Differentiating biological correlates of risk, PTSD, and resilience following trauma exposure

Journal of Traumatic Stress, Vol. 20, No. 4, August 2007, pp. 435–447 ( C© 2007)

Differentiating Biological Correlates of Risk,PTSD, and Resilience Following Trauma Exposure

Rachel YehudaDepartment of Psychiatry, Mount Sinai School of Medicine, New York, and Departmentof Psychiatry, Bronx VAMC, Bronx, NY

Janine D. FloryDepartment of Psychiatry, Mount Sinai School of Medicine, New York, and Departmentof Psychology, Queens College, CUNY, Flushing, NY

Risk and resilience factors presumably explain the individual differences in the response to adversity.However, little is known about how such factors are related. Risk and protective factors may reflect aquantitative difference along a single dimension (e.g., low IQ might be associated with risk and high IQwith resilience); however, they may also refer to orthogonal constructs that interact and/or moderate stresseffects to increase or diminish the probability of developing trauma-related psychopathology (e.g., goodcoping could offset low IQ). The authors illustrate experimental strategies for distinguishing betweenthese possibilities for any putative measure relating to symptom development, using a database thatincludes published and unpublished psychological and biological variables from a relatively homogenouscohort of exposed and nonexposed veterans.

Describing a universal psychological or mental health

response following exposure to a traumatic event has turned

out to be an unattainable goal because no single response

exists. Indeed, it is now clear that there are individual dif-

ferences in vulnerability as well as resilience factors that

preclude a description of a response to an event that would

affect persons uniformly. Furthermore, the very assertion

that trauma exposure can result in mental health symp-

toms has become somewhat provocative, in that it can be

stigmatizing to those who do not believe they have been ad-

versely affected in this manner. It is, therefore, noteworthy

that the emergence of interest in the concept of resilience

This work was supported by NIH grants, R01 MH064675-02, R01 MH64104-01, VA Merit Funds, and DOD funds (Dr. Yehuda). The authors wish to thank Ms. Amanda Bell forher assistance with this manuscript. The data presented here for reanalysis represents published findings from efforts involving several investigators including Drs. Julia Golier, LindaBierer, Monte Buchsbaum, Ren Kui Yang, and Iouri Makotkine.

Correspondence concerning this article should be addressed to: Rachel Yehuda, Psychiatry OOMH, Bronx Veteran Affairs Medical Center, 130 West Kingsbridge Road, Bronx, NY10468. E-mail: [email protected].

C© 2007 International Society for Traumatic Stress Studies. Published online in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/jts.20260

comes at the peak of success of the concept of posttrau-

matic stress disorder (PTSD), serving as a reminder that

there is a wide range of possible responses to the same ob-

jective event. At the same time, little is known about the

nature of individual responses to trauma or even the more

specific questions regarding associations among risk and

resilience factors, trauma exposure, and the development

of psychopathology.

In this article, we suggest that the current interest

in resilience may reflect a backlash towards explanations

about stress effects that underemphasize individual differ-

ences, i.e., that trauma exposure invariably results in a bad

435

436 Yehuda and Flory

outcome. We suggest potential strategies that allow the

focus of inquiry regarding effects of events to be geared to-

wards individual responses, and accordingly, a better sepa-

ration between more universal or prototypic responses, and

those that occur at the extreme ends of the spectrum (for

example, and are more appropriately classified as patholog-

ical or resilient). We provide examples of specific research

designs that can lead to more clarity regarding effects of

extreme trauma, and then demonstrate, with one data set

containing multiple variables, how to distinguish factors

associated with risk, symptom severity, recovery, and stress

resistance, among various dependent variables.

