International Journal of Developmental Neuroscience 78 (2019) 100–108

Contents lists available at ScienceDirect

International Journal of Developmental Neuroscience

journal homepage: www.elsevier.com/locate/ijdevneu

Review

T
Neglect, HPA axis reactivity, and development
Emily B. Reilly, Megan R. Gunnar
⁎

Institute of Child Development, University of Minnesota, Minneapolis, MN, 55455, United States

A R T I C LE I N FO A B S T R A C T

Keywords: Neglect is a common and frequently chronic form of child maltreatment that can compromise child development
Neglect and increase the risk of physical and psychological problems. In this review, we discuss one of the potential ways
HPA axis neglect becomes biologically embedded by shaping the development of a key stress responsive system: namely,
Child development the hypothalamic-pituitary-adrenal (HPA) axis. Several potential mediators and moderators of this process are
examined, including inflammation, attachment and social buffering, self-regulation, child sex and age, and
genetics.

Maltreatment (e.g., physical abuse, sexual abuse, neglect) in child- likely that many children identified because of physical neglect have
hood can compromise psychosocial and cognitive development and also experienced some degree of psychosocial neglect.
increase the risk of psychological, behavioral, and physical problems in Because neglect tends to be chronic and may co-occur with other
childhood and later in life (Bruce et al., 2013; Cicchetti, 2016; Danese forms of maltreatment – 14% of children receiving protective services
and Tan, 2014). Neglect is the most common form of child maltreat- responses in 2017 experienced more than one type of maltreatment
ment; in the US, 7 of every 1000 children experience neglect, versus 1 (U.S. Department of Health and Human Services, 2019)— it can be
of every 1000 for physical and sexual abuse (Child Trends, 2019) and difficult for researchers to isolate the timing- and maltreatment-specific
75% of children receiving a Child Protective Services (CPS) response effects of neglect in community samples (Gunnar et al., 2015). Re-
are neglected (U.S. Department of Health and Human Services, 2019). searchers use animal models to gain experimental control over early
When severe, neglect is one of the most damaging forms of maltreat- care conditions, thus much of the research investigating the impact of
ment (Shonkoff et al., 2012). However, there are marked individual neglect on the HPA axis has been conducted with animals (Doom and
differences in outcomes, with some children exhibiting resilience in Gunnar, 2015). While animal models are crucial for unpacking caus-
some or all domains. There are multiple routes through which neglect ality, they should not be directly applied to humans, although they can
may operate to influence neurobehavioral development. In this review, provide a roadmap of where to look to understand causal mechanisms
we discuss one potential major pathway, the activation and subsequent in human development. As such, the accumulation of evidence in both
alterations in the stress-mediating hypothalamic-pituitary-adrenal animal models and human research is the most instructive to our un-
(HPA) system. We will also explore several mediators and moderators derstanding of the influence of neglect. Notably, there are increasing
of the impact of neglect on the HPA axis and evidence that HPA activity efforts to test the translation of the observed changes to the HPA axis in
is involved in mediating the impact of neglect on physical and mental animal models of early neglect to humans (Hostinar and Gunnar, 2013;
health. McLaughlin et al., 2015; Hostinar et al., 2015; Leneman et al., 2018).
Children reared in institutions (e.g., orphanages) with low-quality
1. Models of neglect caregiving provide a human model for disentangling psychological and
physical neglect, as well as investigating the timing- and maltreatment-
CPS defines neglect as physical neglect— the failure of a caregiver specific effects of neglect when examining those children who subse-
to provide food, shelter, clothing, medical care, or supervision (Child quently move into higher quality care (i.e., via adoption or fostering).
Welfare Information Gateway, 2016). Much of the research on neglect Children in such institutions typically experience significant social de-
with community samples relies on this definition and so is primarily privation and neglect, which, at least during infancy is not typically
focused on physical neglect and is unable to separate its psychosocial accompanied by other forms of maltreatment (Rus et al., 2017). These
and physical facets (M. Dozier, personal communication, April 2019). children primarily experience psychosocial neglect, although some ex-
Although child welfare defines neglect as failure of physical care, it is perience physical neglect as well. Whether there are differences in the

⁎
Corresponding author.
E-mail address: [email protected] (M.R. Gunnar).

https://doi.org/10.1016/j.ijdevneu.2019.07.010

Available online 30 July 2019

Received 28 February 2019; Received in revised form 27 July 2019; Accepted 29 July 2019

0736-5748/ © 2019 ISDN. Published by Elsevier Ltd. All rights reserved.

