peer article - Paper Answers

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/275971785

The Enduring Effects of Abuse and Related Adverse Experiences in Childhood:

A Convergence of Evidence from Neurobiology and Epidemiology

Article in European Archives of Psychiatry and Clinical Neuroscience · April 2006

DOI: 10.1007/s00406-005-0624-4.

CITATIONS

225
READS

4,969

8 authors, including:

Some of the authors of this publication are also working on these related projects:

MBSR in PTSD View project

Neuro-Biobehavioural CV Medicine View project

James Douglas Bremner

Emory University

479 PUBLICATIONS 46,271 CITATIONS

SEE PROFILE

Charles L. Whitfield

52 PUBLICATIONS 9,265 CITATIONS

SEE PROFILE

Bruce Duncan Perry

The ChildTrauma Academy

99 PUBLICATIONS 10,292 CITATIONS

SEE PROFILE

Shanta R Dube

Georgia State University

157 PUBLICATIONS 29,711 CITATIONS

SEE PROFILE

All content following this page was uploaded by James Douglas Bremner on 16 December 2015.

The user has requested enhancement of the downloaded file.

https://www.researchgate.net/publication/275971785_The_Enduring_Effects_of_Abuse_and_Related_Adverse_Experiences_in_Childhood_A_Convergence_of_Evidence_from_Neurobiology_and_Epidemiology?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_2&_esc=publicationCoverPdf

https://www.researchgate.net/project/MBSR-in-PTSD?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_9&_esc=publicationCoverPdf

https://www.researchgate.net/project/Neuro-Biobehavioural-CV-Medicine?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_9&_esc=publicationCoverPdf

https://www.researchgate.net/?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_1&_esc=publicationCoverPdf

https://www.researchgate.net/profile/James-Bremner?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_4&_esc=publicationCoverPdf

https://www.researchgate.net/institution/Emory_University?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_6&_esc=publicationCoverPdf

https://www.researchgate.net/profile/Charles-Whitfield?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_4&_esc=publicationCoverPdf

https://www.researchgate.net/profile/Bruce-Perry-2?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_4&_esc=publicationCoverPdf

https://www.researchgate.net/profile/Shanta-Dube?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_4&_esc=publicationCoverPdf

https://www.researchgate.net/institution/Georgia-State-University?enrichId=rgreq-49a43c862f2597e76e654c0e38b6ed2a-XXX&enrichSource=Y292ZXJQYWdlOzI3NTk3MTc4NTtBUzozMDczNDYxMTc0NjQwNjRAMTQ1MDI4ODQzMjQyNg%3D%3D&el=1_x_6&_esc=publicationCoverPdf

Eur Arch Psychiatry Clin Neurosci (2006) 256 : 174–186 DOI 10.1007/s00406-005-0624-4

■ Abstract Background Childhood maltreatment ha

been linked to a variety of changes in brain structure
and function and stress-responsive neurobiological sys-
tems. Epidemiological studies have documented the im-
pact of childhood maltreatment on health and emo-
tional well-being. Methods After a brief review of the
neurobiology of childhood trauma, we use the Adverse

Childhood Experiences (ACE) Study as an epidemiolog-
ical “case example” of the convergence between epi-
demiologic and neurobiological evidence of the effects
of childhood trauma. The ACE Study included 17,337
adult HMO members and assessed 8 adverse childhood
experiences (ACEs) including abuse, witnessing domes-
tic violence, and serious household dysfunction. We
used the number of ACEs (ACE score) as a measure of
cumulative childhood stress and hypothesized a “dose-
response” relationship of the ACE score to 18 selected
outcomes and to the total number of these outcomes
(comorbidity). Results Based upon logistic regressio

analysis, the risk of every outcome in the affective, so-
matic, substance abuse, memory, sexual, and aggression-
related domains increased in a graded fashion as the
ACE score increased (P < 0.001). The mean number of comorbid outcomes tripled across the range of the ACE score. Conclusions The graded relationship of the ACE score to 18 different outcomes in multiple domains the- oretically parallels the cumulative exposure of the de- veloping brain to the stress response with resulting im- pairment in multiple brain structures and functions.

■ Key words child development · neurobiology ·
stress · childhood abuse · domestic violence · substance
· mental health

Introduction

The organization and functional capacity of the human
brain depends upon an extraordinary set and sequence
of developmental and environmental experiences that
influence the expression of the genome (Perry and Pol-
lard 1998; Teicher 2000, 2002). Unfortunately, this ele-
gant sequence is vulnerable to extreme, repetitive, or
abnormal patterns of stress during critical or circum-
scribed periods of childhood brain development that
can impair, often permanently, the activity of major neu-
roregulatory systems, with profound and lasting neu-
robehavioral consequences (Teicher 2000; Heim and Ne-

O R I G I N A L P A P E R

Robert F. Anda · Vincent J. Felitti · J. Douglas Bremner · John D. Walker ·
Charles Whitfield · Bruce D. Perry · Shanta R. Dube · Wayne H. Giles

The enduring effects of abuse and related adverse
experiences in childhood
A convergence of evidence from neurobiology and epidemiology

Received: 11 April 2005 / Accepted: 1 September 2005 / Published online: 29 November 2005

E
A

P
C

N
6

R. F. Anda, MD, MS (�) · Sh. R. Dube, MPH · W. H. Giles, MD, MS
Centers for Disease Control and Prevention
National Center for Chronic Disease Prevention
and Health Promotion
Division of Adult and Community Health
4770 Buford Highway, N.E., MS K-67
Atlanta, Georgia 30341-3717, USA
Tel.: + 1-770/488-5527
Fax: + 1-770/488-5965

V. J. Felitti, MD, FACP
Dept. of Preventive Medicine
Southern California Permanente Medical Group (Kaiser Permanente)
San Diego, CA, USA

J. D. Bremner, MD
Depts. of Psychiatry and Radiology
Emory Center for Positron Emission Tomography
Emory University School of Medicine, Atlanta, GA
Atlanta VA Medical Center
Decatur, GA, USA

J. D. Walker, MD
Dept. of State Health Services
Texas Health and Human Services Commission
Austin, TX, USA

Ch. Whitfield, MD
Private Practice in Addiction and Trauma Medicine
Atlanta, GA, USA

B. D. Perry, MD, PhD
The Child Trauma Academy
Houston, TX, USA
and
B. D. Perry, MD, PhD
Ministry of Children’s Services
Alberta, Canada

The ACE study was supported under cooperative agreement
#TS-44–10/11 from the CDC through the Association of Teachers of
Preventive Medicine and a grant from the Garfield Memorial Fund.

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 174

175

meroff 2001; Repetti 2002; Gutman and Nemeroff 2002;
Gorman 2002; De Bellis and Thomas 2003a; Bremner
and Vermetten 2001). Now, converging evidence from
neurobiology and epidemiology suggests that early life
stress such as abuse and related adverse experiences
cause enduring brain dysfunction that, in turn, affects
health and quality of life throughout the lifespan.

An expanding body of evidence from rodent, pri-
mate, and human research suggests that early stressors
cause long term changes in multiple brain circuits and
systems (Sanchez 2001; Bremner 2003a). The amygdala
mediates fear responses, and the prefrontal cortex is in-
volved in mood as well as emotional and cognitive re-
sponses (Bremner 2003b). The hypothalamic-pituitary-
adrenal (HPA) axis plays a critical role in the stress
response. There is an important interaction between de-
velopment and stress, e. g., young infants do not have a
fully developed glucocorticoid (cortisol in humans) re-
sponse to stress, although other markers such as c-fos
show that they do respond to stressors (Smith 1997).
Substantial research has focused on the relationship be-
tween development, early stress, the HPA axis, and the
hippocampus, a stress-sensitive brain region that plays
a critical role in learning and memory (McEwen 1992;
Sapolsky 1990, 1996; Gould and Tanapat 1999). The hip-
pocampus has the capacity to grow new neurons in
adulthood (neurogenesis), but stress inhibits neurogen-
esis (Nibuya 1995; Duman 1997; Gould 1997) and mem-
ory function (Diamond 1996; Luine 1994). Early stres-
sors cause long-term increases in glucocorticoid
responses to stress (Plotsky and Meaney 1993; Ladd
1996) as well as decreased genetic expression of cortisol
receptors in the hippocampus and increased genetic ex-
pression of corticotrophin-releasing factor in the hypo-
thalamus, both of which may contribute to dysregula-
tion of the hypothalamic-pituitary-adrenocortical
(HPA) system (Ladd 1996; Liu 1997). Early environmen-
tal deprivation inhibits hippocampal neurogenesis; con-
versely, neurogenesis is enhanced by enriched environ-
ment (Kempermann 1997), learning (Gould 1999a) and,
at times, some antidepressant treatments (Malberg
2000; Czeh 2001). The noradrenergic/locus coeruleus
system also plays a key role in stress (Bremner 1996a)
and early stressors lead to long-term decreases in ge-
netic expression of alpha-2 noradrenergic receptors in
the locus coeruleus, which may lead to loss of feedback
inhibition of noradrenergic activity with associated in-
creases in noradrenergic responses to subsequent stres-
sors (Sanchez 2001; Caldji 2000; Francis 1999). Alter-
ations in serotonergic (Rosenblum 1994; Bennett 200

and GABAergic (Caldji 2000) receptors also contribute
to deficits in social attachment and regulation of mood
and affect following early stress. Cognitive problems
have also been identified in children with PTSD (Beers
2002).

Studies in clinical populations of abuse survivors
with posttraumatic stress disorder (PTSD) are consis-
tent with animal studies. Smaller hippocampal volume
is found among adults with early abuse-related PTSD

(Bremner 1997, 2003a; Stein 1997), adult women with
early abuse and depression (Vythilingam 2002), and
borderline personality disorder (Driessen 2000;
Schmahl 2003) but not in children with PTSD (De Bellis
1999a, 2002; Carrion 2001) suggesting that early abuse
with chronic long-term stress-related psychiatric disor-
der is required for this finding. Consistent with deficits
in hippocampal function are deficits in verbal declara-
tive memory (Bremner 1995) and failure of hippocam-
pal activation with memory tasks (Bremner 2003a) in
adult women with early abuse-related PTSD. Children
with PTSD have smaller whole brain and corpus callo-
sum volume (Carrion and Steiner 2000; De Bellis 2002)
and alterations in structure of the cerebellum (Ander-
son 2002) and frontal cortex. (De Bellis and Thomas
2003b; Carrion 2001). Abused children also show alter-
ations in EEG activity in the frontal cortex (Teicher 1994,
1997; Ito 1998). Studies in adult women with early abuse-
related PTSD have shown altered function in the ante-
rior cingulate/medial prefrontal cortex while they were
remembering their childhood trauma (Bremner 1999;
Shin 1999). Similar to animal studies there is evidence of
dysregulation of the sympathetic nervous system in hu-
mans; early abuse and PTSD is associated with increased
cortisol and norepinephrine levels in children (Carrion
2002; De Bellis 1999, Gunnar 2001), down-regulated
platelet alpha-2 adrenergic receptors (Perry 1994), and
increased resting heart rate (Perry 2001) while adults
with early abuse and PTSD have low baseline (Bremner
2003b) and increased stress-induced cortisol responses
(Elzinga 2003; Bremner 2003c) and increased norepi-
nephrine at baseline (Lemieux and Coe 1995; El-Sheikh
2001). Women with early abuse and depression also have
increased cortisol reactivity to stress (Heim 2000, 2001).

