PTSD in women is associated with a block in conversion of progesterone to the GABAergic neurosteroids allopregnanolone and pregnanolone measured in plasma.

There is a need to identify new and more effective treatments for posttraumatic stress disorder (PTSD). Allopregnanolone and its stereoisomer pregnanolone (together termed ALLO) are metabolites of progesterone that positively and allosterically modulate GABA effects at GABAA receptors, thereby reducing anxiety and depression. Previous research revealed that women with PTSD had low cerebrospinal fluid (CSF) ALLO levels and a low ratio of ALLO to the allopregnanolone precursor 5α-DHP, consistent with deficient activity of the ALLO synthetic enzyme 3α-hydroxysteroid dehydrogenase (3α-HSD). The current study examined ALLO and the ratio of ALLO to 5α-DHP in plasma at rest and in response to psychophysiological stressors in trauma-exposed, medication-free women with and without PTSD. Participants were examined twice in random order during the early follicular phase (eFP) and mid-luteal phase (mLP) of the menstrual cycle. Plasma neurosteroids were measured using gas chromatography-mass spectrometry. Results indicate that the ALLO to 5α-DHP ratio in plasma increases between the eFP and mLP. In addition, women with PTSD have a lower ratio of ALLO to 5α-DHP than trauma-exposed healthy women, as well as blunted increases in this ratio in response to a moderately stressful laboratory procedure, i.e., differential fear conditioning, across the menstrual cycle. Clinically feasible testing for 3α-HSD dysfunction is critical to translating this line of research into clinical care. Measurement of this ratio in plasma could facilitate patient stratification in clinical treatment trials, as well as precision medicine targeting of treatments that address ALLO synthesis deficits in women with PTSD.

Diminished medial prefrontal cortex activation during the recollection of stressful events is an acquired characteristic of PTSD.

BACKGROUND: Previous research has shown relatively diminished medial prefrontal cortex activation and heightened psychophysiological responses during the recollection of personal events in post-traumatic stress disorder (PTSD), but the origin of these abnormalities is unknown. Twin studies provide the opportunity to determine whether such abnormalities reflect familial vulnerabilities, result from trauma exposure, or are acquired characteristics of PTSD. METHODS: In this case-control twin study, 26 male identical twin pairs (12 PTSD; 14 non-PTSD) discordant for PTSD and combat exposure recalled and imagined trauma-unrelated stressful and neutral life events using a standard script-driven imagery paradigm during functional magnetic resonance imaging and concurrent skin conductance measurement. RESULTS: Diminished activation in the medial prefrontal cortex during Stressful v. Neutral script-driven imagery was observed in the individuals with PTSD, relative to other groups. CONCLUSIONS: Diminished medial prefrontal cortex activation during Stressful v. Neutral script-driven imagery may be an acquired characteristic of PTSD. If replicated, this finding could be used prospectively to inform diagnosis and the assessment of treatment response.

Decreased regional cerebral blood flow in medial prefrontal cortex during trauma-unrelated stressful imagery in Vietnam veterans with post-traumatic stress disorder.

BACKGROUND: Neuroimaging research has demonstrated medial prefrontal cortex (mPFC) hyporesponsivity and amygdala hyperresponsivity to trauma-related or emotional stimuli in post-traumatic stress disorder (PTSD). Relatively few studies have examined brain responses to the recollection of stressful, but trauma-unrelated, personal events in PTSD. In the current study, we sought to determine whether regional cerebral blood flow (rCBF) abnormalities in mPFC and amygdala in PTSD could be observed during the recollection of trauma-unrelated stressful personal events. METHOD: Participants were 35 right-handed male combat veterans (MCVs) and female nurse veterans (FNVs) who served in Vietnam: 17 (seven male, 10 female) with current military-related PTSD and 18 (nine male, nine female) with no current or lifetime PTSD. We used positron emission tomography (PET) and script-driven imagery to study rCBF during the recollection of trauma-unrelated stressful versus neutral and traumatic events. RESULTS: Voxelwise tests revealed significant between-group differences for the trauma-unrelated stressful versus neutral comparison in mPFC, specifically in the anterior cingulate cortex (ACC). Functional region of interest (ROI) analyses demonstrated that this interaction in mPFC represented greater rCBF decreases in the PTSD group during trauma-unrelated stressful imagery relative to neutral imagery compared to the non-PTSD group. No differential amygdala activation was observed between groups or in either group separately. CONCLUSIONS: Veterans with PTSD, compared to those without PTSD, exhibited decreased rCBF in mPFC during mental imagery of trauma-unrelated stressful personal experiences. Functional neuroanatomical models of PTSD must account for diminished mPFC responses that extend to emotional stimuli, including stressful personal experiences that are not directly related to PTSD.

