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Psychoneuroendocrinology. 2015 January ; 51: 495–505. doi:10.1016/j.psyneuen.2014.09.030.
Conditioned fear and extinction learning performance and its

association with psychiatric symptoms in active duty Marines
D.T. Achesona, M.A. Geyera,c, D.G. Bakera,b, C.M. Nievergelta,b, K. Yurgilb, V.B.
Risbrougha,b,*, and MRS-II Team
aDepartment of Psychiatry, University of California San Diego, United States
bCenter for Excellence in Stress and Mental Health, United States
cMental Illness Research, Education and Clinical Center, VA San Diego Healthcare System,
United States
Summary
Background—Posttraumatic Stress Disorder (PTSD) is a major public health concern,

especially given the recent wars in Iraq and Afghanistan. Nevertheless, despite a sharp increase in
the incidence of psychiatric disorders in returning veterans, empirically based prevention
strategies are still lacking. To develop effective prevention and treatment strategies, it is necessary
to understand the underlying biological mechanisms contributing to PTSD and other trauma
related symptoms.
Methods—The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013)

Neurocognition project is an investigation of neurocognitive performance in Marines about to be
deployed to Afghanistan. As part of this investigation, 1195 Marines and Navy corpsmen
underwent a fear conditioning and extinction paradigm and psychiatric symptom assessment prior
to deployment. The current study assesses (1) the effectiveness of the fear potentiated startle
paradigm in producing fear learning and extinction and (2) the association of performance in the
paradigm with baseline psychiatric symptom classes (healthy: n = 923, PTSD symptoms: n = 42,
anxiety symptoms: n = 37, and depression symptoms: n = 12).
Results—Results suggest that the task was effective in producing differential fear learning and
fear extinction in this cohort. Further, distinct patterns emerged differentiating the PTSD and
anxiety symptom classes from both healthy and depression classes. During fear acquisition, the
PTSD symptom group was the only group to show deficient discrimination between the
conditioned stimulus (CS+) and safety cue (CS−), exhibiting larger startle responses during the
safety cue compared to the healthy group. During extinction learning, the PTSD symptom group
© 2014 Published by Elsevier Ltd.

*Corresponding author at: Department of Psychiatry, 9500 Gilman Dr. Mail Code 0804, La Jolla, CA 92093-0804, United States. Tel.:
+1 619 543 2900; fax: +1 619 543 2475. [email protected] (V.B. Risbrough).
Conflict of interest
The rest of the authors report no conflicts of interest associated with the current manuscript.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.psyneuen.
2014.09.030.
Acheson et al. Page 2
showed significantly less reduction in their CS+ responding over time compared to the healthy
group, as well as reduced extinction of self-reported anxiety to the CS+ by the end of the
extinction session. Conversely, the anxiety symptom group showed normal safety signal
discrimination and extinction of conditioned fear, but exhibited increased baseline startle
reactivity and potentiated startle to CS+, as well as higher self-reported anxiety to both cues. The
depression symptom group showed similar physiological and self-report measures as the healthy
group.
Discussion—These data are consistent with the idea that safety signal discrimination is a
relatively specific marker of PTSD symptoms compared to general anxiety and depression
symptoms. Further research is needed to determine if deficits in fear inhibition vs. exaggerated
fear responding are separate biological “domains” across anxiety disorders that may predict
differential biological mechanisms and possibly treatment needs. Future longitudinal analyses will
examine whether poor learning of safety signals provides a marker of vulnerability to develop
PTSD or is specific to symptom state.
Keywords
Extinction; Fear; PTSD; Anxiety; Military; Fear inhibition; Safety signal; Startle
1. Introduction
Posttraumatic Stress Disorder (PTSD) is a major public health concern among current and
former military members, including those who have recently experienced combat in Iraq and
Afghanistan (Baker et al., 2012). For instance, while most service members remain resilient
following deployment, the incidence of psychiatric disorders among active-duty service
members has increased by 62% since these wars began in 2001. Specifically, there has been
an increase of 656% for PTSD and 226% for anxiety disorders. In addition, the cost to the
Department of Defense (DoD) for treating these service members doubled between 2007
and 2012 (Blakeley and Jansen, 2013 Congressional Research Service Report). The
Department of Veterans Affairs (VA) and society at large will continue to bear the cost of
treating service members with chronic psychiatric issues long after these individuals are
discharged from the military. According to a recent report by the Institute of Medicine, DoD
prevention efforts are hampered by an insufficient empirical base (National Research
Council, 2014). Identifying the underlying biological mechanisms of PTSD from other
stress-related disorders is a key step in developing an evidence base on which to design

more effective prevention and treatment efforts.
The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013) Neurocognition
project is an investigation of neurocognitive performance in Marines about to be deployed to
Afghanistan. Similar to the original MRS (Baker et al., 2012), Marines were assessed in a
3.5 h test battery in which clinical assessment, self-report, and biological assays are
combined with comprehensive neurocognitive assessments once before deployment and then
again 3–6 months after deployment. The purpose of MRS-II is to discriminate between
biological markers that predict risk/resiliency for development of combat-stress related
disorders and markers associated specifically with symptom state. Here we focus on one

