Research on neurobiological development is providing insight into the nature and mechanisms of human neural plasticity. These mechanisms appear to support two different forms of developmental learning. One form of learning could be described as externalizing, in which neural representations are highly responsive to environmental influences, as the child typically operates under a mode of hedonic approach. A second form of learning supports internalizing, in which motive control separates attention and self-regulation from the immediate influences of the context, particularly when the child faces conditions of avoidance and threat. The dorsal cortical networks of externalizing are organized around dorsal limbic (cingulate, septal, lateral hypothalamic, hippocampal, and ventral striatal) circuits. In contrast, the ventral cortical networks of internalizing are organized around ventral limbic (anterior temporal and orbital cortex, extended amygdala, dorsal striatal, and mediodorsal thalamic) circuits. These dual divisions of the limbic system in turn self-regulate their arousal levels through different brain stem and forebrain neuromodulator projection systems, with dorsal corticolimbic networks regulated strongly by locus coeruleus norepinephrine and brain stem raphe nucleus serotonin projection systems, and ventral corticolimbic networks regulated by ventral tegmental dopamine and forebrain acetylcholine projections. Because the arousal control systems appear to regulate specific properties of neural plasticity in development, an analysis of these systems explains differences between externalizing and internalizing at multiple levels of neural and psychological self-regulation. In neuroscience, the concept of critical periods has been applied to times when experience is essential for the maturation of sensory systems. In a more general neuropsychological analysis, certain periods of the child's development require successful self-regulation through the differential capacities for externalizing and internalizing.

Building upon the transactional model of brain development, we explore the impact of early maternal deprivation on neural development and plasticity in three neural systems: hyperactivity/impulsivity, executive function, and hypothalamic–pituitary–adrenal axis functioning across rodent, nonhuman primate, and human studies. Recognizing the complexity of early maternal–infant interactions, we limit our cross-species comparisons to data from rodent models of artificial rearing, nonhuman primate studies of peer rearing, and the relations between these two experimental approaches and human studies of children exposed to the early severe psychosocial deprivation associated with institutional care. In addition to discussing the strengths and limitations of these paradigms, we present the current state of research on the neurobiological impact of early maternal deprivation and the evidence of sensitive periods, noting methodological challenges. Integrating data across preclinical animal models and human studies, we speculate about the underlying biological mechanisms; the differential impact of deprivation due to temporal factors including onset, offset, and duration of the exposure; and the possibility and consequences of reopening of sensitive periods during adolescence.

Sensitive periods (SP) in behavioral development appeared in the biological sciences during the first decade of the 20th century, and research in animal models beginning in the 1950s provide terminology and evidence for SP effects. This paper proposes a rigorous program for human SP research and argues that the complexity of the human brain and variability of the human ecology necessitate that SP effects must be studied in humans, employ longitudinal designs starting at birth, test mechanism-based hypotheses based on animal studies that manipulate early environments, and utilize high-risk conditions as “natural experiments.” In light of research on the molecular basis of critical periods and their sequential cascades, it is proposed that the oxytocin (OT) system, an ancient and integrative system that cross-talks with the stress, reward, immune, and brain stem mediated homeostatic systems and supports mammalian sociality, plays a unique role in experience-dependent plasticity that buttresses SP effects due to its (a) dendritic mode of release leading to autoregulated functioning primed by early experience, (b) pulsatile pattern of activity, and (c) special role in neural plasticity at the molecular and network assembly levels. Synchrony, the coordination of biology and behavior during social contact, is suggested as a mechanism by which SP exert their effect on OT functionality, the social brain, and adult sociality. Findings from four high-risk birth cohorts, each followed repeatedly from birth to 10 years, provide unique “natural experiments” for human SP research based on specific programs in animal models. These include prematurity (maternal proximity), multiple birth (peer rearing), postpartum depression (low licking and grooming), and chronic unpredictable trauma (maternal rotation, variable foraging demands). In each cohort, hypotheses are based on the missing environmental component during SP, and findings on social synchrony, OT functionality, stress response, emotion regulation, and mental health accord with the multilevel and dynamic principles of developmental psychopathology. The results on the potential for reparation versus chronicity following early deprivation highlight a flexible conceptualization of resilience based on human SP research. Consideration of SP effects at the molecular, endocrine, brain, and behavioral levels and in relation to the neural plasticity and multifinality of human social functions may assist in fine-tuning early detection and the construction of targeted individualized interventions.

