Title

Effect of the Nature of Subsequent Environment
on Oxytocin and Cortisol Secretion in MaltreatedChildren

Author(s)水島, 栄Citation

大阪大学, 2016, 博士論文

Version Type VoR
URL

https://doi.org/10.18910/56159

rights
Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

Effect of the Nature of Subsequent Environment on Oxytocin and Cortisol
Secretion in Maltreated Children(不適切な養育を受けた子どものその後の環境が唾液中のオキシトシンとコルチゾール分泌に与える影響)

大阪大学大学院
大阪大学・金沢大学・浜松医科大学・千葉大学・福井大学
連合小児発達学研究科

水島2016 年 3 月

栄博士学位論文Original Research
published: 11 December 2015
doi: 10.3389/fpsyt.2015.00173

E

Sakae G. Mizushima1,2 , Takashi X. Fujisawa1,2 , Shinichiro Takiguchi2 , Hirokazu Kumazaki1,2 ,Shiho Tanaka2 and Akemi Tomoda1,2*
Division of Developmental Higher Brain Functions, United Graduate School of Child Development, Osaka University,
Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Fukui, Japan,
2
Research Center for Child Mental Development, University of Fukui, Fukui, Japan
1

Edited by:
Ashok Mysore,
St. John’s Medical College Hospital,
India
Reviewed by:
Marco Grados,
Johns Hopkins University School of
Medicine, USA
Preeti Jacob,
National Institute of Mental Healthand Neurosciences, India*Correspondence:
Akemi Tomoda
atomoda@u-fukui.ac.jp
Specialty section:
This article was submitted to Childand Neurodevelopmental Psychiatry,a section of the journal
Frontiers in Psychiatry
Received: 02 July 2015
Accepted: 26 November 2015
Published: 11 December 2015
Citation:
Mizushima SG, Fujisawa TX,
Takiguchi S, Kumazaki H, Tanaka S
and Tomoda A (2015) Effect of the
Nature of Subsequent Environment
on Oxytocin and Cortisol Secretion in
Maltreated Children.
Front. Psychiatry 6:173.
doi: 10.3389/fpsyt.2015.00173

Frontiers in Psychiatry | www.frontiersin.org

Childhood maltreatment (CM), including abuse and neglect, is a crucial factor that distorts child development. CM is associated with alterations in numerous brain regions,and may be associated with hormonal dysregulation. This study aimed to investigate
differences in secretion patterns of cortisol (CT) and oxytocin (OT) among children who
experienced CM, children living in residential care facilities and in unstable environments.
Among 38 maltreated children, 23 (mean age = 12.2 years, SD = 3.0) were categorized
as “Settled” and 15 (mean age = 13.1 years, SD = 2.2) as “Unsettled.” Twenty-six
age- and gender-matched (mean age = 12.6 years, SD = 2.1), typically developing(TD) children were also included. Clinical and psychological assessments, including IQ
and trauma evaluations, were conducted for all participants. Age, gender, and full-scale
IQ were used as covariates in hormone analysis. Two saliva samples were collected,
one on awakening and the other at bedtime. There were significant differences in theawakening CT levels of the “Unsettled” group, and in bedtime OT levels in the “Settled”
group as compared with TD children, and between CM groups. Furthermore, there wasa significant difference in trauma-symptomatic depression scores between the “Settled”
and “Unsettled” CM group. These results suggest that CT diurnal secretions tend to
be reactive to current stress rather than previous experience. OT diurnal secretions arepresumably hyper-regulated for coping with the environment to survive and thrive. Bymeasuring salivary CT/OT diurnal patterns, hormonal dysregulation of CM children livingin “Settled” environments and “Unsettled” environments was indicated.
Keywords: child maltreatment, cortisol, oxytocin, residential care facility, hormones

INTRODUCTION
Childhood and adolescence is a time of remarkable change in physical and psychological development, brain structure, and neuroendocrine function. Although the process is guided by genetic
factors, the final form is determined by life experience and the living environment. From birth,parent–infant interaction modulates fundamental brain processes (1, 2), whereas more complex
psychological development occurs in socializing with peers (3).

