ was attributed to shared environment, and genetic effects were negligible; in affluent families the reverse was true. Thus, the concept of gene-environment interaction, however defined, is difficult to apply in studies of human development (Caspi et al. 2002, 2003; Gunnar 2003; Kagan 2003). A further limitation of simple G × E interaction models arises from by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. the fact that gene expression is dynamic over time. This is illustrated by studies of

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org the effects of caloric restriction on longevity. When mice were placed on restricted diets, there was a rapid change in the expression of genes associated with longevity, including genes involved in metabolism, signal transduction, stress response, and inﬂammation (Dhahbi et al. 2004). To introduce a dimension of time into human developmental models and to allow for changes in both the environment and the expressed genotype, the concept of epigenesis is rapidly supplementing the ideas of gene-environment interaction.

Epigenesis The term epigenesis originated with embryological theories suggesting that complex organisms originate from undifferentiated cells, and the term has been broadly 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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defined to include all the forces that lead to the phenotypic expression of an individual’s genotype (Petronis 2000, 2004; Waddington 1957). Gottesman & Shields (1972) transduced this concept of epigenesis into human behavioral genetics in the early 1970s, with later elaboration (Gottesman et al. 1982). The definition of epigenetic continues to evolve and, to many molecular biologists, the term refers to the mechanisms by which cells change form or function and then transmit that form or function to future cells in that cell line (Jablonka & Lamb 2002, Jaenisch & Bird 2003, Morange 2002). Examples include transformation of an undifferentiated embryo cell into a liver cell or transformation of a normal liver cell into a cancerous cell. Once a cell type acquires a new form through selective gene expression and environmental influences, that cell, through cell division, transmits that acquired characteristic to future cells in the lineage. The previously spurned concept of the inheritance of acquired characteristics is resurfacing at the molecular level (Varmuza 2003). The best-studied mechanisms for the epigenetic regulation of mammalian gene expression involve the addition of a methyl group to cytosine that, along with ade- nine, thiamine, and guanine, forms the four-letter alphabet of DNA. This methylation of cytosine changes the configuration of the DNA such that the genetic information encoded in that area cannot be read and is nullified (Jaenisch & Bird 2003, Jones & Takai 2001)—the gene essentially is turned off. Conversely, remov- ing DNA methylation allows the gene to be expressed. The variety of factors that influence DNA methylation is huge and includes such things as developmental processes, diet, viral infections, aging, and chance. Failure of methylation systems leads to clinical syndromes, such as Rett syndrome, that involve mental retardation, autistic-like behaviors, and other neurodevelopmental anomalies in girls (Shahbazian & Huda 2002). The impact of prenatal and early postnatal nutrition on the adult development of type 2 diabetes, cardiovascular disease, obesity, and cancer are also thought to be mediated by epigenetic factors mediated by DNA methylation (Waterland & Jirtle 2004). Such epigenetic mechanisms may explain why maternal behavior toward young offspring affects the size of the offspring’s hippocampus in adulthood, depending on the offspring’s genotypes (Weaver et al. 2002). More speculatively, epigenetic theorizing is being applied to the develop- by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. ment of schizophrenia (Petronis et al. 2003) and depression (Caspi et al. 2003,

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org Charney & Manji 2004). Although not approaching a biochemical analysis, even traits such as talent are being rethought in epigenetic terms (Simonton 1999). Epigenetic perspectives grapple with the complexities of how multiple genetic factors and multiple environmental factors become integrated over time through dynamic, often nonlinear, sometimes nonreversible, processes to produce behaviorally relevant endophenotypes and phenotypes. How an embryonic cell differen- tiates into a liver cell while a genetically identical cell in the same embryo develops into a neuron is an epigenetic question. Identical twins discordant for a given trait or disease provide other examples of epigenetic processes (Cannon et al. 2002, Pol et al. 2004, van Erp et al. 2004). Diverse reviews of epigenetic concepts relevant to human development are available (Gottesman & Gould 2003, Nijhout 2003, Petronis 2000, Petronis et al. 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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2003, Sing et al. 2003). A stellar example of a systems biology approach to studying epigenesis is in the research mapping the developmental sequences in the sea urchin from fertilized egg onward (Davidson et al. 2002). Epigenetic thinking builds on the notion that only a small fraction of our DNA codes for structures (proteins, en- zymes, etc.) while, in keeping with the central theme of adaptation, the majority of our DNA codes for regulatory processes. In response to transduced environmental stimuli, genes are turned on or off as the organism proceeds through life. At any time, any one genotype may have a wide array of potential phenotypes. The actual phenotype will depend on the influence of the individual’s other genes and on the specific contexts of environments experienced among a wide range of possible environments. Which environment is experienced may be stochastic (luck) or may be a function of the individual’s past phenotypes. Indeed, an individual’s phenotype (which is partially a result of his or her genotype) may lead the individual to select environments, thereby establishing a correlation between genotype and environment (Carey 2003). The array of possible outcomes could be plotted, in theory, in multidimensional space, as functions of genotypes, environments, and time. The plot would produce an undulating surface that would represent the phenotype for that unique combination of genotype, environment, and time. Such a surface has been referred to as a reaction surface (Gottesman & Gould 2003, Sing et al. 2003) or phenotypic surface (Nijhout 2003); these articles provide informative graphics. Figure 1 provides such an example (Manji et al. 2003) applied to the ontogenesis of schizophrenia with provision for the changing reaction surface and a threshold, suggested endophenotypes, some already connected to candidate genes, and a dimension of environmental inputs (harmful versus protective), all “bathed” in epigenetic influences. Endophenotypes One of the primary obstacles to progress in connecting the genotypic contributors to many human phenotypes is that the traits submitted to genetic analyses lack biological meaning. It is a long road from genotype through epigenetic pathways to ultimate phenotype, as seen above. When we study the product of this process that