H I S T O R I C A L P E R S P E C T I V E : W H Y R E S I L I E N C EH A S B E C O M E S O R E L E V A N T N O W

Before PTSD became a diagnosis in 1980, the general

mental health paradigm asserted that persons were funda-

mentally resilient; that is, that those exposed to adversity

had the ability to bounce back from these experiences. Al-

though it would be difficult to find an authoritative state-

ment to this effect (i.e., representing this succinct view

of the entire field), the idea that persons are fundamen-

tally resilient was implied by the lack of a diagnostic cat-

egory in the Diagnostic and Statistical Manual of Mental

Disorders, Second Edition (DSM-II ; American Psychiatric

Association [APA], 1968) describing a failure to recover

from mental health problems resulting from stress expo-

sure (Yehuda & McFarlane, 1995). This omission did not

reflect a failure to understand the negative contribution

of stress to mental health symptoms, as this had been a

cornerstone of the biopsychosocial model of mental illness

since the DSM-I (APA, 1952). In fact, the DSM-I, pub-

lished in 1952, did have a category for gross stress reaction,

but this was replaced by transient situational disturbance in

the DSM-II (Bloom, 2000). Indeed, the prevailing view

in mental health was that symptoms in response to en-

vironmental stress resolved with time, particularly if the

stressors were no longer present, consistent with contem-

porary ideas about the relationship between stressors and

stress responses (Cannon, 1914; Selye, 1936). The term

transient situational disturbances in the DSM-II ultimately

became the forerunner of adjustment disorders, which were

originally aimed at categorizing reactions to distressing life

events (APA, 1968). In contrast, persistent symptoms were

interpreted as reflecting an underlying neurosis that could

not be directly attributed to event exposure, but was merely

precipitated by it. Even the first documented term used

to describe a posttraumatic-like syndrome (railway spine)

was eventually reconceptualized as a hysterical response,

or a situational neurosis (Marlowe, 2001). That even the

effects of combat “shell shock” were likely transient was

also implied by the treatment regimens for this condition

during the Civil War, World War I, and World War II,

which largely involved allowing soldiers or veterans to rest

briefly before returning them to the front, or back to their

lives (Marlowe, 2001).

The events leading up to the establishment of the diag-

nosis in 1980 have been previously described (e.g., Yehuda

& McFarlane, 1995). In brief, however, it appeared that

in the decades preceding the formal diagnosis of PTSD,

persons with chronic symptoms following a life event felt

stigmatized by the assertion that an underlying character

weakness or constitutional vulnerability was to blame for

their symptoms, rather than the event itself. The lack of

an appropriate category for describing long-term effects

resulting from an extremely stressful event resulted in the

conception of PTSD. The PTSD paradigm maintained

that the exposure to a watershed life event, such as rape,

physical assault, torture, or combat, could produce severe

and long-lasting mental health consequences because trau-

matic events were pathogens. This idea was embraced by

many trauma survivors—Vietnam veterans, rape victims,

survivors of the Nazi concentration camps, and other vic-

tims of torture—who then felt validated, felt more hopeful

that they could be properly treated by the mental health

community, and could subsequently even make the argu-

ment for compensation to the extent that the occurrence of

an event could be verified and/or a perpetrator identified

(reviewed in Bloom, 2000).

Whether it was the intention of the DSM-III (1980)

to describe a universal response to exposure is not clear,

but the language of the text—“The stressor producing

Journal of Traumatic Stress DOI 10.1002/jts. Published on behalf of the International Society for Traumatic Stress Studies.

Risk, PTSD, and Resilience 437

this syndrome would evoke significant symptoms of dis-

tress in most people, and is generally outside the range of

such common experiences as simple bereavement, chronic

illness, business losses, or marital conflict” (p. 236)—

implied this. We now know that subsequent epidemi-

ologic studies certainly did not support such an idea

(Breslau, Davis, Andreski, & Peterson, 1991; Kessler, Son-

nega, Bromet, Hughes, & Nelson, 1995). However, it is

informative to understand the thinking that went into es-

tablishing the diagnosis of PTSD. For example, concern-

ing the potential overlap with adjustment disorder, the

DSM-III (1980) stated, “the stressor is usually less severe

and within the range of common experience. . . the char-

acteristic re-experiencing symptoms are missing” (p. 237).

Thus, in the absence of data on the prevalence of both trau-

matic event exposures and PTSD, PTSD quickly came to

represent a normal response to catastrophic trauma. In fact,

the presence of PTSD could almost be used to infer trau-

matic exposure (which led to a rather stressful, and certainly

unfortunate chapter in mental health histories during

which time it was believed by many that memories of abuse

could be recovered based on suspicions of trauma resulting

from the presence of intrusive, avoidance, or hyperarousal

symptoms).

