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Original Article |

Alterations in Neural Processing and Psychopathology in Children Raised in Institutions FREE

Natalie Slopen, ScD; Katie A. McLaughlin, PhD; Nathan A. Fox, PhD; Charles H. Zeanah, MD; Charles A. Nelson, PhD
[+] Author Affiliations

Author Affiliations: Center on the Developing Child, Harvard University, Cambridge (Drs Slopen, McLaughlin, and Nelson), Children's Hospital Boston/Harvard Medical School, Boston (Drs McLaughlin and Nelson), Massachusetts; Department of Human Development, University of Maryland, College Park (Dr Fox); and Department of Psychiatry and Behavioral Sciences, Tulane University School of Medicine, New Orleans, Louisiana (Dr Zeanah).


Arch Gen Psychiatry. 2012;69(10):1022-1030. doi:10.1001/archgenpsychiatry.2012.444.
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Context Young children raised in institutional settings experience severe deprivation in social, emotional, and cognitive stimulation. Although this deprivation is likely to disrupt brain development in ways that increase the risk for psychopathology, neurodevelopmental mechanisms linking adverse early environments to psychopathology remain poorly understood.

Objective To examine whether abnormalities in the neural processing of facial and emotional stimuli are related to the high rates of psychopathology observed among institutionally reared children.

Design, Setting, and Participants Data were drawn from the Bucharest Early Intervention Project, a cohort of children raised in institutions in Romania and an age-matched sample of community control subjects. At entry to the study (mean age, 22 months), event-related potentials were used to measure neural processing in 2 tasks: familiar and unfamiliar faces (n = 114) and facial displays of emotion (n = 74).

Main Outcome Measures Psychiatric symptoms were assessed using the Preschool Age Psychiatric Assessment among children aged 54 months.

Results As previously reported, institutionally reared children had elevated symptoms of attention-deficit/hyperactivity disorder (ADHD), anxiety, depression, and disruptive behavior compared with control children, and peak amplitudes of the P100 and P700 in response to facial stimuli were blunted among institutionalized children compared with community children in both tasks. Current analyses reveal that children with reduced P100 and P700 amplitudes in response to facial stimuli exhibited higher levels of ADHD and anxiety symptoms. Peak amplitude of the P700 in response to facial stimuli significantly mediated the association between institutional rearing and ADHD symptoms at 54 months.

Conclusion Exposure to institutional rearing disrupts the P700, conferring risk for the onset of psychopathology. The high levels of ADHD symptoms among children exposed to early life deprivation may be attributable, in part, to abnormal patterns of neurodevelopment generated by these adverse rearing environments.

Figures in this Article

Early life experiences are increasingly understood as important determinants of psychopathology with consequences that persist throughout development. Institutional rearing often represents an extreme form of early life adversity, characterized by severe psychosocial deprivation. The United Nations Children's Fund estimates that 8 million children worldwide reside in institutions.1 The harmful effects of institutional rearing have been well documented across numerous developmental outcomes, including growth,2,3 social and emotional functioning,4,5 cognitive and language ability,6,7 neural structure8 and functioning,9 and facial processing.10,11 The prevalence of psychiatric problems among previously institutionalized children is particularly elevated,1216 and recent evidence suggests that these elevations in psychopathology are explained, at least in part, by alterations in specific aspects of neurodevelopment—including pervasive cortical hypoactivation—resulting from early life deprivation.3,17 For example, atypical patterns of brain electrical activity related to cortical hypoactivation are associated with attention-deficit/hyperactivity disorder (ADHD)3 and indiscriminate social behavior17 among children with histories of institutionalization. We examined whether atypical processing of facial stimuli is another such neurodevelopmental mechanism linking institutional rearing to psychopathology.

The processing of faces and facial emotion provides essential information for effective and appropriate social interactions,18 and this developmental domain has been shown to be sensitive to the early social environment. Children exposed to severe early life adversity, including abuse and neglect, exhibit disruptions in processing facial emotion,18,19 which has been documented in both behavioral20 and electrophysiological10,11 studies. Studies of institutionalized and abused children suggest that event-related potentials (ERPs), such as the P100, N170, P400, and P700 components, are sensitive to facial stimuli and are influenced by environmental experiences.18,19 In a series of studies from the Bucharest Early Intervention Project (BEIP), institutionalized children exhibited reduced ERP amplitudes when viewing familiar and unfamiliar faces and emotional facial expressions compared with community-reared children.21,22 Blunted ERP responses to faces among institutionalized children may be a consequence of insufficient social interaction, a common experience of institutional life.23 Neuroimaging studies suggest that recognizing and perceiving emotions depend on the amygdala and its connections to and from occipitotemporal regions, the thalamus, the superior temporal gyrus, and the orbitofrontal cortex.24,25 Children exposed to severe adversity show structural and functional abnormalities in these systems.24,26

Atypical processing of visual stimuli, and faces in particular, may reflect or lead to disrupted socioemotional functioning. Social impairment is common in children with psychiatric disorders,27,28 and this impairment may be a precursor or a consequence of deficits in the processing of faces or facial emotion. Indeed, several studies have documented alterations in behavioral2932 and neural responses3336 to facial emotion among children with psychiatric disorders relative to unaffected children. For example, children with ADHD exhibit deficits in facial emotion recognition relative to typically developing children.29,30 Abnormal ERP responses to emotional stimuli have also been observed among children with autism spectrum disorders.33,36 The specific neural substrates that underlie these associations are not yet clear. Limbic circuitry, and particularly the amygdala, may play a role given its importance for social perception and recognition of facial expressions37 and evidence that it is related to the pathophysiology of ADHD38,39 and autism.40 Because disruptions in the neural processing of facial stimuli have been documented in children exposed to adverse rearing environments and in children with psychiatric disorders, alterations in facial processing may be a neurodevelopmental factor linking adverse environments to the later onset of psychopathology. Although processing of facial stimuli is a plausible mechanism linking early life adversity to psychiatric disorders, we are unaware of previous research examining this issue.

We addressed this gap in the literature using data from the BEIP, a longitudinal study of children reared in institutions in Romania and a matched sample of community-reared children. Prior research in this sample has documented elevated rates of psychopathology14 and atypical neural responses to facial stimuli10,11 among institutionally reared children relative to those raised in the community. We examined whether abnormalities in neural processing of faces, assessed using ERPs during recognition and emotion tasks, were associated with psychopathology and whether these visual processing abnormalities were a mechanism linking institutionalization to psychopathology. We anticipated that reduced ERP amplitudes in both face recognition and emotion recognition tasks would be associated with elevated psychiatric symptoms.