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Adverse experience in the form of childhood maltreatment(CM) has been reported to bring several lifelong difficulties (4).
For example, CM distorts attachment to, and sense of intimacy
toward, “significant others.” Therefore, many maltreated children
suffer from interpersonal communication problems throughout
their lives. Thus, exposure to CM is acknowledged to impact
mental health (5), causing repercussions in social environments,
including parents, family, and local communities.
Childhood Maltreatment is also associated with alterations inthe size (6, 7) and functional activity of a variety of brain regions(8), and with hormonal dysregulation (9). Prior studies (10–14)
have demonstrated that CM leads to abnormal reactivity of hormones, such as cortisol (CT) and oxytocin (OT). These effects
extend into adulthood (10–12) as well as influencing childhood(13, 14). Thus, early life stress is crucial in exacerbating mental
health issues in the general population, as well as in psychiatricpopulations.
Cortisol is released in response to stress via the hypothalamic–pituitary–adrenal (HPA) axis. The secretion is regulated
by capturing negative feedback relating to stress. CT levels are
relatively high in the morning and decrease by evening (15, 16).
Reportedly, children’s CT reactivity to stress is an important
mediator of depression risk (17, 18). In addition, several studies
of children with adverse childhood experiences (ACEs), such as
institutionalized children in Romania (19, 20) and foster children(13, 21, 22), have indicated atypical “blunted” CT diurnal secretions. Prior CT studies related to CM have shown high CT levels in
maltreated children with PTSD (23, 24) and elevated morning CT
levels (25) in foster children who experienced severe emotional
maltreatment. Although there exist inconsistencies regarding CT
levels in maltreated children, previous studies of CM and depression in childhood suggest HPA axis dysregulation as a result ofCT stress reactions.
The neuropeptide OT is secreted from the posterior pituitary gland, and has physiological functions during labor andlactation. There is a growing body of evidence that OT plays
an important role in regulating social behavior in diverse
species (26, 27). In humans, many studies have suggested that
OT modulates mother–infant bonding, and OT receptors are
involved in social behavior, including reproductive and maternal behaviors, as well as affiliation and attachment (28–31). It
has been suggested that OT plays an important role in attachment formation or bonding with a “primary care-giver,” andindividuals who have experienced that CM have atypical OT
secretion patterns (32).
According to a Japanese government child welfare report in2015 (33), more than 29000 children are institutionalized, suchas in residential care homes, and 60% of those children haveexperienced CM. Before placing a child in institutionalized care,the child guidance center separately conducts several assessmentsof the children and their families; children are removed fromtheir homes and placed with other children in temporary custodyduring the assessment. After the assessment, less than 30% of thechildren are placed in institutions [for more information about
the institutionalized care system in Japan, see Suzuki and Tomoda(34)]. The remaining 67% of children return to their biologicalfamily homes.

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Although the association between stressful events in childhood and abnormal hormonal levels are well established, few
studies have examined the influence of CM on neuroendocrine
function and pathways. Thus, developmental psychopathologists are highly interested in elucidating children’s HPA axis
dysregulation, indexed via CT and/or OT reactivity, with two
distinct literatures (13, 35) emerging on role of the environment
following CM experiences, especially regarding differences inliving environment.
This study explored the effect of the subsequent environment(i.e., stable or unstable placement) on salivary CT/OT secretion
patterns in maltreated children. We hypothesized that differencesin neuroendocrine function would be present when comparing
those children in stable versus unstable environments. We divided
the maltreated children into two groups according to their living
environments, and analyzed salivary CT/OT secretion patterns
as well as their association with psychological scales. Typicallydeveloping (TD) children acted as control subjects in our study.

MATERIALS AND METHODS
Ethics Statement

The study protocol approved by the Ethics Committee of the
University of Fukui (Assurance No. FU25-149). All participants’parent(s) and the caregivers who took custody of the child gave
written informed consent for participation in the study. The
experimental protocol was conducted in accordance with the
Declaration of Helsinki.