S T R E S S S E V E R I T Y A N D S T R E S S R E S P O N S E S :T H E I M P O R T A N C E O F I N D I V I D U A LD I F F E R E N C E S

It could be further mentioned, as an aside, that basic science

was not helpful in clarifying matters relating to the rela-

tionship between stressors and stress responses. In the years

immediately preceding and following the establishment of

PTSD, the emphasis in basic science studies was generally

aimed at delineating the normative (i.e., typical, universal)

response to a variety of provocations. As relevant biological

systems became identified, the nature and severity of stres-

sors were reinterpreted in relation to the intensity of the bi-

ologic response (Yehuda, 1997). Thus, just as the presence

of PTSD symptoms constituted evidence that a trauma oc-

curred, the degree of stress hormone response provided in-

formation on the severity of the stressor. To the extent that

different provocations produced different levels of stress re-

sponses, this information was also interpreted as reflecting

responses owing to event severity. The idea of individual

differences in response to a similar provocation was largely

popularized in the late 1980s and 1990s by early handling

paradigms (Aitken, Bodnoff, Iny, Tatarewicz, & Sapolsky,

1985; Meaney et al., 1985), following the seminal obser-

vations of John Mason published in the 1960s (Handlon

et al., 1962; Mason, 1968; Sidman, Mason, Brady, &

Thach, 1962; Wolff, Friedman, Hofer, & Mason, 1964).

Prior to this time, although individual variation had been

noted, it was not the focus of systematic investigation in

basic science studies of stress. The idea that controllabil-

ity, predictability, and other parameters could alter the

stress responses was the beginning of understanding that

stress responses could be modified. In particular, the above

observations pointed to what appeared to be paradoxical

response of the adrenal gland (e.g., low cortisol levels) in

situations that were extremely stressful and/or capable of

eliciting profound distress. Such individual differences in

response to stress have more recently become the focus in

contemporary animal studies (see Bush, Sotres-Bayon, &

LeDoux, 2007; Lyons & Parker, 2007), in response to the

difficulty in the clinical arena of applying universal descrip-

tions of event outcomes based on the nature and severity

of the stressor itself.

That it was subsequently determined after the establish-

ment of PTSD that only a minority of persons exposed to

traumatic events developed (i.e., as defined by the persis-

tence of early symptoms for more than a month) or, more

importantly, maintained PTSD, required a reevaluation of

the idea that PTSD was a prototypic response to stress.

Certainly, PTSD was one possible response. Furthermore,

the demonstrations of a relationship between trauma type

and the development of PTSD (with rape associated with

the greatest lifetime prevalence of PTSD), implied a rela-

tionship between trauma severity and PTSD. However, the

line demarking stressor severity based on objective charac-

teristics of the event versus the subjective response of the

victim has never been clear. Although it is intuitively easy



to understand why being raped twice rather than once, or

by two perpetrators rather than one, or with versus with-

out a weapon, or with versus without penetration or injury

would be considered more severe, not all traumatic expo-

sures lend themselves to this type of analysis of trauma

severity. The meaning of these experiences for any individ-

ual victim may amplify or attenuate the subjective distress

as well. In cases of experiences occurring over longer peri-

ods (e.g., combat), such itemizations become less accurate

in capturing the overall horror, life threat, or experiential

quality of what transpired. What was learned from combat

veterans, for example, was that a single moment could be

life-altering whether that moment occurred in the context

of a chronic combat exposure, or not. Thus, trauma sever-

ity could theoretically be somewhat helpful in explaining

the threshold at which persons might develop PTSD, or

why risk for PTSD was greater among persons who were

exposed compared to unexposed to trauma, but was less

helpful in explaining why PTSD was sustained or why

there were different levels of PTSD symptom severity.

D E F I N I N G R E S I L I E N C E : A P R E R E Q U I S I T E T OE L U C I D A T I N G I N D I V I D U A L D I F F E R E N C E SR E S U L T I N G F R O M T R A U M A E X P O S U R E

The above discussion suggests that the interest in resilience

in both the clinical and basic neurosciences reflects the

recognition that there are multiple responses to adversity.

In the psychosocial literature, resilience has been defined

as the process of adapting well in the face of adversity,

trauma, tragedy, threats of harm, or even significant sources

of stress. Psychological resilience is generally characterized

by the ability to bounce back from a negative experience,

or even significant adversity, through flexible adaptation to

the ever-changing demands of life (Block & Kremen, 1996;

Lazarus, 1993; Luthar, Cicchetti, & Becker, 2000; Masten,

2001). These definitions suggested that the concept of re-

silience may offer the counterweight to the idea that expo-

sure to such life events can produce negative consequences,

including psychopathology. However, such definitions do

not address per se, the relationship between resilience, risk,

and the development (or recovery from) psychopathology.