SAMPLE

The BEIP was initiated as a randomized controlled trial of foster care for children who were raised in institutions from early infancy.41 Children were recruited from all 6 institutions for young children in Bucharest, Romania, and a total of 187 children were screened for eligibility with physical examinations. Of these 187 children, 51 were excluded owing to medical reasons, including genetic syndromes (ie, Down syndrome), microcephaly, and fetal alcohol syndrome. The institutionalized sample comprised 136 children (institutionalized group [IG]) aged 6 to 30 months at entry to the study, and a sample of 72 age-matched comparison children from the community (never-institutionalized group [NIG]) was recruited from local pediatric clinics (N = 208). Exclusion criteria for institutionalized children were also applied to the selection of comparison children. Institutionalized children had lived in an institution for at least half of their life, and more than half had resided in an institution for their entire life. At baseline, comprehensive assessments of health, cognitive ability, and brain development were completed. Half of the children in the institutionalized group were randomized to be placed in high-quality foster care that was developed and monitored by the BEIP team (n = 68) and the other half remained in institutional care (n = 68).14 Details of randomization procedures are described elsewhere.41 No differences in sex, age, birth weight, or percentage of life spent in an institution were observed between the intervention and control groups. By age 54 months, 25 children were lost to follow-up, largely as the result of adoption or reintegration with biological parents.11,14

The BEIP was developed with support from the Secretary of State for Child Protection in Romania. Numerous procedures were established to ensure ethical integrity,4244 and study methods were approved by the Romanian Ministry of Health, the local commissions on child protection in Bucharest, an ethical committee with appointees from Bucharest University and several government departments, and the institutional review boards at the institutions of the 3 primary investigators.

FACIAL AND EMOTION PROCESSING TASKS

Prior to randomization, participants engaged in 2 tasks during which ERPs were recorded. The first was a recognition task that presented children with color images of familiar and unfamiliar comparably aged faces displaying neutral expressions. Pictures of the familiar faces were of the respondent's mother (NIG) or the preferred institutional caregiver (IG), as determined by staff consensus. Unfamiliar faces were of a woman with whom the child had no contact (eg, face of a different mother/caregiver). Familiar and unfamiliar faces each were presented in 35 separate trials in random order. The second was an emotional processing task that presented children with standardized images of a female expressing anger, sadness, fear, and happiness drawn from the MacBrain Face Stimulus Set.45 These emotions were chosen because they are salient and meaningful to young children.46 Each emotion was presented in 25 separate trials in random order. All children had visual acuity that permitted discrimination of the stimuli (ie, exceeded the task requirements).

Children were excluded from analyses owing to technical errors, having fewer than 10 artifact-free trials per stimulus condition, excessive eye movements or body artifacts, blinking while the picture was on the screen for more than 25% of the trials, or fussiness resulting in the inability to complete the task. A total of 60 children who participated in the recognition task and 100 of the children who participated in the emotion task were excluded for these reasons. Event-related potential data are available for 114 children for the recognition task (78 in the IG [37 females] and 36 in the NIG [18 females]), and ERP data are available for 74 children for the emotion task (54 in the IG [25 females] and 20 in the NIG [8 females]).

ELECTROPHYSIOLOGICAL RECORDING

Continuous electroencephalogram (EEG) was recorded at 12 scalp sites (F3, F4, Fz, C3, C4, P3, P4, Pz, O1, O2, T7, and T8), in addition to the right and left mastoids, with the reference site at the vertex (Cz) and anterior midline (AFz). Electroencephalography was recorded using a Lycra stretchable cap with tin electrodes sewn into it. Abrasive gel was applied to electrode and mastoid sites. Impedance was measured at each electrode and was deemed acceptable at the level of 10 kΩ or less. All channels were digitized at 512 Hz onto a computer hard drive using a 12-bit A/D converter (±2.5) and Snap-Master acquisition software (HEM Data Corporation). The vertical electroculogram was recorded using electrodes above and below the left eye to record blinks and other eye movements. Using custom bioelectric amplifiers (SA Instrumentation Company), EEG and electroculogram signals were amplified by factors of 5000 and 2500, respectively. Amplifier filter settings were 0.1 Hz (high pass) to 100 Hz (low pass) for all channels.

Subsequent processing of the EEG signal was performed using ERP Analysis Systems (James Long Company). Blinks in the electroculogram were regressed out of the EEG using standard procedures.47 Trials with an EEG signal that exceeded ±200 μV were excluded. Individual averages of ERP peak amplitude, relative to a 100-millisecond baseline, were computed for each stimulus type. In the recognition task, the amplitudes of ERP responses to familiar caregiver and unfamiliar faces were computed; in the emotion task, amplitudes were computed for the 4 emotions. We evaluated 5 ERP components shown previously to be involved in facial processing and attention19: 4 occipital components (measured at O1 and O2), including the P100 (90-200 milliseconds), N170 (150-300 milliseconds), P400 (250-500 milliseconds), P700 (675-850 milliseconds), and 1 frontocentral component (Nc; 350-650 milliseconds, measured at F3, F4, and Fz).

PROCEDURE

Each child was tested while sitting on the parent or caregiver's lap facing a computer monitor (approximately 40 cm away). The monitor was surrounded by black panels that blocked the child's view of the room. Above the monitor, a small hole in the screen allowed an observer to watch the child's behavior. For both tasks, trials consisted of a 100-millisecond baseline, followed by a 500-millisecond presentation of the stimulus and 1200 milliseconds of a blank blue screen. The intertrial interval varied randomly from 500 to 1000 milliseconds. The observer watched the infant from the hole in the screen and deleted trials in which the infant looked away. If necessary, the observer tapped on the screen or shook a rattle to attract the child's attention. The sessions ended once the child observed the maximum number of trials or was too fussy or uninterested to continue. The average durations of the recognition and emotion tasks were 3 and 4 minutes, respectively.

PSYCHIATRIC ASSESSMENT

At 54 months, signs of ADHD, anxiety disorders, major depression, oppositional defiant disorder/conduct disorder were assessed using the Preschool Age Psychiatric Assessment (PAPA), a structured diagnostic interview of caregivers.48,49 The PAPA collects information about the timing of onset, frequency, and duration of psychiatric symptoms from a child's caregiver. The PAPA is the most widely used psychiatric assessment for young children, and it is as reliable as diagnostic interviews for older children.48 For the BEIP, the PAPA was translated into Romanian and then translated back into English to ensure that the original meaning was retained. Trained BEIP staff administered the PAPA to biological (NIG) or foster care mothers (for IG children who were placed in foster homes), and institutional caregivers for IG children who remained in institutions. An institutional caregiver who knew the child well or who was identified as the favorite caregiver by staff consensus was selected to complete the interview.

