Dramatic gains in knowledge have been made in the fields of neuroscience, human development, and developmental psychopathology during the past quarter of a century. Despite the advances that have been achieved in each discipline separately, considerably less progress has occurred in understanding the relation between neurobiological and behavioral development in normal and atypical populations. Research has increasingly demonstrated that abnormalities that occur early in development may result in the emergence of aberrant neural circuitry that eventuates in relatively enduring forms of psychopathology. Knowledge of normal neurobiological development provides a powerful foundation for understanding the contributions that neurodevelopmental processes make to the etiology and sequelae of psychopathology across the life course. An integrated perspective wherein an appreciation of the complex neural, psychological, and social-contextual processes that cohere to bring about normal and pathological outcomes is necessary in order to advance understanding of the genesis and epigenesis of mental disorders. Such an approach will require a reduction of the schisms that so often separate neurobiological and behavioral research.

The basic principles of the development of the central nervous system (CNS) are reviewed, and their implications for both normal and abnormal development of the brain are discussed. The goals of this review are (a) to provide a set of concepts to aid in understanding the variety of complex processes that occur during CNS development, (b) to illustrate how these concepts contribute to our knowledge of the normal anatomy of the adult brain, and (c) to provide a basis for understanding how modifications of normal developmental processes by traumatic injury, by environmental or experiential influences, or by genetic variations may lead to modifications in the resultant structure and function of the adult CNS.

In this paper I review evidence and viewpoints on developmental plasticity in the cerebral cortex. Although there is some degree of plasticity in the cortex during early postnatal life in the human infant, this plasticity is constrained by various factors. Three working hypotheses about postnatal cortical specialization of function are advanced, and some specific predictions about the limits and extent of plasticity are assessed through both empirical evidence from infants and simulations on simple cortical network models.

Growing epidemiological, genetic, and clinical neurobiological evidence indicates that abnormalities in brain development play determining roles in the pathobiology of schizophrenia. Neuropathological research has made significant progress in delineating cellular and molecular abnormalities in schizophrenia that have relevance to neurodevelopment. This paper reviews the neurodevelopmental processes of neurogenesis, neuronal migration, differentiation, synaptogenesis, neuron and synaptic pruning, and myelination and the reported neuropathological findings in schizophrenia that may be a consequence of disturbances in these processes. While many neuropathological findings in schizophrenia are controversial or await confirmation, reported abnormalities in neuron density, number and morphology, cytoarchitecture, dendritic arbors and spines, synapse-related proteins, and the well-established absence of gliosis or any other evidence of neurodegeneration or neural injury all provide support for the neurodevelopmental model of schizophrenia.

Our findings in the Helsinki Influenza Study and the Danish Forty Year Study lead us to conclude that a 2nd-trimester maternal influenza infection may increase risk for adult schizophrenia or adult major affective disorder. More recently we have also reported an increase of unipolar depression among offspring who were exposed prenatally to a severe earthquake (7.8 on the Richter scale) in Tangshan, China. Among the earthquake-exposed males (but not the females), we observed a significantly greater depression response for those individuals exposed during the 2nd trimester of gestation. These findings suggest that maternal influenza infection and severe maternal stress may operate (in different ways) as teratogens, disrupting the development of the fetal brain and increasing risk for developing schizophrenia or depression in adulthood.

A number of lines of evidence converge in implicating neurodevelopmental processes in the etiology and epigenesis of schizophrenia. In this study we used a prospective, longitudinal design to examine whether adverse obstetric experiences predict schizophrenia and whether there is a deviant functional–developmental trajectory during the first 7 years of life among individuals who manifest schizophrenia as adults. The 9,236 members of the Philadelphia cohort of the National Collaborative Perinatal Project were screened for mental health service utilization in adulthood, and chart reviews were performed to establish diagnoses according to DSM-IV criteria. The risk for schizophrenia increased linearly with the number of hypoxia-associated obstetric complications but was unrelated to maternal infection during pregnancy or fetal growth retardation. Preschizophrenic cases (and their unaffected siblings who were also cohort members) manifested cognitive impairment, abnormal involuntary movements and coordination deficits, and poor social adjustment during childhood. There was no evidence of intraindividual decline in any domain, but preschizophrenic cases did show deviance on an increasing number of functional indicators with age. Together, these findings suggest that both genetic and obstetric factors participate in creating a neural diathesis to schizophrenia, the phenotypic expressions of which are age dependent, probably reflecting the maturational status of a number of interconnected brain systems.

