Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Brain Mechanisms of Social Threat Effects on Working Memory.

Social threat can have adverse effects on cognitive performance, but the brain mechanisms underlying its effects are poorly understood. We investigated the effects of social evaluative threat on working memory (WM), a core component of many important cognitive capabilities. Social threat impaired WM performance during an N-back task and produced widespread reductions in activation in lateral prefrontal cortex and intraparietal sulcus (IPS), among other regions. In addition, activity in frontal and parietal regions predicted WM performance, and mediation analyses identified regions in the bilateral IPS that mediated the performance-impairing effects of social threat. Social threat also decreased connectivity between the IPS and dorsolateral prefrontal cortex, while increasing connectivity between the IPS and the ventromedial prefrontal cortex, a region strongly implicated in the generation of autonomic and emotional responses. Finally, cortisol response to the stressor did not mediate WM impairment but was rather associated with protective effects. These results provide a basis for understanding interactions between social and cognitive processes at a neural systems level.

Post-traumatic stress disorder, child abuse history, birthweight and gestational age: a prospective cohort study.

OBJECTIVE: To determine the extent to which prenatal post-traumatic stress disorder (PTSD) is associated with lower birthweight and shorter gestation, and to explore the effects of childhood maltreatment as the antecedent trauma exposure. DESIGN: Prospective three-cohort study. SETTING: Ann Arbor and Detroit, Michigan, United States. SAMPLE: In all, 839 diverse nulliparas in PTSD-positive (n = 255), trauma-exposed, resilient (n = 307) and non-exposed to trauma (n = 277) cohorts. METHODS: Standardised telephone interview before 28 weeks of gestation to ascertain trauma history, PTSD, depression, substance use, mental health treatment history and sociodemographics, with chart abstraction to obtain chronic condition history, antepartum complications and prenatal care data, as well as outcomes. MAIN OUTCOME MEASURES: Infant birthweight and gestational age per delivery record. RESULTS: Infants born to women with PTSD during pregnancy had a mean birthweight 283 g less than infants of trauma-exposed, resilient women and 221 g less than infants of non-exposed women (F(3,835) = 5.4, P = 0.001). PTSD was also associated with shorter gestation in multivariate models that took childhood abuse history into account. Stratified models indicated that PTSD subsequent to child abuse trauma exposure was most strongly associated with adverse outcomes. PTSD was a stronger predictor than African American race of shorter gestation and a nearly equal predictor of birthweight. Prenatal care was not associated with better outcomes among women abused in childhood. CONCLUSIONS: Abuse-related PTSD may be an additional or alternative explanation for adverse perinatal outcomes associated with low socio-economic status and African American race in the USA. Biological and interventions research is warranted along with replication studies in other nations.

Differential subjective and psychophysiological responses to socially and nonsocially generated emotional stimuli.

Sociality may determine the subjective experience and physiological response to emotional stimuli. Film segments induced socially and nonsocially generated emotions. Comedy (social positive), bereavement (social negative), pizza scenes (nonsocial positive), and wounded bodies (nonsocial negative) elicited four distinct emotional patterns. Per subjective report, joy, sadness, appetite, and disgust were elicited by the targeted stimulus condition. The social/nonsocial dimension influenced which emotional valence(s) elicited a skin conductance response, a finding that could not be explained by differences in subjective arousal. Heart rate deceleration was more responsive to nonsocially generated emotions. Taken together, these findings suggest that sociality affects the physiological profile of responses to emotional valence.

Psychophysiologic responsivity in posttraumatic stress disorder: generalized hyperresponsiveness versus trauma specificity.