Sex-specific influences of vasopressin on human social communication.

Arginine vasopressin (AVP) and related peptides affect social behaviors in numerous species, but AVP influences on human social functions have not yet been established. Here, we describe how intranasal AVP administration differentially affects social communication in men and women, and we propose a mechanism through which it may exert those influences. In men, AVP stimulates agonistic facial motor patterns in response to the faces of unfamiliar men and decreases perceptions of the friendliness of those faces. In contrast, in women, AVP stimulates affiliative facial motor patterns in response to the faces of unfamiliar women and increases perceptions of the friendliness of those faces. AVP also affected autonomic responsiveness to threatening faces and increased anxiety, which may underlie both communication patterns by promoting different social strategies in stressful contexts in men and women.

An fMRI study of anterior cingulate function in posttraumatic stress disorder.

BACKGROUND: Several recent neuroimaging studies have provided data consistent with functional abnormalities in anterior cingulate cortex in posttraumatic stress disorder (PTSD). In our study, we implemented a cognitive activation paradigm to test the functional integrity of anterior cingulate cortex in PTSD. METHODS: Eight Vietnam combat veterans with PTSD (PTSD Group) and eight Vietnam combat veterans without PTSD (non-PTSD Group) underwent functional magnetic resonance imaging (fMRI) while performing the Emotional Counting Stroop. In separate conditions, subjects counted the number of combat-related (Combat), generally negative (General Negative), and neutral (Neutral) words presented on a screen and pressed a button indicating their response. RESULTS: In the Combat versus General Negative comparison, the non-PTSD group exhibited significant fMRI blood oxygenation level-dependent signal increases in rostral anterior cingulate cortex, but the PTSD group did not. CONCLUSIONS: These findings suggest a diminished response in rostral anterior cingulate cortex in the presence of emotionally relevant stimuli in PTSD. We speculate that diminished recruitment of this region in PTSD may, in part, mediate symptoms such as distress and arousal upon exposure to reminders of trauma.

Multivariate assessment of explicit memory function in combat veterans with posttraumatic stress disorder.

Declarative memory impairment is a frequent complaint of patients suffering from posttraumatic stress disorder (PTSD). We assessed memory, attention, visual spatial skills, and executive function in Vietnam combat veterans with (n = 19) and without (n = 13) PTSD. Although PTSD subjects demonstrated a "generalized impairment" relative to non-PTSD subjects on a majority of tasks, only attention and memory provided unique and independent prediction of PTSD versus non-PTSD status. Our findings suggest that memory functioning represents a neurocognitive domain of specific relevance to the development of PTSD in trauma-exposed individuals, which can be distinguished from generalized attentional impairment as well as the effects of trauma exposure severity, IQ, comorbid depression, history of alcohol use, and history of developmental learning problems.

Psychophysiologic assessment of posttraumatic stress disorder in breast cancer patients.

The authors performed psychodiagnostic, psychometric, and psychophysiologic evaluations on 37 patients referred by local surgeons approximately 2 years after tissue diagnosis of Stage I to III breast cancer. The Clinician-Administered Posttraumatic Stress Disorder (PTSD) Scale (CAPS) was used to classify patients into the following groups: "Current PTSD" (n = 5) "Past PTSD" (n = 7), and "Never had PTSD" (n = 25). Individualized "scripts" portraying personal life events were tape recorded and played back to the patients in the laboratory. Current PTSD patients showed significantly higher heart rate, skin conductance, and corrugator electromyogram responses during imagery of their personal breast cancer experiences than Past and Never patients. Physiologic responses were significantly and positively correlated with CAPS scores. These results provide psychophysiologic support for the proposition that a diagnosis of with a life-threatening illness can cause PTSD.

Psychophysiologic assessment of posttraumatic stress disorder in Vietnam nurse veterans who witnessed injury or death.

This study examined whether witnessing death and injury could produce psychophysiologically responsive posttraumatic stress disorder (PTSD). Participants consisted of medication-free female Vietnam nurse veterans with a diagnosis of current PTSD (n = 17) and who never had PTSD (n = 21), related to their military service. Individualized scripts describing personal traumatic military nursing events, a standard military nursing event, and other life events were tape recorded and played back to the participant while heart rate, skin conductance, and facial electromyograms were recorded. Nurses with PTSD showed significantly larger physiologic responses than non-PTSD nurses only during imagery of military-related nursing events. The groups' self-reported emotional responses did not differ during imagery. Psychophysiologic results support the proposition that witnessing death and serious injury to others is sufficiently stressful to cause PTSD.

