Manchester VA Medical Center

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.

The present study was designed to investigate the relationship among physiologic concordance, patient-perceived therapist empathy, and social-emotional process during psychotherapy. Simultaneous measures of skin conductance (SC) were obtained from 20 unique and established patient-therapist dyads during a live therapy session followed by patient ratings of therapist empathy. Paired SC data of hypothetical dyads were used to test the reliability of the proposed measure of SC concordance. Observer microanalyses of social-emotional process were used to compare short segments of high versus low physiologic concordance. Results show a significant positive correlation (r=0.47, p=0.03) between SC concordance and patient ratings of perceived therapist empathy. Microanalyses suggest that during moments of high versus low SC concordance, there were significantly more positive social-emotional interactions for both patients and therapists (p=0.01). The results support a biological model of perceived patient empathy and patient-therapist social-emotional process during psychotherapy.

Recent studies have reported memory deficits and reduced hippocampal volumes in posttraumatic stress disorder (PTSD). The goal of the current research was to use functional neuroimaging and a validated explicit memory paradigm to examine hippocampal function in PTSD. We used positron emission tomography (PET) and a word-stem completion task to study regional cerebral blood flow (rCBF) in the hippocampus in 16 firefighters: 8 with PTSD (PTSD group) and 8 without PTSD (Control group). During PET scanning, participants viewed three-letter word stems on a computer screen and completed each stem with a word they had previously encoded either deeply (High Recall condition) or shallowly (Low Recall condition). Relative to the Control group, the PTSD group exhibited significantly smaller rCBF increases in the left hippocampus in the High vs Low Recall comparison. However, this finding reflected relatively elevated rCBF in the Low Recall condition in the PTSD group. Collapsing across High and Low Recall conditions, (1) the PTSD group had higher rCBF in bilateral hippocampus and left amygdala than the Control group, and (2) within the PTSD group, symptom severity was positively associated with rCBF in hippocampus and parahippocampal gyrus. The groups did not significantly differ with regard to accuracy scores on the word-stem completion task. The PTSD group had significantly smaller right (and a trend for smaller left) hippocampal volumes than the Control group. The results suggest an abnormal rCBF response in the hippocampus during explicit recollection of nonemotional material in firefighters with PTSD, and that this abnormal response appears to be driven by relatively elevated hippocampal rCBF in the comparison condition.

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.

Rapidly evolving brain neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are proving fruitful in exploring the pathogenesis and pathophysiology of posttraumatic stress disorder (PTSD). Structural abnormalities in PTSD found with MRI include nonspecific white matter lesions and decreased hippocampal volume. These abnormalities may reflect pretrauma vulnerability to develop PTSD, or they may be a consequence of traumatic exposure, PTSD, and/or PTSD sequelae. Functional neuroimaging symptom provocation and cognitive activation paradigms using PET measurement of regional cerebral blood flow have revealed greater activation of the amygdala and anterior paralimbic structures (which are known to be involved in processing negative emotions such as fear), greater deactivation of Broca's region (motor speech) and other nonlimbic cortical regions, and failure of activation of the cingulate cortex (which possibly plays an inhibitory role) in response to trauma-related stimuli in individuals with PTSD. Functional MRI research has shown the amygdala to be hyperresponsive to fear-related stimuli in this disorder. Research with PET suggests that cortical, notably hippocampal, metabolism is suppressed to a greater extent by pharmacologic stimulation of the noradrenergic system in persons with PTSD. The growth of knowledge concerning the anatomical and neurochemical basis of this important mental disorder will hopefully eventually lead to rational psychological and pharmacologic treatments.

We used psychophysiologic techniques to assess responses to imagery of psychologically stressful past experiences in medication-free Vietnam combat veterans classified, on the basis of DSM-III-R criteria into posttraumatic stress disorder (PTSD; n = 7) or non-PTSD anxiety disorder (anxious; n = 7) groups. Scripts describing each individual's combat experiences were recorded and played back in the laboratory. Ss were instructed to imagine the events the scripts portrayed while heart rate, skin conductance, and frontalis electromyogram were recorded. PTSD Ss' physiologic responses were higher than those of anxious Ss. A discriminant function derived from a previous study of PTSD and mentally healthy combat veterans identified 5 of the 7 current PTSD Ss as physiologic responders and all 7 of the anxious Ss as nonresponders. Results of this study replicate and extend results of the previous study and support the validity of PTSD as a separate diagnostic entity.