ParticipantsThis study involved 38 children who experienced CM, consisting of 19 boys and 19 girls. The children were subcategorized as“Unsettled” or “Settled.” The “Unsettled” group was defined as
children who have been living with their biological parent(s),and also children living in residential childcare homes where thelength of stay was less than 1 year. The reason for adopting thestay length of less than 1 year was based on our unpublished datafrom our previous study (34): we found that depressive mental
state within the first year of institutionalization was significantly
higher than that from the second year and more. Fifteen children(six boys and nine girls; mean age 13.1 years, SD 2.1) were categorized as “Unsettled.” The “Settled” group was defined as children
who were settled in residential care homes instead of their original family homes. The duration within the settled environment
ranged from a minimum of 1 year to a maximum of the child’s
current age (the longest duration was 15 years). Twenty-threechildren (13 boys and 10 girls; mean age, 12.2 years, SD = 2.9)
were categorized as “Settled.” Furthermore, 26 TD children (12boys and 14 girls; mean age, 12.7 years, SD = 2.2) were included
as healthy controls. The clinical patients who had experienced
CM were recruited following their referral to the Department ofChild and Adolescent Psychological Medicine at the Universityof Fukui Hospital via the local authority’s child guidance centers,other children were recruited to the CM group after their parents
brought them to the hospital for medical attention related todifficulties in child rearing. Almost all CM group children were2

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primarily screened regarding their ACE by the child guidance
center before referral. The types of abuse experienced in the
CM group were as follows: neglect (62%), physical abuse (35%),
emotional abuse (16%), and sexual abuse (14%). In the publicchild welfare system in Japan, detailed duration of maltreatment
experiences by a child is protected, along with the identity of theabuser, socioeconomic status, and home environment, so we
could not access this information even though our purpose isacademic, and the children’s identities would be protected.
The healthy age- and gender-matched TD controls wererecruited from the general community in Fukui prefecture. They
were recruited from the community through advertisements in a
local newspaper and on our website homepage.
All participants’ race/ethnicity was Japanese. Participants wereprimarily screened by the MINI-International NeuropsychiatricInterview for children and adolescents (MINI-KID: Japaneseversion) (36, 37). None of the TD children had any history ofDiagnostic and Statistical Manual of Mental Disorders, Fourth
Edition, Text Revision (DSM-IV-TR) (38) Axis I Disorders,
including developmental disorders, or any history of any formof abuse or drug abuse, head injury, any physical or abnormal
developmental milestones, or fetal drug exposure. The intellectual ability of the participants was assessed by the Wechsler
Intelligence Scale for Children-Fourth Edition (WISC-IV) (39).

and directly stimulates children; therefore, they are able to disclose their experiences naturally. IES-R is also structured by the
diagnostic criteria of PTSD from the DSM-IV. This self-rating
consists of 22 questions that ask how the individual’s thoughts
and emotional state during the past week are influenced byprevious trauma. TSCC consists of 54 questions, split into the six
subcategories Anxiety, Depression, Anger, Post-traumatic Stress(PTS), Dissociation, and Sexual Concerns. These scales wereapplied during the structured interview by a licensed clinicalpsychologist (first author).

Saliva Sampling

Awakening and bedtime saliva CT/OT data were obtainedusing Salivettes® (Sarstedt, Rommelsdorft Corp., Germany). The
awakening saliva sample was taken on waking, before breakfast(within 1 h of awakening). The bedtime saliva sample was taken
before bedtime. The saliva sampling procedures were the sameas those in our previous study (52). Before using Salivettes,
instructions were given to all participants. Saliva samples werefrozen and stored at −80°C in the laboratory. Salivary CT and
OT levels were measured by enzyme-linked immune sorbent
assay (ELISA). Before assay, each saliva sample was restored toroom temperature. The assay was conducted using an all-in-one
CT kit (SalimetricsTM). These protocols are based on prior studies
of children (53–55). The saliva samples were also used for OT
analysis. After completing CT data analysis, the samples werelyophilized overnight and kept at −20º C to concentrate them two
to four times. Afterwards, the dry samples were reconstructedin the assay buffer immediately before analysis, using an OT
enzyme immunoassay commercial kit (Assay Designs Inc., Ann
Arbor, MI, USA). The CT sample assay was duplicated, whereas
the OT assay was executed in singlicate. The data were calculatedusing a SpectraMax® (Molecular Device, Sunnyvale Corp., CA,
USA) micro plate reader, according to relevant standard curves.
Average intra- and inter-assay coefficients of variation were 9.6
and 8.6%, respectively.