De novo conditioning in trauma-exposed individuals with and without posttraumatic stress disorder.

Differential conditioning was assessed in 15 medication-free individuals meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed.; American Psychiatric Association, 1994) criteria for chronic posttraumatic stress disorder (PTSD) and 18 trauma-exposed individuals who never developed PTSD (non-PTSD). Conditioned stimuli (CSs) were colored circles, and the unconditioned stimulus was a "highly annoying" electrical stimulus. Individuals with PTSD had higher resting heart rate (HR) and skin conductance (SC) levels and produced larger SC orienting responses. During conditioning, the PTSD group showed larger differential SC, HR, and electromyogram responses to the reinforced vs. nonreinforced stimuli (CS+ vs. CS-) compared with the non-PTSD group. Only PTSD participants continued to show differential SC responses to CS+ vs. CS- during extinction trials. Results suggest that individuals with PTSD have higher sympathetic nervous system arousal at the time of conditioning and are more conditionable than trauma-exposed individuals without PTSD.

Activation of anterior paralimbic structures during guilt-related script-driven imagery.

BACKGROUND: Several recent neuroimaging studies have examined the neuroanatomical correlates of normal emotional states, such as happiness, sadness, fear, anger, anxiety, and disgust; however, no previous study has examined the emotional state of guilt. METHODS: In the current study, we used positron emission tomography and the script-driven imagery paradigm to study regional cerebral blood flow (rCBF) during the transient emotional experience of guilt in eight healthy male participants. In the Guilt condition, participants recalled and imagined participating in a personal event involving the most guilt they had ever experienced. In the Neutral condition, participants recalled and imagined participating in an emotionally neutral personal event. RESULTS: In the Guilt versus Neutral comparison, rCBF increases occurred in anterior paralimbic regions of the brain: bilateral anterior temporal poles, anterior cingulate gyrus, and left anterior insular cortex/inferior frontal gyrus. CONCLUSIONS: These results, along with those of previous studies, are consistent with the notion that anterior paralimbic regions of the brain mediate negative emotional states in healthy individuals.

Exaggerated amygdala response to masked facial stimuli in posttraumatic stress disorder: a functional MRI study.

BACKGROUND: Converging lines of evidence have implicated the amygdala in the pathophysiology of posttraumatic stress disorder (PTSD). We previously developed a method for measuring automatic amygdala responses to general threat-related stimuli; in conjunction with functional magnetic resonance imaging, we used a passive viewing task involving masked presentations of human facial stimuli. METHODS: We applied this method to study veterans with PTSD and a comparison cohort of combat-exposed veterans without PTSD. RESULTS: The findings indicate that patients with PTSD exhibit exaggerated amygdala responses to masked-fearful versus masked-happy faces. CONCLUSIONS: Although some previous neuroimaging studies of PTSD have demonstrated amygdala recruitment in response to reminders of traumatic events, this represents the first evidence for exaggerated amygdala responses to general negative stimuli in PTSD. Furthermore, by using a probe that emphasizes automaticity, we provide initial evidence of amygdala hyperresponsivity dissociated from the "top-down" influences of medial frontal cortex.

Psychophysiologic assessment of aversive conditioning in posttraumatic stress disorder.

BACKGROUND: The objective of this study was to evaluate the acquisition, generalization, and extinction of conditioned physiologic responses to aversive stimuli in posttraumatic stress disorder (PTSD). METHODS: Thirty-six PTSD patients, 20 individuals with past trauma and no current PTSD, and 30 mentally healthy individuals without exposure to major trauma underwent a differential aversive conditioning experiment. Bursts of 105 dB white noise were used as unconditioned stimuli (UCSs), and 35x24 mm slides of different colors served as either CS+ (paired) or CS- (unpaired) stimuli. Heart rate (HR) and nondominant palm skin conductance (SC) were measured at rest and between 1 and 4 sec following each CS presentation. RESULTS: The PTSD group showed higher levels of resting SC and resting HR, larger SC responses to the initial presentation of unpaired CSs, larger HR responses following paired CS+ stimuli, larger SC responses to unpaired CS- during acquisition and extinction, and larger SC and HR responses to CS+ during extinction. The group differences in responses to CS+ during extinction remained statistically significant after controlling for age, resting physiologic levels, and initial responsivity. CONCLUSIONS: PTSD is associated with elevated autonomic responses to both innocuous and aversive stimuli, with larger responses to unpaired cues and with reduced extinction of conditioned responses.

