Effects of Early Life Stress on Cognitive and Affective Function: An Integrated Review of Human Literature
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Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, Belmont, MA, USA
Pia Pechtel, Ph.D., Center for Depression, Anxiety, and Stress Research, McLean Hospital, Harvard Medical School, De Marneffe Building, Room 233B, 115 Mill Street, Belmont, MA 02478-9106, Phone: (617) 855-4234, Fax: (617) 855-4231, ude.dravrah.naelcm@lethcepp
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The investigation of putative effects of early life stress (ELS) in humans on later behavior and neurobiology is a fast developing field. While epidemiological and neurobiological studies paint a somber picture of negative outcomes, relatively little attention has been devoted to integrating the breadth of findings concerning possible cognitive and emotional deficits associated with ELS. Emerging findings from longitudinal studies examining developmental trajectories of the brain in healthy samples may provide a new framework to understand mechanisms underlying ELS sequelae.
The goal of this review was two-fold. The first was to summarize findings from longitudinal data on normative brain development. The second was to utilize this framework of normative brain development to interpret changes in developmental trajectories associated with deficits in cognitive and affective function following ELS.
Five principles of normative brain development were identified and used to discuss behavioral and neural sequelae of ELS. Early adversity was found to be associated with deficits in a range of cognitive (cognitive performance, memory, and executive functioning) and affective (reward processing, processing of social and affective stimuli, and emotion regulation) functions.
Three general conclusions emerge: (1) higher-order, complex cognitive and affective functions associated with brain regions undergoing protracted postnatal development are particularly vulnerable to the deleterious effects of ELS; (2) the amygdala is particularly sensitive to early ELS; and (3) several deficits, particularly those in the affective domain, appear to persist years after ELS has ceased and may increase risk for later psychopathology.
Keywords: Early life stress, brain, child abuse, cognitive function, emotion regulation
When a person is challenged in their emotional or physical well-being to an extent that exceeds their ability to cope, stress ensues ( Gunnar and Quevedo 2007 ). Early life stress (ELS) is the exposure to a single or multiple events during childhood that exceeds the child’s coping resources and leads to prolonged phases of stress. Commonly studied early childhood stressors include physical, sexual, emotional or verbal abuse, neglect, social deprivation, disaster or household dysfunctions (including witnessing of violence, criminal activity, parental separation, parental death or illness, poverty, substance abuse) ( Brown et al. 2009 ).
Due to the array of stressors subsumed by the term ELS, obtaining a clear estimate of how many children experience ELS remains challenging. In 2007, 3.5 million (22.5%) children came to the attention of Child Protective Services in the United States alone. The rate of abuse and neglect, not considering household dysfunction, reached 10.6 % in 2007 ( U.S. Department of Health and Human Services 2009 ). Due to low rates of disclosure, these figures likely underestimate the incidence of childhood trauma ( Finklehor 1994 ; Pereda et al. 2009 ).
ELS can be studied behaviorally and biologically. While the acute activation of the body’s stress response systems is considered an adaptive mechanism that mobilizes resources to increase chances of survival, high or chronic levels of stress may disturb brain development and affect mental health ( Anda et al. 2006 ; De Bellis et al. 1999a ; De Bellis et al. 1999b ; Lupien et al. 2009 ; Maniglio 2009 ; Pirkola et al. 2005 ; Spataro et al. 2004 ). Although epidemiological and neurobiological studies portray a somber picture of negative outcomes following ELS ( De Bellis 2005 ; Grassi-Oliveira et al. 2008 ; Teicher et al. 2003 ; Weber and Reynolds 2004 ), relatively little attention has been devoted to evaluating putative cognitive and emotional outcomes of ELS. Such knowledge could prove pivotal in tailoring early intervention and preventing long-term sequelae. In this review, we adopt a developmental approach in which we summarize recent findings on normative brain development in childhood and adolescence to assist later discussion on the disruptions of developmental trajectories of the brain following ELS.