DATA ANALYSIS

Standard tests of statistical mediation were used to evaluate neural processing of facial stimuli as a mechanism linking institutional rearing to psychopathology.50,51 All analyses adjusted for birth weight, head circumference, and age at ERP measurement. First, we report previously established findings that demonstrate differences in psychiatric symptoms as a function of institutionalization using between-group analysis of variance. Second, we present previously reported differences in ERPs during the 2 tasks as a function of institutional rearing. For occipital components, 2 (hemisphere: right or left) × 2 (group: institutionalized vs control children) × 2 (condition: caregiver or stranger) and 2 × 2 × 4 (condition: anger, happy, fear, and sad) repeated-measure analyses of variance were conducted. Similar analyses were performed for the frontocentral component (Nc). However, we used data from left, right, and central electrodes. The associations between ERPs during the facial and emotion processing tasks at baseline and psychopathology at 54 months were examined using linear regression. Finally, we evaluated the degree of attenuation in the association between institutionalization and psychiatric symptoms in models that included ERP responses during recognition and emotion tasks. The significance of the mediator was evaluated using a boot-strapping method that calculated bias-corrected confidence intervals for the indirect effect.52 Confidence intervals that do not include zero indicate a significant indirect effect of the exposure on the outcome through the mediator.52 When multiple ERP measures were related to a single psychiatric outcome, we computed a multiple mediation model that included all relevant ERP components.52 Statistical significance was evaluated at P < .05 using 2-sided tests.

INSTITUTIONALIZATION AND PSYCHOPATHOLOGY

As previously reported,3,14 children reared in institutions had elevated symptoms of ADHD, anxiety, depression, and oppositional defiant disorder/conduct disorder relative to community control children (P < .05) (Table 1).

Table Graphic Jump LocationTable 1. Psychiatric Symptoms Among Children Reared in Institutions and Community Control Childrena
INSTITUTIONALIZATION AND NEURAL PROCESSING OF FACIAL STIMULI

As previously reported, for both recognition and emotional tasks, children exposed to institutionalization had significantly smaller peak amplitudes compared with community control children for 2 of the 5 ERP components considered (Table 2 and Figure 1 and Figure 2). Specifically, in the recognition task, there was a main effect of group for P100 (F1,93 = 5.07; P = .03) and P700 (F1,92 = 11.48; P = .001); and, similarly in the emotion task, there was a main effect of group for P100 (F1,57 = 4.98; P = .03) and P700 (F1,57 = 7.61; P = .01]. For these components, we did not observe a significant effect of hemisphere, task condition, interactions between hemisphere and group, or interactions between task condition and group on either task. In contrast, we did not observe a main effect of group for peak amplitudes of N170, P400, and Nc during either task.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Grand averaged event-related potential waveforms of institutionalized and never-institutionalized children at the baseline assessment over the right occipital electrode collapsed across familiar and unfamiliar faces.

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Figure 2. Grand averaged event-related potential waveforms of institutionalized and never-institutionalized children at the baseline assessment over the right occipital electrode collapsed across happy, sad, angry, and fearful emotions.

Table Graphic Jump LocationTable 2. Peak Amplitude ERP Values Among Children Reared in Institutions and Community Control Childrena

The P100 and P700 were thus the only ERP components that met the criteria for mediators of the institutionalization-psychopathology associations. Accordingly, we evaluated the associations of the P100 and P700 with psychiatric outcomes. We used mean peak amplitudes collapsed across conditions in subsequent analyses because no effect of hemisphere, task condition, interactions between hemisphere and group, or interactions between task condition and group were observed for P100 or P700 components on either task.

ERPs AND PSYCHOPATHOLOGY

Parameter estimates for the associations of ERPs at baseline and psychiatric symptoms at 54 months are presented in Table 3. In the recognition task, lower P700 peak amplitude in response to caregiver faces was associated with elevated symptoms of ADHD (β = −0.25; P = .001). In the emotion task, baseline models show that lower P100 peak amplitude was associated with ADHD (β = −0.21; P = .04) and anxiety (β = −0.11; P = .02) symptoms. And lower P700 peak amplitude was associated with symptoms of anxiety (β = −0.16; P = .04).

Table Graphic Jump LocationTable 3. Associations Between Peak Amplitude ERPs During Recognition and Emotion Tasks at Baseline and Symptoms of Psychopathology at 54 Monthsa

Prior to carrying out the mediation analyses, we constructed interaction terms to examine whether the associations between ERPs and psychiatric symptoms were consistent for institutionally reared children compared with children from the community. There were no significant interactions for P700 (Table 3). However, there was a strong pattern of statistical interaction between P100 and history of institutionalization, such that lower P100 amplitude was associated with psychiatric symptoms only among institutionally reared children. On this basis, only P700 was evaluated as a potential mediator between institutionalization and psychiatric symptoms.

MEDIATION MODELS

To examine whether atypical facial processing contributes to elevated rates of psychiatric symptoms among children reared in institutions, we evaluated mediation models for outcomes and mediators that met the first 3 criteria for mediation. Table 4 presents the total effect of institutionalization on psychopathology and the indirect effect through P700 in response to facial stimuli. We first examined the mediating role of ERPs assessed during the recognition task. The total effect of institutionalization on ADHD symptoms was attenuated when P700 amplitude was added to the models, and a significant indirect effect of institutionalization on psychopathology through P700 was observed (95% CI, 0.19 to 2.88). We next evaluated the mediating role of P700 assessed during the emotion task on the association between institutionalization and anxiety symptoms. P700 during the emotion task was not a significant mediator of anxiety symptoms (95% CI, −0.06 to 1.72).

Table Graphic Jump LocationTable 4. Mediation of the Effect of Institutionalization on Symptoms of Psychopathology Through P700; Presented for ERPs and Outcomes That Met Criteria for Potential Mediationa

In sensitivity analyses, we explored whether time spent in home prior to institutionalization influenced mental health outcomes and ERP responses. There was no evidence that it was necessary to adjust for the proportion of life spent in an institution prior to baseline assessment in these models.

