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The Neurobiology of Stressand DevelopmentMegan Gunnar and Karina QuevedoInstitute of Child Development, University of Minnesota, Minneapolis, Minnesota55455; email: [email protected], [email protected]
Annu. Rev. Psychol. 2007. 58:145–73
First published online as a Review inAdvance on August 11, 2006
The Annual Review of Psychology is onlineat http://psych.annualreviews.org
This article’s doi:10.1146/annurev.psych.58.110405.085605
Copyright c© 2007 by Annual Reviews.All rights reserved
0066-4308/07/0110-0145$20.00
Key Words
HPA axis, psychopathology
AbstractStress is a part of every life to varying degrees, but individuals differin their stress vulnerability. Stress is usefully viewed from a biologicalperspective; accordingly, it involves activation of neurobiological sys-tems that preserve viability through change or allostasis. Althoughthey are necessary for survival, frequent neurobiological stress re-sponses increase the risk of physical and mental health problems,perhaps particularly when experienced during periods of rapid braindevelopment. Recently, advances in noninvasive measurement tech-niques have resulted in a burgeoning of human developmental stressresearch. Here we review the anatomy and physiology of stress re-sponding, discuss the relevant animal literature, and briefly outlinewhat is currently known about the psychobiology of stress in humandevelopment, the critical role of social regulation of stress neurobi-ology, and the importance of individual differences as a lens throughwhich to approach questions about stress experiences during devel-opment and child outcomes.
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Contents
INTRODUCTION. . . . . . . . . . . . . . . . . 146NEUROANATOMY AND
PHYSIOLOGY . . . . . . . . . . . . . . . . . . 146The Sympathetic Adrenomedullary
System. . . . . . . . . . . . . . . . . . . . . . . . 147The Limbic Hypothalamic-
Pituitary-AdrenocorticalAxis . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Psychosocial Stressors: The Role ofCorticotrophin-ReleasingHormone . . . . . . . . . . . . . . . . . . . . . 150
Summary . . . . . . . . . . . . . . . . . . . . . . . . 152ANIMAL STUDIES OF EARLY
EXPERIENCE AND STRESSNEUROBIOLOGY. . . . . . . . . . . . . . 152The Rodent Model . . . . . . . . . . . . . . . 152Early Adverse Experience in
Nonhuman Primates . . . . . . . . . . 154POSTNATAL HUMAN
DEVELOPMENT ANDSTRESS BIOLOGY . . . . . . . . . . . . . 154Infancy and Early Childhood. . . . . . 155Later Childhood and
Adolescence . . . . . . . . . . . . . . . . . . . 156SOCIAL REGULATION OF
STRESS NEUROBIOLOGY INHUMANS . . . . . . . . . . . . . . . . . . . . . . . 157The Role of Caregivers . . . . . . . . . . . 157Peers and Early Socialization
Experiences . . . . . . . . . . . . . . . . . . . 158STRESS NEUROBIOLOGY AND
ADVERSE EXPERIENCE:PARENTAL NEGLECT ANDABUSE . . . . . . . . . . . . . . . . . . . . . . . . . . 159The Stress Neurobiology of Adult
Survivors. . . . . . . . . . . . . . . . . . . . . . 159Child Maltreatment and Stress
Neurobiology . . . . . . . . . . . . . . . . . 160INDIVIDUAL DIFFERENCES:
CONTRIBUTIONS FROMTEMPERAMENT ANDGENETICS . . . . . . . . . . . . . . . . . . . . . 161
CONCLUSIONS AND FUTUREDIRECTIONS . . . . . . . . . . . . . . . . . . 162
INTRODUCTION
Threats to well-being, whether physical orpsychological, are components of life expe-rience. Individuals differ markedly, however,in the frequency with which they experiencestressful life events and their vulnerabilityor resilience to stressful challenges (Akil &Morano 1995). Stress, although often studiedas a psychological construct, may be viewedfrom a biological perspective (Dantzer 1991).Accordingly, stress responses are composedof the activation of neurobiological systemsthat help preserve viability through changeor allostasis (McEwen & Seeman 1999). Al-though necessary for survival, the effects offrequent physiological stress responses mayincrease the risk of future physical and mentalhealth problems. The impact of physiologi-cal stress reactions on the developing brainmay be of particular note, helping to explainhow adverse rearing experiences heighten therisk of behavioral and emotional problemsin children and adolescents (Gunnar 2000,Heim & Nemeroff 2001, Sanchez et al. 2001).In the past 20 years, advances in measure-ment techniques have allowed developmen-tal researchers to assess physiological stressresponses in children both in the laboratoryand under naturalistic conditions (Gunnar &Talge 2006). Consequently, the field of devel-opmental stress research has burgeoned. Inthe following review, we outline the anatomyand physiology of stress, discuss the animal lit-erature relevant to the study of stress in humanpsychobiological research, and briefly outlinewhat is currently known about the develop-ment of stress reactivity and regulation, thesocial regulation of stress in human develop-ment, the impact of maltreatment on stressneurobiology, and the importance of individ-ual differences as a lens through which to ap-proach questions about stress and experienceduring development.
NEUROANATOMY ANDPHYSIOLOGY
Stress responses in mammals are effectedby two distinct but interrelated systems:
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the sympathetic-adrenomedullary (SAM;Frankenhaeuser 1986) system and the hypo-thalamic-pituitary-adrenocortical (HPA;Stratakis & Chrousos 1995) system. TheSAM system is a component of the sym-pathetic division of the autonomic nervoussystem, releasing epinephrine (adrenaline)from the medulla or center of the adrenalgland. Increases in circulating epinephrinefacilitate rapid mobilization of metabolicresources and orchestration of the fight/flightresponse (Cannon 1929). The HPA system,in contrast, produces glucocorticoids (cor-tisol in humans, corticosterone in rodents;hereafter GCs) which are steroid hormones.Unlike epinephrine, which does not cross theblood-brain barrier to a significant degree,the brain is a major target of GCs (Bohuset al. 1982). Also unlike epinephrine, GCsproduction takes some time (approximately25 minutes to peak levels), and many ofits impacts on the body and brain occurthrough the changes in gene expression (deKloet 1991). Consequently, the impacts ofGCs are slower to develop and continuefor longer periods (de Kloet et al. 1996).As discussed more fully below, the role ofthe HPA system in stress is complex, and itsfunctions are not fully captured by referenceto the fight/flight response (Sapolsky et al.2000). Regulation of both the SAM andHPA systems converges at the level of thehypothalamus, which integrates autonomicand endocrine functions with behavior(Palkovits 1987). Furthermore, inputs to thehypothalamic nuclei that orchestrate HPAand SAM responses to psychosocial stressorsinvolve cortico-limbic pathways (Gray &Bingaman 1996). Each system is described indetail below.
The Sympathetic AdrenomedullarySystem
The chromaffin cells of the adrenal medullaare secretor cells developmentally and func-tionally related to postganglionic sympa-thetic neurons and are considered part
Stress:psychologicalcondition in whichthe individualperceives orexperienceschallenges tophysical oremotional well-beingas overwhelmingtheir ability andresources for coping
SAM: sympatheticadrenomedullary(system)
Hypothalamic-pituitary-adrenocortical(HPA) system:describes thecomplex chain ofphysiological eventsthat characterizesone of the stressresponse systems
Glucocorticoids(GCs): a family ofsteroid hormones(such as or cortisol inhumans andcorticosterone inrodents) produced bythe adrenal cortex
Cortico-limbicpathways:interconnectedgroup of cortical andsubcortical structuresin the human brainthat constitute theneural substrate foremotion, motivation,emotional learning,and regulation
Epi: epinephrine
NE: norepinephrine
CRH:corticotrophin-releasinghormone
ACTH:adrenocorticotropichormone
of the sympathetic nervous system (seeFigure 1) (Vollmer 1996). They are inner-vated by sympathetic preganglionic neuronsresiding in the intermediolateral gray matterof the spinal cord (Tasaptsaris & Breslin 1989).Sympathetic preganglionic neurons send ax-ons through the ventral root of the spinalcord and form cholinergic synapses with thechromaffin cells. When these cells are stimu-lated, they secrete catecholamines, predomi-nantly epinephrine (Epi) but also some nor-epinephrine (NE) (Vollmer 1996). Epi andNE bind to various adrenoreceptors in multi-ple target organs and thus play multiple rolesin fight/flight reactions (Tasaptsaris & Breslin1989). For example, they both increase heartrate and stroke volume (and hence, cardiacoutput) and cause vasodilatation in musclesand constriction of blood vessels in the skinand gut. These changes ensure blood supplyto the brain and muscles. Critically, Epi stim-ulates glycogenolysis in the liver, resulting inincreased serum levels of glucose and there-fore energy to fuel defensive responses. Al-though neither Epi nor NE cross the blood-brain barrier, the peripheral actions of thesecatecholamines are paralleled in the brain byNE produced by the locus coeruleus (Morilaket al. 2005). Its role in response to psychoso-cial threats is to support vigilance, arousal, andnarrowing of attention, along with participat-ing in processes that activate the other arm ofthe mammalian stress system, the HPA axis.