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. may have encompassed decades, we often have too much “pheno” and not enough “geno” to make sense of the trait. What is needed is some kind of intermediate Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org trait that sits closer to the genotype in the developmental scheme. In spite of the best efforts to improve the reliability of psychiatric classiﬁcation, the diagnoses in the ofﬁcial nomenclatures are still syndromal and lack validating pathophys- iological markers. Traits such as IQ and personality have demonstrable genetic effects, but efforts to understand the genetic component suffer from the lack of any intermediary connection between the behavior and the biological underpinnings. The missing links have been referred to as “endophenotypes” (Gottesman & Gould 2003). Alternative concepts with similar but different meanings include “biological markers,” “intermediate phenotypes,” “risk factors,” “vulnerability markers,” and “subclinical traits.” Attempts to develop those that are genetically mediated endophenotypes would require that: 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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1. Endophenotypes would be associated with the trait in the population. 2. The endophenotype would be demonstrably heritable. 3. The endophenotype is present whether the trait/disease is or is not present (e.g., vulnerability marker). 4. Within families, endophenotype and trait cosegregate (but not perfectly; see 3 above). 5. The endophenotype found in families with the trait (especially an illness) is found in nonaffected family members at a higher rate than in the general population.

An instructive example comes from cardiology and the long QT syndrome. It was known that phenotypes including syncope, ventricular arrhythmias, and sudden death aggregated in families. The common denominator turned out to be QT elongation on electrocardiogram. Using QT elongation as the endophenotype, and by excluding or including family members with this finding, genetic linkage studies were successful in identifying the associated genes (Keating et al. 1991, Keating & Sanguinetti 2001). Putative endophenotypes for schizophrenia include, but are not limited to, those shown in Figure 1. Current strategies for identifying behavioral phenotypes such as psychiatric diagnoses, cognitive abilities, personality traits, or special talents all lack a biological “handle” to submit to genetic analysis. A search for endophenotypes will move us closer to establishing the biological underpinnings of these traits. Returning to the criteria for an endophenotype, we can observe that most implicate features that are closer to the phenotype end of the genotype-to-phenotype pathway. What will we do when we finally traverse the entire phenotype-to-gene pathway and discover the genetic contributors to the trait under study? More than 40 years ago, in a remarkably prescient anticipation of epigenetic and endophenotype thinking, Paul Meehl (1962) emphasized a perspective closer to the genotype end of the pathway. Writing about schizophrenia, he cautioned that knowing “specific (genetic) etiology” does not imply any of the following (p. 828):

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. 1. The etiological factor always, or even usually, produces clinical illness.

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org 2. If illness occurs, the particular form and content of symptoms is derivable by reference to the specific etiology alone. 3. The course of the illness can be influenced materially only by the procedures directed against the specific etiology. 4. All persons who share the specific etiology will have closely similar histories, symptoms, and course. 5. The largest single contributor to symptom variance is the specific etiology.

Meehl offered these cautions not to suggest hopeless complexity but to challenge us to rethink our received paradigms (Hanson 2004) and to underscore the importance of epigenetic perspectives. 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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Generation and Degeneration as a Continuum of Development Concepts of epigenesis and endophenotypes help us climb out of our paradigm ruts toward understanding disease states. When things go wrong in the course of our lives, we tend to classify the cause of the problem either as a phenomenon of faulty assembly (developmental models) or of breakdown after normal function (degenerative models). Degenerative models of adaptive failure imply that after a period of normal development, the organism, or one of its parts, takes an unhappy turn in life trajectory and begins to disintegrate. This, of course, describes the eventual outcome for all life forms and is a biological restatement of the second law of thermodynamics. Because degeneration is (eventually) universal, stating that an illness is degenerative is not particularly enlightening. It would be helpful to determine when in the life course the degeneration begins, and how. Answers to the “when” and “how” questions would describe the degenerative process in developmental terms. Developmental models of adaptive dysfunction (Grossman et al. 2003) implicate early brain development as setting the stage for the future (Monk et al. 2001, Webb et al. 2001). The proponents of the developmental models further argue that the perturbations of development are limited to the early times of development and are not continuous. Without this qualiﬁer, developmental models are indistin- guishable from degenerative models where the degeneration starts early in the life span (Lewis & Levitt 2002). The early abnormalities are not necessarily the cause of adaptive failure, but instead create a vulnerable risk state for future dysfunction. Consequently, there must be factors later in life that convert the vulnerability to an actuality. These additional factors are presumed to somehow damage development in such a way that dysfunction becomes manifest (cf. Sing et al. 1994). To gain a complete understanding of the syndrome, we must return to the questions of what happens and when. Following this line of reasoning, the distinction between degenerative and developmental models blurs. In fact, a medical-behavioral condition can be both developmental and degenerative, as exempliﬁed by Down syndrome (Head & Lott

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. 2004, Kornberg et al. 1990, Opitz & Gilbert-Barness 1990). Individuals with tri-