The objective of this study was to evaluate a potential neurodevelopmental mechanism underlying the association between institutional rearing and psychopathology. Neural processing of familiar and unfamiliar faces and of displays of emotion was evaluated using ERPs. The peak amplitudes of P100 and P700 in response to facial stimuli were diminished among institutionalized children compared with community control children in both tasks, and P700 in the caregiver/stranger task was associated with symptoms of ADHD independent of institutionalization history or placement into foster care. Lower P700 peak amplitudes in response to facial stimuli among institutionally reared children partially explained elevations in ADHD symptoms at 54 months. This aspect of neural processing of facial stimuli did not explain the relations between institutionalization and symptoms of oppositional defiant disorder/conduct disorder, depression, or anxiety. These findings contribute to a growing literature suggesting the presence of specific neurodevelopmental pathways that explain the heightened risk for psychopathology among institutionally reared children.3

The P100 is involved in the early stages of visual sensory processing, and the amplitude of this component reflects directed attentional resources to a stimulus.19,53 The reduced P100 amplitude among institutionally reared children suggests reduced allocation of attention to facial stimuli among institutionally reared compared with community-reared children. Developmental studies suggest that face-sensitive ERP components are shaped by life experiences18,19; therefore, a blunted P100 in response to faces among the institutionalized children may be a consequence of insufficient social interaction, a common experience of institutional life.23 However, a blunted P100 amplitude in response to facial stimuli was only associated with psychiatric symptoms among institutionally reared children. This pattern suggests that blunted neural processing has different functional significance for children raised in institutional settings than those raised in the community, potentially because the blunted P100 reflects a more generalized pattern of neural hypoactivation among the institutionally reared children, which has been previously documented as a neurodevelopmental factor linking institutionalization to psychopathology in the BEIP sample.3

Compared with the P100, little is known about the functional significance of the P700 in early childhood or in relation to psychopathology in childhood or adulthood. In one study, Nelson and Nugent54 examined the P700 among children ages 4 to 6 years in a task requiring recognition of happy and angry faces. The P700 distinguished between target and nontarget events (with lower amplitude for nontarget stimuli), which suggests that it may have a role in the allocation of attention and memory resources. Based on ERP patterns and scalp topography in comparable studies, researchers have hypothesized that the P700 in children may be analogous to the P300 component in adults,54 with the difference in latency resulting from physiological, anatomic, and cognitive differences between children and adults (ie, resulting in faster processing of information among adults). In the case that P700 in children is comparable to P300 in adults, our findings may be consistent with research showing a relationship between reduced P300 in a variety of performance tasks and psychopathology, including ADHD and other externalizing symptoms in youth5558 and adults.59 At present, we are unaware of prior evidence showing that a reduced P700 (or P300) mediates the relationship between adverse early experiences and psychopathology.

Our results are broadly consistent with prior research documenting deleterious effects of adverse early experiences, such as maltreatment and institutionalization, on neurodevelopment.18,60 In this study, we cannot establish whether blunted P100 and P700 are specific to facial stimuli. It is plausible that children who are raised in deprived environments that lack stimulation may later become less responsive or attentive to both facial and nonfacial stimuli. The blunted P100 and P700 ERP responses in our sample may reflect lower automatic and controlled attention to visual information, which may serve to recruit attentional and cognitive control for emotion regulation and behavioral inhibition. At present, the underlying neural substrates that may explain these findings are unknown. It is plausible that the amygdala may be indirectly involved, in light of evidence that (1) the amygdala is particularly sensitive to social adversity in early life,24,26 (2) the amygdala is involved in the perception of faces,61 and (3) abnormal amygdala structure and function is associated with psychopathology, including ADHD.35,39 However, it is possible that disruptions in brain regions involved in more basic sensory processing of visual information, such as the thalamus and visual cortex, are also contributing to these findings.

Our findings contribute to a small but growing literature suggesting a role for differences in neurodevelopment as a mechanism linking adverse early experiences to the onset of psychopathology in children and adolescents. For example, in a study of female adolescents, greater left hemisphere EEG coherence significantly mediated the association between childhood maltreatment and psychiatric impairment.62 A previous study in the BEIP found that reductions in alpha-relative power and elevations in theta-relative power, assessed using EEG, mediated the association between institutionalization and symptoms of ADHD.3 Our findings build on this initial report by showing that neural hypoactivation in the occipital region to facial stimuli contributes to elevations in ADHD symptoms among institutionally reared children. Taken together, these studies are beginning to clarify the pathways through which early experiences become biologically embedded to increase risk for psychopathology. Identifying these links is critical for advancing knowledge about the neural processes involved in the development of mental disorders among institutionalized youth. A more robust neurobiologic model of early life deprivation may help researchers identify aspects of neural processing that could be targeted by interventions for children exposed to adverse conditions to ameliorate the negative impact of adverse experiences on neural function and psychopathology.

Although our study focused on children exposed to a particularly extreme adverse rearing environment, the findings have relevance for understanding the neural mechanisms that link less severe forms of early life deprivation to psychopathology.60 Child poverty and neglect are associated with elevated rates of childhood externalizing problems,63,64 and similar neurodevelopmental mechanisms may underlie the associations between these exposures and externalizing psychopathology. Indeed, children from families with low maternal education exhibited blunted ERP amplitudes in a selective auditory attention task compared with children from families with higher levels of maternal education.65 Further clarifying the effects of these other types of early life adversity on neural processing is an important goal for future research. Moreover, because the institutionalized children in the BEIP were exposed to pervasively disadvantaged conditions involving deprivation in social, emotional, language, and sensory stimulation, it is not possible for us to pinpoint the specific features of environmental deprivation that contributed to the abnormal processing patterns observed in this sample. This is another important objective for future research, given the relevance for targeting prevention efforts to children in high-risk environments.

The results of this study should be interpreted in light of several limitations. First, the BEIP only assessed ERPs during the presentation of facial stimuli; as a consequence, the results cannot differentiate whether deficits in neural functioning are face specific or represent more general visual-processing anomalies. Additional research that contrasts ERPs to face and nonface stimuli is needed to understand whether mediation is specific to facial perception. Second, the study focused on children reared in Romanian institutions characterized by significant deprivation. Our findings may not generalize to children who experience less severe forms of deprivation, and thus warrant replication in other populations. Third, it is possible that group differences in psychiatric symptoms and ERPs may have resulted from factors other than the rearing environment in early childhood, such as prenatal exposure to toxins,66 malnutrition,67 or genetic factors.68 There is no evidence that Romanian families who place their children in institutional care experience more harmful prenatal exposures relative to families who do not. Importantly, the cultural and political context in Romania when the study was initiated was one in which institutionalization of children was common owing to chronic poverty and economic stagnation as well as a legacy of punitive laws regarding contraception and government policies that encouraged families to place children in institutional care.41 Thus, these selection factors were less likely to have influenced our results than they might in other samples of institutionalized children. Moreover, we controlled for potential prenatal factors by controlling for birth weight and head circumference in all analyses.

Fourth, the BEIP did not assess mental health status at baseline because of the children's ages; therefore, the extent to which abnormal ERPs are a cause vs consequence of psychiatric symptoms requires further investigation. However, given the young age of children at the ERP assessment, the hypothesized association of abnormal neural processing leading to later psychopathology is most plausible. Fifth, variation in the duration, extent, and timing of exposure to preferred caregiver vs mother is a limitation in using the caregiver as the familiar facial stimuli and reporting on the PAPA; however, caregivers are the adults who most resemble parents for institutionalized children, so this was the best available option. Great care was taken to select a caregiver who knew each child well. Finally, the relatively small size of our sample limited our statistical power to detect significant associations. For this reason, we examined continuous psychiatric symptom scores as outcomes rather than categorical diagnoses. Several future research questions arise from this study. Research is needed to examine the mechanisms by which abnormal ERPs to faces relate to ADHD symptoms. At present, it is unknown whether this mechanism functions at a behavioral level or if this association is largely a function of perturbations at the circuit level (in limbic circuitry or other regions) that are not evident in behavioral measures. In addition, more research is needed to understand the functional significance of P700 in children.