Deprivation of developmentally appropriate experi-
ence may reduce neuronal activity, resulting in a gene-
ralized decrease in neurotrophin production, synaptic
connectivity, and neuronal survival (Gould and Tanapat
1999; Nibuya 1995; Duman 1997; Gould 1997) resulting
in profound abnormalities in brain organization and
structure (Perry 2002; Read 2001). Thus, childhood
abuse and exposure to domestic violence can lead to nu-
merous differences in the structure and physiology of
the brain that expectedly would affect multiple human
functions and behaviors (Perry and Pollard 1998;
Teicher 2000, 2002).

Numerous studies have established that childhood
stressors such as abuse or witnessing domestic violence
can lead to a variety of negative health outcomes and be-
haviors, such as substance abuse, suicide attempts, and
depressive disorders (Brodsky 1997; Kingree 1999; van
der Kolk 1991; Kendall-Tackett 1993; Osofsky 1999; Hef-
ferman 2000; Kendler 2000; Putnam 2003; Rohsenow
1988). This paper presents a conceptual framework that
integrates findings from recent studies of the neurobio-
logical effects of childhood abuse and exposure to do-
mestic violence on brain structure and function (as
reviewed above) with epidemiologic data from the Ad-
verse Childhood Experiences (ACE) Study. Although the

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 175

176

literature about the effects of childhood maltreatment is
extensive (Bremner 2000, 2003a, 2003b; Kendall-Tackett
1993), we use the data and findings from the ACE Study
as series of epidemiologic “case examples” in this paper
because it simultaneously assessed a wide range of in-
terrelated adverse experiences including abuse (emo-
tional, physical, or sexual); witnessing domestic vio-
lence; parental marital discord; growing up with
mentally ill, substance abusing, or criminal household
members (Dong 2003a; Dube 2004a, 2002b) whereas
most prior studies have focused on single forms of
abuse. In addition, the ACE Study assessed numerous so-
cial, behavioral, and health outcomes (Anda 1999, 2001,
2002a, 2002b; Dube 1999, 2002a, 2003a, 2003b; Felitti
1998; Dietz 1999; Hillis 2000, 2001, 2004; Dong, 2003b;
Edwards 2003a, 2003b; Chapman 2004; Whitfield 2003a)
that would necessarily involve the performance of mul-
tiple brain functions and neuroregulatory systems.
These aspects of the study design along with a large
sample size allow for the illustration of how the effects
of multiple forms of abuse and related stressors are cu-
mulative and affect a wide variety of outcomes that
might be expected based upon the neurobiological al-
terations reviewed above.

We used data from the ACE Study to test the follow-
ing hypotheses, which have their basis in the neuro-
sciences:
� The damaging effects of adverse childhood experi-

ences (ACEs) would be nonspecific, thereby affecting
a variety of functions and behaviors, because
abuse/traumatic stress affect a variety of brain struc-
tures and functions.

� The likelihood of disturbances in any given function
or behavior such as anxiety, sleep disturbances, sub-
stance abuse, sexuality, and hyperarousal or aggres-
sion would have a cumulative or “dose-response” re-
lationship to the number of ACEs, theoretically
paralleling the total exposure of the developing cen-
tral nervous system to the activated stress response
during childhood.

� The number of comorbidities (Lilienfeld 2003)
(mean number of human behaviors and functions af-
fected), which theoretically parallels the number of
brain systems and associated functions affected,
would also have a dose-response relationship to the
number of ACEs.

Methods

The ACE Study is an ongoing collaboration between Kaiser Perma-
nente’s Health Appraisal Center (HAC) in San Diego, California, and
the U. S. Centers for Disease Control and Prevention. The objective is
to assess the impact of numerous, interrelated, ACEs on a wide vari-
ety of health behaviors and outcomes and on health care utilization
and the methods of the study have been described in detail elsewhere.
(Anda 1999; Dube 1999; Felitti 1998).

The study population was drawn from the HAC, which provides
preventive health evaluations to adult members of Kaiser Health Plan
in San Diego County. All persons evaluated at the HAC complete a
standardized questionnaire, which includes health histories and

health-related behaviors, a medical review of systems, and psychoso-
cial evaluations which are a part of the ACE Study database.

Two weeks after their evaluation, each person evaluated at the
HAC between August 1995 and March 1996 (survey wave 1; response
rate 70 %) and June and October 1997 (survey wave 2; response rate
65 %) received the ACE Study questionnaire by mail. The question-
naire collected detailed information about ACEs including abuse, wit-
nessing domestic violence, and serious household dysfunction as well
as health-related behaviors from adolescence to adulthood. Wave 2 re-
spondents were asked detailed questions about health topics that
analysis of wave 1 data had shown to be important (Anda 2003a; Fe-
litti 1998; Dube 2003a; Dong 2003b). The response rate for both sur-
vey waves combined was 68 %, for a total of 18175 responses.

We excluded 754 respondents who coincidentally underwent ex-
aminations during the time frames for both survey waves, leaving an
unduplicated total of 17421. After exclusion of 84 respondents with
missing demographic information, the final sample included 95 % of
the respondents (17337/18175); (wave I = 8 708, wave II = 8 629).

■ Definitions of Adverse Childhood Experiences (ACEs)

Questions used to define ACEs are listed in Table 1. All questions
about ACEs pertained to the respondents’ first 18 years of life (≤ 18
years of age). For questions adapted from the Conflict Tactics Scale
(CTS) (Strauss and Gelles 1990) there were 5 response categories:
“never”, “once or twice”, “sometimes”, “often”, or “very often”. We de-
fined 3 types of childhood abuse: emotional abuse (2 questions),
physical abuse (2 questions), or contact sexual abuse (4 questions) by
Wyatt (1985). We defined 5 exposures to household dysfunction dur-
ing childhood: exposure to alcohol or other substance abuse (defined
by 2 questions) (Schoenborn 1991), mental illness (2 questions), vio-
lent treatment of mother or stepmother (4 questions) (Strauss 1990),
criminal behavior in the household (1 question), and parental sepa-
ration or divorce (1 question). Respondents were defined as exposed
to a category if they responded “yes” to 1 or more of the questions. De-
spite the sensitivity of these questions, the test-retest reliability for
every ACE and the ACE score were in the good to excellent range
(range of Cohen’s kappa: 0.46–0.86) (Dube 2004). Furthermore, a
comparison of respondents and nonrespondents to the ACE Study
questionnaire found no evidence of response rate bias or that re-
spondents were biased toward attributing their health problems to
childhood experiences (Edwards and Anda 2001).

The number of ACEs (range: 0–8) was summed to create the ACE
scores, with scores of 4 or more included as one category (≥ 4). Analy-
ses were conducted treating the ACE score as 4 dichotomous variables
(yes or no for scores of ≥ 4, 3, 2, and 1) with a score of 0 (no ACEs) as
the referent.

■ Epidemiological evidence of disordered brain function in adulthood

The data and definitions used for the outcomes that provide evidence
of disordered function were selected on an a priori basis using a gen-
eral framework of health and social problems that likely represent
dysfunction of specific brain systems and/or improper integration
between systems. We recognize that functional neuroanatomical and
physiologic systems are interactive and integrated and that behaviors
and health problems cannot generally be attributed to the function of
any single or particular system.

To define the health-related behaviors or problem sources, we
used information from the medical review of systems (ROS), the
physical examination (PE), and the ACE Study questionnaire (ACEQ).
In the definitions of these problems that follow, the source of the data
is in parentheses.

Mental health disturbances

■ Panic reactions (ROS). A “yes” response to the question: “Have you
had or do you now have special circumstances in which you find your-
self panicked?”

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 176

177

■ Depressed affect (ROS). A “yes” to the question,“Have you had or do
you now have depression or feel down in the dumps?”

■ Anxiety (ROS). A “yes” to the question, “Do you have much trouble
with nervousness?”

■ Hallucination (ROS). A “yes” response to the question, “Have you
ever had or do you have hallucinations (seen, smelled, or heard things
that weren’t really there)?”

Somatic disturbances

■ Sleep disturbance (ROS). A “yes” to “Do you have trouble falling
asleep or staying asleep” or a “yes” to “Tiredness, even after a good
night’s sleep?”

■ Severe obesity (PE). Body mass index (kg/m2) ≥ 35.

■ Multiple somatic symptoms (ROS). A total of 6 or more somatic
symptoms in at least 2 different organ systems in the absence of a di-
agnosis specific to those systems.

Substance abuse

■ Current Smoking–Nicotine (ACEQ). A “yes” to the question, “Do you
currently smoke cigarettes?”

■ Self-reported alcoholic (ACEQ). A “yes” to the question, “Have you
ever considered yourself to be an alcoholic?”

■ Ever used illicit drugs (ACEQ). A “yes” to the question,“Have you ever
used street drugs?”

■ Injected drug use (ACEQ). A “yes” to the question,“Have you ever in-
jected street drugs?”

Impaired memory of childhood

■ Impaired memory of childhood (ACEQ). A “yes” to the question, “Are
there large parts of your childhood after age 4 that you can’t remem-
ber?”

■ Number of age periods affected (ACEQ). Those who responded “yes”
to the previous were asked to check boxes indicating age periods (in
years) of impaired memory (4–6, 7–9, 10–12, 13–15, and 16–18). We
summed the number of boxes checked to assess the relationship of
the ACE score to the mean number of age periods affected. Informa-
tion about impaired memory was available only for the wave 1
(N = 8708).

Sexuality

■ Early intercourse (ACEQ). Age at first intercourse of 14 years or
younger.

