Transgenerational transmission of cortisol and PTSD risk. Prog

Article (PDF Available)inProgress in brain research 167:121-35 · February 2008with261 Reads
DOI: 10.1016/S0079-6123(07)67009-5 · Source: PubMed
Abstract
Parental posttraumatic stress disorder (PTSD) appears to be a relevant risk factor for the development of PTSD, as evidenced by a greater prevalence of PTSD, but not trauma exposure, in adult offspring of Holocaust survivors with PTSD, compared to children of Holocaust-exposed parents without PTSD. This paper summarizes recent neuroendocrine studies in offspring of parents with PTSD. Offspring of trauma survivors with PTSD show significantly lower 24-h mean urinary cortisol excretion and salivary cortisol levels as well as enhanced plasma cortisol suppression in response to low dose dexamethasone administration than offspring of survivors without PTSD. In all cases, neuroendocrine measures were negatively correlated with severity of parental PTSD symptoms, even after controlling for PTSD and even other symptoms in offspring. Though the majority of our work has focused on adult offspring of Holocaust survivors, recent observations in infants born to mothers who were pregnant on 9/11 demonstrate that low cortisol in relation to parental PTSD appears to be present early in the course of development and may be influenced by in utero factors such as glucocorticoid programming. Since low cortisol levels are particularly associated with the presence of maternal PTSD the findings suggest the involvement of epigenetic mechanisms.

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E.R. de Kloet, M.S. Oitzl & E. Vermetten (Eds.)
Progress in Brain Research, Vol. 167
ISSN 0079-6123
Copyright r2008 Elsevier B.V. All rights reserved
CHAPTER 9
Transgenerational transmission of cortisol and
PTSD risk
Rachel Yehuda
and Linda M. Bierer
The Traumatic Stress Studies Program, Department of Psychiatry, Mount Sinai School of Medicine and Bronx Veterans
Affairs, James J. Peters VAMC, 116-A, OOMH-PTSD, 130 West Kingsbridge Road, Bronx, NY 10468, USA
Abstract: Parental posttraumatic stress disorder (PTSD) appears to be a relevant risk factor for the
development of PTSD, as evidenced by a greater prevalence of PTSD, but not trauma exposure, in adult
offspring of Holocaust survivors with PTSD, compared to children of Holocaust-exposed parents without
PTSD. This paper summarizes recent neuroendocrine studies in offspring of parents with PTSD. Offspring
of trauma survivors with PTSD show significantly lower 24-h mean urinary cortisol excretion and salivary
cortisol levels as well as enhanced plasma cortisol suppression in response to low dose dexamethasone
administration than offspring of survivors without PTSD. In all cases, neuroendocrine measures were
negatively correlated with severity of parental PTSD symptoms, even after controlling for PTSD and even
other symptoms in offspring. Though the majority of our work has focused on adult offspring of Holocaust
survivors, recent observations in infants born to mothers who were pregnant on 9/11 demonstrate that low
cortisol in relation to parental PTSD appears to be present early in the course of development and may be
influenced by in utero factors such as glucocorticoid programming. Since low cortisol levels are particularly
associated with the presence of maternal PTSD the findings suggest the involvement of epigenetic mech-
anisms.
Keywords: posttraumatic stress disorder; glucocorticoid programming; epigenetics; cortisol; intergenerational
effects; risk factors
Introduction
Biological alterations in posttraumatic stress dis-
order (PTSD) were initially conceptualized as be-
ing caused by trauma exposure. With the
realization that only a proportion of trauma-
exposed persons develop PTSD, it became clear
that trauma exposure alone could not account for
either the existence of PTSD, or its concomitant
neurobiology (Yehuda and McFarlane, 1995).
This recognition has prompted the search to iden-
tify risk factors that influence the development of
PTSD following trauma, and subsequently, eluci-
date their biological basis.
Some studies have suggested that dissociation or
panic attacks during trauma exposure, lack of so-
cial support subsequent to it, avoidant coping be-
haviors, or the development of maladaptive
cognitions, increase the likelihood of developing
PTSD (Brewin et al., 2000). Far more provocative
is the idea that there are pre-traumatic risk factors
that contribute to, or even possibly predict PTSD.
Several studies have suggested that pre-existing
Corresponding author. Tel.: +1 718 584 9000 x 6964;
Fax: +1 718 741 4775; E-mail: Rachel.yehuda@va.gov
DOI: 10.1016/S0079-6123(07)67009-5 121
personality, behaviors, and psychological traits
contribute to the development of PTSD (McFarlane,
1989;Breslau et al., 1998). Other pre-traumatic
risk factors include exposure to adversity prior
to the ‘‘focal’’ trauma (i.e., the event that imme-
diately precipitated the PTSD (Bremner et al.,
1993) or family history of psychiatric disorder
(McFarlane, 1988;Davidson et al., 1998). The
latter finding, in particular, presents a gateway to
detection of longstanding molecular, genetic, or
epigenetic phenomena that might be informative
about biological mechanisms of PTSD and/or risk
for this disorder.
To date there are no established biological risk
factors for PTSD. However, about a decade ago,
our group reported an association between paren-
tal PTSD and the subsequent development of
PTSD in adult offspring of Holocaust survivors
(Yehuda et al., 1998a). There was a higher prev-
alence of PTSD in adult offspring of Holocaust
survivors compared to demographically similar
comparison subjects even though there were no
group differences in trauma exposure (Yehuda
et al., 1998b). This paper reviews findings that
support the idea that parental PTSD may be as-
sociated with biological changes that render off-
spring more vulnerable to the effects of trauma
exposure, and discusses the implications of these
findings.
The evidence for parental PTSD as a risk
factor for PTSD
The finding that trauma survivors who develop
PTSD following exposure to adversity are more likely
to have a family history of psychopathology was
first made in 1918 (Oppenheimer and Rothschild,
1918;Wolfsohn, 1918). These initial observations
were replicated by other investigators who found
similar associations in World War I and World
War II veterans and their families (Swan, 1921;
Cohen et al., 1948). More contemporary commu-
nity-based studies confirmed that respondents
with PTSD are on average three times more likely
than trauma survivors without PTSD to report
family mental illness of anxiety, depression,
psychosis, and antisocial behavior. This has been
demonstrated in studies of PTSD following rape
(Davidson et al., 1998), disaster (McFarlane,
1988), and combat exposure (Reich et al., 1996).