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org somy 21 exhibit a number of developmental anomalies, including cardiac malfor- mations, abnormal dermatoglyphics, skeletal changes, and muscular hypotonia. As infants with trisomy 21 mature, they exhibit mental retardation. By about age 50, these individuals invariably develop Alzheimer-like CNS degenerative changes. Given the above cited evidence that prenatal and neonatal nutritional deﬁciencies (developmental) lead to adult diseases such as cancer and heart disease (usually thought of as degenerative), we need to redirect our thinking away from developmental versus degenerative dichotomies just as we have moved away from the nature versus nature mind-sets (Gottesman 2001). In his book Unheard Cry for Meaning,Viktor Frankl (1978) suggested we are not fully developed until we die—we continue to change right up to the last moment of life. Generation and degeneration go hand in hand as we traverse our own epigenetic landscapes. 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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BUILDING THE BRAIN FROM THE GENES UP Cellular Differentiation and Migration Our brains can be simpliﬁed schematically into three primary components: neurons, glia, and the vascular system. Conventionally, the neuron has been the target of attention in the study of human behavior. This is especially apparent in the various neuronal transmission theories of mental illness where there has been a preponderant focus on dopaminergic function in schizophrenia, and serotoner- gic and noradrenergic transmission in affective (mood) disorders (Schatzberg & Nemeroff 2004). However, neurons comprise only about 50% of brain volume. Glial cells, which comprise close to the additional 50%, are receiving increasing attention for their possible role in behavioral disorders (Moises et al. 2002). A third component of the CNS, the vascular system, comprises only about 0.1% of total brain volume, but this small component forms the “blood brain barrier” and plays a vital role in regulation of brain metabolism (Schusta & Boado 2002). Development of the brain starts in the primordial inner layer of the neural tube with totipotent stem cells that differentiate into neurons and glial cells (Monk et al. 2001, Webb et al. 2001). Brain development proceeds through prolifera- tion and migration of neurons and glia responding to epigenetic regulation of a large spectrum of genes coding for growth factors. Some neuroblasts move by radial migration, building tissue from the inner depths to the outer layers of cortex (Mehler & Kessler 1999, Nadarajah & Parnavelas 2002). In radial migration, neurons formed in proliferative tissues zones move perpendicular to the brain surface following radially oriented glial ﬁbers. Tangential migration connects brain components across regions when neurons moving parallel to the brain surface following precursor neurons. A multitude of genetic factors guides the migratory processes. Mutations in these genes prevent normal migration and have behavioral consequences (Nadarajah & Parnavelas 2002, Taylor et al. 2004). One of the migration modulators, reelin, has received particular attention in relation to autism and schizophrenia. Glial cells continue to play important roles in regulation and repair in the adult

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. brain (Jessen & Richardson 2001, Levine et al. 2001). Additionally, astroglia

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org cells act as intermediaries between neurons and the vascular system. The cell bodies have two arms; one reaches out and embraces the neuron while the other reaches out to the microcapillaries and is interspersed with cells of the capillary endothelium.

Angiogenesis The brain does not work well if deprived of adequate blood ﬂow. Because the CNS has virtually no reserves of energy and cannot function on anaerobic metabolism, the brain requires constant and precise delivery of glucose and oxygen. Devel- opmentally, the CNS vascular system originates from mesodermic capillary endothelial cells that migrate into developing neuroexoderm under the inﬂuence of 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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neuron-derived trophic factors such as vascular endothelial growth factor (Risau et al. 1998) and erythropoietin (Sasaki 2003), both produced by astroglia. Rather than being a passive conduit, the CNS vascular system is the most pre- cisely managed and complex fluid dynamic system known. Regulation of cerebral blood flow (Kety & Schmidt 1948) is managed primarily by a partnership between astrocytic glial cells (Coyle & Schwarcz 2002, Haydon 2001, Kurosinski & Gotz 2002) and capillary endothelium (Abott 2002, Kety & Schmidt 1948, Medhora et al. 2001, Paulson 2002, Virgintino et al. 2002, Yoder 2002, Zonta et al. 2003). Astrocytes sense local neuronal metabolic activity and adjust blood flow as needed. Cerebral vessels change diameter in response to vasoactive substances released by astrocytes activated by glutamate receptors, serotonin (Cohen et al. 1999), acetylcholine (Elhusseiny et al. 1999), and dopamine (Bacic 1991, Favard 1990). When neuronal activation of discrete areas is sustained over longer periods, vasoactive substances stimulate angiogenesis (blood vessel formation), resulting in capillary density increases (Harder et al. 2002) and thus enhancing local neuronal circuitry. Conversely, a decrease in capillary density is likely to reduce the functional capac- ity of brain areas so affected (Harder et al. 2002). Consequently, capillary beds in the cortex are not distributed uniformly (Cavaglia et al. 2001). Close relationships exist among local neuronal activity, density of capillary bed, and the distribution of valve-like flow control structures (Harrison et al. 2002). The growing awareness of the dynamic circulation of the CNS vascular flow has important consequences for studying CNS metabolic activity. Imaging studies (e.g., fMRI, positron emission tomography) assume the vascular flow is a constant, so a measured change in cerebral blood flow is attributed to reduction in neural activity. However, we must consider reversals of the causal arrow, with the possibility that a primary vascular disease leads to the deranged cell metabolism, as is being considered in Alzheimer disease (Borroni & Akkawi 2002, Preston & Steart 2003).

