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1.  Extinction of Conditioned Fear is Better Learned and Recalled in the Morning than in the Evening 
Journal of psychiatric research  2013;47(11):1776-1784.
Sleep helps emotional memories consolidate and may promote generalization of fear extinction memory. We examined whether extinction learning and memory might differ in the morning and evening due, potentially, to circadian and/or sleep-homeostatic factors. Healthy men (N=109) in 6 groups completed a 2-session protocol. In Session 1, fear conditioning was followed by extinction learning. Partial reinforcement with mild electric shock produced conditioned skin conductance responses (SCR) to 2 differently colored lamps (CS+), but not a third color (CS−), within the computer image of a room (conditioning context). One CS+ (CS+E) but not the other (CS+U) was immediately extinguished by un-reinforced presentations in a different room (extinction context). Delay durations of 3 hr (within AM or PM), 12 hr (morning-to-evening or evening-to-morning) or 24 hr (morning-to-morning or evening-to-evening) followed. In Session 2, extinction recall and contextual fear renewal were tested. We observed no significant effects of the delay interval on extinction memory but did observe an effect of time-of-day. Fear extinction was significantly better if learned in the morning (p=.002). Collapsing across CS+ type, there was smaller morning differential SCR at both extinction recall (p=.003) and fear renewal (p=.005). Morning extinction recall showed better generalization from the CS+E to CS+U with the response to the CS+U significantly larger than to the CS+E only in the evening (p=.028). Thus, extinction is learned faster and its memory is better generalized in the morning. Cortisol and testosterone showed the expected greater salivary levels in the morning when higher testosterone/cortisol ratio also predicting better extinction learning. Circadian factors may promote morning extinction. Alternatively, evening homeostatic sleep pressure may impede extinction and favor recall of conditioned fear.
PMCID: PMC3791331  PMID: 23992769
Sleep; fear conditioning; extinction; circadian rhythm; sleep homeostasis; cortisol; testosterone
2.  Trauma Reactivation Plus Propranolol Is Associated With Durably Low Physiological Responding During Subsequent Script-Driven Traumatic Imagery 
In a previous, double-blind, placebo-controlled study, patients with posttraumatic stress disorder (PTSD) showed lower physiological response during script-driven traumatic imagery 1 week after receiving a single dose of propranolol given after the retrieval of a traumatic memory. We hypothesized that this effect would extend beyond 1 week using a modified treatment approach.
Twenty-eight participants with PTSD read an account of their traumatic event once weekly for 6 consecutive weeks under the influence of open-label propranolol. One week and 4-months later, skin conductance, heart rate, and left corrugator electromyogram responses were measured while participants engaged in script-driven mental imagery of their traumatic event. Results from the 22 study participants were compared with results from treated and untreated participants in a previously published trial.
Most participants in our study were classified as non-PTSD cases at posttreatment and follow-up according to a psychophysiological discriminant function analysis. Posttreatment skin conductance and heart rate responses of the current (propranolol-treated) participants were lower than those of placebo participants from the previous study. No difference was observed between physiological responding measured posttreatment and at follow-up.
Low physiological responding during script-driven traumatic imagery after treatment extends up to 4 months, demonstrating the durability of the treatment effect’s. Limitations include the absence of a placebo-controlled group and lack of physiological baseline measures. Despite these limitations, results point to the need for future trials examining the clinical efficacy of trauma reactivation plus propranolol, as it has the potential to become a novel, cost- and time-effective treatment for PTSD.
PMCID: PMC4079131  PMID: 25007116
posttraumatic stress disorder; treatment; reconsolidation; memory; propranolol; traumatic stress
3.  A model of amygdala-hippocampal-prefrontal interaction in fear conditioning and extinction in animals 
Brain and cognition  2012;81(1):10.1016/j.bandc.2012.10.005.