Auditory startle response in trauma survivors with posttraumatic stress disorder: a prospective study.

OBJECTIVE: Previous studies have shown elevated autonomic responses to startling tones in trauma survivors with chronic posttraumatic stress disorder (PTSD). The origin of these abnormal responses is obscure. The present study attempted to clarify this issue by prospectively evaluating responses to sudden, loud tones in individuals who arrived at a hospital emergency room after psychologically traumatic events. METHOD: By using a previously established protocol, autonomic and muscular responses to the tones were evaluated at 1 week, 1 month, and 4 months after the traumatic event. Structured diagnostic interviews performed at 4 months classified subjects into groups with (N=36) and without (N=182) PTSD, which were further subdivided according to the presence or absence of major depressive disorder as follows: neither PTSD nor depression (N=166), depression alone (N=16), PTSD alone (N=21), and both PTSD and depression (N=15). RESULTS: The groups showed comparable physiological responses to the tones at 1 week posttrauma. However, at 1 and 4 months posttrauma, the subjects with PTSD showed a greater heart rate response and required more stimulus trials to reach the criteria of skin conductance and orbicularis oculi electromyogram nonresponse. These findings were not significantly influenced by comorbid depression and were not explained by the severity of the traumatic event or by the intensity of the initial symptoms. CONCLUSIONS: Differences in physiological response to startling tones develop along with PTSD in the months that follow a traumatic event. This pattern supports the theories that associate PTSD with progressive neuronal sensitization.

Neurologic soft signs in chronic posttraumatic stress disorder.

BACKGROUND: Subtle neurologic impairment has been reported in several mental disorders. The goals of the present study were to evaluate neurologic status in patients of both sexes with chronic posttraumatic stress disorder (PTSD) from different traumatic experiences. METHODS: Twenty-one adult women who were sexually abused as children (12 with PTSD, 9 without) and 38 male Vietnam War combat veterans (23 with PTSD, 15 without) underwent examination for 41 neurologic soft signs, which were scored by the examiner as well as a blind rater observing videotapes. Subject history was obtained with special attention to neurodevelopmental problems. Psychometrics included the Wender Utah Rating Scale for symptoms of childhood attention-deficit/hyperactivity disorder and the Michigan Alcoholism Screening Test. Veterans also completed the Combat Exposure Scale and subtests of the Wechsler Adult Intelligence Scale-Revised. RESULTS: Average neurologic soft sign scores (interrater reliability = 0.74) of women with PTSD owing to sexual abuse in childhood (mean [SD], 0.77 [0.32]) and veteran men (0.72 [0.20]) with combat-related PTSD were comparable and significantly (P<.001) higher than those of women sexually abused as children (0.42 [0.10]) and combat veteran men (0.43 [0.17]) without PTSD. This effect could not be explained by a history of alcoholism or head injury. Subjects with PTSD reported more neurodevelopmental problems and more childhood attention-deficit/hyperactivity disorder symptoms and had lower IQs, all of which were significantly correlated with neurologic soft signs. CONCLUSION: Neurologic compromise is evident from subject history and findings from physical examination in both women and men with chronic PTSD who had experienced different kinds of traumatic events in childhood and adulthood.

Five-year follow-up study of eye movement desensitization and reprocessing therapy for combat-related posttraumatic stress disorder.

This study reports the results of a 5-year follow-up evaluation of 13 Vietnam combat veterans with chronic posttraumatic stress disorder (PTSD) who participated in a study of eye movement desensitization and reprocessing (EMDR) therapy previously reported in this journal. Pretreatment and follow-up psychometric outcome measures were compared with those of a demographically matched control group of 14 combat veterans with chronic PTSD who did not receive EMDR. Analysis of variance showed that the modest to moderate therapeutic benefits that were manifest immediately following EMDR were lost at the 5-year follow-up evaluation, and there was an overall worsening of PTSD symptomatology over the 5-year period in both EMDR-treated and nontreated control subjects.

Psychophysiological assessment: clinical applications for PTSD.

