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CHAPTER 14

Beyond the Stress Concept: Allostatic


Load—A Developmental Biological and
Cognitive Perspective
SONIA J. LUPIEN, ISABELLE OUELLET-MORIN, ALMUT HUPBACH, MAI T. TU, CLAUDIA BUSS,
DOMINIQUE WALKER, JENS PRUESSNER, and BRUCE S. MCEWEN

THE ALLOSTATIC LOAD MODEL 578 Allostatic Load and Externalized Behaviors/Conduct
Stress: Historical Background 578 Disorder in Children 598
The Hypothalamic-Pituitary-Adrenal Axis 579 Genetic Inf luences on the Hypothalamic-Pituitary-Adrenal
Stress, Stressor, Stress Response, Eustress, and Distress 579 Axis: Results from Twin Studies 607
Allostasis versus Homeostasis 581 FUTURE DIRECTIONS 611
Allostatic Load: When Things Turn Bad 582 The Hormonal Milieu of the Mother in the Prenatal and
Conclusion 590 Postnatal Periods 611
EARLY ADVERSITY AND THE DEVELOPMENT Inf luences of Early Adversities on Brain Development 614
OF ALLOSTATIC LOAD 590 GENERAL CONCLUSION 615
The Subjective Nature of Reality: The Human REFERENCES 616
Information-Processing System 593

Stress is a popular topic these days. A week seldom passes ple who are extremely stressed by time pressure and others
without hearing or reading about stress and its deleterious who actually seek time pressure to perform adequately (so-
effects on health. Given this negative impact of stress on called procrastinators). This shows that stress is a highly in-
human health, many types of stress management therapies dividual experience that does not depend on a particular
have been put forward to decrease stress and thus promote event such as time pressure; rather, it depends on specific
health. However, there is a great paradox in the field of psychological determinants that trigger a stress response.
stress research, and it relates to the fact that the popular
definition of stress is very different from the scientific def-
THE ALLOSTATIC LOAD MODEL
inition of stress. This has left a multitude of people and ex-
perts talking about, and working on, very different aspects
The allostatic load model proposed by McEwen and Stellar
of the stress response.
(1993) refers to the wear and tear that the body experiences
In popular terms, stress is mainly defined as time pres-
due to the repeated use of adaptive responses to stress, as
sure. We feel stressed when we do not have the time to per-
well as the inefficient turning on or shutting off of these re-
form the tasks we want to perform. This time pressure
sponses. Allostatic load refers to the cost the body pays for
usually triggers a set of physiological reactions (see discus-
this adaptation, when this adaptation needs to be main-
sion) that give us the indication that we are stressed. Al-
tained for long periods of time.
though this definition is certainly accurate in terms of one
component of the stress response, it is important to acknowl-
Stress: Historical Background
edge that in scientific terms, stress is not equivalent to time
pressure. If this were true, every individual would feel Prior to becoming part of our day-to-day conversations, the
stressed when pressured by time. However, we all know peo- term “stress” was used by engineers to explain forces that

578
The Allostatic Load Model 579

can put strain on a structure. For example, one could place stress hormones. There are two main stress hormones, the
strain on a piece of metal in such a way that it would break glucocorticoids (corticosterone in animals and cortisol in
like glass when it reached its stress level. In 1936, Hans humans) and the catecholamines (epinephrine and norepi-
Selye (reproduced in Selye, 1998) borrowed the term from nephrine). In humans, cortisol secretion shows pronounced
the field of engineering and talked about stress as being a circadian rhythmicity, where concentrations are at their
nonspecific phenomenon representing the intersection of highest in the morning (the circadian peak), progressively
symptoms produced by a wide variety of noxious agents. decline from late afternoon to early nocturnal periods (the
For many years, Selye tested various conditions (e.g., fast- circadian trough), and show abrupt elevations after the
ing, extreme cold, operative injuries, and drug administra- first few hours of sleep. The acute secretion of glucocorti-
tion) that would produce morphological changes in the coids and catecholamines in response to a stressor consti-
body that were representative of a stress response, such as tutes the primary mediators in the chain of hormonal
enlargement of the adrenal gland, atrophy of the thymus, events triggered in response to stress. When these two hor-
and gastric ulceration. Selye’s view of the concept of stress mones are secreted in response to stress, they act on the
was that the determinants of the stress response are non- body to give rise to the fight-or-flight response, whereby
specific; that is, many unspecific conditions can put strain one would, for instance, experience an increase in heart
on the organism and lead to disease, the same way that rate and blood pressure.
many unspecific conditions can put strain on a piece of By summarizing the results of studies measuring the cir-
metal and break it like glass. culating levels of these hormones before and after individ-
Not all researchers agreed with Selye’s model, particu- uals were exposed to various jobs or situations that were
larly with the notion that the determinants of the stress re- deemed to be stressful (e.g., air-traffic controllers and
sponse are nonspecific. The reason for this was simple. parachute jumping), Mason (1968) was able to describe
Selye spent his entire career working on physical stressors three main psychological determinants that would induce a
(e.g., heat, cold, and pain), but we all know that some of the stress response in any individual exposed to them. Using
worst stressors we encounter in life are psychological in na- this methodology, he showed that for a situation to induce a
ture and are induced by our interpretation of events. For stress response, it has to be interpreted as being novel
this reason, a psychologist named John Mason (1968) spent and/or unpredictable, and/or the individual must have the
many years measuring stress hormone levels in humans feeling that he or she does not have control over the situa-
subjected to various conditions that he thought would be tion. Although this work led to a general debate between
stressful; he intended to describe the psychological charac- Selye (1975a) and Mason, further studies confirmed that
teristics that would make any condition stressful to anyone the determinants of the stress response are highly specific
exposed to it. This work was made possible in the early and, therefore, potentially predictable and measurable.
1960s due to the development of new technology that al-
lowed scientists to measure levels of hormones that are re- Stress, Stressor, Stress Response, Eustress,
leased during reactivity to stress. The release of stress and Distress
hormones is made possible through activation of a neuroen-
docrine axis named the hypothalamic-pituitary-adrenal From this short historical background, it is becoming clear
(HPA) axis. that various definitions have been given to stress. In the
past few years, a growing number of scientists started to
feel the need to clarify these concepts to increase our un-
The Hypothalamic-Pituitary-Adrenal Axis
derstanding of the effects of stress on human health. Based
When a situation is interpreted as being stressful, it trig- on recent reviews, McEwen and Wingfield (2003) proposed
gers the activation of the HPA axis, whereby neurons in the a clarification of these different concepts of stress that we
hypothalamus, a brain structure often termed the “master use in this review. Thus, we define stress as a threat, real or
gland,” releases corticotropin-releasing hormone (CRH). implied, to homeostasis. In this sense, stress can be ab-
The release of CRH triggers the subsequent secretion and solute (a real threat induced by an earthquake in a town,
release of another hormone, adrenocorticotropin (ACTH), leading to a significant stress response in every person fac-
from the pituitary gland, also located in the brain. When ing this threat), or it can be relative (an implied threat in-
ACTH is secreted by the pituitary gland, it travels in the duced by the interpretation of a situation as being novel
blood and reaches the adrenal glands, which are located and/or unpredictable and/or uncontrollable, for example, a
above the kidneys, and triggers secretion of the so-called public speaking task).
580 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

Absolute versus Relative Stressors more to the cognitive interpretation given to the situation
(as being positive or negative to the individual) than to the
Absolute stressors serve adaptive purposes and are those
physical consequence of it. To date, very few studies have
events or situations that will necessarily lead to a stress re-
been performed to assess the body’s different responses
sponse in the majority (if not the totality) of individuals
to eustress or distress. However, a study performed in
when they are first confronted with it. Being in or witness-
1989 by Berk and collaborators assessed the hormonal re-
ing an accident, confronting a dangerous animal, being sub-
sponse to a mirthful laughter experience in 10 healthy
mitted to extreme cold or heat are all examples of absolute
male subjects. In this study, half of the participants
stressors. These extreme and particular situations constitute
viewed a 60-minute humorous video and the other half
absolute stressors in that, due to their aversive nature, a
did not. Measures of cortisol, 3,4-dihydrophenylacetic
stress response has to be elicited for one’s survival and/or
acid (dopac, the major serum neuronal catabolite of the
well-being. In Western societies, absolute stressors are rare
neurotransmitter dopamine), epinephrine, and norepi-
but are nonetheless those that elicit the greatest physiologi-
nephrine were assessed before and after exposure to the
cal response. Conversely, relative stressors are those events
experimental or control conditions. The results showed
or situations that will elicit a stress response only in a cer-
that cortisol and dopac in the experimental group de-
tain proportion of individuals. Moreover, this response may
creased more rapidly from baseline than in the control
be mild or strong. For example, having to unexpectedly de-
group, whereas epinephrine levels in the experimental
liver a speech that will be videotaped may be very stressful
group were significantly lower than in the control group at
for one individual and not at all for another. Large interindi-
all time points. Although the authors stated that these bio-
vidual variations in the stress response to psychological
chemical changes have implications for the reversal of the
challenges have been frequently reported (Hellhammer,
neuroendocrine and classical stress hormone response, it
Buchtal, Gutberlet, & Kirschbaum, 1997; Kirschbaum &
has to be noted that the study was performed with a very
Hellhammer, 1989; Kirschbaum, Klauer, Filipp, & Hellham-
small sample of participants (5 in each group), and the
mer, 1995; Kirschbaum, Kudielka, Gaab, Schommer, &
cortisol changes in response to the funny movie were not
Hellhammer, 1999; Kirschbaum, Prussner, et al., 1995;
compared to the cortisol changes after exposure to a sad
Kudielka, Buske-Kirschbaum, Hellhammer, & Kirschbaum,
or aggressive movie. Consequently, it is not clear at this
2004; Kudielka, Schommer, Hellhammer, & Kirschbaum,
time whether feelings of eustress or distress lead to dif-
2004; Lupien et al., 1997; M. Pruessner, Hellhammer,
ferent hormonal responses in humans.
Pruessner, & Lupien, 2003; Rohleder, Wolf, & Kirschbaum,
2003; Roy, Steptoe, & Kirschbaum, 1998). As discussed in Stressor versus Stress Response
section II of this chapter, these individual differences in re-
sponse to relative stressors may be due to differences in past The stressor is the event itself, such as the earthquake in
experiences, learning, or genetic or cognitive processes. the case of the absolute stress or the public speaking task in
However, most of the relative stressors that lead to large in- the case of the relative stress. The stress response is the
terindividual variations are those stressors that imply a cog- body’s reaction to the event (Selye, 1975b, 1998) and can
nitive and/or psychosocial component (Dickerson & be measured by monitoring levels of cortisol and ACTH in
Kemeny, 2002). It may be argued that absolute stressors are blood or cortisol in saliva or urine. Activity within the
closely linked to physiological systems due to their life- or sympathetic nervous system is measurable as levels of cate-
self-threatening nature. On the contrary, relative stressors, cholamines in blood, urine, or saliva or by monitoring heart
because they are milder or because they necessitate a cogni- rate and blood pressure. Although the subjective experi-
tive interpretation to elicit a response, will not necessarily ence of stress does not always correlate with the output of
lead to a physiological response, and the presence or absence the physiological mediators of stress (Kirschbaum et al.,
of a physiological response will depend on the outcome of 1999), the measurement of the body’s physiological re-
the cognitive analysis. sponses to environmental challenges (real or implied)
nonetheless constitutes the primary means of connecting
experience with resilience or the risk of disease.
Eustress versus Distress
Situations can be interpreted as being positive, leading to Acute versus Chronic Stress
eustress (good stress), or as being negative, leading to dis- Activation of the stress response in the face of a threat
tress ( bad stress). The nature (eustress versus distress) of (real or implied) is primordial for the survival of
the stress response elicited by these situations relates the species. This acute stress response, which has been
The Allostatic Load Model 581

called the fight-or-flight response, allows the individual to ing literally “maintaining stability through change,” de-
mobilize the energy required to deal with threat. However, scribes the process of adaptation to challenge. It was in-
chronic exposure to these threats can have detrimental ef- troduced by Sterling and Eyer in 1988 to describe how the
fects on the body. Although a wealth of data has been gath- cardiovascular system adjusts to resting and active states
ered on the effects of chronic stress on the body, almost no of the body. This notion was generalized to other physio-
model has been offered to explain, predict, and measure logical mediators, such as the secretion of cortisol and
the impact of chronic stress on the body. The main reason catecholamines (McEwen, 1998a, 1998b; McEwen & See-
for this is the fact that no model has proposed a clear dis- man, 1999; McEwen & Stellar, 1993).
tinction between the positive impact of an acute response Allostasis is positive and necessary to life. It is different
to stress and the negative impact of a chronic activation of from homeostasis in that it supports homeostasis; that is, it
the stress systems. Moreover, in many cases, a stressor is supports those physiological parameters essential for life, as
thought to refer to any situation that challenges the body’s environments and/or life history stages change. Indeed,
homeostasis and consequently is seen as being negative. homeostasis keeps “set-points” and various boundaries of
However, in recent years, a new model has been developed control (such as pH), whereas allostasis allows for a modifi-
to disentangle these different concepts and allow for a cation of these set-points in order to face challenges. Conse-
clearer description of the positive and negative effects of quently, homeostasis involves systems that are essential for
acute and chronic stress on the organism. This is the allo- life, and allostasis maintains these systems in balance as en-
static load model (McEwen & Stellar, 1993), but to under- vironment and life history stage change (McEwen & Wing-
stand what allostatic load is, one has to first understand the field, 2003).
notion of allostasis and how it differs from the notion of For each system of the body, allostasis allows for short-
homeostasis. term adaptive actions of the organism in response to envi-
ronmental change. As presented in Table 14.1, for the
Allostasis versus Homeostasis cardiovascular system, one good example of allostasis is
the role of catecholamines in promoting adaptation by ad-
In 1929, Cannon introduced the term “ homeostasis” to justing heart rate and blood pressure to various conditions
refer to the operation of coordinated physiological such as sleeping, waking, and physical exertion (Sterling &
processes that maintain most of the steady states of the Eyer, 1988). For the metabolic system, one example of
organism. Consequently, homeostasis is the stability of allostasis is the role of glucocorticoids at enhancing
physiological systems that maintain life, such as pH, body food intake and facilitating the replenishment of energy re-
temperature, glucose levels, and oxygen tension. These serves after an environmental challenge (Beauman, 2000;
physiological systems are truly essential for life and are Kuenzel, Beck, & Teruyama, 1999). For the brain, a good
therefore maintained within an optimal range. The daily example of allostasis is the involvement of both glucocorti-
routines of animals and humans include nutritional inputs coids and catecholamines in promoting memory for emo-
to maintain normal activities and to anticipate additional tionally meaningful events related to the environmental
requirements (such as breeding, acclimating to environ- changes (Cahill, Prins, Weber, & McGaugh, 1994; Maheu,
mental changes) during the day-night cycle and the sea- Joober, Beaulieu, & Lupien, 2004; Maheu & Lupien, 2003;
sons. These homeostatic mechanisms allow the individual Roozendaal, 2000, 2003; Roozendaal, Hahn, Nathan, de
to maintain physiological and behavioral stability despite Quervain, & McGaugh, 2004; van Stegeren, Everaerd,
fluctuating environmental conditions. Cahill, McGaugh, & Gooren, 1998). For the immune sys-
However, life is not always stable, and superimposed tem, an example of allostasis is the role of glucocorticoids
on these predictable events are facultative physiological and catecholamines in promoting trafficking of immune
and behavioral responses to unpredictable events that cells to organs and tissues where they are needed to fight
have the potential to be stressors. To respond to these un- an infection or other challenges (Dhabhar & McEwen,
predictable events, the system requires extra energy from 1999). All these body responses go above homeostatic
endogenous stores of fat, glycogen, and protein. Conse- functions and serve to maintain the stability of the various
quently, to survive, an organism must be able to maintain systems of the body in response to environmental chal-
such emergency responses. The capacity to maintain lenges. It is because allostasis allows for a change in the
these emergency responses has been called “allostasis” set-points of these various physiological systems that
(Sterling & Eyer, 1988), which implies the process of homeostasis is kept, and the body can respond adequately
adaptation (McEwen & Stellar, 1993). Allostasis, mean- to environmental changes.
582 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

TABLE 14.1 Examples of Allostasis and Allostatic Load Processes, along with the Primary Stress Mediators Involved, for the
Cardiovascular, Metabolic, Immune, and Brain Systems

System Primary Stress Mediator Involved Allostasis Allostatic Load


Cardiovascular Catecholamines Act by promoting adaptation by adjusting Repeated surges of BP accelerates
heart rate (HR) and blood pressure (BP) atherosclerosis and synergizes with
to sleeping, waking, and physical exertion. metabolic hormones to produce Type II
diabetes.
Metabolic Glucocorticoids Enhance food intake and facilitate Repeated HPA activity leads to insulin
replenishment of energy reserves. resistance, accelerating toward
progression of Type II diabetes, including
abdominal obesity, atherosclerosis, and
hypertension.
Immune Glucocorticoids and Catecholamines Promote trafficking (movement) of Chronic overactivity of these mediators
immune cells to organs and tissues where leads to immunosuppressive effects.
they are needed to fight infections or other
challenges and modulate the expression of
the hormones of the immune system, i.e.,
the cytokines and the chemokines.
Brain Glucocorticoids and Catecholamines Promote retention of memories for Overactivity of these mediators lead to
emotionally charged events, both positive cognitive dysfunction, reduces neuronal
and negative. excitability, induces neuronal atrophy, and
in extreme cases, causes death of brain cells.

Allostatic Load: When Things Turn Bad acute and/or prolonged activation of these systems on the
body and the brain).
In 1993, McEwen and Stellar proposed the term “allostatic
Top-Down Processing and Allostasis
load” to refer to the wear and tear that the body experiences
due to the repeated use of allostatic responses as well as the The first factor in McEwen and Stellar’s (1993) model is the
inefficient turning on or shutting off of these responses. Al- reaction of the individual to physical and psychological stim-
lostatic load refers to the cost the body pays for this adapta- uli. As presented in Figure 14.1, this reaction is in part de-
tion, when this adaptation needs to be maintained for long termined by the social context and the social status of the
periods of time. From the standpoint of survival and health individual. Second, the stimulus will have an effect on the
of the individual, the most important feature of the primary individual’s information-processing system (the “proces-
stress mediators associated with allostasis is that they have sor ”). The response of the processor will be determined by
protective effects in the short run. However, they can have genetic makeup, stage of biological development, gender,
damaging effects at longer time intervals if there are many past learning, and social history. If the stimulus is perceived
adverse life events or if the secretion of hormones is dysreg- as a threat and the source of the threat is unknown, the indi-
ulated due to sustained stress responses. When this happens, vidual will become highly vigilant and try to determine the
it leads to allostatic load. As presented in Figure 14.1, real nature (threat versus nonthreat) of the stimulus. If the
McEwen and Stellar’s model describes the operating factors stimulus is perceived as a threat and its source is known, the
and the general sequence of events that occurs under condi- individual will try to find a coping response to the threat. If
tions of acute and chronic stress (for reviews of the concept, no response is available, helplessness or hopelessness may
see McEwen, 1998a, 1998b; McEwen & Seeman, 1999; appear, with its altered physiologic responses. If a response
McEwen & Stellar, 1993; McEwen & Wingfield, 2003; See- is available, the outcome of it will depend on the cost of that
man, McEwen, Rowe, & Singer, 2001). The model comprises response. If a low-cost response is appropriate, no stress re-
a behavioral side, on which the individual interprets and re- sponse will be initiated. If a high-cost response is needed, it
acts to a challenge, and a biological side, on which the body may necessitate the appearance of aggression or sensation-
reacts to the perceived stress. The model thus comprises seeking or risk-taking behaviors. However, the available re-
both a top-down processing side (interpretation of a situa- sponse can also be thwarted, which will eventually lead to
tion as being stressful, leading to activation of the various displaced frustration or aggression. So, perceptions of threat
stress systems) and a bottom-up side (the effects of the and choice of response are central aspects of the assessment
The Allostatic Load Model 583

Social context Physical and which will help trigger a stress response allowing the indi-
Social status Stimulus psychological vidual to deal with the threat. What is important to under-
challenges
stand here is that the same mediators (glucocorticoids and
Genetic predisposition Learning, individual, catecholamines) that are protective and adaptive in the short
Developmental stage Processor and social history run can have extremely damaging consequences if they are
Gender
overproduced and/or are dysregulated for a longer period of
Threat
time (McEwen, 1998a), leading to biphasic actions of the
No Threat
primary stress mediators.
The long-term cost to the body from allostatic load may
Source Known Source Unknown
be subdivided into at least four subtypes (McEwen, 1998a),
as summarized in Figure 14.1. The first type is simply too
Response Unavailable Response Available much stress in the form of repeated, novel events that cause
repeated elevations of stress mediators. For example, the
Low Cost High Cost amount and frequency of economic hardship predicts de-
Thwarted
cline of physical and mental functioning as well as mortal-
Response ity (Adler et al., 1994). A second type of allostatic load
involves a failure to habituate or adapt to the multiple oc-
currences of the same stressor. This leads to the overexpo-
Activation of Primary Stress Mediators
(cortisol, epinephrine, norepinephrine, DHEA)
sure to stress mediators because the body fails to dampen
or eliminate the hormonal stress response to a repeated
Response

event. For example, when confronted with repeated public


Allostasis

speaking challenges, most individuals habituated their cor-


tisol response, but a few individuals continued to show cor-
Stress Recovery
tisol response (Kirschbaum, Prussner, et al., 1995). A third
Primary Mediators and Effects

type of allostatic load involves the failure to shut off either


Primary Effects
Long-Term Activation of

the hormonal stress response or the normal trough of the


(cellular events regulated by primary mediators)
diurnal cortisol pattern. Examples of this include blood
pressure elevations in work-related stress (Gerin, Litt,
Deich, & Pickering, 1996; Kunz-Ebrecht, Kirschbaum, &
Repeated Lack of Prolonged Inadequate
Hits Adaptation Response Response Steptoe, 2004; Lundberg, 1996; Ming et al., 2004; Picker-
ing, 1996a, 1996b; Pickering et al., 1996; Schwartz, Picker-
Secondary Outcomes
ing, & Landsbergis, 1996; Steptoe, Siegrist, Kirschbaum,
(waist-hip ratio, blood pressure, cholesterol, glucose) & Marmot, 2004; Steptoe & Willemsen, 2004), sleep dep-
rivation leading to elevated evening cortisol and hyper-
Allostatic