Assessment Measures

Previous studies have suggested that maltreated children havesymptoms in common with neurodevelopmental disorders,such as attention-deficit hyperactivity disorder (ADHD) (40)and autism spectrum disorder (ASD) (41). In order to evaluate
ADHD traits and ASD traits, the Japanese version of the ADHD
Rating Scale-IV (42) and the Autism-Spectrum Quotientchildren’s version (AQ) (43) were administered. The ADHD-RS(44) scale screens for children’s behavior during their routine
activities. It consists of 18 questions, which are divided into
two subcategories, consisting of nine inattention items and nine
hyperactivity–impulsivity items. The AQ measures autistic traitsof children (45) via 50 questions that are rated by the child’s parent or caretaker.
To assess behavioral problems, parents or caregivers completed
the Strengths and Difficulties Questionnaire (SDQ) (46) which
consists of 25 questions, split into 5 categories that assess children’sinternalized (emotional and peer relationships) and externalized(conduct and hyperactivity) problems (“difficulties”). The prosocial score is excluded from the total score, because the former
is categorized as a positive quality of the individual. SDQ data
were obtained from the children and via their parent or caretaker
as well. Depressive mental state was assessed via the Depression
Self-Rating Scale for Children (DSRS-C: Japanese version) (47),which contains 18 questions that probe emotional and physicalreactions associated with the current mood of children.
Traumatic experiences related to CM were evaluated by the
UCLA PTSD Index for DSM-IV (UPID) (48), the Impact ofEvent Scale Revised (IES-R) (49, 50), and the trauma symptom
checklist for children (TSCC) (51). UCLA PTSD Index consistsof 47 questions, which follow the diagnostic criteria for PTSD
from the DSM-IV (38). The evaluation usually takes 20–30 min

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Statistical ProcedureThree different groups were defined, in order to determine characteristic features of maltreated children (“Unsettled,” “Settled,” andTD). Differences among the three groups in the clinical variables
were assessed using one-way analysis of covariance (ANCOVA).
Analysis of biological data (i.e., salivary CT and OT) involved
repeated-measures two-way ANCOVA. Statistical analyses wereconducted using IBM SPSS Statistics 21.0 software (SPSS Inc.,
Chicago, IL). All p-values were two-tailed; p-values less than.05
were considered significant.

RESULTS
Demographic Data and Clinical
Assessments

Table 1 shows the demographic and clinical characteristics
of each group. The three groups were well matched in genderand age. ANOVA revealed that both CM groups (“Settled”
and “Unsettled”) exhibited significantly lower full-scale IQ

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Table 1 | Demographic data and clinical ratings of maltreated children (unsettled and settled) and typically developing children.
Ratings

Unsettled

SettledTD

Statistics

p-value–

Number

15

23

26

–

Gender(M:F)

6:9

13:10

12:14

–

–

Age (mean ± SD)