The objective of this review was to review and integrate changes in the neurobiological pathways associated with cognitive and emotional functioning following ELS within the framework of recent longitudinal studies of normal human brain development. Priority was given to studies examining structural or functional sequelae of early adversity in conjunction with cognitive or emotional correlates. While ELS may affect an array of functions, due to space constraints, we have focused on behavioral phenotypes most widely investigated in both the psychological and neuroscientific literature so that inferences about primary pathways of early neurobiological disruptions affecting later well-being could be advanced. In the first section, recent findings of longitudinal studies in healthy samples are reviewed to identify overarching principles of normative brain development. Mechanisms potentially disrupting the trajectory of brain development in those with a history of ELS are also discussed. In the second section, we specifically focus on structural and functional changes associated with deficits in cognitive function (cognitive performance, memory, and executive functioning) and affective functions (reward processing, processing of social and affective stimuli, and emotion regulation). In each section, behavioral, neuroimaging and psychophysiological data are integrated, and selected animal findings are discussed (see other contributions in this issue for more comprehensive reviews of the animal literature on ELS). The review ends with a discussion of future directions of research on ELS.
Early life stress and psychopathology
The recent National Comorbidity Survey highlighted that childhood adverse experiences explain nearly 32% of psychiatric disorders, and an even higher percentage (44%) of disorders with childhood onset ( Green et al. 2010 ). Various forms of early adversity account for about 67% of the population-attributable risk for suicide ( Dube et al. 2001 ). Exposure to multiple episodes of ELS can significantly increase the risk of mental illness and somatic disturbances ( Anda et al. 1999 ; Anda et al. 2006 ; Anda et al. 2007 ; Chapman et al. 2004 ; Cutrona et al. 2005 ; Dong et al. 2004 ; Edwards et al. 2003 ; Pirkola et al. 2005 ). Notably, adults with more than six adverse childhood events had a higher likelihood of dying 20 years earlier than those without such histories ( Anda et al. 2009 ; Brown et al. 2009 ). Others have emphasized the need for more differentiated research methods in order to investigate how common clusters of co-occurring ELS experiences are related to psychopathology ( Green et al. 2010 ; Wright et al. 2009 ).
The sequelae of ELS often depend on the type of adversity, the number of exposures, and, in particular, the age at the time of occurrence. For example, adults who were sexually abused in childhood after the age of 12 were 10 times more likely to develop severe symptoms of post-traumatic stress disorder (PTSD) compared to those who experienced sexual abuse prior to the age of 12 ( Schoedl et al. 2010 ). Teicher and colleagues conducted extensive studies on “sensitive periods” emphasizing that the timing of ELS may especially affect those brain regions undergoing specific growth spurts at the time ( Teicher et al. 2006a , 2006b ). For example, among females, experience of sexual abuse between the ages of 3–5 (and marginally between 11–13 years) was related to smaller hippocampal volume. Conversely, sexual abuse occurring between age 9–10 and 11–14 years was linked to dysfunctions in the corpus callosum and prefrontal cortex (PFC), respectively ( Andersen et al. 2008 ). Based on these and other data, it was concluded that brain regions with extended postnatal development are particularly vulnerable to long-term effects of stress ( Teicher et al. 2003 ).
While research has emphasized the outcomes of ELS on mental health, less attention has been devoted to explaining the link between cognitive and emotional sequelae of ELS and brain development. Before summarizing findings on normative brain development in childhood and adolescence, we would like to emphasize several key points relevant to understanding the limitation of the following discussion. First, neuroimaging research commonly focuses on changes in regional brain volume or cortical thickness. It should be kept in mind that while these volumetric changes are an important mean to identify possible abnormalities, little is known about the specific mechanisms underlying these changes. Disruptions in neurogenesis, myelination, and synaptic pruning are often invoked to explain structural changes, but modest empirical support exists for these claims ( Gogtay and Thompson 2010 ). Furthermore, while delineating structural abnormalities in single regions is an important first step for investigating cognitive and affective deficits following ELS, our limited understanding of the effects of ELS on functional connectivity and development of neural circuits remains an important challenge for the future. Lastly, throughout the review, and consistent with recent publications, we refer to primary, lower-order functions vs. complex, higher-order functions ( Gogtay and Thompson 2010 ; Marsh et al 2008 ). This differentiation should not imply that primary brain functions are deemed as less critical, especially as they become increasingly involved in complex computations during maturation. Instead we emphasize that regional brain development mirrors the immediate needs of each developmental stage which, in turn, may help to explain the diversity in outcomes depending on the timing of ELS.
