Unsupervised fuzzy clustering analysis supports behavioral cutoff criteria in an animal model of posttraumatic stress disorder.

BACKGROUND: Unsupervised fuzzy clustering (UFC) analysis is a mathematical technique that groups together objects in the multidimensional feature space according to a specified similarity measurement, thereby yielding clusters of similar data points that can be represented by a set of prototypes or centroids. METHODS: Since clinical studies of mental disorders distinguish between affected and unaffected individuals, we designed an inclusion/exclusion criteria (cutoff behavioral criteria [CBC]) approach for animal behavioral studies. The effect of classifying the study population into clearly affected versus clearly unaffected individuals according to behaviors on two behavioral paradigms was statistically significant. RESULTS: Here the raw data from previous studies were subjected to UFC algorithms as a means of objectively testing the validity of the concept of the CBC for our experimental model. The first UFC algorithm yielded two clearly discrete clusters, found to consist almost exclusively of the exposed animals in the one and unexposed animals in the other. The second algorithm yielded three clusters corresponding to animals designated as clearly affected, partially affected, and clearly unaffected. The algorithm for physiological data in addition to behavioral data failed to elicit discrete clusters. CONCLUSIONS: The UFC analysis yielded data that support the conceptual contention of the CBC and lends additional validity to our previous behavioral studies.     

Single prolonged stress: toward an animal model of posttraumatic stress disorder

Although selective serotonin reuptake inhibitors (SSRIs) are reported to be effective in decreasing posttraumatic stress disorder (PTSD) symptoms, a subgroup of PTSD patients remain chronically symptomatic and maintain conditioned fear responses to traumatic stimuli. In this context, the establishment of an appropriate animal model of PTSD is necessary to promote better understanding of the mechanisms of the disorder and to facilitate the development of more effective therapeutic alternatives to SSRIs. Although no single widely accepted animal model of PTSD has been established to date, the single prolonged stress (SPS) animal model has been partially validated as a model for PTSD. SPS rats mimic the pathophysiological abnormalities and behavioral characteristics of PTSD, such as enhanced anxiety‐like behavior and glucocorticoid negative feedback, and they exhibit the expected therapeutic response to paroxetine on enhanced fear memory. In addition, SPS rats exhibit enhanced freezing in response to contextual fear conditioning, and impaired extinction of fear memory, which is alleviated by D ‐cycloserine. The enhanced consolidation and impaired extinction of fear memory found in SPS rats suggests that this model has additional value because recent studies of PTSD indicate that memory abnormalities are a central feature. In this study, we summarize the behavioral and pathophysiological PTSD‐like symptoms in SPS, focusing on memory abnormalities, and evaluate the validity of SPS as an animal model of PTSD. Depression and Anxiety, 2009. © 2009 Wiley‐Liss, Inc.     

Social trauma and its association with posttraumatic stress disorder and social anxiety disorder

The key characteristic of a traumatic event as defined by the Diagnostic and Mental Manual of Mental Disorders (DSM) seems to be a threat to life. However, evidence suggests that other types of threats may play a role in the development of PTSD and other disorders such as social anxiety disorder (SAD). One such threat is social trauma, which involves humiliation and rejection in social situations. In this study, we explored whether there were differences in the frequency, type and severity of social trauma endured by individuals with a primary diagnosis of SAD (n = 60) compared to a clinical control group of individuals with a primary diagnosis of obsessive compulsive disorder (OCD, n = 19) and a control group of individuals with no psychiatric disorders (n = 60). The results showed that most participants in this study had experienced social trauma. There were no clear differences in the types of experiences between the groups. However, one third of participants in the SAD group (but none in the other groups) met criteria for PTSD or suffered from clinically significant PTSD symptoms in response to their most significant social trauma. This group of SAD patients described more severe social trauma than other participants. This line of research could have implications for theoretical models of both PTSD and SAD, and for the treatment of individuals with SAD suffering from PTSD after social trauma.     