Prenatal tobacco exposure (PTE) has a well-documented association with disruptive behavior in childhood, but the neurocognitive effects of exposure that underlie this link are not sufficiently understood. The present study was designed to address this gap, through longitudinal follow-up in early childhood of a prospectively enrolled cohort with well-characterized prenatal exposure. Three-year-old children (n = 151) were assessed using a developmentally sensitive battery capturing both cognitive and motivational aspects of self-regulation. PTE was related to motivational self-regulation, where children had to delay approach to attractive rewards, but not cognitive self-regulation, where children had to hold information in mind and inhibit prepotent motor responses. Furthermore, PTE predicted motivational self-regulation more strongly in boys than in girls, and when propensity scores were covaried to control for confounding risk factors, the effect of PTE on motivational self-regulation was significant only in boys. These findings suggest that PTE's impact on neurodevelopment may be greater in boys than in girls, perhaps reflecting vulnerability in neural circuits that subserve reward sensitivity and emotion regulation, and may also help to explain why PTE is more consistently related to disruptive behavior disorders than attention problems.

The human brain undergoes a remarkable transformation during fetal life and the first postnatal years from a relatively undifferentiated but pluripotent organ to a highly specified and organized one. The outcome of this developmental maturation is highly dependent on a sequence of environmental exposures that can have either positive or negative influences on the ultimate plasticity of the adult brain. Many environmental exposures are beyond the control of the individual, but nutrition is not. An ever-increasing amount of research demonstrates not only that nutrition shapes the brain and affects its function during development but also that several nutrients early in life have profound and long-lasting effects on the brain. Nutrients have been shown to alter opening and closing of critical and sensitive periods of particular brain regions. This paper discusses the roles that various nutrients play in shaping the developing brain, concentrating specifically on recently explicated biological mechanisms by which particularly salient nutrients influence childhood and adult neural plasticity.

Resilience and adaptation in the face of early genetic or environmental risk has become a major interest in child psychiatry over recent years. However, we still remain far from an understanding of how developing human brains as a whole adapt to the diffuse and widespread atypical synaptic function that may be characteristic of some common developmental disorders. The first part of this paper discusses four types of whole-brain adaptation in the face of early risk: redundancy, reorganization, niche construction, and adjustment of developmental rate. The second part of the paper applies these adaptation processes specifically to autism. We speculate that key features of autism may be the end result of processes of early brain adaptation, rather than the direct consequences of ongoing neural pathology.

The development of attention has been strongly linked to the regulation of emotion and behavior and has therefore been of particular interest to researchers aiming to better understand precursors to behavioral maladjustment. In the current paper, we utilize a developmental psychopathology and neural plasticity framework to highlight the importance of both intrinsic (i.e., infant neural functioning) and extrinsic (i.e., caregiver behavior) factors for the development of attentional control across the first year. We begin by highlighting the importance of attention for children's emotion regulation abilities and mental health. We then review the development of attention behavior and underscore the importance of neural development and caregiver behavior for shaping attentional control. Finally, we posit that neural activation associated with the development of the executive attention network may be one mechanism through which maternal caregiving behavior influences the development of infants’ attentional control and subsequent emotion regulation abilities known to be influential to childhood psychopathology.

Lexical processing deficits in children with developmental language disorder (DLD) have been postulated to arise as sequelae of their grammatical deficits (either directly or via compensatory mechanisms) and vice versa. We examined event-related potential indices of lexical processing in children with DLD (n = 23) and their typically developing peers (n = 16) using a picture–word matching paradigm. We found that children with DLD showed markedly reduced N400 amplitudes in response both to auditorily presented words that had initial phonological overlap with the name of the pictured object and to words that were not semantically or phonologically related to the pictured object. Moreover, this reduction was related to behavioral indices of phonological and lexical but not grammatical development. We also found that children with DLD showed a depressed phonological mapping negativity component in the early time window, suggesting deficits in phonological processing or early lexical access. The results are partially consistent with the overactivation account of lexical processing deficits in DLD and point to the relative functional independence of lexical/phonological and grammatical deficits in DLD, supporting a multidimensional view of the disorder. The results also, although indirectly, support the neuroplasticity account of DLD, according to which language impairment affects brain development and shapes the specific patterns of brain responses to language stimuli.

