Stress at the synapse : signal transduction mechanisms of adrenal steroids at neuronal membranes

As the key neuron-to-neuron interface, the synapse is involved in learning and memory, including traumatic memories during times of stress. However, the signal transduction mechanisms by which stress mediates its lasting effects on synapse transmission and on memory are not fully understood. A key component of the stress response is the increased secretion of adrenal steroids. Adrenal steroids (e.g., cortisol) bind to genomic mineralocorticoid and glucocorticoid receptors (gMRs and gGRs) in the cytosol. In addition, they may act through membrane receptors (mMRs and mGRs), and signal transduction through these receptors may allow for rapid modulation of synaptic transmission as well as modulation of membrane ion currents. mMRs increase synaptic and neuronal excitability; mechanisms include the facilitation of glutamate release through extracellular signal-regulated kinase signal transduction. In contrast, mGRs decrease synaptic and neuronal excitability by reducing calcium currents through N-methyl-D-aspartate receptors and voltage-gated calcium channels by way of protein kinase A- and G protein-dependent mechanisms. This body of functional data complements anatomical evidence localizing GRs to the postsynaptic membrane. Finally, accumulating data also suggest the possibility that mMRs and mGRs may show an inverted U-shaped dose response, whereby glutamatergic synaptic transmission is increased by low doses of corticosterone acting at mMRs and decreased by higher doses acting at mGRs. Thus, synaptic transmission is regulated by mMRs and mGRs, and part of the stress signaling response is a direct and bidirectional modulation of the synapse itself by adrenal steroids.

High and low fear phenotypes show differences in phosphorylated (p44/42 ERK) MAPK-expressing neurons in the lateral amygdala

Post traumatic stress disorder (PTSD) is a serious medical condition effecting both military and civilian populations. While its etiology remains poorly understood it is characterized by high and prolonged levels of fear responding. One biological unknown is whether individuals expressing high or low conditioned fear memory encode the memory differently and if that difference underlies fear response. In this study we examined cellular mechanisms that underlie high and low conditioned fear behavior by using an advanced intercrossed mouse line (B6D2F1) selected for high and low Pavlovian fear response. A known requirement for consolidation of fear memory, phosphorylated mitogen activated protein kinase (p44/42 (ERK) MAPK (pMAPK)) in the lateral amygdala (LA) is a reliable marker of fear learning-related plasticity. In this study, we asked whether high and low conditioned fear behavior is associated with differential pMAPK expression in the LA and if so, is it due to an increase in neurons expressing pMAPK or increased pMAPK per neuron. To examine this, we quantified pMAPK-expressing neurons in the LA at baseline and following Pavlovian fear conditioning. Results indicate that high fear phenotype mice have more pMAPK-expressing neurons in the LA. This finding suggests that increased endogenous plasticity in the LA may be a component of higher conditioned fear responses and begins to explain at the cellular level how different fear responders encode fear memories. Understanding how high and low fear responders encode fear memory will help identify novel ways in which fear-related illness risk can be better predicted and treated.

Mice behaviorally selected for high Pavlovian fear memory exhibit fear generalization, HPA-axis alterations and increased basal activity in cortico-limbic circuits