Though parental trauma and PTSD were not
measured specifically in the above studies, the
findings are consistent with the idea that a trauma
survivor’s risk for PTSD might be related to family
history of PTSD-like symptoms.
The link between PTSD in offspring and trauma
exposure in parents was first made by Solomon
et al. (1988), who reported that war veterans who
were children of Holocaust survivors had higher
rates of PTSD, and a different clinical picture,
compared to Lebanon War veterans whose parents
were not survivors. Our previous observations ex-
tended this finding by demonstrating not only that
Holocaust offspring were more likely to have
PTSD following their own traumatic events than
offspring of demographically comparable Jewish
controls (Yehuda et al., 1998a), but that PTSD in
Holocaust offspring was specifically related to
the presence of PTSD in the Holocaust survivor
(Yehuda et al., 1998b).
Is parental PTSD a genetic risk factor?
The finding of a familial association with PTSD is
not, per se, evidence of genetics. However, this
possibility becomes more plausible in considering
findings of an increased prevalence of PTSD
among trauma survivors who also had a twin with
PTSD compared to trauma survivors whose
exposed twin did not develop PTSD. An increased
risk for the development of PTSD in monozygotic
than dizygotic twins has been demonstrated in
combat veterans (True et al., 1993), and in pop-
ulation-based studies of civilians (Koenen et al.,
2002;Stein et al., 2002).
Nonetheless, to date, very few genes have been
identified as associated with PTSD. Significant as-
sociations were found with a variable number
tandem repeat (VNTR) polymorphism in an
untranslated region of the dopamine transporter
gene in a relatively small convenience sample of
subjects with PTSD compared to those without
PTSD (Segman and Shalev, 2003). In another
small study, no association was found between two
122
glucocorticoid receptor (GR) polymorphisms,
N363S and BclI, and the diagnosis of PTSD
although PTSD patients homozygous for the
BclI GG genotype tended to be more responsive
to a peripheral test of glucocorticoid sensitivity
and displayed more severe PTSD symptoms
(Bachmann et al., 2005).
The limited number of gene-related findings in
PTSD may reflect the complexity involved in ex-
ecuting research in this area. Alternatively, the
failure to find susceptibility loci for PTSD may
suggest that PTSD risk is not related to differences
in genetic polymorphisms. Indeed, there are alter-
native explanations even for the twin findings. For
example, though PTSD was more likely to be con-
cordant in monozygotic than dizygotic twins, there
was also a genetic association with exposure to
interpersonal violence (Stein et al., 2002). In con-
trast, the concordance rate of exposure to acci-
dents or disaster among identical and fraternal
twins was not different. Thus, genetic risk for as-
sault trauma reflected personality traits — anger
or irritability — that increased the likelihood for
assault, which then increases the likelihood of
PTSD (Stein et al., 2002). By linking genetic pre-
disposition to the risk of assaultive trauma the
findings imply the biological factors that predict
exposure characteristics may be distinct from those
that are associated with the development of PTSD.
In considering Holocaust survivors, for example,
the primary risk for exposure to the Holocaust was
being Jewish and living in Nazi-occupied Europe
in the 1930s. While it may be that persons who
developed PTSD in response to Holocaust expo-
sure did so based on specific pre-trauma risk fac-
tors, it is implausible that the same genetic
predisposition that explains Holocaust exposure
also explains the development of PTSD.
Alternative explanations for the association
between parental PTSD and PTSD in offspring
There are several potential explanations for the
finding of a greater prevalence rate of PTSD
among offspring of Holocaust survivors that do
not necessarily implicate genetic mechanisms. The
development of PTSD following exposure to a
traumatic event requires a subjective perception of
threat, which includes feelings of helplessness, or
lack of competence for survival from such expe-
riences. Individual differences in the presence of
cognitive schemas such as, whether the world is
fundamentally safe or not, or whether persons are
to blame for traumatic events that befall them,
have been demonstrated to underlie difference in
PTSD prevalence according to trauma type. Thus,
a rape victim who feels she may have provoked her
assailant, or is in some other way responsible for
what happened, may be more likely to develop
PTSD than another victim who does not have this
perception. Arguably, prior experience is a major
contributor to such subjective interpretations.
The presence of a parental trauma — particu-
larly one as life altering as was exposure to the
Nazi Holocaust — can also influence an off-
spring’s response to trauma in that perspective
about the world, such as whether it is fundamen-
tally a dangerous place and/or whether individuals
are competent to deal with adversity, can be trans-
mitted from parent to child. Children can also
‘‘learn’’ symptoms from seeing them in parents.
The increased prevalence of PTSD in Holocaust
offspring may also reflect deficits in child rearing
that are experienced as abuse or neglect, and in-
crease the likelihood of exposure to subsequent
events, as well as the vulnerability to develop
PTSD symptoms, in the same way that prior trau-
matization has been described as a risk factor for
subsequent trauma and for PTSD (Clancy et al.,
2006;Koenen et al., 2007). Children can also be-
come traumatized by Holocaust-related stories
themselves, or by visualizing what their parents
experienced. Such forms of vicarious traumatiza-
tion have been known to occur even among ther-
apists exposed to traumatic material of their
patients, and may be particularly salient sources
of vulnerability in children. Thus, even before
entertaining specific models of biological trans-
mission of vulnerability, including heritable or
developmental genetic alterations, there are several
possible mechanisms to account for the observa-
tion of increased risk for PTSD in relation to
parental exposure and/or PTSD.