aspect of these assessments, measurement of fear conditioning and extinction learning and
its association with psychiatric symptom groups prior to deployment.
Increased responses to conditioned fear cues and reduced ability to inhibit these responses
are well-known features of PTSD in civilian and combat-veteran populations (for review see
VanElzakker et al., 2013). Reduced ability to inhibit fear has recently been suggested to be a
potential “biomarker” specific to PTSD, with PTSD subjects exhibiting poor learning of
safety signals (cues that predict absence of threat) compared to depressed subjects
(Jovanovic and Norrholm, 2011; Jovanovic et al., 2009, 2010). Studies in high trait anxious
participants or other anxiety disorders are inconsistent, showing either normal or reduced
fear inhibition as measured by safety signal learning (Kindt and Soeter, 2014; Gazendam et
al., 2013; Lissek et al., 2009). Reduced inhibition in PTSD patients is thought to reflect
disruption of frontal cortical and hippocampal circuits to inhibit amygdala activation and
concomitant fear responses (Admon et al., 2013; Acheson et al., 2012a,b). However,
increased fear responding to conditioned cues, aversive contexts, or over-generalization of
fear responses are shown across multiple anxiety disorders and thus may reflect biological
processes that are shared across disorders (McTeague and Lang, 2012; Lissek et al., 2013;
Grillon et al., 1998). Results are less clear however for depression, with reports of lower,
normal, and higher aversive responding or fear conditioning (McTeague and Lang, 2012;
Grillon et al., 2013; Robinson et al., 2012; Jovanovic et al., 2010) depending on the type of
conditioned cues and aversive stimuli. Heightened fear responding may be due to increased
amygdala, extended amygdala, and/or dorsal anterior cingulate activity in these disorders
(Admon, 2013; Grillon, 2008). Understanding the differential patterns of fear conditioning
and inhibition between symptom types will help identify specific endophenotypes for further
biological interrogation across stress-related disorders (Cuthbert and Kozak, 2013;
McTeague and Lang, 2012; Admon et al., 2013). Given that MRS-II is a longitudinal study,
we will ultimately be able to determine in future analyses if these putatively differential
phenotypes are vulnerability factors or related specifically to symptom state after trauma.
To test the hypothesis that PTSD, depression, and general anxiety symptoms may reflect
distinct biological mechanisms and subsequent differential patterns of fear conditioning and
inhibition abnormalities, we used a cross-sectional design to directly compare fear
conditioning and extinction across participants endorsing symptoms of general anxiety,
depression, and PTSD at pre-deployment. We used the fear potentiated startle (FPS)
paradigm established by Norrholm et al. (2006), as this paradigm is sensitive to both the
reduced fear inhibition (i.e., safety signal learning and extinction) and increased fear
conditioning described in PTSD patients (Norrholm et al., 2011). This protocol uses an
aversive air-puff as the unconditioned aversive stimulus. Though other fear conditioning
paradigms have used aversive electrical shock as the unconditioned stimulus (i.e., Milad et
al., 2007), we chose to use air puff for a number of reasons. One, use of an air puff increased
the feasibility of testing such a large active duty population in a time-limited manner as it
does not require initial “customization” of shock stimuli. Lack of required customization
reduced setup time as well as technical difficulty. Two, we anticipated that shock stimuli
would be less acceptable to study participants and to local and military institutional review
boards given the special population status of active duty military. Third, this protocol uses
startle reactivity as the operational measure of conditioned fear, a cross species measure of

fear conditioning for translational applications in animal models, and which may be more
sensitive to “automatic” or implicit fear learning compared to other measures such as skin
conductance (Sevenster et al., 2014; Glover et al., 2011).
2. Methods
2.1. Participants
1195 infantry Marines and Navy Corpsmen enrolled in a longitudinal study of the health
effects of deployment to Afghanistan and completed the pre-deployment assessment. Data
was collected on two separate infantry battalions, identified with the assistance of Marine
Corps leadership, 1–2 mo prior to deployment. The first battalion was deployed from March
2012 to October 2012, and the second battalion from September 2012 to April 2013. At the
time of this collection period all Marine infantry were male, thus females did not participate.
All data collection occurred on a single day, with the entire testing battery (of which only a
portion is being presented here) was completed over the course of approximately 4 h. This
study was approved by the institutional review boards of the University of California San
Diego, VA San Diego Research Service, and the Naval Health Research Center. Written
informed consent was obtained from all participants.
2.2. Fear conditioning and extinction procedure

Apparatus—Startle pulses (108 dB, 40 ms) were delivered using a San Diego Instruments
(SDI, San Diego, CA, USA) SR-HLAB Electromyography (EMG) system. Sound levels
were measured using continuous tones calibrated with a Quest Sound Level Meter on the A
scale, coupled to the headphones with an artificial ear. The air puff was set at 250 psi and
delivered via a plastic tube positioned 2.5 cm from the center of the throat. Air-puff onset
was controlled by a solenoid system triggered by the same Acer laptop computer that
controlled the startle stimuli. Conditioned stimuli were presented via E-Prime software
(Psychology Software Tools, Inc., Sharpsburg, PA, USA) run on a Dell desktop computer
with a 48 cm monitor positioned directly in front of the participant. Presentation of the
stimuli by the E-Prime software was triggered by signals from the EMG system to control
synchronization of conditioned, startle, and air-puff stimuli.
Eyeblink EMG responses were recorded via Ag/Ag 3 M Red Dot electrodes placed at the
orbicularis oculi muscles at the left eye connected to the SDI SR-HLAB EMG system and
Acer laptop computer (Acheson et al., 2013, 2012a,b). A reference electrode was placed at
the mastoid bone behind the left ear. Before electrode placement, skin was cleaned with an
alcohol swab and gently exfoliated with 3M electrode prep tape. All electrode resistances
were <10kΩ. EMG data were recorded at a sampling rate of 1 kHz, amplified (0.5 mV
electrode input was amplified to 2500 mV signal output), band-pass filtered (100–1000 Hz),
rectified, and then smoothed with a 5-point rolling average. Expectancy responses were
recorded on a trial-by-trial basis via the participant’s responses on a key pad linked to E-
Prime software. Additional self-report responses were recorded at the end of each
experimental phase via the same keypad.