The relationship between developmental exposure to adversity and affective disorders is reviewed. Adversity discussed herein includes physical and sexual abuse, neglect, or loss of a caregiver in humans. While these stressors can occur at any point during development, the unique temporal relationship to specific depressive symptoms was the focus of discussion. Further influences of stress exposure during sensitive periods can vary by gender and duration of abuse as well. Data from animal studies are presented to provide greater translational and causal understanding of how sensitive periods, different types of psychosocial stressors, and sex interact to produce depressive-like behaviors. Findings from maternal separation, isolation rearing, chronic variable stress, and peer–peer rearing paradigms clarify interpretation about how various depressive behaviors are influenced by age of exposure. Depressive behaviors are broken down into the following categories: mood and affect, anhedonia, energy, working memory, sleep–wake, appetite changes, suicide, and general malaise. Cross-species evidence from humans, nonhuman primates, rats, and mice within each of these categories is discussed. In conclusion, sensitive periods for affective-related behaviors (anxiety, mood, and controllability) occur earlier in life, while other aspects of depression are associated with adversity later during adolescence.

Maltreatment in childhood is associated with a significantly increased likelihood of psychiatric disorder that endures across the life span. If disorders emerge they tend to be more severe and less responsive to treatment. We introduce the concept of latent vulnerability as a way of conceptualizing the nature of this psychiatric risk. We argue that vulnerability to mental health problems can be understood as changes in a suite of neurocognitive systems that reflect adaptation or altered calibration to early neglectful or maltreating environments. Altered threat processing is presented as one exemplar candidate system. Heightened neurocognitive vigilance to threat is argued to reflect a calibration to an early at-risk environment that becomes maladaptive (and instantiates vulnerability) in the longer term. Other neurocognitive domains, including reward and memory processing, represent equally promising candidates for indexing latent vulnerability and warrant future enquiry. We suggest that the operationalization of latent vulnerability has the potential to guide a preventative psychiatry approach. Intervention currently occurs at two stages when maltreatment is confirmed: first, by addressing issues of risk; and second, by providing clinical intervention if a child meets criteria for psychiatric disorder. We argue that indexing latent vulnerability represents a third intervention opportunity, with the potential to target an indicated prevention approach for the most vulnerable children, offsetting risk trajectories before psychiatric disorders emerge.

We present new empirical data and meta-analytic evidence for the association of childhood maltreatment with reduced hippocampal volume. In Study 1, we examined the effects of maltreatment experiences reported during the Adult Attachment Interview on hippocampal volume in female twin pairs. We found that reduced hippocampal volume was related to childhood maltreatment. In addition, individuals who reported having experienced maltreatment at older ages had larger reductions in hippocampal volume compared to individuals who reported maltreatment in early childhood. In Study 2, we present the results of a meta-analysis of 49 studies (including 2,720 participants) examining hippocampal volume in relation to experiences of child maltreatment, and test the moderating role of the timing of the maltreatment, the severity of maltreatment, and the time after exposure to maltreatment. The results of the meta-analysis confirmed that experiences of childhood maltreatment are associated with a reduction in hippocampal volume and that the effects of maltreatment are more pronounced when the maltreatment occurs in middle childhood compared to early childhood or adolescence.

Childhood maltreatment represents a complex stressor, with the developmental timing, duration, frequency, and type of maltreatment varying with each child (Barnett, Manly, & Cicchetti, 1993; Cicchetti & Manly, 2001). Multiple brain regions and neural circuits are disrupted by the experience of child maltreatment (Cicchetti & Toth, in press; DeBellis et al., 2002; McCrory & Viding, 2010; Teicher, Anderson, & Polcari, 2012). These neurobiological compromises indicate the impairment of a number of important cognitive functions, including working memory and inhibitory control. The present study extends prior research by examining the effect of childhood maltreatment on neurocognitive functioning based on developmental timing of maltreatment, including onset, chronicity, and recency, in a sample of 3- to 9-year-old nonmaltreated (n = 136) and maltreated children (n = 223). Maltreated children performed more poorly on inhibitory control and working-memory tasks than did nonmaltreated children. Group differences between maltreated children based on the timing of maltreatment and the chronicity of maltreatment also were evident. Specifically, children who were maltreated during infancy, and children with a chronic history of maltreatment, exhibited significantly poorer inhibitory control and working-memory performance than did children without a history of maltreatment. The results suggest that maltreatment occurring during infancy, a period of major brain organization, disrupts normative structure and function, and these deficits are further instantiated by the prolonged stress of chronic maltreatment during the early years of life.