There are two broad conceptions that may be
applicable to biological transmission of risk from
123
parent to child. The first is that the same biological
alteration that explains symptoms in parents (e.g.,
a genetic polymorphism) is transmitted to the off-
spring. The second is that the response in the off-
spring is a consequence of a change in the parents,
such as ‘‘programming’’ due to early environmen-
tal modifications, in either the parent or child,
which may produce permanent and transmissible
changes. An example is the type of glucocorticoid
programming, recently demonstrated to be influ-
enced by maternal care that is determined by epi-
genetic mechanisms. It is this latter possibility of
programming that has become particularly inter-
esting based on the convergence of findings con-
cerning hypothalamic-pituitary-adrenal (HPA) axis
alterations in PTSD. This possibility can be dis-
cussed in light of findings relating to the association
between HPA measures and parental PTSD.
Biological correlates of parental PTSD:
studies of Holocaust offspring
Though observations of low cortisol levels in
PTSD (Mason et al., 1986) were initially inter-
preted as reflecting pathophysiology of the disor-
der, cortisol-related alterations in PTSD may
reflect pre-existing vulnerability factors that in-
crease the probability of developing PTSD follow-
ing trauma exposure. In several prospective,
longitudinal studies, lower cortisol levels in the
acute aftermath of trauma were associated with
either the subsequent development of PTSD, or
with the well-established risk factor of prior
trauma exposure (Resnick et al., 1995;Delahanty
et al., 2003). These findings suggested that reduced
cortisol levels at the time of a trauma may com-
promise the inhibition of stress-induced biological
responses (e.g., during and following a traumatic
event), resulting in a prolonged physiological/
emotional distress which would then facilitate the
development of PTSD in at least some at risk
persons (Yehuda, 2002). The question that arose
from the above findings, however, concerns the
origin of low cortisol levels in at risk persons. In
consideration of the above observations pertaining
to reduced cortisol, and in light of the findings that
parental PTSD is a risk factor for PTSD, we set
out to examine HPA axis parameters in adult
children of Holocaust survivors.
In an initial study, we examined mean 24-h uri-
nary cortisol excretion in 11 Holocaust offspring
with no parental PTSD and 24 offspring with
parental PTSD, compared to 15 demographically
similar offspring of Jews born to parents who did
not undergo the trauma of the Holocaust (Yehuda
et al., 2000). Holocaust offspring were born after
World War II, or after their parents had escaped
to safety during the War, and were raised through
adolescence by at least one biological parent
who had been interned in a Nazi concentration
camp during World War II or faced comparably
severe threats in hiding. These offspring subjects
were further subdivided based on whether at least
one parent met the diagnostic criteria for lifetime
PTSD according to the Parental PTSD Questionnaire
(PPQ), completed by the offspring. This scale has
recently been validated against 58 clinical inter-
views of the parents using the Clinician Adminis-
tered PTSD Scale (CAPS) (Blake et al., 1995)and
found to have extremely high predictive strength
for PTSD diagnosis, with 15 out of 17 items show-
ing significant correlations between offspring-rated
and clinician-rated parental symptoms based on
direct interview of the parents (Yehuda et al.,
2006). Offspring with parental PTSD were further
subdivided into those with and without PTSD
(based on their own life events). The offspring with
PTSD (and parental PTSD) had significantly
lower cortisol levels than the two groups without
parental PTSD. However, offspring without any
lifetime PTSD who had the risk factor of parental
PTSD also had significantly lower cortisol levels
than the latter two groups, and showed cortisol
levels that were only slightly (but not significantly)
higher than offspring with PTSD. We concluded
from this study that low cortisol levels were asso-
ciated with the risk factor of parental PTSD.
Findings of studies examining urinary cortisol
excretion in PTSD and trauma survivors have been
highly variable, possibly because of the room for
methodological error in procedures that place re-
sponsibility for complete collections in the subjects’
hands. We were therefore interested in replicating
the observation of low cortisol in relation to paren-
tal PTSD using a different subject group, but also a
124
different collection procedure, in which we would
examine cortisol output over the diurnal cycle. We
hypothesized that alterations in plasma cortisol
levels and chronobiological parameters would be
observed only in the offspring with parental PTSD,
and that offspring without parental PTSD would
demonstrate chronobiological parameters similar to
the comparison sample (Yehuda et al., 2007b).
A total of 23 men and 26 women (33 offspring,
16 comparison subjects) were examined. In this
study, as well, we subdivided offspring on the basis
of presence or absence of parental PTSD, using the
PPQ. However, we did not include any subjects
with current or lifetime PTSD so that we could
focus exclusively on biological signals resulting
from parental Holocaust exposure and/or PTSD.
The procedures of the study involved admission to
the general clinical research center on the evening
before the study, insertion of an i.v. at 5:30 a.m.,
and, after a stabilization period of approximately
60 min, collection of blood samples every 30 min
for a 24-h period. As described in Yehuda et al.
(2007b), lower cortisol values were observed for
offspring with parental PTSD than for offspring of
survivors without PTSD or comparison subjects.
We also examined responsivity of the HPA axis
using the low dose (0.50 mg) dexamethasone (DEX)
suppression test. The study group was comprised of
25 offspring (16 with, 12 without, parental PTSD)
and 16 comparison subjects, with similar inclusion/
exclusions described above (Yehuda et al., 2007a).
There were significant group differences in pre- and
post-DEX cortisol values. Moreover, greater corti-
sol suppression was found in offspring with paren-
tal (but not their own) PTSD than in offspring
without parental PTSD or comparison subjects.
Cortisol levels in Holocaust offspring:
cause or effect of vulnerability conferred
by parental PTSD?
Not only do offspring of Holocaust survivors with
PTSD demonstrate a greater frequency of PTSD
than offspring of survivors without PTSD and
controls, they have also, in some studies, endorsed
more childhood traumatic antecedents (Yehuda
et al., 1998a). Accordingly, it has not been possible
to rule out that cortisol levels may reflect responses
of offspring to their own early experiences of
adversity. In all the above studies, however, we
attempted to examine the relationship between
cortisol and parental PTSD by controlling for
either endorsement of childhood trauma [scores on
the Childhood Trauma Questionnaire (CTQ),
Bernstein et al., 1994] and/or current symptoms
in the offspring. In all three cohorts studied above
using mean 24-h urinary cortisol excretion, 24-h
plasma cortisol mean, and cortisol suppression in
response to DEX, the relationships with parental
PTSD were maintained or strengthened after
considering the contribution of childhood trauma.