Biological factors underlying individual variability in fearfulness and anxiety have important implications for stress-related psychiatric illness including PTSD and major depression. Using an advanced intercross line (AIL) derived from C57BL/6 and DBA/2J mouse strains and behavioral selection over 3 generations, we established two lines exhibiting High or Low fear behavior after fear conditioning. Across the selection generations, the two lines showed clear differences in training and tests for contextual and conditioned fear. Before fear conditioning training, there were no differences between lines in baseline freezing to a novel context. However, after fear conditioning High line mice demonstrated pronounced freezing in a new context suggestive of poor context discrimination. Fear generalization was not restricted to contextual fear. High fear mice froze to a novel acoustic stimulus while freezing in the Low line did not increase over baseline. Enhanced fear learning and generalization are consistent with transgenic and pharmacological disruption of the hypothalamic-pituitary-adrenal axis (HPA-axis) (Brinks, 2009, Thompson, 2004, Kaouane, 2012). To determine whether there were differences in HPA-axis regulation between the lines, morning urine samples were collected to measure basal corticosterone. Levels of secreted corticosterone in the circadian trough were analyzed by corticosterone ELISA. High fear mice were found to have higher basal corticosterone levels than low line animals. Examination of hormonal stress response components by qPCR revealed increased expression of CRH mRNA and decreased mRNA for MR and CRHR1 in hypothalamus of high fear mice. These alterations may contribute to both the behavioral phenotype and higher basal corticosterone in High fear mice. To determine basal brain activity in vivo in High and Low fear mice we used manganese-enhanced magnetic resonance imaging (MEMRI). Analysis revealed a pattern of basal brain activity made up of amygdala, cortical and hippocampal circuits that was elevated in the High line. Ongoing studies also seek to determine the relative balance of excitatory and inhibitory tone in the amygdala and hippocampus and the neuronal structure of its neurons. While these heterogeneous lines are selected on fear memory expression, HPA-axis alterations and differences in hippocampal activity segregate with the behavioral phenotypes. These differences are detectable in a basal state strongly suggesting these are biological traits underlying the behavioral phenotype (Johnson et al, 2011).

Virtual business role-play : leveraging familiar environments to prime stakeholder memory during process elicitation

Business process models have traditionally been an effective way of examining business practices to identify areas for improvement. While common information gathering approaches are generally efficacious, they can be quite time consuming and have the risk of developing inaccuracies when information is forgotten or incorrectly interpreted by analysts. In this study, the potential of a role-playing approach for process elicitation and specification has been examined. This method allows stakeholders to enter a virtual world and role-play actions as they would in reality. As actions are completed, a model is automatically developed, removing the need for stakeholders to learn and understand a modelling grammar. Empirical data obtained in this study suggests that this approach may not only improve both the number of individual process task steps remembered and the correctness of task ordering, but also provide a reduction in the time required for stakeholders to model a process view.

Using conversation analysis for understanding children’s talk about traumatic events

This chapter provides a theoretical overview of literature that uses conversation analysis (CA) to explore children’s interactions related to trauma and associated mental health matters. The relatively new approach of using CA to understand trauma reveals the importance of talk in the process of recovery, and also how the participants co-construct talk about traumatic experiences. The chapter will explore literature using a CA approach to investigate children’s trauma talk with professionals as well as literature specifically discussing children’s talk about their traumatic experiences with people who are not qualified therapists or psychiatrists. We conclude by calling for more research using a CA approach for investigating children’s traumatic experiences due to the insight it provides into each child’s personal sense making of traumatic events with a range of people.

Single voxel Magnetic Resonance Spectroscopic (1H-MRS) analysis of deep brain structures after traumatic prefrontal brain injury (TBI) in rat

Chronic difficulties arising from mild brain injury (TBI) are difficult to predict because the processes underlying changes after TBI are poorly understood. In mild brain injury the extent of neuropsychiatric and cognitive symptoms correspond poorly to overt tissue loss (Barth 1983; Liu 2010). Cellular, immune and hormonal cascades occurring after injury and continuing during the healing process may impact uninjured brain regions sensitive to the effects of physiological and emotional stress, which receive projections from the injury site. Changes in these most basic properties due to injury or disease have profound implications for virtually every aspect of brain function through disruption of neurotransmitter, neuroendocrine and metabolic systems. In order to screen for changes in transmitter and metabolic activity, in this study we developed Single voxel proton Magnetic Resonance Spectroscopy (1H-MRS) for use in both injured and control animals. We first evaluated if 1H-MRS could be used to evaluate in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus in both control and injured animals after controlled cortical impact injury to the rat prefrontal cortex. We found that metabolite measurements for Myo-Inositol, Choline, creatine, Glutamate+Glutamine, and N-acetyl-acetate are attainable in deep brain structures in vivo in injured and controls rats. We next seek to evaluate longitudinally, in vivo, alterations in brain metabolism and catabolism of the prefrontal cortex, amygdala and ventral hippocampus during the first month after controlled cortical impact injury to the rat prefrontal cortex. These ongoing studies will provide data on the changes in transmitters and metabolites over time in injured and non-injured subjects. These studies address some of the fundamental questions about how mild brain injury has such diverse effects on overall brain health and function.

