The hypocretin/orexin antagonist almorexant promotes sleep without impairment of performance in rats.

The hypocretin receptor (HcrtR) antagonist almorexant (ALM) has potent hypnotic actions but little is known about neurocognitive performance in the presence of ALM. HcrtR antagonists are hypothesized to induce sleep by disfacilitation of wake-promoting systems whereas GABAA receptor modulators such as zolpidem (ZOL) induce sleep through general inhibition of neural activity. To test the hypothesis that less functional impairment results from HcrtR antagonist-induced sleep, we evaluated the performance of rats in the Morris Water Maze in the presence of ALM vs. ZOL. Performance in spatial reference memory (SRM) and spatial working memory (SWM) tasks were assessed during the dark period after equipotent sleep-promoting doses (100 mg/kg, po) following undisturbed and sleep deprivation (SD) conditions. ALM-treated rats were indistinguishable from vehicle (VEH)-treated rats for all SRM performance measures (distance traveled, latency to enter, time within, and number of entries into, the target quadrant) after both the undisturbed and 6 h SD conditions. In contrast, rats administered ZOL showed impairments in all parameters measured compared to VEH or ALM in the undisturbed conditions. Following SD, ZOL-treated rats also showed impairments in all measures. ALM-treated rats were similar to VEH-treated rats for all SWM measures (velocity, time to locate the platform and success rate at finding the platform within 60 s) after both the undisturbed and SD conditions. In contrast, ZOL-treated rats showed impairments in velocity and in the time to locate the platform. Importantly, ZOL rats only completed the task 23-50% of the time while ALM and VEH rats completed the task 79-100% of the time. Thus, following equipotent sleep-promoting doses, ZOL impaired rats in both memory tasks while ALM rats performed at levels comparable to VEH rats. These results are consistent with the hypothesis that less impairment results from HcrtR antagonism than from GABAA-induced inhibition

Preliminary Evidence of Increased Hippocampal Myelin Content in Veterans with Posttraumatic Stress Disorder.

Recent findings suggest the formation of myelin in the central nervous system by oligodendrocytes is a continuous process that can be modified with experience. For example, a recent study showed that immobilization stress increased oligodendrogensis in the dentate gyrus of adult rat hippocampus. Because changes in myelination represents an adaptive form of brain plasticity that has a greater reach in the adult brain than other forms of plasticity (e.g., neurogenesis), the objective of this "proof of concept" study was to examine whether there are differences in myelination in the hippocampi of humans with and without post-traumatic stress disorder (PTSD). We used the ratio of T1-weighted/T2-weighted magnetic resonance image (MRI) intensity to estimate the degree of hippocampal myelination in 19 male veterans with PTSD and 19 matched trauma-exposed male veterans without PTSD (mean age: 43 ± 12 years). We found that veterans with PTSD had significantly more hippocampal myelin than trauma-exposed controls. There was also found a positive correlation between estimates of hippocampal myelination and PTSD and depressive symptom severity. To our knowledge, this is the first study to examine hippocampal myelination in humans with PTSD. These results provide preliminary evidence for stress-induced hippocampal myelin formation as a potential mechanism underlying the brain abnormalities associated with vulnerability to stress

Prospective Prediction of Posttraumatic Stress Disorder Symptoms Using Fear Potentiated Auditory Startle Responses

Background: Posttraumatic stress disorder (PTSD) has been most consistently associated with exaggerated physiologic reactivity to startling sounds when such sounds occur in threatening contexts. There is conflicting evidence about whether startle hyperreactivity is a preexisting vulnerability factor for PTSD or an acquired result of posttrauma neural sensitization. Until now, there have been no prospective studies of physiologic reactivity to startling sounds in threatening contexts as predictors of PTSD symptoms. Methods: One hundred and thirty-eight police academy cadets without current psychopathology were exposed to repeated 106-dB startling sounds under increasing (low, medium, or high) threat of mild electric shock while their eye-blink electromyogram, skin conductance, heart rate, and subjective fear responses were recorded. Measures of response habituation were also calculated. Following 1 year of exposure to police-related trauma, these participants were assessed for PTSD symptom severity. Results: After accounting for other baseline variables that were predictive of PTSD symptom severity (age and general psychiatric distress), more severe PTSD symptoms were prospectively and independently predicted by the following startle measures: greater subjective fear under low threat, greater skin conductance under high threat, and slower skin conductance habituation. Conclusions: These results imply that hypersensitivity to contextual threat (indexed by greater fear under low threat), elevated sympathetic nervous system reactivity to explicit threat (indexed by larger responses under high threat), and failure to adapt to repeated aversive stimuli (evidenced by slower habituation) are all unique preexisting vulnerability factors for greater PTSD symptom severity following traumatic stress exposure. These measures may eventually prove useful for preventing PTSD