Descriptions of anxiety disorders clearly recognize the physiological features of anxiety, yet in most clinical practice and research there is little actual use of physiological measurement. This is unfortunate because a potentially important source of information is thereby unavailable and is likely to result in judgements about emotional experience that are less accurate, complete, and reliable than those that include physiological information. The neglect of physiological measures may result from a variety of concerns regarding test attributes such as reliability, validity, utility, and complexity. Promising results from studies of posttraumatic stress disorder (PTSD) demonstrate that physiological assessment can provide valuable clinical and theoretical insight. Numerous studies have now shown that heightened physiological reactivity to trauma-related cues is highly indicative of a diagnosis of PTSD. Physiological tests have achieved some success in predicting the development and persistence of PTSD, and in predicting and assessing treatment response. Studies of the startle response, aversive conditioning, and brain potentials during cognitive processing have identified several potentially important differences between PTSD patients and controls. This paper provides an overview of psychophysiological findings in PTSD and considers potential clinical applications of psychophysiological assessment for this disorder.

Psychophysiological alterations in post-traumatic stress disorder.

Psychophysiological research in trauma-exposed populations has provided objective data supporting the validity of the post-traumatic stress disorder (PTSD) diagnostic concept. Consistent with a conditioning model, PTSD patients show specific increased peripheral physiological responding to audio-visually and imaginally presented stimuli symbolizing or resembling the etiologic traumatic event. PTSD patients respond to startling stimuli with larger autonomic and electromyographic responses, especially under threat conditions. Electroencephalographic event-related potential (ERP) response abnormalities in PTSD include reduced P2 amplitude at high stimulus intensities, impaired P1 habituation, and attenuated P3 amplitude to target auditory stimuli. However, larger P3 and N1 amplitude responses and shorter P3 and N1 latencies have been reported in PTSD subjects in response to trauma-related stimuli. These ERP findings suggest sensory, cognitive, and affective processing abnormalities in PTSD. Polysomnographic sleep studies have revealed increased awakenings, reduced sleep time, and increased motor activity, or in some cases, paradoxical deepening of sleep. There is also evidence for increased phasic eye movement activity during rapid eye movement (REM) sleep and disrupted REM continuity in PTSD. Psychophysiological studies are offering valuable insights into the pathophysiology of this important neuropsychiatric condition.

Neural activation during sexual and competitive arousal in healthy men.

To investigate the mediating neuroanatomy of positively valenced arousal, we used script-driven imagery in conjunction with positron emission tomography to measure relative regional cerebral blood flow (rCBF) during sexual and competitive arousal, as well as neutral comparison states. Subjects were eight healthy right-handed men. Psychophysiologic responses and subjective ratings confirmed that the desired state manipulations were achieved. Statistical parametric mapping revealed similar patterns of rCBF changes for both positively valenced arousal conditions: increases were found within anterior cingulate and anterior temporal cortex as well as the ventral globus pallidus; decreases were found within widespread heteromodal association areas. These results complement findings from studies of other normal and pathological emotional states, and provide new insights regarding the neural substrates of pleasurable arousal in healthy men.

Anger in healthy men: a PET study using script-driven imagery.

BACKGROUND: An understanding of the neurobiological basis of normal emotional processing is useful in formulating hypotheses regarding the pathophysiology of psychiatric illnesses. METHODS: This study examined the mediating functional neuroanatomy of anger in eight healthy men. Narrative scripts were developed from autobiographical information to induce anger and neutral states. The subjects imagined the content of the narrative scripts to induce anger during positron emission tomography to measure normalized regional cerebral blood flow (rCBF). Psychophysiologic responses and subjective ratings of emotional state were measured for each condition. Statistical parametric maps were constructed to reflect the Anger versus Neutral state contrast. RESULTS: Anger was associated with activation of the left orbitofrontal cortex, right anterior cingulate cortex affective division, and bilateral anterior temporal poles. CONCLUSIONS: These results suggest that the subjective experience of anger is associated with rCBF increases in anterior paralimbic regions of the brain.

Physiologic reactivity to startling tones in women with posttraumatic stress disorder.

Autonomic and eyeblink reactivity to startling tones were investigated in women with histories of childhood sexual abuse (CSA). Twenty-one women with current posttraumatic stress disorder (PTSD), 23 with lifetime but not current PTSD, and 13 women who never had PTSD listened to 15 95-dB, 500-ms, 1000-Hz tones with a 0-ms rise time while heart rate (HR), skin conductance (SC), and orbicularis oculi electromyogram (EMG) responses were measured. Participants in the current and lifetime PTSD groups produced larger HR responses across tones and showed slower absolute habituation of SC response magnitude compared with the never PTSD group. EMG response magnitudes did not differ among groups. Women with CSA-related PTSD showed increased autonomic reactivity and slower habituation to high-intensity tones similar to that observed in primarily male, combat PTSD samples. This suggests that heightened autonomic responsivity to startling stimuli in PTSD is not gender or event specific.