PLASTICITY

Psychologist D.O. Hebb postulated more than a half century ago that experience by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. modiﬁes cortical connections (Hebb 1947, 1949), yet the adult brain has been

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org primarily viewed as a ﬁxed structure (Grossman et al. 2003, Webb et al. 2001). Recent developments indicate Hebb was correct and that the brain is constantly changing in response to experience. The changes in synaptic connections and recruitment of expanded representational areas devoted to a particular function are referred to as plasticity. Plastic changes are associated with learning/memory, skill acquisition, recovery from injury, and even addiction. A myriad of factors inﬂuence brain plasticity, including pre- and postnatal experience, genes, drugs, hormones, maturation/aging, diet, disease, stress, and trauma (Kolb et al. 2003). Details of the molecular mechanisms of CNS plasticity are beyond the scope of this chapter; we limit ourselves to a few examples. Hodge & Boakye (2001) and Johansson (2000) review details about molecular mechanism. Thompson & 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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Nelson (2001), Shonkoff (2003), and Grossman et al. (2003) summarize many of the social-political ramifications of the growing understanding of brain plasticity. Much of the recent progress in understanding brain plasticity in humans has been made possible by advances such as fMRI (Casey 2002), which has been used to demonstrate and map plasticity, as well as to partial out effects due to maturation, per se, versus experience/practice. Some of the most detailed research on plasticity comes from studies of musicians; their skill development involves unlearning of existing synaptic connections and establishment of new sensory-motor-memory-affective connections (cf. Peretz & Zatorre 2005). The virtuoso performance involves memorizing the music at the motor level, coordinating tactile and auditory sensory inputs, and adding an emotional interpretation that transcends the mechanical reproduction of notes. However, remodeling the brain to achieve such feats involves risks as well. Gui- tar players, for example, are subject to dystonic movements of their hands that, alternatively, are described as an overuse syndrome. Pascual-Leon (2001) has demonstrated with fMRI that musicians with motor dystonias showed significantly greater activation of contralateral sensorimotor cortex and conspicuous bilateral underactivation of premotor areas. The authors suggest that extensive practice of coordinated hand motions in which fingers function as a single unit might induce changes in sensory-motor field representation of the hand with blurring of the normal separation of each digit. Another illustration of the downside of CNS plasticity comes from addiction research (Ujike et al. 2002). Behavioral sensitization to addicting drugs arises from structural modification of neural networks. Repeated exposure to amphetamines and cocaine alter the cytoarchitecture of the nucleus accumbens and frontal cortex by increasing the length of dendrites and the density of dendritic spines. These changes are regulated by a host of genetic factors regulating synaptogenesis, including genes for neurite sprouting, neuritic elongation, and cell division regulators throughout the brain. The tenacity of addictions is then explained by the difficulty of remodeling these drug-induced structural changes or, possibly, by long-term al- teration in gene expression supporting the CNS-mediated behavioral sensitization to the drugs. by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. Responses to stress, including the development of depression and stress syn-

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org dromes such as posttraumatic stress disorder, are attributed to failures in CNS plasticity, more so in predisposed persons. Chronic stress is implicated in CNS signal transduction cascades that normally allow neuronal plasticity. Chronic stress dam- ages a wide variety of plasticity modulators and, at the biochemical level, causes a reduction in expression of genes associated with synaptic plasticity, resulting in diminished frontal cortical activity (Kuipers et al. 2003). Assembling and maintaining the brain involves a sometimes choreographed and sometimes extemporaneous dance among the partners of neuron, glia, vascular supply, and experience. Damage to the brain interrupts this performance. Repair may be more an issue of probabilities than of potentials. Damage does not mean that the dancers will never dance again. However, the probability of exactly 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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repeating the prior performance is extremely low. Efforts focused on CNS repair are increasingly using epigenetic strategies to modulate gene expression in tissues combined with intensive rehabilitative experiences. It is too early to talk about gene transplants.

EXAMPLE: AUTISM

Some 30 years ago, we (Hanson & Gottesman 1976) reviewed the scant literature on the genetics of autism and early onset schizophrenia and concluded that autism was not connected genetically to schizophrenia, an opinion that has been sustained (Gousse et al. 2003). We also found little in the extant literature providing convinc- ing evidence for genetic factors in autism. Over the ensuing years, this opinion has been overruled so that it is common to ﬁnd opinions in the literature that autism is strongly genetic (Muhle et al. 2004). Within the Annual Reviews series, there are numerous comprehensive reviews of genetic factors in autism (Cowan et al. 2002, Plomin & McGufﬁn 2003, Veenstra-VanderWeele et al. 2004) and it would be redundant to repeat them. Instead, we will take an epigenetic perspective to examine the consensus evidence and highlight topics needing more research.

