Patterns of altered cortical perfusion and diminished subcortical integrity in posttraumatic stress disorder: an MRI study.

Posttraumatic stress disorder (PTSD) accounts for a substantial proportion of casualties among surviving soldiers of the Iraq and Afghanistan wars. Currently, the assessment of PTSD is based exclusively on symptoms, making it difficult to obtain an accurate diagnosis. This study aimed to find potential imaging markers for PTSD using structural, perfusion, and diffusion magnetic resonance imaging (MRI) together. Seventeen male veterans with PTSD (45 ± 14 years old) and 15 age-matched male veterans without PTSD had measurements of regional cerebral blood flow (rCBF) using arterial spin labeling (ASL) perfusion MRI. A slightly larger group had also measurements of white matter integrity using diffusion tensor imaging (DTI) with computations of regional fractional anisotropy (FA). The same subjects also had structural MRI of the hippocampal subfields as reported recently (W. Zhen et al. Arch Gen Psych 2010;67(3):296-303). On ASL-MRI, subjects with PTSD had increased rCBF in primarily right parietal and superior temporal cortices. On DTI, subjects with PTSD had FA reduction in white matter regions of the prefrontal lobe, including areas near the anterior cingulate cortex and prefrontal cortex as well as in the posterior angular gyrus. In conclusion, PTSD is associated with a systematic pattern of physiological and structural abnormalities in predominantly frontal lobe and limbic brain regions. Structural, perfusion, and diffusion MRI together may provide a signature for a PTSD marker.

Suppressed monocyte gene expression profile in men versus women with PTSD.

There have been several attempts to use gene microarrays from peripheral blood mononuclear cells to identify new biological pathways or targets for therapy in Posttraumatic Stress Disorder (PTSD). The few studies conducted to date have yielded an unclear pattern of findings, perhaps reflecting the use of heterogeneous samples of circulating immune cells for analysis. We used gene microarrays on a homogeneous sample of circulating monocytes to test the hypothesis that chronic PTSD would be associated with elevated inflammatory activity and to identify new pathways dysregulated in the disorder. Forty-nine men (24 PTSD+ and 25 age-matched trauma-exposed PTSD- controls) and 18 women (10 PTSD+ and 8 age-matched PTSD- controls) were recruited. Gene expression microarray analysis was performed on CD14+ monocytes, immune cells that initiate and respond to inflammatory signaling. Male subjects with PTSD had an overall pattern of under-expression of genes on monocytes (47 under-expressed versus 4 over-expressed genes). A rigorous correction for multiple comparisons and verification with qPCR showed that of only 3 genes that were differentially expressed, all were under-expressed. There was no transcriptional evidence of chronic inflammation in male PTSD+ subjects. In contrast, preliminary data from our pilot female PTSD+ subjects showed a relatively balanced pattern of increased and decreased expression of genes and an increase in activity of pathways related to immune activation. The results indicate differential patterns of monocyte gene expression in PTSD, and the preliminary data from our female pilot subjects are suggestive of gender dimorphism in biologic pathways activated in PTSD. Changes in immune cell gene expression may contribute to medical morbidity in PTSD.

Changes in brain anatomy during the course of posttraumatic stress disorder.

The goal of this study was to determine whether posttraumatic stress disorder (PTSD) was associated with an increase in time-related decline in macrostructural brain volume and whether these changes were associated with accelerated cognitive decline. To quantify brain structure, three-dimensional T1-weighted MRI scans were performed at baseline and again after a minimum of 24months in 25 patients with PTSD (PTSD+) and 22 controls (PTSD-). Longitudinal changes in brain volume were measured using deformation morphometry. For the group as a whole, PTSD+ patients did not show significant ongoing brain atrophy compared to PTSD-. PTSD+ patients were then subgrouped into those with decreasing or increasing symptoms. We found little evidence for brain markers of accelerated atrophy in PTSD+ veterans whose symptoms improved over time, with only a small left parietal region showing greater ongoing tissue loss than PTSD-. PTSD patients whose symptoms increased over time showed accelerated atrophy throughout the brain, particularly brainstem and frontal and temporal lobes. Lastly, for the sample as a whole, greater rates of brain atrophy were associated with greater rates of decline in verbal memory and delayed facial recognition.