(insulin, immune capacity, glucose tolerance) glycemia within 5 days (Leproult, Copinschi, Buxton, &
Load

Van Cauter, 1997; Van Cauter, Polonsky, & Scheen, 1997),


Tertiary Outcomes and depressive illness leading to chronically elevated corti-
(cardiovascular disease, severe cognitive decline, sol and loss of bone mineral mass (Coelho, Silva, Maia,
diabetes, hypertension, cancer) Prata, & Barros, 1999; Michelson et al., 1996; Robbins,
Hirsch, Whitmer, Cauley, & Harris, 2001; Wong et al.,
Figure 14.1 Schematic representation of the Allostatic Load
model. 2005). The fourth type of allostatic load involves an inade-
quate hormonal stress response which allows other sys-
of risk and making choices leading to health-damaging or tems, such as the inflammatory cytokines, to become
health-promoting behaviors. overactive (Chrousos & Elenkov, 2000; Elenkov, Chrousos,
& Wilder, 2000). The Lewis rat is an example of an animal
Bottom-Up Effects and Allostatic Load strain in which increased susceptibility to inflammatory
When a given situation is perceived as stressful or threaten- and autoimmune disturbances is related to inadequate lev-
ing, there will be activation of the primary stress mediators els of cortisol (for a review, see Fournie et al., 2001). Next,
(glucocorticoids, catecholamines, dehydroepiandrosterone we give an example of allostasis turning into allostatic load
[DHEA]; a complete description of these mediators follows), for the primary stress mediator glucocorticoids.
584 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

Glucocorticoids and Allostatic Load: An Example. It is when a dysregulation of other hormones occurs in re-
The traditional role of glucocorticoids is to promote con- sponse to the long-term secretion of the primary stress me-
version of protein and lipids to usable carbohydrates. In the diators that allostatic load appears. Other examples of
short run, this is a positive aspect of this stress mediator allostatic load are depicted in Table 14.1 for the cardiovas-
as glucocorticoids will serve to replenish energy reserves cular, metabolic, immune, and brain systems.
after a period of activity such as running away from a
house on fire. The same glucocorticoid will also act on the When Top-Down Processing Meets Bottom-Up Effects
brain during this period to increase appetite for food (to re- As we have summarized above, once a situation has been
plenish energy reserves) and to increase locomotor activity interpreted as being threatening, a stress response will be
and food-seeking behavior (to increase energy expendi- activated, which might lead to allostatic load. What is in-
tures; Leibowitz & Hoebel, 1997; Tang, Akabayashi, Man- teresting to take into account in this context is that some of
itiu, & Leibowitz, 1997). These effects of glucocorticoids the hormones secreted during the stress response will ac-
are very beneficial when we have to run as fast as we can cess the brain and will modify the way that further upcom-
from a house on fire and when we have to replenish our en- ing information is processed.
ergy after this intense running to maintain our daily activi-
ties. However, these effects can be detrimental when the
stress response is triggered chronically by an absolute (e.g., Allostatic Load and the Brain. As we noted earlier,
always having to run away from a predator) or relative (e.g., one of the most important parts of the allostatic load model
a low sense of control at work) stressor. is the cognitive processor, which acts by deciding whether
There is an important point to make with regard to the a situation constitutes a threat or not. Once this processing
impact of relative stressors on allostasis and allostatic has been done, there will be activation (threat) or not (non-
load. The primary stress mediator ( here, glucocorticoids) threat) of the primary stress mediators.
does not distinguish between a real (a house on fire) and an It is important to note here that these primary mediators
implied ( low sense of control) threat; consequently, its ac- (particularly glucocorticoids and catecholamines) have
tivation will occur at each occurrence of the stressor (real been shown to have important effects on the brain, leading
or implied), leading to long-term secretion of glucocorti- to changes in cognitive processing. Here again, a process of
coids. Moreover, the action of glucocorticoids will be the allostasis and allostatic load has been observed with regard
same, that is, action on the brain to increase appetite for to the effects of the primary stress mediators on the brain.
food (replenishment of energy reserves) and increase loco-
motor activity (energy expenditures). Given that, in the Allostatic Effects on the Brain. Given the lipophilic
case of a relative stressor, the stress response has been trig- properties of glucocorticoids, these adrenal hormones can
gered by a psychological situation rather than a real threat easily cross the blood-brain barrier and enter the brain,
to survival (absolute stressor), the energy expenditure is where they can influence brain function and behavior by
less, but the glucocorticoids have been secreted at the same way of binding to different receptor types. Three of the
levels, activating the brain in the same way to increase food most important brain areas containing glucocorticoid re-
intake, with a preference for carbohydrates. Given that in ceptors are the hippocampus, amygdala, and frontal lobes,
Western societies, food is easily available and does not ne- which are brain structures known to be involved in learning
cessitate a lot of food-seeking behaviors, the energy expen- and memory (for reviews, see Lupien & Lepage, 2001;
diture resulting from food-seeking behavior is low. In the Lupien & McEwen, 1997). Although epinephrine does not
long run, inactivity and lack of energy expenditure, along readily access the brain due to absence of lipophilic prop-
with increased secretion of glucocorticoids, creates a situ- erties, it can still act on the brain through its action on the
ation where chronically elevated glucocorticoids can im- sensory vagus outside of the blood-brain barrier, with in-
pede the action of insulin to promote glucose uptake. One formation transmitted into the brain via the nucleus of the
of the results of this interaction is that insulin levels in- solitary tract (for a review, see Roozendaal, 2000). The
crease and, together, high insulin and glucocorticoids con- most important brain area containing adrenergic receptors
centrations promote the deposition of body fat. This is the amygdala, which has been shown to play an impor-
combination of hormones will also promote the formation tant role in fear processing (for a recent review, see
of atherosclerotic plaques in coronary arteries, increasing LeDoux, 2003) and memory for emotionally relevant infor-
the risk for coronary diseases (Brindley & Rolland, 1989). mation (for a recent review, see McGaugh, 2000).
The Allostatic Load Model 585

Because of their actions on brain structures known to Gould and collaborators (1999) reported that training on
be involved in fear detection and memory for emotionally a task that requires the hippocampal formation results in an
relevant information, the stress mediators enhance the for- increase in the number of adult-generated granule cells.
mation of the so-called flashbulb memories of events asso- Of particular importance, these authors showed that in un-
ciated with strong emotions, including fear but also trained adult laboratory animals, the majority of generated
positive emotions. This process involves the amygdala, cells degenerate within 2 weeks of production, whereas
and the pathway for encoding these memories involves the training on hippocampal-dependent tasks rescued a signifi-
interaction between neurotransmitters in the amygdala cant proportion of these cells. In line with experiments
and in related brain areas such as the hippocampus along showing experience-dependent changes in hippocampal
with circulating stress hormones of the adrenal cortex and volumes, studies performed in adult neurogenesis show that
adrenal medulla (McGaugh, 2000; Roozendaal, Hahn, learning can enhance the number of granule neurons. Also,
et al., 2004; Roozendaal, McReynolds, & McGaugh, 2004; comparative studies of different species show that hip-
van Stegeren et al., 1998). The importance of these stress pocampal volume is increased in mammalian and avian
mediators on memory for emotionally relevant informa- species that depend critically on spatial memory for sur-
tion has been recently confirmed by studies in which vival. Examples of such critical memory skills involve
blockade of either glucocorticoid (Maheu et al., 2004) or home-range navigation, migration, brood parasitism, and
norepinephrine (Cahill et al., 1994) activity impaired the memory-based cache recovery in birds that hide food
recall of emotionally relevant information. Consequently, (Suzuki & Clayton, 2000). This association between per-
secretion of these primary stress mediators is necessary formance of spatial tasks and hippocampal size could
for the adequate encoding of emotionally relevant infor- be explained in terms of the impact of environmental de-
mation. This enhancement of memory for stimuli inducing mands on hippocampal volume, rather than the converse.
stressful and/or emotional responses may be essential for For example, Clayton and collaborators (Clayton & Krebs,
a species’ survival. 1994; Gerlai & Clayton, 1999) reported that the hippocam-
At the same time as the brain encodes information and pus of titmice and chickadees increases in volume in asso-
controls the behavioral responses, it is also changed struc- ciation with the experience of storing and recovering food
turally and chemically by those experiences. Although for a caches. This result shows that in animals, there can be an
long time it was thought that the brain of adult mammals does experience-dependent hippocampal growth that occurs at
not generate new nerve cells, more recent evidence showed a relatively late stage in development. Similar results of
that neurons are born in the adult mammalian brain (Altman experience-based changes in hippocampal volumes were
& Das, 1965). Interestingly, in the adult brain, the generation recently reported by Maguire and collaborators (2000) in
of new neurons (called neurogenesis) occurs in two regions. humans. These authors tested the hypothesis that the abil-
The first region is the subventricular zone in the wall of the ity of London taxi cab drivers to navigate to a specific des-
lateral ventricle, where new interneurons are generated for tination correlates with hippocampal volume. They showed
the olfactory bulb; the second region is the subgranular zone that compared to age-matched controls, the taxi drivers had
of the dentate gyrus of the hippocampus, which gives rise larger posterior hippocampi. Although these results surely
to the granule cells. Moreover, recent evidence shows that do not confirm that the experience of driving a taxi in the
adult neurogenesis in the dentate gyrus of the hippocampus complex streets of London has a significant effect on hip-
is a feature of all mammalian species, occurring in rats, pocampal volumes, they nonetheless raise the intriguing
mice, tree shrews, marmosets, macaques, and humans (H. A. possibility of hippocampal plasticity in response to envi-
Cameron, Woolley, McEwen, & Gould, 1993; Eriksson et al., ronmental demands.
1998; Gould, McEwen, Tanapat, Galea, & Fuchs, 1997;
Gould et al., 1999; Gould, Tanapat, McEwen, Flugge, & Allostatic Load Effects on the Brain. Although
Fuchs, 1998; Kempermann, Kuhn, & Gage, 1997). Although short-term responses of the brain to novel and potentially
the functional significance of hippocampal neurogenesis has threatening situations may be adaptive and result in new
been questioned in the past, a study published in the March learning and acquired behavioral strategies for coping,
2001 issue of Nature reported that neurogenesis in the adult as may be the case for certain types of fear-related memo-
is involved in the formation of trace memories, suggesting ries, repeated stress can cause both cognitive impairments
that the new neurons actually contribute to the function of and structural changes in the hippocampus. Each of these
the adult brain (Shors et al., 2001). processes may be occurring somewhat independently of
586 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

each other and contribute in various degrees to different in the dentate gyrus of the adult tree shrew (Fuchs, Uno,
pathophysiological situations involving traumatic stress, & Flugge, 1995). Stress-induced decreases in dentate
depression, or aging. gyrus cell proliferation could also contribute, in line with
The cognitive effects of long-term elevations of gluco- atrophy of the pyramidal cells of the hippocampus, to
corticoids in human populations have been studied in disor- changes in hippocampal volumes observed after chronic
ders affecting glucocorticoid levels and using exogenous exposure to stress.
administration of the synthetic compound to healthy sub- Smaller hippocampal volumes associated with chronic
jects (for a review, see Lupien & Lepage, 2001). Mental elevations of glucocorticoids have also been reported in hu-
disturbances mimicking mild dementia (such as decre- mans. Over the past 2 decades, many studies revealed the
ments in simple and complex attentional tasks, verbal and presence of smaller hippocampal volumes in various psy-
visual memory, encoding, storage, and retrieval) have been chiatric disorders, such as depression (Krishnan et al.,
described in depressed patients with hypercortisolism (R. 1991; Sheline, 1996; Sheline, Gado, & Kraemer, 2003; She-
M. Cohen, Weingartner, Smallberg, Pickar, & Murphy, line, Sanghavi, Mintun, & Gado, 1999; Sheline, Wang,
1982; Rubinow, Post, Savard, & Gold, 1984; Vythilingam Gado, Csernansky, & Vannier, 1996; Vythilingam et al.,
et al., 2004; Weingartner, Cohen, Murphy, Martello, & 2004), Posttraumatic Stress Disorder (Bremner, 2002,
Gerdt, 1981; Wolkowitz et al., 1988; Wolkowitz et al., 2003; Vythilingam et al., 2002), and Schizophrenia (Heck-
1990) and in steroid psychosis following glucocorticoid ers, 2001; Nelson, Saykin, Flashman, & Riordan, 1998), all
treatment (Hall, Popkin, Stickney, & Gardner, 1979; Ling, of which involve glucocorticoid-level dysregulations. Hip-
Perry, & Tsuang, 1981; Varney, Alexander, & MacIndoe, pocampal atrophy associated with chronic exposure to high
1984; Wolkowitz, Reus, Canick, Levin, & Lupien, 1997). levels of glucocorticoids is also reported in patients with
Similar cognitive deficits are also reported in patients suf- Cushing’s disease (Starkman et al., 1992; Starkman et al.,
fering from Cushing’s disease (O. G. Cameron, Starkman, 1999) and elderly individuals (Lupien et al., 1998). A re-
& Schteingart, 1995; Starkman, Gebarski, Berent, & cent study of Cushing’s patients revealed that surgical
Schteingart, 1992; Starkman, Giordani, Berent, Schork, & treatment of hypercortisolism in these patients leads to a
Schteingart, 2001; Starkman et al., 1999; Starkman, Gior- reversal of the glucocorticoid-induced hippocampal atro-
dani, Gebarski, & Schteingart, 2003). During human aging, phy reported to occur in this population, with an average
a significant proportion of elderly individuals present an volume increase of 3.2% and variations up to 10% in some
endogenous increase of glucocorticoid levels (Lupien et al., patients (Starkman et al., 1999). This is a significant find-
1996), and this increase has been related to impaired mem- ing as it implies the possibility of functional reorganization
ory performance (Lupien et al., 1994). of the hippocampus once the allostatic load process has
Although an allostatic process has been shown to lead been taken away. Reversibility and/or preventability of
to positive structural changes of the hippocampus, it is im- such atrophy is a major topic for future research, as is the
portant to note that an allostatic load process has also implication of such treatment for cognitive function.
been shown to have significant detrimental effects on this
brain structure. For example, treatment of adult rats with Chronology of the Allostatic Load Process. As we
corticosterone decreases the proliferation of granule cell have stated in previous sections, the activation of the pri-
precursors (H. A. Cameron & Gould, 1994), and removal mary stress mediators represents an allostatic process
of adrenal steroids stimulated the generation of new gran- whereby an adaptive response to an environmental threat is
ule neurons (H. A. Cameron & McKay, 1999). Given the organized. However, after repeated exposure to various sit-
suppressive actions of glucocorticoids on hippocampal uations that lead to activation of these stress mediators
neurogenesis, stressful experiences have been suggested to (either through repetitive hits, failure to habituate, pro-
inhibit cell proliferation in adulthood, a hypothesis that longed response, or inadequate response), allostatic load
has been demonstrated. Long-term stressful experience will develop. Consequently, there exists a chronology of
decreases the number of adult-generated neurons in the hormonal and cellular events in the development of allosta-
dentate gyrus in various species, including the rat (Heale, tic load that can allow for a measure of the level of allosta-
Vanderwolf, & Kavaliers, 1994; Sgoifo, de Boer, Haller, & tic load in any given individual. The chain of events in the
Koolhaas, 1996), tree shrew (Gould et al., 1997), and mar- allostatic load process begins with the allostatic activation
moset (Gould et al., 1998). In a similar vein, repeated of primary mediators, with the resulting primary effects.
stress produces prolonged suppression of cell proliferation After prolonged allostatic attempts at adaptation, other
The Allostatic Load Model 587

hormonal and cellular processes will become dysregulated,


TABLE 14.2 Various Stages of Allostatic Load and the
leading to secondary and tertiary outcomes. We summarize Physiological and Clinical Markers Used to Assess the
these next. Degree of Allostatic Load
Stages of Allostatic Load Physiological and Clinical Markers
Primary Mediators of Allostatic Load. The primary Primary mediators Glucocorticoids
mediators of allostatic load are those chemical messengers DHEA
that are released as part of allostasis (see Table 14.2). At Adrenaline
present, there are four primary mediators included in the Noradrenaline
assessment of allostatic load: cortisol, epinephrine, norepi- Cytokines
nephrine (the catecholamines), and DHEA. These chemical Primary effects Cellular events (enzymes, receptors, ion
messengers are primary mediators because they have wide- channels, structural proteins) that are reg-
ulated by the primary mediators as part of
spread influence throughout the body and are very useful
allostasis (not well studied).
(when measured correctly) at predicting a variety of sec-
Secondary outcomes Ref lect the cumulative outcomes of the
ondary and tertiary outcomes. primary effects and the outcomes of more
As summarized earlier, cortisol (the most important glu- than one primary mediator.
cocorticoid in humans) has wide-ranging effects through- Waist-hip ratio
out the body. Receptors for glucocorticoids are present in Blood pressure (systolic and diastolic)
virtually every tissue and organ in the body and mediate ef- Heart rate
fects ranging from the induction of liver enzymes involved Glycosylated hemoglobin
HDL (High Density Lipoprotein)
in energy metabolism to regulating the trafficking of im-
Total cholesterol
mune cells and cytokine production to facilitating the for-
Glucose
mation of fear-related memories.
Insulin
DHEA is a functional antagonist of cortisol (May, Poor glucose tolerance
Holmes, Rogers, & Poth, 1990; Wright, Porter, Browne, & Nitric oxide
Svec, 1992) that may also have effects via other signaling Fibrinogen
pathways (Araneo & Daynes, 1995); generally, low DHEA Immune delayed-type hypersensitivity
is considered deleterious, as is chronically high cortisol Immunization challenge response
(Morales, Nolan, Nelson, & Yen, 1994). Blood level of Frequency and severity of common cold
DHEA, most of which is present in the sulfated form Mild cognitive decline unrelated to age
(DHEAS), peaks at approximately 20 years of age and de- Tertiary outcomes Actual diseases or disorders that are the
clines rapidly and markedly after age 25 (Orentreich, result of the allostatic load that are pre-
dicted from the extreme values of the sec-
Brind, Rizer, & Vogelman, 1984). The accumulation of ondary outcomes and of the primary
abdominal fat increases with aging, and abdominal obesity mediators.
increases the risk for development of insulin resistance, Cardiovascular disease
diabetes, and atherosclerosis (Cefalu et al., 1995). In Severe cognitive decline
rats, DHEA has protective effects against both the insulin Decreased physical capacity
resistance induced by a high-fat diet (Hansen, Han, Nolte, Cancer

Chen, & Holloszy, 1997) and the decrease in insulin Note: It is important to note that there are other primary mediators that
may be included in the allostatic load model, but we have selected a
responsiveness that occurs with advancing age (Han,
subset of these for clarity. These potential additional mediators are pre-
Hansen, Chen, & Holloszy, 1998). sented in italics and are not discussed in the text. Also, it is important
The catecholamines epinephrine and norepinephrine are to underline that all these mediators operate as an interacting network
released by the adrenal medulla and sympathetic nervous and not necessarily in a linear fashion, as the table might suggest.