BACKGROUND: Clinically, subjects with posttraumatic stress disorder (PTSD) are viewed as hyperresponsive to a variety of stimuli. Psychophysiologic studies, however, have demonstrated hyperresponsiveness only to stimuli that are closely related to the original trauma. METHODS: This set of experiments uses a variety of stimuli that vary in trauma-relatedness, arousal level, sensory modality stimulated, and degree of cognitive processing demanded to assess the extent of generalization of physiologic responses. Heart rate (HR), frontal electromyogram (EMG), and skin conductance (EDG) responses were measured during presentation of each stimulus. RESULTS: PTSD subjects (n = 15) had an elevated baseline EDG and increased HR and EMG responses to the trauma-related stimulus (combat sounds) compared to normal control subjects (n = 11) and combat control subjects (n = 10). No significant differences were noted between PTSD and control groups in response to non-trauma-related arousing stimuli. CONCLUSIONS: These results suggest that the physiologic hyperresponsivity of PTSD subjects is limited to stimuli closely associated with the inciting trauma.

Serotonin 1A receptor messenger RNA regulation in the hippocampus after acute stress.

BACKGROUND: When rats are subjected to chronic stress for 2 weeks, a significant decrease in hippocampal serotonin (5-HT)1A messenger RNA (mRNA) is observed. We wanted to investigate whether stress, administered for shorter periods of time, would result in decreases in 5-HT1A gene expression in hippocampus. METHODS: In one experiment, rats were either stressed daily for 1 week or implanted with two corticosterone pellets to produce elevated corticosterone levels. In another experiment, rats were subjected to a severe acute stressor and sacrificed 1 day or 1 week after the stressor. RESULTS: We found that 24 hours after the acute stress, rats showed a significant decrease in 5-HT1A mRNA levels in CA1 and the dentate gyrus compared to controls. No significant changes in 5-HT1A mRNA levels were detected in any of the other groups. CONCLUSIONS: Although 1 week of chronic stress is not sufficient to cause significant decreases in hippocampal 5-HT1A mRNA levels, a severe and prolonged acute stress is capable of down-regulating, at least transiently, 5-HT1A mRNA gene expression in hippocampus.

Brain activation in PTSD in response to trauma-related stimuli.

BACKGROUND: Repetitive recall of traumatic memories and chronic intermittent hyperarousal are characteristic of posttraumatic stress disorder (PTSD). Hyperarousal and memory dysfunction implicates "limbic" brain regions, including the amygdaloid complex, hippocampal formation, and limbic cortex, such as the orbitofrontal and anterior cingulate areas. To investigate the neurobiologic role of these brain regions in PTSD, we measured regional cerebral blood flow in PTSD with single photon emission computerized tomography (SPECT) during a symptom provocation paradigm. METHODS: Fourteen Vietnam veterans with PTSD, 11 combat control subjects, and 14 normal control subjects were studied with [99mTc]HMPAO in two sessions 48 hours apart: one session after exposure to white noise and the other following exposure to combat sounds. Skin conductance, heart rate, and subjective experience were recorded at the time of the studies. RESULTS: Activation for all three groups occurred in the anterior cingulate/middle prefrontal gyrus. Activation in the region of the left amygdala/nucleus accumbens was found in PTSD patients only. Deactivation was found in all three groups in the left retrosplenial region. CONCLUSIONS: These findings implicate regions of the "limbic" brain, which may mediate the response to aversive stimuli in healthy individuals and in patients suffering from PTSD.

The effect of graded aversive stimuli on limbic and visual activation.

Activation studies have shown that in response to evocative visual stimuli, brain activity increases in the visual cortex and limbic areas. However, non-affective characteristics of these images, such as color composition and visual complexity, confound the interpretation of these results. To address this issue, we had subjects rate over 100 images on aversive intensity (facial mutilation, dead bodies) and semantic complexity (number of objects subjects could name). From these images, we assembled digitized image sets of non-aversive, mild and strong intensity, balanced on semantic complexity and content (human faces and figures), and adjusted for color composition. A fourth condition consisted of a fixation cross on a blank screen. Thirteen subjects underwent eight positron emission tomography scans using the [(15)O] water methodology. Measurement of skin conductance was recorded simultaneously. All picture conditions, relative to the blank screen, activated the amygdalae and bilateral orbitofrontal cortex, while we found activation trends associated with increasing aversive content in the sub-lenticular region. Skin conductance increased during all picture conditions. Relative to the non-aversive pictures, aversive image content caused modulation of occipital and occipital-temporal cortex. These results demonstrated activation of the amygdala to salient, arousing stimuli, and not just aversive stimuli. In addition, they suggest that pictorial complexity, as indexed by our semantic measure, does not account for the modulation of visual cortex by aversive, emotional stimuli.

