Effects of trauma exposure on the cortisol response to dexamethasone administration in PTSD and major depressive disorder

Objective: To evaluate cortisol suppression following 0.5 mg of dexamethasone (DEX) in trauma survivors (N = 52),with posttraumatic stress disorder (PTSD), major depressive disorder (MDD), both, or neither disorder, and in subjects never exposed to trauma (N = 10), in order to examine interactions between diagnosis and trauma history on cortisol negative feedback inhibition. Method: Lifetime trauma exposure and psychiatric diagnoses were assessed and blood samples were obtained at 8:00 a.m. for the determination of baseline cortisol. Participants ingested 0.5 mg of DEX at 11:00 p.m. and blood samples for determination of cortisol and DEX were obtained at 8:00 a.m. the following day. Results: PTSD was associated with enhanced cortisol suppression in response to DEX Among trauma survivors, the presence of a traumatic event prior to the "focal" trauma had a substantial impact on cortisol suppression in subjects with MDD. Such subjects were more likely to show cortisol alterations similar to those associated with PTSD, whereas subjects with MDD with no prior trauma were more likely to show alterations in the opposite direction, i.e. relative non-suppression. Conclusions: Cortisol hypersuppression in PTSD appears not to be dependent on the presence of traumatic events prior to the focal trauma. However, prior trauma exposure may affect cortisol suppression in MDD. This finding may have implications for understanding why only some depressed patients show non-suppression on the DST. Published by Elsevier Ltd.

The ACTH response to dexamethasone in PTSD

Objective: Enhanced negative feedback and reduced adrenal output are two different models that have been put forth to explain the paradoxical observations of increased release of corticotropin-releasing factor in the face of low cortisol levels in posttraumatic stress disorder (PTSID). To discriminate between these models, the authors measured levels of adrenocorticopic hormone (ACTH) and cortisol at baseline and in response to dexamethasone in medically healthy subjects with and without PTSID. Under conditions of enhanced negative feedback inhibition, ACTH levels would not be altered relative to cortisol levels, but the ACTH response to dexamethasone would be augmented, in concert with the enhanced cortisol response to dexamethasone. In contrast, under conditions of reduced adrenal output, ACTH levels would be expected to be higher at baseline relative to cortisol levels, but the ACTH response to dexamethasone would be unchanged in PTSID relative to healthy comparison subjects. Method: The ACTH and cortisol responses to 0.50 mg of dexamethasone were assessed in 19 subjects (15 men and four women) with PTSID and 19 subjects (14 men and five women) without psychiatric disorder. Results: The ACTH-to-cortisol ratio did not differ between groups before or after dexamethasone, but the subjects with PTSD showed greater suppression of ACTH (as well as cortisol) in response to dexamethasone. Conclusions: The data support the hypothesis of enhanced cortisol negative feedback inhibition of ACTH secretion at the level of the pituitary in PTSD. Pituitary glucocorticoid receptor binding, rather than low adrenal output, is implicated as a likely mechanism for this effect.

The temporal impulse response underlying saccadic decisions

Models of perceptual decision making often assume that sensory evidence is accumulated over time in favor of the various possible decisions, until the evidence in favor of one of them outweighs the evidence for the others. Saccadic eye movements are among the most frequent perceptual decisions that the human brain performs. We used stochastic visual stimuli to identify the temporal impulse response underlying saccadic eye movement decisions. Observers performed a contrast search task, with temporal variability in the visual signals. In experiment 1, we derived the temporal filter observers used to integrate the visual information. The integration window was restricted to the first similar to 100 ms after display onset. In experiment 2, we showed that observers cannot perform the task if there is no useful information to distinguish the target from the distractor within this time epoch. We conclude that (1) observers did not integrate sensory evidence up to a criterion level, (2) observers did not integrate visual information up to the start of the saccadic dead time, and (3) variability in saccade latency does not correspond to variability in the visual integration period. Instead, our results support a temporal filter model of saccadic decision making. The temporal impulse response identified by our methods corresponds well with estimates of integration times of V1 output neurons.

Integrative views on dual-task costs

In this paper, we introduce a special issue about unique and shared mechanisms underlying the performance limitations observed in dual tasks. In particular, the relationship between task-switching costs, the attentional-blink effect, and the psychological refractory period effect is reviewed. These costs are traditionally attributed to fixed and unique capacity limitations for task set reconfiguration, target identification, and response selection, respectively However, we argue that more global attentional processes play a role that cuts across these paradigms. This is reason for a more paradigm-independent approach to processing limitations in dual tasks.

