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1.  Resting amygdala and medial prefrontal metabolism predicts functional activation of the fear extinction circuit 
The American journal of psychiatry  2012;169(4):415-423.
Objective
Individual differences in ability to control fear have been linked to activation of dorsal anterior cingulate cortex, ventromedial prefrontal cortex, and amygdala. This study investigated whether functional variance in this network can be predicted by resting metabolism in these same regions.
Methods
Healthy subject volunteers were studied with positron emission tomography using [18F]-deoxyglucose to measure resting brain metabolism. This was followed by a two-day fear conditioning and extinction training paradigm in a functional magnetic resonance imaging scanner to measure brain activation during fear extinction and its recall. Skin conductance response was used to index conditioned responding. Resting metabolism in amygdala, dorsal anterior cingulate cortex and ventromedial prefrontal cortex were used to predict responses during fear extinction and extinction recall.
Results
During extinction training, resting amygdala metabolism positively predicted ventromedial prefrontal cortex, and negatively predicted dorsal anterior cingulate cortex, activation. In contrast, during extinction recall, resting amygdala metabolism negatively predicted ventromedial prefrontal cortex, and positively predicted dorsal anterior cingulate cortex, activation. Resting dorsal anterior cingulate cortex metabolism predicted fear expression (skin conductance response) during extinction recall.
Conclusions
Brain metabolism at rest predicts neuronal reactivity and skin conductance changes associated with recall of the fear extinction memory.
doi:10.1176/appi.ajp.2011.10121780
PMCID: PMC4080711  PMID: 22318762
2.  Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder 
Neuropsychopharmacology  2012;37(13):2789-2796.
Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an α2-adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.
doi:10.1038/npp.2012.145
PMCID: PMC3499710  PMID: 22871915
clonidine; memory; reconsolidation; fear conditioning; α2-adrenoreceptor agonist; posttraumatic stress disorder; psychopharmacology; psychiatry & behavioral sciences; mood/anxiety/stress disorders; learning & memory; reconsolidation; a2-adrenoreceptor agonist; fear conditioning; posttraumatic stress disorder; clonidine
3.  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.
doi:10.1111/j.1469-8986.2008.00720.x
PMCID: PMC3807820  PMID: 18803598
Twin studies; Posttraumatic stress disorder; Event-related potentials; P3b
4.  Resting Metabolic Activity in the Cingulate Cortex and Vulnerability to Posttraumatic Stress Disorder 
Archives of general psychiatry  2009;66(10):1099-1107.
Context
Recent neuroimaging research has revealed functional abnormalities in the anterior cingulate cortex, amygdala and hippocampus in posttraumatic stress disorder (PTSD).
Objective
To determine whether resting functional abnormalities found in PTSD are acquired characteristics or familial risk factors.
Design
Cross-sectional design including identical twins discordant for trauma exposure.
Setting
Academic medical center.
Participants
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).
Results
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.
Conclusions
Enhanced resting metabolic activity in dACC/MCC appears to represent a familial risk factor for developing PTSD after exposure to psychological trauma.
doi:10.1001/archgenpsychiatry.2009.138
PMCID: PMC3752096  PMID: 19805700
stress disorders; post-traumatic; twins; monozygotic; positron-emission tomography; fluorodexoyglucose F18; metabolism; cingulate gyrus
5.  Extinction memory is impaired in schizophrenia 
Biological psychiatry  2008;65(6):455-463.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2008.09.017
PMCID: PMC3740529  PMID: 18986648
schizophrenia; fear; conditioning; extinction; emotion; memory
6.  Propranolol’s effects on the consolidation and reconsolidation of long-term emotional memory in healthy participants: a meta-analysis 
Background
Considering the pivotal role of negative emotional experiences in the development and persistence of mental disorders, interfering with the consolidation/reconsolidation of such experiences would open the door to a novel treatment approach in psychiatry. We conducted a meta-analysis on the experimental evidence regarding the capacity of the β-blocker propranolol to block the consolidation/reconsolidation of emotional memories in healthy adults.