Dose response of adrenocorticotropin and cortisol to the CCK-B agonist pentagastrin.

Cholecystokinin (CCK) is an abundant neurotransmitter in brain. Its functional significance in humans is incompletely understood, but it may modulate activity in the hypothalamic-pituitary-adrenal (HPA) axis. To explore this hypothesis, we examined the effects of varying doses (0 to 0.8 microgram/kg) of the CCK-B agonist pentagastrin on adrenocorticotropin (ACTH) and cortisol release in healthy human subjects. We also examined anxiety, heart rate (HR), and blood pressure (BP) responses. Pentagastrin induced large (up to 520% increase over baseline), significant and very rapid, dose-dependent elevations in ACTH and cortisol levels. Significant elevations in HR and BP were seen at all doses, without clear dose-response relationships. Anxious distress and symptom responses were also somewhat dose dependent; but hormonal responses were more robustly linked to pentagastrin dose than to these subjective measures. The HPA axis response to the CCK-B agonist pentagastrin may be a direct pharmacological effect. Further work is needed to determine the mechanisms and the physiological significance of CCK-mediated modulation of the human neuroendocrine stress axis.

Motivational properties of oxytocin in the conditioned place preference paradigm.

We hypothesized that oxytocin might have intrinsic reinforcing properties and studied it using a conditioned place preference. Three studies examining motivational properties of oxytocin in nonpreferred, preferred, and balance designs were performed utilizing two compartment apparatus. On alternate days, compartments were paired with subcutaneously injected oxytocin (6 mg/kg) or saline, and animal pre- and post-conditioning place preference was compared. Whereas in animals paired with saline there was a shift to a lack of preference, oxytocin-treated animals reversed their preference, spending more time in a previously unpreferred, compartment. In preferred compartment design, oxytocin-treated animals further increased their preference, whereas saline-treated animals decreased their preference toward a nonpreference for either compartment. Our results demonstrate that oxytocin produces a reliable and robust preference for the environment with which it is repeatedly associated, and has rewarding or potentially anti-aversive properties. Future studies are needed to distinguish among these possibilities.

Limbic activation and psychophysiologic responses to aversive visual stimuli. Interaction with cognitive task.

We mapped regional brain activity and peripheral psychophysiologic responses, occurring in response to evocative emotional stimuli, and examined whether task instructions could modulate limbic activation. Ten subjects viewed pictures with neutral or aversive emotional content during simultaneous measurement of peripheral psychophysiology and brain activity with [15O]water positron emission tomography (PET). Cognitive task was manipulated by having the subjects rate the pictures or perform a recognition memory task. Aversive pictures, relative to neutral pictures, increased cerebral activity in bilateral amygdala, thalamic/hypothalamic area, midbrain, and left lateral prefrontal cortex, along with greater skin conductance responses (SCR). Voxel-by-voxel correlation coefficients between regional brain activity and SCR showed significant positive correlation peaks in the thalamus and right amygdala. Limbic activation was significantly greater during the rating condition compared to the recognition condition, suggesting that when task demands modify emotional responses, this modulation can occur at the level of limbic activity.

Neuroendocrine and psychophysiologic responses in PTSD: a symptom provocation study.