Brain development in healthy children and adolescents
Brain development is an exceedingly complex process as the organism needs to respond to the challenges and demands of the environment ( Teicher et al. 2006b ). In this section, we highlight five principles of brain development derived from recent findings in healthy longitudinal and cross-sectional samples, which represent the framework along which ELS acts.
Principle 1: Human brain development is largely a nonlinear process
( Giedd et al. 1999 ; Gogtay and Thompson 2010 ; Shaw et al. 2008 ). While the developmental trajectory of grey matter (GM) volume follows an inverted U-shape, white matter (WM) volume increases steadily throughout childhood and adolescence and is likely to reflect improved connectivity and integration of disparate neural circuits ( Gerber and Peterson. 2009 ; Giedd et al. 1999 ). More specifically, different brain regions have been shown to develop along three main patterns of maturation. Cubic developmental trajectories are characterized by an early increase in GM cortical thickness followed by a decrease in adolescence and stabilization in adulthood. This applies, for example, to lateral frontal, lateral temporal, parietal and occipital cortex ( Shaw et al. 2008 ). Cortical thickness in the insula and anterior cingulate follows a quadratic developmental course, increasing over childhood, decreasing in adolescence but demonstrating no phase of stabilization of cortical thickness within first three decades of life. Finally, a linear developmental trajectory corresponding to increased cortical thickness with age is characteristic of a large number of brain regions (e.g., posterior orbitofrontal, frontal operculum, portions of piriform cortex, subgenual cingulate areas) ( Shaw et al. 2008 ). With various brain regions undergoing different patterns of maturation, neural consequences of ELS depend on the developmental stage at which the stress occurred ( Teicher et al. 2003 ). Stress may therefore have a greater impact in childhood and adolescence as the brain experiences critical changes compared to adulthood (e.g., cubic developmental trajectory).
Principle 2: Higher-order association cortices develop only after lower-order sensorimotor cortices have matured in structure and function
( Gogtay et al. 2004 ; Gogtay and Thompson 2010 ; Shaw et al. 2008 ). During the process of development, essential structures such as sensorimotor cortex and occipital poles develop first. The remainder of the cortex matures in a back-to-front direction (parietal to frontal). This ensures the child’s early availability of primary motor and sensory function including vision, taste and smell followed by areas involving spatial orientation, speech, language, and attention. Higher-order structures that contain complex, association sites develop very late in the brain’s trajectory. Among the last areas to develop are frontal lobe structures (e.g. dorsolateral prefrontal cortex (DLPFC)) involved in executive functioning, attention, motor coordination as well as heteromodal association regions (e.g., superior temporal cortex). Association areas mature until basic earlier-developing sensory regions, whose function they integrate, are developed ( Gogtay et al. 2004 ; Gogtay and Thompson 2010 ; Shaw et al. 2008 ). It can thus be hypothesized that complex functions in higher-order structures are more susceptible to the effects of ELS due to protracted periods of postnatal development.
Principle 3: Ontogeny recapitulates phylogeny
( Gogtay et al. 2004 ; Gogtay and Thompson 2010 ; Lenroot et al. 2009 ; Shaw et al. 2008 ). The brain regions latest to mature in development – including the DLPFC, orbitofrontal cortex (OFC), temporal lobes, and superior parietal lobes – are the most recent areas from an evolutionary point of view ( Lenroot et al. 2009 ). Again, these evolutionary ‘young’ structures are linked to higher-order, complex skills such as decision-making, executive functioning, and inhibition ( Gogtay et al. 2004 ; Gogtay and Thompson 2010 ; Shaw et al. 2008 ) and are at greater risk of impairment following ELS.