The Limbic Hypothalamic-Pituitary-Adrenocortical Axis
The cascade of events that leads to the pro-duction of glucocorticoids by the adrenal cor-tex begins with the release of corticotrophin-releasing hormone (CRH) and arginine va-sopressin (AVP) by cells in the paraventricu-lar nuclei of the hypothalamus (see Figure 2;reviewed in Gunnar & Vazquez 2006). CRHand AVP travel through small blood vesiclesto the anterior pituitary, where they stimu-late the release of adrenocorticotropic hor-mone (ACTH) (Stratakis & Chrousos 1995).
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T1
T5
L3
Spinal Cord
GreaterSplanchnicNerve
AdrenalMedulla
LesserSplanchnicNerve
Epinephrine andNorepinephrinereleased to general circulation
Dorsal rootSpinal cord
Preganglionicneuron
Intermediolateralgray matter
Ventralroot
AdrenalMedulla
Prevertebralganglion Postganglionic
neuron
Postganglionicfibers to peripheral autonomiceffector organs
T12
T9
Paravertebralganglia
PrevertebralCeliacganglion
Paravertebralganglion
Figure 1Anatomy of the sympathetic adrenomedullary (SAM) system. The SAM system is a component of thesympathetic nervous system. Its cell bodies (preganglionic neurons) are located in the interomediolateral(IML) cell column and exit the spinal cord via the ventral root to form cholinergic direct synapses on thechromaffin cells of the medulla of the adrenal glands. When stimulated, these chromaffin cells secretecatecholamines, epinephrine (80%), and norepinephrine (20%). The chromaffin cells of the adrenalmedulla thus are equivalent to postganglionic sympathetic neurons. Secreted into general circulation,they act as hormones, affecting organs and tissues via adrenergic receptors (alpha and beta) that areactivated at lower levels of epinephrine than norepinephrine. Adrenomedullary output greatly enhancessympathetic neural activity.
Sympathetic-adrenomedullarysystem: a primarybiological systemcontrolling stressresponse. Outflow ofsympatheticautonomic nervoussystem that triggersrapid physiologicaland behavioralreactions toimminent danger orstressors
MRs:mineralocorticoidreceptors
GRs: glucocorticoidreceptors
ACTH interacts with receptors on the cortexof the adrenal gland to stimulate the produc-tion and release of GCs into general circula-tion. GCs enter into the cytoplasm of cellsthroughout the body and the brain, wherethey interact with their receptors (de Kloet1991). The activated receptors then enter thenucleus of the cell, where they regulate thetranscription of genes with GC-responsive re-gions. The action of GCs on target tissues in-volves changes in gene transcription, whichexplains why the effects of elevated GCs maytake many minutes to hours to be producedand may continue to exert effects on phys-iology and behavior for prolonged periods(Sapolsky et al. 2000).
The effect of GCs depends upon the re-ceptors with which they bind. There aretwo GC receptors: mineralocorticoid recep-tor (MR) and glucocorticoid receptor (GR)(de Kloet 1991). Outside the brain, GCs op-erate through GRs because of the presence ofan enzyme, 11-beta hydroxysteroid dehydro-genase (11β-HSD), that prevents GCs frombinding to MRs. In the brain, where 11β-HSD is minimally expressed, GCs bind toboth MR and GR. Indeed, GCs have higheraffinity (i.e., bind more readily) to MRs thanto GRs, a fact that is critical in the regula-tion of both basal and stress responses of theHPA system (reviewed in Gunnar & Vazquez2006). Because of their differential affinities
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Figure 2The anatomy of the hypothalamic-pituitary-adrenocortical (HPA) system and the structures that areimportant in its regulation. Also depicted is the activation (+) and negative feedback inhibition (−)pathways of the HPA system. Increases in glucocorticoids (GCs) are initiated by the release ofcorticotropin-releasing hormone/arginine vasopressin (CRH/AVP) from the medial parvocellular regionof the paraventricular nucleus (PVN) in the hypothalamus. Negative feedback inhibition operatesthrough GCs acting at the level of the pituitary, hypothalamus (HYP), and hippocampus (HC). ACTH,adrenocorticotropic hormone; AMY, amygdala; GABA, gamma aminobutyric acid; HC, hippocampus;HYP, hypothalamus; NTS, nucleus of the tractus solitarius; PFCtx, prefrontal cortex. Reprinted withpermission from Gunnar & Vazquez 2006.
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for GCs, MRs are 80%–90% occupied whenGCs are in basal ranges (de Kloet 1991). Bycontrast, GRs are occupied only at the peakof the circadian cycle or when stressors stimu-late GC elevations over basal concentrations.GRs mediate most of the stress effects ofglucocorticoids, whereas MRs tend to medi-ate most basal effects, which include effectssuch as maintaining responsiveness of neu-rons to their neurotransmitters, maintainingthe HPA circadian rhythm (highest at wak-ening and lowest 30 minutes after the onsetof the long sleep period each day), and main-taining blood pressure (Sapolsky et al. 2000).Although these basal effects are often consid-ered distinct from stress effects of GCs, theyplay a permissive role in stress. Basal levels al-low effective fight/flight responses by allow-ing NE and Epi to have maximal impacts ontheir target tissues.
GR-mediated effects often oppose theones effected through MR, leading some re-searchers to argue that stress resilience andvulnerability involve the ratio of MR-to-GRactivation (de Kloet 1991). For example, GRsimpair neural plasticity and the processes in-volved in learning and memory as evidencedby their impact on hippocampal neurons. Bycontrast, basal levels of GCs acting via MRsenhance synaptic plasticity as evidenced bya reduction of the refractory period of hip-pocampal neurons. MRs facilitate cerebralglucose availability, whereas GRs inhibit glu-cose utilization throughout the brain, thusendangering cell survival. GRs also activatepathways back to the PVN, which results ininhibition of CRH production (negative feed-back) and thus a termination of the HPA stressresponse. It has long been a mystery why GRs,which are activated during stress responses ofthe HPA system, should operate to producesuch deleterious effects. Why would this sys-tem have evolved to impair functioning underconditions of threat? One argument is thatthe suppressive effects mediated by GRs arenecessary to reverse acute response to stres-sors and ultimately facilitate the recovery ofcellular homeostasis (Sapolsky et al. 2000).
Only when stress is prolonged do the costsof suppressive effects begin to outweigh theirbenefits.
Maintaining viability through activation ofSAM and HPA reactions has been termedallostasis, or the maintenance of stabilitythrough change (McEwen & Seeman 1999).The costs imposed by frequent or prolongedstress responses are described as allostaticload. In addition, the opposing effects of MRsand GRs combined with the differential affin-ity of GCs for these receptors explains why therelationship between GCs and adaptive func-tioning frequently takes an inverted-U func-tion (Sapolsky 1997). Both chronically lowand high levels of GCs are associated withnonoptimal adaptation. In contrast, moderate(or controlled elevations) are associated withphysical and behavioral health.
Psychosocial Stressors: The Role ofCorticotrophin-Releasing Hormone
Both the SAM and HPA systems are cen-trally modulated by limbic brain circuitsthat involve the amygdala, hippocampus, andorbital/medial prefrontal cortex [see Figure 3(as reviewed in Gunnar & Vazquez 2006)].These structures/circuits allow psychologicalstressors to activate stress responses. The fast,SAM-mediated, fight/flight response utilizesCRH-producing neurons located in the cen-tral nucleus of the amygdala, the noradren-ergic neurons located in the locus coeruleus,and other aminergic cells in the brain stem(Morilak et al. 2005). The locus coeruleusregulates the SAM response through itsprojecting NE neurons. These pathways,flowing through the lateral hypothalamus, ac-tivate sites in the brain stem, which in turn di-rectly activate the sympathetic preganglionicneurons unleashing the release of Epi fromthe adrenal medulla. The central nucleus ofthe amygdala and CRH-mediated changes arealso involved in activating the HPA responseto psychosocial stressors (Shekhar et al. 2005).Here, however, pathways to hypothalamicCRH-producing cells that stimulate the HPA
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NE
NE
CRH
Anteriorcingulate
Orbital PFC
Amygdala Hippocampus
Locuscoeruleus
Hypothalamus
ACTH Pituitary EPI
GC
Medulla
Cortex
Adrenal
Brain stemnuclei
Spinal cord
BNST
ACH
Figure 3Three levels of neurobiological organization of the stress system responsive to psychological stressors.The cortico-limbic level of organization involves the anterior cingulate (ACC) and orbital frontal cortex(OFC), which relay information to subcortical structures involved in the stress response. The ACC andOFC are reciprocally interconnected with each other and with the amygdala, which has connections withthe hippocampus and bed nucleus of the stria terminalis (BNST). The hypothalamic–brain stem level oforganization involves the hippocampus and brain stem structures such as the locus coeruleus (LC), whichreleases norepinephrine (NE) to brain areas involved in alerting. The BNST provides pathways into theparaventricular nucleus (PVN) of the hypothalamus, which produces corticotrophin-releasing hormone(CRH) and arginine vasopressin (AVP), while the hippocampus and regions in the medial frontal cortex(e.g., ACC) maintain feedback control of the PVN. Considering the neural-to-adrenal level of analysis,nuclei in the lateral hypothalamus activate highly interconnected nuclei in the brain stem, including theparabrachial nuclei, that regulate the sympathetic (NE and epinephrine, Epi) and parasympathetic(acetylcholine, Ach) nervous systems via pathways traveling through the spinal cord to preganglionicnuclei or to target organs (e.g., the adrenal medulla). The production of CRH and AVP by the PVNregulates activity of the hypothalamic-pituitary-adrenocortical (HPA) axis and the production ofglucocorticoids (GCs) as depicted more fully in Figure 2. Adapted with permission from Gunnar &Davis 2003.