Cortisol response to acute trauma and risk of posttraumatic stress disorder

This study sought to characterize the variability of the acute cortisol response following trauma and its relationship to posttraumatic stress disorder (PTSD). Forty eight participants were recruited within 24h of a traumatic accident requiring hospital admission. A saliva sample was collected at 08.00 h and 16.00 h 2 days, 1 month and 6 months after hospital admission, together with 24-h urine collection. Participants completed a dexamethasone suppression test (0.5mg DEX at 21.00 h) at each follow up, together with self-report questionnaires. The Clinician Administered PTSD Scale (CAPS) was administered at 1 and 6 months to identify PTSD. Prevalence of PTSD was 27% at 1 month and 21% at 6 months. PTSD symptoms at 6 months were negatively correlated with salivary cortisol at 08.00 h on day 2 (r=-0.36, p=0.04), but positively correlated with 16.00 h cortisols (r=0.41, p=0.03). A lower rise in cortisol at 08.00 h on day 2 was associated with an increase in risk of PTSD at both 1 month (OR=1.411 (1.017, 1.957)) and 6 months (OR=1.411 (1.066, 1.866)). At 1 month, 70% of participants with PTSD suppressed cortisol to more than 90% of pre-dex levels compared with 25% without PTSD (χ(2)=6.77, p=0.034). Urinary cortisol excretion was not different between groups at any time point. The findings support a hypothesis that sensitization of the HPA axis and enhanced suppression of cortisol following the dexamethasone suppression test are established early in the disease process.     

Blunted HPA axis response to stress influences susceptibility to posttraumatic stress response in rats.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with low levels of circulating cortisol, and recent studies suggest that cortisol administration may reduce PTSD symptoms. This study investigated the role of cortisol in the manifestation of anxiety- and fear-like symptoms in an animal model of PTSD. METHOD: Magnitude of changes in prevalence of anxiety-like behaviors on the elevated plus-maze and nonhabituated exaggerated startle reaction were compared in three strains of rats exposed to predator stress, with and without prior corticosterone treatment. Extreme behavioral changes in both paradigms implied an extreme behavioral response (EBR), representing PTSD-like symptoms. RESULTS: Lewis rats exhibited greater baseline anxiety-like behaviors and greater stress-induced increases in anxiety-like behaviors than Fischer F344 or Sprague-Dawley rats, with only minor corticosterone increases following stress. Prevalence of EBR was 50% among Lewis rats compared with 10% of Fischer F344 and 25% of Sprague-Dawley rats. Administering corticosterone 1 hour before stress exposure reduced the prevalence of EBR from 50% to 8% in the Lewis rats. CONCLUSIONS: These results suggest that a blunted HPA response to stress may play a causal role in this model of PTSD and that this susceptibility may be prevented by administration of cortisol before stress exposure.     

Alterations in the hippocampal glycinergic system in an animal model of posttraumatic stress disorder

Previous studies have demonstrated that rats subjected to single prolonged stress (SPS) exhibit posttraumatic stress disorder (PTSD)-like symptoms, such as enhanced contextual fear in response to trauma-related and trauma-unrelated events. Furthermore, we previously reported that upregulation of hippocampal glycine transporter 1 (GlyT-1) mRNA after context exposure could be the initial mechanism underlying impaired fear extinction in SPS rats. To clarify the involvement of the hippocampal glycinergic system in impaired fear extinction in SPS rats, we measured the time course of changes in the duration of freezing and the hippocampal levels of Gly-T1 mRNA using contextual fear conditioning (FC) and extinction training. We also used in vivo microdialysis to measure the concentration of extracellular glycine in the hippocampus during the time interval between FC and the first context exposure. SPS rats exhibited increased and sustained contextual fear responses. The enhanced contextual fear response in SPS rats was associated with a sustained increase in hippocampal levels of Gly-T1 mRNA after FC relative to sham rats, and by a decrease in the extracellular glycine concentration. GlyT-1 mRNA levels in rats that underwent repeated extinction training were significantly lower than in rats that did not undergo extinction training. These findings indicate that reduced activity of the hippocampal glycinergic system could be closely involved in impaired fear extinction in SPS rats, suggesting that activation of the glycinergic system by d-cycloserine or GlyT-1 inhibitors may ameliorate the impairment of fear extinction.     