Evidence that indirect inhibition of saccade initiation improves saccade accuracy

Saccadic eye-movements to a visual target are less accurate if there are distracters close to its location (local distracters). The addition of more distracters, remote from the target location (remote distracters), invokes an involuntary increase in the response latency of the saccade and attenuates the effect of local distracters on accuracy. This may be due to the target and distracters directly competing (direct route) or to the remote distracters acting to impair the ability to disengage from fixation (indirect route). To distinguish between these we examined the development of saccade competition by recording saccade latency and accuracy responses made to a target and local distracter compared with those made with an addition of a remote distracter. The direct route would predict that the remote distracter impacts on the developing competition between target and local distracter, while the indirect route would predict no change as the accuracy benefit here derives from accessing the same competitive process but at a later stage. We found that the presence of the remote distracter did not change the pattern of accuracy improvement. This suggests that the remote distracter was acting along an indirect route that inhibits disengagement from fixation, slows saccade initiation, and enables more accurate saccades to be made.

Glycogen synthase kinases 3α and 3β in cardiac myocytes: regulation and consequences of their inhibition

Inhibition of glycogen synthase kinase 3β (GSK3β) as a consequence of its phosphorylation by protein kinase B/Akt (PKB/Akt) has been implicated in cardiac myocyte hypertrophy in response to endothelin-1 or phenylephrine. We examined the regulation of GSK3α (which we show to constitute a significant proportion of the myocyte GSK3 pool) and GSK3β in cardiac myocytes. Although endothelin increases phosphorylation of GSK3 and decreases its activity, the response is less than that induced by insulin (which does not promote cardiac myocyte hypertrophy). GSK3 phosphorylation induced by endothelin requires signalling through the extracellular signal-regulated kinase 1/2 (ERK1/2) cascade and not the PKB/Akt pathway, whereas the reverse is true for insulin. Cardiac myocyte hypertrophy involves changes in morphology, and in gene and protein expression. The potent GSK3 inhibitor 1-azakenpaullone increases myocyte area as a consequence of increased cell length whereas phenylephrine increases both length and width. Azakenpaullone or insulin promotes AP1 transcription factor binding to an AP1 consensus oligonucleotide, but this was significantly less than that induced by endothelin and derived principally from increased binding of JunB protein, the expression of which was increased. Azakenpaullone promotes significant changes in gene expression (assessed by Affymetrix microarrays), but the overall response is less than with endothelin and there is little overlap between the genes identified. Thus, although GSK3 may contribute to cardiac myocyte hypertrophy in some respects (and presumably plays an important role in myocyte metabolism), it does not appear to contribute as significantly to the response induced by endothelin as has been maintained.

The roles of feature-specific task set and bottom-up salience in attentional capture: An ERP study

We investigated the roles of top-down task set and bottom-up stimulus salience for feature-specific attentional capture. Spatially nonpredictive cues preceded search arrays that included a color-defined target. For target-color singleton cues, behavioral spatial cueing effects were accompanied by cueinduced N2pc components, indicative of attentional capture. These effects were only minimally attenuated for nonsingleton target-color cues, underlining the dominance of top-down task set over salience in attentional capture. Nontarget-color singleton cues triggered no N2pc, but instead an anterior N2 component indicative of top-down inhibition. In Experiment 2, inverted behavioral cueing effects of these cues were accompanied by a delayed N2pc to targets at cued locations, suggesting that perceptually salient but task-irrelevant visual events trigger location-specific inhibition mechanisms that can delay subsequent target selection.

Manual response preparation and saccade programming are linked to attention shifts: ERP evidence for covert attentional orienting and spatially specific modulations of visual processing

The premotor theory of attention claims that attentional shifts are triggered during response programming, regardless of which response modality is involved. To investigate this claim, event-related brain potentials (ERPs) were recorded while participants covertly prepared a left or right response, as indicated by a precue presented at the beginning of each trial. Cues signalled a left or right eye movement in the saccade task, and a left or right manual response in the manual task. The cued response had to be executed or withheld following the presentation of a Go/Nogo stimulus. Although there were systematic differences between ERPs triggered during covert manual and saccade preparation, lateralised ERP components sensitive to the direction of a cued response were very similar for both tasks, and also similar to the components previously found during cued shifts of endogenous spatial attention. This is consistent with the claim that the control of attention and of covert response preparation are closely linked. N1 components triggered by task-irrelevant visual probes presented during the covert response preparation interval were enhanced when these probes were presented close to cued response hand in the manual task, and at the saccade target location in the saccade task. This demonstrates that both manual and saccade preparation result in spatially specific modulations of visual processing, in line with the predictions of the premotor theory.