Since in all three reports, the attribution of
parental PTSD was made by the offspring who
rated parental symptoms, a concern arises regard-
ing the contribution of offspring attribution of
parental PTSD to cortisol measures we obtained.
Although we have previously established that there
is strong agreement between offspring ratings of
parental PTSD and independent clinician ratings
of the parent, if offspring cortisol levels were also
associated with their perception of parental PTSD,
this could lead to a circularity of inference. For
example, if having low cortisol reflected offspring
characteristics, such as irritability or emotional
withdrawal, or psychopathology, this might result
in a greater projection of (or sensitivity to) anal-
ogous parental characteristics so that ‘‘parental’’
PTSD would partly reflect offspring characteris-
tics. Controlling for offspring PTSD symptoms
and diagnosis of other mood and anxiety disorders
in the analysis of the relationship between cortisol
and parental PTSD only partially addresses this
concern. However, in the aftermath of 9/11, a
unique opportunity arose to examine the relation-
ship between maternal PTSD and PTSD in the
infant offspring, addressing the above issue of
attribution, since the group assignment of parental
(maternal PTSD) could now be made independ-
ently from the offspring’s assessment.
Cortisol levels in mothers and babies
It was not possible in our studies of Holocaust
offspring, who were already adults at assessment
125
to know whether the phenomenon we had ob-
served would have also been present early in life
(Yehuda et al., 2005). Measuring cortisol levels in
infants who had recently been born to mothers
experiencing trauma and PTSD in pregnancy and
in the early post-partum period therefore provided
a unique opportunity to determine the origin of
low cortisol in offspring.
Examination of the relationship between mater-
nal PTSD symptoms and salivary cortisol levels
obtained at awakening and at bedtime in 38 infants
(ranging in age from 9 months to 1 year) and
their mothers who were directly exposed to the
World Trade Center (WTC) collapse on 9/11 dur-
ing their pregnancy revealed that salivary cortisol
levels were significantly lower in the offspring of
women with PTSD than in those whose mothers
had not developed PTSD. Interestingly, there was a
significant correlation between severity of maternal
PTSD symptoms and cortisol levels in infants, but
no correlations between infant cortisol and mater-
nal depression severity. The finding of lowered co-
rtisol among infants with maternal PTSD suggested
that the similar findings observed in adult offspring
of Holocaust survivors were probably unrelated to
their own ‘‘trauma’’ history or parental conse-
quences (e.g., poor parenting) that occur well after
the immediate postnatal period. Rather, the find-
ings likely implicated earlier and possibly more
subtle influences relating to mother–infant attach-
ments or early social regulation.
When data were examined including trimester of
maternal exposure to 9/11 a significant effect of
maternal PTSD status in infants born to mothers
pregnant in the third trimester was observed.
Cortisol levels in these mothers with PTSD were also
significantly lower than in mothers without PTSD.
These findings suggest the possibility of in utero
transmission of this effect. This was plausible since
the human HPA axis appears to be programmed by
early life influences (Francis et al., 1999;Weaver
et al., 2002;Seckl, 2004). In both animal and hu-
man studies, maternal exposure to glucocorticoids
during pregnancy can result in lower birth weight
and higher glucocorticoid levels in offspring, lead-
ing ultimately, to adult disease (e.g., hypertension,
insulin resistance, and hyperlipidemia) (O’Regan
et al., 2001) and depression (Halligan et al., 2004).
Are cortisol levels more related to maternal than
paternal PTSD?
Because the above-findings implicated a role for in
utero factors in that associations between low co-
rtisol and maternal PTSD were greatest in those
exposed in the third trimester, we reconsidered the
Holocaust offspring finding in relation to parental
gender (Yehuda et al., 2007b). This was accom-
plished by subdividing data from offspring re-
ported above on the basis of whether the father
only, mother only, both, or neither parent had
PTSD, compared to controls. The analysis dem-
onstrated that offspring with only paternal PTSD
(n¼6) were not significantly different in mean
cortisol release than offspring with no parental PTSD
or comparison subjects (n¼16). Mean cortisol re-
lease was similar for offspring with PTSD in both
parents (n¼9) and those with only maternal
PTSD (n¼8), whereas both of these groups
differed from offspring with no parental PTSD
and comparison subjects (Yehuda et al., 2007b).
Even after controlling for Body Mass Index (BMI),
current depression or anxiety diagnosis, and CAPS
lifetime total score in regression analysis, there
were significant negative partial correlations be-
tween mean cortisol level and the presence of both
maternal and paternal PTSD. However, in a re-
gression analysis, after additionally controlling for
the presence of PTSD in the other parent, only
maternal PTSD retained its significant negative as-
sociation with offspring mean cortisol. The results
here must be interpreted with caution since obvi-
ously the number of subjects in some subgroups is
very small, but when considered in the context
of the findings of infants from mothers exposed to
9/11 while pregnant, they suggest that there may be
unique contributions of maternal PTSD to lowered
cortisol levels in offspring.
Potential mechanisms for transgenerational
transmission
The above findings of lower cortisol levels in off-
spring of persons with PTSD could be explained
by early social regulation in that babies being
raised under conditions of neglect or abusive care
126
have lower ambient cortisol levels than normal
(Gunnar and Vazquez, 2001), presumably mirror-
ing findings from non-human primates. Marmoset
monkeys exposed to early maternal separations
also show reduced basal cortisol 3–5 months later
(Dettling et al., 2002), as do monkeys who were
exposed to the more stressful peer vs. mother
rearing condition (Clarke et al., 1998). In rodents
as well, results of cross-fostering studies demon-
strate that even relatively brief exposures to alter-
ations in postnatal maternal care during a critical
period can have permanent behavioral and neuro-
endocrine alterations in offspring (Meaney, 2001).
Therefore, it may be that PTSD symptoms in
mothers — that may lead to the display of stress-
reactive behavior toward their offspring during a
critical developmental window(s) — may have
long-lived effects on glucocorticoid regulation in
offspring.