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

influence of physical and psychosocial neglect on the developing HPA history theory and the biological sensitivity to context hypothesis (Del
axis remains speculative. Both physical and psychosocial neglect in Giudice et al., 2011). The latter hypothesis argues that stressors during
infancy may signal to the organism that their environment is not safe early development shape stress reactivity. According to this hypothesis,
because they are not being taken care of or responded to, thereby a moderate amount of stress, typical of our evolutionary past, results in
chronically activating the HPA axis, which can lead to its dysregulation. a somewhat buffered system. However, both very little stress and high
Beyond this, recent work conceptualizes neglect as dimensional. In levels of stress produce more highly reactive systems (Boyce and Ellis,
one framework, psychosocial neglect is theorized as two dimensions – 2005). Accordingly, the ACM argues that patterns of stress activation
cognitive and emotional – that predict different child outcomes (King early in life calibrate stress response systems to take different life his-
et al., 2019). Specifically, King et al. (2019) hypothesize that cognitive tory strategies. For example, frequent activation of the HPA axis early
input (e.g., developmentally appropriate language) will best predict in life would convey to the organism an unpredictable environment
child language development and executive function skills and emo- characterized by high mortality risk, leading to an accelerated life
tional input (e.g., expressing affect attuned to their child’s signals) will history strategy and the corresponding calibration of the stress response
better predict emotional regulation. More broadly, McLaughlin and system to adapt to a risky environment.
Sheridan (2016) conceptualize early adversity (i.e., including physical This accelerated life history strategy is theorized to include early
abuse, neglect, poverty) as consisting of two dimensions – threat and onset puberty so that offspring may be produced earlier and in greater
deprivation- of which neglect is a part. They categorize neglect as low number. There is, indeed, some evidence for earlier puberty following
threat, high deprivation. However, because many children identified as childhood experiences of threat or abuse, especially in girls (Henrichs
neglected by CPS are also maltreated in other ways, without in- et al., 2014; Sumner et al., 2018). However, recent studies of children in
dependently scoring CPS records, it is difficult to know where to place a institutional care have provided no evidence of an advance in puberty,
child on these two dimensions who has experienced neglect. The thus suggesting that neglect as the predominant stimulus is not asso-
McLaughlin and Sheridan framework classifies the experience of ne- ciated with such a shift in life history strategy (Johnson et al., 2018).
glect within the broad range of adverse experiences but does not dis- The ACM is appealing because it considers development in a way
tinguish between types of neglect; the King framework classifies types the ALM lacks. However, adopting the ACM in its entirety is challenging
of psychosocial neglect specifically but does not address the broader because, as will be shown, some of its predictions are not born out. For
taxonomy of adverse experiences. As such, these two conceptualizations example, according to the ACM high levels of adversity are predicted to
can be integrated to address the dimensions of adversity more broadly create hyper-responsiveness of the HPA axis. Only at very high levels of
and the dimensions of psychosocial neglect within McLaughlin and abuse do they predict that some individuals, those that are more callous
Sheridan’s larger framework. The influence of both of these dimen- and unemotional, will develop a hypo-responsive axis (Del Giudice
sional models of neglect on the HPA axis have yet to be determined and et al., 2011). As will be described in this review, this runs counter to
so will not be a focus of this review. There is, nonetheless, consensus much of the evidence demonstrating HPA axis hyporesponsivity fol-
that neglect is species atypical and acts as a stressor. lowing early expereinces of neglect.

2. Theoretical perspectives 3. The HPA Axis

There are two theoretical models that guide much of the research on The HPA axis is a key component of the mammalian stress system.
early life adversity, stress reactivity, and development. The first is the When we encounter stress, our bodies respond in part by releasing the
allostatic load model (McEwen, 1998). According to this model, allos- hormone cortisol (CORT) in humans, corticosterone (CORT) in rodents,
tasis is the maintenance of stability through change. That is, when to activate processes that help us respond to the threat. Here we provide
confronted with a stressor, stress-mediating systems increase their ac- a cursory overview of the HPA axis, there are many good reviews that
tivity (i.e., change) to allow the organism to sustain functioning (i.e., describe the axis and its regulation in more detail (see Neigh et al., 2009
stability) during the stressful experience. This is a highly adaptive for a review that also addresses maltreatment). CORT increases are
process. However, if activated frequently or for too long, modifications achieved through a cascade of signals that begin in the paraventricular
occur in the various stress-mediating and stress-reactive systems that nucleus (PVN) in the hypothalamus, which releases corticotropin-re-
impair their functioning. They either become hyper-reactive or, often leasing hormone (CRH) and arginine vasopressin (AVP) (Gunnar et al.,
following periods of chronic hyper-activity, hypo-reactive. Regardless, 2015). CRH and AVP then bind to cells in the anterior pituitary gland,
these changes are conceived of as reflecting the load (allostatic load) of releasing adrenocorticotropic hormone (ACTH) into circulation. ACTH
frequent responding. The allostatic load model (ALM) pertains at any then stimulates the production of CORT by binding to receptors in the
point in life. To make it a developmental model, it is combined with adrenal gland, causing CORT to be manufactured and released into the
evidence that stress-mediating systems, like the HPA axis, are being blood stream. Much of circulating CORT is immediately bound to cor-
organized early in life (Danese and McEwen, 2012). Adverse care tisol binding globulin: the bound fraction of the hormone has limited
during those sensitive periods, such as neglect, shapes these systems, biologic activity. In its unbound form, CORT, like other steroid hor-
which then respond differently from those of individuals who were not mones, is lipid soluble. It enters all cells of the body and binds to its
exposed to adverse early care. As a result, there may be a more rapid receptors, which largely reside in the cell body. Once bound, the hor-
accumulation of allostatic load and earlier presentation of physical and mone-receptor complex translocates to the nucleus of the cell and in-
psychological disorders that such load fosters. It is important to note teracts with glucocorticoid responsive elements in the promotor regions
that while the ALM posits impacts on both physiology and psycholo- of numerous genes (Doom and Gunnar, 2015). There are two types of
gical function, there is evidence that under some circumstances, re- receptors for CORT: mineralocorticoid (MR) and glucocorticoid re-
maining psychologically and behaviorally resilient to chronic adversity ceptors (GR). In the periphery, MRs only bind aldosterone, a salt-water
can come at an allostatic cost that is predominantly manifested in im- balance hormone, because an enzyme surrounding the receptor protects
paired physical health (Brody et al., 2013). This evidence indicates that it from CORT. In the brain, however, both MR and GR can bind CORT.
in studying early life adversity, we cannot focus solely on cognitive, CORT has a higher affinity for MRs which, in the brain, regulate many
behavioral, and psychological functioning. A focus on physical health is of the non-stress actions of CORT. GR have a lower affinity and thus in
also needed. the brain are only bound as CORT rises into stress levels and at the peak
The second model that has garnered attention is more explicitly of the diurnal rhythm. In a typical stress response, CORT levels sharply
developmental: the adaptive calibration model (ACM). The ACM is an increase following the onset of a stressor, reaching their peak after
evolutionary-developmental model. This model incorporates life about 20–25 minutes before slowly decreasing back to baseline levels.