Childhood maltreatment has lasting negative effects throughout the life span. Early intervention research has demonstrated that these effects can be remediated through skill-based, family-centered interventions. However, less is known about plasticity during adolescence, and whether interventions are effective many years after children experience maltreatment. This study investigated this question by examining adolescent girls' ability to make advantageous decisions in the face of risk using a validated decision-making task; performance on this task has been associated with key neural regions involved in affective processing and executive functioning. Maltreated foster girls (n = 92), randomly assigned at age 11 to either an intervention designed to prevent risk-taking behaviors or services as usual (SAU), and nonmaltreated age and socioeconomic status matched girls living with their biological parent(s) (n = 80) completed a decision-making task (at age 15–17) that assessed risk taking and sensitivity to expected value, an index of advantageous decision making. Girls in the SAU condition demonstrated the greatest decision-making difficulties, primarily for risks to avoid losses. In the SAU group, frequency of neglect was related to greater difficulties in this area. Girls in the intervention condition with less neglect performed similarly to nonmaltreated peers. This research suggests that early maltreatment may impact decision-making abilities into adolescence and that enriched environments during early adolescence provide a window of plasticity that may ameliorate these negative effects.

Prior research has found inconsistent evidence regarding the association among childhood adversity, inflammation, and internalizing symptoms, perhaps because previous studies have yet to adequately integrate important factors such as the timing of the adversity, genetic variation, and other relevant processes such as neuroendocrine regulation. The aims of the present study were threefold: (a) to determine whether the effect of the timing of child maltreatment on C-reactive protein (CRP), an inflammatory marker, varies by CRP gene variation; (b) to explore whether links between salivary CRP and childhood internalizing symptoms depend on the presence and timing of maltreatment experiences; and (c) to investigate the role of CRP in the relations between child neuroendocrine regulation and internalizing symptoms and examine whether these associations are moderated by the presence and timing of child maltreatment. Participants included a sample of 267 maltreated and 222 nonmaltreated children (M age = 9.72, SD = 0.99; 52.4% male; 66% African American) who attended a summer day camp research program designed for school-aged low-income children. Department of Human Services records were examined to determine the onset and recency of maltreatment for children in the maltreated group. The results indicated that among children with recent onset maltreatment, those with at least one A allele from CRP single nucleotide polymorphism rs1417938 evidenced significantly higher CRP levels compared to recently maltreated children carrying the TT genotype. Moreover, higher levels of CRP were associated with higher levels of internalizing symptoms only for recently maltreated children. Finally, we did not find support for salivary CRP as a mechanism in the relation between neuroendocrine regulation and childhood internalizing symptoms. Our findings highlight the importance of the timing of child maltreatment and have important implications for characterizing variability in inflammation and internalizing symptoms among youth.

Exposure to early life adversity is linked to impaired affective, cognitive, and behavioral functioning and increases risk for various psychiatric and medical conditions. Stress-induced increases in pro-inflammatory cytokines may be a biological mechanism of these effects. Few studies have examined cytokine levels in children experiencing early life adversity, and very little research has investigated cytokines or other markers of inflammation in saliva. In the present study, we examined salivary interleukin (IL)-1β and C-reactive protein (CRP) levels in relation to stress exposure in 40 children aged 3 to 5 years who were enrolled in a larger study of early life adversity. Childhood maltreatment status was assessed via review of child welfare records. Contextual stress exposure, traumatic life event history, and symptoms of psychopathology were assessed via caregiver interviews at a home visit. In a subsequent visit, salivary IL-1β and CRP were obtained before and after participation in four emotion-eliciting tasks. The number of past-month contextual stressors, lifetime contextual stressors, and traumatic life events each demonstrated a significant main effect on IL-1β. Baseline IL-1β was positively associated with each of the significant main-effect adversities. Postchallenge IL-1β displayed positive associations with each adversity variable, but these were not significant. CRP was not significantly associated with any of the adversity variables. Given the evidence suggesting the involvement of IL-1β in the neuropathology of psychiatric conditions, these results may have important implications for developmental outcomes.