Effects of metyrapone on hypothalamic-pituitary-adrenal axis and sleep in women with post-traumatic stress disorder.

BACKGROUND: Metyrapone blocks cortisol synthesis which results in removal of negative feedback, a stimulation of hypothalamic corticotropin releasing factor (CRF) and a reduction in delta sleep. We previously reported a diminished delta sleep and hypothalamic-pituitary-adrenal (HPA) response to metyrapone in men with post-traumatic stress disorder (PTSD). In this study, we aimed to extend these findings to women. METHODS: Three nights of polysomnography were obtained in 17 women with PTSD and 16 controls. On day 3, metyrapone was administered throughout the day up until bedtime. Plasma adrenocorticotropic hormone (ACTH), cortisol, and 11-deoxycortisol were obtained the morning following sleep recordings the day before and after metyrapone administration. RESULTS: There were no significant between-group differences in hormone concentration and delta sleep at baseline. Relative to controls, women with PTSD had decreased ACTH and delta sleep responses to metyrapone. Decline in delta sleep was associated with the magnitude of increase in ACTH across groups. CONCLUSIONS: Similar to our previous findings in men, the ACTH and sleep electroencephalogram response to metyrapone is attenuated in women with PTSD. These results are consistent with a model of downregulation of CRF receptors in an environment of chronically increased CRF activity or with enhanced negative feedback regulation in PTSD.

No improvement of posttraumatic stress disorder symptoms with guanfacine treatment.

OBJECTIVE: The authors report an 8-week, double-blind, randomized controlled trial of guanfacine versus placebo for posttraumatic stress disorder (PTSD). METHOD: Veterans with chronic PTSD who were medication-free or receiving stable pharmacotherapy were randomly assigned to guanfacine (N=29) versus placebo (N=34). RESULTS: Guanfacine had no effect on PTSD symptoms, subjective sleep quality, or general mood disturbances. Guanfacine was associated with a number of side effects. CONCLUSIONS: These results do not support the use of alpha 2 agonists in veterans with chronic PTSD.

Association between alexithymia and neuroendocrine response to psychological stress in police academy recruits.

Alexithymia has been associated with both posttraumatic stress disorder and neuroendocrine responses to stress. This study examined the relationship of alexithymia to salivary cortisol and 3-methoxy-4-hydroxy-phenylglycol (MHPG) in a sample of police academy recruits exposed to a video stress challenge. Alexithymia scores were negatively associated with catecholamine response to the video challenge but no association was found between alexithymia scores and cortisol reactivity.

Hypothalamic-pituitary-adrenal axis activity and sleep in posttraumatic stress disorder.

Alterations of the hypothalamic-pituitary-adrenal (HPA) axis and sleep disturbances have been described separately in post-traumatic stress disorder (PTSD). It is not known if HPA alterations and sleep disturbances are associated in PTSD. This study examined sleep and HPA activity in 20 male medication-free subjects with PTSD and 16 matched healthy controls. Two nights of polysomnography were obtained and 24-h urinary cortisol was collected during day 2. Subjects self-administered a low-dose (0.5 mg) salivary dexamethasone test at home. Compared with controls, PTSD subjects had higher 24-h urinary microg cortisol/g creatinine (mean+/-SD 40+/-17 vs 28+/-12, p=0.03) but not significantly higher 24-h urinary cortisol (mean+/-SD 52+/-15 microg/day vs 43+/-23, p=0.19). PTSD subjects showed a trend towards less cortisol suppression after dexamethasone (73%+/-18 vs 83%+/-10, p=0.06). In the combined sample, delta sleep was significantly and negatively correlated with 24-h urinary cortisol (r=-0.36, p=0.04), and with 24-h urinary cortisol/g creatinine on a trend level (r=-0.34, p=0.06). Our results suggest that increased cortisol is negatively associated with delta sleep. This may contribute to sleep abnormalities in conditions associated with elevated cortisol, possibly including PTSD. Future studies should explore the temporal relationship between HPA activity, sleep disturbances, and psychopathology after a traumatic event.