Biological research on post-traumatic stress disorder (PTSD) has focused on autonomic, sympatho-adrenal, and hypothalamo-pituitary-adrenal (HPA) axis systems. Interactions among these response modalities have not been well studied and may be illuminating. We examined subjective, autonomic, adrenergic, and HPA axis responses in a trauma-cue paradigm and explored the hypothesis that the ability of linked stress-response systems to mount integrated responses to environmental threat would produce strong correlations across systems. Seventeen veterans with PTSD, 11 veteran controls without PTSD, and 14 nonveteran controls were exposed to white noise and combat sounds on separate days. Subjective distress, heart rate, skin conductance, plasma catecholamines, ACTH, and cortisol, at baseline and in response to the auditory stimuli, were analyzed for group differences and for patterns of interrelationships. PTSD patients exhibited higher skin conductance, heart rate, plasma cortisol, and catecholamines at baseline, and exaggerated responses to combat sounds in skin conductance, heart rate, plasma epinephrine, and norepinephrine, but not ACTH. The control groups did not differ on any measure. In canonical correlation analyses, no significant correlations were found between response systems. Thus, PTSD patients showed heightened responsivity to trauma-related cues in some, but not all, response modalities. The data did not support the integrated, multisystem stress response in PTSD that had been hypothesized. Individual response differences or differing pathophysiological processes may determine which neurobiological system is affected in any given patient.

Effects of stress and glucocorticoids on CNS oxytocin receptor binding.

Oxytocin receptors in several regions of the limbic system are regulated by gonadal steroids and play an important role in the mediation of maternal, sexual and affiliative behaviors. We have previously reported oxytocin receptor regulation by glucocorticoids in hippocampus and subiculum-neuroanatomical regions implicated in memory and stress regulation. In the current study we examined oxytocin receptor regulation by stress and high glucocorticoid concentration in adrenally intact male rats. Single prolonged stress and chronic non-habituating stress were used as experimental conditions in the first study, and chronic non-habituating and high dose corticosterone implants in the second. Oxytocin receptor concentration was assessed using in vitro receptor autoradiography with [125I]OVTA at the approximate KD concentration. Both stress paradigms increased oxytocin receptor binding (F = 3.7, df = 2, p = .03) across brain regions in the first study. Chronic non-habituating stress and corticosterone implants increased oxytocin receptor binding in the ventral hippocampus only (one-way ANOVA, F = 3.88, df = 2, p < .05). The current studies demonstrate that stress increases oxytocin receptor binding in areas of the CNS that are rich in glucocorticoid receptors, such as hippocampus. This suggests differential regulation of oxytocin receptors in CNS, depending upon their functional role in different regions. Oxytocin receptor modulation could mediate some of the long-term effects of stress on memory, and possibly play a role in the regulation of hypothalamo-pituitary-adrenal stress response. The ability of circulating glucocorticoids to up-regulate these receptors suggests a plausible mechanism for this stress-sensitive regulation.

Stress-restress: effects on ACTH and fast feedback.

Glucocorticoid secretion is tightly regulated by negative feedback. Glucocorticoid feedback has been found to be altered in depression and post-traumatic stress disorder (PTSD). While hyposensitive glucocorticoid feedback has been found in depression, hypersensitive or enhanced negative feedback was described in PTSD. Enhanced negative feedback, can be seen as a sensitization of the inhibitory elements of HPA axis, and stress-restress or time dependent sensitization (TDS) model, has been suggested as an animal model for PTSD. We have studied the effects of this model on the HPA axis to determine whether it will produce increased sensitivity to negative feedback as found in PTSD patients. Adult Sprague-Dawley male rats were exposed to a single session of prolonged stress (restraint followed by a forced swim and exposure to ether vapors) and briefly restressed 7 days later. The effects of single prolonged stress on plasma ACTH and corticosterone responses (0, 5, and 30 min) and on glucocorticoid fast feedback (cortisol vs. saline pretreatment) were assessed in two studies. Animals exposed to single prolonged stress showed enhanced negative feedback in comparison to naive animals (F = 4.6371, df = 3, p = .0107), but there was no difference in ACTH or corticosterone responses during the restress. Pretreatment with cortisol, in the first stress session, did not prevent the development of the enhanced fast feedback when restressed. This can be seen as a sensitization of the inhibitory elements of HPA axis, suggesting that stress-restress paradigm might serve as a good animal model for HPA abnormalities found in PTSD patients.