13.1 ± 2.2

12.2 ± 3.0

12.1 ± 2.1

F2,61 = 0.60

ns

FSIQ

91.00 ± 13.3b

91.87 ± 9.6b102.23 ± 9.0a

F2,61 = 8.26

<0.0006

12.87 ± 10.6

a10.83 ± 9.8

2.50 ± 2.4b

F2,60 = 6.78

<0.0022

ADHD-RSda

AQa

19.80 ± 5.7

20.22 ± 8.9

13.50 ± 5.7

F2,60 = 2.52

ns

SDQ (self-rating)d

17.00 ± 6.9a

15.70 ± 7.3a

7.50 ± 4.8bF2,60 = 10.77<0.0001

SDQ (parent-rating)d14.00 ± 4.0a

13.70 ± 9.0a

6.04 ± 3.9b

F2,60 = 7.48

<0.0013

DSRS-C14.00 ± 7.3

10.65 ± 6.7

6.96 ± 4.7bF2,60 = 5.97

<0.0043dab

IES-Rd25.47 ± 25.5a

16.30 ± 14.9a

2.65 ± 5.0b

F2,60 = 11.15<0.0001

TSCC-anxietyd

54.07 ± 19.4a

48.13 ± 13.8a

39.42 ± 5.7bF2,60 = 6.35

<0.0031

TSCC-depressiond

52.87 ± 17.1a

43.04 ± 9.8b

37.19 ± 2.5c

F2,60 = 13.24<0.0000

TSCC-angerd

48.80 ± 13.5a

43.65 ± 7.1a

36.81 ± 2.5bF2,60 = 9.67

<0.0002

TSCC-post-traumatic stressd

50.60 ± 14.7a

44.74 ± 8.4a

37.58 ± 3.9b

F2,60 = 10.99<0.0001

TSCC-dissociationd

48.47 ± 13.4a

47.26 ± 11.3a

37.50 ± 2.5bF2,60 = 11.09<0.0001

TSCC-sexual concernsd

41.47 ± 3.9

44.04 ± 9.7

38.85 ± 2.3

F2,60 = 1.80

ns

FSIQ, full-scale IQ; ADHD-RS, attention-deficit hyperactivity disorder rating scale; AQ, autism-spectrum quotient-children’s version; SDQ, strength and difficulties questionnaire;
DSRSC, depression self-rating scale for children (Birleson); IES-R, impact of event scale revised; TSCC, trauma symptom checklist for children. a > b (p < 0.05), a > c (p < 0.05),b> c (p < 0.05), dCovariate items: FSIQ.

Salivary Cortisol and Oxytocin(FSIQ) scores than the TD group [F (2, 61) = 8.22, p < 0.0006].
For the clinical characteristics analysis among groups, FSIQ
was adjusted using ANCOVA. Both CM groups (“Settled”
and “Unsettled”) showed significantly higher scores than the
TD group on ADHD-RS [F (2, 60) = 6.78, p = 0.0022], SDQ[Self-rating: F (2, 60) = 10.77, p < 0.0001, Parental-rating:F (2, 60) = 7.48, p = 0.0013]. However, for the DSRS-C, the“Unsettled” group scored significantly higher than the “Settled”
group and TD children [F (2, 60) = 5.97, p = 0.0043]. There
were no significant differences in AQ scores [F (2, 60) = 2.52,
p = 0.0893]. These results suggest that CM group children(“Settled” and “Unsettled”) suffered from more behavioral andmood-related problems than the TD children, whereas the“Settled” CM group reported less severe difficulties than the“Unsettled” CM group.
For the trauma evaluation, according to the UPID (48), of the
38 subjects in the CM group, 3 met the full diagnostic criteria
for PTSD, 6 were categorized as having partial PTSD, and 9 had
a traumatic symptom above the UPID cut-off. Overall, 18 of 38(47%) CM subjects had relatively mild to moderate PTSD symptoms. Both CM groups showed significantly higher scores than
the TD group on the IES-R [F (2, 60) = 11.15 p < 0.0001] andmost of TSCC sub-scales [Anxiety: F (2, 60) = 6.35, p = 0.0031;
Anger: F (2, 60) = 9.67, p < 0.0002; PTS: F (2, 60) = 10.99,
p < 0.0001; Dissociation: F (2, 60) = 11.09, p < 0.0001]. However,the “Unsettled” group generated significantly higher scores for
TSCC-depression than the “Settled” group and TD group [F (82,60) = 13.24, p < 0.00001]. This result suggests that “Unsettled”
children tended to be more depressive than “Settled” CM andTD group children. No significant differences were found in thenumber of exposures to different types of maltreatment in the
CM children [neglect; F (1, 36) = 2.97, p = 0.093, physical abuse
F (1, 36) = 0.52, p = 0.477, psychological abuse F (1, 36) = 0.32.
p = 0.578, sexual abuse F (1, 36) = 1.53, p = 0.224].