Temporal instability of auditory and visual event-related potentials in posttraumatic stress disorder.

BACKGROUND: We examined P300 measures in patients with posttraumatic stress disorder (PTSD) and control subjects at two different time points to determine event-related potential (ERP) stability over time and the relationship of changes in ERPs to changes in symptom levels. METHODS: Auditory and visual P300 was recorded in a three-condition novelty oddball task in 25 male subjects with combat-related PTSD and 15 male combat-exposed normal control subjects at two time points separated by 6-12 months. Regression analyses were conducted to compare the temporal stability of ERP measures in PTSD and control subjects. Variability in ERP measures over time within PTSD subjects was examined for association with changes in symptom levels. RESULTS: There were no significant differences in P300 amplitude or latency in PTSD versus control subjects at either time point, regardless of stimulus type (target, novel) or modality (auditory, visual). Nine of 24 P300 measures were significantly less predictable over time in the PTSD group compared to control subjects. Variability of P300 measures over time was not associated with fluctuations in symptoms of depression or PTSD. CONCLUSIONS: P300 ERPs are more variable cross-sectionally and over time in PTSD subjects compared to trauma exposed control subjects. Measures of variability about the group mean appear to be more informative about the cognitive electrophysiology of PTSD than measures of central tendency.

Effects of post-traumatic stress disorder on occipital lobe function and structure.

Although there is evidence for strong connectivity between the amygdala and the visual cortex and some evidence for reduced occipital lobe gray matter volume in patients with post-traumatic stress disorder (PTSD), few studies have directly examined the effects of PTSD on occipital function. The current study used functional and structural MRI to examine occipital cortex function and structure in male combat veterans with and without PTSD. Left occipital gray matter volume was reduced in PTSD patients relative to the controls and correlated negatively with the severity of PTSD symptoms. Functional activity in the lateral occipital complex to aversive and nonaversive pictures presented in novel and repeated presentations was not altered by PTSD. These findings suggest that PTSD adversely affects occipital lobe volume but not the reactivity of the lateral occipital complex to generally aversive, trauma nonspecific stimuli.

Transcriptional control of monocyte gene expression in post-traumatic stress disorder.

Post-traumatic stress disorder (PTSD) confers an increased risk for disorders with an inflammatory etiology. PTSD-related dysregulation of the sympathetic nervous system (SNS) and hypothalamic-pituitary adrenal (HPA) axis and associated alterations in inflammatory activity may contribute to this increased risk. However, little is known about convergent SNS, HPA and inflammatory signaling at the level of the immune cell transcriptome in PTSD. To explore such signaling, we examined the prevalence of specific transcription factor binding motifs in the promoter regions of differentially expressed genes in monocytes from individuals with PTSD and matched controls. Participants included 49 men (24 PTSD+ and 25 trauma-exposed controls) and 18 women (10 PTSD+ and 8 controls). Men with PTSD showed up-regulation of target genes for the NF-κB/Rel family of transcription factors, which convey inflammatory signals, up-regulation of target genes for CREB/ATF transcription factors, which convey adrenergic signals from the SNS, and down-regulation of target genes for the glucocorticoid receptor, which conveys glucocorticoid signals from the HPA axis. Women with PTSD also showed significant up-regulation of target genes for NF-κB and non-significant down-regulation of target genes for GR, but significant down-regulation of target genes for CREB/ATF. Altered transcriptional control of monocyte gene expression could contribute to exaggerated inflammatory activity in PTSD.

Childhood trauma associated with short leukocyte telomere length in posttraumatic stress disorder.