■ Promiscuity (ACEQ). Lifetime sexual partners ≥ 30 (approximately
the 90th percentile for males and the 95th percentile for females).

■ Sexual dissatisfaction (ROS). A “no” to the question: “Are you cur-
rently satisfied with your sex life?”

Perceived stress, anger control, and risk of intimate partner violence

■ High level of perceived stress (ROS). A response indicating “high” to
the instruction,“Please fill in the circle that best describes your stress
level (high, medium, low).”

■ Difficulty controlling anger (ROS). A “yes” to the question, “Do you
have or have you had reason to fear your anger getting out of control?”

■ Risk of perpetrating intimate partner violence (ROS). A “yes” to the
question, “Have you ever threatened, pushed, or shoved your part-
ner?” Data about the risk of perpetrating intimate partner violence
was available only for wave 2 (N = 8629).

Number of comorbid outcomes

We summed the number of outcomes (range: 0–18) for each respon-
dent to quantitate the amount of comorbidity (mean number of dis-
ordered functions) associated with increasing ACE scores.

■ Statistical analysis

Adjusted odds ratios (OR) and 95 % confidence intervals (CI) were
obtained from logistic regression models using The SAS System Ver-
sion 8.2, which assessed the associations between the ACE score (0, 1,
2, 3, or ≥ 4) and each of the 18 outcome measures. We used multiple

Table 1 Definition and prevalence of each category of adverse childhood experi-
ence and the ACE score

Total
Childhood abuse N = 17,337

Emotional abuse 10.6
(Did a parent or other adult in the household . . .)

1) Often or very often swear at you, insult you, or put you
down?

2) Sometimes, often, or very often act in a way that made
you fear that you might be physically hurt?

Physical 28.3
(Did a parent or other adult in the household . . .)

1) Often or very often push, grab, slap, or throw something
at you?

2) Often or very often hit you so hard that you had marks or
were injured?

Sexual 20.7
(Did an adult or person at least 5 years older ever . . .)

1) Touch or fondle you in a sexual way?
2) Have you touch their body in a sexual way?
3) Attempt oral, anal, or vaginal intercourse with you?
4) Actually have oral, anal, or vaginal intercourse with you?

Household dysfunction
Substance abuse 26.9

1) Live with anyone who was a problem drinker or alcoholic?
2) Live with anyone who used street drugs?

Mental illness 19.4
1) Was a household member depressed or mentally ill?
2) Did a household member attempt suicide?

Mother treated violently 12.7
(Was your mother (or stepmother)):

1) Sometimes, often, or very often pushed, grabbed,
slapped, or had something thrown at her?

2) Sometimes, often, or very often kicked, bitten, hit with a
fist, or hit with something hard?

3) Ever repeatedly hit over at least a few minutes?
4) Ever threatened with or hurt by a knife or gun?

Incarcerated household member 4.7
1) Did a household member go to prison?

Parental separation or divorce 23.3
1) Were your parents ever separated or divorced?

Number of adverse childhood experiences (ACE score)
0 36.1
1 26.0
2 15.9
3 9.5

≥ 4 12.5

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 177

178

linear regression to estimate the number of comorbid outcomes by
ACE score. Covariates in all multivariate models included age, sex,
race (other versus white), and education (high school diploma, some
college, or college graduate versus less than high school).

Results

The final study sample included 9367 (54 %) women and
7970 (46 %) men. The mean age was 56 years for women
and 58 years for men. Seventy-three percent of women
and 76 % of men were white; 34 % of women and 45 % of
men were college graduates, and another 37 % and 34 %,
respectively had some college education.

■ Prevalence of the adverse childhood experiences

At least 1 ACE was reported by 64 % of respondents. The
prevalence of each ACE is shown in Table 1.

■ ACE score and the risk of health
and behavioral outcomes

The ACE score had a strong, graded relationship to the
prevalence and risk (adjusted OR) of affective disturb-
ances (P < 0.001; Table 2, mental health disturbances). For persons with ≥ 4 ACEs, the risk of panic reactions, depressed affect, anxiety, and hallucinations were in- creased 2.5-, 3.6-, 2.4 and 2.7-fold, respectively (Table 2).

The ACE score also had a graded relationship to the
prevalence and risk (adjusted OR) each of the somatic
disturbances (P < 0.001; Table 2, somatic health distur- bances). The risk of sleep disturbance, severe obesity, and multiple somatic symptoms were increased 2.1-, 1.9-, and 2.7-fold, respectively, for persons with 4 or more ACEs.

Substance use and abuse also increased as the ACE
score increased. The risk of smoking, alcoholism, illicit
drug use, and injected drug use were increased 1.8-,
7.2-, 4.5-, and 11.1-fold, respectively, for persons with ≥ 4
ACEs (Table 3, substance abuse).

Similarly, all three measures of sexuality were associ-
ated with the ACE score (Table 3, sexuality). The risk of
early intercourse, promiscuity, and sexual dissatisfac-
tion were increased 6.6-, 3.6-, and 2-fold, respectively, for
persons with ≥ 4 ACEs (Table 3).

The risk of impaired memory of childhood was in-
creased 4.4-fold for persons with ≥ 4 ACEs (Table 4). The
number of age periods affected for memory disturb-
ances increased in a graded fashion as the ACE score
increased (P < 0.0001; Table 4).

High perceived stress, difficulty controlling anger,
and the risk of perpetrating intimate partner violence
(IPV) were increased 2.2-, 4.0-, and 5.5-fold, respectively,
for persons with ≥ 4 ACEs (Table 5). We found (data not
shown) that the adjusted odds ratio (95 % CI) for the re-
lationship between difficulty controlling anger and the
risk of perpetrating IPV were 6.3 (4.4–9.0) for men and Ta

b
le

2
Re

la
tio

ns
hi

p
of

th
e

A
CE

s
co

re
to

th
e

pr
ev

al
en

ce
a

nd
re

la
tiv

e
ris

k
(a

dj
us

te
d

od
ds

ra
tio

)*
o

d
is

tu
rb

an
ce

s
in

tw
o

m
aj

or
d

m
ai

ns
o

f d
ys

fu
nc

tio
n:

m
en

ta
l a

nd
s

m
at

ic
h

ea
lth

d
is
tu
rb
an
ce
s

M
en

ta
l h

ea
lth
d
is
tu
rb
an
ce

s
So

m
at
ic
h
ea
lth
d
is
tu
rb
an
ce
s

Pa
ni

c
re

ac
tio

ns
D

ep
re

ss
ed

a
ff

ec
t

A
nx

ie
ty

H
al

lu
ci

na
tio

ns
Sl

ee
p

di
st

ur
ba

nc
e

Se
ve

re
o

be
si

ty
M

ul
tip

le
s

om
at

ic
s

ym
pt

om
s

A
CE

)
%

A
dj

us
te

d
%

A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te

d
sc

or
e

od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio

0
(6

8.
3

1.
0

(r
ef

er
en

4
1.

0
(r

ef
er

en
t)

7.
8

1.
0
(r
ef
er
en

t)
1.

3
1.

0
(r
ef
er
en
t)

36
.3

1.
0
(r
ef
er
en

t)
5.

6
1.

0
(r
ef
er
en
t)

5.
1

1.
0
(r
ef
er
en
t)

1
(4

51
4)

10
.9

1.
3

(1
.2

–
1.

5)
25

2
1.

5
(1

.3
–

9.
1

1.
2

(1
.1

–
1.

4)
1.

5
1.

1
(0

8
–

1.
5)

41
.6

1.
2
(1
.1
–
1.

3)
7.

4
1.

3
(1

.1
–

1.
5)

6.
4

1.
3
(1
.1
–
1.
5)

2
(2

75
8)

13
.6

1.
7

(1
.4

–
1.

9)
34

1
2.

2
(2

.0
–

2.
4)

12
.4

1.
7
(1
.4
–
1.

9)
2.

3
1.

6
(1

.2
–

2.
3)

47
.5

1.
6

(1
.4
–
1.

)
8.

3
1.

4
(1

.2
–

1.
7)

8.
6

1.
8

(1
.5

–
2.

3
(1

16
.8

2.
0

(1
.7

–
2.

4)
38

.8
2.

5
(2

.2
–

2.
8)

14
.1

1.
8

(1
.6

–
2.

2)
2.

9
2.

0
(1

4
–

2.
9)

51
.1

1.
8
(1
.6
–
2.

0)
8.

8
1.

5
(1
.2
–

1.
8)

8.
1

1.
6

(1
.3

–
2.
0)

≥
4

(2
16

0)
20

.9
2.

5
(2
.2
–
2.
9)

49
.0

3.
6

(3
.2

–
4.

0)
19

.0
2.

4
(2

.1
–
2.
8)

4.
0

2.
7

(1
.9

–
3.

7)
56

.1
2.

1
(1

.9
–

2.
4)

11
.9

1.
9

(1
.6
–
2.

2)
13

.9
2.

7
(2

.3
–

3.
2)

To
ta

l
(1

73
37

)
12

.2
–

28
.4

–
10

.9
–

2.
0

–
43

.3
–

7.
6

–
7.

4
–

*
A

ll
od

ds
ra

tio
s

ar
e

ad
ju

st
ed

fo
r a

ge
, s

ex
, r

ac
e,

a
nd

e
du

ca
tio

na
l a

tt
ai

nm
en

t u
si

ng
lo

gi
st

ic
re

gr
es

si
on

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 178

179

7.6 (5.3–11.1) for women (P < 0.001). Similarly (data not shown), the adjusted odds ratio (95 % CI) for the rela- tionship between perceived high stress and the risk of perpetrating IPV was the same for both men and women: 1.8 (1.4–2.3), (P < 0.001).

■ ACE score and number of comorbid outcomes

As the ACE score increased, the mean number of co-
morbid outcomes increased in a graded fashion (Fig. 1),
nearly tripling between ACE scores of 0 and ACE scores
of 7–8.

Ta
b

le
3

Re
la

tio
ns

hi
p

of
th

e
A

CE
s

co
re

to
th

e
pr

ev
al

en
ce

a
nd

re
la

tiv
e

ris
k

(a
dj

us
te

d
od

ds
ra

tio
)*

o
f d

is
tu

rb
an

ce
s

in
tw

o
do

m
ai

ns
: s

ub
st

an
ce

a
bu

se
a

nd
s

ex
ua

lit
y

Su
bs

ta
nc

e
ab

us
e

Se
xu

al
ity

Sm
ok

in
g

A
lc

oh
ol

is
m

Ill
ic

it
dr

ug
u

se
In

je
ct

ed
d

ru
g

us
e

Ea
rly

in
te

rc
ou

rs
e

Pr
om

is
cu

ity
(≥

30
p

ar
tn

er
s)

Se
xu

al
d

is
sa

tis
fa

ct
io

n
A
CE

(N
)
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
%
A
dj
us
te
d
sc
or
e
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
od
ds
ra
tio
0
(6

25
5)

6.
5

1.
0
(r
ef
er
en

t)
2.