Empirical research has shown that the amygdala, hippocampus, and ventromedial prefrontal cortex (vmPFC) are involved in fear conditioning. However, the functional contribution of each brain area and the nature of their interactions are not clearly understood. Here, we extend existing neural network models of the functional roles of the hippocampus in classical conditioning to include interactions with the amygdala and prefrontal cortex. We apply the model to fear conditioning, in which animals learn physiological (e.g. heart rate) and behavioral (e.g. freezing) responses to stimuli that have been paired with a highly aversive event (e.g. electrical shock). The key feature of our model is that learning of these conditioned responses in the central nucleus of the amygdala is modulated by two separate processes, one from basolateral amygdala and signaling a positive prediction error, and one from the vmPFC, via the intercalated cells of the amygdala, and signaling a negative prediction error. In addition, we propose that hippocampal input to both vmPFC and basolateral amygdala is essential for contextual modulation of fear acquisition and extinction. The model is sufficient to account for a body of data from various animal fear conditioning paradigms, including acquisition, extinction, reacquisition, and context specificity effects. Consistent with studies on lesioned animals, our model shows that damage to the vmPFC impairs extinction, while damage to the hippocampus impairs extinction in a different context (e.g., a different conditioning chamber from that used in initial training in animal experiments). We also discuss model limitations and predictions, including the effects of number of training trials on fear conditioning.
PMCID: PMC3808183  PMID: 23164732
fear conditioning; computational model; hippocampus; amygdala; ventromedial prefrontal cortex; extinction
4.  Sex differences in fear conditioning in posttraumatic stress disorder 
Women are twice as likely as men to develop Posttraumatic Stress Disorder (PTSD). Abnormal acquisition of conditioned fear has been suggested as a mechanism for the development of PTSD. While some studies of healthy humans suggest that women are either no different or express less conditioned fear responses during conditioning relative to men, differences in the acquisition of conditioned fear between men and women diagnosed with PTSD has not been examined.
Thirty-one participants (18 men; 13 women) with full or subsyndromal PTSD completed a fear conditioning task. Participants were shown computer-generated colored circles that were paired (CS+) or unpaired (CS−) with an aversive electrical stimulus and skin conductance levels were assessed throughout the task.
Repeated measures ANOVA indicated a significant sex by stimulus interaction during acquisition. Women had greater differential conditioned skin conductance responses (CS + trials compared to CS− trials) than did men, suggesting greater acquisition of conditioned fear in women with PTSD.
In contrast to studies of healthy individuals, we found enhanced acquisition of conditioned fear in women with PTSD. Greater fear conditioning in women may either be a pre-existing vulnerability trait or an acquired phenomenon that emerges in a sex-dependent manner after the development of PTSD. Characterizing the underlying mechanisms of these differences is needed to clarify sex-related differences in the pathophysiology of PTSD.
PMCID: PMC3806498  PMID: 23107307
Sex differences; Learning; Conditioning; Fear; Posttraumatic stress disorder; Galvanic skin response
5.  Event-Related Potentials to Auditory Stimuli in Monozygotic Twins Discordant for Combat: Association with PTSD 
Psychophysiology  2008;46(1):10.1111/j.1469-8986.2008.00720.x.
Studies have demonstrated ERP abnormalities related to concentration difficulties in post-traumatic stress disorder (PTSD). We used an identical-twin, case-control design to investigate whether these abnormalities reflect pre-trauma vulnerability or the acquired consequence of PTSD. Vietnam combat veterans and their non-combat-exposed, identical twins completed a three-tone oddball task. Veterans with PTSD had delayed target N2 latencies compared to veterans without PTSD. In a small non-medicated, non-smoking subsample, veterans with PTSD also had significantly diminished target P3b amplitudes. A mixed-model, random-effects analysis on the non-medicated, non-smoking subsample that included the combat-unexposed co-twins showed a significant Diagnosis × combat Exposure interaction for target P3b amplitude. Results replicate increased N2 latency and diminished P3b amplitude in PTSD and suggest that diminished P3b amplitude is an acquired condition in PTSD.
PMCID: PMC3807820  PMID: 18803598
Twin studies; Posttraumatic stress disorder; Event-related potentials; P3b
6.  Exaggerated Activation of Dorsal Anterior Cingulate Cortex During Cognitive Interference: A Monozygotic Twin Study of Posttraumatic Stress Disorder 
The American journal of psychiatry  2011;168(9):979-985.
Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of the current research was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or familial risk factor.