Abnormal neural processing of visual stimuli (in this study, faces) partially explained elevations in ADHD symptoms among children reared in institutional settings in Bucharest, Romania, relative to children raised in the community. Our results highlight the urgency of improving environmental conditions and the caregiving context for abandoned and orphaned children to prevent a cascade of deleterious effects on psychosocial and neural development that ultimately culminate in psychopathology. Greater understanding of the adverse effects of early adversity on brain development has the potential to inform interventions aimed at altering the social and biological pathways that link detrimental environments to the later onset of psychopathology.

Correspondence: Natalie Slopen, ScD, Center on the Developing Child, Harvard University, 50 Church St, 4th Fl, Cambridge, MA 02138 (nslopen@hsph.harvard.edu).

Submitted for Publication: June 16, 2011; final revision received March 27, 2012; accepted March 28, 2012.

Published Online: June 4, 2012. doi:10.1001 /archgenpsychiatry.2012.444

Financial Disclosure: None reported.

Funding/Support: This research was supported by a grant from the John D. and Catherine T. MacArthur Foundation Research Network on Early Experience and Brain Development (Dr Nelson, network chairman), grant 1R01MH091363 from the National Institute of Mental Health (Dr Nelson), research support from the Robert Wood Johnson Foundation (Dr Slopen), grant MH092526 from the National Institute of Mental Health (Dr McLaughlin), and support from the Binder Family Foundation (Dr Nelson). These funders provided support for all data collection and analysis.

Additional Contributions: We thank members of the MacArthur Foundation Research Network on Early Experience and Brain Development for input regarding the conceptualization, design, and implementation of the project; the caregivers and children who participated in this project; Alissa Westerlund, BA, for her expertise and help in creating event-related potential waveforms; Elizabeth Furtado, BA, for her assistance with data management; and Bucharest Early Intervention Project staff members for their tireless work on our behalf.