Cortisol levels in response to starting school in children at increased risk for social phobia

Background: Research on depression has identified hyperactivity of the HPA axis as a potential contributory factor to the intergenerational transmission of affective symptoms. However, this has not yet been examined in the context of social phobia. The current study compared HPA axis activity in response to a universal social stressor (starting school) in children of 2 groups of women: one with social phobia and one with no history of anxiety (comparison group). To determine specificity of effects of maternal social phobia, a third group of children were also examined whose mothers had generalised anxiety disorder (GAD). Method: Children provided salivary cortisol samples in the morning, afternoon and at bedtime across 3 time-blocks surrounding the school start: a month before starting school (baseline), the first week at school (stress response), and the end of the first school term (stress recovery). Child behavioural inhibition at 14 months was also assessed to explore the influence of early temperament on later stress responses. Results: All children displayed an elevation in morning and afternoon cortisol from baseline during the first week at school, which remained elevated until the end of the first term. Children in the social phobia group, however, also displayed an equivalent elevation in bedtime cortisol, which was not observed for comparison children or for children of mothers with GAD. Children in the social phobia group who were classified as 'inhibited' at 14 months displayed significantly higher afternoon cortisol levels overall. Summary: A persistent stress response to school in the morning and afternoon is typical for all children, but children of mothers with social phobia also display atypical elevations in evening cortisol levels when at school - signalling long-term disruption of the circadian rhythm in HPA axis activity. This is the first study to report HPA axis disruption in children at risk of developing social phobia, and future research should aim to determine whether this represents a pathway for symptom development, taking early temperament into account.

Thromboxane A2 inhibition of SKCa after NO synthase block in rat middle cerebral artery

NO/prostanoid independent, EDHF-mediated hyperpolarization and dilation in rat middle cerebral arteries is mediated solely by endothelial cell IK(Ca). However, when the NO-pathway is also active, both SK(Ca) and IK(Ca) contribute to EDHF responses. As the SK(Ca) component can be inhibited by stimulation of thromboxane A(2) (TxA(2)) TP receptors and NO has the potential ability to inhibit thromboxane synthesis, we investigated whether TxA(2) might explain loss of functional input from SK(Ca) during NOS inhibition in cerebral arteries. EXPERIMENTAL APPROACH: Rat middle cerebral arteries were mounted in a wire myograph. Endothelium-dependent responses to the PAR2 agonist, SLIGRL were assessed as simultaneous changes in smooth muscle membrane potential and tension. KEY RESULTS: Responses were obtained in the presence of L-NAME as appropriate. Inhibition of TP receptors with either ICI 192,605 or SQ 29,548, did not affect EDHF mediated hyperpolarization and relaxation, but in their presence neither TRAM-34 nor apamin (to block IK(Ca) and SK(Ca) respectively) individually affected the EDHF response. However, in combination they virtually abolished it. Similar effects were obtained in the presence of the thromboxane synthase inhibitor, furegrelate, which additionally revealed an iberiotoxin-sensitive residual EDHF hyperpolarization and relaxation in the combined presence of TRAM-34 and apamin. CONCLUSIONS AND IMPLICATIONS: In the rat middle cerebral artery, inhibition of NOS leads to a loss of the SK(Ca) component of EDHF responses. Either antagonism of TP receptors or block of thromboxane synthase restores an input through SK(Ca). These data indicate that NO normally enables SK(Ca) activity in rat middle cerebral arteries.

Can Rachman’s indirect pathways be used to un-learn fear? A prospective paradigm to test whether children’s fears can be reduced using positive information and modelling a non-anxious response

This study investigated whether children’s fears could be un-learned using Rachman’s indirect pathways for learning fear. We hypothesised that positive information and modelling a non-anxious response are effective methods of un-learning fears acquired through verbal information. One hundred and seven children aged 6–8 years received negative information about one animal and no information about another. Fear beliefs and behavioural avoidance were measured. Children were randomised to receive positive verbal information, modelling, or a control task. Fear beliefs and behavioural avoidance were measured again. Positive information and modelling led to lower fear beliefs and behavioural avoidance than the control condition. Positive information was more effective than modelling in reducing fear beliefs and both methods significantly reduced behavioural avoidance. The results support Rachman’s indirect pathways as viable fear un-learning pathways and supports associative learning theories.