Neurobiological correlates of encoding strength of Pavlovian fear conditioned memory

Emotionally significant memories, especially those induced in conjunction with physical and mental trauma, are frequently retained for an individual’s lifetime. How these memories are organized and encoded within neural networks is a fundamental question. The lateral amygdala (LA) is a key nucleus for acquisition and maintenance of associative emotional memories. We used Pavlovian fear conditioning to study how ‘weaker’ and ‘stronger’ memories are encoded in neural networks of the LA. In Pavlovian fear conditioning a neutral stimulus, in this case a tone, is temporally paired with an aversive unconditioned stimulus (US), such as a foot shock. The previously neutral stimulus becomes a conditioned stimulus (CS) capable of eliciting defensive responses. We used time spent freezing when the CS is presented in a neutral context as a dependent variable measure of memory ‘strength’.

Current pre-hospital traumatic brain injury management in China

BACKGROUND Traumatic brain injury (TBI) is associated with mo st trauma-related deaths. Secondary brain injury is the leading cause of in-hospital deaths after traumatic brain injury. By early prevention and slowing of the initial pathophysiological mechanism of secondary brain injury, pre- hospital service can signifi cantly reduce case-fata lity rates of TBI. In China, the incidence of TBI is increasing and the proportion of severe TBI is much higher than that in other countries. The objective of this paper is to review the pre-hospital management of TBI in China. DATA SOURCES A literature search was conducted in January 2014 using the China National Knowledge Infrastructure (CNKI). Articles on the assessment and treatment of TBI in pre-hospital settings practiced by Chinese doctors were identified. The information on the assessment and treatment of hypoxemia, hypotension, and brain hern iation was extracted from the identifi ed articles. RESULTS Of the 471 articles identified, 65 met the selecti on criteria. The existing literature indicated that current practices of pre-hospital TBI management in China were sub-optimal and varied considerably across different regions. CONCLUSION Since pre-hospital care is the weakest part of Chinese emergency care, appropriate training programs on pre-hospital TBI management are urgently needed in China.

Practices and knowledge levels of prehospital doctors in traumatic brain injury management in Hubei, China

This thesis is a cross-sectional questionnaire survey of pre-hospital doctors' knowledge and practice of managing traumatic brain injury in two major cities of Hubei province, China. This study provides evidence for future research on improving the quality of pre-hospital management in China.

In loving memory of Corfu

A travel story about a return journey to the Greek island of Corfu. "THEY say it doesn’t pay to go back. The more a place meant to you in the past, the more likely it is that you’ll be disappointed when you return. Recently I tested the theory, and endangered my memories of the Greek island of Corfu with a second visit..."--publisher website

The Ex/centric fixations project # 2 - Memory, language and polyvocal performative writing

In this paper, Bree Hadley discusses The Ex/centric Fixations Project, a practice-led research project which explores the inadequacy of language as a technology for expressing human experiences of difference, discrimination or marginalisation within mainstream cultures. The project asks questions about the way experience, memory and the public discourses available to express them are bound together, about the silences, failures and falsehoods embedded in any effort to convey human experience via public discourses, and about how these failures might form the basis of a performative writing method. It has, to date, focused on developing a method that expresses experience through improvised, intertextual and discontinous collages of language drawn from a variety of public discourses. Aesthetically, this method works with what Hans Theis Lehmann (Postdramatic Theatre p. 17) calls a “textual variant” of the postdramatic “in which language appears not as the speech of characters – if there are still definable characters at all – but as an autonomous theatricality” (Ibid. 18). It is defined by what Lehmann, following Julia Kristeva, calls a “polylogue”, which presents experience as a conflicted, discontinuous and circular phenomenon, akin to a musical fugue, to break away from “an order centred on one logos” (Ibid. 32). The texts function simultaneously as a series of parts, and as wholes, interwoven voices seeming almost to connect, almost to respond to each other, and almost to tell – or challenging each other’s telling – of a story. In this paper, Hadley offers a performative demonstration, together with descriptions of the way spectators respond, including the way their playful, polyvocal texture impacts on engagement, and the way the presence or non-presence of performing bodies to which the experiences depicted can be attached impacts on engagement. She suggests that the improvised, intertextual and experimental enactments of self embodied in the texts encourage spectators to engage at an emotional level, and make-meaning based primarily on memories they recall in the moment, and thus has the potential to counter the risk that people may read depictions of experiences radically different from their own in reductive, essentialised ways.