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

However, because the genomic effects of CORT can take minutes to et al., 2014). In rodent models of neglect, prolonged daily separations
hours to be come to fruition, the impact of CORT on the brain and body from the dam of 3 to 6 h are used to simulate psychosocial neglect.
are experienced long after CORT has returned to baseline. Recently, fast When imposed during the first two weeks of life, these animals are
effects of CORT on some neuronal populations have been noted via hyper-reactive to stressors as adults (Sánchez et al., 2001). Similar
migration of MRs to cell membranes where, when activated by CORT, findings are obtained with the offspring of dams who spontaneously
they mediate rapid, non-genomic CORT effects (Joëls and de Kloet, engage in low levels of mothering. In both cases, these effects have been
2017). traced to epigenetic changes in the glucocorticoid receptor in the hip-
CORT also follows a diurnal pattern that contributes to our circa- pocampus (Meaney and Szyf, 2005). The first few weeks of a rodent’s
dian rhythm (Gunnar et al., 2015). CORT increases sharply upon life, however, are roughly equivalent to the third trimester for primates,
waking, peaking 30–45 minutes after wake-up (Doom and Gunnar, including humans. Neglect during postnatal development in primates,
2015). This pattern is termed the cortisol awakening response (CAR). including humans, produces a different outcome— hypocortisolimia.
Following this initial peak, CORT decreases throughout the day, Thus, in Rhesus macaque monkeys repeatedly and unpredictably se-
reaching the lowest levels 30 min after the start of sleep. parated from their mothers in a psychosocial neglect model, CORT is
There are multiple pathways that activate the HPA axis to produce lower, which has been traced to a down-regulation of the ACTH re-
CORT (Joëls and Baram, 2009). Systemic stressors activate the axis sponse to CRH challenge at the level of the pituitary (Sánchez et al.,
through brainstem pathways, while emotional and cognitive stressors 2001). These monkeys also display a flattening of the diurnal CORT
operate through limbic pathways with the amygdala and bed nucleus of rhythm after repeated maternal separation (Sánchez et al., 2005). The
the stria teriminalis (i.e., extended amygdala) playing critical activating effects of long-term maternal separation on the HPA axis has also been
roles. HPA responses are terminated via negative feedback mechanisms studied in animal models. Rhesus monkeys separated from their mo-
operating at the level of the pituitary gland, hypothalamus, and also thers for the first 7 months of life followed by 3 years of normal social
extra-hypothalamically, involving the hippocampus and regions of the life show low baseline CORT levels and delayed peak CORT in response
prefrontal cortex. The multiple pathways to activate and terminate the to a stressor (Feng et al., 2011). Finally, in a study of birth cohorts of
HPA response mean that CORT responses are stressor-specific and are Rhesus infants born at the primate facility in Davis, California, re-
also influenced by prior exposure to threat and the individual’s ex- searchers found that the animals reared in the nursery with no maternal
periences of control and coping. There are two forms of CORT dysre- care had hypo-responsive HPA axes at both the pituitary and adrenal
gulation following a stressor: a failure to respond robustly (i.e., a level (Capitanio et al., 2006).
blunted CORT response) or a hyper-response in which CORT either In the human literature, it is often difficult to separate neglect from
overshoots or reaches the same peak level but takes much longer to abuse. However, a recent study using the Fragile Family data set at-
recover. The latter indicates an impairment in CORT negative feedback. tempted to do so. This study investigated hair cortisol levels, a measure
of chronic HPA axis function over three months, in an adolescent
4. HPA Axis development sample. In those who scored higher on neglect, hair cortisol at age 15
was blunted; however, hair cortisol was elevated in those who scored
The HPA axis is critical to survival and adaptation as early as the higher on abuse (Doom et al., under review). A number of studies of
fetal period. There is accumulating evidence in support of the fetal children reared in orphanages have also observed a flatter diurnal
programming hypothesis, which posits that fetal exposure to stress rhythm and lower cortisol responses to stressors (Gunnar et al., 2015;