Epidemiology Published prevalence rates for autism and autism spectrum disorders have sky- rocketed from early estimates of 1 case in 10,000 to rates as high as 60 in 10,000 (Fombonne 2003). This rise in a few decades is much too fast to be blamed on genomic changes. If the increase is real and anywhere near this dramatic, it would implicate a dramatic rise in the environmental contributors that could involve epigenetic regulation of genetic factors. Continuing public expressions of concerns that agents used to immunize infants could be such a factor cannot be substanti- ated by careful epidemiology (DeStefano 2002, DeStefano & Thompson 2004). An analysis of pervasive developmental disorders in Israeli residents compared to immigrants to Israel from Ethiopia found much lower rates in the Ethiopians,

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. which could point to environmental factors in the industrialized setting compared to nonindustrial environments; barriers to migration of Ethiopian families with PDD Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org children is an alternate explanation (Kamer et al. 2004). The consensus explanation for the increased rate of autism-like disorders is that the changes are most likely due to broader definitions of the illness and improved case finding (Fombonne 2003, Gernsbacher et al. 2004, Lingam et al. 2003, Wing & Potter 2002). One epidemiological finding that remains undisputed is the higher rate of autism (299.00 in the DSM) in males as compared to females, a factor of about 4:1. The difference may even be greater as broader definitions of the disorder are applied (Veenstra-VanderWeele et al. 2004). Despite common knowledge of this fact, gender is rarely taken into consideration in genetic analyses of autism spectrum disorders. Countless linkage studies implicate loci on autosomes (especially chromosomes 2, 3, and 7). However, autosomes are freely exchanged between the 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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genders and could not account for the gender differences in prevalence of autism. If autosomal factors were involved, then gender-related epigenetic differences, possibly hormonal, would have to be invoked to explain the gender differences. Alternatively, genes on the X chromosome could explain the gender differences if they were expressed as partial Mendelian recessive traits. Genetic modeling for X-linkage would lead to testable hypotheses. Alternatively, multifactorial threshold models of transmissions would lead to the prediction that the lower frequency group (females in this case) would have higher loadings of the risk factors, thus their siblings would have higher risk compared to the siblings of affected males. Future genetic studies will benefit from capitalizing on the clues provided by the apparent different expressivity in girls versus boys. Simply invoking the notion that males appear more vulnerable to development insults is not a sufficient response because there still must be detailed explanation for the vulnerability. Twin Data Paradoxes Much of the support for a genetic component in autism came from the study of twins (see reviews cited in the Epidemiology section above). The twin data consistently show high concordance rates in identical twins (monozygotic, MZ) in the range of 60%–90%. By contrast, fraternal twins (dizygotic, DZ) have a low concordance rate, typically close to zero and ranging up to 10% with large standard errors, given the rarity of such samples. Fraternal twins are genetically no more similar than ordinary siblings, and the DZ twin concordance falls in the same ballpark rate of 4%–5% as siblings of autistic people also being affected. Two issues arise. First, for twin studies to be valid, the trait under study cannot be an outcome simply of the twinning process. Twin pregnancies are considered high risk and are associated with increased rates of a wide range of developmental disorders, including mental retardation and cerebral palsy. Two recent reports indicate that autism is more prevalent in twins, suggesting the twin method may not be completely valid for this trait (Betancur et al. 2002, Greenberg et al. 2001). Counterarguments suggest diagnosis inflation and that sampling artifacts could explain the perceived increased rate of twins with autism (Visscher 2002). Other studies fail to find increased

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. twinning among people with autism (Hallmayer et al. 2002). Patience is called for as the debate goes on (Hodge et al. 2002) and we await the deﬁnitive answer from Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org population-based international collaborative studies of autism in twins following the precedents applied to the study of cerebral palsy (Petterson et al. 1993, Scher et al. 2002) and the discovery of how environmental factors such as infection, in combination with inherited variations in response to infection, can lead to cerebral palsy (Gibson et al. 2003, Nelson & Willoughby 2000). The very high concordance rates for autism in MZ twins in contrast to very low concordance rates in DZ twins gives rise to very high heritability estimates for autism when these twin rates are plugged into standard formulas for com- puting heritability from twin data (Carey 2003). At the same time, the low DZ concordance rates (often zero) and low sibling risk rates suggest that autism has low recurrence risks or transmissibility. As a counterpoint, consider a trait like 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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Huntington disease. This also rare autosomal dominant disorder is little modified by environmental factors (highly genetic), and the disorder conveys risks of 50% to DZ twins or siblings (highly transmissible). For autism, the high heritability contrasted with the low transmissibility creates dissonance in genetic theorizing, especially given the “background noise” of 3%–5% rates of serious developmental disabilities in the general population. A simple explanation is that genes really are not so important after all. Alternatively, epistasis (gene x gene interaction within and across loci) could be invoked—it is more the combination of genes than the specific genes that holds the key to this illness. Another possibility is that an epigenetic or chance change in the germ line leads to autism (Keller & Persico 2003). Once we figure out the heritability versus transmissibility issue, we will then have to understand why it affects males more than females.

Phenotypes and Endophenotypes Autism is certainly heterogeneous, etiologically and clinically. Known genetic conditions with autism-like characteristics include syndromes of tuberous sclerosis, fragile-X, and Prader-Willi, Angelman, Rett, and various chromosomal abnormalities, to name a few (Gillberg & Coleman 2000). Individuals with the syndrome may or may not have evidence of in utero growth retardation, EEG abnormalities or epilepsy, profound (IQ < 50) intellectual impairment, increased head growth in infancy (Courchesne et al. 2003, Lainhart 2003), altered immune systems (Licinio et al. 2002, Lipkin & Hornig 2003), structural brain abnormalities on MRI (Brambilla et al. 2003), and altered neuroarchitecture (Casanova et al. 2002, 2003). Developmental characteristics such as these may point to endophenotypes that are more suitable for genetic analysis than are the phenotypes based on overt behavioral syndromes utilized by our current clinical diagnoses (Baird et al. 2003). While we laud the efforts to further reﬁne the behaviorally based assessment strategies (Constantino et al. 2004), it is our bias to look for classiﬁcation strategies that incorporate biological as well as behavioral characteristics. The use of eye tracking technology to assess social visual pursuit in autism (Klin et al. 2002) is one such example. Returning to our earlier comments on adaptation, we can view behavior

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. itself as an evolutionary strategy to maximize adaptability. However, the resulting

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org variability of human behavior may mean that strictly behavioral phenotypes are too imprecise to lead us to the neurobiological and genetic underpinnings of disorders such as autism.