Differential regulation of hippocampal glucocorticoid receptors mRNA and fast feedback: relevance to post-traumatic stress disorder.

Hippocampal glucocorticoid receptors (GR and MR) play an important role in glucocorticoid negative feedback. Abnormalities in negative feedback are found in depression and in post-traumatic stress disorder (PTSD), suggesting that GR and MR might be involved in the pathophysiology of these disorders. Enhanced negative feedback, the PTSD-specific neuroendocrine abnormality, can be induced in animals using a single prolonged stress (SPS) paradigm (a number of different stressors in one prolonged session, 'no stress' interval and a testing session one week later). In the current study, we examined hippocampal GR and MR mRNA distribution in the same animals that exhibited altered negative feedback following the SPS. Seven groups of adult Sprague-Dawley male rats (seven animals each) were used in two studies, comparing unstressed controls to acutely stressed animals (SPS: 24 h group), SPS animals (seven and 14 days), and SPS + chronic stress animals. GR and MR mRNA distribution across hippocampal subfields was studied using in-situ hybridization with 35S-labelled cRNA probes. Acute stress produced down-regulation of GR and MR mRNA across all hippocampal subfields. Seven days later (SPS-7 group), there was a differential recovery, with GR mRNA reaching higher than the prestress levels, and MR mRNA remaining down-regulated. The same differential regulation was present in the 14-day group. Chronically stressed animals that exhibited normal fast feedback also had normalization in their GR and MR mRNA levels. The MR/GR ratio was decreased only in animals that had enhanced fast feedback. These findings suggest that the increase in GR, in hippocampus is involved in the fast feedback hypersensitivity observed in the SPS animals, and might also underlie enhanced dexamethasone sensitivity found in PTSD. Since differential activation of GR and MR can modulate memory, behavioural responsivity, anxiety and fear, change in MR/GR ratio might also explain other PTSD-related phenomena.

Summary of a National Institute of Mental Health workshop: developing animal models of anxiety disorders.

RATIONALE: There exists a wide range of animal models and measures designed to assess anxiety or fearfulness. However, the relationship between these models and clinical anxiety symptoms and syndromes is unclear. The National Institute of Mental Health convened a workshop to discuss the relationship between existing behavioral models of anxiety and the clinical profile of anxiety disorders. A second goal of this workshop was to outline various approaches towards modeling components of anxiety disorders. OBJECTIVES: To briefly describe epidemiological and behavioral manifestations of clinical anxiety syndromes and how they relate to commonly employed animal models of anxiety. To describe approaches and considerations for developing, improving, and adapting anxiety models to better understand the neurobiology of anxiety. METHODS: Clinicians, psychiatrists and clinical and basic neuroscientists presented data exemplifying different approaches towards understanding anxiety and the role of animal models. Panel members outlined what they considered to be critical issues in developing and employing animal models of anxiety. RESULTS: This review summarizes the discussions and conclusions of the workshop including recommendations for improving upon existing models and strategies for developing novel models. CONCLUSIONS: The probability of developing comprehensive animal models that accurately reflect the relative influences of factors contributing to anxiety disorder syndromes is quite low. However, ample opportunity remains to better define and extend existing models and behavioral measures related to specific processes that may be disrupted in anxiety disorders and to develop new models that consider the impact of combined factors in determining anxious behaviors.

Attenuation of hypoxic ventilation by hyperbaric O2: effects of pressure and exposure time.

Hyperoxia affects O2 chemoreception in the highly perfused carotid bodies and causes a reduction of the ventilatory hypoxic drive (HD) as was shown for anesthetized cats and awake rats. We looked for a quantitative description of such an effect on HD as a function of both O2 pressure and exposure duration. Ventilation of rats was measured using the barometric method before and after hyperbaric O2 (HBO) exposure, at either air, 80% O2, or 4% O2. We used three exposure durations: 180, 550 and 900 min. The O2 pressure ranged between 1.2 and 3.0 ATA. At each time duration we used four to five groups of rats at a range of O2 pressures that yielded the full scale of effect on HD but avoided obvious lasting difficulties in breathing. HBO caused a reduction of breathing frequency and elevation of tidal volume in both air and 80% O2 but almost no change in minute ventilation. Hypoxic minute ventilation (4% O2) decreased after HBO, mainly through reduced frequency. HD was described by a power function of O2 pressure for each HBO duration. HD did not decline below 20% of the full control response. Ventilatory HD diminution is pictured as a function of both O2 pressure and HBO duration. The dependency of HD on exposure time and on pressure is similar to other known toxic effects of HBO.