hormones, such as maternal cortisol and placental CRH, programs Koss et al., 2016; although for counter example see Gunnar et al.,
lifelong stress physiology (Howland et al., 2017). The reasons that lead 2001). In foster children, physical neglect was found to be correlated
mothers to be neglectful (e.g., their own stress, anxiety, financial and/ with lower morning CORT levels in at least one study (Bruce et al.,
or social problems) may also result in their experiencing heightened 2009).
stress during pregnancy, which may act as another pathway by which Chronic activation of the HPA axis may lead to a reprogramming of
children who are neglected develop HPA axis regulation. axis activity, such that the axis exhibits blunted responses to threat
In first postnatal months, the infant HPA axis is highly reactive to (Doom and Gunnar, 2015). Some have argued that this may be due in
perturbations, but by the third month, most likely because of matura- part to hypothalamic damage inflicted by high levels of glucocorticoids,
tion of fast negative feedback mechanisms, the axis is better regulated thereby limiting the ability of the hypothalamus to regulate HPA axis
(Doom and Gunnar, 2015; Gunnar et al., 2015; Hostinar and Gunnar, function (Sowder et al., 2018). However, it most likely reflects nor-
2013). At birth, the diurnal rhythm can be discerned, but is not aligned mative down-regulation of the axis following prolonged periods of
to day-night cycles; this seems to be accomplished by 6–12 weeks hyper-responsivity (Miller et al., 2007), consistent with allostatic load
postnatal (Gunnar et al., 2015). However, it is not until the child gives as described in the ALM.
up the afternoon nap that the fully adult pattern is observed (Gunnar Longitudinal studies with previously institutionalized (PI) youth
et al., 2015). As will be discussed, the axis comes under strong social following their placement into high quality caregiving has uncovered
regulation over the course of infancy, which allows CORT to be well the timing specific nature of exposure to psychosocial neglect on HPA
regulated under most everyday stressor conditions, even those that axis function; namely, the first 1.5 to 2 years appears to be a sensitive
elicit marked behavioral distress (Gunnar and Donzella, 2002). With period for programming the axis in response to institutional depriva-
puberty, basal CORT levels increase along with other steroid hormones, tion. PI children demonstrate HPA axis dysregulation in social situa-
although evidence of whether the HPA axis becomes more reactive in tions even years after being placed in a high-quality care environment
adolescence is mixed (Gunnar et al., 2015). (Hostinar and Gunnar, 2013). A study in Romania that involved
random assignment of institutionally-reared children to high quality
5. Neglect and the HPA Axis foster homes noted that in middle childhood the children had a blunted
CORT and autonomic response to a standard social stress test. However,
The developing HPA axis is believed to have its set point for reg- this was only true for those who were removed from the institution
ulation and reaction established early in life by genes and experience. later, after the median age in their study, which was two years
As described in Fig. 1, the axis may play a critical role in biologically (McLaughlin et al., 2015). A similar trend was noted for children
embedding neglect and in transducing subsequent stressor exposure adopted at 18 months or later in a study conducted with 9- and 10-year
into impacts on physical and mental health (Miller et al., 2011). Psy- old PI children (Hostinar et al., 2015). Likewise, in studying the CAR in
chological stressors activate the HPA axis via the medial and central PI children, we noted a blunted CAR only for those children adopted out
amygdala, both of which are involved in HPA axis control (Hostinar of institutions after our median age, which was 16 months (Leneman

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

Fig. 1. Interactions between neglect, HPA axis function, and mediators and moderators of this relationship across development. On the left side of the figure: neglect
in the infancy acts as a stressor, activating the HPA axis and leading to hyper-reactivity. This chronic hyper-reactivity leads to down regulation of the axis and hypo-
reactivity, which then carries forward and characterizes the child’s response to other stressors later in childhood.