Altered cortisol awakening response in posttraumatic stress disorder

An altered function of the hypothalamic-pituitary-adrenal axis is assumed to be characteristic for Posttraumatic Stress Disorder (PTSD), although there is inconsistent empirical evidence. Only few studies examined the awakening cortisol response and a daytime profile in PTSD. Salivary cortisol levels were measured at seven intervals from awakening until 8 PM in trauma-exposed subjects with (N=29) and without PTSD (N=19) and in 15 non-exposed controls. While the three groups did not differ with respect to their first cortisol level immediately after awakening, the expected cortisol increase to awakening 15-60 min later was significantly lower in PTSD patients compared to non-PTSD subjects and healthy controls. This effect remained stable when trauma-exposed subjects with comorbid major depression were excluded from the analysis. A significant negative correlation between the overall cortisol secretion (AUC(G)) and overall PTSD symptomatology and hyper-arousal symptoms was found. The findings are discussed in light of the hypothesis of a counterregulation of hyper-arousal symptoms and chronic stress in PTSD.     

Cerebellar volumes in pediatric maltreatment-related posttraumatic stress disorder.

BACKGROUND: The results of previous studies suggest structural brain differences in pediatric maltreatment-related posttraumatic stress disorder (PTSD) However, posterior fossa volumes were not examined, despite the consensus that the cerebellum is important in emotional and cognitive development. We investigated the relationship between structural volumes of the cerebellum hemispheres, vermis, brainstem, and clinical variables in pediatric maltreatment-related PTSD. METHODS: Fifty-eight psychotropic-na?ve maltreated children and adolescents with DSM-IV PTSD were compared with two groups of pediatric subjects who had no DSM-IV criteria A trauma histories: 1) 13 with pediatric generalized anxiety disorder, and 2) 98 healthy non-abused children and adolescents. Subjects underwent a comprehensive psychiatric assessment and an anatomical magnetic resonance image brain scan. RESULTS: Unadjusted means of the left, right, and total cerebellum were smaller in the PTSD group. The group differences remained significant in the left cerebellum, right cerebellum, and total cerebellum in the analyses adjusted for cerebral volume, sociodemographic, and IQ variables. Cerebellar volumes positively correlated with age of onset of the trauma that lead to PTSD and negatively correlated with the duration of the trauma that lead to PTSD. Cerebellar volumes were larger in boys versus girls, but there was no group x gender interaction. There were significant positive correlations between IQ measures and volumetric variables. CONCLUSIONS: The results support cerebellar volume differences in maltreated children and adolescents with PTSD. Further studies are warranted.     

Daytime prazosin reduces psychological distress to trauma specific cues in civilian trauma posttraumatic stress disorder.

BACKGROUND: Persons with posttraumatic stress disorder (PTSD) whose trauma-related nightmares improve or resolve with bedtime administration of the alpha-1 adrenergic antagonist prazosin often continue to experience PTSD symptoms during the day. This study addressed whether daytime prazosin compared to placebo would alleviate psychological distress provoked experimentally by a trauma-related word list included in the emotional Stroop (E-Stroop) paradigm. METHODS: Eleven persons with civilian trauma PTSD who continued to experience daytime PTSD symptoms despite a stable bedtime prazosin dose that suppressed trauma-related nightmares were studied. Prazosin and placebo were administered on two different occasions in the early afternoon followed two hours later by the E-Stroop. Effects of drug on psychological distress were assessed by the Profile of Mood States (POMS). RESULTS: POMS total score and an "emotional distress" POMS subscale score following trauma-related words were significantly lower in the prazosin than placebo condition. There were no treatment effects on E-Stroop completion time. In 10 subjects who continued open label daytime prazosin, there was a reduction in global PTSD illness severity at 2-week follow-up. CONCLUSIONS: Daytime prazosin pretreatment reduced psychological distress specifically to trauma cues. Adding daytime prazosin to bedtime prazosin may further reduce overall PTSD illness severity and distress.     