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We, first, explored differences between the CM and TD groups insalivary levels of CT and OT, by using ANCOVA with covariates
consisting of age, gender, and FSIQ, which revealed no significant
differences (awakening CT, p = 0.079, bedtime CT, p = 0.333;
awakening OT, p = 0.119, bedtime OT, p = 0.213). Second, in order
to examine differences in salivary levels of CT and OT between“Unsettled,” “Settled,” and TD groups, each salivary level was compared using repeated-measures two-way ANCOVA with covariates
consisting of age, gender, and FSIQ; secretion slope (awakening
and bedtime) as a within-participants factor, and environmental
category (“Unsettled,” “Settled,” and TD) as a between-participants
factor. For CT levels (Figure 1A), we found a main effect of the timeof day [F (2, 58) = 5.18, p = 0.008]. This indicates that the average
CT level was significantly higher on awakening than at bedtime. The
main effect of environmental category (i.e., CM influence) was not
significant, however, the interaction effect with time of day was significant [F (2, 58) = 5.18, p = 0.008], indicating that the “Unsettled”
environment effect was greater on awakening than at bedtime. For
OT levels (Figure 1B), there was a significant difference in thebedtime OT level between CM groups [“Settled” and “Unsettled”; F(2, 58) = 4.00, p = 0.05]. This result indicates that “Settled” children’s
OT secretions markedly increased from awakening to bedtime.
Additional analyses were conducted to determine whether
there were between-group differences in diurnal patterns of CT
and OT secretion. For CT and OT secretions, the area under the
curve (AUC) and diurnal slope (change in levels from awakening
to the bedtime) were calculated, and group-wise effects investigated using between-participants one-way ANOVAs. For the
AUC, there was no significant difference in CT and OT hormone
levels among the groups. However, a significant difference in
the CT slopes was found [F (2, 58) = 4.16, p = 0.02], as shownin Table 2, whereas the OT slopes did not differ among groups[F (2, 58) = 1, p = 0.374]. Post hoc analysis using Bonferroni

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correction indicated that the decline in CT level from awakening
to bedtime was significantly larger in the “Unsettled” group than
the TD children [F (2, 58) = 4.16, p = 0.019]. This result indicates that the “Unsettled” children’s CT secretion levels dropped
sharply compared to the other groups (Figure 1A). There wereno significant correlations between TSCC-depression scores andsalivary CT or OT levels, adjusting FSIQ as a covariate (N = 64;
CT awakening: r = 0.087, p = 0.501; CT bedtime: r = 0.084,
p = 0.518; OT awakening: r = −0.101, p = 0.433; OT bedtime:r = −0.039, p = 0.764).

The present study demonstrated distinct patterns of salivary
levels of CT and OT secretions among maltreated children living in different environments (“Unsettled” and “Settled”), andTD children. There were significantly higher levels of awakening
CT in the “Unsettled” group compared with the “Settled” groupand TD group. Similarly, the “Unsettled” group had significantly
higher DSRS-C scores than TD group, and higher TSCCdepression scores than the “Settled” and TD groups. These results
suggest that children living in “Unsettled” environments may
have hyper-regulation of the HPA axis as an adaptation to copewith their environment and this hyper-regulation may induce a
depressive mental state. Moreover, our results also demonstratethat children in “Settled” environments have a marked increasein the bedtime salivary OT level compared with TD children.
This result suggests that the formation of stable interpersonal
relationships with facility staff and their peers may lead to atypical patterns of OT diurnal secretions. Thus, maltreated children
living in different environments may differ in their hormonal
dysregulation.