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PubMed   |  Link to Article
Rutter ML, Kreppner JM, O’Connor TG.English and Romanian Adoptees (ERA) Study Team.  Specificity and heterogeneity in children's responses to profound institutional privation.  Br J Psychiatry. 2001;179:97-103
PubMed   |  Link to Article
Kreppner JM, Rutter M, Beckett C, Castle J, Colvert E, Groothues C, Hawkins A, O’Connor TG, Stevens S, Sonuga-Barke EJS. Normality and impairment following profound early institutional deprivation: a longitudinal follow-up into early adolescence.  Dev Psychol. 2007;43(4):931-946
PubMed   |  Link to Article
Zeanah CH, Egger HL, Smyke AT, Nelson CA, Fox NA, Marshall PJ, Guthrie D. Institutional rearing and psychiatric disorders in Romanian preschool children.  Am J Psychiatry. 2009;166(7):777-785
PubMed   |  Link to Article
Stevens SE, Sonuga-Barke EJS, Kreppner JM, Beckett C, Castle J, Colvert E, Groothues C, Hawkins A, Rutter M. Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence.  J Abnorm Child Psychol. 2008;36(3):385-398
PubMed   |  Link to Article
Gunnar MR, Van Dulmen MHM.International Adoption Project Team.  Behavior problems in postinstitutionalized internationally adopted children.  Dev Psychopathol. 2007;19(1):129-148
PubMed   |  Link to Article
Tarullo AR, Garvin MC, Gunnar MR. Atypical EEG power correlates with indiscriminately friendly behavior in internationally adopted children.  Dev Psychol. 2011;47(2):417-431
PubMed   |  Link to Article
Cicchetti D, Curtis WJ. An event-related potential study of the processing of affective facial expressions in young children who experienced maltreatment during the first year of life.   Dev Psychopathol. 2005;17(3):641-677
PubMed
Nelson CA III, McCleery JP. Use of event-related potentials in the study of typical and atypical development.  J Am Acad Child Adolesc Psychiatry. 2008;47(11):1252-1261
PubMed   |  Link to Article
Pollak SD, Sinha P. Effects of early experience on children's recognition of facial displays of emotion.  Dev Psychol. 2002;38(5):784-791
PubMed   |  Link to Article
Parker SW, Nelson CA.Bucharest Early Intervention Project Core Group.  An event-related potential study of the impact of institutional rearing on face recognition.  Dev Psychopathol. 2005;17(3):621-639
Link to Article
Parker SW, Nelson CA.Bucharest Early Intervention Project Core Group.  The impact of early institutional rearing on the ability to discriminate facial expressions of emotion: an event-related potential study.  Child Dev. 2005;76(1):54-72
PubMed   |  Link to Article
Smyke AT, Koga SF, Johnson DE, Fox NA, Marshall PJ, Nelson CA, Zeanah CH.BEIP Core Group.  The caregiving context in institution-reared and family-reared infants and toddlers in Romania.  J Child Psychol Psychiatry. 2007;48(2):210-218
PubMed   |  Link to Article
Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature.  Psychopharmacology (Berl). 2011;214(1):55-70
PubMed   |  Link to Article
Adolphs R. Neural systems for recognizing emotion.  Curr Opin Neurobiol. 2002;12(2):169-177
PubMed   |  Link to Article
Tottenham N, Hare TA, Quinn BT, McCarry TW, Nurse M, Gilhooly T, Millner A, Galvan A, Davidson MC, Eigsti IM, Thomas KM, Freed PJ, Booma ES, Gunnar MR, Altemus M, Aronson J, Casey BJ. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation.  Dev Sci. 2010;13(1):46-61
PubMed   |  Link to Article
Nagar S, Sherer JT, Chen H, Aparasu RR. Extent of functional impairment in children and adolescents with depression.  Curr Med Res Opin. 2010;26(9):2057-2064
PubMed   |  Link to Article
de Boo GM, Prins PJM. Social incompetence in children with ADHD: possible moderators and mediators in social-skills training.  Clin Psychol Rev. 2007;27(1):78-97
PubMed   |  Link to Article
Da Fonseca D, Seguier V, Santos A, Poinso F, Deruelle C. Emotion understanding in children with ADHD.  Child Psychiatry Hum Dev. 2009;40(1):111-121
PubMed   |  Link to Article
Cadesky EB, Mota VL, Schachar RJ. Beyond words: how do children with ADHD and/or conduct problems process nonverbal information about affect?  J Am Acad Child Adolesc Psychiatry. 2000;39(9):1160-1167
PubMed   |  Link to Article
Guyer AE, McClure EB, Adler AD, Brotman MA, Rich BA, Kimes AS, Pine DS, Ernst M, Leibenluft E. Specificity of facial expression labeling deficits in childhood psychopathology.  J Child Psychol Psychiatry. 2007;48(9):863-871
PubMed   |  Link to Article
Rich BA, Grimley ME, Schmajuk M, Blair KS, Blair RJR, Leibenluft E. Face emotion labeling deficits in children with bipolar disorder and severe mood dysregulation.  Dev Psychopathol. 2008;20(2):529-546
PubMed   |  Link to Article
Dawson G, Webb SJ, Carver L, Panagiotides H, McPartland J. Young children with autism show atypical brain responses to fearful versus neutral facial expressions of emotion.  Dev Sci. 2004;7(3):340-359
PubMed   |  Link to Article
Rich BA, Vinton DT, Roberson-Nay R, Hommer RE, Berghorst LH, McClure EB, Fromm SJ, Pine DS, Leibenluft E. Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder.  Proc Natl Acad Sci USA. 2006;103(23):8900-8905
PubMed   |  Link to Article
Brotman MA, Rich BA, Guyer AE, Lunsford JR, Horsey SE, Reising MM, Thomas LA, Fromm SJ, Towbin K, Pine DS, Leibenluft E. Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder.  Am J Psychiatry. 2010;167(1):61-69
PubMed   |  Link to Article
Webb SJ, Dawson G, Bernier R, Panagiotides H. ERP evidence of atypical face processing in young children with autism.  J Autism Dev Disord. 2006;36(7):881-890
PubMed   |  Link to Article
Morris JS, Friston KJ, Büchel C, Frith CD, Young AW, Calder AJ, Dolan RJ. A neuromodulatory role for the human amygdala in processing emotional facial expressions.  Brain. 1998;121(pt 1):47-57
PubMed   |  Link to Article
Plessen KJ, Bansal R, Zhu HT, Whiteman R, Amat J, Quackenbush GA, Martin L, Durkin K, Blair C, Royal J, Hugdahl K, Peterson BS. Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder.  Arch Gen Psychiatry. 2006;63(7):795-807
PubMed   |  Link to Article
Frodl T, Stauber J, Schaaff N, Koutsouleris N, Scheuerecker J, Ewers M, Omerovic M, Opgen-Rhein M, Hampel H, Reiser M, Möller HJ, Meisenzahl E. Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers.  Acta Psychiatr Scand. 2010;121(2):111-118
PubMed   |  Link to Article
Baron-Cohen S, Ring HA, Bullmore ET, Wheelwright S, Ashwin C, Williams SCR. The amygdala theory of autism.  Neurosci Biobehav Rev. 2000;24(3):355-364
PubMed   |  Link to Article