Neurobiological findings in posttraumatic stress disorder: a review

Since posttraumatic stress disorder (PTSD) was first recognized as a psychiatric disorder, it has generated a great deal of scientific interest. Recent studies on the neurobiology of PTSD provide evidence that PTSD is biologically distinct from other types of traumatic and nontraumatic stress responses. This paper reviews three important directions of neurobiological research in PTSD: noradrenergic axis changes and associated alterations in autonomic responsivity neuroendocrine changes involving the hypothalamic-pituitary-adrenocortical (HPA) axis, and neuroanatomy changes involving the hippocampus. Each section reviews the salient aspects of preclinical research on the biology of stress and their bearing on the understanding of PTSD, and summarizes prominent findings from clinical biological studies of PTSD, Tentative models that integrate current findings from the clinical study of PTSD are reviewed. To conclude, the important methodological and empirical issues that need to be addressed by future studies are indicated

Current posttraumatic stress disorder and exaggerated threat sensitivity associated with elevated inflammation in the Mind Your Heart Study

OBJECTIVE: Elevated inflammation has been repeatedly observed in posttraumatic stress disorder (PTSD), and it may drive the development of both psychiatric symptoms and physical comorbidities. However, it is not clear if elevated inflammation is a feature of both remitted and current PTSD, and little is known about relationships between specific clusters of PTSD symptoms and inflammation. Exaggerated threat sensitivity, as indexed by threat reactivity and avoidance of perceived threats, may be particularly closely associated with inflammation. METHODS: We assessed PTSD symptoms and threat sensitivity using the Clinician Administered PTSD Scale in 735 Veterans Affairs patients (35% current PTSD; 16% remitted PTSD) who participated in the Mind Your Heart Study (mean age=59±11; 94% male). High sensitivity C-reactive protein (hsCRP), white blood cell count (WBC), and fibrinogen were used as indices of inflammation. Analysis of covariance models with planned contrasts were used to examine differences in inflammation by PTSD status, adjusting for age, sex, race, kidney function and socioeconomic status

Association between Sleep Duration and 24-Hour Urine Free Cortisol in the MrOS Sleep Study

Context Short sleep duration is associated with adverse health outcomes, but the mechanisms involved are unknown. It has been postulated that short sleep duration may elevate cortisol levels, but studies have had conflicting results. It is unclear whether these differing findings may be due to methodological issues, such as assessment of sleep duration. Specifically, objective versus subjective methods of measuring habitual sleep duration may account for the conflicting results found in epidemiological studies. Objective: Our goal was to determine whether habitual sleep duration, measured objectively (by actigraphy) and subjectively (by self-report), was associated with 24-hour urine free cortisol (UFC), a measure of integrated cortisol secretion. Our secondary goal was to determine whether slow wave sleep (SWS, determined by polysomnography) was associated with 24-hour UFC. Design/Setting Cross sectional study of community dwelling older men. Patients/Participants 325 men (mean age = 76.6 years, SD = 5.5) from the Portland site of the MrOS Sleep Study, who underwent 24-hour urine collection, polysomnography, actigraphy and sleep questionnaire. Primary Outcome 24-hour UFC. Results: In this study of community dwelling older men, self-reported sleep duration was inversely related to 24-hour UFC levels. Participants reporting 5 to 8 hours of habitual sleep. However, sleep duration determined by actigraphy was not associated with 24-hour UFC in either univariable or multivariable regression models. SWS was not associated with 24-hour UFC. Conclusion: Objectively measured (i.e., actigraphic) sleep duration is not associated with 24-hour UFC in these community dwelling older men. This finding, together with prior studies, suggests that elevated levels of integrated cortisol secretion is not the mechanisms by which short sleep duration leads to adverse health outcomes