cascade are indirect, operating through mul-tisynaptic pathways via the bed nucleus of thestria terminalis that converge on the paraven-tricular nuclei in the hypothalamus (Herman& Cullinan 1997, Herman et al. 2002). Thesemultiple, converging pathways allow modula-tion of the strength of the HPA responses inrelation to the state of the body, time of day,and current levels of circulating hormone.
Because of the critical role of amygdalarCRH in the activating pathways for both SAMand HPA responses, there is increasing atten-tion to the role of amygdalar CRH and its fam-ily of receptors in orchestrating stress reac-tions (Heinrichs et al. 1995, Nemeroff 1996,Swiergiel et al. 1993). Reacting to psycho-logical stressors requires appraisal by higherbrain structures such as the cingulate cor-tex and the orbital/medial prefrontal cortex(Barbas 1995, Diorio et al. 1993). Threatappraisal also involves subcortical structures
such as the bed nucleus of the stria terminalisand the hippocampus, as well as the furtherintegration by hypothalamic and brain stemstructures (Davis et al. 1997). CRH receptorsin all of these regions affect components ofstress responding (Bale & Vale 2004). For ex-ample, CRH infused into the locus coeruleusin rodents intensifies anxiety-related behav-iors, and neurons in the locus coeruleus aresensitized to CRH after being exposed to psy-chological stressors (Butler et al. 1990). Aswith GCs, there are two prominent CRHreceptors (CRH-1 and CRH-2), which tendto mediate opposing actions (Bale & Vale2004). CRH-1 appears to mediate many of theanxiety-related actions of CRH, while CRH-2 mediates more of the stress effects on vege-tative functions. Consistent with this distinc-tion, CRH-1 receptors are more abundant incortico-limbic pathways that mediate fear andanxiety-related behaviors, whereas CRH-2
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receptors are found predominantly in sub-cortical brain regions (Sanchez et al. 2000,Vythilingam et al. 2002). It is unfortunate forstudents of human development that CRHcannot be noninvasively measured. Further-more, although CRH can be assayed in sam-ples of cerebral spinal fluid (CSF), CSF con-centrations do not allow differentiation of thebrain locus of production.
Summary
The neuroanatomy and neurophysiology ofthe stress system involves the SAM and HPAsystems. Both systems involve the adrenalgland and its secretions that are released intothe bloodstream. Both also are orchestratedby activity in the central nervous system. Un-like the SAM system, however, the brain is amajor target organ for the steroid hormonesproduced by the HPA axis. Also, unlike theSAM system, whose role in stress can befairly simply described as “fight/flight,” therole of the HPA system is more complex. Itsbasal activity appears to support or permitacute fight/flight responses, while its responseto stressors serves to suppress the impact offight/flight reactions. Over prolonged periodsof chronic activation, the suppressive effectsof the elevated GCs and the wear and tearof frequent SAM responses can have delete-rious effects on physical and mental health.However, in the short term, robust, well-orchestrated activations of these systems tendto support adaptive functioning. This, plusthe well-described inverted U-shaped func-tions relating SAM and HPA stress responsesto a variety of adaptive functions, should cau-tion researchers against thinking of increasesin SAM and HPA activity as necessarily index-ing risk of poor outcomes. Finally, our increas-ing understanding of the role of amygdalarCRH in orchestrating responses to psychoso-cial threats suggests that in many cases it isthe activity of CRH that should be tracked byresearchers studying links between emotionalbehavior and physiological responses to stres-sors. Unfortunately, CRH cannot be nonin-
vasively measured and thus is not a part of thetoolbox for researchers studying psychosocialstress and development in humans.
ANIMAL STUDIES OF EARLYEXPERIENCE AND STRESSNEUROBIOLOGY
More than a decade of research using animalmodels has shown that in many mammalianspecies, early experiences shape the neuro-biological systems involved in stress reactiv-ity and regulation, and some of these effectsappear permanent. The results of these stud-ies have shaped the formulation of questionsabout early experiences and stress vulnerabil-ity in human development; thus, it is usefulto outline the findings of the animal modelshere.
The Rodent Model
The rat has been the focus of much of thisresearch (Sanchez et al. 2001). In the rat,the period between 4 and 14 days after birthis one during which it is difficult to pro-duce elevations in ACTH and GCs to stres-sors that provoke responses in older animals(Rosenfeld et al. 1992). Termed the rela-tive stress hyporesponsive period (SHRP), ithas been assumed that this period evolvedto protect the developing brain from poten-tially deleterious effects of elevated GCs andthe other neurochemicals associated with themammalian stress response (de Kloet et al.1988). The SHRP appears to be maintainedby very specific stimuli that pups receive fromthe dam. If the dam is removed for 12 to 24hours, marked activation of the HPA systemand elevated brain levels of CRH are noted(Suchecki et al. 1993). However, if duringthis time maternal stimulation is mimicked bystroking the pup with a wet paintbrush andinfusing milk into its stomach via a cannula,HPA and central (brain) CRH responses arecontrolled (Cirulli & Alleva 2003).
We now know that not only deprivationof maternal care but also normal variations
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in rat mothering impact the developing neu-robiology of stress (see review by Meaney &Szyf 2005). Dams vary in how much theylick and groom their pups. In comparisonwith low-licking and -grooming dams, high-licking and -grooming dams have pups that,as adults, are less fearful and better able tocontain and terminate stress reactions of theHPA axis (Caldji et al. 1998). The molecu-lar events set into motion by maternal careare increasingly understood. Particularly dur-ing the first week of the life in the rat,maternal licking and grooming regulate theextent to which GR genes in the hippocam-pus become methylated (Weaver et al. 2001).Methylation effectively silences genes. Lick-ing and grooming reduce methylation of hip-pocampal GR genes. GR genes determinehow many hippocampal glucocorticoid recep-tors an animal will have. Because hippocam-pal GRs are involved in terminating stressresponses of the HPA system, high levels ofhippocampal GRs mean efficient control ofHPA stress response, whereas low levels meanpoor or sluggish regulation, more prolongedstress reactions, and vulnerability to allostaticload over the animal’s lifetime (Meaney & Szyf2005, Weaver et al. 2001). These epigeneticeffects of maternal care are potentially irre-versible, except through pharmacological ma-nipulations that induce widespread demethy-lation (Weaver et al. 2005). This is a power-ful example of how stress neurobiology canbe programmed by social experiences duringsensitive periods of development.
The impact of early social stimulation be-comes obvious when typical caregiving pat-terns are disrupted (for reviews, see Cirulli &Alleva 2003, Sanchez et al. 2001). Two closelyrelated paradigms have been studied most:daily separations extending over the period ofthe SHRP that last for 3 to 15 minutes andsimilar daily separations that last for several(typically 3) hours. Strikingly, 15 minutes hasa markedly different consequence than does180 minutes of separation daily. In compari-son with nonmanipulated dams and pups, thepups who experience 15 minutes of separa-
Sensitive periods ofdevelopment:periods during whichan experience (or itsabsence) has a moremarked impact onthe neuralorganizationunderlying aparticular skill orcompetence
tion daily (termed “handling”) become morestress resilient, whereas those experiencing180 minutes of separation daily (termed “ma-ternally separated”) become more stress vul-nerable. Relevant findings include evidencethat separated animals, compared with con-trol and handled animals, exhibit larger air-puff startle responses, greater freezing andanxiety behaviors to cat odor, and two- tothreefold greater ACTH and glucocorticoidresponses to restraint stress as adults (Cirulli& Alleva 2003). In addition, they also displayevidence of anhedonia; mild cognitive im-pairments, especially on hippocampally me-diated tasks; and greater consumption of al-cohol (Sanchez et al. 2001). These behaviorscorrespond to increased CRH expression inthe amygdala and bed nucleus of the stria ter-minalis, decreased GR in the hippocampusand consequently impaired negative feedbackregulation of the HPA axis, increased NE inthe locus coeruleus, and down-regulation ofadrenergic receptors, among other changesthat reflect shaping of hyperstress reactivityat multiple levels of the central nervous sys-tem (Ladd et al. 2000).