Using a case-control twin design, we studied combat-exposed veterans with PTSD (n=12) and their identical combat-unexposed co-twins (n=12), as well as combat-exposed veterans without PTSD (n=14) and their identical combat-unexposed co-twins (n=14). Participants underwent functional magnetic resonance imaging during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate.
Combat veterans with PTSD and their co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to non-PTSD veterans and their co-twins. Dorsal anterior cingulate activation in the exposed twins was positively correlated with their PTSD symptom severity. Dorsal anterior cingulate activation in the unexposed twins was positively correlated with their combat-exposed co-twins’ PTSD symptom severity, but not with depression or alcohol use severity in the combat-exposed co-twins.
Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.
PMCID: PMC3773363  PMID: 21724666
magnetic resonance imaging; limbic system; stress disorders; post-traumatic; twins; monozygotic; gyrus cinguli; Multi-Source Interference Task
7.  Learning to Obtain Reward, but Not Avoid Punishment, Is Affected by Presence of PTSD Symptoms in Male Veterans: Empirical Data and Computational Model 
PLoS ONE  2013;8(8):e72508.
Post-traumatic stress disorder (PTSD) symptoms include behavioral avoidance which is acquired and tends to increase with time. This avoidance may represent a general learning bias; indeed, individuals with PTSD are often faster than controls on acquiring conditioned responses based on physiologically-aversive feedback. However, it is not clear whether this learning bias extends to cognitive feedback, or to learning from both reward and punishment. Here, male veterans with self-reported current, severe PTSD symptoms (PTSS group) or with few or no PTSD symptoms (control group) completed a probabilistic classification task that included both reward-based and punishment-based trials, where feedback could take the form of reward, punishment, or an ambiguous “no-feedback” outcome that could signal either successful avoidance of punishment or failure to obtain reward. The PTSS group outperformed the control group in total points obtained; the PTSS group specifically performed better than the control group on reward-based trials, with no difference on punishment-based trials. To better understand possible mechanisms underlying observed performance, we used a reinforcement learning model of the task, and applied maximum likelihood estimation techniques to derive estimated parameters describing individual participants’ behavior. Estimations of the reinforcement value of the no-feedback outcome were significantly greater in the control group than the PTSS group, suggesting that the control group was more likely to value this outcome as positively reinforcing (i.e., signaling successful avoidance of punishment). This is consistent with the control group’s generally poorer performance on reward trials, where reward feedback was to be obtained in preference to the no-feedback outcome. Differences in the interpretation of ambiguous feedback may contribute to the facilitated reinforcement learning often observed in PTSD patients, and may in turn provide new insight into how pathological behaviors are acquired and maintained in PTSD.
PMCID: PMC3754989  PMID: 24015254
8.  Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder 
Archives of general psychiatry  2009;66(10):1099-1107.
Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala and hippocampus in posttraumatic stress disorder (PTSD).
To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors.
Cross-sectional design including identical twins discordant for trauma exposure.
Academic medical center.
Combat-exposed veterans with PTSD (n=14) and their identical, combat-unexposed co-twins (n=14), as well as combat-exposed veterans without PTSD (n=19) and their identical, combat-unexposed co-twins (n=19).
Main Outcome Measures
We used positron emission tomography and [18F]-fluorodeoxyglucose to examine resting regional cerebral metabolic rates for glucose (rCMRglu).
Veterans with PTSD and their co-twins had significantly higher resting rCMRglu in dorsal anterior cingulate/mid cingulate cortex (dACC/MCC) compared to non-PTSD veterans and their co-twins. Resting rCMRglu in dACC/MCC in the combat-unexposed co-twins was positively correlated with combat exposure severity, PTSD symptom severity, and alcohol use in their exposed twins.
Enhanced resting metabolic activity in dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.
PMCID: PMC3752096  PMID: 19805700
stress disorders; post-traumatic; twins; monozygotic; positron-emission tomography; fluorodexoyglucose F18; metabolism; cingulate gyrus
9.  Extinction memory is impaired in schizophrenia 
Biological psychiatry  2008;65(6):455-463.
Schizophrenia is associated with abnormalities in emotional processing and social cognition, which may result from disruption of the underlying neural mechanism(s) governing emotional learning and memory. To investigate this possibility, we measured the acquisition and extinction of conditioned fear responses and delayed recall of extinction in schizophrenia and control subjects.