Hippocampal Volume Differences in Gulf War Veterans with Current Versus Lifetime Posttraumatic Stress Disorder Symptoms

Background: Decreased hippocampal volume is described in posttraumatic stress disorder (PTSD) and depression. However, it is not known whether it is a risk factor for the development of PTSD or a consequence of PTSD. We sought to determine the effects of PTSD and depressive symptoms on hippocampal volume. Methods: Clinical and magnetic resonance imaging data were collected in a cross sectional study of 244 GulfWarveterans. Measures included lifetime and current Clinician Administered PTSD Scale, Hamilton Depression Scale, Life Stressor Checklist, and Lifetime Drinking History. Magnetic resonance imaging data were acquired with a 1.5-T scanner and analyzed with automated and semiautomated image processing techniques. Results: Eighty-two veterans had lifetime PTSD, 44 had current PTSD, and 38 had current depression. In the linear regression analysis, current PTSD symptoms (standardized coefficient B= .25, p =.03) but neither lifetime PTSD symptoms nor current depression were associated with smaller hippocampal volume. Gender, age, history of early life trauma, education, lifetime and current alcohol use, current marijuana use, and treatment with antidepressants did not have independent effects. Participants with chronic PTSD had, on average, a smaller hippocampus compared with those with remitted PTSD. Conclusions: The finding that current but not lifetime PTSD symptom severity explains hippocampal size raises two possibilities: either a small hippocampus is a risk factor for lack of recovery from PTSD (trait) or PTSD effects on hippocampal volume are reversible once PTSD symptoms remit and the patient recovers (state)

Effects of traumatic brain injury and posttraumatic stress disorder on development of Alzheimer's disease in Vietnam Veterans using the Alzheimer's Disease Neuroimaging Initiative: Preliminary report

Introduction Traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD) have previously been reported to be associated with increased risk of Alzheimer's disease (AD). We are using biomarkers to study Vietnam Veterans with/without mild cognitive impairment with a history of at least one TBI and/or ongoing PTSD to determine whether these contribute to the development of AD. Methods Potential subjects identified by Veterans Administration records underwent an initial telephone screen. Consented subjects underwent clinical evaluation, lumbar puncture, structural magnetic resonance imaging, and amyloid positron emission tomography (PET) scans. Results We observed worse cognitive functioning in PTSD and TBI + PTSD groups, worse global cognitive functioning in the PTSD group, lower superior parietal volume in the TBI + PTSD group, and lower amyloid positivity in the PTSD group, but not the TBI group compared to controls without TBI/PTSD. Medial temporal lobe atrophy was not increased in the PTSD and/or TBI groups. Discussion Preliminary results do not indicate that TBI or PTSD increase the risk for AD measured by amyloid PET. Additional recruitment, longitudinal follow-up, and tau-PET scans will provide more information in the future

Combined effects of genotype and childhood adversity shape variability of DNA methylation across age

Lasting effects of adversity, such as exposure to childhood adversity (CA) on disease risk, may be embedded via epigenetic mechanisms but findings from human studies investigating the main effects of such exposure on epigenetic measures, including DNA methylation (DNAm), are inconsistent. Studies in perinatal tissues indicate that variability of DNAm at birth is best explained by the joint effects of genotype and prenatal environment. Here, we extend these analyses to postnatal stressors. We investigated the contribution of CA, cis genotype (G), and their additive (G+CA) and interactive (GxCA) effects to DNAm variability in blood or saliva from five independent cohorts with a total sample size of 1074 ranging in age from childhood to late adulthood. Of these, 541 were exposed to CA, which was assessed retrospectively using self-reports or verified through social services and registries. For the majority of sites (over 50%) in the adult cohorts, variability in DNAm was best explained by G+CA or GxCA but almost never by CA alone. Across ages and tissues, 1672 DNAm sites showed consistency of the best model in all five cohorts, with GxCA interactions explaining most variance. The consistent GxCA sites mapped to genes enriched in brain-specific transcripts and Gene Ontology terms related to development and synaptic function. Interaction of CA with genotypes showed the strongest contribution to DNAm variability, with stable effects across cohorts in functionally relevant genes. This underscores the importance of including genotype in studies investigating the impact of environmental factors on epigenetic marks.Peer reviewe