However, glucocorticoid programming in utero
(Drake and Walker, 2004;Seckl, 2004) may also be
important. In that alterations in GR sensitivity are
known to occur very early during the postnatal
period, possibly coinciding with the period in
which normal maternal infant attachments are de-
veloping, it is possible that low cortisol levels in
offspring is mediated through alterations in GR
sensitivity (Mathews, 2002). In animal models,
maternal behaviors, which alter the infants ‘‘envi-
ronment,’’ in turn result in long-lived changes in
hippocampal GR expression and HPA function
that are subsequently transmitted intergeneration-
ally (Meaney, 2001). The hippocampal GR gene is
particularly sensitive to postnatal ‘‘programming’’
because it has complex tissue-specific promoters
that are susceptible to epigenetic modification
(Sutherland and Costa, 2003). Modifications of
these promoters during development have been
shown to alter the ‘‘set-point’’ of receptor function
in feedback sites and hence glucocorticoid secre-
tion (McCormick et al., 2000). It is also possible
that changes in GR sensitivity have even earlier
origins than the postnatal period. It is important
to consider such mechanisms based on the effects
of PTSD on cortisol in mothers exposed in the
third trimester of pregnancy, where stress induced
increases in maternal glucocorticoids may have
begun a process of glucocorticoid programming.
This hypothesis is supported by the well known
influences of maternal stress (glucocorticoids) on
fetal brain development, which are, in part,
dependent on the gestational age of the fetus (Drake
and Walker, 2004;Seckl, 2004).
Early handling in rats and vulnerability to
psychopathology in offspring: a crisis in translation?
One of the issues that has arisen in the ‘‘translation’’
of the early handling work to mental health-
related issues is the interpretation of a manipulation
of maternal behaviors induced by ‘‘early handling.’’
The consequence of early handling in mothers
is to increase maternal licking and grooming.
This behavior has been widely interpreted as
beneficial, as are associated biological outcomes in
the adult offspring rat. As a result, it is has been
challenging to draw the appropriate inferences
from the early handling model to psychopathol-
ogy, or even consider the nature of the relationship
(if any) between these observations and transgene-
rational effects that might be operational with re-
spect to cortisol and PTSD. However, insofar as
early handling in rodents results in HPA altera-
tions in the same direction as those described in
PTSD [e.g., increased GR sensitivity, enhanced
cortisol (corticosterone) suppression following
DEX administration, lower ambient glucocorti-
coid levels (Meaney et al., 1985, 1991)], it is com-
pelling to attempt to do so.
The presence of a similar behaviorally transmit-
ted effect that is deemed positive in the rat, but
might be problematic for humans, is not a trans-
lational crisis. The essential point of linking the
early handling phenomenon in rats with trans-
generational vulnerability in humans is to offer
proof of principle that environmental exposures
can result in persisting alterations in GR expres-
sion that underlie individual differences in endo-
crine function (Macri and Wurbel, 2006). That
these differences may be associated with increased
vulnerability to the development of PTSD follow-
ing trauma exposure in humans is noteworthy, and
underscores the necessity of highlighting that con-
sequences to the individual of glucocorticoid pro-
gramming may be context-dependent. That is,
127
maternal PTSD may confer risk for PTSD in the
offspring by influencing the predisposition to a
modification that may later influence the response
to a traumatic event, though not necessarily in an
adverse manner. What gets ‘‘programmed’’ may
simply be the set point of glucocorticoid secretion
and an enhanced capacity for responsiveness of the
HPA axis, which might be more adaptive to off-
spring who continue to live in a similar (danger-
ous) environment as their parents. For example, it
would be adaptive for a Holocaust survivor parent
to ‘‘transmit’’ the tendency or capacity for hyper-
vigilance to seemingly ‘‘neutral’’ stimuli (e.g., a
uniformed police officer) to an offspring that
might be reared in the same environment as the
parent (i.e., Nazi-occupied Europe), yet easy to see
how this transmitted tendency for hypervigilance
might interfere with functioning in a different en-
vironment (e.g., urban township during peace-
time).
It is also possible that specific aspects of appar-
ently similar behaviors in rodent and human
mothers have different consequences. That in-
creased ‘‘licking and grooming’’ of the handled
mother is interpreted to result in positive effects is
a reflection of anthropomorphic notions of more
infant contact being associated with ‘‘better’’
parenting, the value placed on lower cortisol re-
sponses to stress as necessarily indicating less dis-
ruption, and our assumptions that superior
cognitive performance on memory tasks are of
greater advantage than higher endocrine responses
to stress and less good cognitive performance. As a
result, this paradigm has become a heuristic model
for environmentally induced developmental effects
that are positive, whereas in reality, the measur-
able alterations interpreted as positive may not be
uniformly so, or may be occurring at the expense
of other more subtle effects that still require de-
lineation.
For example, observing Holocaust mothers and
babies, one might similarly conclude that mothers
with PTSD form attachment to infants marked by
enhanced attention and contact (i.e., rather than
relative emotional neglect or physical abuse).
Though we have previously demonstrated in-
creased emotional abuse and neglect, there were
in fact no differences in Holocaust offspring with
or without parental PTSD with respect to physical
or sexual abuse, compared to controls (Yehuda
et al., 2001). Thus, increased attention by the
mother and possibly a greater reluctance to un-
dergo voluntary separations from such offspring is
not a contradiction with the finding of greater
emotional abuse and neglect. Quite the opposite
may be true. The strong need to protect offspring
within the context of a great sense of loss or treat,
and fear of loss of one’s offspring, may compro-
mise the mother’s ability to create the space that is
critical for the offspring’s ultimate separation and
individuation. Moreover, the clinical characteris-
tics of adult Holocaust offspring who present for
psychotherapy are consistent with issues relating
to attachment. Such patients typically complain of
difficulties in physically and emotionally separat-
ing from parents, implying strong attachments,
though not attachments that protect from the risk
of developing psychopathology. Thus, their clini-
cal complaints are not incompatible with mothers
who are excessively ‘‘licking and grooming,’’ but
unlike rodents who cannot be asked their opinion
regarding the impact of such behavior on their
ability to form social relationships or on other ar-
eas of adaptive functioning, human offspring can
be quite clear that such contacts can lead to im-
pairments in circumscribed domains (though not
necessarily with regard to subsequent cognitive
development, which is the usual outcome meas-
ured in early handled rats to demonstrate positive
long-term effects of this manipulation).