Characterizing self-reported sleep disturbance after mild traumatic brain injury

Sleep disturbance after mild traumatic brain injury (mTBI) is commonly reported as debilitating and persistent. However, the nature of this disturbance is poorly understood. This study sought to characterize sleep after mTBI compared with a control group. A cross-sectional matched case control design was used. Thirty-three persons with recent mTBI (1–6 months ago) and 33 age, sex, and ethnicity matched controls completed established questionnaires of sleep quality, quantity, timing, and sleep-related daytime impairment. The mTBI participants were compared with an independent sample of close-matched controls (CMCs; n=33) to allow partial internal replication. Compared with controls, persons with mTBI reported significantly greater sleep disturbance, more severe insomnia symptoms, a longer duration of wake after sleep onset, and greater sleep-related impairment (all medium to large effects, Cohen's d>0.5). No differences were found in sleep quantity, timing, sleep onset latency, sleep efficiency, or daytime sleepiness. All findings except a measure of sleep timing (i.e., sleep midpoint) were replicated for CMCs. These results indicate a difference in the magnitude and nature of perceived sleep disturbance after mTBI compared with controls, where persons with mTBI report poorer sleep quality and greater sleep-related impairment. Sleep quantity and timing did not differ between the groups. These preliminary findings should guide the provision of clearer advice to patients about the aspects of their sleep that may change after mTBI and could inform treatment selection.

Combined pharmacotherapy and psychological therapies for post traumatic stress disorder (PTSD)

BACKGROUND PTSD is an anxiety disorder related to exposure to a severe psychological trauma. Symptoms include re-experiencing the event, avoidance and arousal as well as distress and impairment resulting from these symptoms.Guidelines suggest a combination of both psychological therapy and pharmacotherapy may enhance treatment response, especially in those with more severe PTSD or in those who have not responded to either intervention alone. OBJECTIVES To assess whether the combination of psychological therapy and pharmacotherapy provides a more efficacious treatment for PTSD than either of these interventions delivered separately. SEARCH STRATEGY Searches were conducted on the trial registers kept by the CCDAN group (CCDANCTR-Studies and CCDANCTR-References) to June 2010. The reference sections of included studies and several conference abstracts were also scanned. SELECTION CRITERIA Patients of any age or gender, with chronic or recent onset PTSD arising from any type of event relevant to the diagnostic criteria were included. A combination of any psychological therapy and pharmacotherapy was included and compared to wait list, placebo, standard treatment or either intervention alone. The primary outcome was change in total PTSD symptom severity. Other outcomes included changes in functioning, depression and anxiety symptoms, suicide attempts, substance use, withdrawal and cost. DATA COLLECTION AND ANALYSIS Two or three review authors independently selected trials, assessed their 'risk of bias' and extracted trial and outcome data. We used a fixed-effect model for meta-analysis. The relative risk was used to summarise dichotomous outcomes and the mean difference and standardised mean difference were used to summarise continuous measures. MAIN RESULTS Four trials were eligible for inclusion, one of these trials (n =24) was on children and adolescents. All used an SSRI and prolonged exposure or a cognitive behavioural intervention. Two trials compared combination treatment with pharmacological treatment and two compared combination treatment with psychological treatment. Only two trials reported a total PTSD symptom score and these data could not be combined. There was no strong evidence to show if there were differences between the group receiving combined interventions compared to the group receiving psychological therapy (mean difference 2.44, 95% CI -2.87, 7.35 one study, n=65) or pharmacotherapy (mean difference -4.70, 95% CI -10.84 to 1.44; one study, n = 25). Trialists reported no significant differences between combination and single intervention groups in the other two studies. There were very little data reported for other outcomes, and in no case were significant differences reported. AUTHORS' CONCLUSIONS There is not enough evidence available to support or refute the effectiveness of combined psychological therapy and pharmacotherapy compared to either of these interventions alone. Further large randomised controlled trials are urgently required.