Principle 4: Brain development is guided by genes but sculpted by the environment
( Lenroot and Giedd, 2008 ; Lenroot et al. 2009 ; Peper et al. 2009 ; Schmitt et al. 2008 ). While early experiences have pivotal effects on brain developmental, recent twin studies in healthy samples also identified substantial genetic influences. For example, a large research study using magnetic resonance imaging (MRI) data from 308 twins, 64 siblings of twins, and 228 singletons with no twin siblings found that a single factor accounted for up to 60% of genetic variance in cortical thickness ( Schmitt et al. 2008 ). Genetic effects were largest for frontal lobes while their influence gradually declined from temporal to parietal lobes with the occipital lobe showing the smallest degree of heritability ( Schmitt et al. 2008 ). Moreover, later-maturing brain regions (e.g., DLPFC, superior parietal cortex, temporal cortex, language-associated regions) involved in complex cognitive processes (e.g., executive function, language) become more heritable with increasing age ( Lenroot and Giedd 2008 ; Lenroot et al. 2009 ). As heritability varies with age, brain regions that develop earlier during development show stronger genetic influences earlier in life, while later developing brain regions are under greater genetic influences later in life ( Lenroot et al. 2009 ). The effects of ELS on brain development may therefore be potentiated or buffered, depending on the strength and timing of genetic influences on specific brain regions.
Principle 5: Trajectories of brain development differ for females and males
( Gerber and Peterson. 2009 ; Lenroot et al. 2007 ; Lenroot and Giedd 2010 ; Marsh et al 2008 ). Gender differences can be found in overall brain volume, with males having a proportionally larger (between 9–12%) mean cerebral volume despite reaching GM peak volume 1–3 years later than females ( Gerber and Peterson. 2009 ; Lenroot and Giedd, 2010 ). However, not all studies found gender differences in total brain volume, especially when controlling for intracranial volume ( Peper et al. 2009 ). Gender specific difference in brain regions occur primarily in areas containing sex steroid receptors (e.g., hypothalamus) or regions with strong connections to areas with high sex steroids receptor density (e.g., amygdala, parts of the nucleus of the stria terminialis) ( Lenroot and Giedd, 2010 ). As developmental trajectories differ for males and females, ELS occurring at the same time may lead to diverse, sex-specific outcomes.
Interim summary: normative brain development
Findings from healthy samples suggest that a given brain region may be affected by ELS differently at different times depending on its pattern of growth. Moreover, high-order cortices and complex functions develop after lower-order cortices and primary functions have matured. Genetic and sex influences jointly contribute to individual differences in brain development. The following section will review the specific mechanisms by which ELS can impact brain development.
Early life stress and brain development
Since the early 1990s, a large body of neurobiological and neuroendocrine studies has highlighted the impact of chronic stress on brain development. The most accepted explanation for alterations in brain structures postulates that ELS interferes with the critical waves of neurogenesis, synaptic overproduction, and pruning of synapses and receptors ( Teicher et al. 2006 ). As the loss in GM often exceeds what can be explained by aberrant increases in synaptic pruning, an expansion in WM through an increase in myelination in intra-cortical axons may also contribute to the apparent loss of GM (for review, see Paus et al. 2008 ). Due to limited resolution of current MRIs, the cellular processes underlying such structural changes, however, remain impenetrable with in vivo neuroimaging techniques ( Gogtay and Thompson 2010 ).