system, respectively, and produce widespread effects


accessible to circulating catecholamines. However, cate-
throughout the body, ranging from vasoconstriction and ac-
cholamines signal the brain through the sensory vagus and
celeration of heart rate to trafficking of immune cells to
the nucleus of the solitary tract, as in learned fear.
targets, as well as enhancement of fear-related memory for-
mation (Cahill et al., 1994). Adrenergic receptors are wide- Primary Effects of Allostatic Load. The primary ef-
spread throughout the body, in blood vessels and target fects of allostatic load have not been measured extensively,
organs such as the liver, pancreas, and brain, which is not but these include cellular events, the actions of enzymes,
588 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

receptors, ion channels, and/or structural proteins that are the detrimental effects of long-term exposure to high
induced genomically or phosphorylated via second messen- levels of glucocorticoids and catecholamines on cognitive
ger systems that are regulated as part of allostasis by the processing in humans (Lupien et al., 1998; Lupien et al.,
primary mediators (see Table 14.2). 1994). More recently, we have also included specific
For example, glucocorticoids regulate gene expression outcomes related to the damaged pathway in cardiovascular
via several pathways, involving interactions with DNA via disease and risk for myocardial infarction (e.g., nitric
the glucocorticoid response elements and also via protein- oxide, fibrinogen). Fibrinogen, one of the blood-clotting
protein interactions with other transcriptional regulators factors, has already been used as an allostatic load measure
(Miner, Diamond, & Yamamoto, 1991). As noted earlier, in relation to job stress and socioeconomic status (Markowe
DHEA antagonizes glucocorticoid actions in a number of et al., 1985). Finally, outcomes related to other systems
systems. Catecholamines act via alpha and beta adrenergic such as the immune system have now been included.
receptors, and beta receptors stimulate the formation of Here, integrated measures of the immune response such
the intracellular second messenger, cyclic AMP (cAMP), as delayed-type hypersensitivity (Dhabhar & McEwen,
which, in turn, regulates intracellular events via phospho- 1999) and immunization challenge (Kiecolt-Glaser, Glaser,
rylation, including transcription regulators via the CREB Gravenstein, Malarkey, & Sheridan, 1996) should reveal the
family of proteins (Siegel, Agranoff, Albers, Fisher, & impact of allostatic load on cellular and humoral immune
Uhler, 1999). function and help distinguish between the immunoenhanc-
In some cases, the glucocorticoid and cAMP pathways ing effects of acute stress and immunosuppressive effects of
converge at the level of gene expression (e.g., see Yamada, chronic stress. Moreover, assessment of the frequency and
Duong, Scott, Wang, & Granner, 1999). Therefore, it is not severity of the common cold (S. Cohen et al., 1997; S.
surprising that secondary outcomes (see later discussion) Cohen, Tyrrell, & Smith, 1991) is another indirect way of
are the result of more than one primary mediator. Conse- assessing immune function, and this might be considered a
quently, primary effects are organ- and tissue-specific, and secondary outcome.
secondary outcomes reflect the integrated actions of the
primary effects. Tertiary Outcomes. The tertiary outcomes are the
actual diseases or disorders that are the results of the allo-
Secondary Outcomes. The secondary outcomes are static load that is predicted from the extreme values of the
the integrated processes that reflect the cumulative out- secondary outcomes and of the primary mediators (see
comes of the primary effects in a tissue/organ-specific Table 14.2). Thus far, the tertiary outcomes that are
manner in response to the primary mediators (see Table thought to result from allostatic load are cardiovascular
14.2). Consequently, they often reflect the actions of more disease, decreased physical capacity, severe cognitive de-
than one primary mediator. Examples of secondary out- cline, and cancer.
comes are evident in waist-hip ratio (abdominal fat deposi- With regard to the chronology of the allostatic load
tion), blood pressure elevation, glycosylated hemoglobin, model, it is important to note that in the allostatic load for-
the ratio of cholesterol to HDL High Density Lipoproteins mulation, the impact on health risk is thought to result not
(HDL), and HDL cholesterol. These are secondary out- only from large and clinically significant deviations from
comes because they reflect the effects of sustained eleva- normal operating ranges, but also from more modest dys-
tions in glucose and the insulin resistance that develop regulations if they are present in multiple systems.
as a result of elevated cortisol and elevated sympathetic McEwen and Stellar (1993) hypothesized that the cumula-
nervous system activity (primary mediators). Blood pres- tive impact on health risk from modest dysregulations in
sure elevation is part of the pathophysiological pathway of multiple systems can be substantial, even if they individu-
metabolic syndrome but is also a more primary indication ally have minimal and insignificant health effects.
of the allostatic load that can lead to accelerated athero-
sclerosis as well as insulin resistance. Cholesterol and Validation of the Allostatic Load Model
HDL cholesterol are measures of metabolic imbalance in Although the concept of allostatic load offers a great op-
relation to obesity and atherosclerosis and also reflect the portunity to explain various stress-related disorders, the
operation of the same primary mediators as well as other model remains static as long as it has not been validated
metabolic hormones. with experimental data. It thus became important to assess
Another important secondary outcome is mild cognitive the predictive power of the allostatic load model in various
decline without dementia; this secondary outcome relates to populations.
The Allostatic Load Model 589

Allostatic Load and Aging. In a first validation sample in the United States. The National Health and Nu-
study, data were used from the MacArthur Successful trition Examination Suvery involved the collection of data
Aging Study that pertains to levels of physiologic activity over the period 1988 to 1994 in 18,000 individuals 20
across a range of important regulatory systems, including years of age and older. Using the data from this study, an
the HPA and sympathetic nervous systems as well as the allostatic load index was constructed using 13 indicators of
cardiovascular system and metabolic processes (Seeman physiological dysregulation and analyzed using the quartile
et al., 1994; Seeman & Chen, 2002; Seeman, McEwen method of Seeman and colleagues (Seeman, McEwen,
et al., 2001; Seeman, Singer, Rowe, Horwitz, & McEwen, et al., 2001; Seeman et al., 1997). Results showed that allo-
1997). In this study, Seeman and collaborators (Seeman, static load score increased with age through the 60s and
Crimmins, et al., 2004) evaluated the capacity of an allo- then leveled off, so that individuals above 60 years of age
static load score to predict four categories of health out- had fairly similar levels of allostatic load. The ratios of one
comes in 1,189 men and women aged 70 to 79 followed over age group to the preceding showed that the increase in al-
a period of 7 years. The measure of allostatic load used in lostatic load score from one age group to the next was .4 or
this first validation study reflected only one of the two as- .5 in the first 2 decades of adulthood, and was .2 to .3 in
pects of physiologic activity postulated to contribute to al- the next decades. The change in allostatic load score after
lostatic load, namely, higher, chronic, steady state levels of these decades (after 60 years) did not change significantly.
activity related to the diurnal variation as well as any Although these results were not linked to subsequent
residual activity reflecting chronic stress or failure to shut health outcomes, they revealed an interesting pattern of in-
off responses to acute stressors. The parameters that were creasing allostatic load score, starting in the early decades
available for determining allostatic load scores included of adulthood.
urinary cortisol, adrenaline, noradrenaline; serum DHEA;
waist-hip ratio, diastolic and systolic blood pressure, glyco- Allostatic Load and Work Conditions. Adverse
sylated hemoglobin, serum HDL, and total cholesterol. For work characteristics and poor social support have been as-
each of the 10 indicators of allostatic load, subjects were sociated with an increased risk for cardiovascular disease
classified into quartiles based on the distribution of scores and other adverse health outcomes. To assess whether an
in the baseline cohort. Allostatic load was measured by allostatic load index could be a good predictor of work
summing the number of parameters for which the subject characteristics, Schnorpfeil and collaborators (2003) per-
fell into the highest risk quartile, leading to an allostatic formed a cross-sectional study with 324 industrial work-
load score for each participant. The results showed that ers in Germany. Psychosocial work characteristics were
higher baseline allostatic load scores were associated with assessed using various validated questionnaires, and an
significantly increased risk for 2.5-year (Seeman et al., allostatic load index was assessed using 14 physiological
1997) and 7-year (Karlamangla, Singer, McEwen, Rowe, & components of the allostatic load model; the analysis was
Seeman, 2002; Seeman, McEwen et al., 2001) mortality, as performed using the quartile method (Seeman, McEwen
well as declines in cognitive and physical functioning, et al., 2001; Seeman et al., 1997). The results revealed
and were marginally associated with incident cardiovascu- that older individuals, particularly men, had significantly
lar disease events. More important, although none of the higher allostatic load scores than younger participants or
10 components of allostatic load exhibited significant asso- women. Of the various work characteristics evaluated,
ciations on its own with health outcome, the summary only job demands related significantly with the allostatic
measure of allostatic load was found to be significantly as- load score. This association persisted after controlling
sociated with these four major health outcomes. These for smoking status and gender and after excluding partic-
findings were consistent with the idea that although a mod- ipants reporting hypertension, cardiovascular disease, or
est deviation in the level of activity of a single physiologic diabetes. However, the authors also showed that the
system may not be predictive of poor future health, the cu- association between job demands and allostatic load was
mulative toll from modest alterations in several physiologic highly dependent on age, with little or no association in
systems is a prognosis of poor health. younger participants, and an increasing effect of job de-
mands on allostatic load score in participants over 45.
Allostatic Load across the Life Span. In a more re- These results go along with the notion that allostatic
cent study, Crimmins and collaborators (Crimmins, John- load results from the cumulative impact of wear and
ston, Hayward, & Seeman, 2003) assessed age differences tear that occurs throughout life and that adds up with in-
in allostatic load from a large nationally representative creasing age.
590 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

Allostatic Load and Socioeconomic Status. In a 71 and older). They used the longitudinal data on levels of
more recent study, the data from the MacArthur Studies of social integration and extent of social support as predictors
Successful Aging were used to assess whether the socioe- of cumulative allostatic load. The results showed that in the
conomic status (SES) differences in mortality can be par- 54 to 70 age group, the presence of a spouse in early years
tially explained by differences in allostatic load (Seeman, (6 to 8 years prior to the collection of data) was associated
Crimmins, et al., 2004). Results showed that the score of al- with lower allostatic load in men, but not women. In the
lostatic load explained 35.4% of the difference in mortality older group of participants (71 years and above), it was
risk between those with higher versus those with lower found that ties with close friends and/or neighbors were
SES. Of importance, it was shown that the cumulative significantly related to lower allostatic load score for both
index provided independent explanatory power over and men and women. Interestingly, although significant, these
above a measure of doctor-diagnosed disease. Here again, relationships between social support and allostatic load
the summary measure (allostatic load score) accounted for were more modest than the associations reported to occur
more variance than individual biological parameters in pre- in Western societies. The authors suggested that contex-
dicting health outcomes, suggesting the high potential value tual, normative influences on social experience may affect
of this multisystem view of biological pathways through the patterns of association between features of these social
which SES ultimately affects morbidity and mortality. worlds and the physiological substrates of health.

Allostatic Load and Social Support. Allostatic load Conclusion


scores have not only been associated with negative out-
comes; new studies now show that the presence of social Many important points result from our analysis of the allo-
support in an individual’s life is a strong predictor of low static load model. First, cumulative wear and tear have ef-
allostatic load scores later in life. The first report of a sig- fects on the body through lifelong exposure to various
nificant association between allostatic load score and so- challenges. Second, the data obtained so far show that allo-
cial support was published by Singer and Ryff in 1999. static load tends to develop in time and increase sharply in
These authors used data from the Wisconsin Longitudinal the later decades of adult life. These data also show that
Study and searched for precursors to allostatic load environmental conditions, such as high job demands and
via ordered categories of cumulative adversity relative to poverty, are associated with higher allostatic load scores.
advantage over the life course. They operationalized life However, the presence of social support, either in early
trajectories via economic circumstances and social rela- life or later in life, is a strong predictor of low allostatic
tionship experiences (e.g., parent-child interactions, qual- load. These results suggest that allostatic load is a process
ity of spousal ties). The results of this study revealed a that could begin very early in life, and that, depending on
strong association between the extent of adversity early in the environmental conditions to which children are ex-
life and the likelihood of high allostatic load later in life. posed, they may develop an allostatic load process very
More important, they showed that resilient individuals with early in development.
economic disadvantage but compensating positive social In the next sections of this chapter, we summarize data
relationship histories showed low prevalence of high allo- and concepts pertaining to the potential pathways by which
static load. In 2001, using data from the MacArthur Study allostatic load can develop in children facing adversities.
of Successful Aging, Seeman and collaborators (Seeman,
Lusignolo, Albert, & Berkman, 2001) reported that greater EARLY ADVERSITY AND THE
baseline emotional support in the participants of this longi- DEVELOPMENT OF ALLOSTATIC LOAD
tudinal study was a significant predictor of better cognitive
function at the 7.5-year follow-up, controlling for baseline Following a definition by Sandler (2001), adversity can be
cognitive function and known sociodemographic, behav- characterized as a condition that threatens the satisfaction
ioral, psychological, and health status predictors of cogni- of basic human needs and goals (including physical safety,
tive aging. Finally, in a recent study using data from the self-esteem, efficacy, and social relatedness) and con-
Social Environment and Biomarkers of Aging Study in Tai- strains the accomplishment of developmental tasks such as
wan, Seeman and collaborators (Seeman, Glei, et al., 2004) school success and positive role functioning at home. Many
examined relationships between social environment charac- conditions have been related to early adversity, the most
teristics and allostatic load in two groups of older Tai- important of them being low SES, child maltreatment, and
wanese individuals split as a function of age (54 to 70, and war. In the following, we discuss some data related to these
Early Adversity and the Development of Allostatic Load 591

different types of early adversities. Although we are aware ated with poor living conditions, overcrowding, exposure to
that each type of adversity may have very different effects environmental hazards, and crime (e.g., Bradley & Cor-
on the body’s response to stress, it is important to note that wyn, 2002; Haan, Kaplan, & Syme, 1989). With regard to
there have not been enough studies performed so far on this sociological /psychological factors, it has been shown that
particular issue to allow us to offer a clear distinction lower SES increases the likelihood of exposure to negative
across these different forms of adversity. Consequently, we events such as social aggression, family conflict, and risk
discuss these adversities generally as conditions very early behaviors (B. S. Dohrenwend & Dohrenwend, 1970). Addi-
in life that threaten the satisfaction of a child’s basic needs tionally, low SES individuals are exposed to a higher rate
and goals (Sandler, 2001). of change and instability in their lives such as family disso-
Many studies on adversity have looked at the effects of lution and household moves. This instability has been
low SES on health and well-being. It has been found that found to produce a higher level of individual distress in
individuals from high SES environments enjoy better these individuals (Broadhead et al., 1983; B. S. Dohren-
health than individuals from low SES environments. Vari- wend & Dohrenwend, 1970). Moreover, individuals who
ous studies have shown that blood pressure (Breier et al., have access to psychological and material support from
1987) increases significantly as employment grade (B. S. family, spouses, or friends during stressful events appear
Dohrenwend, 1973), occupational status (Adelstein, 1980), to be in better health compared to individuals without sig-
income (Folkman, Schaefer, & Lazarus, 1979), or years of nificant support (Broadhead et al., 1983; S. Cohen, 1988;
education (Adelstein, 1980) decrease. Although most of Schwarzer & Leppin, 1989; Starfield, 1982). Individuals
the literature has concentrated on systemic diseases, other low on the SES hierarchy have fewer of these social and
studies have shown a significant relationship between SES psychological resources to cope with stressful life events
and mental health. For instance, inverse associations have than individuals higher in the SES hierarchy (S. Cohen,
been reported between SES and the prevalence of Schizo- 1988; House et al., 1994; McLeod & Kessler, 1990).
phrenia, Posttraumatic Stress Disorder, Major Depression, To assess whether the development of the relationship
alcoholism, substance abuse, Antisocial Personality Disor- between SES and mental health is sustained, at least in
der, and nonspecific distress (B. P. Dohrenwend, 2000). part, by exposure to high levels of glucocorticoids, Lupien
With regard to developmental pathways, the exposure to and collaborators (Lupien, King, Meaney, & McEwen,
adverse conditions in childhood is closely related to the de- 2000; Lupien et al., 2001) measured morning salivary cor-
velopment of physical and mental health problems in adult- tisol levels and cognitive function (memory, attention, lan-
hood (Sandler, 2001). The relationship is of a cumulative guage, and emotional processing) in 396 children (from 6
nature; that is, the greater the number of adverse experi- to 16 years of age) from low versus high SES in the Mon-
ences, the more likely is development of a variety of prob- treal area in Canada (Lupien et al., 2001). Depressive
lems later in life. For instance, Felitti et al. (1998) reported symptomatology and exposure to stressful events were also
a 4- to 12-fold increased risk for alcoholism, drug abuse, assessed in each child’s mother through a semistructured
depression, and suicide attempts in adults who had experi- phone interview. The results revealed that low SES chil-
enced four or more adversities in childhood. dren from 6 to 10 years old presented significantly higher
Although the relationship between early adversity and salivary cortisol levels when compared to children from
health is well documented, the mechanisms that account for high SES. This difference disappeared at the time of school
the relationship are not clearly understood (e.g., Sandler, transition, that is, at 12 years old, and no SES differences
2001). One possible pathway that links adversity to health were observed at 12, 14, and 16 years of age. The absence
problems is stress (e.g., Lupien, King, Meaney, & McEwen, of SES differences in cortisol levels during high school
2001; McLoyd, 1998). As stated earlier, adversity is a could be due to changes in cortisol secretion in relation to
condition that threatens the satisfaction of basic human social roles (importance of peers over family, youth cul-
needs. The consequence of perceiving such a threat is a ture, etc.; see Lupien et al., 2001), or to the fact that those
state of stressful arousal (e.g., Sandler, 2001). With re- teenagers from low SES who were available to perform
spect to SES, it has been shown that low SES individuals this study were the most resilient, that is, were those
are exposed to a greater amount of chronic and acute teenagers who decided not to quit school. Neuropsychologi-
threats/stressors than high SES individuals (e.g., Bradley cal data showed that although children from low and high
& Corwyn, 2002). Environmental as well as social /psycho- SES do not differ with regard to memory, attentional, and
logical factors contribute to the increased stress levels. linguistic functions, children from low SES (at all ages)
With regard to environmental factors, low SES is associ- presented a significantly higher level of negative emotional
592 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

processing (Lupien et al., 2005). Scores on the depression exposed to high levels of concurrent actual maternal stress
and stress questionnaires were significantly higher for low and who were initially exposed to high maternal stress in
SES mothers, when compared to high SES mothers. More infancy (thus exposed to high maternal stress both in in-
important, the authors reported a significant positive cor- fancy and at 4.5 years of age) were the only group that had
relation between the mother’s depressive symptomatology significantly higher cortisol levels. No effects of maternal
and her child’s cortisol level (Lupien et al., 2000). This stress on child’s cortisol levels were observed for children
showed that the higher the score of the mother on the de- exposed to maternal stress in infancy only. These results
pressive scale, the higher the cortisol level of her child. Al- suggest that exposure to concurrent maternal stress is asso-
together, these results showed that low SES in young ciated with increased cortisol levels only for children
children is related to increased cortisol secretion and nega- whose exposure began in infancy. The authors then ad-
tive emotional processing. Moreover, they showed that de- dressed the potential association between child’s cortisol
pression in the mother is, in conjunction with low SES, a levels and behavioral problems. Results showed that the
significant factor predicting high cortisol levels in children. preschoolers with high cortisol levels presented greater in-
Other studies have reported a significant association be- ternalizing and externalizing symptoms when assessed 2
tween early adversities and/or mother’s depression on a years later. Finally, the link reported between low SES and
child’s glucocorticoid levels. For example, numerous retro- higher cortisol levels in children (Lupien et al., 2001) was
spective studies of adults and children have shown that replicated in this study.
increased reactivity of the HPA system is associated with In a more recent study, G. W. Evans and Marcynyszyn
early trauma (Cicchetti & Rogosch, 2001; Heim et al., 2000; (2004) analyzed cross-sectional data from 216 third-
Kaufman et al., 1997; Yehuda, Halligan, & Grossman, through fifth-grade low- and middle-income children
2001), as well as severe deprivation (Gunnar, Morison, in upstate New York. The data of this study included
Chisholm, & Schuder, 2001). Moreover, studies of infants overnight urinary neuroendocrine levels, noise levels, res-
and toddlers suggest that maternal postpartum depression idential crowding (people per room), and housing quality.
and behaviors, with the insecure mother-child attachments The authors calculated an index of cumulative environ-
that can result from these conditions, are positively associ- mental risk exposure based on the number of risk factors
ated with children’s cortisol levels (Field, 1994; Spangler & (i.e., crowding, indoor noise, and housing quality). Risk
Grossmann, 1993). In a longitudinal study of children of de- exposure for each factor was designated as greater than 1
pressed mothers, Hessl and collaborators (1998) found that standard deviation above the mean and given a score of 1.
postpartum depression was positively associated with chil- The other exposure levels were considered lower risk and
dren’s cortisol at 3 years of age, although another study re- coded as 0. The results revealed that cumulative environ-
ported no effect of maternal depression on cortisol levels mental risk exposure was significantly greater for low-in-
when the children were age 7 (Ashman, Dawson, Panagi- come children. More important, the authors showed that
otides, Yamada, & Wilkinson, 2002). cumulative environmental risk was positively correlated
However, in another study, Essex and collaborators with elevated overnight epinephrine, norepinephrine, and
(Essex, Klein, Cho, & Kalin, 2002) measured salivary cor- cortisol in the low-income sample but not in the middle-in-
tisol levels in 282 children age 4.5 years and 154 of their come sample. These results remained significant after
siblings. The authors were able to obtain maternal reports controlling for income, maternal education, family struc-
of stress when the children were ages 1, 4, and 12 months ture, age, and gender.
and again at 4.5 years. Finally, they assessed the child’s Altogether, these results strongly suggest that early ex-
mental health symptoms in the first grade of school. In the posure to adversity (through low SES, maternal stress/de-
first cross-sectional analysis of the association between ac- pression, or maltreatment) can have potent and long-lasting
tual maternal stress and the actual child’s cortisol levels, effects on the secretion of glucocorticoids in children. Al-
Essex and collaborators found that at 4.5 years of age, the though these studies provide very interesting results with
children exposed to high levels of concurrent maternal regard to the influence of early adversities on a child’s
stress presented significantly higher cortisol levels than basal cortisol levels, they do not provide an answer to a very
children exposed to moderate or low levels of maternal important question about the allostatic load model: What
stress. Very interestingly, they also revealed a similar asso- determines the initial processing of an information as being
ciation of exposure to concurrent maternal stress and corti- threatening ( leading to the secretion of the primary stress
sol levels in the siblings of these children. The analysis of mediators) or nonthreatening? Indeed, as we have dis-
the longitudinal data revealed that the children who were cussed in previous sections, various situations can be real
Early Adversity and the Development of Allostatic Load 593

threats (a house on fire) or implied threats (interpretation found between adversity and allostatic load/ health dam-
of a situation as being novel and/or unpredictable and/or age. We introduce an information-processing model of
uncontrollable), and both types of stressors will lead to the adaptation to threatening information that highlights two
activation of primary stress mediators and potentially to different adaptation pathways that can lead to allostatic
allostatic load. It is thus becoming extremely important to load. We argue that both pathways are likely to be found in
understand the mechanisms by which early adversities individuals who grew up in disadvantaged and/or adverse
might shape a child’s cognitive processing and lead to a environments and who lacked protective mechanisms that
healthy or biased processing of incoming information and, could counteract the influence of adversity.
consequently, to cumulative allostatic load due to repeated
An Information-Processing Model of Adaptation to
activation of the primary stress mediators when situations
Threatening Information
are interpreted most of the time as being stressful.
As described earlier, individuals growing up in disadvan-
taged environments frequently face threatening situations:
The Subjective Nature of Reality: The Human
instability, financial problems, limited residential choices,
Information-Processing System
crime, conflict, social aggression, and so on. Some of these
Cognitive psychology is concerned with how people per- threats constitute absolute stressors (e.g., maltreatment,
ceive, learn, remember, and think about information. Since crime); others constitute relative stressors (e.g., instabil-
the 1960s, the human brain has often been conceptualized ity, financial problems). As presented in Figure 14.2, the
as an information-processing device. From studies in cog- frequent encounter with threatening information will likely
nitive psychology, we have learned that what we perceive is result in a cognitive system that reacts hypersensitively to
not an exact replica of the external world. Instead, percep- threatening information. This is accomplished by an atten-
tual processes transform and interpret information from tional system that is highly vigilant, because the individual
the external world. Additionally, our mental capacities are is expecting threatening information. The expectation of
limited, and to further process information, we have to al- threats and a bias toward interpreting situations as threat-
locate our mental resources to certain stimuli, a process ening is probably due to a memory system that contains a
called selective attention. Stimuli we attend to enter a variety of highly interconnected and easily accessible
short-term or working memory store; from there, some of threat-related information (Pollak & Sinha, 2002). A cog-
the information will eventually be transferred into long- nitive system that is biased toward the detection and pro-
term memory, the memory system that stores our experi- cessing of threatening information can be viewed as
ences (episodic memory) and factual knowledge (semantic adaptive in the short run (allostasis), because an early and
memory; for criticism and modifications of this view of
memory, see, e.g., Baddeley, 1999, chap. 2). The content of
the long-term memory store will also determine how the Disadvantaged environments
Frequent encounter with threatening information
incoming information is interpreted and what behavioral
responses are elicited. In sum, what has become clear is
Sensitization Habituation
that incoming information is modulated at every stage of
the information-processing flow, finally resulting in an in- Hypersensitivity Hyposensitivity
dividual’s very own construction of reality. to possible threats to possible threats