EXAMPLE: OFFSPRING OF SCHIZOPHRENIC PARENTS, CHILDHOOD ONSET CASES, AND COTWINS AS “MEDIA” FOR GROWING ENDOPHENOTYPES

Systems Biology Our next exemplars maintain a focus on the biological and genetic processes that affect developmental psychopathology by examining recent research on the 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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precursors to adult schizophrenia, childhood onset schizophrenia, and pervasive developmental disorders (but not autism, already discussed above). We have tried to select research that emphasizes a systems biological strategy (Sing et al. 1994, Zerba et al. 2002)—everything involving brain and behavior is connected to everything else—to integrate across the regions of Figure 1. Excellent reviews com- plement our selections (Cowan et al. 2002, Erlenmeyer-Kimling 2000, Kennedy et al. 2003, Lewis et al. 2003, Walker et al. 2004). Keeping track of the “gene of the month” in regard to the psychoses is a full-time occupation that can be mentioned only brieﬂy. Contrary to some jaundiced views of such enterprises, replications of candidate genes and new candidates are here to stay; a good two-dozen candidate genes, each of modest impact on total liability to developing schizophrenia in their respective populations, deserve attention and following up (Lewis et al. 2003, McGufﬁn 2004, Moises et al. 2004, Owen et al. 2004, Sklar 2002).

Prospective High-Risk Studies Prospective longitudinal studies of the offspring born to schizophrenic parents have been a staple in the search for antecedent traits and endophenotypes related to schizophrenia even though they may require 30 or more years of intensive efforts. The high-risk strategy exempliﬁes a systems approach by the breadth of variables studied including genetics, birth and pregnancy complications, and a host of behavioral variables followed developmentally over decades. The strategy (Pearson & Kley 1957) was suggested with the foreknowledge that 10% or so of such children in such cohorts would go on to develop the illness, thus permitting the observation of illness precursors unconfounded by the effects of the illness per se. Adoption strategies reinforced the continuing efforts by showing that rearing by ill parents was not essential for the dire outcomes (Ingram & Kety 2000, Tienari et al. 2003), and left open the question as to the role of other contributors to liability that were not genetic (cf. Murray et al. 2003). The theme of the endophenotype strategy (Glahn et al. 2004, Gottesman & Gould 2003, Lenox et al. 2002)

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. embedded within a systems biology context is straightforward: deconstruct the disease phenotype into its precursors and correlates not available to the naked Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org eyeorear (neurocognitive tasks, measured personality indicators, fMRI, neuronal growth factors, etc.), and focus on those that are heritable with implied genes and their polymorphisms as distal causes in the complex genes-to-behaviors pathways. Identify the polymorphisms and then explore their expression over the life course, sensitive to the agents of epigenetics. The process may also begin at the genotype level, reversing the plan of research, and starting with those genes now being implicated by whole genome scans that rely on patients and controls without involving relatives (Lewis et al. 2003, Owen et al. 2004). Many of the genes identiﬁed do not yet have known disease polymorphisms or CNS-impacting functions, as it is still early in the game (Merikangas & Risch 2003, Varmus 2002). The New York High-Risk Project systematically sampled 358 children ages 7to12, starting in 1971, whose mothers or fathers were in one of three groups: 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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schizophrenics or affectively ill who had been admitted to a state hospital, and community controls without psychiatric diagnoses or treatment. Erlenmeyer-Kim- ling (2000), after Herculean efforts, followed these offspring through seven rounds of testing until the late 1990s (when the mean age of the offspring was the early thirties), by which time 15%, 7%, and 1% of each of the respective risk groups had developed a schizophrenia-related psychosis (only Sample A, the first half, is reported here). Because their data were gathered prospectively, the researchers could look back to see which neuropsychological indicators (cf. Meehl 1962), if any, would have predicted the outcomes. Briefly, three sets of indicators, when con- figured, yielded noteworthy results. Using a criterion of failure on all three indicators in early childhood—attentional deviance index, verbal short-term or working memory index, and impairment (subtle) in gross motor skills index—the sensitiv- ity of the battery correctly predicted for 50% of the offspring of schizophrenics, with a false positive rate of 10.4%. The battery was 100% accurate in not predict- ing any child in the other two groups as a future sufferer from a schizophrenia- related psychosis. Thus, a foundation has been laid for carrying out the remaining steps in the larger strategy, with some of the evidence for success illustrated in Figure 1.