Posttraumatic stress disorder and pregnancy complications.

OBJECTIVE: To assess the associations between specific pregnancy complications and posttraumatic stress disorder based on neurobiologic and behavioral characteristics, using Michigan Medicaid claims data from 1994-1996. METHODS: Two thousand, two hundred nineteen female recipients of Michigan Medicaid who were of childbearing age had posttraumatic stress disorder on the basis of International Classification of Diseases, 9th Revision (ICD-9) codes. Twenty percent (n = 455) of those recipients and 30% of randomly selected comparison women with no mental health diagnostic codes (n = 638; P <.001) had ICD-9 diagnostic codes for pregnancy complications. We used multiple logistic regression to investigate associations between specific pregnancy complications and posttraumatic stress disorder, controlling for demographic and psychosocial variables. Obstetric complications were hypothesized based on high-risk behaviors and neurobiologic alterations in stress axis function in posttraumatic stress disorder. RESULTS: After controlling for demographic and psychosocial factors, women with posttraumatic stress disorder had higher odds ratios (ORs) for ectopic pregnancy (OR 1.7, 95% confidence interval [CI] 1.1, 2.8), spontaneous abortion (OR 1.9, 95% CI 1.3, 2.9), hyperemesis (OR 3.9, 95% CI 2.0, 7.4), preterm contractions (OR 1.4, 95% CI 1.1, 1.9), and excessive fetal growth (OR 1.5, 95% CI 1.0, 2.2). Hypothesized labor differences were not confirmed and no differences were found for complications not thought to be related to traumatic stress. CONCLUSIONS: Pregnant women with posttraumatic stress disorder might be at higher risk for certain conditions, and assessment and treatment for undiagnosed posttraumatic stress might be warranted for women with those obstetric complications. Prospective studies are needed to confirm present findings and to determine potential biologic mechanisms. Treatment of traumatic stress symptoms might improve pregnancy morbidity and maternal mental health.

Medial frontal cortex involvement in PTSD symptoms: a SPECT study.

The regional cerebral blood flow (rCBF) responses to a combat stress-related auditory stimulus was examined in Vietnam veterans diagnosed with posttraumatic stress disorder (PTSD). Based on prior data in healthy subjects, we hypothesized that the medial prefrontal cortex may be involved in the processing of stress responses. Twelve male veterans diagnosed with PTSD, 11 age-matched, combat-exposed subjects without PTSD, and 12 healthy control subjects were studied with single-photon emission tomography and the blood flow tracer [99mTc]-HMPAO. Subjects were studied twice, while listening to combat sounds or white noise. Significant increases in the blood flow to the medial prefrontal cortex were observed in PTSD patients, but not in the control groups, which correlated at trend levels with psychophysical measures of stress response. These data support the involvement of the medial prefrontal cortex in the pathophysiology of PTSD, possibly mediating some of its symptoms.

Glucocorticoid regulation of hippocampal oxytocin receptor binding.

The effects of glucocorticoid hormones on oxytocin receptors in rat hippocampus were investigated. Oxytocin receptor autoradiography (using 0.1 and 1.2 nM concentrations of [125I]OVTA) revealed a significant (P < 0.02) decrease in oxytocin receptor binding in adrenalectomized animals 7 days after the surgery. Corticosterone replacement at the time of adrenalectomy prevented the decrease in oxytocin binding. The findings were significant in hippocampus and subiculum. These findings suggest regulation of oxytocin receptors, and possibly oxytocin-regulated behaviors by glucocorticoids.