BACKGROUND: Posttraumatic stress disorder (PTSD) is associated with increased risk for age-related diseases and early mortality. An accelerated rate of biological aging could contribute to this increased risk. To investigate, we assessed leukocyte telomere length (LTL), an emerging marker of biological age, in men and women with and without PTSD. We also examined childhood trauma, a risk factor for both PTSD and short LTL, as a potential contributor to short LTL in PTSD. METHODS: Participants included 43 adults with chronic PTSD (n = 18 with multiple categories of childhood trauma) and 47 control subjects (none with multiple categories of childhood trauma) (mean age = 30.55, SD = 7.44). Exclusion criteria included physical illness, medication use, obesity, alcohol or substance abuse, and pregnancy. Structured clinical interviews were conducted to assess PTSD and other psychiatric disorders and childhood trauma exposure. LTL was measured with a quantitative polymerase chain reaction method. RESULTS: As predicted, participants with PTSD had shorter age-adjusted LTL than control subjects. Exposure to childhood trauma was also associated with short LTL. In fact, childhood trauma seemed to account for the PTSD group difference in LTL; only participants with PTSD and exposure to multiple categories of childhood trauma had significantly shorter LTL than control subjects. CONCLUSIONS: Childhood trauma is associated with short LTL in individuals with PTSD. Chronic exposure to the psychobiological sequelae of childhood trauma could increase risk for PTSD and short LTL. Thus, the lasting psychological impact of exposure to trauma in childhood might be accompanied by equally enduring changes at the molecular level.

Magnetic resonance imaging of hippocampal subfields in posttraumatic stress disorder.

CONTEXT: Most neuroimaging studies of posttraumatic stress disorder (PTSD) have focused on potential abnormalities in the whole hippocampus, but the subfields of this structure, which have distinctive histological characteristics and specialized functions, have not been investigated. Studies of individual subfields may clarify the role of the hippocampus in PTSD. OBJECTIVE: To determine if PTSD is associated with structural alterations in specific subfields of the hippocampus. DESIGN: Case-control study. PARTICIPANTS: A total of 17 male veterans with combat trauma and PTSD (mean [SD] age, 41 [12] years) and 19 age-matched male veterans without PTSD who were recruited from the outpatient mental health clinic of the San Francisco Veterans Affairs Medical Center and by advertising in the community. INTERVENTIONS: High-resolution magnetic resonance imaging at 4 T. MAIN OUTCOME MEASURE: Volumes of hippocampal subfields. RESULTS: Posttraumatic stress disorder was associated with 11.4% (1.5%) (P = .02) smaller mean (SD) cornu ammonis 3 (CA3)/dentate gyrus subfield volumes, irrespective of age-related alterations, whereas other subfields were spared. Age was associated with reduced volume of the CA1 subfield (P = .03). Total hippocampal volume was also reduced in PTSD by a mean (SD) of 6.5% (0.6%) but, related to both PTSD (P = .05) and age (P = .01), was consistent with the measurements in the subfields. CONCLUSIONS: The findings indicate for the first time in humans that PTSD is associated with selective volume loss of the CA3/dentate gyrus subfields, consistent with animal studies, implying that chronic stress suppresses neurogenesis and dendritic branching in these structures.

Adaptation effects to sleep studies in participants with and without chronic posttraumatic stress disorder.

The "first night effect" (FNE) is the alteration of sleep architecture observed on the first night of polysomnographic (PSG) studies. It is unclear whether the FNE reflects adaptation to the equipment, sleeping environment, or both. Moreover, it is possible that certain patient populations, such as those with posttraumatic stress disorder (PTSD), demonstrate greater adaptation effects that are highly context dependent. We assessed FNE in participants with PTSD and healthy controls in a cross-sectional study consisting of PSG testing at home and in the hospital. Contrary to our expectations, the PTSD group showed no adaptation effects in either setting. Only the control group assigned to the "hospital first" condition showed significant decreases in total sleep time on night 1 versus night 2 of the study. The results suggest that the FNE is related to adaptation to the combination of the hospital environment and the recording equipment.