To the extent that psychiatric illness results from en-

vironmental exposures, resilience may be a mediator that

may explain why psychopathology does not always de-

velop. To the extent that biomarkers of resilience can be

identified, these could be used to either predict (if they

are trait-related) or track (if they are state-related) recov-

ery from traumatic events. Identifying true correlates of

resilience-related factors, particularly those that can be de-

veloped, could certainly provide important insights to how

resilience or recovery from traumatic stress could be pro-

moted. Moreover, if resilience is an enduring characteristic

or trait that is identifiable even before trauma exposure,

it could be used to predict responses to adversity in those

who may be at high risk for occupational or other hazards.

A P P R O A C H I N G T H E S T U D Y O F R E S I L I E N C E

Optimally, such studies are best designed by investigators

who have specific hypotheses with regard to whether re-

silience refers to a state or a trait. Indeed, resilience can refer

to either a state or trait. The ability to bounce back may

be a trait. However, resilience may also refer to the process

of adapting or the product of successful adaptations. The

trait, process, or product of resilience may each have dif-

ferent psychological and/or biological underpinnings that

may operate quite differently in the context of other traits

or states. In some sense, the inability to distinguish trait

from state aspects of resilience is due to the lack of prospec-

tive or even longitudinal research examining psychological

aspects of resilience over time that can determine what fea-

tures of resilience predict better outcomes in response to

adversity.

The study of resilience also requires formulating a hy-

pothesis concerning the relationship between resilience and

exposure to stress. Related to the state versus trait issue is

that it is not clear whether resilient people are born with

capacities for adaptation or whether they acquire them as a

result of the necessity arising from having to cope with ad-

versity. It is helpful to distinguish between resilience factors

that may be present before exposure and influence stress



recovery, and those that may only be manifest following ex-

posure to trauma; indeed, the former may be pretraumatic

predictors of resilience.

In cross-sectional studies, distinguishing trait versus

state features of resilience may not be possible within

the confines of a single experimental design, but rather

using sequential studies that carefully differentiate be-

tween trauma-exposed and nonexposed persons. If putative

resilience-related measures are preexisting traits that are un-

affected by trauma exposure, these would presumptively be

measurable in at least some nonexposed persons, perhaps

making exposed and nonexposed groups indistinguishable

on this measure. Conversely, if resilience markers reflect

trauma exposure because they are correlated with exposure

or activated by exposure, group differences may not be

discernable if a nonexposed group is excluded from study.

These factors suggest that cross-sectional studies should in-

clude nonexposed and exposed individuals, although only

a prospective, longitudinal approach can evaluate the im-

pact of trauma exposure as well as assess resilience-related

factors as they may develop and change over time.

Is Resilience the Opposite of Psychopathology?

Possibly the most important consideration in experimental

designs for resilience-related research is determining the ex-

tent to which resilience is the opposite of psychopathology.

It is often inferred from the way the term resilience is used

in trauma-related research, that this refers to the state (or

trait) of not having psychopathology (e.g., PTSD). How-

ever, whether or not resilience can be characterized in this

manner is an empirical question.

It is problematic to assume that resilience reflects the op-

posite of psychopathology (i.e., stress-resistance) because

persons with psychopathology may, in fact, be quite re-

silient according to many conceptualizations and defini-

tions of this construct. For example, Holocaust survivors

can be classified according to whether they meet current of

lifetime criteria for psychopathology—but this is only one

distinction that does not necessarily affect other resilience-

related outcomes. In studies of Holocaust survivors, the

presence or absence of PTSD or depressive symptoms did

not prevent survivors from establishing a new life, getting

married, having children, earning a living, educating their

children and ensuring their placement into society, form-

ing and participating in the community, and even giving

back to society to the best of their ability. There are indi-

vidual differences related to symptom severity. These are

usually in the domain of coping abilities, social support,

intellectual capacities, or medical comorbidities. Some of

these differences may reflect PTSD risk factors or be re-

lated to exposure. Thus, although it is difficult to argue that

there is a lack of overall resilience simply as a function of

symptoms—and one might hypothesize that their occur-

rences in the presence of mental health symptoms makes

other life accomplishments all the more remarkable—it is

certainly important to understand the factors that do con-

tribute to the development of symptoms and determine

their relationship to overall resilience and outcome. Thus,

the question becomes one of identifying the extent to which

presence and/or absence of psychopathology affects specific

resilience-related variables. Such an exploration can then

determine whether resilience is associated with absence of

psychopathology, or rather, whether it is associated with

other variables that directly or indirectly influence mental

health outcomes.