The aspects of a situation an individual attends to, the High vigilance Low vigilance
interpretation of these aspects, and the behavioral re-
sponses that follow are largely determined by the individ- Low High anxiety Low anxiety Low
protective High responsiveness Low responsiveness protective
ual’s history and previous experiences. It can be assumed mechanisms to real and to real and mechanisms
that the cognitive systems are largely “shaped” during fictive threats fictive threats
childhood (e.g., Cicchetti, 2002), when those neurological
systems (frontal lobe, amygdala, and hippocampus) Maladaptive behavior
Allostatic load
undergo major developmental changes that subserve atten-
tion and memory as well as other higher-order cognitive
Figure 14.2 Schematic representation of how early adversity
processes such as problem solving and decision making. can modify the processing of threatening information, leading
In the following, we describe cognitive processes that to habituation or sensitization of detection of threatening
we think can explain parts of the association that has been information.
594 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

facilitated threat detection might give individuals the nec- such a way that the individual is more susceptible to stress,
essary time to counteract the threat (Pollak & Sinha, 2002). and is not meant to give a comprehensive overview of the
This cognitive system, however, has at least two drawbacks complex literature on adversity and cognitive development.
in the long run. First, a hypervigilant system is likely to Throughout the chapter, the reader should keep in mind
wear out quickly (allostatic load; McEwen, 1998b). Sec- that high adversity alone has only a weak predictive value
ond, the cost of high vigilance is false alarms to relative for poor developmental outcome. Only the combination of
stressors; that is, nonthreatening information might be high adversity and weak protective resources leads to mal-
falsely identified as threatening (Pollak & Kistler, 2002). adaptive profiles (Masten, 2001).
Protective mechanisms, such as well-functioning parent- Before describing the studies, we briefly review the
child relationships and cognitive abilities, are often com- brain structures that are involved in the stress response and
promised as a consequence of adversity. If protective that might therefore be modified by early adversities.
mechanisms fail, sensitization to threatening information These brain structures play an important role in interpret-
is likely to result in maladaptive psychological (e.g., stress, ing situations and selecting possible responses.
anxiety) and behavioral (e.g., aggressive, health-damaging)
Brain Structures Involved in the Stress Response
responses (e.g., Masten, 2001). Prolonged states of anxiety
and anticipation of negative events can result in allostatic Three brain structures are critically involved in the stress
load (McEwen, 1998b). response: the prefrontal cortex, the amygdala, and the hip-
One can think of another, and in some sense opposite pocampal formation. Each of these brain structures is af-
way of dealing with frequent exposure to threatening infor- fected by stress hormones and/or involved in the regulation
mation, namely, habituation (see Figure 14.2). Habituation of stress hormone secretion. At the same time, these brain
is the tendency to become accustomed to a stimulus, structures play a crucial role in the interpretation of a situ-
resulting in the stimulus becoming less and less noticed. ation (as being stressful) and in the subsequent selection
Individuals from disadvantaged environments might get ac- and inhibition of possible responses.
customed to threatening situations and might filter out The prefrontal cortex is sometimes described as the
threatening stimuli. This can be adaptive in the short run, highest part of the brain as it is involved in most higher cog-
because the individual will be less anxious and less vigilant nitive functions such as reasoning, planning, attention,
(allostasis). On the other hand, the late detection of and the working memory, and some aspects of language (e.g., Con-
general hyporesponsiveness to real threats prevent individ- nolly, Goodale, Menon, & Munoz, 2002; Owen, Doyan,
uals from proactive planning of adequate responses. Petrides, & Evans, 1996). For instance, the prefrontal cor-
The consequence is that no stress response is initiated in tex determines which information will be considered and
situations where such a response would be adequate. The which information will be inhibited during the perfor-
inadequate response of allostatic systems is one pathway mance of goal-directed behaviors (e.g., Bunge, Ochsner,
that has been linked to allostatic load (Type 4 allostatic Desmond, Glover, & Gabrieli, 2001). It also plays an im-
load, inadequate response; McEwen, 1998b). Furthermore, portant role in retrieval processes, especially in recalling
the hyporesponsiveness to threatening information might the temporal order and source of memories (e.g., Fan,
promote risk-taking and thrill-seeking behaviors that can Snodgrass, & Bilder, 2003). Many other specific functions
lead to further health damage and greater allostatic load, of the prefrontal cortex could be named. Because of its in-
especially when protective mechanisms fail. volvement in nearly all higher cognitive processes, some
Next, we review some empirical evidence for the adap- authors regard the prefrontal cortex as the “ frontal moral
tive processes described in the model. We describe studies guidance system” that regulates social /moral behaviors
that demonstrate the specific influence that adversity has (e.g., Bigler, 2001, p. 610).
on the development of several cognitive processes, includ- The amygdala is critically involved in assessing the
ing attention, perception, memory, language, and theory of emotional significance of events (e.g., Anderson & Phelps,
mind. The research reviewed here comprises a rather het- 2001). It is especially important for the processing of the
erogeneous set of studies covering very different aspects of emotions of anger, aggression, and fear. Recent studies
adversity, from low SES to different kinds of child mal- with rats suggest that the amygdala also plays a crucial role
treatment. We are aware of the fact that different experi- in forming associations between cues and outcomes
ences lead to very specific outcomes. The heterogeneous (Schoenbaum, Setlow, Saddoris, & Gallagher, 2003).
sample of studies we describe serves the purpose of illus- The hippocampal formation is involved in learning and
trating how the environment shapes cognitive processes in memory. It specifically subserves the formation and re-
Early Adversity and the Development of Allostatic Load 595

trieval of episodic memories, that is, the human ability to more fear than nonabused controls when watching video-
mentally travel back in time and remember where (spatial tapes of adults in angry interactions. Over time, the frequent
component) and when (temporal component) a specific event experience of fear and the accompanying stress response
occurred (e.g., Tulving, 2002). During encoding, the hip- can result in allostatic load (e.g., McEwen, 1998b).
pocampal formation is engaged in relational learning mecha- It is important to note that the studies by Pollak and col-
nisms that bind the different components of an event into an leagues (2000) show that abused children do not experience
integrated memory trace (e.g., Davachi & Wagner, 2002). a general attentional deficit. Rather, abused children’s at-
Damage to the hippocampal formation results in profound tention is biased toward the detection of anger cues. Addi-
amnesia, especially an inability to remember new episodes tionally, abused children have difficulties exerting control
(e.g., Vargha-Khadem et al., 1997). over their attentional processes when faced with threaten-
Roughly speaking, the described brain structures are ing information. In the next section, we describe how this
critically involved in evaluating a situation and selecting an sensitization to threat affects perceptual and memory
appropriate response (prefrontal cortex) with regard to the processes in abused children.
emotional content of the situation (amygdala) and in rela-
Effects of Adversity on Perceptual and
tion to past experiences ( hippocampal formation, pre-
Representational Systems
frontal cortex).
As described earlier, the long-term memory store contains
Selective Attention to Threatening Information in an individual’s knowledge about the world and past experi-
Maltreated Children ences. It can be hypothesized that the long-term memory
As described earlier, it is impossible to process all informa- store differs greatly in its content for children facing
tion to which an individual is exposed because attentional re- adversities when compared to children in less adverse con-
sources are limited. Therefore, some environmental cues are ditions. Whereas children living in adverse conditions
filtered out or attenuated and other stimuli are selected for may experience a lot of stressful situations and daily has-
further processing (e.g., Treisman, 1964). Which stimuli are sles and acquire a lot of factual knowledge about how to
attended to is a function of the physical and psychological survive in threatening environments, children living in
state of the individual, as is the saliency of these cues. Chil- more favorable conditions may experience a great variety
dren’s information-processing capacities are much more lim- of nonstressful situations. Thus, it can be assumed that the
ited than those of adults (e.g., Case, 1985). Therefore, they memory content of children facing adversity is biased to-
are much more selective in their attentional processes. Pollak ward threatening/stressful information. It can be further
and Sinha (2002) argue that children selectively attend to speculated that children facing adversity are more likely to
those features of the environment that are closely linked with interpret a situation as threatening and to select threat-ori-
highly positive or highly negative outcomes. ented coping strategies, whereas children living in more fa-
Pollak and colleagues (Pollak, Cicchetti, Hornung, & vorable conditions are more likely to interpret a situation
Reed, 2000; Pollak & Tolley-Schell, 2003) have demon- as nonthreatening and to select a nonthreat strategy to meet
strated in several studies using a variety of methods that the situational demands.
early experiences shape attentional processes and deter- The assumption that memory processes are shaped or
mine which stimuli children select for attention. They fine-tuned by early experiences is again supported by the
found that maltreated and nonmaltreated children differed work of Pollak and colleagues (Pollak et al., 2000; Pollak &
in their attention allocation to certain emotional stimuli. Sinha, 2002), who studied emotion recognition in children.
Specifically, physically abused children were highly sensi- Pollak et al. presented physically abused, neglected, and
tive to information that signals threat and possible harm, nonmaltreated children with several emotional stories. After
namely, angry facial expressions. At the same time, these hearing each story, the children were shown photographs de-
children had problems shifting their attentional focus away picting facial expressions of different emotions and were
from angry faces; that is, they had less control over their at- asked to select the photograph that would best fit what the
tentional processes than nonabused controls. story’s protagonist felt. Neglected children, who have expe-
Physically abused children are not only especially sensi- rienced a lack of care and responsiveness from their parents,
tive to anger cues, they also experience more fear than had difficulties recognizing different emotional states. In
nonabused controls when witnessing angry interactions. For contrast, physically abused children were as sensitive as
instance, in a study by Hennessy, Rabideau, Cicchetti, and controls in differentiating emotions, and they performed es-
Cummings (1994), physically abused children reported pecially well in recognizing anger-related situations. Both
596 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

maltreated groups showed a response bias: Neglected chil- mechanism is often spontaneously used with family and
dren displayed a response bias for sad facial expressions, and friends, and it is a basic element of many psychological coun-
physically abused children showed a tendency toward select- seling approaches (e.g., client-centered therapy; Rogers,
ing angry facial expressions. This study clearly shows that 1951). For this coping mechanism to work, individuals need
early experiences shape how individuals interpret emotional to be able to verbally express their problems and feelings;
signals in a very specific way. For instance, the response that is, communicative skills play an important role.
bias for anger in physically abused children might be due to Language develops in a very constrained and pre-
their experience of frequent anger outbursts that are often dictable way in all normally developing children, and
unpredictable and that appear not to be related to the spe- many researchers have emphasized the biological-matura-
cific situation. tional component of language acquisition (e.g., Chomsky,
Physically abused children do not only show a response 1972; Pinker, 1994). This component might explain why
bias for anger. Already at a perceptual level, these children individuals reared in very different cultural and linguistic
are especially sensitive to anger cues. This was experimen- environments all acquire their native language. Although
tally shown by Pollak and Sinha (2002), who asked physi- almost all individuals become fluent speakers, environ-
cally abused and nonabused children to recognize emotions mental factors likely influence the grade of linguistic
from degraded pictures of happy, angry, sad, and fearful proficiency that is reached. It has been shown that disad-
faces in a priming task. Faces were initially presented in vantaged environments can influence the pathways of lan-
highly degraded formats. Over time, the pictures became guage acquisition, possibly resulting in language and
more organized and easier to identify. Physically abused communicative deficits later in life. For instance, children
children were able to correctly identify angry facial expres- from lower SES families show slower rates of vocabulary
sions on the basis of more degraded picture versions than growth than children from higher SES families (Hoff,
were nonmaltreated children. Physically abused children 2003). This effect is mediated by the speech children hear
needed more information than controls to recognize sad- at home. Hoff showed that the speech of mothers from
ness. No group differences were found for happiness or lower and higher SES differs in quantity, lexical richness,
fearfulness. and sentence complexity, and that these differences ex-
Taken together, these studies show that an abusive envi- plained over 20% of the variance in 2-year-olds’ size of
ronment makes children especially sensitive for the detec- productive vocabulary.
tion of anger. According to Pollak and Sinha (2002), this is Cicchetti and colleagues (Beeghly & Cicchetti, 1994;
accomplished by a memory system that is fine-tuned by Coster, Gersten, Beeghly, & Cicchetti, 1989) looked at lan-
early experiences to allow for facilitated access to the rep- guage development in maltreated children and found delays
resentation of anger. Physically abused children grow up in in language structure, expressive vocabulary, and expres-
an environment that is characterized by uncontrollable sud- sion of internal states. Eigsti and Cicchetti (2004) extended
den outbursts of violence. The early detection of anger these findings by showing that not only the content but also
might give children additional time to prepare for hostile the linguistic form is affected by maltreatment and SES: 5-
interactions. In this sense, abused children’s early detec- year-old maltreated children and nonmaltreated children
tion of threatening information can be viewed as adaptive. from low SES both scored below age-expected levels of
However, it becomes maladaptive when premature deci- syntactic abilities, with maltreatment causing a signifi-
sions about facial expressions are made (see Pollak & cantly greater amount of developmental delay.
Sinha, 2002, for these arguments). In cases of uncertainty, What are the long-term effects of these developmental
abused children tend to interpret facial expressions as delays? Because longitudinal studies are missing, there is
angry, a bias that restricts them from considering other no definite answer to that question. However, Eigsti and Ci-
possible interpretations (Pollak & Kistler, 2002). Later in cchetti (2004) suspect that language delays lead to later
life, a bias toward interpreting situations as threatening emotional, social, and cognitive delays and exacerbate ex-
and therefore stressful is likely to result in allostatic load isting problems. The observation that the speech of moth-
and situational-inadequate responses such as conduct dis- ers from lower and higher SES differs in many aspects
orders, aggressive behavior, depression, and anxiety. (Hoff, 2003) further supports long-lasting detrimental ef-
fects of disadvantaged environments on language skills.
Effects of Adversity on Language Development
The less an individual is able to communicate his or her
Interpersonal communication is one mechanism that helps problems and internal states, the more difficulties he or she
individuals to cope with stressful situations. This coping might have coping with stressful situations, because inter-
Early Adversity and the Development of Allostatic Load 597

personal communication might not lead to the desired sall, 1991) found that individual differences in the amount
stress-releasing effect. of family discussions about feelings and emotions pre-
dicted young children’s understanding of other people’s
Effects of Adversity on False Belief Understanding
feelings and beliefs, even when children’s language skills
A 3-year-old child’s understanding of the mind is very were controlled for analytically. From these results, it is
different from that of a 5-year-old child. Whereas 3-year- becoming clear that a child does not necessarily need to be
old children roughly assume that all people share the same exposed to significant adversities (e.g., maltreatment) in
knowledge, 5-year-old children have realized that peo- order to present weaknesses in the development of verbal
ple’s beliefs may be true or false and that people’s behav- abilities and emotional understanding, but that exposure to
ior is based on these beliefs rather than on reality. In their a family environment lacking the richness of interactions
now-classic set of experiments on false belief understand- necessary to develop these skills may be sufficient to pre-
ing, Gopnik and Astington (1988) showed children of dif- vent adequate cognitive and emotional abilities later in life.
ferent ages a box with pictures of candy on it and asked Also, given the fact that the ability to make judgments
the children what they thought was in the box. The chil- about mental states is critical to social interactions, it may
dren assumed that the box contained candy and were sur- be possible that a lack of adequate development of this skill
prised when they opened the box and found crayons. may prevent children from coping efficiently in the face of
When asked what another child who has not yet looked in- the various stressors of life.
side the box would think was in the box, 5-year-old chil- Second, neurobiological maturation processes might be
dren seemed to understand the concept of deception and more directly altered by maltreatment in that “children
said “candy.” Three-year-old children, in contrast, an- subjected to pathological care giving may acquire neu-
swered that the other child would think that the box con- ropathological connections instead of functional neural
tained crayons. Moreover, 3-year-old children also denied connections” (Cicchetti et al., 2003, p. 1087). This path-
their own original deception; that is, they said they had al- way could explain why an onset of maltreatment during the
ways thought that the box contained crayons. Since the toddler years is especially detrimental to the development
original work by Gopnik and Astington several studies of false belief understanding, because the toddler period is
have shown that major changes in false belief understand- a time of rapid creation and modification of neuronal con-
ing take place around 4 years of age (Wellman, Cross, & nections (see also Cicchetti, 2002), and many of the pre-
Watson, 2001). cursors of false belief understanding develop during that
Does false belief understanding follow a different devel- period, for example, language development (especially the
opmental pattern in maltreated children? In a recent study verbal expression of internal states), conceptual develop-
by Cicchetti and colleagues (Cicchetti, Rogosch, Maughan, ment, increased individuation, and self-other differentia-
Toth, & Bruce, 2003), 3- to 8-year-old maltreated and non- tion (Cicchetti, 1991).
maltreated children performed two false belief tasks. Regarding the influence of SES on theory of mind de-
Among children with a verbal mental age of 49 months or velopment, findings are somewhat mixed. For instance,
greater, maltreated children demonstrated less false belief Cutting and Dunn (1999) found differences in false belief
understanding than nonmaltreated children. Performance understanding in relation to parental occupational class
was worst for children who were physically abused and and mother’s education (see also Pears & Moses, 2003).
whose maltreatment started during the toddler years. Cic- Other researchers have found that SES and performance in
chetti et al. suggest two possible pathways by which mal- theory of mind tasks were not (Cicchetti et al., 2003) or
treatment can affect false belief understanding. First, only weakly (Murray, Woolgar, Briers, & Hipwell, 1999)
deficits in caregiving, especially the lack of parental empa- related and that parental behaviors (Hughes, Deater-
thy and sensitivity to the child’s internal experiences, and Deckard, & Cutting, 1999) or general and verbal intelli-
the limited communication of feelings and emotions by gence (Murray et al., 1999) were better predictors of
the parents may contribute to a delay in the child’s under- theory of mind performance.
standing of beliefs of self and others. This suggestion is Taken together, studies have shown that adversity can
strengthened by studies showing that maternal language alter false belief understanding and other aspects of theory
to toddlers about internal states mirrors their children’s of mind development in children. For the case of maltreat-
abilities to become increasingly other-oriented (Beeghly, ment, the pathways through which maltreatment con-
Bretherton, & Mervis, 1986; J. Dunn, Bretherton, Munn, tributes to developmental delays have been specified. For
1987). Dunn and collaborators (J. Dunn, Brown, & Beard- low SES, the literature is less clear and the multifaceted
598 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