(ng/ml)

A 5.0
4.0

*

3.0

Salivary c

2.0
1.0

Cortisol Studies

0.0
Awakening

Bed

Our results are consistent with previous findings that higher
cortisol is associated with depressive problems (56, 57). Bernard(13) conducted a similar comparative study of CT patterns inmaltreated children who live with their birth parents and thosein foster care. However, the results were in complete opposition to ours. This may be because Bernard’s study targetedvery young children. According to Jessop’s (58) review, HPA
axis development is not mature in children who are younger
than 4 years of age. Prior studies have suggested that maltreatedchildren’s CT is unusually low in the morning and slightly highin the evening (13, 19–22). However, children with PTSD (24,59) tend to show an elevated or hyperactive pattern. Thus, aconsistent picture of maltreated children’s CT secretion pattern
is currently unavailable. Empirical studies (18, 25) have suggested hyperactivity in children who internalize problems. Our“Unsettled” children surely struggle with emotional burdens,
unpredictable threats, and a lack of social support. They not
only confront the concomitants of CM but also experience
numerous stresses within their environments. By contrast, the“Settled” children stay in residential care facilities, protecting
them from their prior CM experiences. Our “Settled” children’s
CT secretion patterns were clearly quite similar pattern to thoseof TD children. This suggests that the CT reactivity prioritizese

Salivary Oxytocin level (pg/ml)

B 100.0

*
80.0

60.0

40.0

20.0

0.0
Awakening
ed

Bed
Se

e
TD

* = p < .05
Figure 1 | Diurnal secretion of salivary hormones in maltreatedchildren (unsettled and settled) and typically developing children:(A) Cortisol and (B) Oxytocin.

Table 2 | Cortisol and Oxytocin measures in maltreated children (unsettled and settled) and typically developing children.
Measures

Unsettled

SettledTD

Statistics

p-value

Cortisol AUC (ng/ml)*

29.96 ± 15.0

25.41 ± 8.3

26.08 ± 9.8

F2,58 = 0.58

ns

Oxytocin AUC (pg/ml)*
Cortisol slope*
Oxytocin slope*385.89 ± 274.9
0.22 ± 0.2a
0.11 ± 1.2

784.71 ± 723.3
0.15 ± 0.1b−2.13 ± 5.9

835.09 ± 886.4
0.12 ± 0.1b
0.33 ± 7.3

F2,58 = 2.55
F2,58 = 4.16
F2,58 = 1.00

ns
<0.02
ns

Cortisol AUC, cortisol’s area under the curve; Oxytocin AUC, oxytocin’s area under the curve. a > b (p < 0.05).
*Covariate items: age, gender, and FSIQ.

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Childhood Maltreatment Hormone Study

current stress exposure and depressive states, rather than previous early life stresses.

of basal salivary CT and OT levels comparing CM children in“Unsettled” and “Settled” environments.
Our study has several limitations, the first of which is ourmodest sample size. Therefore, the relationship between thesubsequent environments of maltreated children and theirhormonal secretion remains tentative. In the preliminary resultsof this study, a positive dose–response association between
the number of CM types and both hormone levels was notobserved. Therefore, the relationship between their levels andabuse history remains unclear. Replication of our result with alarger sample would be worthwhile. Second, we did not control
for pubertal influences in the participants. Pubertal transitions(68) are potentially important, because hormonal development
is dramatically changed during this period. Previous studies
have suggested that child sexual abuse, physical abuse, and astressful family environment may accelerate sexual maturation(69, 70). Third, this was not a longitudinal study and, therefore,
resilience was not assessed in our study groups; no information related to outcomes in late adolescence is available formaltreated children. However, the resilience and post-traumatic
growth issues of those children must be very important from aphysiological, as well as a psychopathological, point of view (71,72). Fourth, the subjects’ socioeconomic status (SES) was not
examined in this study because of inadequate information onparents’ data among children in residential care facilities. While
childhood SES has been associated with neurocognitive andbrain development, recent evidence from neurodevelopmental
cohort studies has suggested that SES might play an importantrole in adolescent neuroendocrine development (73, 74).
Finally, we primarily screened severity of CM using ACE (75),but we did not find any significant differences of environmental
factors between CM groups. If we were able to obtain onset andduration of abuse information for those children more precisely,
this would better indicate cause and effect relationships withinchild maltreatment. These limitations should be addressed in
the future studies.