Characteristics of maternal attachment related
to ambient cortisol levels in adult offspring
In order to explore further the possibility that the
quality of maternal attachment might influence
offspring cortisol levels, we examined responses on
the Parental Bonding Scale (Parker et al., 1979)
among offspring of Holocaust survivors with
(n¼23) and without (n¼18) maternal PTSD
and comparison subjects (n¼19). This scale iden-
tifies both positive parental bonding (as reflected
by scores for maternal and paternal care), as well
the presence of more insecure parental attach-
ments (as reflected by scores for maternal and
128
paternal overprotection). As in previous studies of
this high-risk group, we chose subjects without
their own PTSD to avoid confounding the inter-
pretation of associations with cortisol findings.
The sample characteristics are shown in Table 1.
Groups differed significantly in age, with compar-
ison subjects being significantly younger, respec-
tively, than offspring groups with and without
PTSD, which did not differ from each other [post-
hoc tests by Least Significant Difference (LSD)].
Gender distribution and BMI did not differ sig-
nificantly among the groups, however the off-
spring groups were preponderantly composed of
women, while the control group was predomi-
nantly male. Groups differed in scores on the
Mississippi PTSD Scale (Keane et al., 1988), which
provides a continuous measure of the effects of
trauma exposure, including trauma-related or
PTSD symptomatology, on a person’s life, with
offspring with maternal PTSD demonstrating sig-
nificantly higher scores than offspring without
maternal PTSD (p¼.014) and controls (p¼.008).
Scores for the Beck Depression Inventory (Beck
et al., 1961) also differed significantly among the
three groups, but in this case scores for offspring
with maternal PTSD differed only from those of
controls in post-hoc testing (p¼.001), with
depression scores for offspring of mothers exposed
to the Holocaust but without PTSD showing scores
non-significantly lower than offspring with mater-
nal PTSD but greater than controls. With respect
to urinary cortisol (Table 1), values for offspring
with maternal PTSD were significantly lower than
controls (p¼.021), and lower than offspring with-
out maternal PTSD at a trend level of significance
(p¼.081). After co-varying for age and BMI, the
results were essentially unchanged.
As had been previously noted for offspring with
parental PTSD, ratings of childhood traumatic
antecedents with the CTQ differed among the
groups, but only for emotional abuse and neglect
and for physical neglect, with scores in each of
Table 1. Childhood abuse, parental care and overprotection, and current symptoms in offspring with and without maternal PTSD and
comparison subjects
Variable Comparison
subjects (n¼19)
Offspring without
maternal PTSD
(n¼18)
Offspring with
maternal PTSD
(n¼23)
ANOVA F(df) p
Mean7SD Mean7SD Mean7SD
Age 44.479.5 49.876.5 50.477.3 3.45 (2,57) .039
Gender (M/F) 12 M/7 F 6 M/12 F 7 M/16 F w
2
¼5.32 (2) .070
BMI 26.074.3 25.075.5 26.074.4 .28 (2,57) ns
a
Paternal PTSD, Y/N (%) na
b
4 Y/14 N (22%) 9 Y/14 N (39%) w
2
¼1.33 (1) ns
Beck Depression Scale 3.273.3 7.176.2 9.476.5 6.18 (2,56) .004
Mississippi PTSD Scale 65.9715.2 67.1713.0 80.5720.3 4.89 (2,56) .011
Childhood Trauma Questionnaire (CTQ)
Emotional abuse 6.972.3 7.073.4 10.175.2 4.36 (2,55) .018
Physical abuse 6.072.2 5.27.4 6.172.3 1.26 (2,55) ns
Sexual abuse 5.672.1 5.17.47 6.673.9 1.48 (2,55) ns
Emotional neglect 8.874.0 7.973.2 11.475.2 3.67 (2,55) .032
Physical neglect 5.67.9 5.671.4 7.372.4 6.29 (2,55) .003
Total score 32.978.1 30.976.8 41.5713.4 6.20 (2,55) .004
Parental Bonding Instrument (PBI)
Maternal care 26.278.9 28.377.7 19.4710.9 5.12 (2,57) .009
Maternal overprotection 11.377.4 13.179.8 18.1711.0 2.76 (2,56) .072
Paternal care 24.778.2 21.578.2 23.1710.0 .56 (2,55) ns
Paternal overprotection 9.876.3 14.0711.0 13.578.2 1.24 (2,55) ns
Urinary cortisol (mg/24 h) 71.31734.71 66.13727.30 49.46727.15 3.13 (2,57) .052
a
ns: non-significant at pZ1.0.
b
na: not applicable.
129
these subscales for offspring with maternal PTSD
being significantly higher than those of offspring
without maternal PTSD or controls (Table 1).
Offspring with maternal PTSD showed signifi-
cantly lower scores than either of the other groups
for maternal care, but higher scores for maternal
overprotection. There were no group differences in
either paternal care or paternal overprotection
ratings.
Figure 1 shows that maternal overprotection
scores were significantly negatively correlated with
urinary cortisol in offspring with maternal PTSD
(r¼537, p¼.008), but this relationship was not
apparent in the other two groups, who demon-
strated positive (though non-significant) associa-
tions, respectively (for offspring without parental
PTSD, r¼.164, ns; and for controls, r¼.249, ns).
In fact, the inverse correlation for cortisol and
maternal overprotection in offspring with mater-
nal PTSD differed significantly from the weakly
positive associations of these variables in offspring
without PTSD (p¼.012) and controls (p¼.022).