Mechanisms of stress
From a biological point of view, encountering a stressful situation activates the sympathetic nervous system and hypothalamic-pituitary adrenal (HPA) axis (for a review on HPA dysfunction, see Yehuda et al. in this issue; Gunnar and Quevedo 2007 ; Heim and Nemeroff 2001 , Lupien et al. 2009 ). While the acute activation of stress response systems is considered an adaptive mechanism that mobilizes resources to increase chances of survival, high or chronic levels of stress can lead to aberrant reactivity of the HPA axis ( Glaser 2000 ; Gunnar and Quevedo, 2007 ). When faced with a stressor, corticotrophin-releasing hormone and arginine vasopressin travel to the anterior pituitary where they stimulate the release of adrenocorticotropic hormone, which in turn interacts with receptors on the cortex of the adrenal gland ( Gunnar and Quevedo 2007 ; Heim and Nemeroff 2001 ; Lupien et al. 2009 ). This cascade releases glucocorticoids throughout the brain and body binding to mineralocorticoid and glucocorticoid receptors. Most importantly, glucocorticoids acting via glucocorticoid receptors can impair neural plasticity ( Gunnar and Quevedo 2007 ). This explains why brain regions with a particularly high density of glucocorticoid receptors and characterized by prolonged phases of postnatal development (e.g., PFC, hippocampus) are more susceptible to disturbances ( Teicher et al. 2003 ; Tottenham and Sheridan 2010 ). Exactly how ELS affects cognitive functioning and emotional well-being via specific neurobiological pathways, however, remains poorly understood. The following sections review how particular cognitive and affective functions may be affected by disruptions in brain development following ELS.
ELS and cognitive functioning
Global cognitive performance
However, not all studies have found reduced hippocampal volume following ELS. Numerous studies have failed to demonstrate volumetric reductions in younger individuals with ELS ( Carrion et al. 2001 ; De Bellis et al. 2002b ; De Bellis et al. in press ; Teicher et al. 2003 ; see meta-analyses by Karl et al. 2006 ; Woon and Hedges 2008 ; Woon et al. in press ). Moreover, some studies failed to demonstrate a link between abnormal hippocampal volume and deficits in memory functioning following maltreatment ( Pederson et al. 2004 ; Stein et al. 1997 ). In the next sections, we briefly explore the potential explanations for these divergent findings.
a. Prolonged exposure to stress
Some have argued that prolonged periods of cortisol secretion and HPA hyper-activation are needed for long-term hippocampal atrophies to be manifested at the level of resolution of current MRI technology ( Carrion et al. 2007 ). This would imply that hippocampal volume loss may be detectable only years after trauma onset, thus explaining why imaging studies have described hippocampal volume decreases in adults but not children. Preliminary support for this hypothesis stems from a longitudinal study of traumatized children in which markers of stress (PTSD symptoms, cortisol levels) predicted reduced hippocampal volume from baseline to follow-up 12–18 months later ( Carrion et al. 2007 ). However, it should be noted that this study used a very small sample of children (n = 15) with PTSD and a short time interval between initial and follow-up assessment.
b. Preexisting vulnerability
Could reduced hippocampal volume be a risk-factor for stress-related pathology rather a consequence of ELS? It is currently a matter of debate whether smaller hippocampi may be a risk factor for stress hypersensitivity. Non-human primate research illustrates that naturally occurring hippocampal volume differences predicted adrenocorticotropic cortisol levels following a restraining stressor ( Lyons et al. 2007 ). Along similar lines, in a monozygotic twin study, Gilbertson and colleagues (2002) found that non-traumatized twin siblings of those who developed PTSD following combat exposure had smaller hippocampi. Although not directly related to ELS, these finding strengthens the argument that small hippocampi may be a risk factor for impaired regulation of the HPA axis and a vulnerability factor to stress-related psychopathology.