The difference between 15 minutes and180 minutes of maternal separation appearsto be conferred via differences in maternal be-havior. After brief separations, dams increasetheir licking and grooming, whereas repeatedthree-hour separations appear to disorganizethe dam, reducing licking and grooming ofher pups. Some of the effects of maternalseparation appear to be relatively permanent.However, some effects appear to be responsiveto postinfancy modification by placing the ju-venile animal in complex environments thatstimulate exploration and expose the animalto high levels of social stimulation and novelty(Francis et al. 2002). Such enrichment expe-riences do not increase the previously mater-nally separated animal’s hippocampal GR, butthe experiences do appear to reduce activationof cortico-limbic fear circuits in response tonovelty and threat in adulthood. Whether thecontinued deficit in hippocampal GR confersa risk for stress vulnerability in response to
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Attachment:psychosocial processresulting in strongemotional bond witha particular personand deriving securityfrom physical andpsychologicalcontact with thatattachment figure
chronic, rather than acute, stressors later inlife is not yet known.
Early Adverse Experience inNonhuman Primates
It is generally assumed that events, whetherthey are positive or negative, have less of aneffect on structures and circuits that are al-ready well developed than on those that arerapidly developing (Dobbing 1981). Nonhu-man primates are born more mature thanare rats; thus, we would expect that post-natal experiences would have somewhat dif-ferent effects in the primate (for reviews,see Gunnar & Vazquez 2006, Sanchez et al.2001). This appears to be true, despite thefact that, as in rats, disruptions of parentalcare in nonhuman primates also affect theneural substrates of stress vulnerability andresilience.
Nonhuman primates form specific attach-ments to caregivers (Suomi 1995). Separationfrom the attachment figure provokes acute be-havioral distress and increases activity of theHPA and SAM systems (Levine & Wiener1988). Behavioral distress, however, does notnecessarily mirror physiological stress reac-tions. For example, if the infant monkey cansee and call to its mother, vocal distress andbehavioral agitation are much greater than ifit is isolated from any contact. Nonetheless,physiological stress responses, particularly ofthe HPA system, are much greater under con-ditions of isolation (Bayart et al. 1990, Smoth-erman et al. 1979). Studies of the impact of dif-ferent pharmacological manipulations duringseparation also demonstrate that behavioraldistress and physiological stress responses aredissociable (Kalin et al. 1988, 1989). Critically,increases in HPA activity appear to corre-spond more closely with activity of amygdalarCRH and activation of fear circuits (Kalinet al. 1989). Notably, infant primates can gainsome reduction in both distress vocalizationsand physiological stress reactions when theyare provided with surrogate caregivers dur-ing separation (reviewed in Levine & Wiener
1988). Consistent with the principles of at-tachment theory (Bowlby 1969), access toa secure base provided by the attachmentfigure or attachment surrogate reduces theprobability of HPA/CRH stress reactions thatcould have long-term consequences on braindevelopment.
Studies of nonhuman primates alsodemonstrate that poor rearing conditions,including peer-only rearing, isolation rear-ing, repeated separations, and conditions thatdisrupt responsive maternal care can havelong-term impacts on the neurobiology ofstress and negative emotionality (reviewed inSanchez et al. 2001). For example, variableforaging paradigms that result in neglectfulmaternal care also produce offspring who asadults are more fearful, low in dominance,high in brain levels of CRH, and who ex-hibit persistent alterations in somatostatin andmetabolites of serotonin, dopamine, and NE(Coplan et al. 1996, Rosenblum & Andrews1994, Rosenblum et al. 1994). However, thelong-term effects of social deprivation on theHPA axis are unclear (Mason 2000). For ex-ample, 2.5-year-old monkeys reared in iso-lation for the first year of life exhibited nodifferences in hypothalamic-CRH expressionwhen compared with maternally reared ani-mals (Sanchez et al. 1999). Similarly, unlike inthe rat, no one has yet to demonstrate changesin hippocampal GR. Rather, the levels of stressneurobiology that are disturbed appear to in-volve the cortico-limbic circuits that evaluateand regulate responses to psychosocial threat,circuits that are still rapidly developing afterbirth in the monkey as they are in the humanchild.
POSTNATAL HUMANDEVELOPMENT AND STRESSBIOLOGY
Neurobiological systems involved in stress in-clude genetic, organ, behavioral, and emo-tional components that mature and becomemore organized as children develop. Belowis an overview of the development of the
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components of the stress system, with partic-ular emphasis on the HPA axis.
Infancy and Early Childhood
In adults, cortisol is usually bound to proteins(e.g., corticosteroid-binding globulin; CBG)(Rosner 1990). However, CBGs in newbornsare initially low, although they increase overthe first six months after birth (Hadjian et al.1975). As a result, unbound levels of corti-sol decrease slightly over the initial monthsafter birth, while plasma or total cortisol in-creases. Only free cortisol can bind to itsreceptors and have biological effects; there-fore, despite low plasma levels of cortisol atbirth, the levels of biologically active cortisolin newborns are enough to have clear phys-iological effects (Gunnar 1992). Newbornscan mount physiologically significant corti-sol and ACTH responses to aversive medicalprocedures (blood draws, physical examina-tions, and circumcision) (reviewed in Gunnar1992). Newborns, however, do not show thetypical adult rhythm in cortisol production,characterized by higher levels in the morningat wake-up that decrease toward the afternoonand evening. They show two peaks, 12 hoursapart, that do not depend upon the time ofday (Klug et al. 2000). But by three months, aqualitative shift in physiological developmenttakes place, and the single early morning cor-tisol peak and evening nadir (lowest level) aregenerally established (Matagos et al. 1998).The diurnal rhythm also continues to developover infancy and early childhood, reflectingchanges in daytime sleep patterns (Watamuraet al. 2004). Specifically, until children give uptheir daytime naps, decreases in cortisol frommid-morning to mid-afternoon are not ob-served; after this, the diurnal rhythm of chil-dren is consistent with that of adults.
As in the newborn period, two-month-old babies increase cortisol significantly tomedical examinations and also fuss and crywhen they are examined (Larson et al. 1998).Around three months, there is a diminishingof the HPA response to stressors such as phys-
Cortisol: arguablythe most powerfulhumanglucocorticoid.Essential forregulation andsupport of vitalfunctions includingmetabolism, immuneresponse, vasculartone, and generalhomeostasis
ical examinations, but this does not extendto decreased behavioral distress (Larson et al.1998). Furthermore, across the first year of lifeit becomes increasing difficult to provoke cor-tisol increases to many mild stressors (strangerapproach, strange events, 3- to 30-minute sep-arations, and inoculations; reviewed in Gun-nar & Donzella 2002). Indeed, by one yearof age many infants show no evidence of in-creases in cortisol to stressors that typicallyprovoke significant behavioral distress reac-tions. Both physiological changes in the sys-tem, such as improved negative feedback reg-ulation of the axis, and decreased sensitivity ofthe adrenal cortex to ACTH may partially ac-count for the diminution of the HPA stress re-sponse (Lashansky et al. 1991). In addition, asdescribed below, the child’s access to support-ive adult care plays an increasingly salient rolein buffering the activity of the HPA compo-nent of the stress system. Indeed, by the end ofthe first year of life, infants in supportive care-giving relationships appear to have enteredthe human functional equivalent of the ro-dent stress-hyporesponsive period (reviewedin Gunnar 2003).
As in the primate and rodent, behavioraldistress is an unreliable index of HPA activa-tion in young children. In the first weeks oflife, this is demonstrated strikingly throughstudying infants with colic (White et al. 2000).Infants with colic, who by definition exhibitmarkedly high levels of crying, tend to ex-hibit low basal levels of cortisol and producechanges similar to those of noncolic babies incortisol and heart rate in response to distress-ing events. By the time infants have formedattachment relationships to one or a few care-givers, the presence and history of responsive-ness of the attachment figure both influenceswhether infants exhibit cortisol increases tostressors and whether behavioral distress cor-relates with these increases (reviewed inGunnar & Donzella 2002). In secure attach-ment relationships (Nachmias et al. 1996) andwith responsive surrogate caregivers (Gunnaret al. 1992), infants exhibit crying directed atsoliciting care but do not exhibit elevations in
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Sensitive andresponsive care:qualities of parentingcharacterized bytimely and adequateresponsiveness to thechild’s needs
Temperament:individual differencesin reactivity andself-regulationassumed to have aconstitutional basis.Develops and isinfluenced over timeby heredity,maturation, andexperience
cortisol. Conversely, in insecure relationshipsor with unsupportive caregivers, stressorscontinue to be capable of producing eleva-tions in cortisol and distress, and heart rateincreases tend to more closely approximateactivations of the HPA system (Spangler &Schieche 1998). This generalization tends tohold for acutely stressful experiences, but maynot be accurate for more prolonged periodsof stress such as those experienced when tod-dlers enter full-time child care. Here it hasbeen noted that the security of the child’s at-tachment relationship does not determine themagnitude of the cortisol increase as the childadjusts to repeated daily separations, and overtime it is the securely attached children whosebehavioral distress corresponds to their in-creases in cortisol during these prolonged pe-riods of separation (Ahnert et al. 2004).