Candidate Genes The COMT gene on the long or q arm of chromosome 22 at band 11 has at- tracted considerable attention as a candidate gene for schizophrenia given (a) its involvement in coding for a dopamine enzyme and its functional mutations, (b) its overlap with the gene deletion leading to velocardiofacial syndrome or DiGeorge syndrome, wherein excess diagnoses of schizophrenia are seen in some samples (Ivanov et al. 2003), and (c) research programs connecting COMT polymorphisms to measures of frontal lobe function such as working memory in patients (Egan et al. 2001, Malhotra et al. 2002). The genetic association with schizophrenia is equivocal in that a box score shows four positive and four negative results (Owen et al. 2004). Studies of mice with a deletion in the equivalent region of their genome

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. provide interesting and encouraging leads (Maynard et al. 2003). The mix of data requiring integration to this COMT story includes data from studies of unaffected Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org relatives of schizophrenic patients (Goldberg et al. 2003) and of normal children. Diamond et al. (2004) looked at COMT polymorphisms in 39 children under age 12 (mean = 9) who had been tested with a variant of the Stroop test and two control tasks. Their results showed that only some of the supposed prefrontal cortex cognitive functions were sensitive to the dopamine levels inferred from the genotypes, adding to the complexity of what is being tested in the brain–behavior relationship. The story and the validity of genes in the 22 q region, as with all of the other promising candidates already in hand and about to be reported, leave many hurdles left to be traversed successfully; many will fail the tests and others will open windows to neighboring genes that were not even suspected beforehand (Mowry et al. 2004). 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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Clues from Childhood Schizophrenia Childhood onset schizophrenia (COS) cases, although rare, are considered especially valuable for casting light on the biology and genetic processes of adult onset cases. Criteria are not different for COS, but the criteria are met before the thir- teenth birthday. Cases of COS appear to be more severe and more homogeneous, with more familiality for schizophrenia spectrum disorders (Asarnow et al. 2001, Hanson & Gottesman 1976, Nicholson et al. 2003). We would expect COS to have a larger dose of the genes that predispose to schizophrenia as well as to have biology that, if different, cannot be attributed to the wear and tear that confound the phenotypes of adult cases. Lingering problems about the diagnostic overlaps in COS are a challenge to unraveling etiologies. Psychosis not otherwise specified (NOS), pervasive developmental disorder (PDD), and numerous organic diseases of the CNS have symptoms that overlap one another (Sporn et al. 2003, 2004). An important observation made on follow-up of psychotic children with an initial diagnosis of psychosis NOS was that 13 of 27 were diagnosed as bipolar disorder (Addington et al. 2004). In that same study, G72—a gene at 13q33.2—was found to be significantly associated with both COS and early onset bipolar cases; the gene is one of those already with replicated positive results in adult cases of schizophrenia (Owen et al. 2004). Sporn et al. (2003) have observed a likely biological marker in 60 COS cases; a “striking progressive reduction in cortical gray matter volume” was detected with MRI at the follow-up time into adolescence of the COS cases. Altered cortical thickness and surface morphology possibly due to aberrant cellular migration patterns may provide another marker (White et al. 2003). With the growing interest in discovering endophenotypes and the availability of advanced imaging techniques has come a renewed interest in studying identical and fraternal twins with the new equipment. The findings are too new to be integrated into this review, but they can be expected to provide important milestones on the research road map in Figure 1 (Cannon et al. 2002, Pol et al. 2004, Torrey et al. 1994).

CONCLUSIONS AND A GLIMPSE AT THE FUTURE by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. The charge of responsibly overviewing—while being limited to a ﬁnite number of Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org words—a “planet” in the solar system of the planet Psychology is both a daunting and enlightening task: daunting because conscientious and highly motivated sci- entists have produced too many important, and less important, advances since the subject was last reviewed; enlightening because it compels opening one’s mind to the fact that our planet is so enmeshed with others in the system that no one or even three topical Annual Reviews chapters could accomplish the mission of summarizing selected and relevant nuggets of wisdom. These points are made obvious by what is present and even more so by what has been omitted from our cited literature. We hope we will be accused of stretching your mind muscles but not of spraining them if our reach sometimes exceeded our grasp. Consider each citation as a seed for turning on an Internet search engine with a mission of 23 Dec 2004 19:46 AR AR231-PS56-10.tex AR231-PS56-10.sgm LaTeX2e(2002/01/18) P1: IKH

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incorporating biology and genetics into your own research program—you will be pleasantly surprised by the planets you encounter and what they are doing there that is relevant to your own work. Incorporation followed by integration will take place, we predict, and you will discover the beneﬁts of hybrid vigor for yourselves.

ACKNOWLEDGMENTS Preparation of this chapter was supported in part by a grant from the Stanley Foundation to DRH. We dedicate this chapter to the memory of Paul E. Meehl (1920–2003). His far-ranging intellect and his self-described interdisciplinary mind (“I am more of a knowledge-absorber, knowledge-integrator, and knowledge-transmitter”) taught us to search widely for answers to questions posed by science and humanity. Paul Meehl’s autobiography can be found in A History of Psychology in Auto- biography, 1989, ed. G. Lindzey, volume 3, pp. 337–389, published by Stanford University Press, Stanford, California.

CONFLICT OF INTEREST STATEMENT

IIG and DRH know of no conﬂicts of interest related to this manuscript.

