© 2009 The Authors. Journal compilation © 2009 Blackwell Publishing Ltd
Developmental Science
Volume 13, Issue 1, pages 46–61, January 2010
Abstract
Early adversity, for example poor caregiving, can have profound effects on emotional development. Orphanage rearing, even in the best circumstances, lies outside of the bounds of a species-typical caregiving environment. The long-term effects of this early adversity on the neurobiological development associated with socio-emotional behaviors are not well understood. Seventy-eight children, who include those who have experienced orphanage care and a comparison group, were assessed. Magnetic resonance imaging (MRI) was used to measure volumes of whole brain and limbic structures (e.g. amygdala, hippocampus). Emotion regulation was assessed with an emotional go-nogo paradigm, and anxiety and internalizing behaviors were assessed using the Screen for Child Anxiety Related Emotional Disorders, the Child Behavior Checklist, and a structured clinical interview. Late adoption was associated with larger corrected amygdala volumes, poorer emotion regulation, and increased anxiety. Although more than 50% of the children who experienced orphanage rearing met criteria for a psychiatric disorder, with a third having an anxiety disorder, the group differences observed in amygdala volume were not driven by the presence of an anxiety disorder. The findings are consistent with previous reports describing negative effects of prolonged orphanage care on emotional behavior and with animal models that show long-term changes in the amygdala and emotional behavior following early postnatal stress. These changes in limbic circuitry may underlie residual emotional and social problems experienced by children who have been internationally adopted.
Introduction
According to data published by the US Department of State, approximately twenty thousand infants and children are adopted from abroad each year – a trend that has increased steadily over the past 15 years. With this growing number of adopted children in the US has come a new wave of studies on the effects of orphanage rearing and growing concerns on the long-term consequences of such early experiences (Ames, 1990). As outlined by Gunnar, Bruce and Grotevant (2000), the social-emotional behavioral domain, including attachment relationships (Smyke, Dumitrescu & Zeanah, 2002), peer interactions, and emotion regulation (Hodges & Tizard, 1989), is a common area of concern for previously institutionalized (PI) children. In a sample of Romanian children, emotional behavior with peers was disrupted even in children adopted before 4 months of age who showed resilience in other non-emotional developmental domains (Ames, 1997). Diagnostically, PI children have an increased prevalence of anxiety disorders (Ellis, Fisher & Zaharie, 2004). Such emotional difficulties may reflect a more general problem of heightened emotional reactivity. These socio-emotional profiles may be ameliorated by living with post-adoption families, but subtle effects tend to remain well into adolescence (Hodges & Tizzard, 1989), a finding that suggests that there may be long-term changes in neural systems associated with processing emotional information following orphanage care.
Even in the best institutions, orphanage care is outside the bounds of species-typical caregiving. As described by Gunnar and colleagues (2000; Gunnar & van Dulmen, 2007), the caregivers are paid employees who rotate shifts and are in charge of an overwhelming number of children (sometimes as high as 20 children:1 caregiver), resulting in continuous instability of caregiving for an infant, and the caregiving in an orphanage lacks in terms of both quality and quantity (Smyke, Koga, Johnson, Fox, Marshall, Nelson, Zeanah & Group, 2007). Lack of a stable caregiver is a potent stressor for the human infant (Johnson, 2002). In fact, unstable caregiving in an otherwise enriched environment (e.g. high staff-to-child ratios, stimulating toys), is sufficient to alter social and emotional behavior years after adoption (Hodges & Tizard, 1989). Studying the emotional development of children who had been institutionalized during infancy and have subsequently been removed from this environment allows us to ask questions regarding the long-term correlates of early adversity (which is often difficult to separate from later-life adversity) in a human sample.
Impact of adversity on emotional processing
Individuals with a history of maltreatment have difficulty regulating their emotions in the context of threatening stimuli (Pollak, Vardi, Putzer Bechner & Curtin, 2005). There is evidence to suggest that the difficulties arise in part because of enhanced processing of negatively valenced information. Maltreated children show a greater attentional bias for negatively valenced stimuli in a dot-probe task (Dalgleish, Moradi, Taghavi, Neshat-Doost & Yule, 2001), a processing bias for threatening stimuli, as measured by decreased amount of perceptual information needed to recognize threat (Pollak & Sinha, 2002), and an increased amplitude of the N170, an event-related potential sensitive to facial expressions (Blau, Maurer, Tottenham & McCandliss, 2007), for fear faces (Parker & Nelson, 2005). The emotional weight negatively valenced stimuli carry for individuals with a history of early adversity can result in emotion regulation difficulties (Williams, Mathews & MacLeod, 1996). Such findings suggest that life stressors increase the emotional salience of negative information, making it more difficult for these individuals to regulate behavior in the context of negative information.