Eyeblink data were scored via SR-HLAB EMG Utilities software as previously described
(Acheson et al., 2012a,b). In brief, eyeblink responses were examined on a trial by trial basis
at a window starting 100 ms before the startle pulse and ending 200 ms after the pulse. Only
responses that peaked within 100 ms of pulse onset were scored as a startle response. Trials
in which excessive baseline noise or artifact obscured the startle response were removed
(2.1% of trials) and replaced with an imputed value based on the average of the immediately
preceding and following trials.
Fear conditioning and extinction task—The fear conditioning and extinction protocol
consisted of two discrete testing sessions or “phases”: acquisition and extinction. Before the
acquisition phase the participants were instructed that one of the colored symbols predicted
when the air puff would appear. Each phase began with 6 startle pulses presented in the
absence of any other stimuli to stabilize startle responding. The acquisition phase consisted
of eight 6-s presentations of the conditioned stimulus (CS+; either a blue or yellow circle or
square, balanced across subjects) that was paired with the air puff in 75% contingency, eight
6-s presentations of a non-reinforced conditioned stimulus (CS−; also either a blue or yellow
circle or square) that was never paired with the air puff, and 8 presentations of the startle
stimulus in the absence of any stimuli (noise alone or “NA” trial) which served as a measure
of baseline startle across the phase. The CS+ and air puff co-terminated on reinforced trials.
Startle pulses were presented approximately 4 s following CS+ or CS− onset. The stimuli
serving as CS+ and CS− (blue or yellow circles or squares) were randomly assigned across
participants. Contingency awareness was measured using a numbered keypad to report at
each CS+ and CS− trial whether or not they expected to receive the air puff. Participants
responded with a “1” if they expected the air puff, “2” if they were unsure, and “3” if they
did not expect the air puff. After the acquisition phase, contingency awareness was again
assessed via a questionnaire asking participants which stimulus predicted the shock. Self-
reported anxiety during the cues was also measured at this time, as was the subjective
aversiveness of the air-puff stimuli.
After completing the acquisition phase, participants were asked to sit quietly for 5min before
beginning the extinction phase. Before the extinction phase began, the subjects were told to
“remember what they learned” in the previous session. The extinction phase consisted of 16
presentations of each stimulus type (CS+, CS−, and NA). No air puffs were presented during
this phase. Presentations of startle pulses were delivered and ratings of air-puff expectancy
were collected in the same fashion as in the acquisition phase. After this phase, participants
again rated their level of anxiety during the cues. After these ratings were made, participants
were disconnected from the apparatus and went on to other assessment stations (see Baker et
al. (2012) for full details of Marine Resiliency Study assessment battery).
2.3. Assessment of psychiatric symptoms

Posttraumatic Stress Disorder—Post-traumatic stress symptoms were assessed using a
structured diagnostic interview, the Clinician Administered PTSD Scale (CAPS; Blake et
al., 1995). CAPS total scores can range from 0 to 136 and can be used as a measure of PTS
symptom severity. PTSD symptom group membership was defined using the partial PTSD
criteria articulated by Stein et al. (1997). Partial PTSD criteria were chosen due to the

relative psychological health of an active duty Marine cohort. Criteria for assignment to the
PTSD symptom group were the presence of at least 1 B symptom, 2 C symptoms, and 2 D
symptoms, with minimum frequency ratings of 1 and minimum intensity ratings of 2. Inter-
rater reliability in MRS was high for both the CAPS total score (intraclass correlation
coefficient = .99) and for PTSD diagnosis (kappa = .714). All interviews were conducted by
study personnel who were trained, certified and supervised by a licensed psychiatrist
(D.G.B.; Baker et al., 2012).
Anxiety—Assignment to the anxiety symptoms group was defined as scoring in the

Moderate to Severe range (>15) on the Beck Anxiety Inventory (BAI; Beck and Steer,
1993). The BAI is a reliable measure of general anxiety symptoms present within the past
week, and discriminates between anxiety vs. depressive symptoms fairly well (Clark et al.,
1994).
Depression—Assignment to the depression symptoms group was defined as scoring in the

Moderate to Severe range (>19) on the Beck Depression Inventory 2 (BDI-2; Beck et al.,
1996). The BDI-2 measures the presence of depressive symptoms within the past 2 weeks.
Trauma history—The Life Events Checklist (LEC; Gray et al., 2004) was used to assess
previous trauma history. The LEC evaluates the participant’s lifetime experience of a wide
range of traumatic events, including civilian traumas and combat or war-zone exposure, and
further assesses whether the event directly happened to the individual, the individual
witnessed the event happening to others, or whether the event was learned about second-
hand. The LEC score reported here was calculated by summing all of the items scored as
“happened to me” and/or “witnessed it”.
2.4. Data analysis