28 schizophrenia and 18 demographically-matched control subjects underwent a two-day fear conditioning, extinction learning and extinction recall procedure, in which skin conductance response (SCR) magnitude was used as the index of conditioned responses.
During fear acquisition, 83% of the controls and 57% of the patients showed autonomic responsivity (‘responders’), and the patients showed larger SCRs to the stimulus that was not paired with the unconditioned stimulus (CS−) than the controls. Within the responder group, there was no difference between the patients and controls in levels of extinction learning; however, the schizophrenia patients showed significant impairment, relative to the controls, in context-dependent recall of the extinction memory. In addition, delusion severity in the patients correlated with baseline skin conductance levels.
These data are consistent with prior evidence for a heightened neural response to innocuous stimuli in schizophrenia and elevated arousal levels in psychosis. The finding of deficient extinction recall in schizophrenia patients who showed intact extinction learning suggests that schizophrenia is associated with a disturbance in the neural processes supporting emotional memory.
PMCID: PMC3740529  PMID: 18986648
schizophrenia; fear; conditioning; extinction; emotion; memory
10.  An alternative scoring method for skin conductance responding in a differential fear conditioning paradigm with a long-duration conditioned stimulus 
Psychophysiology  2009;46(5):984-995.
Researchers examining skin conductance (SC) as a measure of aversive conditioning commonly separate the SC response into two components when the CS-UCS interval is sufficiently long. This convention drew from early theorists who described these components, the first- and second-interval responses, as measuring orienting and conditional responses, respectively. The present report critically examines this scoring method through a literature review and a secondary data analysis of a large-scale study of police and firefighter trainees that used a differential aversive conditioning procedure (n = 287). The task included habituation, acquisition, and extinction phases, with colored circles as the CSs and shocks as the UCS. Results do not support the convention of separating the SC response into first- and second-interval responses. It is recommended that SC response scores be derived from data obtained across the entire CS-UCS interval.
PMCID: PMC2868319  PMID: 19558401
Conditioning; Electrodermal response (skin electric response); Scoring methods
11.  Intensity dependence of auditory P2 in monozygotic twins discordant for Vietnam combat: Associations with posttraumatic stress disorder 
Two studies have reported decreased intensity dependence of the P2 event-related potential (ERP) in male combat veterans with posttraumatic stress disorder (PTSD), a response pattern presumed to reflect central nervous system-induced protective inhibition and heightened central serotonergic activity. We used an identical twin, case-control design to investigate whether intensity dependence abnormalities reflect pretrauma vulnerability or are an acquired consequence of PTSD. ERPs were measured in male Vietnam combat veterans and their noncombat-exposed monozygotic twin brothers during a four-tone, stimulus-intensity modulation procedure. Contrary to previous findings in male veterans, the PTSD group had significantly steeper P2 amplitude intensity slopes, similar to those reported for female veterans and abused children with PTSD. Additionally, increased P2 amplitude intensity slope was associated with increased PTSD symptom severity, particularly the severity of reexperiencing symptoms. A mixed-model, random-effects analysis that included the combat-unexposed twins revealed a significant diagnosis by combat exposure interaction. Inspection of group means suggests that the observed increased P2 intensity dependence is a consequence of PTSD. Our findings further suggest that low serotonergic tone may emerge as one potential consequence of this disorder.
PMCID: PMC2861279  PMID: 18629752
5-HT; auditory intensity dependence; combat disorder; event-related potentials; posttraumatic; PTSD; rehabilitation; serotonin; stress disorders; twin studies
12.  Personality and fear responses during conditioning: Beyond extraversion 
The personality domain of introversion-extraversion has been theorized to be associated with the strength of fear conditioning, but the literature on this topic has been equivocal. Furthermore, except for extraversion and neuroticism, relationships of the other Big Five personality domains with fear response acquisition have not been explored. In the current study, multi-level modeling was used to examine the relationships of facets of the Big 5 domains to fear response acquisition. Participants were 217 police and firefighter trainees who completed the Revised NEO Personality Inventory (NEO-PI-R; Costa & McCrae, 1992) and a fear conditioning task as part of a larger study. Results indicated that several facets of extraversion have opposing associations with fear response acquisition of an electrodermal response– possibly contributing to the mixed results in the literature. Additionally, facets of other Big Five domains were found to be associated with fear response acquisition.