5
1.
0
(r
ef
er
en
t)

7.
9

1.
0
(r
ef
er
en

t)
0.

2
1.
0
(r
ef
er
en
t)

2.
3

1.
0
(r
ef
er
en

t)
3.

9
1.

0
(r
ef
er
en
t)

23
.0

1.
0
(r
ef
er
en
t)
1
(4
51
4)
7.
6

1.
1

(0
.9

4–
1.

3)
5.

1
2.
0
(1

.6
–

2.
4)

13
.8

1.
6
(1
.4
–
1.

8)
0.

6
2.

3
(1
.2
–

4.
4)

5.
1

2.
1

(1
.7
–
2.

6)
5.

2
1.
3
(1
.1
–
1.
5)

24
.8

1.
1
(1
.1
–
1.
2)
2
(2
75
8)

9.
3

1.
3
(1
.1
–
1.

5)
7.

4
2.

9
(2

.4
–

3.
6)

20
.0

2.
2

(1
.9
–
2.

6)
1.

4
4.

5
(2
.4
–

8.
4)

6.
6

2.
7

(2
.2

–
3.

4)
7.

4
1.

9
(1

.5
–

2.
3)

28
.9

1.
5

(1
.3
–
1.
6)
3
(1

65
0)

11
.9
1.
6
(1
.3
–
1.

9)
10

.5
4.

5
(3

.6
–

5.
6)

24
.9

2.
9

(2
.5

–
3.
4)
1.

6
5.

3
(2

.7
–

10
.2

)
8.

5
3.

7
(2
.9
–

4.
7)

8.
7

2.
5

(2
.0

–
3.

0)
28

.1
1.

5
(1
.3
–
1.
7)
≥
4
(2
16

0)
14

.5
1.

8
(1

.5
–

2.
1)

15
.3

7.
2

(5
.9

–
8.

9)
35

.2
4.

5
(3
.9
–

5.
2)

3.
7

11
.1

(6
.2

–
19

.9
)

14
.2

6.
6

(5
.3

–
8.

2)
10

.8
3.

6
(3

.0
–
4.
4)

32
.3

2.
0

(1
.8

–
2.
2)
To
ta
l
(1
73
37
)
8.
8
–

6.
3

–
16

.5
–

1.
1

–
5.

8
–

6.
1

–
26

.0
–
*
A
ll
od
ds
ra
tio
s
ar
e
ad
ju
st
ed
fo
r a
ge
, s
ex
, r
ac
e,
a
nd
e
du
ca
tio
na
l a
tt
ai
nm
en
t u
si
ng
lo
gi
st
ic
re
gr
es
si
on

Table 4 Relationship of the ACE score to the prevalence and relative risk (adjusted
odds ratio)* of problems with memory impairment for childhood and to the mean
number of age periods affected

Prevalence and risk of memory Number of age
impairment periods affected**

ACE score (N)*** % Adjusted odds ratio Mean** (SD)

0 (3202) 9.7 1.0 (referent) 0.19 (0.02)

1 (2246) 12.0 1.3 (1.1–1.5) 0.23 (0.02)

2 (1379) 18.9 2.1 (1.8–2.6) 0.35 (0.02)

3 (834) 22.1 2.6 (2.1–3.1) 0.40 (0.03)

≥ 4 (1047) 34.0 4.4 (3.7–5.2) 0.69 (0.03)

Total (8708) 15.8 – –

* All odds ratios are adjusted for age, sex, race, and educational attainment using
logistic regression; ** The mean number of age periods affected was adjusted for
the same demographic variables using linear regression; *** The sample size is
8708 because data about memory impairment were available for the wave 1 sur-
vey only

Fig. 1 The mean number of comorbid outcomes in the study sample was 2.1
(range: 0–14); means are adjusted for age, sex, race, and educational attainment.
The trend in the means is significant (P < 0.0001); vertical error bars represent 95 % confidence intervals

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 179

180

Discussion

These epidemiological findings converge with evidence
from neurobiology about numerous effects of child-
hood stress on brain and physical systems (Glaser 2000).
Extreme, traumatic or repetitive childhood stressors
such as abuse, witnessing or being the victim of domes-
tic violence, and related types of ACES are common,
tend to be kept secret, and go unrecognized by the out-
side world. Likewise, the fight-or-flight response among
children exposed to these types of stressors, and the at-
tendant release of endogenous catecholamines and
adrenal corticosteroids are both uncontrollable and in-
visible (Perry 1998; Teicher 2002; De Bellis 1994, 1997;
Scaer 2001). Furthermore, the detrimental effects of

traumatic stress on developing neural networks and on
the neuroendocrine systems that regulate them have un-
til recently remained hidden even to the eyes of most
neuroscientists. However, the information and data that
we present herein suggest that this veiled cascade of
events represents a common pathway to a variety of im-
portant long-term behavioral, health, and social prob-
lems (Table 6).

The convergence of evidence from neurobiology and
epidemiology calls for an integrated perspective on the
origins of health and social problems throughout the
lifespan. This constellation of effects from childhood
stressors calls to mind the wisdom of Occam’s razor, a
celebrated dictum in medicine, which holds that if a sin-
gle unifying explanation can be found for multiple
symptoms and problems, then it is likely that the correct

High level of Difficulty Risk of perpetrating
perceived stress controlling anger intimate partner violence

ACE score (N) % Adjusted % Adjusted (N)* % Adjusted
odds ratio** odds ratio** odds ratio**

0 (6255) 10.5 1.0 (referent) 3.5 1.0 (referent) (3053) 1.6 1.0 (referent)

1 (4514) 13.5 1.2 (1.1–1.4) 4.9 1.4 (1.1–1.7) (2268) 3.0 1.8 (1.2–2.6)

2 (2758) 16.0 1.4 (1.3–1.6) 8.0 2.2 (1.8–2.7) (1379) 4.0 2.4 (1.6–3.5)

3 (1650) 17.8 1.5 (1.3–1.8) 8.5 2.3 (1.9–2.9) (816) 5.4 3.3 (2.1–5.0)

≥ 4 (2160) 24.7 2.2 (1.9–2.5) 14.4 4.0 (3.3–4.8) (1113) 8.8 5.5 (3.8–7.8)

Total (17337) 14.6 – 6.4 – (8629) 3.6 –

* All odds ratios are adjusted for age, sex, race, and educational attainment using logistic regression. The adjusted
odds ratio (95 % CI) for the relationship between difficulty controlling anger and the risk of perpetrating IPV were:
6.3 (4.4–9.0) for men; 7.6 (5.3–11.1) for women. The adjusted odds ratio (95 % CI) for the relationship between
high perceived stress and the risk of perpetrating IPV was the same for both men and women: 1.8 (1.4–2.3).
** The sample size is 8629 because data about memory impairment were available for the wave 2 survey only

Table 5 Relationship of the ACE score to the preva-
lence and relative risk (adjusted odds ratio)* of high
perceived stress, difficulty controlling anger, and risk
of perpetrating intimate partner violence during
adulthood

Table 6 Summary of the convergence between neurobiological effects of childhood maltreatment with ACE study epidemiological findings

Area of function or dysfunction studied Demonstrated neurobiological defects from early trauma ACE study findings

Anxiety, panic, depressed affect, Repeated stress & childhood trauma → hippocampus, Tables 2 and 3
hallucinations, and substance abuse amygdala & medial prefrontal cortex atrophy and Unexplained panic, depression, anxiety,

dysfunction that mediate anxiety & mood problems hallucinations & alcohol & other drug problems

Smoking, alcoholism, illicit drug use, Repeated stress & childhood trauma → Increased locus Table 3
injected drug use coeruleus & norepinephrine activity, decreased by Increased smoking, alcohol and other drug use

heroin & alcohol

Early intercourse, promiscuity, sexual Repeated stress & childhood trauma → amygdala defects; Tables 3 and 5
dissatisfaction, perpetration of intimate role in sexual & aggressive behavior and deficits in oxytocin Risky sexual behavior, anger control, risk for
partner violence with impaired pair bonding aggression against intimate partners

Memory storage and retrieval Hippocampus role in memory storage and retrieval; Table 4
hippocampal & amygdala size reduction in childhood Impaired memory of childhood and number age
trauma; deficits in memory function periods affected increases as the ACE score increase

Body weight and obesity Repeated stress & distress, via glucocorticoid pathways, Table 2
leads to increased intra-abdominal & other fat deposits Increased obesity

Sleep, multiple somatic symptoms, Repeated stress & distress, via several pathways, leads to Tables 2 and 5
high perceived stress increase in other physical problems Increased somatic symptoms and disorders, including

sleep problems

Co-morbidity/Trauma spectrum disorders Multiple brain and nervous system structure and function Fig. 1
defects, including monoamine neurotransmitter systems The graded relationship of the ACE score to psychiatric

and physical symptoms or disorders, including
multiple co-occurring problems (comorbidity)

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 180

181

explanation lies in the simplest account (Lo Re and
Bellini 2002). In the context of what we present herein,
the application of this dictum has the potential to unify
and improve our understanding of many seemingly un-
related, but often co-morbid health and social problems
that have historically been seen and treated as categori-
cally independent in Western culture.

Certain neurobiological findings are especially con-
gruent with the data from the ACE Study reported
herein (Table 6). Magnetic resonance imaging (MRI) has
revealed reductions in hippocampus (Bremner 1997,
2003a; Stein 1997), and amygdala (Driessen 2000;
Schmahl 2003) volumes as well as deficits in verbal de-
clarative memory measured with neuropsychological
testing (Teicher 2000; Heim and Nemeroff 2001) among
women who were sexually abused as children. The hip-
pocampus plays a role in memory storage and retrieval;
we found that impaired memory of childhood increases
as the ACE score increases. Neurobiological evidence
supports the hypothesis of dysfunction in hippocam-
pus, amygdala, medial prefrontal cortex, and other lim-
bic structures believed to mediate anxiety and mood
dysregulation following early abuse (Teicher 2002). We,
in turn, demonstrated a graded relationship of the ACE
score to affective symptoms and unexplained periods of
panic among our study participants. We found that a
history of hallucinations increases as the ACE score in-
creases; these symptoms may be related to alterations in
hippocampal and/or prefrontal cortical function. The
amygdala plays a critical role in fear responses and prob-
ably sexual and aggressive behaviors (Pinchus and
Tucker 1978) and in the current study we show strong re-
lationships of the ACE score to sexual behaviors, poor
anger control, and the risk for perpetrating intimate
partner violence.