This processing bias for negatively valenced information increases the risk of developing an anxiety disorder. It has been shown that both anxious adults (Bradley, Mogg, White, Groom & de Bono, 1999; Derryberry & Reed, 2002) and anxious children (Vasey, el-Hag & Daleiden, 1996) have this bias. Even in a non-referred population of children, higher trait anxiety produces faster search times for threatening faces (Hadwin, Donnelly, French, Richards, Watts & Daley, 2003). Thus, both anxious individuals and those with a history of adversity are more affected by negative information in such a way that perception and orientation toward negative information is enhanced. The neurobiological systems that support these changes in behavior have largely been investigated in animal models. In this article, we present neurobiological and behavioral data that show a relationship between early-life adversity and changes in anxiety-related phenotypes within a population of children.
Animal models of deprivation have provided evidence within a laboratory-controlled setting that the quality of an environment has drastic, long-lasting effects on behavior (Greenough, Black & Wallace, 1987; Greenough, Hwang & Gorman, 1985; Greenough, McDonald, Parnisari & Camel, 1986). The large numbers of changes that occur early in development make this period of life particularly sensitive to environmental effects. Poor or non-existent maternal care produces lifelong alterations in emotion regulation, as evidenced by increased stress reactivity and fearful behavior in the offspring in rodents (Caldji, Tannenbaum, Sharma, Francis, Plotsky & Meaney, 1998; Francis, Champagne, Liu & Meaney, 1999; Huot, Thrivikraman, Meaney & Plotsky, 2001) and in non-human primates that experience stressors while parenting (Rosenblum, Forger, Noland, Trost & Coplan, 2001). Other work has examined the effects of manipulating timing of maternal separation on emotion regulation and showed that while all maternally deprived juvenile rhesus monkeys show increases in anxious behaviors, the timing of maternal deprivation has specific effects on subsequent socio-emotional behavior (Nelson, Bloom, Cameron, Amaral, Dahl & Pine, 2002). The effects of stress on emotional behavior may be mediated by morphologic and neurofunctional changes that follow stressful experiences. These neural phenotypes may, in part, account for the anxiety and emotion regulation difficulties that often characterize the behavior of PI children (Smyke et al., 2002).
Impact of adversity on limbic regions
Stressful experiences produce specific changes in the brain, particularly in limbic regions like the amygdala and hippocampus (McEwen, 2004). The amygdala, a structure implicated in processing and responding to emotional information (Davis & Whalen, 2001), has been shown to be important in learning about the emotional environment and safety of that environment. In adult animals, psychological stressors or direct administration of stress hormones increases dendritic arborization and formation of new spines (Mitra, Jadhav, McEwen, Vyas & Chattarji, 2005; Vyas, Bernal & Chattarji, 2003; Vyas, Mitra, Shankaranarayana Rao & Chattarji, 2002) and activity of the amygdala (Rosen, Hamerman, Sitcoske, Glowa & Schulkin, 1996; Rosen & Schulkin, 1998). Early-life stress has long-term effects, and rat pups who were separated from their mothers during the neonatal period show greater amygdala response to stress as adults than non-separated rats (Sanders & Anticevic, 2007). In contrast, stress decreases hippocampal arborization in rodents (Vyas et al., 2002). Decreased hippocampal volumes have been observed in adult humans who have experienced high levels of stress or trauma (Bremner, Randall, Scott, Bronen, Seibyl, Southwick, Delaney, McCarthy, Charney & Innis, 1995; Bremner, Randall, Vermetten, Staib, Bronen, Mazure, Capelli, McCarthy, Innis & Charney, 1997; Gurvits, Shenton, Hokama, Ohta, Lasko, Gilbertson, Orr, Kikinis, Jolesz, McCarley & Pitman, 1996), although not all studies show this association (Bonne, Brandes, Gilboa, Gomori, Shenton, Pitman & Shalev, 2001; De Bellis, Keshavan, Clark, Casey, Giedd, Boring, Frustaci & Ryan, 1999). Smaller hippocampal volumes have not been reported in children with early-life stress; in fact, one report shows larger hippocampal volume in previously stressed children (Tupler & De Bellis, 2006). Animal models suggest that differences in hippocampal volumes attenuate once the stressor has ended, unlike the stress-related growth in amygdala volume, which seems more resistant to recovery (Vyas, Pillai & Chattarji, 2004). Based on this recovery effect and the lack of evidence of smaller hippocampal volume in previously stressed children, we predict that amygdala changes, but not necessarily hippocampal ones, will be observed in PI children who have been adopted out of orphanages into families.