PMCID: PMC2598742  PMID: 20046207
fear conditioning; Big 5; personality; extraversion; neuroticism; multi-level modeling; psychophysiology
13.  The relationship between Hippocampal asymmetry and working memory processing in combat-related PTSD – a monozygotic twin study 
PTSD is associated with reduction in hippocampal volume and abnormalities in hippocampal function. Hippocampal asymmetry has received less attention, but potentially could indicate lateralised differences in vulnerability to trauma. The P300 event-related potential component reflects the immediate processing of significant environmental stimuli and has generators in several brain regions including the hippocampus. P300 amplitude is generally reduced in people with PTSD.
Our study examined hippocampal volume asymmetry and the relationship between hippocampal asymmetry and P300 amplitude in male monozygotic twins discordant for Vietnam combat exposure. Lateralised hippocampal volume and P300 data were obtained from 70 male participants, of whom 12 had PTSD. We were able to compare (1) combat veterans with current PTSD; (2) their non-combat-exposed co-twins; (3) combat veterans without current PTSD and (4) their non-combat-exposed co-twins.
There were no significant differences between groups in hippocampal asymmetry. There were no group differences in performance of an auditory oddball target detection task or in P300 amplitude. There was a significant positive correlation between P300 amplitude and the magnitude of hippocampal asymmetry in participants with PTSD.
These findings suggest that greater hippocampal asymmetry in PTSD is associated with a need to allocate more attentional resources when processing significant environmental stimuli.
PMCID: PMC3582553  PMID: 23198722
14.  Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology 
Most individuals exposed to a traumatic event do not develop post-traumatic stress disorder (PTSD), although many individuals may experience sub-clinical levels of post-traumatic stress symptoms (PTSS). There are notable individual differences in the presence and severity of PTSS among individuals who report seemingly comparable traumatic events. Individual differences in PTSS following exposure to traumatic events could be influenced by pre-trauma vulnerabilities for developing PTSS/PTSD.
Pre-trauma psychological, psychophysiological and personality variables were prospectively assessed for their predictive relationships with post-traumatic stress symptoms (PTSS). Police and firefighter trainees were tested at the start of their professional training (i.e., pre-trauma; n = 211) and again several months after exposure to a potentially traumatic event (i.e., post-trauma, n = 99). Pre-trauma assessments included diagnostic interviews, psychological and personality measures and two psychophysiological assessment procedures. The psychophysiological assessments measured psychophysiologic reactivity to loud tones and the acquisition and extinction of a conditioned fear response. Post-trauma assessment included a measure of psychophysiologic reactivity during recollection of the traumatic event using a script-driven imagery task.
Logistic stepwise regression identified the combination of lower IQ, higher depression score and poorer extinction of forehead (corrugator) electromyogram responses as pre-trauma predictors of higher PTSS. The combination of lower IQ and increased skin conductance (SC) reactivity to loud tones were identified as pre-trauma predictors of higher post-trauma psychophysiologic reactivity during recollection of the traumatic event. A univariate relationship was also observed between pre-trauma heart rate (HR) reactivity to fear cues during conditioning and post-trauma psychophysiologic reactivity.
The current study contributes to a very limited literature reporting results from truly prospective examinations of pre-trauma physiologic, psychologic, and demographic predictors of PTSS. Findings that combinations of lower estimated IQ, greater depression symptoms, a larger differential corrugator EMG response during extinction and larger SC responses to loud tones significantly predicted higher PTSS suggests that the process(es) underlying these traits contribute to the pathogenesis of subjective and physiological PTSS. Due to the low levels of PTSS severity and relatively restricted ranges of outcome scores due to the healthy nature of the participants, results may underestimate actual predictive relationships.
PMCID: PMC3412748  PMID: 22738068
Stress disorders, Post-traumatic; Conditioning; Startle; Imagery; Psychophysiology; Risk factors
15.  Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder 
Biological psychiatry  2009;66(12):1075-1082.