Attentional deficits are well-established characteristics of patients with schizophrenia and their at-risk offspring, suggesting a biological connection between attention and schizophrenia. The goal of this study is to clarify the developmental role of attention in the illness. Data has been collected from 87 subjects at high and low risk for schizophrenia who have participated in the New York High-Risk Project from 1977 to the present. Individuals are considered to be at high risk if either or both of their parents has schizophrenia. Analyses of attention and global behaviors, measured at intervals from about 12 to 26 years of age, indicate (a) attentional deficits can be reliably detected in high-risk children who will develop future schizophrenia-spectrum disorders (the prespectrum [PSP] group); (b) these deficits are stable, enduring over time, and appear to reflect a compromised attentional capacity; (c) attention is not affected by the onset of illness in the PSP group; (d) for all subjects, attention and global behaviors follow independent developmental pathways; and (e) behavioral difficulties, but not attention deficits, appear to be highly sensitive to environmental factors, especially rearing by a mentally ill parent. It is concluded that in PSP individuals impaired attention probably results from prenatal developmental abnormalities (possibly on the cellular level) and is likely to be a marker of a biological vulnerability to schizophrenia. In addition, attentional deficits, as opposed to early behavioral difficulties, are concluded to be a useful first step in screening for youngsters in need of early intervention.

Motor dysfunction is associated with schizophrenia, and recent longitudinal studies indicate that it precedes the onset of clinical symptoms. Of particular interest is the heightened occurrence of involuntary movements, which are apparent as early as infancy and suggest the presence of subcortical brain abnormalities. In this article, we present the results of a study of spontaneous movements in adolescents with schizotypal personality disorder (SPD). SPD is a syndrome that has been shown to be genetically linked with schizophrenia and is often observed prior to the early adult onset of schizophrenia. Systematic coding of videotapes of diagnostic interviews revealed that the SPD group showed significantly more involuntary movements of the head, trunk, and upper limbs than did normals and adolescents with other personality disorders. There were no diagnostic group differences in the rate of voluntary movements. Salivary cortisol, measured before the interview, was positively correlated with involuntary movements. Taken together, the findings provide further support for the hypothesized etiologic relation between SPD and schizophrenia. Based on a neural diathesis-stress model, potential underlying mechanisms are discussed.

The central feature of schizophrenia is its onset in adolescence. Although this clinical observation is consistent with the view that schizophrenia may be a neurodevelopmental disorder, debate has focused on when the proposed brain maturational deviations may begin and what might be the nature of such defective development. Conflicting models of this illness (e.g., the early and late neurodevelopmental models) have been proposed. In this paper, we will first review concepts from basic developmental neurobiology pertinent to these issues; we then summarize aspects of the neurobiology of schizophrenia that have a particular bearing on the adolescent onset of this illness. We propose that the schizophrenic syndrome may result from early brain adversity and late maturational processes of brain development interacting with adverse humoral, biochemical, and psychosocial factors during adolescence and early adulthood. The onset of schizophrenia in adolescence may be related to the “plasticity switch” secondary to the peripubertal brain maturational changes, perhaps involving an alteration in glutamate receptor function. This loss of plasticity could result in social and nonsocial cognitive deficits that are central to the pathophysiology of schizophrenia; the vulnerable person may therefore utilize prepubertal processing styles that are insufficient to the adaptive and “gistful” abstraction requirements of adult cognition. Schizophrenia onset might occur in the context of psychosocial developmental challenges to a delayed social cognitive capacity among neurodevelopmentally compromised individuals. We review therapeutic implications as well as testable predictions generated by this model, and discuss research strategies that might further our understanding of the brain maturational abnormalities in schizophrenia.