Zeanah CH, Nelson CA, Fox NA, Smyke AT, Marshall P, Parker SW, Koga S. Designing research to study the effects of institutionalization on brain and behavioral development: The Bucharest Early Intervention Project.  Dev Psychopathol. 2003;15(4):885-907
PubMed   |  Link to Article
Zeanah CH, Koga SF, Simion B, Stanescu A, Tabacaru CL, Fox NA, Nelson CA.BEIP Core Group.  Ethical considerations in international research collaboration: The Bucharest Early Intervention Project.  Infant Ment Health J. 2006;27(6):559-576Link to Article
Link to Article
Miller FG. The randomized controlled trial as a demonstration project: an ethical perspective.  Am J Psychiatry. 2009;166(7):743-745
PubMed   |  Link to Article
Millum J, Emanuel EJ. Ethics: the ethics of international research with abandoned children.  Science. 2007;318(5858):1874-1875
PubMed   |  Link to Article
Tottenham N, Tanaka JW, Leon AC, McCarry T, Nurse M, Hare TA, Marcus DJ, Westerlund A, Casey BJ, Nelson C. The NimStim set of facial expressions: judgments from untrained research participants.  Psychiatry Res. 2009;168(3):242-249
PubMed   |  Link to Article
Denham SA, Couchoud EA. Young preschoolers' understanding of emotions.  Child Study J. 1990;20(3):171
Gratton G, Coles MGH, Donchin E. A new method for off-line removal of ocular artifact.  Electroencephalogr Clin Neurophysiol. 1983;55(4):468-484
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Egger HL, Erkanli A, Keeler G, Potts E, Walter BK, Angold A. Test-retest reliability of the Preschool Age Psychiatric Assessment (PAPA).  J Am Acad Child Adolesc Psychiatry. 2006;45(5):538-549
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Egger H, Ascher B, Angold A. The Preschool Age Psychiatric Assessment: Version 1.1. Durham, North Carolina: Duke University Medical Center; 1999
MacKinnon DP, Lockwood CM, Hoffman JM, West SG, Sheets V. A comparison of methods to test mediation and other intervening variable effects.  Psychol Methods. 2002;7(1):83-104
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Baron RM, Kenny DA. The moderator-mediator variable distinction in social psychological research: conceptual, strategic, and statistical considerations.  J Pers Soc Psychol. 1986;51(6):1173-1182
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Preacher KJ, Hayes AF. Asymptotic and resampling strategies for assessing and comparing indirect effects in multiple mediator models.  Behav Res Methods. 2008;40(3):879-891
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Mangun GR. Neural mechanisms of visual selective attention.  Psychophysiology. 1995;32(1):4-18
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Nelson CA, Nugent KM. Recognition memory and resource allocation as revealed by children's event-related potential responses to happy and angry faces.  Dev Psychol. 1990;26(2):171-179Link to Article
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Brandeis D, Banaschewski T, Baving L, Georgiewa P, Blanz B, Warnke A, Steinhausen HC, Rothenberger A, Scheuerpflug P. Multicenter P300 brain mapping of impaired attention to cues in hyperkinetic children.  J Am Acad Child Adolesc Psychiatry. 2002;41(8):990-998
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Patrick CJ, Bernat EM, Malone SM, Iacono WG, Krueger RF, McGue M. P300 amplitude as an indicator of externalizing in adolescent males.  Psychophysiology. 2006;43(1):84-92
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Iacono WG, Carlson SR, Malone SM, McGue M. P3 event-related potential amplitude and the risk for disinhibitory disorders in adolescent boys.  Arch Gen Psychiatry. 2002;59(8):750-757
PubMed   |  Link to Article
Barry RJ, Johnstone SJ, Clarke AR. A review of electrophysiology in attention-deficit/hyperactivity disorder, II: event-related potentials.  Clin Neurophysiol. 2003;114(2):184-198
PubMed   |  Link to Article
Szuromi B, Czobor P, Komlósi S, Bitter I. P300 deficits in adults with attention deficit hyperactivity disorder: a meta-analysis.  Psychol Med. 2011;41(7):1529-1538
PubMed   |  Link to Article
Nelson CA. A neurobiological perspective on early human deprivation.  Child Dev Perspect. 2007;1(1):13-18Link to Article
Link to Article
Thomas KM, Drevets WC, Whalen PJ, Eccard CH, Dahl RE, Ryan ND, Casey BJ. Amygdala response to facial expressions in children and adults.  Biol Psychiatry. 2001;49(4):309-316
PubMed   |  Link to Article
Miskovic V, Schmidt LA, Georgiades K, Boyle M, Macmillan HL. Adolescent females exposed to child maltreatment exhibit atypical EEG coherence and psychiatric impairment: linking early adversity, the brain, and psychopathology.  Dev Psychopathol. 2010;22(2):419-432
PubMed   |  Link to Article
Costello EJ, Compton SN, Keeler G, Angold A. Relationships between poverty and psychopathology: a natural experiment.  JAMA. 2003;290(15):2023-2029
PubMed   |  Link to Article
Repetti RL, Taylor SE, Seeman TE. Risky families: family social environments and the mental and physical health of offspring.  Psychol Bull. 2002;128(2):330-366
PubMed   |  Link to Article
Stevens C, Lauinger B, Neville H. Differences in the neural mechanisms of selective attention in children from different socioeconomic backgrounds: an event-related brain potential study.  Dev Sci. 2009;12(4):634-646
PubMed   |  Link to Article
Nomura Y, Marks DJ, Halperin JM. Prenatal exposure to maternal and paternal smoking on attention deficit hyperactivity disorders symptoms and diagnosis in offspring.  J Nerv Ment Dis. 2010;198(9):672-678
PubMed   |  Link to Article
Lukas WD, Campbell BC. Evolutionary and ecological aspects of early brain malnutrition in humans.  Hum Nat. 2000;11(1):1-26Link to Article
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Ilott NE, Saudino KJ, Asherson P. Genetic influences on attention deficit hyperactivity disorder symptoms from age 2 to 3: a quantitative and molecular genetic investigation.  BMC Psychiatry. 2010;10:102
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. Grand averaged event-related potential waveforms of institutionalized and never-institutionalized children at the baseline assessment over the right occipital electrode collapsed across familiar and unfamiliar faces.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Grand averaged event-related potential waveforms of institutionalized and never-institutionalized children at the baseline assessment over the right occipital electrode collapsed across happy, sad, angry, and fearful emotions.