A clinical characteristic of posttraumatic stress disorder (PTSD) is persistently elevated fear responses to stimuli associated with the traumatic event. The objective herein is to determine whether extinction of fear responses is impaired in PTSD and whether such impairment is related to dysfunctional activation of brain regions known to be involved in fear extinction, viz., amygdala, hippocampus, ventromedial prefrontal cortex (vmPFC), and dorsal anterior cingulate cortex (dACC).
Sixteen individuals diagnosed with PTSD and 15 trauma-exposed non-PTSD controls (TENCs) underwent a two-day fear conditioning and extinction protocol in a 3T fMRI scanner. Conditioning and extinction training were conducted on day 1. Extinction recall (or extinction memory) test was conducted on day 2 (extinguished conditioned stimuli presented in the absence of shock). Skin conductance response (SCR) was scored throughout the experiment as an index of the conditioned response.
SCR data revealed no significant differences between groups during acquisition and extinction of conditioned fear on day 1. On day 2, however, PTSD subjects showed impaired recall of extinction memory. Analysis of fMRI data showed greater amygdala activation in the PTSD group during day 1 extinction learning. During extinction recall, lesser activation in hippocampus and vmPFC, and greater activation in dACC, was observed in the PTSD group. The magnitude of extinction memory across all subjects was correlated with activation of hippocampus and vmPFC during extinction recall testing.
These findings support the hypothesis that fear extinction is impaired in PTSD. They further suggest that dysfunctional activation in brain structures that mediate fear extinction learning, and especially its recall, underlie this impairment.
PMCID: PMC2787650  PMID: 19748076
conditioning, classical; stress disorders, post-traumatic; magnetic resonance imaging; amygdala; hippocampus; prefrontal cortex
16.  Magnetic Resonance Imaging Study of Hippocampal Volume in Chronic, Combat-Related Posttraumatic Stress Disorder 
Biological psychiatry  1996;40(11):1091-1099.
This study used quantitative volumetric magnetic resonance imaging techniques to explore the neuroanatomic correlates of chronic, combat-related posttraumatic stress disorder (PTSD) in seven Vietnam veterans with PTSD compared with seven nonPTSD combat veterans and eight normal nonveterans. Both left and right hippocampi were significantly smaller in the PTSD subjects compared to the Combat Control and Normal subjects, even after adjusting for age, whole brain volume, and lifetime alcohol consumption. There were no statistically significant group differences in intracranial cavity, whole brain, ventricles, ventricle:brain ratio, or amygdala. Subarachnoidal cerebrospinal fluid was increased in both veteran groups. Our finding of decreased hippocampal volume in PTSD subjects is consistent with results of other investigations which utilized only trauma-unexposed control groups. Hippocampal volume was directly correlated with combat exposure, which suggests that traumatic stress may damage the hippocampus. Alternatively, smaller hippocampi volume may be a pre-existing risk factor for combat exposure and/or the development of PTSD upon combat exposure.
PMCID: PMC2910907  PMID: 8931911
Stress disorders; posttraumatic; magnetic resonance imaging; hippocampus
17.  Smaller hippocampal volume predicts pathologic vulnerability to psychological trauma 
Nature neuroscience  2002;5(11):1242-1247.
In animals, exposure to severe stress can damage the hippocampus. Recent human studies show smaller hippocampal volume in individuals with the stress-related psychiatric condition posttraumatic stress disorder (PTSD). Does this represent the neurotoxic effect of trauma, or is smaller hippocampal volume a pre-existing condition that renders the brain more vulnerable to the development of pathological stress responses? In monozygotic twins discordant for trauma exposure, we found evidence that smaller hippocampi indeed constitute a risk factor for the development of stress-related psychopathology. Disorder severity in PTSD patients who were exposed to trauma was negatively correlated with the hippocampal volume of both the patients and the patients’ trauma-unexposed identical co-twin. Furthermore, severe PTSD twin pairs—both the trauma-exposed and unexposed members—had significantly smaller hippocampi than non-PTSD pairs.
PMCID: PMC2819093  PMID: 12379862
18.  Basal and suppressed salivary cortisol in female vietnam nurse veterans with and without PTSD 
Psychiatry research  2008;161(3):330-335.