c. Impact on other neurobiological systems
Most recently, Tottenham and Sheridan (2010) argued that hippocampus development lags behind the developmental trajectory of the amygdala. In a study of the Israeli Defense forces, 50 healthy recruits were studied upon their entry to the military and 18 months after serving as combat paramedics during which they were exposed to high levels of stress ( Admon et al. 2009 ). The authors found that pre-exposure amygdalar, but not hippocampal, reactivity predicted a greater increase in stress symptoms over time. Moreover, hippocampal alteration in response to stress-related pictures following the stress exposure was predicted by higher amygdala pre-stress reactivity ( Admon et al. 2009 ). Although this military-related stress experience does not resemble ELS, it could be speculated that amygdala hyperreactivity precedes volumetric changes in the hippocampus following stress exposure ( Tottenham and Sheridan 2010 ). This, in turn, could explain why research fails to detect changes in hippocampal volume in children. Similar to the argument of prolonged stress exposure, ELS may lead to hippocampal atrophy only in later life
Hippocampal size may also be associated with psychiatric illness or substance abuse. Unfortunately, studies examining memory performance or hippocampal volume often fail to control for psychiatric illness, such as PTSD ( Stein et al. 1997 ) or borderline personality disorder ( Driessen et al. 2000 ). Only a few studies have controlled for the presence of clinical disorders, or used non-clinical samples in order to attribute reductions in hippocampal volume to ELS ( DeBellis et al. 2009 ; Vythilingam et al. 2002 ). Some studies did not find volumetric differences even when controlling for common psychopathology such as PTSD (e.g., Pederson et al. 2004 ).
e. Genetic factors
Finally, animal studies have demonstrated that at least 54% of hippocampal size variance is attributable to genetics ( Lyons et al. 2001 ). In humans, several genetic markers have been associated with smaller hippocampi (Principle 4). For example, Met carriers of the BDNF polymorphism were found to exhibit smaller hippocampal volumes in the presence of stress, trait depression and neuroticism ( Joffe et al. 2009 ). Depressed adults exposed to ELS carrying the short allele of the serotonin transporter gene also displayed smaller hippocampal volumes than adults who had only one risk factor (ELS or short allele) ( Frodl et al. 2010 ). Notably, among healthy controls, emotional neglect and 5HTTLPR allele jointly explained 57% of variance in hippocampal WM, while neither variable alone explained significant variance ( Frodl et al. 2010 ).
In sum, based on data reviewed above, it is clear that longitudinal studies controlling for comorbidity and investigating genetic influences will be required to disentangle how ELS contributes to long-term structural changes in the hippocampus. Most importantly, more research is needed to explain how changes in different sub-regions of the hippocampus relate to specific impairments in memory function.
Global deficits in executive functioning following ELS are frequently reported ( Bos et al. 2009 ; Colvert et al. 2008 ; Pollak et al. 2010 ). Executive functions (e.g., inhibitory control, cognitive flexibility, sustained attention) are subserved by a network of brain regions, including various PFC and striatal regions ( Leh et al. 2010 ). Accordingly, the development of executive functions is thought to coincide with growth spurts in the maturation of the frontal cortex occurring between birth and 2 years, 7–9 years, during adolescence, and continue into the third decade of life ( Jurado and Rosselli 2007 ; Marsh et al. 2008 , Shaw et al. 2008 ). Two developmental characteristics make the PFC particularly vulnerable to stress effects: First, PFC circuits progress in a back-to-front direction and which are marked by long developmental trajectories supporting higher-order functions (Principle 2; Gogtay et al. 2004 ). Second, the PFC has a high density of glucocorticoid receptors and dopaminergic projections that are stress-susceptible ( Brake et al. 2000 ).
Frontostriatal circuits and inhibitory control
A recent study by Mueller and colleagues (in press) explored the perturbations in cognitive control and their underlying neural correlates in ELS. In an fMRI study, adolescents were asked to inhibit a prepotent response (Go) and initiate a non-prepotent alternative (Change). Individuals with ELS not only displayed longer reaction times on the Change trials, but also demonstrated greater activations in regions involved in cognitive control, in particular, the inferior frontal cortex (cognitive inhibitory control) and striatum (response control). Greater activation only occurred during the Change trials compared to Go trials, thus suggesting a specific impairment in inhibitory control rather than simple motor function ( Mueller et al, in press ). Interestingly, diminished inhibitory capacity was also found in a sample of high-functioning college women with sexual abuse histories ( Navalta et al. 2006 ).
Inhibitory control is thought to improve with age due to increasing activity in the frontostriatal circuits; however, the development of these circuits may be affected by early stress experiences even in high functioning abuse survivors ( Marsh et al. 2008 ). Both studies revealed impairments to aspects of cognitive control and prefrontal-striatal networks that can also be found in psychopathologies related to ELS such as depression ( Langendecker et al. 2007 ) and PTSD ( Falconer et al. 2008 ).