The authors evaluated eyeblink and autonomic components of the acoustic startle response in combat-related posttraumatic stress disorder (PTSD). Thirty-seven Vietnam combat veterans with current PTSD and 19 combat veterans without PTSD were exposed to 15 consecutive 95-dB, 500-ms, 1000-Hz tones with 0-ms rise and fall times, while orbicularis oculi electromyogram, skin conductance, and heart rate responses were measured. PTSD veterans produced larger averaged electromyographic and heart rate responses, and a slower decline in skin conductance responses, across the 15 tone presentations compared to non-PTSD veterans. Results of this study provide laboratory support for an exaggerated startle response in PTSD and replicate and extend previous findings of increased autonomic responses to loud tone stimuli in this disorder.

Neuropsychological deficits have been reported among trauma survivors with posttraumatic stress disorder (PTSD). It is often assumed that these cognitive difficulties are toxic consequences of trauma exposure. Alternatively, they may reflect preexisting characteristics that contribute to the likelihood of developing PTSD. To address this possibility, the authors evaluated cognitive performance in monozygotic twin pairs who were discordant for combat exposure. Pairs were grouped according to whether the combat-exposed brother developed PTSD. The combat-unexposed cotwins of combat veterans with PTSD largely displayed the same performance as their brothers, which was significantly lower than that of non-PTSD combat veterans and their brothers. The results support the notion that specific domains of cognitive function may serve as premorbid risk or protective factors in PTSD.

A biological abnormality found to be associated with posttraumatic stress disorder (PTSD) may be, among other things, a pretrauma 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.

INTRODUCTION: Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β-adrenergic blocker propranolol, to reduce this overconsolidation. AIMS: In this randomized, placebo-controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty-one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post-trauma, PTSD symptoms were assessed. One week later, participants engaged in script-driven imagery of their traumatic event while psychophysiological responses were measured. RESULTS: Physiological reactivity during script-driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5-week posttrauma assessment, physiological reactivity was significantly lower during script-driven imagery in the propranolol than in the placebo subjects. CONCLUSIONS: The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.

Nefazodone is an antidepressant medication which received approval from the Food and Drug Administration for treatment of major depressive disorder in 1994. This article summarizes the pharmacodynamics, pharmacokinetics, adverse effects, and drug interactions of nefazodone as well as its administration and dosing schedule. The potential efficacy of nefazodone in treating anxiety, premenstrual syndrome, chronic pain conditions, and sleep disturbances also is summarized. Nefazodone has a favorable side effects profile which makes it an attractive alternative option for patients who withdraw from treatment when they develop adverse effects to other available antidepressants.

OBJECTIVE: Neuroimaging studies have revealed functional abnormalities in the anterior cingulate cortex in posttraumatic stress disorder (PTSD). The goal of this study was to determine whether hyperresponsivity of the dorsal anterior cingulate in PTSD is an acquired characteristic or a familial risk factor. METHOD: Using a case-control twin design, the authors 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 MRI during completion of the Multi-Source Interference Task, which reliably activates the dorsal anterior cingulate. RESULTS: Combat-exposed veterans with PTSD and their unexposed co-twins had significantly greater activation in the dorsal anterior cingulate and tended to have larger response time difference scores, as compared to combat-exposed veterans without PTSD 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. CONCLUSIONS: Hyperresponsivity in the dorsal anterior cingulate appears to be a familial risk factor for the development of PTSD following psychological trauma.

Heart rate, skin conductance, and left lateral frontalis and corrugator facial electromyogram responses were measured during script-driven imagery of personal childhood sexual abuse (CSA) and other life experiences among women with and without Diagnostic and Statistical Manual of Mental Disorders (3rd ed., rev., American Psychiatric Association, 1987)--diagnosed posttraumatic stress disorder (PTSD) resulting from CSA. Women with current PTSD (n = 29) showed larger physiologic responses than those who never had PTSD (n = 18) during personal sexual abuse imagery but not during imagery of stressful, nonabuse-related life experiences. Responses of individuals with lifetime, but not current, PTSD (n = 24) fell between the other groups. An a priori discriminant function, derived from physiologic responses of previously studied individuals, correctly classified 66% of women with current PTSD and 78% of women who never had PTSD.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

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.

Pierre Janet's classic contribution to the understanding of obsessive-compulsive disorder, Obsessions and Psychasthenia (1903), remains untranslated as well as unappreciated by American psychiatry, despite increasing recognition of the importance of this mental health problem. Herein the work is summarized and discussed. Although it tends to be remembered for its theoretical ideas, most of which have become dated, the most valuable aspect of Obsessions and Psychasthenia is its clinical discoveries. These include the important role played in the disorder by symptoms that are closely related to, but yet cannot properly be called, obsessions and compulsions (the "forced agitations"); the underlying psychasthenic mental state; and the obsessive-compulsive person's specific failure to adapt to reality. Despite the passage of nearly a century, these observations, and Janet's suggestions regarding treatment, are as timely now as when they were made.