Recent studies have focused on the behavioral and neurobiological sequella of exposure to early adverse events. We hypothesize that early adverse experiences result in an increased sensitivity to the effects of stress later in life and render an individual vulnerable to stress-related psychiatric disorders. This vulnerability may be mediated by persistent changes in corticotropin-releasing-factor (CRF)-containing neurons, the hypothalamic–pituitary–adrenal axis, and the sympathetic nervous system. We therefore present an overview of the CRF system and its role as a mediator in the development of the stress response, major depression, and posttraumatic stress disorder. The literature pertaining to behavioral and neurobiological alterations associated with exposure to early adverse life events in rodents, nonhuman primates, and humans is reviewed. We focus on animal models that precipitate depressive and anxiety symptoms while producing neuroendocrine alterations that mimic those seen in adults with those disorders. The literature integrating neurobiological and behavioral consequences of early life stress is also reviewed, focusing primarily on infants born to mothers with depression and on infants who were abused or neglected.

Autism is a developmental disorder with variable severity, occurring at all levels of cognitive ability and having a number of slightly different clinical presentations. It is associated with neuropsychological deficits that occur in other conditions also, but its pattern may be specific to autism. Genetic and environmental early insults to brain development are etiological determinants of the disorder. Brain circuitries important for social, communicative, and integrational purposes have been suggested to be dysfunctional in autism. There could be at least two different pathways to autism, one connected with primary temporofrontal dysfunction (and late prenatal–early postnatal origins) and another linked to primary brain-stem dysfunction (and early prenatal origins). Further study of neurodevelopmental and neuropsychological processes in autism will help elucidate not only the pathological mechanisms involved in the specific syndromes but also the underpinnings of normal brain development.

In previous studies, infants of depressed mothers have been found to exhibit reduced left frontal brain electrical activity (EEG). The left frontal region has been hypothesized to mediate social approach behaviors and positive affective expression. These findings raise important questions about the cause and nature of atypical EEG patterns in infants of depressed mothers. The present study begins to address some of these questions by examining whether or not variations in patterns of frontal brain activity in infants of depressed and nondepressed mothers are related to variations in infant behavior as observed in naturalistic situations. If such relations exist, are they specific to certain behaviors hypothesized to be mediated by the frontal region (i.e., positive approach behaviors)? Frontal and parietal brain electrical activity was recorded from 14- to 15-month old infants of depressed versus nondepressed mothers during a baseline condition and during conditions designed to elicit interest and positive affect. Infant behavior was observed in naturalistic play conditions, with and without mother, on a separate day from EEG testing. Mothers provided information on infant temperament. Infants of depressed mothers showed less affection and touching of their mothers. For infants of depressed mothers only, reduced left frontal brain activity was found to be related to lower levels of affection toward mother, but not to infant temperament. Furthermore, increased generalized frontal activation was found to be related to higher levels of negative affect, hostility, and tantrums and aggression. Relations between infant brain activity and behavior were not found for parietal EEG activity. These results suggest that infant frontal electrical brain activity is related to variations in infant behavior, especially those involved in positive affiliative behavior and the expression and regulation of negative affect. The nature and cause of atypical patterns of brain activity and question of whether such atypical patterns of frontal brain activity predispose infants to affective disorders in later life are discussed.

Recent research on the disorders of attention and activity has indicated inherited variants of genes controlling aspects of neurotransmission, abnormalities of structure and function in regions of frontal lobes and basal ganglia, failures to suppress inappropriate responses, and a cascade of failures in various kinds of cognitive performance and organization of behavior. This review integrates the neurodevelopmental findings with findings from developmental psychopathology. It outlines several developmental tracks by which constitutional factors interact with the psychological environment. In one set of tracks, altered brain states lead to cognitive alteration. An understimulating environment is evoked by (and may be genetically associated with) an inattentive and cognitively impulsive style during early childhood. In another track, impulsive and inattentive behavior shows direct continuity through childhood into late adolescence. In yet another track, impulsiveness evokes (and may be genetically associated with) critical expressed emotion from parents and inefficient coping strategies, which in turn contribute to the development of antisocial conduct. This formulation emphasizes the need for several types of research: the mapping of biological findings onto different components of disorder, the combination of genetically informative designs with direct measurement of relevant aspects of the environment, and the use of longitudinal studies to examine predictive and mediating factors separately for different aspects of outcome.

This paper reviews what is known about developmental dyslexia at three levels of analysis: cognitive, neurological, and genetic. It also considers the difficult problem of establishing causal links between these levels of analysis, and argues that solving the gene–behavior problem is paradoxically easier than solving the brain–behavior problem.