Cerebellum and planning
Bauer and colleagues (2009) found an association between deficits in planning and a smaller right superior-posterior cerebellar lobe in early institutionalized children. In addition to motor learning, balance, and coordination, the cerebellum is also involved in affective and cognitive processes such as language, visual-spatial learning and working memory ( Tiemeier et al. 2010 ). Of note, the cerebellum demonstrates one of the most drawn-out developmental time courses ( Gogtay and Thompson 2010 ), with total volume peaking at about 12 years for females and 16 years for males ( Tiemeier et al. 2010 ). Interestingly, this implies that the cerebellum peaks approximately 2 years later than cerebral volume ( Gerber and Peterson. 2009 ). It could be argued that the prolonged development of the cerebellum leaves it susceptible to long-term stress exposure and altered cytoarchitecture (Principle 2) and may therefore interfere with the later developing cognitive functions, e.g., planning ( Bauer et al. 2009 ) or learning and working memory ( Tiemeier et al. 2010 ) associated with the cerebellum.
Interim summary: cognitive functioning
A substantial number of studies have demonstrated that ELS can be associated with global cognitive difficulties, including decreased intellectual performance, academic success, language abilities and aspects of executive functioning (e.g., inhibitory control, planning). These higher-order functions are subserved by association sites (PFC, STG) and regions that undergo protracted development (corpus callosum, cerebellum), which could explain the increased risk for global impairment as a consequence of ELS (Principle 2 and 3). Findings of memory deficits and hippocampal volume reductions have been more inconsistent, particularly as hippocampal volume reduction has been found in adults but not in children.
ELS and affective functioning
The ability to evaluate and learn from rewarding outcomes and respond to reward-predicting cues is vital to survival and contributes to adaptive, goal-directed decision-making ( Ernst and Paulus 2005 ). Key components of the reward circuit, including basal ganglia regions involving the ventral (e.g., nucleus accumbens) and dorsal (e.g., caudate) striatum, amygdala, and OFC, undergo significant changes throughout childhood and adolescence ( Forbes and Dahl 2005 ; Giedd et al. 1999 ). Some basal ganglia structures (e.g., caudate) and the amygdala are also subject to volumetric sex differences possibly suggesting differences in reward responsiveness (Principle 5; Lenroot and Giedd 2010 ).
The mesolimbic dopaminergic (DA) system, in particular, plays a crucial role in various aspects of reward processing, including attributing incentive salience to reward-related stimuli (“wanting”; Berridge 2007 ). DA cell bodies in the ventral tegmental area project heavily to the nucleus accumbens, and both midbrain and striatal DA cells fire to both reward-predicting cues and unpredictable rewards. Blunted mesolimbic DA transmission has been postulated in depression, particularly in the presence of anhedonia, low energy, loss of libido and apathy ( Dunlop and Nemeroff 2007 ; Hasler et al. 2008 ; Pizzagalli et al. 2009a , 2009b ). Of major relevance to this review, animal studies have shown that chronic stressors and early adverse rearing environments lead to anhedonia-like behavior (including reduced motivation to pursue reward) and dysfunction in mesolimbic DA pathways in adulthood ( Anisman and Matheson 2005 ; Matthews and Robbins 2003 ; Pryce et al. 2004 ; Strekalova et al. 2004 ). In light of these preclinical data, two recent studies have probed putative dysfunction in reward-related brain activation in adults exposed to ELS.
In a study with a longitudinal component, Dillon and colleagues (2009) found that, relative to non-abused individuals, maltreated subjects were characterized by decreased anticipatory reward-related activity in the left pallidus and putamen, two key regions in the basal ganglia that have been implicated in processing of reward-predicting cues ( Figure 1 ). Maltreated subjects, who reported more symptoms of anhedonia than non-abused subjects, also rated reward cues as less positive. Based on prior data, we speculated that the abnormal pallidus activity might weaken the ability of reward-predicting cues to elicit goal-directed behavior.