factors that may lead to successful or unsuccessful devel- in childhood. Academic achievement is negatively associ-
opment need further specification. ated with mental health problems (Sandler, 2001). Most in-
teresting, high intellectual functioning in childhood was a
Positive Outcome in the Context of Adversity: The
protective factor against developing conduct problems in
Concept of Resilience
adolescence, thus pointing to the long-term moderating ef-
Not everybody reared in disadvantaged environments will fect of early cognitive functioning on adversity. This find-
face problems later in life. In the literature, the phenomenon ing also replicates previous studies that have shown that
that similar stressful experiences can lead to very different intellectual functioning is an important moderating vari-
individual outcomes is referred to as multifinality (Curtis & able of antisocial behavior in high-risk groups (White,
Cicchetti, 2003). At the same time, not everybody who expe- Moffitt, & Silva, 1989). As Masten et al. (1999, p. 163)
riences problems later in life has faced adversity, a phenom- point out, “Numerous processes could underlie this effect:
enon referred to as equifinality (Curtis & Cicchetti, 2003). Good verbal, learning or problem solving aptitude could
Both concepts highlight the important fact that early experi- play a role in assessing threat, accessing resources, effec-
ences do not ultimately determine further developmental tive seeking of healthier environments or relationships for
pathways. This brings us to the concept of resilience. Re- development, appealingness to teachers, etc.”
silience can be defined as successful adaptation or compe- In summary, the data suggest that the capacity to detect
tent developmental outcome in the face of risk and adversity. threatening and nonthreatening information develops very
Curtis and Cicchetti conceptualize resilience as “a dynamic early in life and is sensitive to environmental conditions.
process that is influenced by neural and psychological self- This modification of the selective attention process will
organization, as well as transactions between the ecological lead to more threatening cues and information being stored
context and the developing organism” (p. 776). Thus, many in long-term memory, with the resulting effect that when
different interdependent factors contribute to resilient func- the time comes to find a response to a threat (relative or ab-
tioning, including biological factors such as genetic makeup, solute, real or implied), a threat-related type of response
brain organization, and neuroendocrine functioning; psy- (aggression, violence, etc.) may be more readily available
chological factors such as emotion regulation, attachment, for immediate action. Although this response may be adap-
and locus of control; and environmental factors such as par- tive in the short run, the frequent detection of threat and/or
enting (for overviews, see, e.g., Curtis & Cicchetti, 2003; threat response may lead to an allostatic load process, af-
Luthar, 2003; Masten, 2001). Here, we focus on cognitive fecting the behavior, the body, and the brain. In terms of
processes that contribute to resilience. behavior, this decision process might lead in the long run to
An interesting longitudinal study on adversity and re- the development of externalizing behaviors and/or a diag-
silience was conducted by Masten et al. (1999), who fol- nosis of a Conduct Disorder. If this is the case, then some
lowed children over 10 years from childhood through bodily markers of allostatic load may be related to exter-
adolescence and assessed three major domains of compe- nalized behaviors in children.
tence: academic achievement, conduct, and peer social To assess whether such a process might occur in devel-
competence. Adversity was measured as the occurrence of oping children, we have reviewed the literature on external-
major life events and experiences that are likely to be ized behavior and Conduct Disorders in children, in
stressful (e.g., death of a family member). The study fo- association with biological processes known to be involved
cused on two possible resources that are assumed to protect in allostatic load. In our literature search, we found various
children from the effects of adversity: intellectual func- markers of allostatic load that have been studied in relation
tioning (intelligence) and parenting quality. The authors to externalized behaviors or Conduct Disorders in children.
found that both resources protected children from develop- Some of these biological processes are primary stress me-
ing competence problems. High-adversity children with diators (cortisol, DHEAS), and others are secondary out-
high intelligence scores and well-functioning parent-child comes (waist-hip ratio, cholesterol, and heart rate). We
relationships were as competent as low-adversity children. summarize these data in the following sections.
At the same time, low-adversity children with low re-
sources developed competence similar to high-resource
Allostatic Load and Externalized
children. This shows that only the combination of high ad-
Behaviors/Conduct Disorder in Children
versity and low resources resulted in competence prob-
lems. Specific to intellectual functioning, intelligence was Conduct Disorder (CD) refers to a group of symptoms or
related to academic achievement and to social competence problematic externalized behaviors. The description of CD
Early Adversity and the Development of Allostatic Load 599

in the Diagnostic and Statistical Manual of Mental Disor- vironmental factors may be mediated by the psychological
ders, fourth edition (DSM-IV), includes four types of be- and physiological stress induced by these adversities, which
havior: (1) aggression toward people or animals, (2) in turn may be responsible for enhanced propensity to
destruction of property, (3) deceitfulness or theft, and (4) manifest externalizing behaviors (G. W. Evans, 2003; G. W.
serious violations of rules; all of these are referred to as ex- Evans & English, 2002).
ternalizing behaviors. Because it is a very heterogeneous A child who manifests externalization problems may
disorder both in its occurrence and in its etiology, Frick react and cope (at physiological, cognitive, or behavioral
(1998) proposed using the plural term Conduct Disorders. levels) differently when confronted by threats as a function
Two different types of CD are nowadays distinguished: the of his or her age. For example, a 10-year-old child with ex-
childhood-onset (DSM-IV) or life-course-persistent type ternalization problems may decide to either fight or lie to
(Caspi & Moffitt, 1995) and the adolescent-onset (DSM- escape negative consequences, whereas an adolescent with
IV) or adolescence-limited type (Caspi & Moffitt, 1995), externalization problems may be prone to select dangerous
each with a different etiology. The spectrum of CD also health-related behaviors (e.g., substance abuse, smoking)
includes more extreme forms of behaviors, such as psycho- or adopt risk behaviors such as antisocial behaviors (e.g.,
pathic behavior. It has been acknowledged that the distinc- stealing, fighting), drop out of school, or engage in sensa-
tion between these two types of CD is of importance for tion-seeking activities. From society’s viewpoint, these
their causal accounts and treatment decisions (Caspi & behaviors may be unacceptable or at least impede access to
Moffitt, 1995; Frick, 1998; Moffitt, Caspi, Harrington, & better living conditions. Nevertheless, in the short run,
Milner, 2002). In our review of allostatic load markers, we some of these behaviors may enhance the child’s or adoles-
focus on the childhood-onset or life-course-persistent type, cent’s perceived adaptation to threats by enhancing self-
and we intermix by sections the results of studies that have esteem or offering an alternative access to prestige or
assessed either externalized behaviors in children or chil- money, being recognized and respected, or having a thrill.
dren diagnosed with Conduct Disorders. However, for the Furthermore, children and adolescents manifesting exter-
sake of clarity, we refer to only Conduct Disorders in each nalized behaviors may also elicit more negative interac-
section’s title. tions and coercion from their environment. In attempting to
Commonly, adverse environmental factors are suggested adapt to threats in a cost-effective way according to their
to contribute, at least partially, to the onset, maintenance, initial individual differences, some of them may exacerbate
and exacerbation of externalizing behaviors among children the likelihood of negative reactions from the environment,
(Haapasalo & Tremblay, 1994; McLeod & Shanahan, 1993). which could eventually lead to a sustained engagement in
The adverse environmental conditions studied in relation externalizing behaviors (Brennan & Raine, 1997). Thus,
to externalizing behaviors include SES (Brooks-Gunn & children with externalization problems may select differ-
Duncan, 1997; McLoyd, 1998), low parental education at- ent coping strategies from children without these problems
tainment (Hanson, McLanahan, & Thomson, 1997), negative as a result of both individual characteristics and adverse
parental behaviors (Lempers, Clark-Lempers, & Simons, environmental conditions.
1989), single motherhood (Corcoran & Chaudry, 1997), ex-
posure to violence (Miller, Wasserman, Neugebauer, Gor- General Cognitive/Brain Dysfunctions in
man-Smith, & Kamboukos, 1999), and low quality of Conduct Disorders
schools and neighborhoods (Bradley & Corwyn, 2002). The three brain structures (prefrontal cortex, amygdala,
Here, it is important to note that the importance of these hippocampal formation) that are involved in the stress re-
environmental variables in the development of externalized sponse (see earlier discussion) have been found to be struc-
behaviors may stem from their actions on parental behavior. turally and/or functionally different in individuals with
For example, economic hardship may decrease the mother’s CD or other forms of antisocial disorders, including crimi-
self-esteem (McLeod & Nonnemaker, 2000) and the par- nal psychopaths, when compared to normal controls.
ents’ investment in the child (Bolger, Patterson, Thompson, With regard to structural differences, right temporal
& Kupersmidt, 1995; Jackson, Brooks-Gunn, Huang, & and prefrontal lobe volumes were reported to be smaller
Glassman, 2000), may induce frequent use of physical disci- in early-onset CD and in Antisocial Personality Disorder
pline (Conger, Patterson, & Ge, 1995; Deater-Deckard, (APD; Kruesi, Casanova, Mannheim, & Johnson-Bilder,
Dodge, Bates, & Pettit, 1996), and may exacerbate moth- 2004; Raine, Lencz, Bihrle, LaCasse, & Colletti, 2000).
ers’ depressive symptoms (McLeod & Nonnemaker, 2000). Bigler (2001) put forward the hypothesis that the prefrontal
So, the response that is induced by exposure to adverse en- cortex as the major instance of moral guidance never
600 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

developed a functional role in individuals with APD, thus duced through modifications of brain chemistry. Yet, a
explaining the deficiency of moral decision making in closer examination of the physiological markers related to
these individuals. It might be speculated that smaller pre- allostatic load is a challenging and promising way to under-
frontal lobe volumes are also related to the impulsive be- stand the mechanisms by which markers of allostatic load
havior seen in individuals with CD and APD, because the may relate to externalizing behaviors.
prefrontal cortex plays a major role in response inhibition.
Cortisol and Conduct Disorder
With regard to functional differences, Kiehl et al.
(2001) showed that criminal psychopaths showed less acti- Among all the components of allostatic load, the primary
vation of the amygdala and hippocampal formation when stress mediator cortisol has been the most widely studied in
processing affective stimuli in comparison to criminal relation to Conduct Disorders in children. To this day, the
nonpsychopaths and controls. As described earlier, the most consistent finding with regard to the secretion of cor-
amygdala is critically involved in fear processing and the tisol levels in children with CD is the presence of lower
formation of associations between cues and outcomes. The basal levels of cortisol, although some discrepancies in the
lower affect-related amygdala activation in criminal psy- results are clearly observable. The first study of children
chopaths therefore goes hand in hand with the finding that with CD was by Kruesi and collaborators in 1989 (Kruesi,
psychopaths are insensitive to several types of fear and Schmidt, Donnelly, Hibbs, & Hamburger, 1989). They
punishment contingencies (e.g., Hare, 1965; Patrick et al., measured 24-hour urinary cortisol excretion in 19 boys
1994). At the same time, in the study by Kiehl et al., crimi- with Attention Deficit and/or CD and 19 age-, race-, and
nal psychopaths showed an overactivation in the prefrontal IQ-matched normal controls. The results revealed no dif-
cortex when processing affective stimuli. According to ference in the 24-hour urinary cortisol secretion between
Kiehl et al., this overactivation might imply that criminal the two groups. However, 2 years later, McBurnett and col-
psychopaths need more cognitive resources to process af- laborators (1991) assessed salivary cortisol levels in 67
fective stimuli. boys (ages 8 to 13 years) with Anxiety Disorders and/or
As discussed earlier, allostatic load is intimately linked CD. The results showed that children with both CD and
to brain integration of the environment. The interpretation Anxiety Disorder had higher levels of salivary cortisol than
of events as threatening or not leads to behavioral re- children with CD without comorbid Anxiety Disorder.
sponses selected to cope with the threat, which in turn After this first report of significantly lower cortisol levels
contribute to an increase of allostatic load in the long run in children with CD, a wealth of studies reported either a
(McEwen, 2000b). Children experiencing externalizing negative correlation between cortisol levels and symptoms
problems may modify in their own way (not necessarily of CD (McBurnett & Lahey, 1994; McBurnett, Lahey, Ca-
consciously) their information-processing system (e.g., se- passo, & Loeber, 1996; McBurnett, Lahey, Rathouz, &
lection of coping behaviors and evaluation of their cost-ef- Loeber, 2000; Pajer, Gardner, Rubin, Perel, & Neal, 2001)
fectiveness) to minimize the intensity/frequency of their or the presence of significantly lower cortisol levels in chil-
subsequent reactions to further threats at physiological, at- dren with CD when compared to children without CD
tentional, and emotional levels. In other words, informa- (Pajer et al., 2001).
tion processes may act to inhibit relevant events initially Although a significant number of studies have reported
processed as threatening ( habituation). As a consequence, a link between low cortisol levels and Conduct Disorders, it
physiological reactions induced by these initial threatening is important to note that, similarly to Kruesi and collabora-
events may be reduced, leading to an allostatic response tors’ (1989) study, other studies did not report such an as-
(inadequate response). This modification of the perception sociation. For example, in 1997, Schulz and collaborators
of threat will likely influence the physiological response of (Schulz, Halperin, Newcorn, Sharma, & Gabriel, 1997)
the child to environmental threats, which may then act tested plasma salivary cortisol levels in aggressive and
to enhance externalizing behaviors through higher toler- nonaggressive boys with Attention Deficit Disorder and re-
ance to negative events (e.g., punishment, pain, emotional ported no differences in cortisol levels between the groups.
arousal), reducing the child’s response to social rules and Other studies performed with adolescent mothers with CD
frequent risky and sensation-seeking behaviors adopted by did not report the negative correlation between cortisol lev-
the child in order to cope with physiological underarousal els and symptoms of CD (Susman et al., 1999) or did not re-
(Raine, 1993). port a significant difference between cortisol levels in
We acknowledge that sustained externalizing problems adolescent mothers with or without CD (Azar et al., 2004).
during childhood and adolescence are not exclusively in- The discrepancy observed in the literature on cortisol and
Early Adversity and the Development of Allostatic Load 601

symptoms of CD may stem from a variety of factors, in- formation on the best method to assess cortisol levels in hu-
cluding the diagnosis of CD, the externalizing behavior mans, see the recent review by Goodyer and collaborators
measured, and the time and method of assessment of corti- (Goodyer, Park, Netherton, & Herbert, 2001).
sol. Indeed, in the various studies that were performed on Be that as it may, some mechanisms have been proposed
the link between cortisol levels and Conduct Disorders, im- to explain the link between low cortisol levels and external-
portant methodological differences are observed, with izing behaviors. Low cortisol levels noted in aggressive in-
some authors assessing the 24-hour urinary pattern of cor- dividuals are understood in the light of an underaroused
tisol secretion (Kruesi et al., 1989), others assessing sympathetic autonomous nervous system and HPA axis
plasma cortisol levels measured immediately to 115 min- (Lahey, McBurnett, Loeber, & Hart, 1995). Consequently,
utes after insertion of a catheter (Pajer et al., 2001; Schulz a dampened HPA axis secretion pattern would constitute
et al., 1997; Susman et al., 1999), and others assessing cor- an adaptive response ( habituation) to aversive situations
tisol in saliva samples taken in the morning period (Azar such as pain and parental coercive behaviors (Vanyukov
et al., 2004; Vanyukov et al., 1993) or at any time (not con- et al., 1993). Moreover, lower reactive secretion in individ-
trolled for) over a 2-year period (McBurnett & Lahey, uals manifesting externalizing behaviors may be explained
1994; McBurnett et al., 1991, 1996, 2000). as a higher HPA axis activation threshold (Kruesi et al.,
Here, we remind the reader that basal levels of cortisol 1989). For these individuals, moderate stressful events may
follow a circadian cycle, with higher levels in the morning be inefficient to induce HPA axis activation. As a result,
and declining levels throughout the day. It is thus extremely those individuals may feel understimulated and be prone to
important when assessing cortisol levels in humans to con- searching for sensation-seeking activities.
trol for the time of day at which the samples are taken. The low cortisol-CD link could also be interpreted as a
Moreover, any cortisol difference pertaining to samples ob- physiological marker of a tendency toward (or an absence
tained in the morning cannot be taken as direct evidence of ) behavioral inhibition (Kagan, Reznick, & Snidman,
that cortisol secretion is lower in children with Conduct 1987). Gray (1982, 1987) suggested that two neurophysio-
Disorders, given that it may be possible that the total excre- logical systems are implicated in antisocial behaviors: the
tion of cortisol throughout the day is not different in these behavior inhibition system (BIS) and the behavior activa-
children when compared to control children. Also, there is a tion system (BAS). The BIS has received considerable at-
major difference between plasma and salivary measures of tention in regard to the low cortisol levels noted in
cortisol, as the plasma concentrations of cortisol include externalizing individuals. One of the main functions of the
both the free ( biologically active) and bound (to carrier pro- BIS is to down-regulate (inhibit) nonreinforced behaviors
teins and thus inactive) portions of cortisol, whereas sali- (e.g., aggressive behaviors) while perceiving aversive cues
vary samples assess the free portion of cortisol. Given that in the environment (e.g., punishment). BIS activation is ex-
it is the free portion of cortisol that will be active, salivary pressed at the behavioral level through inhibition responses
cortisol may represent a better measure of the biologically and at the physiological level in cortisol, serotonin, and no-
active cortisol levels than plasma cortisol levels. Moreover, radrenalin secretion (King, Barkley, & Barrett, 1998).
cortisol levels have been shown to present a significant in- Convergent with the BIS, higher cortisol levels appear to be
crease at 30 and 60 minutes after waking (called the cortisol a protective feature against manifesting externalizing be-
awakening response; J. C. Pruessner et al., 1997), and this havior problems ( because facilitating inhibition of these
pronounced cortisol increase during the first hour after behaviors), and lower cortisol levels may be a marker of a
waking in the morning has been found to be associated with behavioral disinhibition already associated with external-
higher measures of self-reported stress (J. C. Pruessner, izing behaviors (King et al., 1998; McBurnett et al., 1996).
Hellhammer, & Kirschbaum, 1999; M. Pruessner et al., Interestingly, most studies assessing the association be-
2003; Schulz, Kirschbaum, Pruessner, & Hellhammer, 1998; tween cortisol levels and the development of disruptive
Wüst, Federenko, Hellhammer, & Kirschbaum, 2000). Fi- behaviors in preschoolers report a positive association be-
nally, venipuncture has been shown to induce a potent re- tween cortisol and some psychological correlates of exter-
sponse of the HPA axis (Meeran, Hattersley, Mould, & nalizing behaviors (e.g., negative affect, aggression,
Bloom, 1993), and it is possible that the cortisol response to difficult or instable temperament; E. P. Davis, Donzella,
venipuncture induces large inter- and intraindividual corti- Krueger, & Gunnar, 1999; de Haan, Gunnar, Tout, Hart, &
sol responses, explaining some of the discrepant findings. Stansbury, 1998; Gunnar, Tout, de Haan, Pierce, & Stans-
For a complete review of the methodological factors that bury, 1997). For example, Dettling, Gunnar, and Donzella
could account for the discrepancies of data and for more in- (1999) reported a positive association between cortisol
602 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

levels secreted during the day and negative affect and ag- that studies of Conduct Disorders in prepubertal children
gression in preschoolers. To explain this result, they sug- should therefore not focus on testosterone, but on adrenal
gested that immature regulation systems and negative peer androgens, such as DHEA and DHEAS. DHEA and
relationships might be correlated with higher cortisol se- DHEAS are also very interesting for the study of Conduct
cretion. In this sense, the higher cortisol levels associated Disorders because, besides being secreted in the adrenal
with aggression in preschoolers may be related to a stress- glands, they are also endogenously synthesized by the brain
induced cortisol release rather than to basal levels of corti- (Robel & Baulieu, 1995). Many studies have shown that
sol. Higher cortisol levels have also been interpreted as DHEA acts by increasing neuronal excitability, enhancing
a marker of the effort to adapt to a demanding and unfamil- neuronal plasticity and having neuroprotective properties
iar social environment (Stansbury & Harris, 2000). Even (Wolf & Kirschbaum, 1999). From the effects of DHEA on
though moderate cortisol secretion may enhance the child’s the body and the brain, many authors have suggested that
capacity to cope with an unfamiliar environment, large se- DHEA / DHEAS should be elevated in individuals who are
cretions of cortisol may be a marker of dysfunctional social aggressive. This suggestion has been confirmed.
adaptation (McEwen, 2002). Consequently, an inverted U- In a study performed in 1998, van Goozen and collabo-
shape relationship between cortisol and social functioning rators examined the relationship between plasma levels of
may best characterize this association in childhood (E. P. testosterone and DHEAS in 15 boys with CD and 25 nor-
Davis et al., 1999) and adulthood (McEwen, 2003). mal controls boys. The intensity of aggression and delin-
In the preschool years, the mechanisms involved in the quency of the boys were rated by parents and teachers over
modified HPA axis resulting from adverse environmental a period of 6 months. The results showed that boys with CD
conditions remain to be clarified. The first years of life had significantly higher levels of DHEAS, although testos-
possibly constitute a sensitive period in which several terone levels did not differ between groups. Also, the au-
physiological systems complete their maturation and show thors reported that levels of DHEAS were significantly and
greater plasticity to environmental factors (De Kloet, positively correlated with the intensity of aggression and
Vreugdenhil, Oitzl, & Joels, 1998; Gunnar & Donzella, delinquency as rated by both parents and teachers. The au-
2002). Consequently, adverse environmental conditions ex- thors interpreted these results as suggesting that adrenal
perienced during this sensitive period may be particularly androgen functioning plays an important role in the onset
determinant in inducing changes in the HPA axis (Heim and maintenance of aggression in young boys. In a second
et al., 2000; Meaney et al., 1996). Essex, Klein, Cho, and study, van Goozen and collaborators (van Goozen, van den
Kalin (2002) observed that children who experienced Ban, et al., 2000) measured DHEAS in children with oppo-
chronic stress during their 1st year of life have higher cor- sitional and antisocial behavior and normal controls. The
tisol levels at 4.5 years of age, suggesting that cumulative results showed that children with oppositional and anti-
rather than acute stressful events are linked to permanent social behavior had higher DHEAS levels than the control
physiological changes (G. W. Evans & English, 2002). groups. An increase in DHEAS in children and adolescents
Modified HPA axis secretion patterns observed in child- with CD was also reported by Dmitrieva et al. (2001).
hood and adulthood are thought to be one of several physio-
Cholesterol and Conduct Disorder
logical outcomes of chronic stress experienced early in life
(Gunnar et al., 2001; Gunnar & Vazquez, 2001). Cholesterol and, more generally, lipid concentrations and
metabolism have received substantial attention in relation
Dehydroepiandrosterone and Conduct Disorder
to externalizing behaviors and more specifically violence
DHEA and its sulfate (DHEAS) is another primary stress and delinquency. Interestingly, while allostatic load in
mediator that has been studied in relation to CD. The ra- adults and older individuals is associated with high choles-
tionale here is that from around age 6, children exhibit a terol levels, a negative relation is usually noted between
gradual increase in androgens, but these androgens are of cholesterol and violence in both young and adults. Golomb,
adrenal origin, a period called the adrenarche. It is not until Stattin, and Mednick (2000) reported that low cholesterol
puberty that gonadal androgens (of gonadal origin), such as levels in males were most frequently associated with violent
testosterone, become more important. Researchers (Buy- crimes committed against others. The participants’ age was
dens-Branchey & Branchey, 2004; Dmitrieva, Oades, related to both cholesterol levels and violent crimes, but the
Hauffa, & Eggers, 2001; Goodyer et al., 2001; van Goozen, association remained significant when age was taken into
Matthys, Cohen-Kettenis, Thijssen, & van Engeland, 1998; account. Similar results were noted in relation to physical
van Goozen, van den Ban et al., 2000) have thus concluded aggression (Hillbrand & Spitz, 1999; Hillbrand, Waite,
Early Adversity and the Development of Allostatic Load 603