Epigenetic modifications to the genome are a key mechanism involved in the biological encoding of experience. Animal studies and a growing body of literature in humans have shown that early adversity is linked to methylation of the gene for the glucocorticoid receptor (GR), which is a key regulator of the hypothalamic–pituitary–adrenal axis as well as a broad range of physiological systems including metabolic and immune function. One hundred eighty-four families participated, including n = 74 with child welfare documentation of moderate-severe maltreatment in the past 6 months. Children ranged in age from 3 to 5 years, and were racially and ethnically diverse. Structured record review and interviews in the home were used to assess a history of maltreatment, other traumas, and contextual life stressors, and a composite variable assessed the number exposures to these adversities. Methylation of regions 1D, 1F, and 1H of the GR gene was measured via sodium bisulfite pyrosequencing. The composite measure of adversity was positively correlated with methylation at exons 1D and 1F in the promoter of the GR gene. Individual stress measures were significantly associated with a several CpG sites in these regions. GR gene methylation may be a mechanism of the biobehavioral effects of adverse exposures in young children.

The emerging field of neurogenetics seeks to model the complex pathways from gene to brain to behavior. This field has focused on imaging genetics techniques that examine how variability in common genetic polymorphisms predict differences in brain structure and function. These studies are informed by other complimentary techniques (e.g., animal models and multimodal imaging) and have recently begun to incorporate the environment through examination of Imaging Gene × Environment interactions. Though neurogenetics has the potential to inform our understanding of the development of psychopathology, there has been little integration between principles of neurogenetics and developmental psychopathology. The paper describes a neurogenetics and Imaging Gene × Environment approach and how these approaches have been usefully applied to the study of psychopathology. Six tenets of developmental psychopathology (the structure of phenotypes, the importance of exploring mechanisms, the conditional nature of risk, the complexity of multilevel pathways, the role of development, and the importance of who is studied) are identified, and how these principles can further neurogenetics applications to understanding the development of psychopathology is discussed. A major issue of this piece is how neurogenetics and current imaging and molecular genetics approaches can be incorporated into developmental psychopathology perspectives with a goal of providing models for better understanding pathways from among genes, environments, the brain, and behavior.

In this paper, we review the history of the concept of neuroplasticity as it relates to the understanding of neuropsychiatric disorders, using schizophrenia as a case in point. We briefly review the myriad meanings of the term neuroplasticity, and its neuroscientific basis. We then review the evidence for aberrant neuroplasticity and metaplasticity associated with schizophrenia as well as the risk for developing this illness, and discuss the implications of such understanding for prevention and therapeutic interventions. We argue that the failure and/or altered timing of plasticity of critical brain circuits might underlie cognitive and deficit symptoms, and may also lead to aberrant plastic reorganization in other circuits, leading to affective dysregulation and eventually psychosis. This “dysplastic” model of schizophrenia can suggest testable etiology and treatment-relevant questions for the future.

This article highlights the defining principles, progress, and future directions in epigenetics research in relation to this Special Issue. Exciting studies in the fields of neuroscience, psychology, and psychiatry have provided new insights into the epigenetic factors (e.g., DNA methylation) that are responsive to environmental input and serve as biological pathways in behavioral development. Here we highlight the experimental evidence, mainly from animal models, that factors such as psychosocial stress and environmental adversity can become encoded within epigenetic factors with functional consequences for brain plasticity and behavior. We also highlight evidence that epigenetic marking of genes in one generation can have consequences for future generations (i.e., inherited), and work with humans linking epigenetics, cognitive dysfunction, and psychiatric disorder. Though epigenetics has offered more of a beginning than an answer to the centuries-old nature–nurture debate, continued research is certain to yield substantial information regarding biological determinants of central nervous system changes and behavior with relevance for the study of developmental psychopathology.