The current study adds support for numerous effects
of childhood adverse experiences on physical health.
Stress is known from animal studies to be associated
with a broad range of effects on physical health, includ-
ing cardiovascular disease, hypertension, hyperlipi-
demia, asthma, metabolic abnormalities, obesity, infec-
tion, and other physical disorders (Musselman 1998;
Kaplan 1982; Rozanski, McEwen and Stellar 1993; Anda
1993). Findings of increased obesity as the ACE score in-
creases in this study and reported elsewhere (William-
son 2002) are consistent with animal studies showing
that stress, acting through the effects of glucocorticoids
on the glucocorticoid receptor on intra-abdominal
adipocytes, leads to increased intra-abdominal fat
which carries its own independent mortality risk.

We found a strong relationship between early adverse
experience and substance use and abuse (illicit drugs,
alcohol, and nicotine) later in life. Studies in animals
show that early stressors lead to increased activity of the
locus coeruleus with resultant increased release of nor-
epinephrine in the brain (Abercrombie and Jacobs
1987). Substances such as heroin and alcohol decrease
firing of the locus coeruleus, while substance with-
drawal has the opposite effect (Bermner 1996). Consis-

tent with this, the onset of substance abuse corresponds
to the time of traumatization in PTSD patients, and
these patients report that heroin and alcohol decrease
symptoms of PTSD (Bremner 1996b). Stress also results
in altered release of dopamine in the nucleus accumbens
(striatum), the primary reward system within the brain
(Deutch and Roth 1990). Smoking causes release of
dopamine in this area, which is felt to underlie the ad-
dictive properties of nicotine (Volkow 2003). Early ad-
verse experiences may disrupt this dopamine circuit,
leading to increased risk of smoking, with its attendant
negative health consequences. In summary, findings
from animal studies provide a physiological rationale
for how early stress can be associated with substance
abuse and smoking in later life.

Another interesting finding is the relationship be-
tween ACE score and sexuality (early intercourse,
promiscuity, sexual dissatisfaction) in adulthood. Ani-
mal studies show that early stressors result in long-term
changes in peptides such as oxytocin that regulate pair
bonding and social attachment (Insel and Winslow 1998;
Francis 2002). Early adverse experiences may disrupt
the ability to form long-term attachments in adulthood.
The unsuccessful search for attachment may lead to sex-
ual relations with multiple partners, with resultant
promiscuity and other issues related to sexuality.

The monoamine neurotransmitter systems (norepi-
nephrine, dopamine, serotonin) (Valentsein 1998) act
within a primary regulatory system of large neural net-
works; these monoamine systems help to orchestrate
complex neural functions. Their ubiquitous patterns of
connectivity originate in the lower regions of the brain
and send projections throughout the brain; in addition,
they receive input from the autonomic nervous system
and peripheral sensory apparatus (Foote 1983). In
young animals, experimental manipulation of these sys-
tems can create behaviors similar to those seen in abuse
victims, including aggression, eating problems, alcohol
use, stress-response dysfunction, hyper-reactivity, an-
ergy, and many other behavioral problems. A similar sit-
uation exists in humans in whom monoamine dysfunc-
tion has been hypothesized in a host of neuropsychiatric
syndromes, including aggressive and violent behavior,
suicidality, alcoholism, substance abuse and depen-
dence, depression, anxiety disorders, and social/rela-
tional problems. We know from several studies that the
functioning of these monoamine systems in adults is in-
fluenced by childhood experiences (De Bellis 1999b;
Whitfield 2003b). In addition, a recent study of a poly-
morphism for the promoter region of the serotonin
transporter (5-HTT) gene found that childhood mal-
treatment increased the risk of depression in early
adulthood for persons with the common “short” allele
compared to persons with the long allele; the short allele
is associated with lower transcriptional efficiency of the
promoter (Caspi 2003). Not surprisingly, many currently
prescribed psychoactive drugs act by altering the dy-
namics of these monoamine systems. In some circum-
stances, the effects of these drugs may have caused an

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 181

182

oversight of the important distinction between under-
standing intermediary mechanisms (alterations in
monoamine neurotransmitter systems) and recognizing
the underlying causes of these alterations (childhood
traumatic stress).

Numerous studies have shown that early abuse sur-
vivors have multiple overlapping psychiatric disorders
(Kessler 1995) which have been described as “comorbid-
ity”. The term comorbidity, however, can imply that these
represent unique disorders with distinct etiologies (Lil-
lienfeld 2003). An alternative explanation is that several
disorders (e. g., depression, PTSD, dissociative disorders,
substance abuse, borderline personality disorder) have
to varying degrees a common etiology and are modu-
lated by genetics (Caspi 2003) and repeated exposure to
stress such as childhood maltreatment. Indeed, the term
“trauma spectrum disorders” has been used to describe
these overlapping conditions (Bremner 2003b). In addi-
tion, the artificial distinction between psychiatric and
physical disorders has represented an impediment to the
effective treatment of the numerous problems among
survivors of childhood maltreatment. Epidemiological
findings are consistent with a need to develop more
broad based approaches to addressing the wide spec-
trum of effects of childhood maltreatment (Fig. 1).

There are several potential limitations with retro-
spective reporting of childhood experiences and self-
reporting of the outcome measures. For example, re-
spondents may have had difficulty recalling certain
childhood events (Edwards 2001) or may choose not to
disclose certain experiences or personal behaviors. Lon-
gitudinal follow-up of adults whose childhood abuse
was documented has shown that their retrospective re-
ports of childhood abuse are likely to underestimate ac-
tual occurrence (DellaFemina 1990; Williams 1995). In-
terestingly, evidence of the effects of traumatic stress in
childhood on the hippocampus provides a neurophysi-
ologic explanation for this phenomenon. Difficulty re-
calling childhood events likely results in misclassifica-
tion (classifying persons truly exposed to ACEs as
unexposed) that would bias our results toward the null
(Rothman and Greenland 1998). Thus, this potential
weakness probably resulted in underestimates of the
true strength of the relationships between ACEs and the
18 outcomes we examined.

The historical mind-body dichotomy that persists in
traditional Western medical training points medical re-
searchers and clinicians away from risk factors that may
be judged psychosocial. Thus, the original traumatic
pathophysiological insults may be “silent” until much
later in life (Brown 2001; Putnam 1998), when they are
likely to be overlooked by investigators and clinicians
who are understandably prone to focus on proximate
determinants of human well-being. This leads to treat-
ment of symptoms without a full understanding of their
potential origins in the disruptive effects of ACEs on
childhood neurodevelopment.

The argument for a causal relationship between ACEs
and a variety of outcomes is strengthened by the com-

bined evidence from neurobiology and epidemiology.
This argument is important because evidence of causa-
tion affects decisions about prognosis, diagnosis, and
treatment and can enhance understanding of the role of
the childhood stressors on the developing brain in pro-
ducing changes in affect, behavior, and cognition (Put-
nam 1998).

We summarize the application of Sir Bradford Hill’s 9
criteria for establishing an argument for causation (van
Reekum 2001) in the context of this converging evi-
dence:
� Demonstration of a strong association between the

causative agent and the outcome. The strength of the
relationship between ACEs and numerous outcomes
is consistently strong as reported herein.

� Consistency of findings across research sites and
methods. Numerous studies in different study popu-
lations and measures of abuse, neglect, and related
experiences have shown relationships of ACEs to a
variety of symptoms and behaviors.

� Specificity. In the context of the converging evidence
from epidemiology and neurobiology, specificity is
lacking, but this in no way detracts from the argu-
ment of causation. The ACE score is a combined score
representing cumulative stress and was not designed
to provide evidence of specificity. Moreover, ACEs
would be expected to be associated with multiple out-
comes because of their effects on a variety of brain
structures and functions.

� Temporal sequence. Most of the outcomes presented
herein occurred during adulthood; the exposures
(childhood experiences) clearly antedate the out-
comes in these cases.

� Biological gradient. The “dose-response” relationship
between the number of ACEs and each of the out-
comes (as well as the number of comorbid outcomes)
is strong and graded. This is consistent with cumula-
tive effects of childhood stress on the developing
brain.

� Biological plausibility. The strength of the conver-
gence between epidemiology and neurobiology is
most evident here. Recent studies from the neuro-
sciences show that childhood stress can affect nu-
merous brain structures and functions providing
convincing biologic plausibility for the epidemio-
logic findings.

� Coherence. “The term coherence implies that a cause
and effect interpretation for an association does not
conflict with what is known about the natural history
and biology of the disease (Rothman 1998).” In fact,
recent research shows that childhood maltreatment
interacts with a common functional polymorphism
in the promoter region of the serotonin transporter
5-HTT, resulting in higher risk of depression and sui-
cidality (Caspi 2003), both of which are associated
with the ACE score. This information is consistent
with an effect of early maltreatment on monoamine
pathways known to be involved in depressive disor-
ders.

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 182

183

� Experimental evidence. This is the most persuasive
evidence, but for ethical reasons randomized experi-
ments depend on animal studies. Evidence from
studies in rodents and primates show that stressful
exposures induce neuroanatomical and neurophysi-
ologic differences as well as aggression and drug
seeking behaviors.

� Analogous evidence. A widely acknowledged analogy
for an exposure causing a multitude of outcomes (as
seen with ACEs, including a dose-response relation-
ship) is the causal relationship of cigarette smoking
to cardiovascular diseases, neoplasms, lung disease,
and other health problems (CDC, 2002).

In conclusion, there is a striking convergence of recent
findings from the neurosciences with those from a large
epidemiologic study of the long-term effects of ACEs
which has the potential to open multidisciplinary ap-
proaches to studying and improving human well-being.
Current practices of medicine and public health are
fragmented by categorical funding, organizational
boundaries, and a symptom-based system of medical
care. Prevention and remediation of our nation’s leading
health and social problems is likely to benefit from un-
derstanding that many of these problems tend to be co-
morbid and may have common origins in the enduring
neurodevelopmental consequences of abuse and related
adverse experiences during childhood.