Changes in other stress-sensitive systemsare also observed over the early months oflife. Notably, corresponding to the diminu-tion of HPA responses to stressors, there isan increase in vagal tone (parasympathetic in-put to the heart) that may allow more nu-anced cardiac and behavioral responses to psy-chosocial threat (Porges 1992, Porges et al.1994). Whether changes in vagal tone arerelated to the emergence of secure-base at-tachment relationships has not been clearlydemonstrated (although see Izard et al. 1991).However, there is evidence that emotion-related patterns of brain electrical activitymeasured over the frontal cortex are relatedto the infant’s history of sensitive and re-sponsive care. Specifically, infants of motherswho are highly sensitive and responsive ex-hibit greater left frontal brain electrical (elec-troencephalogram, or EEG) activity patternsassociated with positive emotionality and ap-proach, whereas those with low-responsivemothers exhibit greater right frontal EEGpatterns associated with negative emotional-ity and fearful, inhibited temperament (Hane& Fox 2006). In nonhuman primates, greaterleft frontal EEG asymmetry has been shownto correlate with lower cortisol reactivity tostressors (Kalin et al. 1998). Higher vagal
tone, lower cortisol reactivity to stressors, andgreater left frontal EEG patterns suggest that,at least under conditions of supportive care,the human child enters a period of relativestress hyporesponsivity by the latter part ofthe first year that may buffer or protect thedeveloping brain and result in a more stress-resilient child.
Later Childhood and Adolescence
There is increasing evidence that the periodof relative stress hyporesponsivity or buffer-ing does not end with infancy but extendsover most of the childhood years. As is thecase with toddlers, it is difficult to find labo-ratory situations that provoke large increasesin cortisol throughout childhood (reviewedin Gunnar & Fisher 2006). Although manychildren may be largely buffered from stressduring infancy and childhood, there is alsoincreasing evidence that this period of rela-tive stress buffering draws to a close as chil-dren transition into adolescence. In additionto the psychosocial changes associated withthe adolescent transition, biological processesassociated with puberty may shift the child’sstress neurobiology to adult-responsive pat-terns (Spear 2000). It is now clear that theincreasing level of basal cortisol shown inchildren between the ages of 6 and 17 yearsis remarkably similar to that of the rodent,which exhibits increases in basal GC levelsat the close of the stress-hyporesponsive pe-riod (Kiess et al. 1995, Legro et al. 2003,Netherton et al. 2004, Shirtcliff 2003). Somestudies suggest that the increases in basal GCspeak between 10 and 14 years or at aroundTanner stage three (Elmlinger et al. 2002,Netherton et al. 2004), whereas others showa more gradual increase with age (Jonetz-Mentzel & Wiedenmann 1993). In additionto increases in basal cortisol levels, there alsois increasing evidence that cortisol responsesto laboratory stressors may increase with ageand pubertal status over the adolescent transi-tion (Klimes-Dougan et al. 2001, Walker et al.2001, Wewerka et al. 2005). Not all studies
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have demonstrated such increases in stress re-sponsivity over the transition into adolescence(for review, see Gunnar & Vazquez 2006), butthe weight of the evidence is beginning to sug-gest that an adolescent emergence out of aperiod of relative stress hyporesponsivity orbuffering is real and may have implicationsfor the heightened risk of psychopathologynoted among adolescent-aged children (Spear2000).
SOCIAL REGULATION OFSTRESS NEUROBIOLOGY INHUMANS
The Role of Caregivers
Children’s development takes place withinthe close social relationships with adult care-givers. One of the functions of the caregiv-ing system is to modulate and enable con-trol of physiological and behavioral responsesto stressors. In humans, social modulationof physiological stress responses may lay thefoundation for the development of emo-tion regulation competencies (Stansbury &Gunnar 1994). Patterns of social relatednessin infancy can be characterized, in part, by thesecurity of the infant-caregiver attachment re-lationship (Ainsworth et al. 1978), and phys-iological stress responses have been found tobe mediated by attachment security (Gunnaret al. 1996, Spangler & Schieche 1998, Sroufe& Waters 1979). In the presence of the at-tachment figure, toddlers who are in secureattachment relationships do not show eleva-tions in cortisol to distress-eliciting events,whereas toddlers in insecure attachment rela-tionships do (reviewed in Gunnar & Donzella2002). The power of secure attachment re-lationships to buffer or prevent elevations incortisol to otherwise mildly stressful eventshas been demonstrated in both laboratory andnaturalistic situations. In comparison to orga-nized but insecure attachment relationships,disorganized/disordered attachment may sig-nal even greater stress vulnerability. Disorga-nized attachment relationships are believed to
arise, in part, from the infant’s experience offrightening behavior and episodes of dissocia-tion in the caregiver (Lyons-Ruth et al. 1995).Children in disorganized/disoriented attach-ment relationships are characterized by theirinability to organize or regulate affect and be-havior toward their caregiver in stressful sit-uations (van Ijzendoorn et al. 1999). Thesechildren are also most likely to exhibit dis-turbances in HPA axis activity (Hertsgaardet al. 1995, Spangler & Grossmann 1997)and are most at risk for behavioral andemotional problems (van Ijzendoorn et al.1999).
There is also evidence that family dynam-ics, beyond attachment security/insecurity, in-fluence cortisol reactivity in developing chil-dren. Naturalistic observations from house-holds of typically developing children (ages2 month to 17 years) yield evidence thattraumatic family events (conflict, punishment,shaming, serious quarrelling, and fighting)are strongly associated with periods of ele-vated cortisol levels when the child’s responseto acutely traumatic events is compared withtheir own levels on less traumatic days in thefamily (Flinn & England 1995). There is alsoevidence that early disruptions in the parent-child relationship may produce increased lev-els of cortisol by the preschool years andthat these heightened levels predict increasedbehavioral and emotional problems in theschool-aged child (Essex et al. 2002). Like-wise, social adversity that results in high ma-ternal expression of depressive symptoms, in-cluding disrupted patterns of parenting, hasbeen shown to be related to higher and less-regulated cortisol activity in school-aged chil-dren and adolescents (Halligan et al. 2004,Lupien et al. 2000). Additionally, in clinicalpopulations of children with behavior prob-lems, cortisol increases during a parent-childconflict-discussion task have been found to beassociated with dysfunctional parenting atti-tudes and symptoms of anxiety and depressionin the child (Granger et al. 1996). In sum-mary, adult caregivers and family influencesare powerful regulators of the HPA system.
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Caregivers can prevent elevations in cortisolfor infants and children even during threat-ening external events. Responsive caregivingallows children to elicit help by expressingnegative emotions, without triggering the en-docrine component of the stress response.Conversely, when the parenting is inadequateand/or is the source of threat, relationshipscan be a major source of physiological stressfor children (Repetti et al. 2002).
Peers and Early SocializationExperiences
As children mature, their social circle expandsto include other children and adults, partic-ularly in the context of school and daycarecenters. This entails the entrance into a com-plex and challenging environment that de-mands the emergence of social skills includingcontrol of inappropriate behaviors, adaptingcommunication to the listener point of view,interpreting emotional cues, and maintain-ing play themes over transitions (Rubin et al.1998). The social challenges posited by peergroups may explain reported cortisol increasesover the day in full-day child-care settings(Dettling et al. 1999, 2000; Tout et al. 1998;Watamura et al. 2002a, 2002b, 2003). Insuch child-care settings, the majority of 2- to4-year-old children showed increases in cor-tisol production over the day, whereas this isnot observed for the same children at homeon days they do not go to child care. As agroup, children 5 to 8 years of age do notshow increases in cortisol in group-care set-tings, although individually some children do.It has been suggested that increases in cor-tisol at child care emerges at the age whenpeer relations become salient. The challengeof managing interactions with others for chil-dren whose social skills are just emergingmay tax the young child’s coping abilities and,combined with long hours of care, may taxthe child’s capacity to maintain basal cortisollevels (also reviewed in Gunnar & Donzella2002). This hypothesis is strengthened by ev-
idence that children with the largest increasesin cortisol over the child-care day have beenrated by multiple adult observers as less so-cially competent and less capable of regulat-ing negative emotions and aggression (Det-tling et al. 1999, 2000). However, consistentwith the argument that support from adults iscritical to psychosocial regulation of stress inearly childhood, elevations in cortisol in child-care settings are not observed when the childreceives individualized, supportive care fromcare providers (Dettling et al. 2000).