Miller, Spitz, & Lingswiler, 2000), past history of aggres- Other mechanisms have been shown to play a role in the
sion in inpatients of a drug rehabilitation unit (Buydens- aggression-cholesterol association. Negative mood states,
Branchey, Branchey, Hudson, & Fergeson, 2000), violent low cognitive efficacy, and a reduced interpersonal in-
offenders with Antisocial Personality Disorder (Virkkunen, volvement are also linked to low cholesterol levels in an in-
1979), violent suicidal attempts (Vevera, Zukov, Morcinek, patient sample (Hillbrand et al., 2000). These results
& Papezova, 2003), and cholesterol-lowering interventions suggest that the association between aggression and choles-
in humans (Golomb, 1998; Muldoon, Manuck, & Matthews, terol may partially be accounted for by other psychological
1990) and in nonhuman primates (Kaplan et al., 1994). and behavioral correlates.
In contrast to the overall negative association generally
Waist-Hip Ratio and Conduct Disorder
reported between cholesterol and aggression, nonsignifi-
cant or positive relationships have been noted between Very few studies have assessed the link between waist-hip
cholesterol and psychological aggression, expressive hos- ratio and Conduct Disorders. In 2001, Ishikawa and collabo-
tility, and anger attacks (C. C. Chen, Lu, Wu, & Chang, rators (Ishikawa, Raine, Lencz, Bihrle, & LaCasse, 2001)
2001; Hillbrand & Spitz, 1999; Wing, Matthews, Kuller, measured height, weight, body mass index, bulk, and psy-
Meilahn, & Plantinga, 1991). These results suggest that chosocial adversity in 44 controls and 43 adolescents and
the cholesterol and aggression association is restricted to adults with antisocial personalities. They reported that adult
physical aggression and violence. antisocial individuals, regardless of age of onset, were sig-
However, previous results obtained on the association nificantly taller and had greater body bulk than controls.
between cholesterol and CD must be accepted cautiously However, they also reported that although groups tended to
for several reasons. First, most of these studies were con- differ on weight, they did not differ on body mass index. In
ducted exclusively with male participants, which limits the 2003, Mustillo and collaborators assessed the association
generalization of results to females. A study conducted by between obesity and the development of psychiatric disor-
Lindberg, Rastam, Gullberg, and Eklund (1992) reported a ders in 991 children ages 9 to 16 who were evaluated annu-
similar negative association between cholesterol and ag- ally over an 8-year period for height, weight, psychiatric
gression in female participants, although the magnitude of disorder, and vulnerabilities for psychiatric disorder. The re-
the association was much weaker. Young age is related to sults showed that of the four developmental trajectories of
the cholesterol-aggression association, but the link remains obesity tested—no obesity (73%), chronic obesity (15%),
significant once age is taken into account, which suggests childhood obesity (5%), and adolescent obesity (7%)—only
that the association between cholesterol and aggression is chronic obesity was associated with Oppositional Defiant
not essentially explained by the age of the child (Golomb Disorder in boys and girls and depressive disorders in boys.
et al., 2000). Note that alcohol use ( linked to increased
Heart Rate and Conduct Disorder
HDL level with no change in cholesterol) and SES levels
(inversely correlated to cholesterol) do not explain the Increased cardiovascular activity is a secondary outcome
overall relation (Golomb, 1998). in the allostatic load model, which is operationalized by
The mechanisms connecting cholesterol to physical ag- higher heart rate and blood pressure ( both systolic and di-
gression are still unknown, but modified serotonin func- astolic). Cardiovascular parameters ( heart rate, blood pres-
tion has been proposed to mediate this association sure, etc.) are easy, noninvasive, and inexpensive to collect.
(Buydens-Branchey et al., 2000; Mysterud & Poleszynski, Despite this apparent simplicity, it has to be noted that the
2003). Low cholesterol levels reduce lipid microviscosity in context in which measures of heart rate are collected (rest-
the brain cell membrane, resulting in dampened activity in ing rate or activation /anticipation heart rate) may have a
serotonergic systems (Kaplan et al., 1994; Vevera et al., major impact on the results obtained in a given study. This
2003). Low serotonin levels are commonly related to a re- makes results harder to interpret and requires at least some
duced capacity to inhibit aggressive behaviors and impul- caution. Also, very few studies have been conducted with
sivity (Coccaro, 1992; Linnoila & Virkkunen, 1992; children showing the full spectrum of Conduct Disorder.
Virkkunen, De Jong, Bartko, & Linnoila, 1989). Cognitive However, various studies have been performed on some of
information and emotional processing are once again the externalizing behaviors present in Conduct Disorders.
thought to be implicated in the serotonin-aggression associ- We summarize these two types of studies next.
ation (Berman, Tracy, & Coccaro, 1997), namely by reduc- A relationship between anger, hostility, elevated heart
ing sensitivity to external clues referring to punishment or rate, and blood pressure has been noted in several studies
norm violation (Spoont, 1992). (M. C. Davis, Matthews, & McGrath, 2000; Galovski,
604 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

Blanchard, Malta, & Freidenberg, 2003). Competition in infancy (Dubreuil et al., 2003; Healy, 1992), childhood
challenge, harassment, and provocative insults are thought (Boomsma & Plomin, 1986; Schieken et al., 1989), and
to be central in the increased physiological reactivity asso- adulthood (An et al., 2000; Ditto, 1993; Somes, Harsh-
ciated with anger (Garcia-Leon, Reyes del Paso, Robles, & field, Alpert, Goble, & Schieken, 1995). Inherited differ-
Vila, 2003). In contrast, instrumental and less emotionally ences in heart rate may enhance the propensity of
aroused antisocial behaviors are associated with lower individuals with lower heart rate to manifest externalizing
heart rate and have been suggested to reflect both an un- behaviors while protecting individuals with higher heart
derarousal state and fearlessness (Scarpa & Raine, 1997). rate from personal involvement in contexts where external-
These sensation-seeking behaviors have been shown to izing behaviors are adaptive or required (Kindlon et al.,
enhance the propensity for risk-taking behaviors (e.g., al- 1995; Raine et al., 1995). These working models appear at
cohol and drugs, sexual promiscuity, extreme sports), phys- first sight hard to reconcile. Yet, although distinct, they
ical aggression, and criminal activities (Raine, Venables, & are not mutually exclusive. From a developmental perspec-
Williams, 1995; Scarpa & Ollendick, 2003). tive, potential factors linked to the onset of externalizing
A meta-analysis conducted by Ortiz and Raine (2004) of problems are generally thought to be multidimensional
40 studies indicated that both resting heart rate (n = 5,868 and influenced simultaneously by genes and environment
with a mean age of 10.8 years) and reactive heart rate (n = throughout one’s lifetime.
578 with a mean age of 12.6 years) were negatively related
to antisocial behaviors. In their prospective study, Raine, Immune Function and Conduct Disorder
Venables, and Mednick (1997) have reported that a low To this day, only one study has assessed the unique influence
resting heart rate assessed at age 3 in 1,795 children was of Conduct Disorder on immune function. Birmaher et al.
associated with higher rates of physical behaviors at age 11. (1994) assessed total white blood cells, lymphocytes sub-
Low resting heart rates have also been linked with fighting sets, natural killer cell activity, and lymphocyte prolifera-
behaviors at age 9 to 12 years in children from low SES tion in adolescents with either Major Depressive Disorder or
(Kindlon et al., 1995). This association is still significant Conduct Disorder and normal adolescents. They reported
when body size and pubertal status are taken into account. that although there were no significant between-group dif-
Interestingly, it has been shown that stressful charac- ferences in any of the cellular immune measurements,
teristics of inner-city environments, compared to subur- natural killer cell activity was significantly negatively cor-
ban and rural area lifestyles and environments, are related with past year and lifetime adverse life events across
generally linked to higher blood pressure (Thomas & all effector-target cell ratios. This result remained signifi-
Groer, 1986). For some children, these adverse environ- cant after controlling for diagnoses and SES.
mental conditions may sensitize them to further threats,
Allostatic Load and Conduct Disorder
contributing to increasing or maintaining higher resting
heart rates. However, other children confronted with the Although the studies performed on the primary stress me-
same adverse conditions may be desensitized ( habitua- diators and secondary outcomes of allostatic load have
tion) to threatening events encountered on a daily basis. shown some associations with Conduct Disorders, it is im-
Convergent with this hypothesis, Cooley-Quille and Lo- portant to remind the reader that the studies that validated
rion (1999) reported that youths exposed to the highest the allostatic load model clearly showed that none of the
levels of community violence have the lowest resting heat components of allostatic load exhibited significant associa-
rate. Such physiological adaptation may be protective in tions on their own with health outcome. Indeed, it was
the short run by dampening physiological activation asso- shown that it is the summary measure of allostatic load that
ciated with stressful environments, but it can become is significantly associated with major health outcomes.
detrimental in the long run, placing these children at risk These findings were consistent with the idea that although
to engage in developmental trajectories characterized by a modest deviation in the level of activity of a single physi-
externalizing problems such as delinquency and violence. ologic system may not be predictive of poor future health,
A second hypothesis for these discrepant results is that the cumulative toll from modest alterations in several
lower heart rates in aggressive and violent individuals may physiologic systems is prognostic for poor health. Conse-
partially be explained through inherited differences in car- quently, it may be possible that some of the discrepant find-
diovascular activity. Moderate to strong heritability esti- ings related to primary stress mediators and/or secondary
mates in cardiovascular indices are noted in several studies outcomes and CD may be due to the fact that only one com-
Early Adversity and the Development of Allostatic Load 605

ponent of the allostatic load model has been assessed. Al- similar in all groups. When exposed to a stressful situation,
though no study has assessed all components of the allosta- children with disruptive behavior disorders presented a
tic load model in children with Conduct Disorders, recent lower increase in heart rate and cortisol, when compared to
studies measured two or more markers of allostatic load, children without disruptive behavior disorder, but they re-
and the results reveal a very interesting pattern of develop- ported higher levels of emotional arousal.
mental allostatic load in childhood Conduct Disorders. We In a more recent study, Snoek and collaborators (Snoek,
summarize these next. Van Goozen, Matthys, Buitelaar, & van Engeland, 2004)
assessed heart rate and cortisol levels in children with
Low Cortisol and High Sulfated Dehydroepiandros- Oppositional Defiant Disorder (ODD) and children with
terone in Conduct Disorder. As we have summarized, Attention-Deficit /Hyperactivity Disorder (ADHD) under
independent studies have reported low cortisol levels and baseline and stressful conditions. The results showed that
high DHEAS in children with Conduct Disorders. This is under baseline conditions, the groups did not differ for cor-
an interesting finding because the opposite pattern is ob- tisol levels, although the group of children with ODD pre-
served in depressed children ages 8 to 16 years, namely, sented lower heart rates than the ADHD group. The results
high levels of cortisol and low levels of DHEA / DHEAS also showed that in response to stress, children with ODD
(Goodyer et al., 1996). A recent study performed in 2004 presented weaker cortisol and heart rate responses to stress
by Buydens-Branchey and Branchey assessed levels of cor- when compared to children with ADHD and control chil-
tisol and DHEAS in 40 adult cocaine addicts with a retro- dren. Altogether, these results suggest the presence of a
spective diagnosis of Antisocial Personality Disorder or hyporeactivity of the primary stress mediators (cortisol
childhood CD. Given that DHEAS and cortisol were as- and catecholamines/ heart rate) in response to stress in
sessed in blood taken with venipuncture, the authors attrib- children with ODD.
uted any group differences in DHEAS and/or cortisol to a
difference in reactivity to the stress induced by the Cortisol and Immune Function in Conduct Disorder.
venipuncture. The results showed that the men who had a In the immune system, white blood cells called lympho-
retrospective diagnosis of CD had significantly increased cytes are very diverse in their functions. The most abun-
DHEAS levels and less cortisol in response to venipunc- dant lymphocytes are the B lymphocytes (B cells) and the
ture. Comparisons between patients who did and did not T lymphocytes (T cells). The B cells are designated as such
meet the APD adult criteria did not reveal any significant because they are produced and mature in the Bone marrow,
difference in DHEAS or in cortisol responsivity. and T cells are designated as such because their precursors
leave the bone marrow and mature in the Thymus. Chief
Low Cortisol and Low Heart Rate in Conduct Disor- among the regulatory T cells are helper/inducer T cells.
der. Again, low cortisol levels and lower heart rate have These cells are needed to activate many immune cells, in-
been reported in children with Conduct Disorders, but very cluding B cells and other T cells. Another subset of regula-
few studies measured these two markers at the same time tory T cells acts to turn off or suppress immune cells.
in children with Conduct Disorder. In 2000, van Goozen There are two types of helper T cells. The Th1 type partic-
and collaborators (van Goozen, Matthys, Cohen-Kettenis, ipates in cell-mediated immunity and are essential for con-
Buitelaar, & van Engeland, 2000) investigated whether a trolling intracellular pathogens such as viruses and certain
pattern of lower autonomic nervous system and HPA axis bacteria. The Th2 type provides help for B cells and, in so
activity can be found in children with disruptive behavior doing, are essential for antibody-mediated immunity. Anti-
disorders under nonstressful and stressful conditions. They bodies are needed to control extracellular pathogens which,
also assessed whether the pattern of hormonal responses to unlike intracellular parasites, are exposed to antibodies in
stress would correspond with the child’s feelings of control blood and other fluids.
and negative emotionality. In this study, they assessed cor- Glucocorticoids have been shown to regulate the expres-
tisol levels, heart rate, skin conductance levels, and subjec- sion of Th1 and Th2 (Chrousos & Elenkov, 2000; Elenkov
tive feelings of control and negative emotionality in 26 et al., 2000; Elenkov, Papanicolaou, Wilder, & Chrousos,
children with disruptive behavior disorder and 26 control 1996; Milburn, Poulter, Dilmec, Cochrane, & Kemeny,
children. The results showed that in the baseline, nonstress- 1997). High levels of glucocorticoids have been shown to
ful condition, heart rate and skin conductance levels were suppress Th1 and favor the expression of a Th2 response (a
lower in children with CD, although cortisol levels were Th2 shift), whereas decreased concentrations of cortisol
606 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

produce a shift toward Th1 function and suppress Th2 (a may be due to differences in psychological characteristics
Th1 shift; Chrousos & Elenkov, 2000; Elenkov et al., of the populations (Conduct Disorders versus normal pop-
2000). This is an interesting finding because Th2 shifts are ulations) or to significant developmental differences in the
associated with susceptibility to infections from most pattern of allostatic load across the life span (younger ver-
types of intracellular pathogens and vulnerability to cancer sus older adults).
(Rabin, 1999; Shurin, Lu, Kalinski, Stewart-Akers, &
Validation of Allostatic Load in Children
Lotze, 1999; Sprietsma, 1999). In contrast, and although a
Th1 shift has been shown to confer some protection from A very interesting study published in 2003 by G. W. Evans
these problems, it has been associated with increased sus- gives us very valuable data about normal childhood and al-
ceptibility to “stress-related” disorders such as fibromyal- lostatic load. Actually, this is the only study published to
gia and chronic fatigue syndrome (Clauw & Chrousos, date that specifically assessed the various components of
1997; Crofford, Jacobson, & Young, 1999; Griep et al., allostatic load in a population of children. In this study,
1998; Lentjes, Griep, Boersma, Romijn, & de Kloet, 1997; 339 low-income children with a mean age of 9 were re-
Scott, Medbak, & Dinan, 1998), as well as autoimmune (al- cruited from public schools in New York State. Evans eval-
Wabel, al-Janadi, & Raziuddin, 1993; Balomenos, Rumold, uated the cumulative environmental risk factors using the
& Theofilopoulos, 1998; Gutierrez, Garcia, Rodriguez, same method previously described for physical environ-
Rivero, & Jacobelli, 1998), and inflammatory (Chrousos, mental risk (crowding, noise, housing quality; see G. W.
1995; Harbuz, Jessop, & Lightman, 1997) disease. Evans & Marcynyszyn, 2004). Moreover, psychological
Given that low cortisol levels have been correlated with risk factors (child separation, turmoil, violence) were also
a shift toward Th1 (predominance of Th1 with suppression assessed, as well as aspects of the home environment and
of Th2), Pajer and collaborators (Pajer, Rabin, & Gardner, personal characteristics (poverty, single parenthood, ma-
2002) recently conducted a study in young girls with anti- ternal high school dropout). As well, two behavioral proto-
social behavior to assess whether the low cortisol profile cols were included to examine self-regulatory behavior and
generally observed in children with Conduct Disorder is learned helplessness. The child’s ability to delay gratifica-
associated with a shift toward Th1. In this study, the au- tion was used as an index of self-regulatory behavior, and
thors used plasma levels of IgG3 and IgG4 as markers for learned helplessness was evaluated with a standard behav-
Th1 and Th2 activity and assessed the IgG 3⬊4 ratios in 42 ioral protocol. Finally, measures of allostatic load included
teenage girls with CD or controls. Results showed that the resting blood pressure (diastolic and systolic), overnight
mean IgG 3⬊4 ratio was higher in the girls with CD and urinary neuroendocrine measures (cortisol, epinephrine,
that cortisol levels were significantly and negatively corre- and norepinephrine), an index of fat deposition ( body mass
lated with IgG 3⬊4 ratio. These new findings indicate that index), and a total allostatic load index (0 to 6) reflecting
immunologic abnormalities are present in relation to low the number of these six singular physiological indicators on
cortisol levels in adolescents with CD. which each child scored in the top quartile of risk. The re-
The various studies that have been performed in rela- sults of this study showed that all three primary stress
tion to hormonal and immune dysfunctions in Conduct mediators (cortisol, epinephrine, norepinephrine) were ele-
Disorders tend to show that lower levels of the primary vated by cumulative risk exposure and that body mass
stress mediators cortisol and catecholoamines (through index was significantly and positively related to cumulative
cardiovascular indices) are associated with Conduct Disor- risk exposure. More important, the author reported that the
ders and that these lower levels of activity are associated total allostatic load index was significantly related to cu-
with higher levels of DHEAS and immune changes. It is in- mulative environmental risk. Interestingly, it was found
teresting to note that the pattern of changes in the media- that children’s own perceptions of self-worth were unre-
tors of allostatic load is different from the pattern that has lated to any allostatic load indicators but were positively
been observed in older adults. Indeed, in older popula- correlated with task persistence on the learned helpless-
tions, increased levels of the primary stress mediators cor- ness puzzle. Besides being the first study specifically as-
tisol and catecholamines and lower levels of DHEAS have sessing allostatic load in normally developing children, this
been reported to predict functional decline later in life study is very important because it shows that in low-income
(Seeman, McEwen et al., 2001; Seeman et al., 1997). It is children without Conduct Disorders (although presence or
therefore possible that the differences in allostatic stress absence of Conduct Disorder was not specifically assessed
mediators reported to occur in children and older adults in this study), higher allostatic load scores on primary
Early Adversity and the Development of Allostatic Load 607