Is Resilience the Opposite of Vulnerability?

Figure 1 (Panel A) presents a schematic drawing that rep-

resents one experimental strategy for determining whether

resilience is the opposite of (i.e., provides a counterweight

for) vulnerability, or rather, whether resilience is the oppo-

site of psychopathology (i.e., whether psychopathology will

occur in the absence of resilience). This approach involves

first differentiating trauma-exposed persons on the basis of

presence or absence of (current and/or lifetime) PTSD (or

psychopathology), and then making a second distinction

based on the presence or absence of a known risk factor

for PTSD. Such subdivision produces four cells reflecting

being positive or negative for psychopathology and/or the

risk factors. Because there are many different kinds of risk

factors for PTSD (and also many forms of posttraumatic

psychopathology), it is certainly possible to anticipate that



Figure 1. Strategy for the study of resilience in trauma-exposed persons. Panel A represents a generic template in which trauma-exposed persons with current or lifetime psychopathology (e.g., posttraumatic stress disorder) can be crossed with a pretraumaticrisk factor for that illness (e.g., prior trauma exposure). The resultant boxes can help distinguish variables associated with extremevulnerability (B), defined as developing psychopathology following exposure (i.e., resulting from exposure) even in the absence ora known risk factor, versus extreme resilience (C), defined as failing to develop psychopathology following exposure despite thepresence of a known vulnerability factor. It could be posited that persons in A represent a resilient group because they do not havea vulnerability factor. In this case, A and C might be comparable. If A and C are different, then factors associated with failingto develop psychopathology are distinct from those associated with risk. Similarly, D might represent an expected outcome ofdeveloping psychopathology because of a risk factor. Persons in D and B would be comparable and different from those in C if theabsence of risk is resilience. In Panel B, we have replaced data from coping scores (positive minus negative coping) as measured bythe Coping Orientation for Problem Experience scale (COPE; Carver et al., 1989). There were significant differences between Band C, which demonstrate that higher scores were observed in resilient compared to vulnerable persons, t(14) = −3.93, p < .01.

trauma survivors might fall into one of the four categories

for any given risk factor or psychopathological outcome.

The experimental strategy here assumes that persons

who develop PTSD in the absence of a risk factor (Box

B) are the most vulnerable persons whereas those who

do not develop PTSD even in the presence of a known

PTSD risk factor (Box C) are the most resilient. Thus,

the question becomes that of comparing persons in Box A

with those in Box C and Box B, respectively. A similarity

on a variable between resilience participants in Box C and

those in Box A, would suggest that the variable is related

to presence or absence of PTSD. However, if persons in

Box C form a distinct group, this constitutes evidence of a

variable uniquely associated with resilience.

This strategy can distinguish between measures reflect-

ing resilience, risk, and psychopathology. To illustrate the

utility of this approach, we apply it to a data set of com-

bat veterans in whom we were interested in measuring

the relationship between psychological and biological mea-

sures associated with risk, PTSD, and resilience. All par-

ticipants (N = 40) were within a relatively narrow age

range (age range = 52–81, mean age = 62.4 years), and

underwent a similar psychological evaluation, magnetic

resonance imaging (MRI) for the determination of hip-

pocampal volume, and provided blood samples for the

determination of glucocorticoid responsiveness assessed in

lymphocytes and plasma neuropeptide Y (NPY), a neuro-

transmitter, and dehydroepiandrosterone (DHEA) levels,

a natural steroid prohormone. The data published from

this effort appear in three different publications: Yehuda,

Brand, & Yang, 2006; Yehuda, Brand, Golier, & Yang,

2006; Yehuda, Yang et al., 2006. Methods for subject



Figure 2. Biological measures putatively associated with risk or resilience by PTSD status. In all panels, open circles representno posttraumatic stress disorder (PTSD; N = 16) and closed circles represent PTSD (N = 17). In this analysis of plasma NPY(Panel C), there are no significant effects of group,F < 1, risk factor, F < 1, or interaction, F < 1. For DHEA (Panel D), thereare no significant effects of group, F (1, 30) = 1.10, ns, risk factor, F < 1, or interaction, F < 1. Data from Panels A and B arepublished in Yehuda, Yang, et al., 2006. Panels C and D represent an analysis of the trauma exposed participants only (N = 29),from the sample of 40 veterans (Yehuda, Brand, Golier et al., 2006; Yehuda, Brand, & Yang, 2006).