et al., 2018). Unfortunately, no study to date has been powered enough likely that the immune system activity may both mediate and moderate
to examine exactly when in the latter part of the second year the sen- the influence of neglect on the HPA axis. Proinflammatory cytokines,
sitive period ends and the system no longer recalibrates when removed notably IL-1β and IL-6, are potent stimulators of CRH, thus triggering
from neglectful conditions. The fact that the HPA axis of children 1.5–2 the cascade of events that ultimately lead to elevations in CORT
years old does not appear to recalibrate once children move into a (Webster et al., 1998). CORT, in turn, prevents inflammatory responses
supportive home environment and that neglect is associated with hypo- from over-reacting (Elenkov and Chrousos, 2002) by inhibiting the
and not hyper-reactivity are both inconsistent with predictions from the release of proinflammatory cytokines (Silverman and Sternberg, 2012).
ACM model, but are not inconsistent with the ALM model. The immune system becomes less regulated following chronic CORT
increases as GR receptors on immune cells become less CORT re-
sponsive (i.e., glucocorticoid resistant), thus reducing CORT’s ability to
6. Mediators and moderators of neglect
restrain the inflammatory response. There is also emerging evidence of
a link between HPA axis and immune system function in children:
When stress is activated through psychological pathways, numerous
factors influence the stress response, from prior experiences that affect higher afternoon cortisol levels are associated with lower antibody le-
vels (Watamura et al., 2010).
perceptions of threat and knowledge of effective coping strategies to
personality factors that affect, for example, attention bias to threat. In While the primary purpose of the immune system is to defend the
body against infection and tissue injury, the immune system also re-
animals and adults, researchers can bypass these psychological med-
sponds to other stressors, including psychosocial stressors.
iators and moderators by pharmacologically challenging the HPA axis
Inflammation is the aspect of the immune system studied most with
and immune system. However, this is not done in healthy children
relation to neglect. Similar to infections or tissue damage, psychosocial
merely for research purposes on ethical grounds. Therefore, all of our
stressors can stimulate the production of pro-inflammatory cytokines
information about neglect and its influences on stress includes the po-
that cause an inflammatory response (Elwenspoek et al., 2017;
tential confounding by current and ongoing psychological processes. Of
Kuhlman et al., 2017). Inflammation is typically measured by the
course, psychological and extra-hypothalamic physiological pathways
concentration of pro-inflammatory cytokines in circulation, such as
are of interest in and of themselves and may suggest targets of inter-
interleukin-1 beta (IL-1β), interleukin-6 (IL-6), and tumor necrosis
vention to improve stress functioning. We have chosen a few extra-
factor (TNF- α), or by indicators of chronic, systemic inflammation like
hypothalamic physiological and limbic psychological processes to focus
C-reactive protein (CRP).
on here based on whether there was evidence to support mediation or
The immune system may also mediate the association between ne-
moderation, as well as theoretical arguments regarding their role as
glect and HPA axis function through chronic inflammation, as well as
mediators of early life adversity (e.g., Wismer Fries et al., 2008;
contribute to the increased risk of physical and psychological problems
Humphreys et al., 2015; Johnson et al., 2018; Kuhlman et al., 2017;
related to neglect. Theoretically, adversity may chronically activate the
McLaughlin et al., 2015; Perry et al., 2019; Silverman and Sternberg,
immune system and lead to chronic low-grade inflammation (Danese
2012; Van Hulle et al., 2012).
and McEwen, 2012; Kuhlman et al., 2017). Chronic low-grade in-
flammation, in turn, is believed to contribute to numerous physical and
6.1. Inflammation –mediator and moderator psychological disorders. Animal model research indicates elevated in-
flammation related to early psychosocial neglect, frequently modeled
The HPA axis and immune system (Fig. 1) are bidirectionally in- using maternal separation paradigms (Kuhlman et al., 2017). Because
tertwined (see Silverman and Sternberg, 2012 for a review). Thus, it is