Methods
Selected studies consisted of randomized, double-blind experiments assessing long-term memory for emotional material in healthy adults and involved at least 1 propranolol and 1 placebo condition. We searched PsycInfo, PubMed, Web of Science, Cochrane Central, PILOTS, Google Scholar and clinicaltrials.org for eligible studies from the period 1995–2012. Ten consolidation (n = 259) and 8 reconsolidation (n = 308) experiments met the inclusion criteria. We calculated effect sizes (Hedges g) using a random effects model.
Results
Compared with placebo, propranolol given before memory consolidation reduced subsequent recall for negatively valenced stories, pictures and word lists (Hedges g = 0.44, 95% confidence interval [CI] 0.14–0.74). Propranolol before reconsolidation also reduced subsequent recall for negatively valenced emotional words and the expression of cue-elicited fear responses (Hedges g = 0.56, 95% CI 0.13–1.00).
Limitations
Limitations include the moderate number of studies examining the influence of propranolol on emotional memory consolidation and reconsolidation in healthy adults and the fact that most samples consisted entirely of young adults, which may limit the ecological validity of results.
Conclusion
Propranolol shows promise in reducing subsequent memory for new or recalled emotional material in healthy adults. However, future studies will need to investigate whether more powerful idiosyncratic emotional memories can also be weakened and whether this weakening can bring about long-lasting symptomatic relief in clinical populations, such as patients with posttraumatic stress or other event-related disorders.
doi:10.1503/jpn.120111
PMCID: PMC3692719  PMID: 23182304
7.  Neurological Soft Signs in Individuals with Pathological Gambling 
PLoS ONE  2013;8(4):e60885.
Increased neurological soft signs (NSSs) have been found in a number of neuropsychiatric syndromes, including chemical addiction. The present study examined NSSs related to perceptual-motor and visuospatial processing in a behavioral addiction viz., pathological gambling (PG). As compared to mentally healthy individuals, pathological gamblers displayed significantly poorer ability to copy two- and three-dimensional figures, to recognize objects against a background noise, and to orient in space on a road-map test. Results indicated that PG is associated with subtle cerebral cortical abnormalities. Further prospective clinical research is needed to address the NSSs' origin and chronology (e.g., predate or follow the development of PG) as well as their response to therapeutic interventions and/or their ability to predict such a response.
doi:10.1371/journal.pone.0060885
PMCID: PMC3617209  PMID: 23593341
8.  Resting cerebral metabolism correlates with skin conductance and functional brain activation during fear conditioning 
Biological Psychology  2011;89(2):450-459.
We investigated whether resting brain metabolism can be used to predict autonomic and neuronal responses during fear conditioning in 20 healthy humans. Regional cerebral metabolic rate for glucose was measured via positron emission tomography at rest. During conditioning, autonomic responses were measured via skin conductance, and blood oxygen level dependent signal was measured via functional magnetic resonance imaging. Resting dorsal anterior cingulate metabolism positively predicted differentially conditioned skin conductance responses. Midbrain and insula resting metabolism negatively predicted midbrain and insula functional reactivity, while dorsal anterior cingulate resting metabolism positively predicted midbrain functional reactivity. We conclude that resting metabolism in limbic areas can predict some aspects of psychophysiological and neuronal reactivity during fear learning.
doi:10.1016/j.biopsycho.2011.12.012
PMCID: PMC3269527  PMID: 22207247
9.  Predicting post-trauma stress symptoms from pre-trauma psychophysiologic reactivity, personality traits and measures of psychopathology 
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1186/2045-5380-2-8
PMCID: PMC3412748  PMID: 22738068
Stress disorders, Post-traumatic; Conditioning; Startle; Imagery; Psychophysiology; Risk factors
10.  An fMRI study of unconditioned responses in post-traumatic stress disorder 
Background
Both fear and pain processing are altered in post-traumatic stress disorder (PTSD), as evidenced by functional neuroimaging studies showing increased amygdala responses to threats, and increased insula, putamen and caudate activity in response to heat pain. Using psychophysiology and functional magnetic resonance imaging, we studied conditioned and unconditioned autonomic and neuronal responses in subjects with PTSD versus trauma-exposed non-PTSD control (TENC) subjects. A design using an electric shock selected by subjects to be 'highly annoying but not painful' as an unconditioned stimulus (US) with partially reinforced cues allowed us to partly disentangle the expectancy- and prediction-error components from sensory components of the unconditioned response.