recruitment, screening, inclusion and exclusion criteria,

and other subject characteristics are well described in the

noted articles’ Method sections, as are descriptions of clin-

ical and biological assessments. The data, or (when noted)

specific subsets, are summarized here again for the purpose

of demonstrating associations among all the variables, as

well as illustrating the different conclusions that can be

made depending on how participants are classified, and

group comparisons are made.

In Figure 1, Panel B we present a proof of concept that

the proposed distinction between resilient and vulnerable

trauma-exposed persons can be discerned in a sample of

trauma-exposed male veterans (i.e., excluding nonexposed

controls) by illustrating differences in the resilience-related

construct, coping, using scores on the Coping Orienta-

tion for Problem Experiences (COPE; Carver, Scheier, &

Weintraub, 1989). It can clearly be seen here that coping

was highest in the resilient group and lowest in the vul-

nerable group. This pattern is consistent with the idea that

good coping might be a countervailing factor that overrides

other PTSD-related risk factors. Interestingly, coping was

not associated directly with the development of PTSD.

In the data presented in Figure 2, we present informa-

tion from the same participants using a slightly different

method of graphing the data. In each of the four pan-

els, veterans are subdivided on the basis of presence or

absence of lifetime PTSD. The x-axis represents a fur-

ther subdivision on the basis of a risk factor (i.e., early

or prior trauma). Panel A shows that, similar to the pat-

tern observed with coping scores, left hippocampal vol-

ume was the highest in the resilient group, and lowest

in the vulnerable group, Group × Risk Factor Interaction:



Figure 3. Inverse relationship between a risk and resiliencefactor in trauma-exposed veterans. Closed circles representveterans with posttraumatic stress disorder (PTSD) and opencircles represent veterans without PTSD (Yehuda, Yang, et al.,2006).

F (1, 32) = 5.13, p < .05 (Yehuda, Brand, & Yang, 2006).

This suggests that prior trauma exposure moderates the

association between PTSD and higher hippocampal vol-

ume. Insofar as hippocampal volume has been linked with

PTSD risk (Gilbertson et al., 2002), it was interesting to

note that this putative measure of risk (small hippocampal

volume) was inversely associated (but yielding a positive

correlation) with a measure of resilience (good coping),

r (28) = .42, p < .05 (Figure 3).

Figure 2, Panel B demonstrates a very different pat-

tern with respect to a measure of glucocorticoid respon-

siveness, the lysozyme IC50 (the outcome measure of an

in vitro dexamethasone suppression test in which live lym-

phocytes are incubated with different concentrations of

dexamethasone to determine the extent to which glucocor-

ticoid receptor influenced activity of the enzyme lysozyme;

Yehuda, Golier, Yang, & Tischler, 2004; Yehuda, Yang,

Guo, Makotkine, & Singh, 2003). Glucocorticoid respon-

siveness was not associated with resilience, again denoted

as the absence of PTSD in the presence of the risk fac-

tor, even though it was related with both PTSD and a

risk factor, main effect of early trauma exposure: F (1,

31) = 9.10, p < .001; group by early trauma interaction:

F (1, 31) = 3.72, p = .06 (Yehuda, Yang et al., 2006). In

this case, although both hippocampal volume and glu-

cocorticoid responsiveness were both associated with risk

factors (prior trauma, early trauma, respectively), but were

inversely related to one another, r (28) = −.54, p < .01

(Yehuda, Brand, & Yang, 2006), the risk factor of smaller

hippocampal volume associated with developing PTSD to

a first trauma exposure is distinct from the risk factor of

glucocorticoid responsiveness that develops from an early

life exposure, whether or not PTSD develops to that or

another event. In any case, it appears that when consider-

ing a group of trauma-exposed persons, the most extreme

distinctions are presently based on parameters relating to

vulnerability (the development of PTSD without the risk

factor) is an inverse relationship between these two dis-

tinct biological measures previously linked to PTSD risk

and those reflecting resilience.