These relationships for cortisol and maternal over-
protection scores, as well as the significance of the
differences among the associations, were retained
when all correlations were controlled for age and
BMI (e.g., for offspring with maternal PTSD,
r¼.538, df ¼19, p¼.012). When paternal
overprotection was examined, there were no sig-
nificant associations with cortisol. Furthermore,
when the above correlations were additionally
controlled for paternal PTSD, the negative rela-
tionship of urinary cortisol with maternal over-
protection was also unchanged (r¼.546,
Fig. 1. Relationship of 24-h cortisol to maternal overprotection scores among offspring with and without PTSD and controls.
130
df ¼18, p¼.013), indicating that the association
is appropriately ascribed to an influence of mater-
nal PTSD.
Finally, among offspring with maternal PTSD,
maternal overprotection scores were not substan-
tially related to those of childhood abuse or ne-
glect, indicating that this subscale describes an
aspect of maternal attachment at least somewhat
independent of childhood trauma that is nega-
tively associated with cortisol.
What has been learned?
PTSD is associated with a distinct profile in that
corticotropin releasing factor (CRF) levels appear
to be increased while ambient urinary and plasma
levels of cortisol have been found to be lower than
in normals in many studies (Yehuda, 2002). PTSD
is also characterized by increased cortisol-suppres-
sion in response to DEX administration in most
studies, likely resulting from increased responsive-
ness of GR. This profile is different from that ob-
served in studies of acute and chronic stress
and depression, which have been associated with
increased CRF and cortisol levels and reduced co-
rtisol suppression to DEX, and GR responsive-
ness. The above findings may in part offer an
explanation for the increased cortisol signaling ca-
pacity in PTSD that results in a more efficient
suppression of the HPA axis despite what appears
to be an attenuated glucocorticoid production
from the adrenal glands.
We have previously suggested that alterations in
GR sensitivity represent primary alterations in
PTSD, but the relationship between this measure
and ambient cortisol levels has remained difficult
to pin down. This is because glucocorticoids such
as cortisol both regulate GR and are further reg-
ulated by them. Furthermore, glucocorticoids ex-
ert their action not only through GR, but also
through the mineralocorticoid receptor (MR).
Both these receptor types are involved in the reg-
ulation of the HPA axis. Of particular relevance to
PTSD is that the MR affinity for cortisol is high,
such that even very low ambient hormone con-
centrations can result in receptor occupancy. This
allows MR to mediate basal glucocorticoid
functions such as circadian regulation, and may
contribute to lower ambient hormone production,
thus affecting the number of available GR binding
sites, and further affecting GR responsiveness
(de Kloet et al., 2005). The phenomenon of increased
GR responsiveness has most recently been dem-
onstrated in PTSD by examining the differential
effects of DEX on the inhibition of lysozyme syn-
thesis in lymphocytes (Yehuda et al., 2004). The
presence of detectable differences in a gene prod-
uct related to the activity of GR (i.e., lysozyme
activity) in any target tissue (i.e., the lymphocyte)
suggests the possibility of an alteration related to
the expression of GR genes, whether it be a nat-
urally occurring variant in GR polymorphisms
that results in increased GR sensitivity or an epi-
genetic modification, such as cytosine methylation
of a GR promoter. Were such changes present in
the brain of vulnerable persons, one could postu-
late that under certain environmental conditions,
such as in response to a traumatic event, increased
cortisol signaling would alter or interact with psy-
chological and biological risk factors to result in
the PTSD clinical phenotype. Such possibilities are
plausible in the context of the transgenerational
findings.
Relevance of epigenetic analyses to PTSD risk
The study of epigenetic modifications may provide
important insights into PTSD risk and pathophys-
iology since it provides a mechanism for trans-
generationally transmissible functional change in
genomic activity that can be induced by environ-
mental events. In particular, methylation of po-
lymerase II promoters (Sutherland and Costa,
2003), which provide an efficient way of gene si-
lencing, provides a concrete molecular mechanism
through which genetic–environmental interactions
occur in PTSD, since this mechanism that appears
to be operative in programming the activity of
hippocampal genes regulating HPA activity by
early life events (i.e., differences in maternal care).
Indeed, when considering that PTSD is funda-
mentally a response to an environmental event
that is likely formed, not so much by the objective
characteristics of the event, but by subjective
131
interpretations of its meaning — it becomes obvi-
ous that neither genetic analyses nor an under-
standing of the normative biological responses to
stress or fear, can provide the information needed
to understand why PTSD results in only a pro-
portion of those exposed. Clearly genetic analyses
alone will simply not detect environment–gene
activity connections, and though endocrine or
other biological markers examining stress effects
can in principle detect them, the response of a
person to trauma exposure in adulthood is often
determined by a lifelong pattern of responding to
life events that may obfuscate the impact of earlier
events. The study of epigenetic modifications may
provide a relatively stable measure that reflects
early life events, rather than the cumulative effects
of stress, that can help delineate developmental
influences on biological alterations in PTSD from
those reflecting pathophysiology.
Abbreviations
BMI Body Mass Index
CAPS Clinician Administered PTSD
Scale
CRF corticotropin releasing factor
CTQ Childhood Trauma Questionnaire
DEX dexamethasone
GR glucocorticoid receptor
HPA hypothalamic-pituitary-adrenal
LSD Least Significant Difference
MR mineralocorticoid receptor
PPQ Parental PTSD Questionnaire
PTSD posttraumatic stress disorder
VNTR variable number tandem repeat
WTC World Trade Center
Acknowledgments
This work was supported by an NIMH R01
MH64675-01 entitled ‘‘Biology of Risk and PTSD
in Holocaust Survivor Offspring, and, in part by a
grant (5 M01 RR00071) for the Mount Sinai
General Clinical Research Center from the National
Institute of Health. The authors acknowledge
Dr. James Schmeidler for statistical consultation
and Amanda Bell for her assistance in the pre-
paration of this manuscript.
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134
Discussion: Chapter 9
RICHTER-LEVIN: I wanted to ask whether it is
not risky to include also this group under the defi-
nition of PTSD. Is it not an additional disorder to
the definition of PTSD that does not have the
same roots, the same mechanism, and so on?