Results
Whereas responses to the conditioned stimulus (CS) were similar in PTSD and TENC, the former displayed higher putamen, insula, caudate and amygdala responses to the US. Reactivity to the US in the anterior insula correlated with PTSD symptom severity. Functional connectivity analyses using the putamen as a seed region indicated that TENC subjects had increased amygdala-putamen connectivity during US delivery; this connection was disengaged in PTSD.
Conclusions
Our results indicate that although neural processing of fear learning in people with PTSD seems to be comparable with controls, neural responses to unconditioned aversive stimuli in PTSD seem to be increased.
doi:10.1186/2045-5380-1-8
PMCID: PMC3384234  PMID: 22738227
11.  The influence of gonadal hormones on conditioned fear extinction in healthy humans 
Neuroscience  2010;168(3):652-658.
Recent rodent studies suggest that gonadal hormones influence extinction of conditioned fear. Here we investigated sex differences in, and the influence of estradiol and progesterone on, fear extinction in healthy humans. Men and women underwent a two-day paradigm in which fear conditioning and extinction learning took place on day 1 and extinction recall was tested on day 2. Visual cues were used as the conditioned stimuli and a mild electric shock was used as the unconditioned stimulus. Skin conductance was recorded throughout the experiment and used to measure conditioned responses (CRs). Blood samples were obtained from all women to measure estradiol and progesterone levels. We found that higher estradiol during extinction learning enhanced subsequent extinction recall but had no effects on fear acquisition or extinction learning itself. Sex differences were only observed during acquisition, with men exhibiting significantly higher CRs. After dividing women into low- and high-estradiol groups, men showed comparable extinction recall to high-estradiol women, and both of these groups showed higher extinction recall than low-estradiol women. Therefore, sex differences in extinction memory emerged only after taking into account women's estradiol levels. Lower estradiol may impair extinction consolidation in women. These findings could have practical applications in the treatment of anxiety disorders through cognitive and behavioral therapies.
doi:10.1016/j.neuroscience.2010.04.030
PMCID: PMC2881679  PMID: 20412837
estrogen; progesterone; sex difference; fear; menstrual cycle; learning and memory
12.  Stress reduction correlates with structural changes in the amygdala 
Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable.
doi:10.1093/scan/nsp034
PMCID: PMC2840837  PMID: 19776221
stress; amygdala; gray matter; MRI; mindfulness
15.  Neurobiological Basis of Failure to Recall Extinction Memory in Posttraumatic Stress Disorder 
Biological psychiatry  2009;66(12):1075-1082.
Background:
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).
Methods:
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.
Results:
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.
Conclusions:
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.
doi:10.1016/j.biopsych.2009.06.026
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.
doi:10.1016/S0006-3223(96)00229-6
PMCID: PMC2910907  PMID: 8931911
Stress disorders; posttraumatic; magnetic resonance imaging; hippocampus
17.  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
18.  Longitudinal MRI Study of Hippocampal Volume in Trauma Survivors With PTSD 
Objective
The authors prospectively explored whether a reduction in the volume of the hippocampus occurs in recent trauma survivors who develop posttraumatic stress disorder (PTSD).
Method
Thirty-seven survivors of traumatic events were assessed within a week of the traumatic event and 6 months later. The assessment included magnetic resonance imaging of the brain (including 124 coronal slices of 1.5-mm thickness), psychometric testing, and structured clinical interviews. The Clinician-Administered PTSD Scale conferred PTSD diagnoses at 6 months.
Results
Ten subjects (27%) had PTSD at 6 months. The subjects with PTSD did not differ from those without PTSD in hippocampal volume (right or left) at 1 week or 6 months. There was no reduction in hippocampal volume in the PTSD subjects between 1 week and 6 months.
Conclusions
Smaller hippocampal volume is not a necessary risk factor for developing PTSD and does not occur within 6 months of expressing the disorder. This brain abnormality might occur in individuals with chronic or complicated PTSD.
PMCID: PMC2819102  PMID: 11481158
19.  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.
doi:10.1038/nn958
PMCID: PMC2819093  PMID: 12379862
20.  Cavum Septum Pellucidum in Monozygotic Twins Discordant for Combat Exposure: Relationship to Posttraumatic Stress Disorder 
Biological psychiatry  2004;55(6):656-658.