Oxytocin Studies

A recent study showed an association between exposure to lesssevere forms of CM and higher OT concentrations, suggestingthat adversity may enhance OT secretions, in order to cope withthe social environment (60). Although our result was partiallyconsistent with their finding, we only found higher levels of OT at
bedtime in the “Settled” CM group. One possible explanation forthe higher levels of OT may be related to alteration of the social
environment of residential care facilities following the adverse
experience.
Previous studies have suggested that OT levels are elevated bysocial interaction with “Significant others,” such as parents (61,62). In addition, OT levels after social exposure among maltreatedchildren were reported to be higher than those in healthy controls(35). A meta-analysis found that oxytocin administration showed
greater attenuation of the cortisol response in laboratory tasks
that strongly activated the HPA axis, suggesting that oxytocin
may play an important role in HPA dysfunction associated withpsychopathology (63). After removal from their homes, “Settled”
group children were living in childcare facilities with other children, and without ongoing child maltreatment exposure. These“Settled” children may have adapted to the stable environment
in order to survive and thrive, explaining the hyperactivity of OT
secretions.

Biological Clocks

Hormone secretion is regulated by circadian rhythms, which
are driven by endogenous biological clocks. A master circadianclock is present in the suprachiasmatic nucleus of the anterior
hypothalamus (64, 65), which regulates many neuroendocrinological, physiological, and behavioral processes. The alterationin circadian time structure likely plays an important role in thepathogenesis of hormone levels. The present study highlights
the need to consider the plight of maltreated children, which is
associated with alterations to the HPA axis that affect maltreatedchildren differently in terms of the living environment. CM likely
diminishes a person’s ability to cope with stress, possibly placing
them at risk for psychopathology and ill health. The effect of CM
on the circadian rhythm can alter neuroendocrine regulation,
produce or diminish HPA axis activity, and change the strengthof post-traumatic growth (12, 66, 67). All these findings suggestthat early adversity affects hormonal function, even after several
years have elapsed to relieve the stress exposure and to adapt tothe social environment.

CONCLUSION
Our study revealed dysfunction in the hormonal secretions of
CM children living in “Settled” environments and “Unsettled”
environments as compared with TD children. Specifically, we
found significantly higher awakening CT secretions in children
in unstable environments, and significantly higher bedtime OT
secretions in children in the residential care facilities. Regarding
psychological evaluations, trauma-related depression scores inthe “Unsettled” CM group were significantly higher than thosein “Settled” CM and TD children. Our study indicates how
early adversity influences children’s neuroendocrine regulation,
physically and psychologically. Longitudinal studies with larger
samples are needed to investigate whether an intervention program or treatment is associated with stable changes in hormonalsecretions related to stable mental health.
This study did not directly investigate the neural mechanisms
underlying any effects. However, hormone release is based onneural function. Combining our experimental paradigm with

Study Strengths and Limitations

A strength of our study is the comprehensive assessment of ourparticipants, by obtaining FSIQ and psychological scale data,
and a full trauma evaluation in order to understand CM’s developmental influence on CT and OT. The present study indicatedlower IQ in maltreated children than in TD children, justifying
our use of FSIQ as a covariate in the psychological scale andsalivary sample analysis. To our knowledge, this is the first study

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Childhood Maltreatment Hormone Study

FUNDINGneuroimaging techniques is necessary to elucidate the association
between neural function and hormone release. Such paradigms
would provide valuable clarification of cause–effect relationships
between development and environment.

This work was supported by a Grant-in-Aid for Challenging
Exploratory Research (Houga) and Scientific Research (C)from the Ministry of Education, Culture, Sports, Science andTechnology (MEXT) of Japan (KAKENHI: grant number
25560386 to AT, grant number 15K01753 to TF). Fundingorganizations had no role in the design or conduct of the study,
such as the collection, management, analysis, or interpretation of the data, or the preparation, review, or approval of themanuscript.

ACKNOWLEDGMENTS
We thank Hidemi Akashi for her great contribution to this study;
also Yumiko Uryu, Kaori Kobayashi, and Yuki Nakamura, forbridging the clinical and research fields, and special thanks to Dr.
Hanako Suzuki for her work.

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Conflict of Interest Statement: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could beconstrued as a potential conflict of interest.
Copyright © 2015 Mizushima, Fujisawa, Takiguchi, Kumazaki, Tanaka and Tomoda.
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