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

proinflammatory cytokines stimulate CRH and therefore CORT pro- (Hostinar et al., 2015). Once children reach puberty, the potency of
duction, such chronic low-grade inflammation may influence HPA axis parents as social buffers of the HPA axis diminishes (Doom et al., 2015).
activity thereby mediating the relationship between neglect and the Animal models indicate that oxytocin, a hormone central to the at-
HPA axis. While there is research investigating the impacts of early life tachment bond, is triggered by both stressors and social buffers and
stress on the immune system in humans, there is a growing literature on plays a role in regulating the HPA axis, explaining, in part, how these
the impact of neglect in particular. social relationships regulate stress responsivity (Carter, 2018;
In general, the model that has been examined is one in which early Crockford et al., 2017). The prefrontal cortex (PFC) also plays a central
life adversity programs stress and immune systems, resulting in hyper- role in social buffering; in rodent models, PFC lesions blocked social
inflammatory activity and ultimately a chronic inflammatory state buffering of the HPA axis (see Hostinar et al., 2014 for review).
leading to diseases of aging appearing earlier in development (Miller Neglect may influence stress system programming by disrupting
et al., 2011). This may reflect a different life course strategy as pro- attachment and depriving young children of a social buffer of stress
posed by the ACM, one in which being constantly at the ready to re- (Flannery et al., 2017). Certainly, this is the case for children while they
spond to a wound or pathogen increases short-term survival at a cost to are living in institutions, as few form secure attachments with car-
long term health. In a meta-analysis of inflammatory markers in chil- egiving staff in the first two years of life, even if a caregiver is pre-
dren and adolescents, the association between early adversity and CRP sumably their favorite one (Zeanah et al., 2005). If children have not
and IL-6 levels was small (Kuhlman et al., 2019). However, there is had the chance to form an attachment relationship in infancy, it is not
burgeoning evidence of an association between neglect in particular clear that later attachment relationships, even if they are to all intents
and elevated IL-6 levels (Chase et al., 2019; Nikulina and Widom, and purposes secure, are as successful at regulating physiology. This
2014). Evidence for elevated CRP is mixed, with some studies reporting was first reported in a study of young children adopted internationally
an association between neglect and greater CRP levels (Pinto Pereira from institutions in Russia and Eastern Europe (Wismer Fries et al.,
et al., 2019), an association limited to certain racial groups (Nikulina 2005). While children born and raised in their birth families showed an
and Widom, 2014), or no association (see Ports et al., 2019 for a re- increase in oxytocin when interacting with their parent, children
view). It is notable that neglect (i.e., institutional deprivation) limited adopted from institutions did not, even though they had been with the
to infancy and early childhood is not associated with increased cyto- parent for several years. This contests the ACM, which posits that
kines or CRP in circulation by adolescence or young adulthood children of preschool age are in a life history stage when recalibration
(Elwenspoek et al., 2017; Slopen et al., 2019). Chronic inflammation will occur. It is not clear that this lack of recalibration was because the
may work to chronically stimulate CRH, thereby providing chronic relationships with adoptive parents were insecure or disorganized. In a
drive on the HPA axis which could lead to a down-regulation at the recent study following children adopted from institutions when they
level of the adrenal and the low cortisol noted in many cases of neglect. were 1.5- to 3-years of age, however, the majority exhibited secure
In this way, chronic inflammation could mediate the impact of neglect behaviors towards their primary caregivers within a year of adoption,
on the HPA axis. although there was an increased percentage (i.e., 23% vs 6%) who were
If the immune system is compromised by early, chronic, and severe categorized as disorganized relative to children reared in families from
neglect, then some have argued that this also reflects a down-regulation birth (Carlson et al., 2014). Thus, it is possible that there is a sensitive
following chronic activation (Sowder et al., 2018). However, these data period in early development during which children’s physiological
so far stand in marked contrast to the argument that neglect programs a regulation by caregivers becomes bound to the formation of the at-
pro-inflammatory state due to chronic inflammation from repeated tachment relationship, giving attachment figures powerful physiolo-
stressors resulting in insensitivity to inhibitory signals (Miller et al., gical regulatory functions in the child’s life. Lack of an attachment
2011). It is unclear whether neglect in a family context and neglect in figure during this time may not preclude the development of a secure
an institution produce the same effects on the immune system. Due to relationships with attachment figures who come into the child’s life
the interactive nature of the HPA axis and immune system (Fig. 1), later, but may preclude those figures being able to regulate the child’s
inflammation could mediate the association between neglect and HPA physiology.
axis activity by stimulating CRH, or could moderate that relationship by Consistent with this argument, PI children’s cortisol response to a
increasing the direct influence of neglect on HPA axis function by way stressor is not buffered by the presence of their attachment caregiver
of a second pathway. It could also be the case that it is not psychosocial (Hostinar et al., 2015). Furthermore, PI children mount a prolonged
neglect, but aspects of neglect that expose the young children to chronic cortisol response following an interaction with their adoptive parent,
infections and parasitic loads that programs the immune system in the whereas never-institutionalized children actually show a decrease in
way observed in previously institutionalized children. Whatever the cortisol following the same interaction (Wismer Fries et al., 2008). It is
case, the immune system may play a role in both moderating HPA axis unclear why this is, but it might relate to the failure of the parent’s
function and mediating the influence of neglect on the HPA axis; ne- presence to activate the oxytocin system. In a separate line of work with
glect could promote inflammation, which in turn further produces community samples of children at risk of neglect but who have a con-
CORT, potentially leading to a spiraling increase in CORT and in- sistent caregiver from birth, the Attachment and Biobehavioral Catch-
flammation as the immune system is less regulated under higher CORT up (ABC) intervention, which aims to improve attachment relationships
levels. Future researchers should investigate the association between by coaching parents to be sensitive, responsive caregivers, produced
CORT and inflammation in the context of neglect to determine the more typical diurnal cortisol patterns in children following the inter-
pattern by which neglect influences the immune system and HPA axis. vention (Bernard et al., 2015). Therefore, the relationship between
neglect and disruptions in HPA axis functioning may be mediated by
6.2. Attachment and social buffering - mediator disruptions in the attachment relationship that interfere with the body’s
ability to use a social buffer to help regular stress responses. For chil-
When children are just developing the capacity to regulate their dren who have had a consistent caregiver, intervening to improve at-
stress response, they require an external regulator, such as a caregiver, tachment may help normalize HPA axis functioning. For children who
to buffer the stress system. Attachment figures provide the most potent have not had a consistent caregiver in infancy, obtaining one later may
stress buffers (Gunnar and Donzella, 2002). This may be why neglect not serve the same physiological stress regulating function even if the
early in life is so salient, because the infant is not able to self-regulate. relationship is secure, again refuting the ACM re-calibration in the early
Sensitive, responsive caregiving forms the basis of secure attachment childhood years hypothesis.
relationships (De Wolff and van Ijzendoorn, 1997), with secure re-
lationships being more powerful stress buffers than insecure ones