Blunted ACTH response to dexamethasone suppression-CRH stimulation in posttraumatic stress disorder

Previous studies have suggested that patients with posttraumatic stress disorder (PTSD) have an enhanced negative feedback sensitivity of the hypothalamic-pituitary-adrenal (HPA) system and a blunted ACTH response to corticotropin releasing hormone (CRH). The effects of two dexamethasone dosages (0.75 and 1.5 mg) on the ACTH and cortisol concentrations after CRH stimulation (100 μg) were studied in eight patients with PTSD and matched healthy control subjects. Compared to healthy subjects, patients with PTSD have a blunted ACTH response to CRH. Cortisol concentrations were only significantly influenced by dexamethasone dosage. Our results give further evidence for a central role of the pituitary in reflecting changes of the negative feedback sensitivity of the HPA system in patients with PTSD.     

Pituitary volumes in pediatric maltreatment-related posttraumatic stress disorder.

BACKGROUND: Previous findings suggest that corticotrophin-releasing hormone (CRH) is elevated in adults with posttraumatic stress disorder (PTSD), maltreated children, and children with maltreatment-related PTSD. METHODS: Magnetic resonance imaging was used to measure pituitary volumes in 61 medication-na?ve maltreated subjects with PTSD (31 male and 30 female subjects) and 121 nontraumatized healthy comparison subjects (62 male and 59 female subjects). RESULTS: Overall, no differences were seen between PTSD and control subjects in pituitary volumes. There was a significant age-by-group effect for PTSD subjects to have greater differences in pituitary volume with age than control subjects. Post hoc analyses revealed that pituitary volumes were significantly larger in pubertal and postpubertal maltreated subjects with PTSD than control subjects but were similar in prepubertal maltreated subjects with PTSD and control subjects. Pituitary volumes were larger in the PTSD subjects with history of suicidal ideation. CONCLUSIONS: These findings may suggest developmental alterations in pituitary volume in maltreatment-related pediatric PTSD. This finding may be associated with stress-related differences in CRH and may be more pronounced in pediatric patients with PTSD comorbid with suicidal ideation.     

Immediate treatment with propranolol decreases posttraumatic stress disorder two months after trauma.

BACKGROUND: This study investigated the efficacy of propranolol prescribed shortly after trauma exposure in the prevention of posttraumatic stress disorder (PTSD) symptoms and diagnosis. METHODS: Eleven patients received 40 mg of propranolol 3 times daily for 7 days, followed by a taper period of 8-12 days. They were compared with eight patients who refused propranolol but agreed to participate in the study. Though nonrandomized, the two groups did not differ on demographics, exposure characteristics, physical injury severity, or peritraumatic emotional responses. RESULTS: Posttraumatic stress disorder rates were higher in the group who refused propranolol (3/8) compared with those who received the medication (1/11), as were the levels of PTSD symptoms (U = 85, p =.037). CONCLUSIONS: Our results are consistent with earlier findings and suggest that propranolol may be useful for mitigating PTSD symptoms or perhaps even preventing the development of PTSD.     