Consistent with these data from animal models of stress, neuroimaging studies show that stress and trauma affect amygdala structure and function in humans. Previously stressed adults have exaggerated amygdala responses to threatening stimuli relative to nonstressed comparison groups (Liberzon, Taylor, Amdur, Jung, Chamberlain, Minoshima, Koeppe & Fig, 1999; Rauch, Whalen, Shin, McInerney, Macklin, Lasko, Orr & Pitman, 2000; Shin, Wright, Cannistraro, Wedig, McMullin, Martis, Macklin, Lasko, Cavanagh, Krangel, Orr, Pitman, Whalen & Rauch, 2005). Given the amygdala’s role in monitoring the environment for emotional significance (Dolan & Vuilleumier, 2003), these findings would predict more anxious and vigilant behavior in stressed individuals.
A large literature suggests that the amygdala is the mediating agent between environmental stress and subsequent self-regulation difficulties, like anxiety and mood disorders. Amygdala volumes are atypically larger and more reactive in anxious children and adolescents relative to typically developing individuals (De Bellis, Casey, Dahl, Birmaher, Williamson, Thomas, Axelson, Frustaci, Boring, Hall & Ryan, 2000; MacMillan, Szeszko, Moore, Madden, Lorch, Ivey, Banerjee & Rosenberg, 2003; Thomas, Drevets, Dahl, Ryan, Birmaher, Eccard, Axelson, Whalen & Casey, 2001), they are larger in adults at the first episode of depression relative to non-depressed adults (Frodl, Meisenzahl, Zetzsche, Bottlender, Born, Groll, Jager, Leinsinger, Hahn & Moller, 2002), and amygdala volumes positively correlate with levels of anxiety in adults (Barros-Loscertales, Meseguer, Sanjuan, Belloch, Parcet, Torrubia & Avila, 2006). Taken together, the behavioral and neurobiological evidence suggests that adversity is followed by atypical amygdala development and these differences result in greater reactivity to emotional information. Better understanding of how the environment impacts the neurobiological systems that support emotional reactivity provides insight into the etiology of anxious behaviors following stress. However, the varying times and durations of the stressful events in most studies make it unclear how timing played a role in the observed effects, and imaging studies of stressed or anxious populations do not consistently find larger amygdala volumes (Bremner et al., 1997; Lindauer, Vlieger, Jalink, Olff, Carlier, Majoie, den Heeten & Gersons, 2004; Schmahl, Vermetten, Elzinga & Bremner, 2003; Wignall, Dickson, Vaughan, Farrow, Wilkinson, Hunter & Woodruff, 2004). The strength of studying a group of internationally adopted children is that the timing of the adverse experience is known and is temporally discrete.
To get at this issue of timing, studies of PI children have often made distinctions between early and late adoptions because duration of institutionalization affects outcome. The cut-off age has varied from study to study and has included early infancy (O’Connor & Rutter, 2000), 1 year old (van Ijzendoorn & Juffer, 2006), and 2 years old (Gunnar & van Dulmen, 2007; Rutter & O’Connor, 2004). These varying ages suggest that there may not be one critical cut-off age of adoption, but the impact of the cut-off age may differ depending on the outcome measure. The current study places the split between early and later adoptions at the median age of adoption.
The current study used structural magnetic resonance imaging (MRI) to examine the development of limbic structures including the amygdala and hippocampus (controlling for cortical size) with relative specificity to a control structure (caudate), following a discrete period of early-life stress. In addition we measured emotion regulation with an emotional go-nogo behavioral paradigm (Hare, Tottenham, Davidson, Glover & Casey, 2005; Hare, Tottenham, Galvan, Voss, Glover & Casey, 2008; Ladouceur, Dahl, Williamson, Birmaher, Axelson, Ryan & Casey, 2006), shown to recruit the amygdala (Hare et al., 2005, 2008), and measured clinical status using parental reports of individual differences in anxiety symptoms and internalizing behaviors. We hypothesized that longer exposure to orphanage rearing would be associated with larger amygdala volume and greater difficulties in regulating behavior in the context of emotional information. Moreover, we predicted that amygdala volume would be related to these behavioral difficulties and to higher levels of anxiety.