It has been suggested that discrepant findings regarding low basal cortisol levels and enhanced suppression of cortisol in response to dexamethasone (DEX) administration in PTSD may reflect individual differences in gender, trauma type, stage of development at trauma occurrence (e.g., childhood vs. adulthood), early pre-traumatic risk factors, or other individual differences. This study examined salivary cortisol levels at 8:00 a.m. and 4:00 p.m. as well as cortisol response to 0.5 mg DEX in 40 female Vietnam nurse veterans who had current, chronic PTSD (Current) vs. 43 who never had PTSD (Never). Repeated measures analyses of covariance did not reveal significant group differences in cortisol levels or cortisol suppression. Given that nurses who served in Vietnam had similar exposures, ages at exposure, and duration since exposure to previously studied male Vietnam combat veterans, the present lack of evidence for low cortisol and cortisol hyper-suppression in nurses with PTSD suggests that previous findings of low cortisol and cortisol hyper-suppression in male Vietnam veterans, females sexually abused as children, and other populations may reflect risk factors beyond simply having PTSD.
PMCID: PMC2621060  PMID: 18951637
stress disorders; post-traumatic; dexamethasone; comorbidity; depressive disorder
19.  Clarifying the Origin of Biological Abnormalities in PTSD Through the Study of Identical Twins Discordant for Combat Exposure 
A biological abnormality found to be associated with post-traumatic stress disorder (PTSD) may be, among other things, a pre-trauma vulnerability factor, that is, it may have been present prior to the event’s occurrence and increased the individual’s likelihood of developing PTSD upon traumatic exposure. Alternately, it may be an acquired PTSD sign, that is, it may have developed after the traumatic exposure, along with the PTSD. We have studied pairs of Vietnam combat veterans and their noncombat-exposed, identical twins in an effort to resolve these competing origins. Combat veterans were diagnosed as current PTSD or non-PTSD (i.e., never had). Average heart rate responses (HRRs) to a series of sudden, loud-tone presentations were larger in Vietnam combat veteran twins with PTSD, but these larger responses were not shared by their noncombat-exposed cotwins, whose responses were similar to those of the non-PTSD combat veterans and their noncombat-exposed cotwins. These results suggest that larger HRRs to sudden, loud tones represent an acquired sign of PTSD. In contrast, increased neurological soft signs (NSSs), diminished hippocampal volume, and presence of abnormal cavum septum pellucidum (CSP) were found in Vietnam combat veteran twins with PTSD and their “high-risk,” unexposed cotwins compared to Vietnam combat veteran twins without PTSD and their “low-risk,” unexposed cotwins. These results support the conclusion that the latter abnormalities represent antecedent, familial vulnerability factors for developing chronic PTSD upon exposure to a traumatic event.
PMCID: PMC2770249  PMID: 16891575
stress disorders; posttraumatic; twins; monozygotic; startle response; neurological examination; magnetic resonance imaging; hippocampus; septum pellucidum
20.  Configural Cue Performance in Identical Twins Discordant for Posttraumatic Stress Disorder: Theoretical Implications for the Role of Hippocampal Function 
Biological psychiatry  2007;62(5):513-520.
A significant subgroup of individuals with posttraumatic stress disorder (PTSD) exhibits chronic, unremitting symptomatology that has also been associated with smaller hippocampal volume. The hippocampus plays a significant role in configural processing of contextual cues that facilitates context-appropriate extinction of conditioned fear. We test the hypothesis that hippocampus-based configural processing deficits are a pre-existing vulnerability factor for unremitting forms of PTSD.
Participants included male monozygotic twin pairs who were discordant for combat trauma. In 18 twin pairs the combat-exposed brother developed unremitting PTSD, whereas in 23 pairs the combat-exposed brother never developed PTSD. Participants were compared in the capacity to solve allocentric spatial processing tasks, and this performance was examined for its relationship to the severity of PTSD symptomatology and hippocampal volume.
Although not completely differentiated from overall IQ, PTSD combat veterans demonstrated significantly impaired performance in configural processing relative to non-PTSD combat veterans. Despite having neither combat-exposure nor PTSD, the unexposed co-twins of combat veterans with PTSD displayed the same decrements as their brothers. Deficits were significantly related to PTSD severity and hippocampal volume.