Final sample—Of the original 1195 Marines and Corpsmen who underwent the fear
conditioning and extinction protocol, data on 21 were rendered unusable due to technical
difficulties during testing. An additional 125 (10.6% of the remaining sample) were
excluded from the analysis because they failed to show a CS+ response greater than baseline
during the last half of the acquisition phase. This failure to potentiate above baseline
suggested that the air puff was ineffective in inducing fear in these subjects that would be
sufficient to support learning in these participants. Further, 35 subjects met our cutoffs for
more than one symptom group and were excluded from the analysis. This approach was
taken to enable comparison of relatively “pure” symptom classes on fear conditioning and
extinction phenotypes. See supplemental materials Table S1 for demographic data on these
excluded subjects. The remaining 1014 subjects were included in all analyses.
Startle—Startle data for the acquisition and extinction phases were analyzed as previously
described in Acheson et al. (2013) by averaging responses to each stimulus type into blocks
of two trials. Within each block, the NA averages were subtracted from the CS+ and CS−
averages to adjust for changes in baseline startle across the session. Thus, each CS+ and CS
− block represented startle above baseline for that block (e.g., (CS+) − (NA)). Thus there

were 4 blocks for the CS+ and CS− during the acquisition phase, and 8 blocks for the CS+
and CS− for the extinction phase.
To compare acquisition across symptom groups, the analysis was simplified by averaging
the last two blocks of the session across both CS types to create a measure of responding
over the last half of the acquisition phase. To assess function of the task, acquisition phase
data were initially analyzed within the healthy group only using a repeated-measures
ANOVA to assess differences in response to each CS type. To assess differences by
symptom group, a 2 (CS type) × 4 (symptom group) mixed ANOVA was conducted on the
entire sample. Significant interactions were followed up with alpha-adjusted post hoc tests to
assess Cue response differences within each symptom group. To assess symptom group
differences in baseline startle, a one-way ANOVA, with appropriate post hoc tests, was
conducted on the average NA trial response across the last half of the extinction phase.
Extinction phase data were analyzed by computing a measure of “% conditioned fear”. This
score is similar to the “extinction retention index” originated by Milad et al. (2007, 2008) in
their studies of fear extinction memory recall, which use a normalization approach to reduce
confounds of differences in fear conditioning on measurement of extinction. For each
subject, the maximal CS+ response during the acquisition phase is identified. A %
conditioned fear is then calculated for each of the 8 extinction blocks using the following
equation: 100* (CS+ response on extinction block/maximum response across acquisition
blocks). For simplicity of presentation and analysis, these scores were further averaged into
4 extinction blocks consisting of 4 trials each. The first block, Early Extinction, consisted of
the first 4 trials of the phase, Mid Extinction 1 trials 5–8, Mid Extinction 2 trials 9–12, and
Late Extinction trial 13–16. To assess function of the task, extinction phase data were
initially analyzed within the healthy group only using a repeated-measures ANOVA to
assess decrease in responding across the phase. To assess differences by symptom group, a 4
(symptom group) × 4 (Extinction Block) mixed ANOVA was conducted on the entire
sample. To assess symptom group differences in baseline startle response during the
extinction phase, a 4 (symptom group) × 4 (Extinction Block) mixed ANOVA, with
appropriate post hoc tests, was conducted on the NA responses averaged into blocks
analogous to those above.
Expectancy and self-report—Expectancy responses were re-coded as: expect air

puff=1, unsure = 0, do not expect air puff = −1. Expectancy responses over the last half of
the acquisition phase (4 trials/stimulus type) were averaged together as with the startle data.
ANOVAs were applied to assess both task effectiveness and differences by symptom group
in the same manner as with the startle responses.
Expectancy responses during the extinction phase were analyzed by trial, including the last 4
trials of the acquisition phase (20 total trials). Task effectiveness was assessed using a
repeated-measures ANOVA on the healthy group only. A 4 (symptom group) × 20 (trial)
mixed ANOVA was used to assess differences by symptom group across the entire sample.
To assess task effectiveness on self-reported anxiety, CS type differences on post-phase

questionnaires were analyzed using repeated measures ANOVA on the healthy group alone.

A 2 (CS type) × 4 (symptom group) mixed ANOVA was used to assess differences across
symptom groups. Task effectiveness in assessing change across phase in self-reported
anxiety was assessed using a repeated-measures ANOVA in the healthy group only.
Differences across phase by symptom group were assessed with 4 (symptom group) × 2
(phase) mixed ANOVA on the entire sample. In all analyses, significant interactions were
followed up with two-tailed Tukey post hoc tests.
3. Results
3.1. Demographics
Sample demographics are displayed in Table 1. There were no differences across symptom
groups on any demographic variable. Differences between symptom groups did emerge on
the LEC [F(3,1010) = 9.03, p < .0001, partial η2 = .03], such that all symptom groups
reported more trauma experience relative to healthy controls (ps< .04). However, the
symptom groups did not differ from one another. Two subjects were taking psychiatric
medication for reasons other than smoking cessation or sleep (1 in the PTSD symptom
group and 1 in the anxiety symptom group). Both of those subjects reported taking
fluoxetine at unknown dosages. As expected from our selection criteria, the symptom groups
had significantly higher scores on their respective assessment measures relative to the other
groups (Table 1; omnibus tests F(3,1010) > 129.55, ps< .0001; ps< .05 for comparisons vs.
reference group). All symptom groups had higher levels of PTSD, anxiety and depression
symptoms compared to controls healthy controls (ps< .05).
3.2. Overall task effectiveness