Tables

Table Graphic Jump LocationTable 1. Psychiatric Symptoms Among Children Reared in Institutions and Community Control Childrena
Table Graphic Jump LocationTable 2. Peak Amplitude ERP Values Among Children Reared in Institutions and Community Control Childrena
Table Graphic Jump LocationTable 3. Associations Between Peak Amplitude ERPs During Recognition and Emotion Tasks at Baseline and Symptoms of Psychopathology at 54 Monthsa
Table Graphic Jump LocationTable 4. Mediation of the Effect of Institutionalization on Symptoms of Psychopathology Through P700; Presented for ERPs and Outcomes That Met Criteria for Potential Mediationa

References

Committee on the Rights of the Child, United Nations Childrens' Fund.  Children Without Parental Care. New York, New York: United Nations High Commissioner for Human Rights; 2004
Johnson DE, Guthrie D, Smyke AT, Koga SF, Fox NA, Zeanah CH, Nelson CA III. Growth and associations between auxology, caregiving environment, and cognition in socially deprived Romanian children randomized to foster vs ongoing institutional care.  Arch Pediatr Adolesc Med. 2010;164(6):507-516
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McLaughlin KA, Fox NA, Zeanah CH, Sheridan MA, Marshall P, Nelson CA. Delayed maturation in brain electrical activity partially explains the association between early environmental deprivation and symptoms of attention-deficit/hyperactivity disorder.  Biol Psychiatry. 2010;68(4):329-336
PubMed   |  Link to Article
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Ghera MM, Marshall PJ, Fox NA, Zeanah CH, Nelson CA, Smyke AT, Guthrie D. The effects of foster care intervention on socially deprived institutionalized children's attention and positive affect: results from the BEIP study.  J Child Psychol Psychiatry. 2009;50(3):246-253
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Marshall PJ, Reeb BC, Fox NA, Nelson CA III, Zeanah CH. Effects of early intervention on EEG power and coherence in previously institutionalized children in Romania.  Dev Psychopathol. 2008;20(3):861-880
PubMed   |  Link to Article
Moulson MC, Westerlund A, Fox NA, Zeanah CH, Nelson CA. The effects of early experience on face recognition: an event-related potential study of institutionalized children in Romania.  Child Dev. 2009;80(4):1039-1056
PubMed   |  Link to Article
Moulson MC, Fox NA, Zeanah CH, Nelson CA. Early adverse experiences and the neurobiology of facial emotion processing.  Dev Psychol. 2009;45(1):17-30
PubMed   |  Link to Article
Rutter ML, Kreppner JM, O’Connor TG.English and Romanian Adoptees (ERA) Study Team.  Specificity and heterogeneity in children's responses to profound institutional privation.  Br J Psychiatry. 2001;179:97-103
PubMed   |  Link to Article
Kreppner JM, Rutter M, Beckett C, Castle J, Colvert E, Groothues C, Hawkins A, O’Connor TG, Stevens S, Sonuga-Barke EJS. Normality and impairment following profound early institutional deprivation: a longitudinal follow-up into early adolescence.  Dev Psychol. 2007;43(4):931-946
PubMed   |  Link to Article
Zeanah CH, Egger HL, Smyke AT, Nelson CA, Fox NA, Marshall PJ, Guthrie D. Institutional rearing and psychiatric disorders in Romanian preschool children.  Am J Psychiatry. 2009;166(7):777-785
PubMed   |  Link to Article
Stevens SE, Sonuga-Barke EJS, Kreppner JM, Beckett C, Castle J, Colvert E, Groothues C, Hawkins A, Rutter M. Inattention/overactivity following early severe institutional deprivation: presentation and associations in early adolescence.  J Abnorm Child Psychol. 2008;36(3):385-398
PubMed   |  Link to Article
Gunnar MR, Van Dulmen MHM.International Adoption Project Team.  Behavior problems in postinstitutionalized internationally adopted children.  Dev Psychopathol. 2007;19(1):129-148
PubMed   |  Link to Article
Tarullo AR, Garvin MC, Gunnar MR. Atypical EEG power correlates with indiscriminately friendly behavior in internationally adopted children.  Dev Psychol. 2011;47(2):417-431
PubMed   |  Link to Article
Cicchetti D, Curtis WJ. An event-related potential study of the processing of affective facial expressions in young children who experienced maltreatment during the first year of life.   Dev Psychopathol. 2005;17(3):641-677
PubMed
Nelson CA III, McCleery JP. Use of event-related potentials in the study of typical and atypical development.  J Am Acad Child Adolesc Psychiatry. 2008;47(11):1252-1261
PubMed   |  Link to Article
Pollak SD, Sinha P. Effects of early experience on children's recognition of facial displays of emotion.  Dev Psychol. 2002;38(5):784-791
PubMed   |  Link to Article
Parker SW, Nelson CA.Bucharest Early Intervention Project Core Group.  An event-related potential study of the impact of institutional rearing on face recognition.  Dev Psychopathol. 2005;17(3):621-639
Link to Article
Parker SW, Nelson CA.Bucharest Early Intervention Project Core Group.  The impact of early institutional rearing on the ability to discriminate facial expressions of emotion: an event-related potential study.  Child Dev. 2005;76(1):54-72
PubMed   |  Link to Article
Smyke AT, Koga SF, Johnson DE, Fox NA, Marshall PJ, Nelson CA, Zeanah CH.BEIP Core Group.  The caregiving context in institution-reared and family-reared infants and toddlers in Romania.  J Child Psychol Psychiatry. 2007;48(2):210-218
PubMed   |  Link to Article
Pechtel P, Pizzagalli DA. Effects of early life stress on cognitive and affective function: an integrated review of human literature.  Psychopharmacology (Berl). 2011;214(1):55-70
PubMed   |  Link to Article
Adolphs R. Neural systems for recognizing emotion.  Curr Opin Neurobiol. 2002;12(2):169-177
PubMed   |  Link to Article
Tottenham N, Hare TA, Quinn BT, McCarry TW, Nurse M, Gilhooly T, Millner A, Galvan A, Davidson MC, Eigsti IM, Thomas KM, Freed PJ, Booma ES, Gunnar MR, Altemus M, Aronson J, Casey BJ. Prolonged institutional rearing is associated with atypically large amygdala volume and difficulties in emotion regulation.  Dev Sci. 2010;13(1):46-61
PubMed   |  Link to Article
Nagar S, Sherer JT, Chen H, Aparasu RR. Extent of functional impairment in children and adolescents with depression.  Curr Med Res Opin. 2010;26(9):2057-2064
PubMed   |  Link to Article
de Boo GM, Prins PJM. Social incompetence in children with ADHD: possible moderators and mediators in social-skills training.  Clin Psychol Rev. 2007;27(1):78-97
PubMed   |  Link to Article
Da Fonseca D, Seguier V, Santos A, Poinso F, Deruelle C. Emotion understanding in children with ADHD.  Child Psychiatry Hum Dev. 2009;40(1):111-121
PubMed   |  Link to Article
Cadesky EB, Mota VL, Schachar RJ. Beyond words: how do children with ADHD and/or conduct problems process nonverbal information about affect?  J Am Acad Child Adolesc Psychiatry. 2000;39(9):1160-1167
PubMed   |  Link to Article
Guyer AE, McClure EB, Adler AD, Brotman MA, Rich BA, Kimes AS, Pine DS, Ernst M, Leibenluft E. Specificity of facial expression labeling deficits in childhood psychopathology.  J Child Psychol Psychiatry. 2007;48(9):863-871
PubMed   |  Link to Article
Rich BA, Grimley ME, Schmajuk M, Blair KS, Blair RJR, Leibenluft E. Face emotion labeling deficits in children with bipolar disorder and severe mood dysregulation.  Dev Psychopathol. 2008;20(2):529-546
PubMed   |  Link to Article
Dawson G, Webb SJ, Carver L, Panagiotides H, McPartland J. Young children with autism show atypical brain responses to fearful versus neutral facial expressions of emotion.  Dev Sci. 2004;7(3):340-359
PubMed   |  Link to Article
Rich BA, Vinton DT, Roberson-Nay R, Hommer RE, Berghorst LH, McClure EB, Fromm SJ, Pine DS, Leibenluft E. Limbic hyperactivation during processing of neutral facial expressions in children with bipolar disorder.  Proc Natl Acad Sci USA. 2006;103(23):8900-8905
PubMed   |  Link to Article
Brotman MA, Rich BA, Guyer AE, Lunsford JR, Horsey SE, Reising MM, Thomas LA, Fromm SJ, Towbin K, Pine DS, Leibenluft E. Amygdala activation during emotion processing of neutral faces in children with severe mood dysregulation versus ADHD or bipolar disorder.  Am J Psychiatry. 2010;167(1):61-69
PubMed   |  Link to Article
Webb SJ, Dawson G, Bernier R, Panagiotides H. ERP evidence of atypical face processing in young children with autism.  J Autism Dev Disord. 2006;36(7):881-890
PubMed   |  Link to Article
Morris JS, Friston KJ, Büchel C, Frith CD, Young AW, Calder AJ, Dolan RJ. A neuromodulatory role for the human amygdala in processing emotional facial expressions.  Brain. 1998;121(pt 1):47-57
PubMed   |  Link to Article
Plessen KJ, Bansal R, Zhu HT, Whiteman R, Amat J, Quackenbush GA, Martin L, Durkin K, Blair C, Royal J, Hugdahl K, Peterson BS. Hippocampus and amygdala morphology in attention-deficit/hyperactivity disorder.  Arch Gen Psychiatry. 2006;63(7):795-807
PubMed   |  Link to Article
Frodl T, Stauber J, Schaaff N, Koutsouleris N, Scheuerecker J, Ewers M, Omerovic M, Opgen-Rhein M, Hampel H, Reiser M, Möller HJ, Meisenzahl E. Amygdala reduction in patients with ADHD compared with major depression and healthy volunteers.  Acta Psychiatr Scand. 2010;121(2):111-118
PubMed   |  Link to Article
Baron-Cohen S, Ring HA, Bullmore ET, Wheelwright S, Ashwin C, Williams SCR. The amygdala theory of autism.  Neurosci Biobehav Rev. 2000;24(3):355-364
PubMed   |  Link to Article
Zeanah CH, Nelson CA, Fox NA, Smyke AT, Marshall P, Parker SW, Koga S. Designing research to study the effects of institutionalization on brain and behavioral development: The Bucharest Early Intervention Project.  Dev Psychopathol. 2003;15(4):885-907
PubMed   |  Link to Article
Zeanah CH, Koga SF, Simion B, Stanescu A, Tabacaru CL, Fox NA, Nelson CA.BEIP Core Group.  Ethical considerations in international research collaboration: The Bucharest Early Intervention Project.  Infant Ment Health J. 2006;27(6):559-576Link to Article
Link to Article
Miller FG. The randomized controlled trial as a demonstration project: an ethical perspective.  Am J Psychiatry. 2009;166(7):743-745
PubMed   |  Link to Article
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