stress mediators and secondary outcomes are observed. overall impact of genes on allostatic load appears prema-
This is a very interesting finding in line with previous data ture and questionable for several reasons. First, no empiri-
summarized in children with Conduct Disorders, suggest- cal evidence allows for the assumption that individuals are
ing that when behavioral problems and/or symptoms be- similarly characterized across primary mediators: Are in-
come apparent in children, most markers of allostatic load dividual differences in primary mediators correlated? Sec-
are decreased. In his study, Evans tested the presence of a ond, primary mediators may have distinct trajectories
curvilinear function between cumulative environmental leading to diseases: Does a dysfunction of the HPA axis in-
risk and allostatic load score, and the quadratic function duce a similar vulnerability for anxiety-related problems
proved to be significant. This result strongly suggests that a compared to an altered catecholamine system? Third, pri-
mechanism of early adaptation to allostatic load may exist, mary mediators may show different etiological patterns:
whereby the organism tries to adapt to environmental de- Are primary mediators regulated by common or different
mands. As we have argued in previous sections of this genes/environments? Are primary mediators regulated by
chapter, this mechanism of adaptation may be closely re- the same genes/environments across the life span? Current
lated to the cognitive interpretation given to adverse events data show that genetic influences on some phenotypes
in order to adapt to the various challenges of life. might be enhanced during development, whereas the ge-
However, another possibility has to be raised with regard netic influence on other phenotypes might be “ turned on”
to the different results obtained on allostatic load in various or “ turned off ” later in life (Plomin, DeFries, McClearn,
populations. Indeed, it is quite possible that these different & McGuffin, 2001). Finally, considering that allostasis and
patterns of allostatic load are due to genetic influences act- allostatic load are probably multifactorial (e.g., influenced
ing on the stress mediators, leading to increased risk for the by several genes and environments), as are most complex
development of CD during childhood. phenotypes, the remaining question in estimating genetic
McEwen and Stellar (1993) have highlighted the idea and environmental influences on individual differences in
that, early in infancy, genetic predispositions and environ- allostatic load should be considered cautiously. Accord-
mental factors contribute to laying down the individual dif- ingly, the genetic influences on allostatic load could be
ferences in subjective perceptions attributed to a threat more efficiently understood through studying their impact
(relevant or not) and then physiologically responding to it. on more elementary neurobiological traits, such as primary
As a result of cumulative threats (or less intense experi- mediators (de Geus, 2002). That is, primary mediators may
ences) over time, initial differences in the response to be referred as endophenotypes of allostatic load, which al-
stressful events could be altered (either minimized or en- lows a more valid examination of the respective roles of
hanced), resulting in vulnerability to diseases (Repetti, etiological factors (environments and genes) to each pri-
Taylor, & Seeman, 2002; Rutter, 1994). To date, re- mary mediator (HPA axis, catecholamine, and DHEA) and
searchers in developmental psychopathology have devoted consequently to the complex construct of allostatic load.
great effort to studying the associations and mechanisms
linking early proximal (e.g., parental behaviors, parent-
Genetic Inf luences on the Hypothalamic-
child relationships) and distal (e.g., poverty, dangerousness
Pituitary-Adrenal Axis: Results from Twin Studies
of neighborhood) environmental characteristics and the in-
dividual differences of presenting pathology. Results ob- The HPA axis is one of the most studied primary media-
tained from animal models (Meaney et al., 1991) and tors. Behavioral genetic analyses offer a powerful tool to
studies conducted with humans (G. W. Evans, 2003; Felitti investigate the etiology of individual variations for a trait
et al., 1998; Gunnar et al., 2001; Hertsgaard, Gunnar, Er- in a population (D. M. Evans, Gillespie, & Martin, 2002).
ickson, & Nachmias, 1995) show promising features in our In behavioral genetic modeling, genetic and environmental
understanding of the trajectories leading to allostatic load. sources of variance of a phenotype (or endophenotype) are
Less is known about the potent influences that genetic fac- disentangled by using measures collected from participants
tors may have on allostatic load. who differ in their degree of genetic relatedness (Plomin
Considering that allostatic load is a complex syndrome et al., 2001). In twin studies, genetic models are based on
involving several physiological mediators, regulatory sys- monozygotic (MZ; identical twins, sharing 100% of their
tems, and stress-related structures (Repetti et al., 2002; genes) and dizygotic (DZ; fraternal twins, sharing approxi-
Seeman, McEwen et al., 2001; Seeman, Singer, Ryff, Dien- mately 50% of their genes) twin intraclass correlation com-
berg Love, & Levy-Storms, 2002), the estimation of the parisons. Typically, four main sources of variance can be
608 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

assessed and generally symbolized by the following capital Sluyter, and Boomsma (2003) recently reported significant
letters (parameters): [A] represents the additive genetic ef- heritability estimates on cortisol levels sampled at several
fect (the effect of an allele is added to the effect of other times on two consecutive days in 12-year-old twin pairs (n
alleles); [D] the nonadditive genetic effect (resulting from = 180). Results showed higher cortisol heritability esti-
interaction between alleles at the same locus, dominance, mates for samples collected 45 minutes after awakening ( h2
or at different loci, epistasis); [C] the common environment = .60), moderate estimates around noon ( h2 = .30), and null
effect, linked to the experience of similar environments estimates in the evening. Other results also suggest moder-
within twin pairs; and [E] the unique environment effect, ate genetic influences for nonreactive cortisol levels (Inglis
which also includes the measurement errors (Posthuma et al., 1999; Young, Aggen, Prescott, & Kendler, 2000). In
et al., 2000). In short, twin design studies allows us to esti- spite of these results, other studies report null heritability
mate the magnitude of the genetic and environmental ef- estimates for basal cortisol levels (Froehlich, Zink, Li, &
fects on a phenotype, and the mode of transmission (i.e., Christian, 2000; Meikle et al., 1988; Pritchard et al., 1998).
additive or nonadditive) that best reflects genetic covaria- Furthermore, some empirical results showed that the day-
tion between participants (for extended description of ge- time cortisol profile is moderately influenced by shared en-
netic modeling in twin design studies, see D. M. Evans vironments (Wüst et al., 2000), although this finding
et al., 2002; Neale & Cardon, 1992; Posthuma et al., 2000). appears inconsistent (Linkowski et al., 1993).
We highlight some empirical results of heritability re- Heritability estimates of reactive cortisol levels (in re-
ported from twin studies about individual differences in sponse to stress) lead to divergent results, although
HPA axis (re)activity, underlining the main limitations most of them suggest no or minor genetic effects in corti-
and interpretations from a heuristic and methodological sol responses to various stressful events or tasks (Nurn-
standpoint, and identifying future areas that will need to be berger et al., 1982; Pritchard et al., 1998). For example,
investigated to initiate a comprehensive conceptual frame- Kirschbaum et al. (1992) found no significant intraclass
work of modulatory influences of genes to allostatic load correlation differences between MZ and DZ twin pairs’
and psychopathology. cortisol levels in response to physical and psychological
Large individual variations are noted in HPA axis stress paradigms. In contrast, they obtained significant
(re)activity (Wüst et al., 2000). Genetic factors are thought intraclass correlation differences during the administra-
to play an important role in the individual differences in tion of corticotropin-releasing factor (CRF; stimulates the
HPA axis (re)activity. Surprisingly few studies have at- HPA axis), suggesting that HPA axis responses to CRF
tempted to estimate the heritability of cortisol levels, al- may be influenced by genes via negative feedback retroac-
though twin designs offer a great opportunity to assess tion loops. In these studies, no significant estimate of
genetic and environmental influences. Concerning nonre- common environmental factors was reported.
active cortisol levels, reported heritability estimates vary Disparities noted for heritability estimates may be ac-
considerably from one study to another, ranging from 0 to counted for by various methodological procedures, such as
74% (for a review, see Bartels, Van den Berg, Sluyter, collection methods (plasma, salivary, and urine samples),
Boomsma, & de Geus, 2003). Wüst and his colleagues have time of collection (at waking, before bedtime, before or
collected saliva samples after awakening on two consecu- after a stressful activity), and small sample size (Bartels,
tive days from 52 MZ and 52 DZ twin pairs ages 8 to 65 Van den Berg et al., 2003). Time of sampling and the nature
years old. They observed moderate genetic effects on of sampling (reactive or not) are particularly important as
saliva cortisol levels for the main increase in awakening we are still unsure whether different genes may influence
cortisol response ( h2 = .40) and for the area under the cortisol levels at different times of the day and what may be
curve ( h2 = .48). This finding is consistent with that of the common or different etiological factors related to non-
Kirschbaum and collaborators (Kirschbaum, Wüst, Faig, & reactive and reactive cortisol levels. Recent results suggest
Hellhammer, 1992), who reported a significant influence of that estimates of genetic and environmental variance com-
genetic factors on the three baseline measures of salivary ponents vary sufficiently across the day to induce distinct
cortisol levels collected before stimulation procedures etiological patterns of cortisol secretion at different times
(CRH test, ergometry, and public speech). Meikle, String- of the day (Bartels, de Geus et al., 2003). Why there are
ham, Woodward, and Bishop (1988) obtained similar heri- differences in genetic and environmental estimates in cor-
tability estimates with plasma cortisol levels ( h2 = .45 for tisol levels sampled at distinct times of the day is still
total cortisol and h2 = .51 for unbound cortisol) in 20 MZ unknown. Small sample size is another issue that could par-
and 20 DZ twin male pairs. Bartels, de Geus, Kirschbaum, tially explain discrepancies between reported heritability
Early Adversity and the Development of Allostatic Load 609

estimates. Most of these studies do not allow sufficient sta- studies’ samples. Bear in mind that environmental and ge-
tistical power to distinguish the variance related to genes netic estimates can be interpreted only in the population
from the variance associated with common environments from whom data have been collected (Plomin et al., 2001).
(Bartels, Van den Berg et al., 2003). As a result, genetic, No generalization of the results can be drawn to other pop-
common, and unique environment variance components are ulations. The majority of the heritability estimates re-
estimated, more often than not, through MZ and DZ intra- ported in twin studies are issued from normative samples
class correlations (except Bartels, de Geus et al., 2003; of twins mostly not confronted with intense and chronic
Bartels, Van den Berg et al., 2003). The main limitation of stressful environments. Accordingly, the reported heri-
estimating heritability through rough comparisons of intra- tability estimates should not be extended or compared to
class correlation is that it does not take into account the clinical samples, which are particularly at risk in light of
dispersion indices related to the evaluated phenotype. highly adverse environments, mainly because it is still un-
Moreover, this statistical procedure does not allow us to es- known if there are relevant differences in genetic and envi-
timate confidence intervals and does not provide any statis- ronmental estimates that result from normative samples in
tical parameters that specify how well the chosen model comparison to clinical samples.
(rather than other tested models) best describes the ob- Another interpretation of the nonsignificant shared
served data (Posthuma et al., 2000). environmental factors reported by twin studies refers to dif-
To overcome these limitations, Bartels and her col- ferent processes by which environmental factors may influ-
leagues (Bartels, Van den Berg et al., 2003) have performed ence the HPA axis (re)activity at different periods of
a simultaneous analysis by using structural equation mod- development. Infancy has long been conceived as a sensitive
eling to fit data collected in five distinct studies selected period of development mostly because several physiological
on the basis of similar methodological characteristics systems have not completed their maturational processes
(Froehlich et al., 2000; Inglis et al., 1999; Linkowski et al., and thus show considerable plasticity to environmental con-
1993; Meikle et al., 1988; Wüst et al., 2000). A heritability ditions (Andersen, 2003; De Kloet et al., 1998). Prenatal
estimate of 62% was obtained for nonreactive cortisol lev- and early environments have been suggested to have impor-
els, suggesting that over half of the individual differences tant organizational and stable effects on primary mediators
observed in basal cortisol levels can be attributed to addi- and, to a greater extent, on several regulatory systems, in-
tive genetic factors. The most parsimonious model includes cluding the stress-related system (e.g., hippocampus,
no parameter for common environment. The remaining amygdala, hypothalamus; Repetti et al., 2002; Weinstock,
variance (38%) was attributed to uniquely experienced en- 1997). Increased sensitivity to environmental conditions
vironment (i.e., environmental factors affecting the chil- may allow the organism to achieve short-term or long-term
dren within the twin pair differently). This result points to adaptations to this environment (Huether, 1998; Teicher
a moderate genetic component of basal cortisol levels et al., 2003). However, the cost of stable modifications in
across a large age span (i.e., 8 to 67 years old). stress-related systems, as induced by environmental factors
experienced during the sensitive period, may not always be
Theoretical Implications and Misleading optimal, sometimes placing the organism in a long-standing
Interpretations of Twin Studies’ Results allostatic load (McEwen, 2003).
No inf luence of the twins’ shared environments on the HPA Although the mechanisms associated with the perma-
axis? In light of the results emerging from twin studies, one nent effects of early environments on individual differ-
might be tempted to conclude that common environmental ences in HPA axis (re)activity have not been fully
factors do not exert a significant influence on individual understood, the role of glucocorticoid receptors is high-
differences in nonreactive cortisol secretion. These find- lighted (Blackhurst et al., 2002; Takahashi, 1998; Welberg
ings are surprising given the fact that other studies have re- & Seckl, 2001). In rodents, postnatal handling during the
ported that adverse environments, including poverty, low 1st week of life has been shown to decrease stress reactiv-
parental education attainment, placement in orphanage, ity later in life, perhaps through alterations in CRF gene
and parental negative behaviors, have a detrimental effect expression in the paraventricular nucleus of the hypothala-
on cortisol levels and circadian rhythms (Flinn & England, mus and the amygdala, resulting in increased glucocorti-
1997; Gunnar et al., 2001; Lupien et al., 2000; Taylor, coid negative feedback via the glucocorticoid receptors
Repetti, & Seeman, 1997). Can we reconcile these diver- (Meaney, 2001; Plotsky & Meaney, 1993; Vallee et al.,
gent conclusions? One interpretation may reside in distin- 1997). In contrast, maternal separation occurring early in
guishing the characteristics of those studies from the twin life induces increased HPA axis responses to stress that are
610 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

sustained in adulthood (Plotsky & Meaney, 1993). Alter- riod in infancy. After this period, individual differences in
ations in CRF gene expression may contribute to this asso- HPA axis (re)activity from both inherited and early envi-
ciation. The effects in HPA axis regulation through ronmentally settled genetic factors are suggested to inter-
manipulations of the pups’ early proximal environments act with incoming environmental factors to determine
have been closely related to the overall modifications in the larger observed individual differences in HPA axis
time and/or quality of maternal care of the offspring (re)activity (Anisman, Zaharia, Meaney, & Merali, 1998;
(Champagne, Francis, Mar, & Meaney, 2003). Further- McEwen, 2000a; Repetti et al., 2002). Interaction between
more, mothers’ individual differences in maternal care genes and the environment refers to the idea that genetic
have been reported to have a nongenomic effect on HPA factors influence the sensitivity of a given phenotype to
axis regulatory functions of their offspring, rather than in- distinct environmental settings (Rutter & Silberg, 2002).
herited common genes related to the phenotype character- For example, a child who inherits a phenotype linked to
izing reactivity to stress (Francis, Champagne, Liu, & high reactive responses to stress may be more vulnerable
Meaney, 1999; Francis, Diorio, Liu, & Meaney, 1999). In when confronted with more adverse stressful environments
other words, pups’ individual differences in (re)activity (e.g., environments exacerbate his or her genotype) relative
are suggested to be genetically encrypted in their geno- to environments that do not present any significant stress
type, not through inherited characteristics but through epi- factors. Bronfenbrenner and Ceci (1994) have gone beyond
genetic programming induced by maternal care (Weaver this assertion to specify that when synergistic effects re-
et al., 2004). sulting from genetic-environment interactions are weak,
Can the results indicating an important influence of genetic potentials related to the phenotype (e.g., genotype)
early environments to later HPA axis (re)activity be recon- remain relatively unrealized. However, the potential should
ciled with those from twin studies indicating nonsignifi- be progressively more actualized when gene-environment
cant contributions of shared environmental factors? Note interactions become more stringent, specifically referring
that the estimations of shared environmental factors’ influ- to more adverse stressful environments in association with
ence in twin studies are exclusively conducted from late in HPA axis (re)activity. No twin studies have tested models
childhood to old age, thus, after the sensitive period high- including a parameter for the gene-environment interac-
lighted in the studies that show considerable organizational tions. In the context of significant genetic-environment in-
effects of early environment to HPA axis (re)activity. This teractions, the variance associated with the interaction
could explain, at least in part, some inconsistencies. Fur- factor is relegated to the genetic component, resulting in
thermore, bear in mind that behavioral genetic modeling spurious inflated estimations of the genetic parameters and
estimating the sources of variance related to genetic and misleading interpretations about shared environment con-
environmental factors in individual differences in HPA axis tributions. Further studies should address the conceptual
(re)activity are conducted without any specific considera- and prospective processes related to individual differences
tion for the organizational effects of environments experi- in HPA axis (re)activity.
enced during the sensitive period. To what extent those
environments increase or decrease similarities within MZ Unique Environments. According to the reported
and DZ twin pairs is therefore unknown. Taken together, studies, a significant proportion of the total individual
these considerations underline the importance of adopting variance in the HPA axis (re)activity is consistently attrib-
a prospective view of genetic and environmental influences uted to the unique environment parameters (Wüst et al.,
in individual differences on HPA axis (re)activity. A closer 2000). Unique environment components include, in addi-
examination of etiological sources of variance in individual tion to all measurement errors (e.g., sampling procedures
differences in HPA axis (re)activity in infancy is then and collecting time), environmental factors not shared
strongly needed because other mechanisms may be associ- within twin pairs. Nonshared environmental factors in-
ated with individual differences in HPA axis throughout volved in the unique environment’s estimate are theoreti-
development. cally unlimited, varying from different classes at school
and distinct significant friends to more complex factors
Gene-Environment Interactions. Early environ- that constitute the cognitive processing of information.
ments have been shown to have organizational and long- Confronted by similar threatening contexts, individuals
standing influences in shaping individual differences in may show different physiological responses according to
HPA axis (re)activity, particularly during the sensitive pe- the unique cognitive schemas activated and to the per-
Future Directions 611

ceived coping response availability and efficiency. Those (Barker et al., 1993; Phillips, 1998). It is interesting to note
nonshared environments contribute to increasing the non- that the physiological disorders observed in low birth-
shared source of variance estimated. However, these non- weight babies have all been associated with secondary
shared environmental factors may represent promising outcomes of allostatic load in adult life (see earlier discus-
areas of interventions (e.g., cognitive therapy). sion). Such an association between IUGR and the appear-
ance of diseases in later life has led to the fetal origin
hypothesis (Barker et al., 1993), which suggests that ad-
FUTURE DIRECTIONS verse environmental factors acting in utero program the de-
velopment of fetal tissues, producing later dysfunctions
Based on our review of the model of allostatic load and our and diseases.
description of the potential effects of allostatic load on The effect sizes of maternal stress on birthweight in
child development as a function of early adversity, we be- well-controlled prospective studies with large sample sizes
lieve that there are two major issues that should be investi- (more than 1,000 women) have typically ranged between
gated in the next decade. The first relates to the importance 1.5-fold and 2-fold increase (Hedegaard et al., 1993; Hede-
of taking into consideration the hormonal milieu of the gaard, Henriksen, Sabroe, & Secher, 1996; Peacock, Bland,
mother ( both pre- and postnatally) when studying stress re- & Anderson, 1995). Most of these studies have shown that
activity and allostatic load in children. The second relates within the range of stressors that are related to low birth-
to the importance of considering how early adversities can weight, the time of exposure to the stressor is the important
impact the developing brain and lead to increased reactiv- variable. Chronic exposure to stress in the pregnant
ity to stress and/or trauma in adulthood. mother, more than exposure to acute stress per se, is the
most important variable related to low birthweight in the
child (Hedegaard et al., 1993; McLean et al., 1995; Paarl-
The Hormonal Milieu of the Mother in the
berg et al., 1995; Rini et al., 1999; Wadhwa et al., 1993). A
Prenatal and Postnatal Periods
human study performed by Wadhwa and collaborators
Pregnancy is associated with major changes in hormone found that, independent of biomedical risk, each unit in-
levels, and the post-partum period that follows birth is also crease of prenatal life event stress (from a possible sample
associated with drastic modifications of hormone levels. range of 14.7 units) was associated with a 55.03 g decrease
Recent studies performed in both animals and humans sug- in infant birthweight and a significant increase in the likeli-
gest that the hormonal milieu of the mother in the prenatal hood of low birthweight (odds ratio = 1.32).
and postnatal period might have significant impact on the Programming is related to a specific time window dur-
child’s development. ing development and persists during the whole life span
(Seckl, Cleasby, & Nyirenda, 2000). One reason the pro-
Prenatal Period gramming effects of prenatal environmental stress are per-
A growing body of empirical evidence, based on method- manent is assumed to be due to enduring effects on the HPA
ologically rigorous studies of pregnant women of different axis (Ader, 1969; De Kloet et al., 1998; Meaney, 2001;
ethnic, socioeconomic, and cultural backgrounds, supports Meaney, Aitken, Viau, Sharma, & Sarrieau, 1989; Meaney
the premise that mothers experiencing high levels of psy- et al., 1996; Menard, Champagne, & Meaney, 2004; Plotsky
chological or social stress during pregnancy are at signifi- & Meaney, 1993; Weaver et al., 2004; Weinstock, 1997)
cantly increased risk for preterm birth or low birthweight and the resulting high secretion of glucocorticoids. Re-
(Hedegaard, Henriksen, Sabroe, & Secher, 1993; McLean cently, it has been shown that these changes in program-
et al., 1995; Paarlberg, Vingerhoets, Passchier, Dekker, & ming are linked to alterations in glucocorticoid receptors in
Van Geijn, 1995; Rini, Dunkel-Schetter, Wadhwa, & Sand- the limbic system (Lesage, Blondeau, Grino, Breant, &
man, 1999; Wadhwa, Sandman, Porto, Dunkel-Schetter, & Dupouy, 2001; Levitt, Lindsay, Holmes, & Seckl, 1996;
Garite, 1993). Recent epidemiological studies in Europe, Lingas, Dean, & Matthews, 1999). Because the hippocam-
North America, and the developing world suggest that ba- pus contains high levels of glucocorticoid receptors and is
bies born at term with low weight (intrauterine growth re- an important regulator of glucocorticoid negative feedback
tardation; IUGR) will develop with high prevalence several (De Kloet et al., 1998; Jacobson & Sapolsky, 1991), it has
pathologies, including insulin resistance, Type 2 diabetes, been assumed that changes in receptor expression will po-
hypertension, and ischemic heart disease, during adult life tentially alter negative feedback thresholds within the HPA
612 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