Aside from normative developmentaltrends and variations associated with socialcompetence, cortisol levels measured whenchildren are in peer group settings also re-flect peer acceptance or rejection (Gunnaret al. 1997, 2003). As early as the preschoolyears, peer-rejected children produce higherlevels of cortisol in the preschool classroomin comparison to average or popular chil-dren. Peer rejection is associated with poor so-cial skills and poor emotion regulation (Coieet al. 1990). This is often expressed as poorlycontained aggression and inability to regulatenegative emotions, all of which is associatedwith poorer peer relations and higher corti-sol levels (Gunnar et al. 2003). Interestingly,in studies of preschool-aged children, there islittle evidence that children who few othersnominate as either liked or disliked (i.e., peer-neglected children) exhibit elevated levels ofcortisol (Gunnar et al. 2003). By contrast, atleast by early as adolescence, children whoare socially neglected and who consequentlyspend hours alone even when they are withpeers (i.e., at school) do exhibit higher lev-els of cortisol production (Adam 2006). Thepsychosocial pathways through which peer-rejected and peer-neglected children experi-ence stress related to their social status arenot yet understood, although it seems likelythat social threats, disappointments, and otheraversive interactions are likely involved. In ad-dition, pathways from poor family relation-ships to poor peer and friendship relationsneed to be considered.
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STRESS NEUROBIOLOGY ANDADVERSE EXPERIENCE:PARENTAL NEGLECT ANDABUSE
Maltreatment during development has beenrepeatedly linked to maladaptive outcomes(Cicchetti 1996). Adult survivors of childhoodmaltreatment reveal greater prevalence ofpsychiatric disorders, including affective dis-orders, eating disorders, somatic complaints,sexual dysfunction, and substance abuse. Al-terations in stress-sensitive neurobiologicalsystems, including regulation of GCs andCRH, have been posited as mechanismsthrough which adverse experience increasesthe likelihood of psychopathology (see re-views by Bremner & Vermetten 2001, DeBellis 2001, Heim & Nemeroff 2001, Teicheret al. 2002).
The Stress Neurobiology of AdultSurvivors
Researchers studying the impact of maltreat-ment during childhood are dealing with astill-developing neural system in which de-velopmental change and effects of maltreat-ment can be difficult to disentangle (Cicchetti& Tucker 1994). It is helpful, therefore,to consider first what is known about thestress neurobiology of adult survivors of child-hood maltreatment. Much of the adult sur-vivor research has focused on adults with de-pression and/or posttraumatic stress disorder(PTSD) pursuant to their maltreatment his-tories (Glaser 2000, Heim & Nemeroff 2001,Heim et al. 2004). Many of these studies lackappropriate controls. For example, adult sur-vivors of childhood maltreatment who havePTSD may be compared to healthy controlsso that differences associated with PTSD andimpacts of childhood abuse cannot be disen-tangled. Nonetheless, the general pattern offindings suggest that severe, early maltreat-ment may have neurobiological consequencesthat last into adulthood and that increase therisk of psychopathology. To understand the
findings, it is important to briefly describealterations in stress neurobiology noted foradults with these disorders who do not havechildhood maltreatment histories.
PTSD and depression appear to share hy-peractivity of CRH at hypothalamic and ex-trahypothalamic levels (Bremner et al. 1997,Heim et al. 2004). Chronic CRH drive onthe pituitary in both disorders appears to re-sult in counter-regulatory down-regulation atthe level of the pituitary, leading to bluntedACTH in response to pharmacological CRHchallenge tests (Heim et al. 2004). However,these disorders differ in the sensitivity of feed-back regulation of the HPA axis. Depressionamong adults is often associated with reducednegative feedback regulation (e.g., Young et al.1991), whereas PTSD appears to be associatedwith increased negative feedback (e.g., Yehuda2000). As a result, adults with depression oftenhypersecrete cortisol and exhibit prolongedcortisol elevations, whereas adults with PTSDoften hyposecrete cortisol and rapidly returnto baseline concentrations following pertur-bation. The question is whether childhoodmaltreatment alters these patterns.
Studies using pharmacological challengetests provide evidence that pituitary down-regulation of ACTH is comparable in adultswith depression and PTSD regardless of theirchildhood maltreatment histories (for a re-view, see Heim et al. 2004). At the level ofthe adrenal and with regard to negative feed-back regulation, the picture is more complex.There is some suggestion that depression plusearly childhood maltreatment may be associ-ated with an exaggerated negative feedbackin comparison with what is observed in de-pression without childhood abuse (Newportet al. 2004). However, this may reflect unmea-sured PTSD in the adult maltreatment sur-vivors (Rinne et al. 2002). The picture changeswhen psychological stressor tests are used.Here hyper-responsiveness of ACTH and insome instances cortisol has been noted, par-ticularly among adult survivors with depres-sion compared with depressed adults with-out childhood abuse histories (Heim et al.
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2000, 2002). Unlike pharmacological chal-lenges, psychological stressors depend on re-cruitment of cortico-limbic activation path-ways. Thus, hyperactivation for psychologicalas opposed to pharmacological challenge sug-gests that adult survivors of maltreatment whohave PTSD and/or depression may have evenmore hyper-responsive threat/stress systemsat the cortico-limbic level than do nonmal-treated adults with these disorders.
Critically, however, a very different pic-ture emerges when one studies adult sur-vivors of childhood maltreatment who arefree from psychopathology (Gunnar & Fisher2006). By definition, such individuals are re-silient. Given their resilience, perhaps it is notsurprising to find that across various stud-ies these adults show evidence of reducedactivity of stress neurobiology. For exam-ple, the CRH challenge test, which producesblunted ACTH responses in individuals withPTSD and/or depression, produces larger-than-average responses in resilient adult sur-vivors of childhood maltreatment (Heim et al.2001). Because the magnitude of the ACTHresponse is inversely proportional to the pitu-itary’s chronic or trait-like exposure to CRH(Newport et al. 2003), these results suggestchronic low CRH production in resilient adultsurvivors. Similar ACTH results have beenobtained in response to psychosocial stres-sors combined with normal to low cortisoland cardiac responses among resilient adultsurvivors (Girdler et al. 2003). Finally, theadrenals of resilient adult survivors also showlower-than-expected production of cortisol toACTH challenge tests (Heim et al. 2001).What is not clear is whether this pattern oflow stress responding is a risk factor for sub-sequent physical and mental disorders or isa reflection of individual differences in stressreactivity that may have protected the devel-oping brain from adverse impacts of maltreat-ment. Both possibilities exist, and the lattershould alert developmental researchers to theimportance of considering individual differ-ences and their genetic substrate in pursuingquestions about the impact of childhood ex-
periences on stress and emotion reactivity andregulation.
Child Maltreatment and StressNeurobiology
It has been hypothesized that traumatizedchildren initially exhibit complex environ-mentally induced developmental disordersthat later branch toward more specific andadult-like pathologies such as depression andanxiety (Cicchetti 1996). This complexity isevidenced in the data on the stress physiologyof abused children, which are often challeng-ing to interpret. For example, sexually abusedgirls evidence blunted ACTH response in re-action to CRH injections, similar to adult sur-vivors of childhood abuse with depression orPTSD (De Bellis et al. 1994). However, en-hanced ACTH responses and normal corti-sol levels to CRH challenges have also beenreported for depressed, abused children ifthey are still experiencing adverse home lives(Kaufman et al. 1997). As it does in adults,concurrent psychopathology contributes tothe heterogeneous presentation of stress func-tioning in maltreated children. For example,in one study, maltreated externalizing boys ata summer camp had higher cortisol levels rel-ative to nonmaltreated boys with externaliz-ing problems; however, they did not have ele-vated cortisol levels relative to nondisorderednonmaltreated boys (Cicchetti & Rogosch2001b). Indeed, hyporesponsiveness of boththe SAM and HPA systems has been relatedto externalizing symptomatology (McBurnett& Lahey 1994, McBurnett et al. 2000, vanGoozen et al. 2000). In a study of maltreatedpreschool-aged children compared with SEScontrols, maltreated children exhibited lesscortisol reactivity and produced even lowercortisol levels on days when there were highlevels of conflict and aggression in their class-rooms (Hart et al. 1995). Furthermore, al-though adults with PTSD and adult survivorsof child maltreatment may exhibit low lev-els of basal cortisol activity, in several stud-ies, children with PTSD pursuant to severe
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childhood maltreatment exhibited elevatedcortisol levels relative to controls (Carrionet al. 2002, De Bellis et al. 1999) and higherurinary excretion of Epi relative to nonmal-treated clinically anxious and nonanxious chil-dren (De Bellis et al. 1999). Researchers haveargued that the adult PTSD-cortisol patternmay emerge with development and/or timesince the trauma exposure (e.g., De Bellis2001). In addition to the HPA and SAM sys-tems, there is also evidence that cortico-limbicstructures involved in emotions and stressare affected by early childhood maltreatment.Prepubertal children with PTSD secondary tomaltreatment evidence smaller cerebral vol-umes, smaller corpus callosa relative to brainvolume, and less asymmetry of the prefrontalcortex than do matched controls (reviewed inDe Bellis 2001).