Figure 2, Panels C and D also graph the results for NPY

and DHEA. Unlike hippocampal volume and glucocor-

ticoid responsiveness, which have been previously linked

with PTSD and/or PTSD risk, NPY and DHEA have

recently been hypothesized as being directly relevant to re-

silience. The release of NPY in response to stress is thought

to facilitate the containment of the negative consequences

of other biological stress effects (Heilig, 2004), as evidenced

by its general anxiolytic actions, and impairing effects on

stress-induced memory retention following microinjection

of NPY to the amygdala of rats (Flood, Baker, Hernandez,

& Morley, 1989). DHEA has also been hypothesized to

be associated with ameliorative effects in the face of stress

(Charney, 2004). Deficiencies in DHEA have been linked

with impairments in cognition and decrements in mood

(Herbert 1997; Van Niekerk, Huppert, & Herbert, 2001),

and pharmacologically induced increases have been asso-

ciated with improvements in these domains (Van Niekerk

et al., 2001).

Interestingly, both NPY and DHEA showed very differ-

ent patterns than had been observed for left hippocampal

volume and glucocorticoid responsiveness. When consid-

ering only trauma-exposed veterans, NPY and DHEA did

not appear to be associated with either PTSD, prior trauma

exposure, or their interaction, respectively. These findings



suggest that NPY and DHEA reflect very different aspects

of PTSD risk and/or resilience than those associated with

more enduring, and possibly pretraumatic factors that have

been linked with hippocampal volume and glucocorticoid

responsiveness.

As stated above, examining differences within a group

of participants in which the distinction between exposed

versus nonexposed persons is not made prevents an ex-

amination of the contribution of trauma exposure to a

measure of risk. Furthermore, failing to distinguish be-

tween current versus lifetime PTSD—which is reasonable

when the dependent variable is hypothesized to reflect an

enduring (preexisting) trait characteristic—obscures group

differences that might be observed if these subgroups are

distinguished. In the analyses discussed thus far, the PTSD

group consisted of veterans with both current and lifetime

PTSD. Thus, measures associated with PTSD in such anal-

yses are more likely associated with factors that explain why

PTSD develops, but not necessarily why PTSD is sustained

or fails to remit. The advantage of combining persons

with current and lifetime is that it is possible to compare

trauma-exposed persons who are resistant to the develop-

ment of any lifetime PTSD with other groups (e.g., those

who develop PTSD at some time in their lives, unexposed

persons). However, the disadvantage is that persons with

lifetime, but not current PTSD, represent a distinct sub-

group of trauma-exposed persons who develop, but then

recover from PTSD. Such persons may also be resilient,

but may be different from those who are resistant to the

development of PTSD following trauma exposure.

In Figure 4, we further highlight how the different sub-

groups of trauma-exposed persons may be similar or differ-

ent based on resistance to PTSD, recovery from PTSD, or

failure to recover. In cross-sectional studies, resilient and

resistant groups can appear similar in current symptom

severity, but they represent different lifespan trajectories.

This is an interesting distinction because cross-sectionally,

persons with past, but not current PTSD may be similar

on measures reflecting risk for PTSD, but may differ in

measures reflecting either state PTSD severity or recov-

ery. Persons with lifetime, but not current, PTSD may

Figure 4. Analysis of current, lifetime posttraumatic stress dis-order (PTSD) severity and symptom improvement (lifetime–current PTSD symptoms). Data are presented from 11 con-trols, 6 veterans with no PTSD, 5 veterans recovered fromPTSD, and 12 veterans with current PTSD (Yehuda, Brand,Golier, et al., 2006; Yehuda, Brand, & Yang, 2006).



Figure 5. Biological measures of risk and resilience subdivided by exposure, resistance, recovery, and current posttraumaticstress disorder (PTSD). Data presented are from 11 controls, 6 veterans with no PTSD, 5 veterans recovered from PTSD, and12 veterans with current PTSD (Yehuda, Brand, Golier, et al., 2006; Yehuda, Brand, & Yang, 2006).

resemble those who never developed PTSD on measures

reflecting symptom severity, but would differ substantially

on measures reflecting recovery, or symptom improvement.