Comorbidity of borderline personality disorder and posttraumatic stress disorder in the U.S. population

While placed on different axes of the DSM classification system, borderline personality disorder (BPD) and posttraumatic stress disorder (PTSD) have important relationships with trauma, and overlap between these disorders has long been recognized. The current study is the first to examine comorbidity of PTSD and BPD in a large nationally representative sample using a reliable and valid method of assessing Axis I and II mental disorders. Data came from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) Wave II (N = 34,653; response rate 70.2%). Multiple regression models were used to examine differences in psychopathology, traumatic events and health-related quality of life across individuals with PTSD alone (n = 1820), BPD alone (n = 1290) and those with comorbid PTSD–BPD (n = 643). The lifetime prevalence of PTSD and BPD were 6.6% and 5.9%, respectively. Of individuals with BPD, 30.2% were also diagnosed with PTSD, whereas 24.2% of individuals with PTSD were also diagnosed with BPD. Individuals with comorbid PTSD–BPD had a poorer quality of life, more comorbidity with other Axis I conditions, increased odds of a lifetime suicide attempt, and a higher prevalence of repeated childhood traumatic events than individuals with either condition alone. These results show that PTSD and BPD have a high degree of lifetime co-occurrence but are not entirely overlapping. Their concurrence is associated with poorer functioning compared to either diagnosis alone, emphasizing the clinical utility of diagnosing both conditions. Future research should explore the determinants of having either or both diagnoses with an aim toward improved identification, prevention, and intervention.     

Women's posttraumatic stress symptoms and autism spectrum disorder in their children

Maternal posttraumatic stress disorder (PTSD) may be associated with autism spectrum disorder (ASD) in offspring through multiple pathways: maternal stress may affect the fetus; ASD in children may increase risk of PTSD in mothers; and the two disorders may share genetic risk. Understanding whether maternal PTSD is associated with child's ASD is important for clinicians treating children with ASD, as PTSD in parents is associated with poorer family functioning. We examined the association of maternal PTSD with offspring ASD in a large US cohort (N ASD cases = 413, N controls = 42,868). Mother's PTSD symptoms were strongly associated with child's ASD (RR 4–5 PTSD symptoms = 1.98, 95% CI = 1.39, 2.81; RR 6–7 symptoms = 2.89, 95% CI = 2.00, 4.18). Clinicians treating persons with ASD should be aware of elevated risk of PTSD in the mother. Genetic studies should investigate PTSD risk alleles in relation to ASD.     

Neural correlates of the classic color and emotional stroop in women with abuse-related posttraumatic stress disorder.

BACKGROUND: The anterior cingulate and medial prefrontal cortex play an important role in the inhibition of responses, as measured by the Stroop task, as well as in emotional regulation. Dysfunction of the anterior cingulate/medial prefrontal cortex has been implicated in posttraumatic stress disorder (PTSD). The purpose of this study was to use the Stroop task as a probe of anterior cingulate function in PTSD. METHODS: Women with early childhood sexual abuse-related PTSD (n = 12) and women with abuse but without PTSD (n = 9) underwent positron emission tomographic measurement of cerebral blood flow during exposure to control, color Stroop, and emotional Stroop conditions. RESULTS: Women with abuse with PTSD (but not abused non-PTSD women) had a relative decrease in anterior cingulate blood flow during exposure to the emotional (but not color) classic Stroop task. During the color Stroop there were also relatively greater increases in blood flow in non-PTSD compared with PTSD women in right visual association cortex, cuneus, and right inferior parietal lobule. CONCLUSIONS: These findings add further evidence for dysfunction of a network of brain regions, including anterior cingulate and visual and parietal cortex, in abuse-related PTSD.     

Variation in SLC1A1 is related to combat-related posttraumatic stress disorder

Candidate gene studies have yet to investigate the glutamate system, the primary excitatory neurotransmitter of the HPA-axis related to PTSD risk. We investigated 13 SNPs in the glutamate transporter gene (SLC1A1) in relation to PTSD among combat-exposed veterans. Participants (n = 418) completed a diagnostic interview and provided a blood sample for DNA isolation and genotyping. A subset of participants (n = 391) had severity and combat exposure data available. In the primary logistic regression gender and rs10739062 were significant predictors of PTSD diagnosis (OR = 0.50; OR = 1.43). In the linear regression analysis, combat exposure was the only significant predictor (β = 0.16) of severity. A computed genetic risk sum score was significant in relation to PTSD diagnosis (OR = 1.15) and severity scores (β = 0.14) above and beyond the effects of combat exposure. This study provides preliminary support for the relationship of glutamate transporter polymorphisms to PTSD risk and the need for further genetic studies within this system.     