Not only physical and sexual maltreatmenthave an impact on the developing neurobi-ology of stress. There is increasing evidencethat severe neglect also alters the stress neur-axis (De Bellis 2005). Children living in or-phanages serve as an example. Cortisol lev-els in orphanage-reared infants and toddlerstend to be low in the early morning and lackthe normal diurnal rhythm (Carlson & Earls1997 and Kroupina et al. 1997, as reviewed inGunnar 2000). Similar low early-morning lev-els have also been noted for domestically ne-glected children soon after placement in fos-ter care (Dozier et al. 2006, Gunnar & Fisher2006). There is increasing evidence that se-vere early neglect affects the developmentof cortico-limbic circuits involved in emo-tion and stress responding (Glaser 2000). Forexample, postinstitutionalized children havebeen found to have larger amygdala volumes,and amygdala size and function (fMRI find-ings) correspond to duration of institutionalcare (Tottenham et al. 2006). It is not clearwhether neglect and abuse have different ef-fects on the neurobiological systems that reg-ulate stress and emotional function or whetherthese effects are comparable. One challenge inanswering this question is that many abusedchildren also suffer from neglect (Cicchetti &
Toth 1995). Indeed, there is some evidencethat neglect and various types of abuse, alongwith exposure to violence, have cumulativeeffects; the most profound effects on stressreactivity and regulation are noted for chil-dren with the largest cumulative exposures(Cicchetti & Rogosch 2001a).
INDIVIDUAL DIFFERENCES:CONTRIBUTIONS FROMTEMPERAMENT ANDGENETICS
As discussed above, adverse early experiencesproduce different patterns of stress respond-ing in different individuals; hyperreactivity insome and seemingly hyporeactivity in oth-ers. Although the nature and timing of ad-verse or maltreating experience may partlyexplain these differences, it is likely that tosome extent they also reflect individual differ-ences that have a genetic contribution. Stud-ies of both temperament as a reflection ofgenetic dispositions and, more recently, can-didate genes have begun to flesh out this hy-pothesis. Most of the temperament work hasfocused on behavioral dispositions, particu-larly extreme shyness or behavioral inhibition,that may increase the risk of anxiety and de-pressive disorders (Kagan et al. 1987). Kaganhas argued that the extreme 5% to 10% ofbehaviorally inhibited children are at risk fordeveloping anxiety disorders, and recent stud-ies have demonstrated that as adults, theseindividuals do show evidence of exaggeratedamygdala responses to social stimuli (i.e., un-familiar faces; Schwartz et al. 2003). In com-parison with extremely noninhibited children,these extremely inhibited children also ex-hibit heightened vigilance, higher heart rates,lower heart-rate variability or vagal tone, andgreater right-frontal EEG activity (Fox et al.2001, Kagan et al. 1988).
Several researchers have suggested that thetransition from extreme temperamental shy-ness or inhibition to pathological anxiety mayinvolve hyperactivity of the HPA axis and itscapacity to increase amygdalar CRH activity,
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thus orchestrating larger fear and stress reac-tions with less provocation (Rosen & Schulkin1998). This would seem to require evidenceof greater HPA reactivity to stressors amongtemperamentally inhibited children, some-thing that has not been reliably found. Re-searchers have reported higher early-morningbasal cortisol levels among more extremely in-hibited children (Kagan et al. 1987, Schmidtet al. 1997). But few studies have found highercortisol increases to psychological stressorssuch as entering a new play group, starting anew school year, or being exposed to labora-tory stressors (for review, see Gunnar 2001).One problem may be that researchers havebeen searching for main effects of inhibitedtemperament, while temperament may moreoften moderate effects of stressors or oper-ate in relation to the social support availableto the child. Thus, as noted above, childrenwith more negative emotional temperamentsare at risk for larger increases in cortisol whenthey are in child-care settings, but this is onlyobserved when the care provider is low in sup-portive and responsive care (Dettling et al.2000).
The need to consider temperament in re-lation to the supportiveness of the care chil-dren receive is mirrored by recent findings re-garding genes that may increase the risk ofemotional disorders. Thus, a common regu-latory variant (5-HTTLPR) in the serotonintransporter gene (SLC6A4) has received at-tention because it may increase the risk foranxiety and depression (Lesch 2001). How-ever, several studies have now shown thatindividuals carrying alleles that result in al-tered transcription and transporter availabil-ity are not at increased risk for depressionunless they have experienced more stressfullife events, including childhood maltreatment(Caspi et al. 2003, Kaufman et al. 2004). Sim-ilarly, among temperamentally inhibited chil-dren there is now evidence that this gene vari-ant is not associated with increasing levels ofbehavioral inhibition with development un-less the child also experiences less social sup-port and supportive care during early child-
hood (Fox et al. 2005). These findings are ofnote because there is evidence that a function-ally equivalent gene variant in rhesus mon-keys is associated with larger HPA responsesto stressors, but only among animals that growup in less-supportive care conditions (Barret al. 2004). This is not the only genetic varia-tion that likely makes important contributionsto individual differences in stress reactivityand regulation; however, as with the work onshy, inhibited temperament and on the sero-tonin transporter allele, it is very possible thattheir consequences need to be considered inthe context of the supportiveness of the child’ssocial relationships.
CONCLUSIONS AND FUTUREDIRECTIONS
In the past 20 years, a tremendous amount hasbeen learned about the development of stressreactivity and regulation during human devel-opment. Stress reactivity is better understoodas the result of intertwined biological and psy-chological processes that ultimately ensurean organism’s survival. Adjusting to externalchallenges through adaptive internal changesis a universal mechanism through which liveorganisms interface with their environment.However there is a cost to frequent physio-logical adjustments (allostatic load). Frequentactivation of neurobiological stress responsesincreases the risk of physical and mental disor-ders, perhaps particularly while organisms aredeveloping. As such, one of the most interest-ing findings emerging from the research onthe psychobiology of stress is that in the ab-sence of supportive care, stressors experiencedduring sensitive periods of development canin fact leave permanent imprints in the neu-ral substrate of emotional and cognitive pro-cesses. Stress that is chronic, severe, and deliv-ered during vulnerable periods of neural de-velopment will ripple through all levels of anorganism’s vital activity—be it a rat’s inabilityto find its way through a maze or a maltreatedchild’s hypersensitive response to angry faces.It would not be an overstatement to say that
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the nervous system of mammals carries theirsingular epigenetic history and expresses it inunique but lawful (i.e. predictable) ways. Thisis manifested both in the way organisms re-act to environmental challenges and in theway their neural structures are organized. Thenegative effects of stress, however, are not al-ways irreversible. The psychobiology of stressreflects both epigenesis and current life cir-cumstances. Improved living conditions andenriched environments have the potential ofcorrecting the impact of early adverse stres-sors. For example, exposing juvenile rats tocomplex environments can reverse the neuro-biological effects of rearing by a low-lickingand -grooming mother. Similarly, maltreatedpreschool children placed in an early inter-vention foster care program (which promotedpositive parenting strategies) showed bothimproved behavioral adjustment and morenormative regulation of the HPA axis in com-parison with children in typical foster care set-tings (Fisher et al. 2000). Intervention at otherlevels of the organism’s functioning may alsocorrect the long-term effects of early stressors.Antidepressants and CRH antagonists, for ex-ample, eliminate many of the behavioral dis-turbances that animals suffer due to early ad-verse experience; other pharmacologic agentsalso may be found to improve stress resilienceamong at-risk children.
A common theme in stress research isthat, consistent with other mammals, dur-ing human development social relationshipsplay critical roles in regulating physiologicalstress reactions and protecting the develop-ing brain from potentially deleterious effectsof the hormones and neurochemicals asso-ciated with stress reactions. Disturbances insupportive care and care environments thatare themselves threatening appear to rob chil-dren of an effective stress buffer and exposethem to the consequences of biological stressresponses that can have deleterious effects forlater development. Caregivers and close rel-atives in a child’s life are both potentially thestrongest sources of stress and the most pow-
erful defense against harmful stressors. Com-plex patterns of social stimulation may bepart of the critical experiential input that (ininteraction with genetic predispositions)shapes children’s emotional and biological re-activity. Children’s stress responses are alsosensitive to social experiences beyond the con-text of the family. Negotiating peer interac-tions in school settings is a potent challengeto the stress system, particularly at the stage indevelopment when social skills are just emerg-ing. Above and beyond these normative chal-lenges, children who are less socially compe-tent and/or rejected might be at risk for morefrequent and prolonged activation of the stressresponse. One of the areas that need integra-tion into models of developmental health andpsychopathology is how stress activation thatis related to social status may affect children’slater adaptation and health.