axis, leading to chronically high levels of glucocorticoids in the establishment of maternal behavior (animal’s nest
prenatally stressed individuals, which could in turn impact building, retrieval, licking and grooming; reviewed by
cognitive development in the child. Numan, 1994), metabolic resetting, and neuroendocrine
Indeed, rats exposed in utero to high levels of glucocor- changes. During human pregnancy and the transition to
ticoids have been shown to present significant memory lactation, major hormonal changes occur within a short pe-
impairments when compared to rats not exposed to stress riod of time. Maternal levels of estrogens and progesterone,
in utero (Lemaire, Koehl, Le Moal, & Abrous, 2000; Szu- which increase gradually during pregnancy (about 10- to
ran, Pliska, Pokorny, & Welzl, 2000; Welberg & Seckl, 20-fold for progesterone and 100-fold for estradiol concen-
2001). In humans, studies reveal an association between trations), suddenly drop at delivery and return to pregravid
prenatal glucocorticoid overexposure and impaired cogni- levels within a few days. Just as in any other mammalian
tive development (for a review, see Buitelaar, Huizink, species, human maternal behavior and changes in mood,
Mulder, de Medina, & Visser, 2003) and between stress emotion, and cognition are then initiated in the preparation
during pregnancy and general cognitive development and for motherhood (Russell et al., 2001).
language functioning in toddlers (Laplante et al., 2004).
Feeding Choice
Both prematurity and IUGR are consistently associated
with cognitive impairments (Buitelaar et al., 2003). Other It is interesting to note that earlier studies conducted in ro-
data suggest that cognitive outcomes are more seriously dents have demonstrated that lactation is associated with a
compromised by growth restriction than by prematurity period of hyporesponsiveness to various stressors in moth-
(Lagercrantz, 1997). Earlier studies, using more global ers (Carter & Lightman, 1987; Higuchi, Honda, Takano, &
measures of cognitive development, such as IQ tests, re- Negoro, 1988; I. D. Neumann et al., 1998; Toufexis et al.,
ported significant impairments among IUGR children 1998). More important, it has been shown that this period
(Breslau, Chilcoat, DelDotto, Andreski, & Brown, 1996; of stress hyporesponsiveness in mothers is associated with
Hutton, Pharoah, Cooke, & Stevenson, 1997; Landry, the same stress hyporesponsiveness period in pups (Dent,
Smith, Miller-Loncar, & Swank, 1997; Martyn, Gale, Smith, & Levine, 2000; Levine, 1994; Schapiro, Geller, &
Sayer, & Fall, 1996; Seidman et al., 1992). As adults, Eiduson, 1962). The main characteristics of this period in
IUGR babies are less likely to hold managerial /profes- pups are very low basal glucocorticoid levels and an inabil-
sional employment and earn less income (Strauss, 2000), ity of many stressors to elicit a glucocorticoid response
suggesting that growth-related impairments in cognitive (Levine, 1994).
development are functionally relevant. The presence of a stress hyporesponsiveness period in
Altogether, these findings provide a strong set of data the mother is related to lactation (Hard & Hansen, 1985;
suggesting that exposure to stress in pregnancy might have Hary, Dupouy, & Chatelain, 1981; Lightman & Young,
a profound influence on birthweight and postnatal cogni- 1989; I. D. Neumann, Toschi, Ohl, Torner, & Kromer, 2001;
tive development, and consequently, that one could use an Shanks et al., 1999; Stern, Goldman, & Levine, 1973;
individual’s birthweight /gestational age as a good proxy Walker, Lightman, Steele, & Dallman, 1992; Walker, Trot-
for exposure to prenatal early adversity. Future studies as- tier, Rochford, & Lavallee, 1995; Windle, Brady, et al.,
sessing the effects of maternal stress during pregnancy and 1997; Windle, Wood, et al., 1997; Witek-Janusek, 1988)
reactivity to stress and cognitive function in the children and to the role of central oxytocin and prolactin release in
should provide very valuable data on the effects of prenatal discrete regions of the hypothalamus throughout lactation
exposure to stress on allostatic load later in life. (for a review, see Torner & Neumann, 2002; Torner, Toschi,
Nava, Clapp, & Neumann, 2002). Oxytocin and prolactin,
Postnatal Period
respectively involved in milk ejection and production, not
Giving birth and caring for a newborn is a highly emotional only have known anxiolytic effects in both male and female
and stressful experience for a new mother. Across all virgin rats, but also play an important role in the onset of
species, physiological and behavioral changes prepare the maternal behavior (Bridges, 1984; Bridges, Numan, Ron-
mother for the arrival of her offspring. In the past few sheim, Mann, & Lupini, 1990; Carter & Lightman, 1987;
decades, animal studies have documented considerable Higuchi et al., 1988; I. D. Neumann, Russell, & Landgraf,
plasticity in the maternal brain during pregnancy and lac- 1993; I. D. Neumann et al., 2001; Torner et al., 2002).
tation (for a review, see Russell, Douglas, & Ingram, Humans differ from animals in their choice to breast-
2001). These changes, which span late gestation through- feed or not. In contrast to bottle-feeding, breast-feeding
out lactation, ensure optimal infant development through will initiate the hormonal response of oxytocin and pro-
Future Directions 613

lactin, which have been shown to be involved in the stress fant feeding mode and stress reactivity in both the mother
hyporesponsive period. Consequently, women who breast- and her child.
feed may present a hyporesponsive response to stress when
Parity
compared to women who bottle-feed. Such a result has
been obtained in human mothers. For example, Wiesenfeld Studies investigating stress responses have concentrated
and collaborators (Wiesenfeld, Malatesta, Whitman, mostly on primiparous mothers, as the most dramatic
Granrose, & Uili, 1985) first showed that breast-feeding changes in lifestyle occur after the first childbirth. Being a
women exposed to infant signals display blunted autonomic mother for the first time can at times be an emotionally in-
skin conductance responses, compared to bottle-feeding tense and stressful experience in a woman’s life. Even
mothers. Along with these findings, about a decade later, it though fatigue and sleep disruption in maternal role “ac-
was shown that, at 8 to 18 weeks postpartum, breast-feed- quisition” in primiparous mothers is comparable to those
ing mothers have blunted HPA axis responses to a stressful experiences associated with the role of “expansion” in
treadmill exercise, compared to bottle-feeding mothers multiparous mothers (Waters & Lee, 1996), women with
(Altemus, Deuster, Galliven, Carter, & Gold, 1995). These prior childbirth experience are less anxious and depressed
findings seem to suggest that women who breast-feed have (Fleming, Ruble, Krieger, & Wong, 1997; Fleming, Steiner,
blunted physiological responses to potentially stressful & Corter, 1997), undergo shorter and less painful labor
events. This could differentially impact reactivity to stress (Mahon, Chazotte, & Cohen, 1994), and are less likely to
directly relevant to the infant and/or impact the child’s hy- experience gestational complications (Da Costa, Larouche,
poresponsivity to stress as well. Dritsa, & Brender, 2000) and delayed lactogenesis in the
Consequently, it could be proposed that by inducing days following delivery (D. C. Chen, Nommsen-Rivers,
stress hyporesponsivity to environmental stressors, breast- Dewey, & Lonnerdal, 1998), compared to primiparous
feeding could serve as a protective factor for the mother mothers. In fact, parity is inversely correlated with the
(and possibly for her child) from repeated and/or excessive amount of life change (Grace, 1993). Thus, it is not surpris-
secretion of plasma and milk glucocorticoids during the ing that multiparous mothers also display lower glucocorti-
postpartum period (Patacchioli et al., 1992; Yeh, 1984). In coid levels during the days following delivery (Grajeda &
contrast, by preventing the emergence of the naturally oc- Perez-Escamilla, 2002) and have more positive maternal
curring hyporesponse to neutral stressors, bottle-feeding attitudes and attractiveness to infant odors (Fleming,
might enhance the woman’s reactivity to stressors and thus Steiner, et al., 1997). However, currently no study has in-
lead to repeated and/or excessive secretion of glucocorti- vestigated the changes in stress responsiveness as a func-
coids. As we have summarized in this review, excessive se- tion of parity. Future studies assessing stress reactivity in
cretion of cortisol levels in humans has been associated both mothers and children as a function of parity could
with memory impairments (Lupien et al., 1997, 2005; lead to very interesting results.
Lupien & Lepage, 2001; Lupien & McEwen, 1997; Maheu Indeed, a few studies in the animal literature have inves-
et al., 2004) and emotional disturbances (Sachar et al., tigated “ habituation” of neuronal functions with respect to
1973). Interestingly, a study published in 1992 reported a parity. This habituation process might also be present in
significant negative correlation between glucocorticoid the human population. Boukydis and Burgess (1982) ob-
levels and the mood of mothers who bottle-fed their babies served higher arousal to infant cries in first-time mothers
(Bonnin, 1992). Breast-feeding is certainly not the only compared to mothers with several children and nonparents.
protective factor during this critical period, but as one that This parity-induced attenuation in responsiveness is not
is easily accessible to all mothers, it might be one that surprising considering the fact that with repetitive expo-
could be strongly encouraged in specific populations ex- sure, the novelty characteristic of a stressful or emotional
posed to high levels of environmental stress (i.e., low SES event is lost as the subject gains experience. This, in turn,
communities). These populations also choose more fre- can alter stress appraisal to the benefit of the mother, so
quently not to breast-feed. It is thus possible that some of that responsiveness to stress should be high only in situa-
the effects of early adversities that are shown in children’s tions of actual child endangerment. On the other hand,
development are due to the hormonal milieu of mothers at multiple demands placed on multiparous mothers increase
the time of birth of the child, induced by the feeding mode fatigue (Sammons, 1990), which could enhance vulnerabil-
chosen by mothers. Clearly, further studies assessing the ity to external stressors and lead to increased risk for post-
impact of infant feeding choice on the child’s behavior are partum depression (Righetti-Veltema, Conne-Perreard,
needed to elucidate this intriguing association between in- Bousquet, & Manzano, 1998). Even though parity does not
614 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

play a significant role in occupational fatigue in working tant to underline that, as summarized earlier, various ani-
women (Newman et al., 2001), increased household de- mal studies have shown differential changes in dendritic
mands, particularly linked to child care, can induce more arborization and cortical thickening of the hippocampus as
daily stressful challenges and are linked to lower morning a function of enriched, stressful, or demanding environ-
glucocorticoid levels (Adam & Gunnar, 2001). Interest- mental experiences. It is thus conceivable that exposure to
ingly, parity is also associated with elevations in the dias- early adversities (prenatally and/or postnatally) in devel-
tolic blood pressure observed during the daytime (James, oping children might impact the development of the brain
Cates, Pickering, & Laragh, 1989), suggesting that multiple structures involved in the response to stress ( hippocampus,
physiological systems, in multiple states (i.e., basal or amygdala, and frontal lobes; see earlier discussion) and
stimulated), can be modified by parity. This result suggests lead them to become more reactive to stress in adulthood.
that parity could have a significant impact on allostatic A recent study by Gilbertson and collaborators (2002)
load in mothers and/or children. goes along with this suggestion. Earlier studies assessing
the volume of the hippocampus in adult individuals who
were exposed to traumatic events and who developed Post-
Inf luences of Early Adversities on
traumatic Stress Disorder (PTSD) revealed that these
Brain Development
individuals present smaller hippocampal volumes when
Every day, parents observe the growing behavioral reper- compared to individuals exposed to the same trauma, but
toire of infants and young children, as well as the corre- who did not develop PTSD (Bremner, 2002, 2003;
sponding changes in cognitive and emotional functions. Vythilingam et al., 2002). These results led to the sugges-
These changes are thought to be related to normal brain de- tion that exposure to a traumatic event induces an atrophy
velopment, particularly to the growth of the hippocampus of the adult hippocampus due to the neurotoxic effects of
and frontal lobe regions from infancy to childhood. Results glucocorticoids on the hippocampus (the “neurotoxicity
of various studies assessing developmental changes in brain hypothesis” or “glucocorticoid-cascade hypothesis”;
structures showed that the volumes of whole brain and Jacobson & Sapolsky, 1991; Sapolsky, Krey, & McEwen,
frontal and temporal lobes increase rapidly during the first 1986). However, in 2002, Gilbertson et al. tested another
2 years after birth, followed by a more gradual expansion possible hypothesis (called the “ vulnerability hypothesis”),
restricted to white matter (Matsuzawa et al., 2001; Pfeffer- whereby predetermined smaller hippocampal volumes
baum et al., 1994). Examination of the spatial and temporal could explain increased reactivity to traumatic events in
patterns of brain growth, brain shrinkage, and cortical adults exposed to trauma, leading them to develop PTSD
thinning over time may help to explain the cognitive and when exposed to a traumatic experience. To test this hy-
behavioral changes that occur from infancy to childhood. pothesis, these authors measured hippocampal volumes in
The volume of the hippocampal formation increases Vietnam War veterans who developed PTSD (PTSD+
sharply until the age of 2 years (Utsunomiya, Takano, group) and in others who did not develop PTSD (the
Okazaki, & Mitsudome, 1999), and the prefrontal volume PTSD− group) in response to the trauma of war. By com-
increases rapidly between 8 and 14 years of age (Kanemura paring the hippocampal volumes of these two groups, they
et al., 1999). Late growth in prefrontal volumes is consis- replicated earlier findings showing that the PTSD+ group
tent with data showing that this region is known to develop had smaller hippocampal volumes then the PTSD− group
latest in terms of myelination and synaptic density (the neurotoxicity hypothesis). However, in the same study,
(Yakovlev, 1967). In summary, by the age of 2 years, the they also measured the hippocampal volumes of the ho-
hippocampal formation has stabilized, and the prefrontal mozygotic twin brother of each of the Vietnam War veter-
cortex volume presents a sharp increase in volume by the ans (PTSD+ and PTSD−), who never went to war. Here,
age of 8. The observed maturation in the frontal lobes has they showed that the homozygotic twin brothers of the
been shown to correlate with measures of cognitive func- PTSD+ group also had small hippocampal volumes when
tioning during childhood and adolescence (Reiss, Abrams, compared to the homozygotic twin brothers of the PTSD−
Singer, Ross, & Denckla, 1996; Sowell, Thompson, Tess- group. These results strongly suggest that the men who
ner, & Toga, 2001). went to war and developed PTSD entered the war zone with
Although the changes in brain structures observed dur- a smaller hippocampal volume to begin with, relative to the
ing childhood and adolescence are likely maturational in men who went to war and did not develop PTSD (the vul-
nature and may be related to pubertal and hormonal nerability hypothesis). Consequently, hippocampal volume
changes that occur during the adolescent years, it is impor- may actually be a preexisting condition that increases vul-
General Conclusion 615

nerability to PTSD upon exposure to a traumatic experi- increased vulnerability to stress in future years. However,
ence, rather than (or along with) being a consequence of if exposure to adverse events pushes the child to search
the trauma. for more appropriate environments (increased demands),
Still, the smaller hippocampal volumes in the men who this could impact positively on the developing hippocam-
developed PTSD on exposure to war could have been deter- pus, lead to larger volumes and, consequently, to a de-
mined by early exposure to stress, which could then have creased vulnerability to stress in future years. If this is
delayed the development of this structure and rendered the case, then for the first time, a structural and biological
these individuals more vulnerable to the effects of stress basis of resilience would be described. However, the pro-
and trauma later in life. Indeed, it is important to remind cess that leads a child to believe that a neglectful environ-
the reader that stress, environmental enrichment, and envi- ment has nothing to offer ( learned helplessness) or that
ronmental demands are among the most potent inducers of pushes him or her to search for a better environment
changes in neurogenesis and/or dendritic arborization in (meeting demands) is one of the most intriguing processes
the hippocampus, documented to lead to changes in hip- that the field of developmental psychopathology might
pocampal volumes. have to face in the next decade.
Based on these data, we believe that there is an urgent
need to test the influence of early adversity on the develop-
ing hippocampus (and other brain structures). Here, two
contradictory hypotheses emerge with regard to the influ- GENERAL CONCLUSION
ence that early adversity might have on the development of
the hippocampus. First, it could be postulated that children The concepts of allostasis and allostatic load are inclusive
facing adversity due to lower levels of environmental en- of what we mean by stress, but they are much broader be-
richment and/or higher levels of stress could eventually cause they include aspects of lifestyle as well as genetic in-
present a delay in the development of the hippocampus fluences and developmental effects, including early life
(either due to a decrease in neurogenesis or a stress-in- experiences and adversities. In this way, allostasis and al-
duced decrease in dendritic arborization), which could lostatic load provide a general conceptual framework that
eventually result in smaller hippocampal volumes in chil- allows us to evaluate the overall impact of the physical and
dren facing early adversity when compared to children who social environment on individuals and groups of individu-
do not. If this is the case, one could predict that smaller als. It should be emphasized that, although most of the
hippocampal volumes in children facing adversities could work done so far has focused on the role of HPA activity
render these children more vulnerable to the effects of and autonomic nervous system reactivity in these nature-
stress on both cognition and mental health. However, an- nurture interactions, the allostasis/allostatic load model
other hypothesis can also be proposed with regard to the can be generalized to other physiological systems that re-
development of the hippocampus in the face of adversity. spond to environmental stimuli. In other words, allostasis
Indeed, a wealth of animal data has now shown that hip- and allostatic load attempt to embody a general biological
pocampal volume increases in relation to environmental de- principle: that the systems that help protect the body and
mands due to the presence of stressful situations (see promote adaptation in the short term can also participate in
earlier discussion). It may thus be possible that growing up pathophysiological processes when they are overused or in-
in adversity could lead to significant changes in hippocam- efficiently managed.
pal neurogenesis and/or growth and contribute to larger The most important feature of allostatic load is that it
hippocampal volumes. If this is the case, one would have to operates gradually over long periods of time in the life
predict that the larger hippocampal volumes in children of an individual. In fact, as summarized in this chapter, in-
facing adversity could render these children less vulnerable fluences of genetic factors and early experiences, when
to the effects of stress on both cognition and mental health. coupled with the subsequent life experiences of each indi-
However, both hypotheses could coexist. Developmen- vidual, exert a lifelong effect on the physiology of an indi-
tal pathways leading to small versus large hippocampi in vidual and alter the risk for developing a variety of
children facing adversities could be determined by the pathophysiological conditions and diseases later in life as
child’s perception of what the adverse environment can well as the rate of certain aspects of the aging process.
offer. If nothing is perceived as coming out of the adverse More important, given that the primary stress mediators of
environment, stress could impact negatively on the devel- allostatic load can access the brain, they can alter the way
oping hippocampus and lead to smaller volumes and to an incoming information is processed, leading to important
616 Beyond the Stress Concept: Allostatic Load—A Developmental Biological and Cognitive Perspective

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(threatening) or nonstressful (nonthreatening). impair enhanced perception of emotionally salient events. Nature,
411, 305–309.
This multidisciplinary view of stress as a form of allo-
Anisman, H., Zaharia, M. D., Meaney, M. J., & Merali, Z. (1998). Do
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in the life of an individual what are the potential risk fac- sponses to stressors? International Journal of Developmental Neuro-
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Araneo, B., & Daynes, R. (1995). Dehydroepiandrosterone functions as
tal health. For example, personality traits such as anger, more than an antiglucocorticoid in preserving immunocompetence
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modify HPA and autonomic nervous system reactivity on Ashman, S. B., Dawson, G., Panagiotides, H., Yamada, E., & Wilkinson,
an acute and/or chronic basis (for an example, see C. W. (2002). Stress hormone levels of children of depressed mothers.
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Kirschbaum, Prussner, et al., 1995). These changes, in turn,
Azar, R., Zoccolillo, M., Paquette, D., Quiros, E., Baltzer, F., & Trem-
contribute to allostatic load when they represent a lifelong blay, R. E. (2004). Cortisol levels and conduct disorder in adolescent
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P. M. (1993). Type 2 (non-insulin-dependent) diabetes mellitus, hy-
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