References

1. Abercrombie ED, Jacobs BL (1987) Single-unit response of no-
radrenergic neurons in the locus coeruleus of freely moving
cats. I. Acutely presented stressful and non-stressful stimuli. J
Neurosci 7:2837–2847

2. Anda RF, Chapman DP, Felitti VJ, Edwards VE, Williamson DF,
Croft JP, Giles WH (2002a) Adverse Childhood Experiences and
Risk of Paternity in Teen Pregnancy. Obstet Gynecol 100:37–45

3. Anda RF, Croft JB, Felitti VJ, Nordenberg D, Giles WH, William-
son DF, Giovino GA (1999) Adverse childhood experiences and
smoking during adolescence and adulthood. J Am Med Assoc
282:1652

4. Anda RF, Felitti VJ, Chapman DP, Croft JB, Williamson DF, San-
telli J, Dietz PM, Marks JS (2001) Abused boys, battered moth-
ers, and male involvement in teen pregnancy. Pediatrics 107(2):
e19

5. Anda RF,Whitfield CL, Felitti VJ, Chapman D, Edwards VJ, Dube
SR, Williamson DF (2002b) Adverse childhood experiences, al-
coholic parents and later risk of alcoholism and depression.
Psychiatr Serv 53:1001–1009

6. Anda RF, Williamson D, Jones D, Macera C, Eaker E, Glassman
A, Marks J (1993) Depressed affect, hopelessness and the risk of
ischemic heart disease in a cohort of US adults. Epidemiology
4:285–294

7. Anderson CM, Teicher MH, Polcari A, Renshaw PI (2002) Ab-
normal T2 relaxation time in the cerebellar vermis of adults
sexually abused in childhood: potential role of the vermis in
stress-enhanced risk for drug abuse. Psychoneuroendocrinol-
ogy 27:231–244

8. Beers SR, De Bellis MD (2002) Neuropsychological function in
children with maltreatment-related posttraumatic stress disor-
der. Am J Psychiatry 159(3):483–486

9. Bennett AJ, Lesch KP, Heils A, Long JC, Lorenz JG, Shoaf SE,
Champoux M, Suomi SJ, Linnoila MV, Higley JD (2002) Early
experience and serotonin transporter gene variation interact to
influence primate CNS function. Mol Psychiatry 7:118–122

10. Bremner JD (2003a) Long-term effects of childhood abuse on
brain and neurobiology. Child Adolesc Psychiatr Clin North Am
12:271–292

11. Bremner JD (2003b) Does Stress Damage the Brain? Under-
standing trauma-based disorders from a neurological perspec-
tive. New York: Norton

12. Bremner JD, Krystal JH, Southwick SM, Charney DS (1996a)
Noradrenergic mechanisms in stress and anxiety: I Preclinical
studies. Synapse 23:28–38

13. Bremner JD, Narayan M, Staib LH, Southwick SM, McGlashan T,
Charney DS (1999) Neural correlates of memories of childhood
sexual abuse in women with and without posttraumatic stress
disorder. Am J Psychiatry 156:1787–1795

14. Bremner JD, Randall P, Scott TM, Capelli S, Delaney R, Mc-
Carthy G, Charney DS (1995) Deficits in short-term memory in
adult survivors of childhood abuse. Psychiatry Res 59:97–107

15. Bremner JD, Randall P,Vermetten E, Staib L, Bronen RA, Mazure
C, Capelli S, McCarthy G, Innis RB, Charney DS (1997) Magnetic
image resonance-based measurement of hippocampal volume
in posttraumatic stress disorder related to childhood physical
and sexual abuse: a preliminary report. Biol Psychiatry 41:
23–32

16. Bremner JD, Southwick M, Darnell MA, Charney DS (1996b)
Chronic PTSD in Vietnam combat veterans: Course of illness
and substance abuse. Am J Psychiatry 153:369–375

17. Bremner JD, Vermetten E (2001) Stress and development: be-
havioral and biological consequences. Dev Psychopathol 13:
473–489

18. Bremner JD, Vythilingam M, Anderson G, Vermetten E, Mc-
Glashan T, Heninger G, Rasmusson A, Southwick SM, Charney
DS (2003) Assessment of the hypothalamic-pituitary-adrenal
(HPA) axis over a 24-hour diurnal period and in response to
neuroendocrine challenges in women with and without early
childhood sexual abuse and posttraumatic stress disorder
(PTSD). Biol Psychiatry 54:710–718

19. Bremner JD,Vythilingam M,Vermetten E, Adil J, Khan S, Nazeer
A, Afzal N, McGlashan T, Elzinga B, Anderson GM, Heninger G,
Southwick SM, Charney DS (2003) Cortisol response to a cog-
nitive stress challenge in posttraumatic stress disorder (PTSD)
related to childhood abuse. Psychoneuroendocrinology 28:
733–750

20. Bremner JD, Vythilingam M, Vermetten E, Southwick SM, Mc-
Glashan T, Nazeer A, Khan S, Vaccarino LV, Soufer R, Garg PK,
Ng CK, Staib LH, Duncan JS, Charney DS (2003) MRI and PET
study of deficits in hippocampal structure and function in
women with childhood sexual abuse and posttraumatic stress
disorder. Am J Psychiatry 160:924–932

21. Brodsky BS, Malone KM, Ellis SP, Dulit RA, Mann JJ (1997)
Characteristics of borderline personality disorder associated
with suicidal behavior. Am J Psychiatry 154:1715–1719

22. Brown D (2001) (Mis)representations of the long-term effects
of childhood sexual abuse in the courts. J Child Sex Abuse 9:
79–107

23. Caldji C, Francis D, Sharma S, Plotsky PM, Meaney MJ (2000)
The effects of early rearing environment on the development of
GABA and central benzodiazepine receptor levels and novelty-
induced fearfulness in the rat. Neuropsychopharmacology 22:
219–229

24. Caldji C, Tannenbaum B, Sharma S, Francis D, Plotsky PM,
Meaney MJ (1998) Maternal care during infancy regulates the
development of neural systems mediating the expression of
fearfulness in the rat. Proc Natl Acad Sci. USA 95:5335–5340

25. Carrion VG, Steiner H (2000) Trauma and dissociation in delin-
quent adolescents. J Am Acad Child Adolesc Psychiatry 39:
353–359

26. Carrion VG, Weems CF, Eliez S, Patwardhan A, Brown W, Ray
RD, Reiss AL (2001) Attenuation of frontal asymmetry in pedi-
atric posttraumatic stress disorder. Biol Psychiatry 50:943–951

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 183

184

27. Carrion VG, Weems CF, Ray RD, Glaser B, Hessl D, Reiss AL
(2002) Diurnal salivary cortisol in pediatric posttraumatic
stress disorder. J Biol Psychiatry 51:575–582

28. Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington
H, McClay J, Mill J, Martin J, Braithwaite A, Poulton R (2003) In-
fluence of life stress on depression: moderation by a polymor-
phism in the 5-HTT gene. Science 301:386–389

29. CDC (2002) Annual smoking-attributable mortality, years of
potential life lost, and economic costs – United States,
1995–1999. MMWR 51:300–303

30. Chapman DP, Anda RF, Felitti VJ, Dube SR, Edwards VJ, Whit-
field CL (2004) Epidemiology of adverse childhood experiences
and depressive disorders in a large health maintenance organi-
zation population. J Affect Disord 82:217–225

31. Czeh B, Michaelis T, Watanabe T, Frahm J, de Biurrun G, van
Kampen M, Bartolomucci A, Fuchs E (2001) Stress-induced
changes in cerebral metabolites, hippocampal volume, and cell
proliferation are prevented by antidepressant treatment with
tianeptine. Proc Nat Acad Sci USA 98:12796–12801

32. De Bellis MD, Baum AS, Birmaher B, Keshavan MS, Eccard CH,
Boring AM, Jenkins FJ, Ryan ND (1999) AE Bennett Research
Award. Developmental traumatology. Part I: Biological stress
systems. Biol Psychiatry 15(45):1259–1270

33. De Bellis MD, Baum AS, Birmaher B, Ryan ND (1997) Urinary
catecholamine excretion in childhood overanxious and post-
traumatic stress disorders. Ann NY Acad Sci 821:451–455

34. DeBellis MD, Chrousos GP, Dorn LD, Burke L, Helmers K, Kling
MA, Trickett PK, Putnam FW (1994) Hypothalamic-pituitary-
adrenal axis dysregulation in sexually abused girls. J Clin En-
docrinol Metab 78:249–255

35. De Bellis MD, Keshavan MS, Clark DB, Casey BJ, Giedd JN, Bor-
ing AM, Frustaci K, Ryan ND (1999) AE Bennett Research
Award. Developmental traumatology. Part II: Brain develop-
ment. Biol Psychiatry 45:1271–1284

36. De Bellis MD, Keshavan MS, Shifflett H, Iyengar S, Beers SR, Hall
J, Moritz G (2002) Brain structures in pediatric maltreatment-
related posttraumatic stress disorder: a sociodemographically
matched study. Biol Psychiatry 52:1066–1078

37. De Bellis M, Thomas L (2003) Biologic findings of post-trau-
matic stress disorder and child maltreatment. Curr Psychiatry
Rep 5:108–117

38. DellaFemina D, Yeager CA, Lewis DO (1990) Child abuse: ado-
lescent records vs. adult recall. Child Abuse Negl 14:227–231

39. Deutch AY, Roth RH (1990) The determinants of stress-induced
activation of the prefrontal cortical dopamine system. Prog
Brain Res 85:367–402

40. Diamond DM, Fleshner M, Ingersoll N, Rose GM (1996) Psy-
chological stress impairs spatial working memory: relevance to
electrophysiological studies of hippocampal function. Behav
Neurosci 110:661–672

41. Dietz PM, Spitz AM, Anda RF, Williamson DF, McMahon PM,
Santelli JS, Nordenberg DF, Felitti VJ, Kendrick JS (1999) Unin-
tended pregnancy among adult women exposed to abuse or
household dysfunction during their childhood. J Am Med As-
soc 282:1359–1364

42. Dong M, Anda RF, Felitti VJ, Dube SR, Giles WH (2003a) The re-
lationship of exposure to childhood sexual abuse to other
forms of abuse, neglect and household dysfunction during
childhood. Child Abuse Negl 27:625–639

43. Dong M, Dube SR, Felitti VJ, Giles WH, Anda RF (2003b) Ad-
verse childhood experiences and self-reported liver disease:
new insights into a causal pathway. Arch Int Med 163:1949–1956