Despite tremendous advances in our un-derstanding of stress neurobiology and de-velopment, there is still a great deal that isnot understood. Principle among our lacu-nae is an adequate understanding of the ge-netic variations among children that moder-ate the reactivity, regulation, and impact ofstress responses. However, numerous candi-date genes are being identified whose im-pacts are now available for study. Integratinggenetic studies into work on temperament,social experiences, stress responses, and be-havioral outcomes will likely be an increas-ing focus of future research. Likewise, theemerging field of developmental affectiveneuroscience has a great deal to offer re-searchers concerned with understanding howthe activity of stress-sensitive systems affectsthe development of brain systems involvedin learning, memory, and emotion (Pollak2005). Together, these foci of future researchon stress should provide developmental re-searchers with a richer understanding of bothnormal and pathological development alongwith increased targets for interventions thatwill improve outcomes for children at risk forbehavioral and emotional problems.
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SUMMARY POINTS
1. Stressors trigger the activation of physiological systems designed to ensure the survivalof the organism to the temporal detriment of systems controlling growth, reproduc-tion, and replenishment. Although these adaptations through internal changes aredesirable, under conditions of chronic stress they are deleterious. Chronic stress cancause inhibition of neurogenesis, disruption of neuronal plasticity, and neurotoxicity.Frequent activation of the stress response tilts the organism toward consuming re-sources without sufficient recovery and increases the risk for physical and behavioralproblems. This has been termed “allostatic load.”
2. Glucocorticoids regulate gene expression in multiple brain structures, thus simul-taneously affecting central regulation of organic processes. The physiological andmolecular events cascading from the activation of the stress systems have a powerfulimpact on neural tissues and the functions they support at any stage of development.However, these effects may be profound during periods of development, when thebrain is undergoing rapid change. Sensitive periods and stages of enhanced brain plas-ticity are particularly vulnerable to the long-term effects of stress hormones. Chronicelevations of stress hormones can affect synaptic connectivity and neurogenesis andcan increase cellular death, effectively altering the typical pathways and organizationof the young brain.
3. Stress neurobiology can be shaped by the social environment experienced by youngorganisms, and adult patterns of stress reactivity can be permanently imprinted bykey social influences (whether positive or negative) early in development. Of thevarious social influences that mammals experience, caregivers are by far the mostpowerful source of stress and the most effective defenseagainst harmful stressors.Disruption of the mother-infant relationship or failure of the caregiver to provideadequate care contributes to individual differences in physiological and behavioralresponses to environmental challenges.
4. Maternal behavior can effectively change gene-controlled patterns of stress respon-sivity. Genetic information linked to neuroendocrine reactivity can be programmedby early maternal stimulation. In rodent models, highly responsive maternal behav-ior actually promotes a stress neurobiology that is less reactive and more resilientto challenges. The mechanisms are highly specific and involve relatively permanentmodification of DNA controlling the expression of glucocorticoid receptors. How-ever, these effects can be temporarily reversed by pharmacological intervention andin some cases by interventions that dramatically alter the care received by youngmammals. The fact that DNA structure can be environmentally programmed positsboth a mechanism for the impact of social stimulations and the molecular basis forintervention and healing.
5. The neurobiology of stress changes with development. Normative changes in theneurobiology of stress provide windows of opportunity and risks that are specific tothat developmental stage. Reorganization of the stress response is species specificand seems to be tied to maturational changes in nervous system activity. For exam-ple, it is likely that with the onset of puberty, the relative low-stress responsivity ofchildhood ends and is marked by an increase in basal cortisol levels and heightened
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neurobiological responses to stressors. If the onset of puberty indeed is characterizedby enhanced stress reactivity, this would place adolescents at a heightened risk forpsychopathology and could partly explain why there is an increase in the incidence ofemotional disorders during adolescence.
6. Stress neurobiology is highly responsive to changes in the environment. Stress neu-robiology, although very sensitive to early social contexts, is not a fixed or inflexiblesystem. It reflects both the organism’s epigenetic history and its new circumstances.Improved living conditions, enriched environments, and corrective emotional expe-riences can reverse the adverse consequences of early adversity.
7. Genes and environment interact in stress neurobiology. Constitutional predisposi-tions intertwine with environmental influences to steer the developing stress neu-robiology. Certain alleles of genes involved in neurotransmitter activity, neuronalconnectivity, and differentiations seem to place children and adults at risk for a widearray of mental and physical disorders, especially when paired with adverse envi-ronments and multiple stressors such as those experienced in neglectful and abusivehomes. Similarly, temperamentally inhibited children seem to be at risk for higherstress reactivity and behavioral inhibition in the context of lack of supportive careduring childhood.
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Contents ARI 8 November 2006 21:2
Annual Review ofPsychology
Volume 58, 2007
Contents
Prefatory
Research on Attention Networks as a Model for the Integration ofPsychological ScienceMichael I. Posner and Mary K. Rothbart � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 1
Cognitive Neuroscience
The Representation of Object Concepts in the BrainAlex Martin � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 25
Depth, Space, and Motion
Perception of Human MotionRandolph Blake and Maggie Shiffrar � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 47
Form Perception (Scene Perception) or Object Recognition
Visual Object Recognition: Do We Know More Now Than We Did 20Years Ago?Jessie J. Peissig and Michael J. Tarr � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 75
Animal Cognition
Causal Cognition in Human and Nonhuman Animals: A Comparative,Critical ReviewDerek C. Penn and Daniel J. Povinelli � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 97
Emotional, Social, and Personality Development
The Development of CopingEllen A. Skinner and Melanie J. Zimmer-Gembeck � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 119
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Contents ARI 8 November 2006 21:2
Biological and Genetic Processes in Development
The Neurobiology of Stress and DevelopmentMegan Gunnar and Karina Quevedo � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 145
Development in Societal Context
An Interactionist Perspective on the Socioeconomic Context ofHuman DevelopmentRand D. Conger and M. Brent Donnellan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 175
Culture and Mental Health
Race, Race-Based Discrimination, and Health Outcomes AmongAfrican AmericansVickie M. Mays, Susan D. Cochran, and Namdi W. Barnes � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 201
Personality Disorders
Assessment and Diagnosis of Personality Disorder: Perennial Issuesand an Emerging ReconceptualizationLee Anna Clark � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 227
Social Psychology of Attention, Control, and Automaticity
Social Cognitive Neuroscience: A Review of Core ProcessesMatthew D. Lieberman � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 259
Inference, Person Perception, Attribution
Partitioning the Domain of Social Inference: Dual Mode and SystemsModels and Their AlternativesArie W. Kruglanski and Edward Orehek � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 291
Self and Identity
Motivational and Emotional Aspects of the SelfMark R. Leary � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 317
Social Development, Social Personality, Social Motivation,Social Emotion
Moral Emotions and Moral BehaviorJune Price Tangney, Jeff Stuewig, and Debra J. Mashek � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 345
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The Experience of EmotionLisa Feldman Barrett, Batja Mesquita, Kevin N. Ochsner,
and James J. Gross � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 373
Attraction and Close Relationships
The Close Relationships of Lesbian and Gay MenLetitia Anne Peplau and Adam W. Fingerhut � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 405
Small Groups
OstracismKipling D. Williams � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 425
Personality Processes
The Elaboration of Personal Construct PsychologyBeverly M. Walker and David A. Winter � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 453
Cross-Country or Regional Comparisons
Cross-Cultural Organizational BehaviorMichele J. Gelfand, Miriam Erez, and Zeynep Aycan � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 479
Organizational Groups and Teams
Work Group DiversityDaan van Knippenberg and Michaéla C. Schippers � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 515
Career Development and Counseling
Work and Vocational Psychology: Theory, Research,and ApplicationsNadya A. Fouad � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 543
Adjustment to Chronic Diseases and Terminal Illness
Health Psychology: Psychological Adjustmentto Chronic DiseaseAnnette L. Stanton, Tracey A. Revenson, and Howard Tennen � � � � � � � � � � � � � � � � � � � � � � � � � � � 565
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Research Methodology
Mediation AnalysisDavid P. MacKinnon, Amanda J. Fairchild, and Matthew S. Fritz � � � � � � � � � � � � � � � � � � � � � 593
Analysis of Nonlinear Patterns of Change with Random CoefficientModelsRobert Cudeck and Jeffrey R. Harring � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 615
Indexes
Cumulative Index of Contributing Authors, Volumes 48–58 � � � � � � � � � � � � � � � � � � � � � � � � � � � 639
Cumulative Index of Chapter Titles, Volumes 48–58 � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � � 644
Errata
An online log of corrections to Annual Review of Psychology chapters (if any, 1997 to thepresent) may be found at http://psych.annualreviews.org/errata.shtml
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