Adjustment to trauma exposure: prevalence and predictors of posttraumatic stress disorder symptoms in mountain guides

OBJECTIVE: The present study was designed to assess the frequency of trauma exposure, the prevalence rates of posttraumatic stress disorder, comorbid symptoms, and sense of coherence (SOC) in Swiss mountain guides. METHOD: All mountain guides (n=1347) were surveyed using of the Posttraumatic Stress Diagnostic Scale (PDS), the General Health Questionnaire (GHQ-28), and the Sense of Coherence Self-Rating Scale (SOC-29). RESULTS: Although Swiss mountain guides are exposed to many traumatic situations, the prevalence rate of PTSD is very low (2.7%), and their SOC total scores are high (157.9+/-18.4). Subgroups differentiated by the extent of traumatic stress symptoms differ significantly in SOC and GHQ total scores. Regression analysis showed SOC total score to be a significant predictor, although it only accounted for 1% of the variance in the number of PTSD symptoms endorsed. CONCLUSION: The low prevalence rate of PTSD is not in line with findings in other high-risk populations for PTSD. SOC seems to be a marker for psychological health rather than a protective factor against PTSD.     

Dissociative subtype of DSM-5 posttraumatic stress disorder in U.S. veterans

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) formally introduced a dissociative subtype of posttraumatic stress disorder (PTSD). This study examined the proportion of U.S. veterans with DSM-5 PTSD that report dissociative symptoms; and compared veterans with PTSD with and without the dissociative subtype and trauma-exposed controls on sociodemographics, clinical characteristics, and quality of life. Multivariable analyses were conducted on a nationally representative sample of 1484 veterans from the National Health and Resilience in Veterans Study (second baseline survey conducted September–October, 2013). Of the 12.0% and 5.2% of veterans who screened positive for lifetime and past-month DSM-5 PTSD, 19.2% and 16.1% screened positive for the dissociative subtype, respectively. Among veterans with PTSD, those with the dissociative subtype reported more severe PTSD symptoms, comorbid depressive and anxiety symptoms, alcohol use problems, and hostility than those without the dissociative subtype. Adjusting for PTSD symptom severity, those with the dissociative subtype continued to report more depression and alcohol use problems. These results underscore the importance of assessing, monitoring, and treating the considerable proportion of veterans with PTSD and dissociative symptoms.     

Self-mutilative behaviors in male veterans with posttraumatic stress disorder

Self-mutilative behaviors (SMB) were examined in a sample of male veterans with posttraumatic stress disorder (PTSD). The primary objective was to determine the prevalence of SMB and any physical, cognitive, or affective antecedents and correlates for these behaviors. Participants included 509 male veterans with PTSD and levels of PTSD, depression, alcohol use, hostility, and impulsivity were evaluated to determine if these variables were related to SMB. Antecedents and sequelae of SMB were also examined to generate hypotheses regarding the functions of these behaviors. A second type of habit behavior, body-focused repetitive behaviors (BFRB), was also examined as part of the study. Findings indicated that veterans who engaged in either type of habit behavior were younger than those who did not engage in SMB or BFRB. Veterans reporting SMB also reported higher levels of PTSD, depression, hostility, and impulsivity compared to the BFRB and no-habit groups. Examination of habit antecedents and sequelae showed support for the automatic-positive reinforcement function of SMB. These findings are discussed in the context of research and treatment involving male veterans with PTSD who engage in SMB.