3.2.1. Acquisition
Startle: As expected, startle responses during the Acquisition phase showed a significant
effect of Cue type, with the CS+ response being elevated relative to the CS−, indicating
successful differential fear conditioning [Fig. 1A, F(1,918) =475.14, p < .0001, partial η2 = .
34].
Expectancy and self-report: For expectancy ratings, participants correctly identified the
CS+ as predictive of the shock [Fig. 2A; F(1,913) = 3916.39, p < .0001, partial η2 = .811].
On a 1 (expect air puff) to −1 (do not expect air puff) scale, participants averaged a 0.59
rating for the CS+ and a −0.78 rating for the CS−.
On the post-phase questionnaire, 88.9% of participants correctly identified the CS+ as

predictive of the air puff. 6.7% of participants were not sure which CS predicted the air puff,
and 3.1% misidentified the CS− as predictive of the air puff. Overall, participants assigned
the air puff an average aversiveness rating of 2.31 out of 5 (SD = 1.02). Participants rated
higher levels of subjective anxiety in the presence of the CS+ relative to the CS−, again
indicative of differential fear conditioning [Fig. 3A; F(1,911) = 1298.43, p < .0001, partial
η2 = .588].

3.2.2. Extinction
Startle: As expected, percentage of conditioned fear (normalized to the fear levels displayed
in the acquisition phase) decreased significantly across the phase, demonstrating successful
fear extinction [Fig. 2A; F(3,2751) = 182.87, p < .0001, partial η2 = .166].
Expectancy and self-report: Expectancy ratings to the CS+ decreased significantly across
the late acquisition and extinction phases [Fig. 2B; F(19,16682) = 573.56, p < .0001, partial
η2 = .395]. From the acquisition to extinction phases, post-phase ratings of anxiety to the CS
+ decreased significantly [Fig. 3B; F(1,902) = 529.15,p < .0001, partial η2 = .37].
3.3. Comparison of task performance between psychiatric symptom groups

3.3.1. Acquisition
Baseline startle: There was a significant difference between symptom groups in average
baseline startle during the last half of the acquisition phase [F(3,1010) = 3.05, p < .03,
partial η2 = .009], such that the anxiety symptom group had a higher magnitude of startle
relative to healthy controls (p < .009). No other symptom group differed from healthy
controls.
Startle potentiation: When participants meeting criteria for inclusion in a symptom group
were examined, a significant symptom group × Cue type interaction emerged [Fig. 1A;
F(3,1005) = 3.4, p < .02, partial η2 = .01]. Post hoc tests revealed that responding to the CS+
was significantly higher than responses to the CS− for the healthy, anxious, and depressed
symptom groups (ps<.001), but not for the PTSD symptom group (p < .09) suggesting
reduced differential fear conditioning in the PTSD symptom group. This deficit in
differential conditioning was driven by higher CS− responses in the PTSD symptom group
relative to the healthy group (p < .004). In contrast, the anxiety symptom group exhibited a
trend for increased CS+ responding (p < 0.06) and no significant differences in CS−
responses compared to healthy controls. Maximum CS+ responding was also calculated
across the groups, and the anxiety symptom group showed significantly larger maximum CS
+ responses compared to the healthy group [supplemental Fig. 1; F(3,1010) = 2.73, p < .05,
partial η2 = .008; anxiety symptoms vs. healthy p < .02]
Expectancy and self-report: For expectancy ratings, there was no symptom group × Cue
type interaction [Fig. 2A; F(3,1000) = 1.62, ns], nor was there an overall effect of symptom
group [F(3,1000) < 1.0, ns]. For self-reported anxiety, there was a significant effect of
symptom group [Fig. 3A; F(3,997) = 5.78, p < .001, partial η2 = .017] with anxious subjects
reporting higher levels of anxiety in response to both cues (p < .001). There was no
symptom group × Cue type interaction [F(3,997) = 1.65, ns].
3.3.2. Extinction
Baseline startle: There was a trend toward differential responding between symptom groups
across the extinction phase [F(3,1010) = 2.09, p < .1, partial η2 = .006], again with the
anxiety symptom group trending toward higher response relative to healthy controls (p < .1).