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

6.3. Self-regulation - moderator effects were examined. In studies of stress and immune functioning in
children reared in institutions, it is typical that institutionalization be-
Emotional and behavioral self-regulation is the capacity to willfully gins at or shortly after birth, first in a hospital and later in an or-
increase and decrease control over the experience and expression of phanage-like facility. Based on animal studies, the first few years of life
emotion and emotion-related behavior (Kochanska et al., 2001). The are expected to be a sensitive period for shaping the HPA axis (Weaver
capacity to self-regulate plays an important role in responding to et al., 2002). As previously noted, there is some evidence that the in-
stressors; however, we should not expect greater self-regulatory com- fancy period constitutes a sensitive period for the HPA axis in humans
petencies to always reduce stress reactions. Mounting an appropriate lasting sometime between 1.5 and 2 years of age (Hostinar et al., 2015;
response to a stressor is adaptive and helps the individual handle that Leneman et al., 2018; McLaughlin et al., 2015). In addition, emerging
stressor, and so does not indicate emotion regulation difficulties. evidence points to puberty as another salient age when stress systems
However, there is evidence that the timing and magnitude of the CORT may be plastic and shaped by experience. For example, PI children
response to a stressor varies with emotion regulation skills. Children demonstrate a recalibration to normative HPA axis reactivity to a
with high goals for their own performance and strong self-regulatory psychosocial stressor following the onset of puberty (DePasquale et al.,
capacities may experience greater physiological stress during perfor- 2018). Somewhat analogous findings have been reported for maltreated
mance stressors because a loss of esteem in their own eyes and the eyes children (King et al., 2017). As the HPA axis exhibits differential pat-
of others may be of higher value to them (Frankenhaeuser et al., 1980). terns of activity related to developmental stage, it is important to
There is also some evidence that emotion regulation modulates CORT consider child age at the time of stress reactivity measurement as well
responses (Doom and Gunnar, 2015). Specifically, those with high as their age at the time of neglect.
emotion regulation time their stress responses differently than those
with less regulation, elevating in anticipation of the stressor and re- 6.5. Child sex - moderator
sulting in less of a response during the stressor and a faster recovery
once the stressor is over (Perry et al., 2019; Susman et al., 1997). On the Evidence of sex differences in outcomes following experiences of
other hand, when encountering the stressor in the first place is a result neglect is emerging, but mixed. Converging evidence from animal
of poor self-regulation (e.g., poor regulation leads to aggression which models and smaller samples of PI children indicate males are more
leads to peer rejection), children with greater self-regulatory abilities impacted by early neglect (Lewis et al., 2000; Reid et al., 2019).
may encounter fewer stressors throughout the day (Gunnar et al., However, it is less clear whether male or female PI youth respond better
2003). Similarly, those who can focus attention on less threatening to foster care interventions because the nature of the sex difference
aspects of situations likely can avoid activating the stress system in depends on the outcome being measured. Specifically, females show
situations that are ambiguously threatening (Suway et al., 2013). greater improvements in attachment quality but males show greater
Overall, greater self-regulation abilities are important for adaptively reductions in callous-unemotional traits following a foster care inter-
responding to stressors; however, careful attention must be paid to the vention (Humphreys et al., 2015; Smyke et al., 2010). Emerging evi-
timing and social evaluation of a stressor when investigating differences dence suggests there are differential impacts of early institutionaliza-
in the stress regulatory effects of self-regulation. tion on the timing of pubertal development based on child sex; there is
Executive functions are thought to be central to the development of evidence of differences in pubertal timing between PI males rando-
self-regulation (Bernier et al., 2010), and PI children have consistently mized to foster care and males randomized to continued institutional
demonstrated lower performance on executive function tasks as early as care, but not in females (Johnson et al., 2018). However, replications of
2.5–4 years of age (Hostinar et al., 2012; Loman et al., 2013; this study are needed to better inform conclusions regarding sex dif-
McDermott et al., 2013). Reduced executive function skills are also ferences in the impacts of early neglect on pubertal timing.
correlated with experiences of physical neglect for children in the child Despite the preliminary state of the research on child sex as a
welfare system, possibly due to a lack of sufficient cognitive stimulation moderator of outcomes following childhood neglect, sex differences in
(Pears and Fisher, 2005). Research with adults with a history of HPA axis function are more established. Because gonadal hormones
childhood emotional neglect has also shed some light on the link be- play a role in HPA axis regulation, gonadal steroids may influence sex
tween neglect and the regulation of emotions. Specifically, aspects of differences in HPA axis activity (see Oyola and Handa, 2017 for a re-
emotion regulation (i.e., behavioral avoidance and antecedent focus) view). Sex differences in HPA axis activity emerge around puberty- with
moderate the relationship between childhood emotional neglect and the CAR shifting from 30 to 45 min after awakening for females (Oskis
outcomes in adulthood, including relationship problems and depression et al., 2009), which results in more cortisol produced after awakening
(Berzenski, 2018; O’Mahen et al., 2015). in females than males (Steptoe and Serwinski, 2016). In adults, sex
Preliminary evidence suggests emotion regulation skills may mod- moderates HPA axis activity in response to certain types of stressors:
erate the relationship between neglect and stress. In adults with a his- males tend to mount greater responses to performance stressors, such as
tory of childhood emotional neglect, emotion regulation skills such as public speaking tasks, while females tend to mount greater responses to
suppression and reappraisal moderated the association between neglect threats of social exclusion (Stroud et al., 2002), although this is not the
and perceived stress, but only in females (Berzenski, 2018). Similarly, case among adolescents (Stroud et al., 2009). However, in many si-
adult women with both a history of childhood maltreatment and tuations there are more similarities in HPA axis function between the
emotion regulation difficulties demonstrated blunted CORT reactivity sexes than there are differences.
(England-Mason et al., 2017). Recent research points to differences in Research into the moderating role of child sex in the relationship
emotion regulation and CORT responsivity in PI children. PI adoles- between neglect and HPA axis function is in its infancy. The ACM model
cents demonstrated less emotion regulation overall compared to ado- proposes different patterns of stress responsivity following early ex-
lescents born and raised in their families. Nonetheless, among PI youth, periences of severe neglect compounded with other forms of abuse re-
those exhibiting higher emotion regulation mounted a greater antici- lated to child sex, with females as highly reactive and males blunted.
patory stress response, possibly due to greater motivation to perform This pattern of sex differences has not yet been clearly demonstrated.
well and greater uncertainty in their ability to do so (Perry et al., 2019). Interestingly, a study comparing a group of PI adolescents to a group of
never-institutionalized adolescents found no evidence of sex differences
6.4. Child age - moderator in the recalibration of cortisol responses during puberty (DePasquale
et al., 2018). Overall, evidence of child sex as a moderator of the in-
The impact of neglect on the regulation of the HPA axis depends on fluence of neglect on HPA axis function is extremely under-examined.
the child’s age when neglect was experienced and the age when its Future investigations should contribute to the literature by testing for