The Annual Review of Psychology is online at http://psych.annualreviews.org

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Figure 1 Sketch of a systems biology approach toward explaining a complex behavior that incorporates dynamic interplay among candidate genes and gene regions, a sampling of endophenotypes (solid lines indicate those downstream of real genes), and the scope of pre- and postnatal environmental and epigenetic influences (harmful versus protective) over the course of development. Question marks indicate gaps in knowledge; p and q indicate regions of interest localized by research to specific numbered chromosomes; QTL = quantitative trait locus. Two planes intersect the reaction surface for the liability to developing schizophrenia over time, demarcating levels above which clinical diagnoses are war- ranted (cf. Gottesman & Gould 2003, Manji et al. 2003 for details). Copyright 2003 by I.I. Gottesman (used with permission). P1: JRX December 8, 2004 12:13 Annual Reviews AR231-FM

Annual Review of Psychology Volume 56, 2005

CONTENTS

Frontispiece—Richard F. Thompson xviii

PREFATORY In Search of Memory Traces, Richard F. Thompson 1

DECISION MAKING Indeterminacy in Brain and Behavior, Paul W. Glimcher 25

BRAIN IMAGING/COGNITIVE NEUROSCIENCE Models of Brain Function in Neuroimaging, Karl J. Friston 57

MUSIC PERCEPTION Brain Organization for Music Processing, Isabelle Peretz and Robert J. Zatorre 89

SOMESTHETIC AND VESTIBULAR SENSES Vestibular, Proprioceptive, and Haptic Contributions to Spatial Orientation, James R. Lackner and Paul DiZio 115

CONCEPTS AND CATEGORIES Human Category Learning, F. Gregory Ashby and W. Todd Maddox 149

ANIMAL LEARNING AND BEHAVIOR:CLASSICAL Pavlovian Conditioning: A Functional Perspective, Michael Domjan 179

by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. NEUROSCIENCE OF LEARNING

Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org The Neuroscience of Mammalian Associative Learning, Michael S. Fanselow and Andrew M. Poulos 207

HUMAN DEVELOPMENT:EMOTIONAL,SOCIAL, AND PERSONALITY Behavioral Inhibition: Linking Biology and Behavior Within a Developmental Framework, Nathan A. Fox, Heather A. Henderson, Peter J. Marshall, Kate E. Nichols, and Melissa A. Ghera 235

BIOLOGICAL AND GENETIC PROCESSES IN DEVELOPMENT Human Development: Biological and Genetic Processes, Irving I. Gottesman and Daniel R. Hanson 263

vii P1: JRX December 8, 2004 12:13 Annual Reviews AR231-FM

viii CONTENTS

SPECIAL TOPICS IN PSYCHOPATHOLOGY The Psychology and Neurobiology of Suicidal Behavior, Thomas E. Joiner Jr., Jessica S. Brown, and LaRicka R. Wingate 287

DISORDERS OF CHILDHOOD Autism in Infancy and Early Childhood, Fred Volkmar, Kasia Chawarska, and Ami Klin 315

CHILD/FAMILY THERAPY Youth Psychotherapy Outcome Research: A Review and Critique of the Evidence Base, John R. Weisz, Amanda Jensen Doss, and Kristin M. Hawley 337

ALT RU ISM AND AGGRESSION Prosocial Behavior: Multilevel Perspectives, Louis A. Penner, John F. Dovidio, Jane A. Piliavin, and David A. Schroeder 365

INTERGROUP RELATIONS,STIGMA,STEREOTYPING, PREJUDICE,DISCRIMINATION The Social Psychology of Stigma, Brenda Major and Laurie T. O’Brien 393

PERSONALITY PROCESSES Personality Architecture: Within-Person Structures and Processes, Daniel Cervone 423

PERSONALITY DEVELOPMENT:STABILITY AND CHANGE Personality Development: Stability and Change, Avshalom Caspi, Brent W. Roberts, and Rebecca L. Shiner 453

WORK MOTIVATION Work Motivation Theory and Research at the Dawn of the Twenty-First Century, Gary P. Latham and Craig C. Pinder 485 by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. GROUPS AND TEAMS Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org Teams in Organizations: From Input-Process-Output Models to IMOI Models, Daniel R. Ilgen, John R. Hollenbeck, Michael Johnson, and Dustin Jundt 517

LEADERSHIP Presidential Leadership, George R. Goethals 545

PERSONNEL EVA L UATION AND COMPENSATION Personnel Psychology: Performance Evaluation and Pay for Performance, Sara L. Rynes, Barry Gerhart, and Laura Parks 571 P1: JRX December 8, 2004 12:13 Annual Reviews AR231-FM

CONTENTS ix

PSYCHOPHYSIOLOGICAL DISORDERS AND PSYCHOLOGICAL EFFECTS ON MEDICAL DISORDERS Psychological Approaches to Understanding and Treating Disease-Related Pain, Francis J. Keefe, Amy P. Abernethy, and Lisa C. Campbell 601

TIMELY TOPIC Psychological Evidence at the Dawn of the Law’s Scientiﬁc Age, David L. Faigman and John Monahan 631

INDEXES Subject Index 661 Cumulative Index of Contributing Authors, Volumes 46Ð56 695 Cumulative Index of Chapter Titles, Volumes 46Ð56 700

ERRATA An online log of corrections to Annual Review of Psychology chapters may be found at http://psych.annualreviews.org/errata.shtml by OCCIDENTAL COLLEGE LIBRARY on 07/20/05. For personal use only. Annu. Rev. Psychol. 2005.56:263-286. Downloaded from arjournals.annualreviews.org