Startle potentiation: A significant main effect of symptom group was apparent on

%conditioned fear during the extinction phase [F(3,1005) = 3.05, p < .03, partial η2 = .009],
such that the PTSD symptom group maintained a higher level of conditioned fear across the
entire session compared to the healthy controls (p < .006). There was also a trend for a block
× symptom group interaction [Fig. 2A; F(9,3015) = 1.66, p < .1, partial η2 = .005].
Exploratory post hoc analyses at each block showed that the PTSD symptom group
maintained a higher level of conditioned fear relative to healthy controls at both the Mid
Extinction 2 and Late Extinction blocks (ps < .05). The anxiety symptom group showed a
trend toward higher responding relative to controls during Mid Extinction 1 (p < .07),
however this trend was not apparent at the later extinction blocks. The depression symptom
group did not differ from healthy controls.
Expectancy and self-report: Expectancy ratings to the CS+ did not vary by symptom group
across the phase [Fig. 2B; F(45,14505) = 1.33, ns], nor was there a main effect of symptom
group [F(3,967)< 1.0, ns]. For self-reported anxiety, there were significant differences in
change across phases by symptom group [Fig. 3B; F(3,988) =4.24, p < .01, partial η2 = .
013], such that all groups showed significant reductions across phase (ps < .05) with the
exception of the PTSD symptom group. The PTSD and anxiety symptom groups had higher
responses to the CS+ during the extinction phase relative to the healthy group (ps<.02). In
addition, there was a significant main effect of symptom group, with the anxiety symptom
group showing higher ratings overall relative to the healthy group [F(3,988) = 5.12, p < .
002, partial η2 = .015].
4. Discussion
As expected, the conditioning paradigm was effective in producing conditioned fear learning
and subsequent extinction learning in our active-duty Marine and Navy volunteers.
Psychiatrically healthy participants acquired differential fear-potentiated startle and self-
reported anxiety responses to the CS+ vs. the CS− and showed contingency awareness
(expectancy ratings). Across the extinction phase, when the air puff was absent, responses to
the CS+ decreased in terms of both potentiated startle and self-reported anxiety. Expectancy
ratings showed intact contingency learning across extinction as well. Successful learning in
this paradigm enables comparisons to be made in the learning patterns among the various
psychiatric symptom groups.
Differential patterns of learning performance emerged between psychiatric symptom groups.

The PTSD symptom group was unique in failing to show a differential potentiated startle
response to CS+ and CS− at the end of fear acquisition. This failure was due to PTSD
symptom group subjects maintaining a relatively high startle response to the CS−. The
observation of high startle responses to the CS− is in line with existing research showing
that individuals with PTSD have difficulty learning to inhibit startle responses in the
presence of a safety signal (Jovanovic et al., 2009, 2010). Though not explicitly termed
“safety signal” in the current paradigm, presentation of the CS− effectively signals the
absence of the air puff, or safety. Interestingly, the participants in the PTSD symptom group
showed intact contingency awareness in the expectancy ratings, as well as intact
discrimination learning as assessed by self-reported anxiety. These findings suggest a

“disconnect” between the participant’s explicit experience and automatic physiological

responses to the safety cue (i.e., potentiated startle).
Across the extinction phase, the PTSD symptom group maintained potentiated startle to the
CS+ overall relative to the healthy group. The finding that conditioned fear responses were
maintained throughout extinction supports existing research suggesting a disruption in fear
extinction learning and recall in PTSD symptom group subjects relative to healthy controls
(Norrholm et al., 2011; Milad et al., 2008; Wessa and Flor, 2007; Orr et al., 2000; Peri et al.,
2000). This greater maintenance of conditioned fear was also apparent in the self-report of
anxiety in response to the CS+, which remained relatively unchanged in the PTSD group
after extinction training, unlike the other groups. Again, the PTSD symptom group showed
normal explicit learning that the CS+ no longer predicted the US (as evidenced by the
expectancy ratings across the extinction session), further supporting a disconnect between
explicit contingency awareness and fear expression. Thus the current findings of deficient
inhibition of potentiated startle to a safety cue and reduced extinction of physiological and
emotional fear responses in the presence of intact contingency awareness supports the theory
that PTSD is characterized by a failure to inhibit automatic, physiological fear responses.
This failure of inhibition is observed even though the subject is explicitly aware of a lack of
threat or danger.
The anxiety symptom group showed significantly higher baseline startle responding and
higher CS+ potentiation compared to the healthy group. This group also reported
significantly higher anxiety to both CS+ and CS− after acquisition relative to the healthy
group. The finding that CS+/− discrimination is normal in participants with high generalized
anxiety symptoms is in line with other report that high trait anxiety participants exhibit
normal CS+/CS− discrimination (Kindt and Soeter, 2014; Gazendam et al., 2013). The
present findings of higher self-reported anxiety to the conditioned cues are also in line with
past reports using a similar protocol (Gazendam et al., 2013). During extinction training, the
anxiety symptom group successfully extinguished ‘both potentiated startle and US
expectancy to the CS+. They also successfully extinguished self-reported anxiety to the CS
+, however overall responding remained high compared to the other groups. Taken together,
this pattern of results is suggestive of greater explicit anxiety responses during aversive
anticipation in this group while fear inhibition and discrimination processes are relatively
normal.
The depression symptom group showed response patterns in all measures that were
indistinguishable from healthy controls. The normal fear inhibition and potentiated startle in
the depression group as assessed by safety signal learning and extinction is in line with
previous studies (Jovanovic et al., 2010, 2012). The present results differ however from a
recent study in major depression patients in a task which incorporates both predictable and
unpredictable aversive stimuli (Grillon et al., 2013). In this task, MDD patients exhibited
higher baseline startle reactivity as well as greater potentiation during the cue that was
predictive (100% contingency) of an aversive event. The increased startle potentiation was
associated with symptom chronicity as well as severity. The different results across this
study and the present study are unlikely due to differences in symptom severity (mean BDI
26 vs. 29 for present and previous studies, respectively) or treatment (both studies used