44. Dube SR, Anda RF, Felitti VJ, Chapman D, Williamson DF, Giles
WH (2001) Childhood abuse, household dysfunction and the
risk of attempted suicide throughout the life span: findings
from the Adverse Childhood Experiences Study. J Am Med As-
soc 286:3089–3096

45. Dube SR, Anda RF, Felitti VJ, Croft JB, Edwards VJ, Giles WH
(2001) Growing up with Parental alcohol abuse: Exposure to
childhood abuse, neglect and household dysfunction. Child
Abuse Negl 25:1627–1640

46. Dube SR, Anda RF, Felitti VJ, Edwards VJ, Croft JB (2002a) Ad-
verse childhood experiences and personal alcohol abuse as an
adult. Addict Behav 27:713–725

47. Dube SR, Anda RF, Felitti VJ, Edwards VJ, Williamson DF
(2002b) Exposure to abuse, neglect and household dysfunction
among adults who witnessed intimate partner violence as chil-
dren. Violence Vict 17:3–17

48. Dube SR, Felitti VJ, Chapman DP, Giles WH, Anda RF (2003a)
Childhood abuse, neglect and household dysfunction and the
risk of illicit drug use: the Adverse Childhood Experience
Study. Pediatrics 111:564–572

49. Dube SR, Felitti VJ, Dong M, Giles WH, Anda RF (2003b) The
impact of adverse childhood experiences on health problems:
evidence from four birth cohorts dating back to 1900. Prev Med
37:268–277

50. Dube SR, Williamson DF, Thompson T, Felitti VJ, Anda RF
(2004) Assessing the Reliability of Retrospective Reports of Ad-
verse Childhood Experiences Among Adult HMO Members At-
tending a Primary Care Clinic. Child Abuse Negl 28(7):729–737

51. Driessen M, Herrmann J, Stahl K, Zwaan M, Meier S, Hill A, Os-
terheider M, Petersen D (2000) Magnetic resonance imaging
volumes of the hippocampus and the Amygdala in women with
borderline personality disorder and early traumatization. Arch
Gen Psychiatry 57:1115–1122

52. Duman RS, Heninger GR, Nestler EJ (1997) A molecular and
cellular theory of depression. Arch Gen Psychiatry 54:597–606

53. Edwards VJ, Anda RF, Felitti VJ, Dube SR (2003a) Adverse child-
hood experiences and health-related quality of life as an adult.
In: Kendall-Tackett K (ed) Victimization and Health, American
Psychological Association, pp 81–94

54. Edwards VJ, Anda RF, Nordenberg DF, Felitti VJ, Williamson DF,
Wright JA (2001) Bias assessment or child abuse survey: factors
affecting probability of response to a survey about childhood
abuse. Child Abuse Negl 25:307–312

55. Edwards VJ, Fivush R, Anda RF, Felitti VJ, Nordenberg DF
(2001) Autobiographical memory disturbances in childhood
abuse survivors. In: Freyd JJ, DePrince AP (eds) Trauma and
Cognitive Science: A meeting of minds, science, and human ex-
perience. Binghamton, NY: Haworth Press. Also published in
Aggression, Maltreatment, and Trauma

56. Edwards VJ, Holden GW, Anda RF, Felitti VJ (2003b) Relation-
ship between multiple forms of childhood maltreatment and
adult mental health in community respondents: results from
the Adverse Childhood Experiences (ACE) Study. Am J Psychi-
atry 160:1453–1460

57. El-Sheikh M, Harger J, Whitson S (2001) Exposure to inter-
parental conflict and children’s adjustment and physical health:
the moderating role of vagal tone. Child Dev 72:1617–1636

58. Elzinga BM, Schmahl CG,Vermetten E, van Dyck R, Bremner JD
(2003) Higher cortisol levels following exposure to traumatic
reminders in abuse-related PTSD. Neuropsychopharmacology
28:1656–1665

59. Felitti VJ, Anda RF, Nordenberg D, Williamson DF, Spitz AM,
Edwards V, Koss MP, Marks JS (1998) Relationship of childhood
abuse and household dysfunction to many of the leading causes
of death in adults. The Adverse Childhood Experiences Study.
Am J Prev Med 14:245–258

60. Finkelhor D, Hotaling G, Lewis IA, Smith C (1990) Sexual abuse
in a national survey of adult men and women: prevalence, char-
acteristics, and risk factors. Child Abuse Negl 14:19–28

61. Foote SL, Bloom E, Aston-Jones G (1983) Nucleus locus
coeruleus: new evidence of anatomical and physiological speci-
ficity. Physiol Behav 63:844–914

62. Francis DD, Caldji C, Champagne F, Plotsky PM, Meaney MJ
(1999) The role of corticotropin-releasing factor-norepineph-
rine systems in mediating the effects of early experience on the
development of behavioral and endocrine responses to stress.
Biol Psychiatry 46:1153–1166

63. Francis DD, Young LJ, Meaney MJ, Insel TR (2002) Naturally oc-
curring differences in maternal care are associated with the ex-
pression of oxytocin and vasopression (V1a) receptors: gender
differences. J Neuroendocrinol 14:349–353

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 184

185

64. Glaser D (2000) Child abuse and neglect and the brain: a review.
J Child Psychol Psychiatry 41:97–116

65. Gorman JM, Mathew S, Coplan J (2002) Neurobiology of early
life stress: nonhuman primate models. Clin Neuropsychiatry 7:
96–103

66. Gould E, Beylin A, Tanapat P, Reeves A, Shors TJ (1999a) Learn-
ing enhances adult neurogenesis in the hippocampal forma-
tion. Nat Neurosci 2:260–265

67. Gould E, McEwen BS, Tanapat P, Galea LA, Fuchs E (1997) Neu-
rogenesis in the dentate gyrus of the adult tree shrew is regu-
lated by psychosocial stress and NMDA receptor activation. J
Neurosci 17:2492–2498

68. Gould E, Tanapat P (1999b) Stress and hippocampal neurogen-
esis. Biol Psychiatry 46:1472–1479

69. Gutman D, Nemeroff CB (2002) Neurobiology of early life
stress: rodent studies. Semin Clin Neuropsychiatry 7:89–95

70. Heffernan K, Cloitre M, Tardiff K, Marzuk PM, Portera L, Leon
AC (2000) Childhood trauma as a correlate of lifetime opiate
use in psychiatric patients. Addict Behav 25:797–803

71. Heim C, Nemeroff CB (2001) The role of childhood trauma in
the neurobiology of mood and anxiety disorders: preclinical
and clinical studies. Biol Psychiatry 49:1023–1039

72. Heim C, Newport DJ, Bonsall R, Miller AH, Nemeroff CB (2001)
Altered pituitary-adrenal axis responses to provocative chal-
lenge tests in adult survivors of childhood abuse. Am J Psychi-
atry 158:575–581

73. Heim C, Newport DJ, Heit S, Graham YP, Wilcox M, Bonsall R,
Miller AH, Nemeroff CB (2000) Pituitary-adrenal and auto-
nomic responses to stress in women after sexual and physical
abuse in childhood. J Am Med Assoc 284:592–597

74. Hillis SD, Anda RF, Dube SR, Felitti VJ, Marchbanks PA, Marks
JS (2004) The association between adolescent pregnancy, long-
term psychosocial outcomes, and fetal death. Pediatrics 113:
320–327

75. Hillis SD, Anda RF, Felitti VJ, Marchbanks PA (2001) Adverse
childhood experiences and sexual risk behaviors in women: a
retrospective cohort study. Fam Plan Perspect 33:206–211

76. Hillis SD, Anda RF, Felitti VJ, Nordenberg D, Marchbanks PA
(2000) Adverse childhood experiences and sexually transmit-
ted diseases in men and women: a retrospective study. Pedi-
atrics 106:E11

77. Insel TR, Winslow J (1998) Serotonin and neuropeptides in af-
filiative behaviors. Biol Psychiatry 44:207–219

78. Ito Y, Teicher MH, Glod CA, Ackerman E (1998) Preliminary ev-
idence for aberrant cortical development in abused children: a
quantitative EEG study. J Neuropsychiatry Clin Neurosci 10:
298–307

79. Kaplan JR, Manuck SB, Clarkson TB, Luss M (1982) Social sta-
tus, environment, and atherosclerosis in cynomolgus monkeys.
Arteriosclerosis 2:359–368

80. Kempermann G, Kuhn HG, Gage FH (1997) More hippocampal
neurons in adult mice living in an enriched environment. Na-
ture 386:493–495

81. Kendall-Tackett KA,Williams LM, Finkelhor D (1993) Impact of
sexual abuse on children: a review and synthesis of recent em-
pirical studies. Psychol Bull 113:164–180

82. Kendler KS, Bulik CM, Silberg J, Hettema JM, Myers J, Prescott
CA (2000) Childhood sexual abuse and adult psychiatric and
substance abuse disorders in women: an epidemiological and
cotwin control analysis. Arch Gen Psychiatry 57:953–959

83. Kessler RC, Sonnega A, Bromet E, Hughes M, Nelson CB (1995)
Posttraumatic stress disorder in the national comorbidity sur-
vey. Arch Gen Psychiatry 52:1048–1060

84. Kingree JB, Thompson MP, Kaslow NJ (1999) Risk factors for
suicide attempts among low-income women with a history of
alcohol problems. Addict Behav 24:583–587

85. Ladd CO, Owens MJ, Nemeroff CB (1996) Persistent changes in
corticotropin-releasing factor neuronal systems induced by
maternal separation. Endocrinology 137:1212–1218

86. Lemieux AM, Coe CL (1995) Abuse-related posttraumatic stress
disorder: Evidence for chronic neuroendocrine activation in
women. Psychosom Med 57:105–115

87. Lilienfeld SO (2003) Comorbidity between and within child-
hood externalizing and internalizing disorders: reflections and
directions. J Abn Child Psychol 32:285–291

88. Liu D, Diorio J, Tannenbaum B, Caldji C, Francis D, Freedman A,
Sharma S, Pearson D, Plotsky PM, Meaney MJ (1997) Maternal
care, hippocampal glucocorticoid receptors, and hypothala-
mic-pituitary-adrenal responses to stress. Science 277:
1659–1662

89. Lo Re V, Bellini LM (2002) William of Occam and Occam’s razor
(letter). Ann Int Med 136:634–635

90. Luine V, Villegas M, Mortinez C, McEwen BS (1994) Repeated
stress causes reversible impairments of spatial memory per-
formance. Brain Res 639:167–170

91. MacMillan HL, Fleming JE, Trocme N, Boyle MH, Wong M,
Racine YA, Beardslee WR, Offord DR (1997) Prevalence of child
physical and sexual abuse in the community: results from the
Ontario Health Supplement. J Am Med Assoc 278:131–135