Prior night sleep duration is associated with psychomotor vigilance in a healthy sample of police academy recruits.

Aviation, military, police, and health care personnel have been particularly interested in the operational impact of sleep restriction and work schedules given the potential severe consequences of making fatigue-related errors. Most studies examining the impact of sleep loss or circadian manipulations have been conducted in controlled laboratory settings using small sample sizes. This study examined whether the relationship between prior night sleep duration and performance on the psychomotor vigilance task could be reliably detected in a field study of healthy police academy recruits. Subjects (N = 189) were medically and psychiatrically healthy. Sleep-wake activity was assessed with wrist actigraphy for 7 days. Subjects performed the psychomotor vigilance task (PVT) for 5 min on a personal digital assistant (PDA) device before and after their police academy workday and on comparable times during their days off. Mixed-effects logistic regression was used to estimate the probability of having > or =1 lapse on the PVT as a function of the previous night sleep duration during the 7 days of field testing. Valid estimates of sleep duration were obtained for 1082 nights of sleep. The probability of a lapse decreased by 3.5%/h sleep the night prior to testing. The overall probability of having a lapse decreased by 0.9%/h since awakening, holding hours of sleep constant. Perceived stress was not associated with sleep duration or probability of performance lapse. These findings demonstrate the feasibility of detecting sleep and circadian effects on cognitive performance in large field studies. These findings have implications regarding the daytime functioning of police officers.

Insomnia severity is associated with a decreased volume of the CA3/dentate gyrus hippocampal subfield.

BACKGROUND: Prolonged disruption of sleep in animal studies is associated with decreased neurogenesis in the dentate gyrus. Our objective was to determine whether insomnia severity in a sample of posttraumatic stress disorder (PTSD) patients and control subjects was associated with decreased volume in the CA3/dentate hippocampal subfield. METHODS: Volumes of hippocampal subfields in 17 veteran men positive for PTSD (41 +/- 12 years) and 19 age-matched male veterans negative for PTSD were measured with 4-T magnetic resonance imaging. Subjective sleep quality was measured by the Insomnia Severity Index (ISI) and the Pittsburgh Sleep Quality Index. RESULTS: Higher scores on the ISI, indicating worse insomnia, were associated with smaller volumes of the CA3/dentate subfields (r = -.48, p < .01) in the combined sample. Adding the ISI score as a predictor for CA3/dentate volume to a hierarchical linear regression model after first controlling for age and PTSD symptoms accounted for a 13% increase in incremental variance (t = -2.47, p = .02). CONCLUSIONS: The findings indicate for the first time in humans that insomnia severity is associated with volume loss of the CA3/dentate subfields. This is consistent with animal studies showing that chronic sleep disruption is associated with decreased neurogenesis and dendritic branching in these structures.

Serum brain-derived neurotrophic factor predicts responses to escitalopram in chronic posttraumatic stress disorder.

INTRODUCTION: Some studies have found that antidepressants increase serum brain-derived neurotrophic factor (BDNF) levels in patients with major depression and the expression of BDNF mRNA in limbic structures of rats. OBJECTIVES: This study addressed whether the SSRI escitalopram increases serum BDNF levels in subjects with PTSD and whether BDNF levels are associated with treatment response. METHODS: Medically healthy male subjects (N=16) with chronic PTSD completed a 12 week open-label trial of flexible dose (5-20 mg/day) escitalopram monotherapy. BDNF levels were obtained at baseline, and at weeks 4, 8 and 12. RESULTS: PTSD symptoms significantly declined over the course of the 12 week escitalopram treatment. Despite a substantial improvement in PTSD symptoms, there was virtually no change in BDNF levels over time. Nevertheless, mean BDNF levels across the trial were strongly correlated with the slope of PTSD symptoms over the 12 weeks (r=0.58, p=0.018). Lower mean BDNF was associated with a greater decrease in PTSD symptoms over the course of the trial. CONCLUSIONS: PTSD subjects with low BDNF levels demonstrated the largest treatment response from an agent with putative neurotrophic effects.