unmedicated participants). It is possible that the difference between the Grillon et al. study
and the present study are due to differences in the chronicity of symptoms, gender
demographics (mixed vs. all male sample respectively) and comorbid anxiety (high vs.
relatively low respectively). The lack of significant differences in the present study must
also be interpreted with caution given the relatively small sample size in this group (N= 12).
The present results suggest differential performance between PTSD and anxiety symptom
groups, with general anxiety symptoms being more associated with exaggerated fear
responses and PTSD symptoms being specifically associated with a failure to appropriately
inhibit fear responses to safety signals and reduced extinction. This differential pattern of
results is suggestive of differences at the neurocircuit level. The higher overall responding in
the anxiety symptom group may reflect hyperactivity in emotion-generating limbic circuits,
consistent with the neuroimaging evidence for heightened amygdala activation to negative
provocation in subjects with generalized anxiety (i.e., Rauch et al., 2003). While PTSD has
also been associated with limbic system hyperactivity (Shin et al., 2006), neuroimaging
studies have shown more pronounced findings of hypoactivation in structures responsible
for inhibition of the limbic system, specifically the medial prefrontal cortex (mPFC) and the
rostral and dorsal regions of the anterior cingulate cortex (Etkin and Wager, 2007). Further,
Milad et al. (2007, 2008) have demonstrated that individuals with PTSD exhibit reduced
ability to recall fear extinction (or fear inhibition) 24 h after initial learning, an ability that is
dependent upon mPFC activation. Reduced activity of ventromedial prefrontal cortex is also
associated with increased potentiation to CS− and reduced extinction of CS+ (Jovanovic et
al., 2013). Thus this pattern of hypoactivation in fear inhibition circuits may be reflected in
the current results of relatively normal magnitude of fear responses but poor safety-signal
learning and reduced extinction in PTSD symptom groups. The present findings also raise
the possibility that this task could identify, via differential patterns of response (exaggerated
fear response vs. impaired fear inhibition), those who are neuro-biologically at risk for
developing a certain class of pathology post-trauma. Previous research has suggested that
impaired fear extinction may be a marker for increased risk of developing PTSD following a
trauma (Guthrie and Bryant, 2006; Pole et al., 2009; Lommen et al., 2013). Future studies
may examine whether these phenotypes predict differential treatment responses to
pharmacological or behavioral therapies.
Some limitations of the current study must be acknowledged. First, the paradigm was not
effective in producing fear-potentiated startle in ∼11% of the study participants tested.

While this failure resulted in a reduction of sample size, the excluded participants did not
appear to differ systematically from the study volunteers as a whole (supplemental Table 1).
Second, the study was conducted on a highly screened cohort of active duty Marines and
Navy corpsmen, which limited the number of participants displaying psychiatric symptoms
of sufficient intensity for inclusion in the symptom groups. Therefore, the number of
participants included in the symptom groups is relatively small, particularly the depression
group. It is possible that low power may have contributed to the inability to detect
significant differences in between the depression and healthy control group. However it is
important to note that the present findings of normal fear inhibition and extinction in the
depression symptom group replicate previous studies with greater subject numbers

(Jovanovic et al., 2009, 2010). Third, the current study did not explicitly examine the effects
of trauma or deployment history on fear conditioning and extinction performance, or on
psychiatric outcomes. All symptom groups exhibited significantly higher trauma burden
severity (i.e., LEC scores) compared to the healthy group, however no differences were
detected between PTSD, anxiety and depression symptom groups, suggesting that trauma
burden alone is unlikely to explain differences in task performance across the symptom
groups. Future analyses will investigate the role of these variables in influencing task
performance, as well as their interaction with psychiatric symptoms. Finally, while the
symptom groups had significantly higher scores on their respective assessment measures
relative to the other groups (Table 1), all symptom groups also differed from healthy
controls across all measures. This elevation across symptom measures speaks to the
difficulty of achieving “pure” symptom categories given the large amount of overlap in
phenomenology among these conditions. However, the current paradigm was effective in
discriminating between symptom classes based on severity, and as whole it appears that the
current results have captured differences between groups characterized by predominant
symptoms unique to anxiety and PTSD. A final limitation is the use of categorical cutoffs
for our symptom groups, which are necessarily arbitrary. However, treating our symptom
indicators as quantitative is problematic given our largely healthy sample. Future research in
other naturalistic samples may wish to examine quantitative relationships between fear
learning indices and symptoms of psychopathology.
In sum, the fear conditioning and extinction paradigm appears to function as anticipated in
this active-duty Marine/Navy cohort. Further, the current study represents the first direct
comparison of fear conditioning and extinction performance across healthy control, PTSD,
anxiety, and ‘ depression symptom groups in a fairly homogenous sample. The results point
to differential biobehavioral “signatures” associated with distinct symptom groups and may
lead toward development of objective markers for classification of psychiatric dysfunction.
Future research in this sample will continue to characterize the nature of fear learning
abnormalities and examine whether poor learning of safety signals provides a marker of
vulnerability to develop PTSD or is specific to symptom state.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
Acknowledgements
This work received support from the Navy Bureau of Medicine and Surgery N62645-11-C-4037 and the VA Center
of Excellence for Stress and Mental Health (DGB, VBR, MAG). Additional support came from a Brain and
Behavior Research Foundation (NARSAD) Young Investigator Award (DTA), and NIH MH042228 (MAG and
VBR). We would like to acknowledge additional contributions from the MRS administrative core (Anjana Patel,
Andrew De La Rosa, and Elin Olsson) as well as the numerous clinician-interviewers and data collection staff who
contributed to the project. We also wish to thank the Marine and Navy Corpsmen volunteers who participated in the
study.
In the past three years, MAG has received consulting compensation from Abbott, Addex, Cerca, Dart, Lund-beck/
Otsuka, Neurocrine, Omeros, Sunovion, Takeda, and Teva, and holds an equity interest in San Diego Instruments.
MAG also has research grant support from Intracellular Therapeutics, Johnson & Johnson, NIDA, NIMH, and the
U.S. Veteran’s Administration VISN 22 Mental Illness Research, Education, and Clinical Center. VBR has
received grant funding from Janssen and Omeros.