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E.B. Reilly and M.R. Gunnar International Journal of Developmental Neuroscience 78 (2019) 100–108

sex differences in stress system function following early experiences of complete pattern of findings described in this review is needed.
neglect. Additionally, key mediators and moderators of this relationship must be
considered. Individual differences in HPA activity following neglect
6.6. Genetics - moderator may be explained in part by mediators and moderators of neglect and
stress reactivity, including the immune system, attachment, self-reg-
Genetics influence HPA axis function, thereby potentially moder- ulation, child age and sex, and genetics.
ating the relationship between neglect and stress responsivity. In re- Future studies that disentangle the influence of physical versus
search with families, it is especially difficult to disentangle the influ- psychological neglect on the developing HPA axis and the pertinent
ence of a neglectful environment on stress system programming from moderators of each type would be hugely beneficial in contributing to
the influence of shared genetics (Danese and Baldwin, 2017). Research both our conceptual understanding of the mechanisms of these asso-
with children demonstrates high heritability of CORT, especially for ciations and more targeted interventions. Increasing our focus on de-
samples taken in the lab or early in the morning (Gustafsson et al., signs that strengthen and test causal interpretations are needed, such as
2011; Van Hulle et al., 2012). However, family adversity moderates the twin designs, adoption studies, and randomized intervention trials.
heritability of HPA axis functioning at different point in development. There is much opportunity for more work to be done investigating the
For example, one group found greater heritability at 6 months among interaction of moderators on neglect and stress physiology across de-
children living in highly adverse contexts, while at 19 months in the velopment, with the possibility of establishing interventions targeted at
same children the relation reversed, with higher heritability in the diminishing the influence of neglect on this developing stress system.
children in less adverse family contexts (Ouellet-Morin et al., 2008, Future longitudinal studies focused on the influence of neglect on both
2009). To our knowledge, no one has used genetically informed designs the developing HPA axis and the inflammatory response and the in-
to examine the impact of neglect on the HPA axis. terplay between the two will help elucidate the mechanisms by which
There are a number of genes involved in regulating the HPA axis neglect becomes biologically embedded. A more comprehensive un-
that may play a role in moderating the association between neglect and derstanding of the influence of neglect on the HPA axis is critical to
HPA axis function, namely, the GR gene, FKBP5 gene, SERPINA6/1 intervening to disrupt the detrimental physical and psychological
gene, and CRHR1 gene (Castro-Vale et al., 2016; Utge et al., 2018; health outcomes related to early neglect.
Bolton et al., 2014). We have not found any study examining whether
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