OBJECTIVE: To compare generalists' and cardiologists' estimates of baseline cardiovascular risk and the outcomes of preventive therapy. DESIGN: Cross-sectional mail survey using written case simulations of typical patients from primary prevention trials for hypercholesterolemia and isolated systolic hypertension, and tertiary prevention studies of coronary artery bypass surgery for chronic stable angina with left main coronary stenosis. PARTICIPANTS: Nationally representative sample of 599 practicing family physicians, general internists, and cardiologists selected from the American Medical Association masterfile. Among eligible physicians, 84 (44%) of 191 family physicians, 77 (40%) of 194 general internists, and 66 (34%) of 194 cardiologists responded. MEASUREMENTS: Estimates of risk at baseline and after therapy, and whether therapy generally would be recommended. RESULTS: For both primary prevention case simulations (scenarios), cardiologists provided lower, more accurate estimates of baseline cardiovascular risk and of absolute therapeutic benefit than either family physicians or general internists. The range of the generalists' estimates was extremely wide. Perceptions of relative risk reduction and treatment recommendations for the primary prevention scenarios did not differ among specialties. Overall, generalists who would not recommend primary preventive therapy in these scenarios appeared to give more accurate estimates than did generalists who would recommend such therapy. CONCLUSIONS: Many generalists have inflated perceptions of cardiovascular risk without treatment and of the benefit of risk-modifying medical treatment. Further study should assess the reasons for these misperceptions and their effect on counseling about primary preventive therapy.

This study investigated neurological status in 27 medication-free outpatient Vietnam veterans meeting DSM-III-R criteria for posttraumatic stress disorder (PTSD) and 15 non-PTSD combat control subjects, all without alcohol or drug dependence or abuse during the past year. Subjects underwent neurological examination, neuropsychological testing, and sleep-deprived EEG. PTSD subjects showed significantly more neurological soft signs than non-PTSD subjects. Neither substance dependence/abuse nor the more frequent history of developmental problems in PTSD subjects accounted for this difference. There were no significant EEG or neuropsychological testing group differences; however, there were significant correlations between several neuropsychological test scores and total neurological soft signs.

Of 156 wounded Vietnam veterans evaluated for posttraumatic stress disorder (PTSD) by a questionnaire and a diagnostic interview in selected cases, 40% had a definite or probable lifetime diagnosis of PTSD. Of the 27 interviewed patients with lifetime PTSD, 81% currently met the PTSD criteria.

BACKGROUND: ASC (autism spectrum conditions) may result from a failure of striatal beta endorphins to diminish with maturation. Many symptoms of ASC resemble behaviours induced in animals or humans by opiate administration, including decreased socialisation, diminished crying, repetitive stereotypies, insensitivity to pain and motor hyperactivity. Naltrexone, an opioid antagonist, has been used in the management of children with ASC and can produce a clinically significant reduction in the serious and life-threatening behaviour of self-injury for individuals who have not been responsive to any other type of treatment and is important for this reason. It was therefore appropriate to reconsider the available evidence and a systematic review was undertaken. METHODS: Four electronic databases were searched for relevant journal articles. In addition, cross-referencing of pertinent reviews and a hand search for articles in major international intellectual disability (ID) journals between the years 2010 and 2012 was carried out to ensure that all relevant articles were identified. We also searched databases for unpublished clinical trials to overcome publication bias. Each database was searched up to present (February 2013) with no restrictions on the date of publication. The search terms consisted of broad expressions used to describe ID and autistic spectrum disorder as well as terms relating to opioid antagonists and specific drugs. All studies identified by the electronic database search and hand search were examined on the basis of title alone for relevance and duplication. The abstracts of the remaining papers were then scrutinised against the inclusion criteria. Where abstracts failed to provide adequate information, the full texts for these papers were obtained. All the full texts were then evaluated against the inclusion proforma. Two reviewers carried out all the stages of the process independently. The reviewers met to discuss their selections and where disagreements arose, these were settled by discussion with a member of the study group. Data from each study meeting the inclusion criteria were extracted on a pre-piloted data extraction form. The quality of each study was further assessed using the Jadad scale, a tool developed to assess the quality of randomised controlled trials. RESULTS: 155 children participated in 10 studies; 27 received placebo. Of the 128 that received naltrexone 98 (77%) showed statistically significant improvement in symptoms of irritability and hyperactivity. Side effects were mild and the drug was generally well tolerated. CONCLUSIONS: Naltrexone may improve hyperactivity and restlessness in children with autism but there was not sufficient evidence that it had an impact on core features of autism in majority of the participants. It is likely that a subgroup of children with autism and abnormal endorphin levels may respond to naltrexone and identifying the characteristics of these children must become a priority.