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Figure 1.
(A) Potentiated startle magnitudes across the last half of the acquisition phase by symptom
group. *p < .05 for CS+ vs. CS− comparisons. #p < .05 for PTSD symptoms vs. healthy
comparison. (B) Expectancy ratings across the last half of the acquisition phase by symptom
groups. *p < .05 for the CS+ vs. CS− main effect. (C) Self-reported anxiety by symptom
groups following the acquisition phase. *p < .05 for CS+ vs. CS− main effect and anxiety
symptoms vs. healthy comparison.

Figure 2.
(A) % acquisition response retained across the extinction phase by symptom group. *p < .05
for PTSD symptoms vs. healthy comparison. #p < .05 for exploratory comparisons vs.
healthy controls. (B) CS+ expectancy ratings across the entire extinction phase. Ratings
have been combined into 4-trial blocks for clarity. (C) Self-reported anxiety following the
acquisition and extinction phases by symptom group. *p < .05 for comparisons across phase

and for the anxiety symptoms vs. healthy comparison. #p < .05 for PTSD and anxiety
symptoms vs. healthy comparisons within the extinction phase.

Table 1
Demographics and symptom measures.

Symptom group
Healthy PTSD Anxiety Depression

N 923 42 37 12
Age (SD) 22.23 (2.81) 22.63 (4.08) 22.4 (3.27) 21.38 (2.33)
Months in the military (SD) 31.29 (26.18) 39.5 (43.89) 32.7 (28.74) 31 (29.64)
Education
<H.S. 3.3% 2.4% 2.7% 8.3%
H.S. 69.3% 76.2% 73% 91.7%
Some college 25% 21.4% 21.6% 0%
B.A. 2.4% 0% 2.7% 0%
Post-graduate 0% 0% 0% 0%
Rank
Junior enlisted 71.3% 76.2% 78.4% 91.7%
NCO 27.5% 23.8% 18.9% 8.3%
Officer 1.2% 0% 2.7% 0%

Race
White 87.4% 85.7% 83.3% 83.3%
African-American 3.7% 0% 0% 0%
Other 8.9% 14.3% 16.2% 16.6%
Ethnicity
Not Hispanic or Latino 75.8% 64.3% 67.5% 75%
Hispanic or Latino 24.2% 35.7% 32.4% 25%
Marital status
Single, never married 68.5% 69% 75.7% 75%
Married 29.3% 28.6% 21.6% 25%
Divorced 1.4% 2.4% 0% 0%
Separated 0.9% 0% 2.7% 0%
Pathology measures (SD)
CAPS total score 9.66a (9.34) 43.74 (11.29) 17.95a (10.91) 27.83a (12.06)
BAI total score 2.87a (4.03) 4.4a (5.54) 20.41 (5.45) 6.67a (4.92)
BDI-2 total score 3.89a (4.19) 9.86a (5.43) 9.65a (5.44) 24.17 (3.33)
LEC score 4.16 (2.80) 5.93b (3.60) 5.54b (3.12) 5.92b (2.27)
a
p < .05 for comparisons vs. category reference group (i.e., PTSD group reference for CAPS score comparisons).
b
p < .05 vs. healthy.

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Psychoneuroendocrinology. 2015 January ; 51: 495–505. doi:10.1016/j.psyneuen.2014.09.030.

Conditioned fear and extinction learning performance and its

Background—Posttraumatic Stress Disorder (PTSD) is a major public health concern,

Methods—The “Marine Resiliency Study II” (MRS-II; October 2011–October 2013)

© 2014 Published by Elsevier Ltd.

stress-related disorders is a key step in developing an evidence base on which to design

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

2.2. Fear conditioning and extinction procedure

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

2.3. Assessment of psychiatric symptoms

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Anxiety—Assignment to the anxiety symptoms group was defined as scoring in the

Depression—Assignment to the depression symptoms group was defined as scoring in the

2.4. Data analysis

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Expectancy and self-report—Expectancy responses were re-coded as: expect air

To assess task effectiveness on self-reported anxiety, CS type differences on post-phase

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

3.2. Overall task effectiveness

On the post-phase questionnaire, 88.9% of participants correctly identified the CS+ as

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

3.3. Comparison of task performance between psychiatric symptom groups

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Startle potentiation: A significant main effect of symptom group was apparent on

Differential patterns of learning performance emerged between psychiatric symptom groups.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

“disconnect” between the participant’s explicit experience and automatic physiological

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

effective in producing fear-potentiated startle in ∼11% of the study participants tested.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

possible etiology for posttraumatic stress disorder. Neuropharmacology. 2012a; 62:674–685.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

from a community survey. Am. J. Psychiatry. 1997; 154:1114–1119. [PubMed: 9247398]

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

Demographics and symptom measures.

Healthy PTSD Anxiety Depression

Officer 1.2% 0% 2.7% 0%

Psychoneuroendocrinology. Author manuscript; available in PMC 2016 January 01.

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