Background
Abnormally large cavum septum pellucidum has been reported in posttraumatic stress disorder; however, the origin of this association is uncertain.
Methods
We utilized magnetic resonance imaging to measure cavum septum pellucidum in pairs of identical twins discordant for combat exposure in Vietnam.
Results
Presence of abnormal cavum septum pellucidum was significantly correlated between exposed and unexposed twins, indicating that it is partially determined by heredity and/or shared environment. There was a greater proportion of cavum septum pellucidum in combat-exposed twins with posttraumatic stress disorder and their noncombat-exposed co-twins.
Conclusions
The presence of abnormally large cavum septum pellucidum is a familial vulnerability factor for posttraumatic stress disorder.
doi:10.1016/j.biopsych.2003.09.018
PMCID: PMC2794416  PMID: 15013837
Septum pellucidum; stress disorders; posttraumatic; magnetic resonance imaging; twins; monozygotic
21.  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.
doi:10.1016/j.psychres.2008.04.020
PMCID: PMC2621060  PMID: 18951637
stress disorders; post-traumatic; dexamethasone; comorbidity; depressive disorder
22.  Somatic panic-attack equivalents in a community sample of Rwandan widows who survived the 1994 genocide 
Psychiatry research  2003;117(1):1-9.
The present study is the first to attempt to determine rates of panic attacks, especially ‘somatically focused’ panic attacks, panic disorder, symptoms of post-traumatic stress disorder (PTSD), and depression levels in a population of Rwandans traumatized by the 1994 genocide. The following measures were utilized: the Rwandan Panic-Disorder Survey (RPDS); the Beck Depression Inventory (BDI); the Harvard Trauma Questionnaire (HTQ); and the PTSD Checklist (PCL). Forty of 100 Rwandan widows suffered somatically focused panic attacks during the previous 4 weeks. Thirty-five (87%) of those having panic attacks suffered panic disorder, making the rate of panic disorder for the entire sample 35%. Rwandan widows with panic attacks had greater psychopathology on all measures. Somatically focused panic-attack subtypes seem to constitute a key response to trauma in the Rwandan population. Future studies of traumatized non-Western populations should carefully assess not only somatoform disorder but also somatically focused panic attacks.
PMCID: PMC2772881  PMID: 12581815
Panic disorder; Stress disorders; post-traumatic; Depression; Rwanda; Holocaust
23.  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.
doi:10.1196/annals.1364.019
PMCID: PMC2770249  PMID: 16891575
stress disorders; posttraumatic; twins; monozygotic; startle response; neurological examination; magnetic resonance imaging; hippocampus; septum pellucidum
24.  Volume of cerebellar vermis in monozygotic twins discordant for combat exposure: Lack of relationship to post-traumatic stress disorder 
Psychiatry research  2006;148(2-3):143-149.
Several functional neuroimaging studies have implicated the cerebellar vermis in post-traumatic stress disorder (PTSD), but there have been no structural neuroimaging studies of this brain structure in PTSD. We utilized magnetic resonance imaging (MRI) with manual tracing to quantify the volumes of three divisions of the mid-sagittal vermis, and their total, within an identical, cotwin control design that employed Vietnam veterans discordant for combat exposure in Vietnam. Each structure’s volume was significantly correlated between twins, indicating a partial familial determination: for anterior superior vermis, r=0.73; for posterior superior vermis, r=0.47; for inferior posterior vermis, r=0.51; and for total vermis, r=0.57. There were no significant differences between the PTSD and non-PTSD veterans for any vermis volume, and no significant main effects or interactions when their non-combat-exposed co-twins were added to the analyses. Thus, the results do not support the structural abnormality of cerebellar vermis in combat-related PTSD.
doi:10.1016/j.pscychresns.2006.01.013
PMCID: PMC2768053  PMID: 17097862
Cerebellum; Vermis; Stress disorders, post-traumatic; Magnetic resonance imaging; Twins; Monozygotic
25.  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.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1016/j.biopsych.2006.12.023
PMCID: PMC2768050  PMID: 17509537
Configural; contextual; hippocampus; neuropsychology; PTSD; twins

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