92. Malberg JE, Eisch AJ, Nestler EJ, Duman RS (2000) Chronic an-
tidepressant treatment increases neurogenesis in adult rat hip-
pocampus. J Neurosci 20:9104–9110

93. McEwen BS, Angulo J, Cameron H, Chao HM, Daniels D, Gan-
non MN, Gould E, Mendelson S, Sakai R, Spencer R (1992) Para-
doxical effects of adrenal steroids on the brain: Protection ver-
sus degeneration. Biol Psychiatry 31:177–199

94. McEwen BS, Stellar E (1993) Stress and the individual: mecha-
nisms leading to disease. Arch Int Med 153:2093–2101

95. Musselman DL, Evans DL, Nemeroff CB (1998) The relationship
of depression to cardiovascular disease. Arch Gen Psychiatry
55:580–592

96. Nibuya M, Morinobu S, Duman RS (1995) Regulation of BDNF
and trkB mRNA in rat brain by chronic electroconvulsive
seizure and antidepressant drug treatments. J Neurosci 15:
7539–7547

97. Osofsky JD (1999) The impact of violence on children. Future
Child 99:33–49

98. Perry BD (1994) Neurobiological Sequelae of Childhood
Trauma: Post Traumatic Stress Disorders in Children. In: Mur-
burg M (ed) Catecholamine Function in Post Traumatic Stress
Disorder: Emerging Concepts. American Psychiatric Press,
Washington, DC, pp 253–276

99. Perry BD (2001) The neurodevelopmental impact of violence in
childhood. In: Schetky D, Benedek EP (eds) Textbook of Child
and Adolescent Forensic Psychiatry. American Psychiatric
Press, Inc, Washington, DC pp 221–238

100. Perry BD (2002) Childhood experience and the expression of
genetic potential: What childhood neglect tells us about nature
and nurture. Brain Mind 3:79–100

101. Perry BD, Pollard R (1998) Homeostasis, stress, trauma, and
adaptation. A neurodevelopmental view of childhood trauma.
Child Adolesc Psychiatr Clin North Am 7:33–51,viii

102. Pinchus JH, Tucker GJ (1978) Behavioral Neurology, New York:
Oxford

103. Plotsky PM, Meaney MJ (1993) Early postnatal experience
alters hypothalamic-corticotropin-releasing factor (CRF)
mRNA, median eminence CRF content and stress-induced re-
leasing in adult rats. Mol Brain Res 18:195–200

104. Putnam FW (1998) Developmental pathways in sexually abused
girls. Presented at Psychological Trauma: Maturational
Processes and Psychotherapeutic interventions. Harvard Med-
ical School, Boston MA. March 20

105. Putnam FW (2003) Ten-year research update review; child sex-
ual abuse. J Am Acad Child Adolesc Psychiatry 4:269–278

106. Read J, Perry BD, Moskowith A, Connolloy J (2001) The contri-
bution of early traumatic events to schizophrenia in some pa-
tients: a traumagenic neurodevelopmental model. Psychiatry
64:319–345

107. Repetti RL, Taylor SE, Seeman TE (2002) Risky families: family
social environments and the mental and physical health of off-
spring. Psychol Bull 128:330–366

108. Rohsenow DJ, Corbett R, Devine D (1988) Molested as children:
a hidden contribution to substance abuse? J Subst Abuse Treat
5:13–18

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 185

186

109. Rosenblum L, Coplan J, Friedman S, Bassoff T, Gormen JM, An-
drews MW (1994) Adverse early experiences affect noradrener-
gic and serotonergic functioning in adult primates. Biol Psychi-
atry 35:221–227

110. Rothman KJ, Greenland S (1998) Modern Epidemiology.
Philadelphia. PA: Lippincott Raven Publications

111. Rozanski A, Blumenthal JA, Kaplan J (1999) Impact of psycho-
logical factors on the pathogenesis of cardiovascular disease
and implications for therapy. Circulation 99:2192–2217

112. Sanchez MM, Ladd CO, Plotsky PM (2001) Early adverse expe-
rience as a developmental risk factor for later psychopathology:
evidence from rodent and primate models. Dev Psychopathol
13:419–449

113. Sapolsky RM (1996) Why stress is bad for your brain. Science
273:749–750

114. Sapolsky RM, Uno H, Rebert CS, Finch CE (1990) Hippocampal
damage associated with prolonged glucocorticoid exposure in
primates. J Neurosci 10:2897–2902

115. Scaer RC (2001) The neurophysiology of dissociation and
chronic disease. Appl Psychophysiol Biofeedback 26:73–91

116. Schmahl CG, Vermetten E, Elzinga BM, Bremner JD (2003)
Magnetic resonance imaging of hippocampal and amygdala
volume in women with childhood abuse and borderline per-
sonality disorder. Psychiatry Res 122:193–198

117. Schoenborn CA (1991) Exposure to alcoholism in the family:
United States, 1988. Adv Data 205:1–13

118. Shin LH, McNally RJ, Kosslyn SM, Thompson WL, Rauch SL,
Alpert NM, Metzger LJ, Lasko NB, Orr SP, Pitman RK (1999) Re-
gional cerebral blood flow during script-driven imagery in
childhood sexual abuse-related PTSD: a PET investigation. Am
J Psychiatry 156:575–584

119. Smith MA, Kim SY, van Oers HJ, Levine S (1997) Maternal dep-
rivation and stress induce immediate early genes in the infant
rat brain. Endocrinology 138:4622–4628

120. Stein MB, Koverola C, Hanna C, Torchia MG, McClarty B (1997)
Hippocampal volume in women victimized by childhood sex-
ual abuse. Psychol Med 27:1–9

121. Straus M, Gelles J (1990) Physical Violence in American Fami-
lies: Risk Factors and Adaptations to Violence in 8,145 Families.
New Brunswick, NJ: Transaction Press

122. Teicher MH (2000) Wounds that time wouldn’t heal: the neuro-
biology of childhood abuse. Cerebrum 2:50–67

123. Teicher MH, Andersen SL, Polcari A, Anderson CM, Navalta CP
(2002) Developmental neurobiology of childhood stress and
trauma. Psychiatr Clin North Am 25:397–426,vii-viii

124. Teicher MH, Ito Y, Glod CA, Andersen SL, Dumont N, Ackerman
E (1997) Preliminary evidence for abnormal cortical develop-
ment in physically and sexually abused children using EEG co-
herence and MRI. Ann N Y Acad Sci 821:160–175

125. Teicher MH, Ito Y, Glod CA, Schiffer F, Ackerman E (1994) Pos-
sible effects of early abuse on human brain development, as as-
sessed by EEG coherence. Am J Neuropsychopharmacol 33:52

126. Valenstein ES (1998) Blaming the Brain: The Truth About Drugs
and Mental Health. Basic Books, NY

127. van der Kolk BA, Perry JC, Herman JL (1991) Childhood origins
of self-destructive behavior. Am J Psychiatry 148:1665–1671

128. van Reekum R, Streiner DL, Conn DK (2001) Applying Bradford
Hill’s criteria for causation to neuropsychiatry: challenges and
opportunities. J Neuropsychiatry Clin Neurosci 12:318–325

129. Volkow ND, Fowler JS, Wang GJ (2003) The addicted human
brain: insights from imaging studies. J Clin Invest 111:
1444–1451

130. Vythilingam M, Heim C, Newport CD, Miller AH, Anderson E,
Bronen R, Brummer M, Staib L, Vermetten E, Charney DS, Ne-
meroff CB, Bremner JD (2002) Childhood trauma associated
with smaller hippocampal volume in women with major de-
pression. Am J Psychiatry 159:2072–2080

131. Whitfield CL, Anda RF, Dube SR, Felitti VJ (2003a) Violent
childhood experiences and the risk of intimate partner vio-
lence in adults: assessment in a large health maintenance orga-
nization. J Interpersonal Violence 18:166–185

132. Whitfield CL (2003b) The Truth about Depression: Choices for
Healing. Deerfield Beach, FL: Health Communications

133. Williams LM (1995) Recovered memories of abuse in women
with documented child sexual victimization histories. J Trauma
Stress 8:649–673

134. Williamson DF, Thompson TJ, Anda RF, Dietz WH, Felitti VJ
(2002) Body weight, obesity, and self-reported abuse in child-
hood. Int J Obesity 26:1075–1082

135. Wyatt GE (1985) The sexual abuse of Afro-American and white-
American women in childhood. Child Abuse Negl 9:507–519

174_186_Anda_EAPCN_624 13.04.2006 11:25 Uhr Seite 186

View publication statsView publication stats

https://www.researchgate.net/publication/275971785

JournalArticle Critique Format

The following will provide you a framework for fulfilling the Journal article review
requirements for this course. You are to select five articles that are of interest to you
and relevant to the nature of your research. For the purposes of this assignment, these
articles must report on empirical investigations from peer-reviewed journals. You are to
submit both your review and a PDF of the journal article. The review should be
submitted through Turnitin using the drop box provided. Please note that Turnitin
percentages should be 18% or lower.

You may want to choose articles that are central to your research question. Consider
the following format and contents for your presentation.

I. Statement of the problem addressed in the journal article:
a. What were the questions that the researchers were attempting to answer?
b. Why did the researchers believe that these questions needed to be

answered?
c. What were the researchers’ hypotheses?

II. Methodology

a. What were the independent and dependent variables?
b. How were these variables operationalized?
c. Who were the participants and how were they selected?
d. How did the researchers collect their data?

III. Summary and results

a. Describe the procedures used to test specific hypotheses and the
statistical tests used.

b. What were the key findings?
c. Were the hypotheses supported?
d. What avenues for future research were suggested?

IV. Critique

a. Did the methods and procedures used seem appropriate?
b. Were there noticeable strengths and weaknesses you identified in the

study?
c. How did the results and conclusions fit into your understanding of the

subject?

Reviews are to be one to three pages double spaced, standard margins, 12 point
font. A page consists of 250 words.

As always, please follow APA Style, sixth edition in writing your reviews and mind
your CUPS:

Capitalization
Utilization
Punctuation
Syntax

All critiques are to be submitted through Turnitin on e-companion.

Turn in your highest-quality paper
Get a qualified writer to help you with

“ peer article ”

Get high-quality paper

NEW! AI matching with writer

Order an Essay Now & Get These Features For Free:

Turnitin Report

Formatting

Title Page

Citation

Outline

Place an Order