Figure 4 shows that the group with the greatest symp-

tom improvement (an estimate that can be achieved by

subtracting current PTSD symptoms from lifetime PTSD

symptoms reflecting symptom severity at the worst lifetime

episode), is the group with lifetime, not current PTSD.

This group is also significantly different from exposed per-

sons who never develop PTSD and nonexposed persons.

It could be hypothesized that measures associated with

risk for, or resistance to, PTSD, would distinguish the re-

sistant group from the other two trauma exposed groups

that developed PTSD. Measures associated with current

PTSD severity would then distinguish the PTSD group

from the other exposed groups. Measures exclusively as-

sociated with recovery from PTSD would distinguish re-

silient from PTSD participants. In theory, a single measure

may reflect two or all three concepts. By including a non-

exposed comparison group and using multiple measures, it

would be possible to evaluate differences between groups

in variables and patterns of associations between variables

so as to inform which measures reflect risk, recovery, and

persistence of PTSD.

This classification clearly yields important information

that could not be obtained by combining participants on

the basis of ever developing PTSD or presence or absence of

current PTSD, as demonstrated in Figure 5. Although sub-

dividing what is a small data set to begin with (N = 40) into

even smaller groups produces unstable findings, we present

results from such a subdivision to illustrate the utility of the

approach being proposed here. Thus, although no conclu-

sive statements can be made about the associations between

risk, resilience, PTSD, and the four biological variables, it



can be clearly seen by contrasting Panels A and B with

C and D that NPY and DHEA are measures of resilience

because they are measures of symptom improvement. That

this could not be ascertained in the previous analysis, which

did not include nonexposed persons, suggests that these

measures are affected or activated by exposure to the focal

trauma (i.e., the event that produces or fails to produce,

PTSD). In tandem, the juxtaposition of these two ana-

lytic approaches provides a strategy for thinking through

state versus trait distinctions as well as determining which

resilience-related measures may be pretraumatic markers

of resilience and which are only apparent in response to

environmental challenge.

The use of multiple analytic strategies of the same vari-

able or analyses of related, but slightly different measures,

amplifies our ability to differentiate between trait versus

state characteristics of resilience and between variables that

are affected by exposure. In particular, the findings demon-

strate the utility of a distinction made rarely in the literature

(except in the treatment literature) between persons who

recover from PTSD and those who do not. Interestingly,

the approach illustrated here could also differentiate be-

tween variables associated with psychopathology and those

associated with resilience. Clearly, plasma NPY and DHEA

are associated with recovery. However, in studies that fail

to distinguish between current versus lifetime PTSD and

between exposed versus nonexposed comparison partici-

pants, it might be possible to reach the conclusion that

NPY and DHEA are associated with PTSD, as they would

be higher in this disorder as a result of trauma exposure,

and their role in helping aid recovery. Such variables can be

clearly distinguished from those that may explain consti-

tutional vulnerability (i.e., resistance to psychopathology)

following exposure (e.g., hippocampal volume), or those

that are related to some risk factors (e.g., early exposure)

even though they are not the opposite of resilience factors

(e.g., glucocorticoid responsiveness).

C O N C L U S I O N S

Ultimately, the approach of collecting multiple measures

on a carefully described, relatively homogenous sample

with clear preexposure, exposure, and postexposure history

and clinical variables is useful in identifying the aggregate

or latent constructs that hang together as correlates—either

psychological or biological—of resilience. To date, we do

not know what these critical variables are or how they inter-

act. Yet clearly, this is within our grasp. Here we have made

the argument for the necessity of distinguishing between

resistance to PTSD and recovery from this condition. We

have demonstrated that different aspects of resilience are as-

sociated with different neurobiologic alterations. We have

further shown that measures associated with PTSD re-

sistance may be used as trait predictors of responses to

adversity, but this must be confirmed by prospective, lon-

gitudinal studies. It is implied by the existence of measures

relating to recovery that are distinct from those associ-

ated with state symptomatology, that it will ultimately be

possible to use measures of recovery. It will be particu-

larly interesting to determine if there are variables that can

be manipulated directly in the service of recovery. These

challenges represent exciting new frontiers for the study of

resilience.

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Differentiating biological correlates of risk, PTSD, and resilience following trauma exposure