The current study provides the first evidence that the relevance of the hippocampus in PTSD might be related to pre-existing configural cue processing deficits that predispose individuals to develop unremitting forms of the disorder.
PMCID: PMC2768050  PMID: 17509537
Configural; contextual; hippocampus; neuropsychology; PTSD; twins
21.  Probing Reward Function in Posttraumatic Stress Disorder: Expectancy and Satisfaction with Monetary Gains and Losses 
Journal of psychiatric research  2008;42(10):802-807.
Post-traumatic stress disorder (PTSD) may be associated with dysfunctional reward processing. The present study assessed for such dysfunction in both the expectancy and outcome phases of reward processing.
Male Vietnam veterans with (n=15) and without (n=11) combat-related PTSD were administered a wheel of fortune-type gambling task. Self-reported ratings of expectancy and satisfaction were collected respectively before and after each experience of monetary gain or loss.
PTSD participants reported both lower expectancy of reward and lower satisfaction with reward when it was received. The latter result was manifest in a failure of PTSD participants to show the greater satisfaction that normally accompanies rewards received under conditions of low expectancy.
These results suggest reward function impairment in PTSD related to expectancy, satisfaction, and the expectancy-satisfaction relationship.
PMCID: PMC2551554  PMID: 18068725
PTSD; reward; emotion; numbing; expectancy; satisfaction
22.  Presence and Acquired Origin of Reduced Recall for Fear Extinction in PTSD: Results of a Twin Study 
Journal of psychiatric research  2008;42(7):515-520.
Recall of fear extinction, which is thought to aid in recovery from a psychologically traumatic event, is hypothesized to be deficient in post-traumatic stress disorder (PTSD), but this has not yet been demonstrated in the laboratory, nor has its origin been investigated. To address these two issues, 14 pairs of monozygotic twins discordant for combat exposure, in 7 of which the combat-exposed twin had PTSD, underwent a two-day fear conditioning and extinction procedure. On Day 1, subjects viewed colored light conditioned stimuli, some of which were paired with mild electric shock, followed by extinction of the conditioned responses. On Day 2, recall of Day 1 extinction learning (i.e., extinction retention) was assessed. Skin conductance response (SCR) was the dependent measure. There were no group differences during acquisition or extinction learning. However, a significant PTSD Diagnosis (in the exposed twin) x combat Exposure interaction emerged during extinction recall, with the PTSD combat veterans having larger SCRs than their own co-twins, and than the non-PTSD combat veterans and their co-twins. These results indicate that retention of extinction of conditioned fear is deficient in PTSD. Furthermore, they support the conclusion that this deficit is acquired as a result of combat trauma leading to PTSD, rather than being a predisposing factor to developing PTSD upon the stress of combat.
PMCID: PMC2377011  PMID: 18313695
Stress disorders, post-traumatic; Fear; Conditioning, classical; Galvanic skin response; Memory; Twins, monozygotic
23.  Prediction of “Fear” Acquisition in Healthy Control Participants in a De Novo Fear-Conditioning Paradigm 
Behavior modification  2007;31(1):32-51.
Studies using fear-conditioning paradigms have found that anxiety patients are more conditionable than individuals without these disorders, but these effects have been demonstrated inconsistently. It is unclear whether these findings have etiological significance, or whether enhanced conditionability is linked only to certain anxiety characteristics. To further examine these issues, we assessed the predictive significance of relevant subsyndromal characteristics in 72 healthy adults, including measures of worry, avoidance, anxious mood, depressed mood, and fears of anxiety symptoms (anxiety sensitivity), as well as the dimensions of neuroticism and extraversion. Of these variables, we found that the combination of higher levels of subsyndromal worry and lower levels of behavioral avoidance predicted heightened conditionability, raising questions about the etiological significance of these variables in the acquisition or maintenance of anxiety disorders. In contrast, we found that anxiety sensitivity was more linked to individual differences in orienting response than differences in conditioning per se.
PMCID: PMC1764631  PMID: 17179530
Fear conditioning; etiology; worry; avoidance; anxiety sensitivity; psychophysiology

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