YEHUDA: Right, well that’s a good point, glad
that you brought that up. I don’t think that all
comes from this kind of risk. This is an example,
one type of group that is vulnerable and for that
reason that makes them vulnerable and their his-
tory and their background might explain why they
might catastrophize the response to trauma. But
not all traumas, practically traumas that involve
long separation and personal violence, right? It
doesn’t necessarily explain why somebody else
would get PTSD. These are not the low IQ, cog-
nitively impaired PTSD people. With the paper
that came out from Mark Gibertson and Roger
Pitman very recently showed cognitive deficits in
the non-exposed co-twins in PTSD Vietnam vet-
erans with PTSD are (end of tape).
RICHTER-LEVIN: Is it a good translation of
what you presented that actually we don’t have
PTSD (posttraumatic). That is, you have a kind of
a syndrome; one of the ways to get to the syn-
drome is trauma (and then it would be posttrau-
matic), but that there are other ways to get to this
same syndrome (without the exposure to a well-
defined trauma), so that the name PTSD is not a
good name for this syndrome.
YEHUDA: In the offspring, or in anyone?
RICHTER-LEVIN: If this population of off-
spring has the same syndrome as someone who is
exposed to trauma but they were not exposed to a
well-defined trauma, then you have a syndrome,
but only one of the ways to get to the syndrome is
posttrauma.
YEHUDA: OK I mean we can keep the initials
and think of it as posttraumatic sensitization dis-
order. You know that kind of work, but that is
why I raised earlier whether there is a final com-
mon pathway and one biology that fits all or
whether what we are looking at are different kinds
of trajectories that look similar and for us to call it
all PTSD. The political history of PTSD was that
prior to the establishment of the diagnosis there
was a diagnosis like concentration camp syn-
drome, and other s; the idea was to bring it all
together under an umbrella, and you are saying
that is maybe not such a good idea, maybe not.
RICHTER-LEVIN: I am asking, not saying.
YEHUDA: You are asking, but it is a testable
hypothesis that should be asked for an answer.
With lot of clinical experience I have been in a
position to really study the typical cultural differ-
ences. I can tell you that holocaust survivors are
different from Vietnam veterans but they share
some PTSD symptoms, but in terms of a biological
basis do I want to go after the differences or do I
want to go after the common you know PTSD.
135
    • "du stress chez ce dernier (Gowin et al., 2013 ;Neigh, Gillespie, & Nemeroff, 2009 ;Yehuda & Bierer, 2008). Au plan transgénérationnel, des altérations du HPA et des taux de cortisol plus bas ont été retrouvés chez les enfants de mères ayant vécu des sévices dans l'enfance – en particulier lorsque jumelés à d'autres psychopathologies (ÉSPT, dépression) ou facteurs de stress chez la mère (Brand et al., 2010) – suggérant que certains phénomènes épigénétiques corrélés aux situations de maltraitance à la première génération pourraient se transmettre à la suivante (Neigh et al., 2009). "
    [Show abstract] [Hide abstract] ABSTRACT: Literature review on clinical issues with parents at risk of child abuse: targeting the generational factor? The prevalence of child abuse is higher in families with psychosocial vulnerabilities or when one or both parents experienced abuse or neglect during childhood. While the most widespread intervention approaches in Canada (e.g. material support or parenting skills programs) show mixed results in providing changes in mistreatment cycles, we examine clinical practice focused on generational repetition of trauma. In order to explore this topic, this paper has 4 objectives and will be supported by a narrative review of the literature: 1) to document the causalities of child maltreatment; 2) to identify the clinical challenges of struggling parents; 3) to develop a critical analysis of the intervention programs commonly spread in Canada; 4) to take into account multifaceted vulnerabilities of these families through innovative practice perspectives.
    Article · Dec 2015
    • "Brave Heart contends the problems facing the Native American peoples are the result chronic trauma and unresolved grief, perpetrated upon the Indigenous peoples by the dominant European culture for almost 500 years (, 1999 Brave Heart & DeBruyn, 1998). However, despite the comprehensive body of research on the transgenerational effects of the Holocaust, by specialists in the transgenerational transmission of trauma, in particular PTSD (Yehuda, 2002; Yehuda, Halligan, & Bierer, 2002; Jablonka & Lamb, 2005; Yehuda, 2006; Yehuda & Bierer, 2008; Jablonka & Raz, 2009; Yehuda et al., 2014), many other so-called experts in the mental health field continue to challenge the validity of the claims that the horrors experienced by their Native American ancestors, continue to be passed down offspring for many generations—resulting in the medical and cultural difficulties mentioned previously (Brave Heart & DeBruyn, 1998). "
    [Show description] [Hide description] DESCRIPTION: This is a completed doctoral dissertation that has been approved for publication by ProQuest--this is the final PDF. it is a survey of the literature on Epigenetic Research with a concentration on the Transgenerational Transmission of Trauma.
    Full-text · Research · Oct 2015 · Pratiques Psychologiques
    • "There are several possible explanations for this. First, PTSD has been linked to impaired hypothalamic-pituitary-adrenal axis functioning (Yehuda, 2003), altered gene expression (Yehuda & Bierer, 2007), and impairment to neural networks implicated in emotion regulation (Lanius, Bluhm, Lanius, & Pain, 2006). It is well documented that these changes can have a broad array of ripple effects on stress responses, physical health, and capacity to manage ongoing stressors in the environment. "
    [Show abstract] [Hide abstract] ABSTRACT: This study investigated whether impairment persists after posttraumatic stress disorder (PTSD) has resolved. Traumatically injured patients (N = 1,035) were assessed during hospital admission and at 3 (85%) and 12 months (73%). Quality of life prior to traumatic injury was measured with the World Health Organization Quality of Life–BREF during hospitalization and at each subsequent assessment. PTSD was assessed using the Clinician-Administered PTSD Scale at 3 and 12 months. After controlling for preinjury functioning, current pain, and comorbid depression, patients whose PTSD symptoms had resolved by 12 months were more likely to have poorer quality of life in psychological (OR = 3.51), physical (OR = 10.17), social (OR = 4.54), and environmental (OR = 8.83) domains than those who never developed PTSD. These data provide initial evidence that PTSD can result in lingering effects on functional capacity even after remission of symptoms.
    Full-text · Article · Aug 2015
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