Carbon monoxide protects against oxidant-induced apoptosis via inhibition of Kv2.1

Oxidative stress induces neuronal apoptosis and is implicated in cerebral ischemia, head trauma, and age-related neurodegenerative diseases. An early step in this process is the loss of intracellular K(+) via K(+) channels, and evidence indicates that K(v)2.1 is of particular importance in this regard, being rapidly inserted into the plasma membrane in response to apoptotic stimuli. An additional feature of neuronal oxidative stress is the up-regulation of the inducible enzyme heme oxygenase-1 (HO-1), which catabolizes heme to generate biliverdin, Fe(2+), and carbon monoxide (CO). CO provides neuronal protection against stresses such as stroke and excitotoxicity, although the underlying mechanisms are not yet elucidated. Here, we demonstrate that CO reversibly inhibits K(v)2.1. Channel inhibition by CO involves reactive oxygen species and protein kinase G activity. Overexpression of K(v)2.1 in HEK293 cells increases their vulnerability to oxidant-induced apoptosis, and this is reversed by CO. In hippocampal neurons, CO selectively inhibits K(v)2.1, reverses the dramatic oxidant-induced increase in K(+) current density, and provides marked protection against oxidant-induced apoptosis. Our results provide a novel mechanism to account for the neuroprotective effects of CO against oxidative apoptosis, which has potential for therapeutic exploitation to provide neuronal protection in situations of oxidative stress.

Prefrontal inhibition of threat processing reduces working memory interference

Bottom-up processes can interrupt ongoing cognitive processing in order to adaptively respond to emotional stimuli of high potential significance, such as those that threaten wellbeing. However it is vital that this interference can be modulated in certain contexts to focus on current tasks. Deficits in the ability to maintain the appropriate balance between cognitive and emotional demands can severely impact on day-to-day activities. This fMRI study examined this interaction between threat processing and cognition; 18 adult participants performed a visuospatial working memory (WM) task with two load conditions, in the presence and absence of anxiety induction by threat of electric shock. Threat of shock interfered with performance in the low cognitive load condition; however interference was eradicated under high load, consistent with engagement of emotion regulation mechanisms. Under low load the amygdala showed significant activation to threat of shock that was modulated by high cognitive load. A directed top-down control contrast identified two regions associated with top-down control; ventrolateral PFC and dorsal ACC. Dynamic causal modeling provided further evidence that under high cognitive load, top-down inhibition is exerted on the amygdala and its outputs to prefrontal regions. Additionally, we hypothesized that individual differences in a separate, non-emotional top-down control task would predict the recruitment of dorsal ACC and ventrolateral PFC during top-down control of threat. Consistent with this, performance on a separate dichotic listening task predicted dorsal ACC and ventrolateral PFC activation during high WM load under threat of shock, though activation in these regions did not directly correlate with WM performance. Together, the findings suggest that under high cognitive load and threat, top-down control is exerted by dACC and vlPFC to inhibit threat processing, thus enabling WM performance without threat-related interference.

Dissociating between object affordances and spatial compatibility effects using early response components

Perception and action are tightly linked: objects may be perceived not only in terms of visual features, but also in terms of possibilities for action. Previous studies showed that when a centrally located object has a salient graspable feature (e.g., a handle), it facilitates motor responses corresponding with the feature's position. However, such so-called affordance effects have been criticized as resulting from spatial compatibility effects, due to the visual asymmetry created by the graspable feature, irrespective of any affordances. In order to dissociate between affordance and spatial compatibility effects, we asked participants to perform a simple reaction-time task to typically graspable and non-graspable objects with similar visual features (e.g., lollipop and stop sign). Responses were measured using either electromyography (EMG) on proximal arm muscles during reaching-like movements, or with finger key-presses. In both EMG and button press measurements, participants responded faster when the object was either presented in the same location as the responding hand, or was affordable, resulting in significant and independent spatial compatibility and affordance effects, but no interaction. Furthermore, while the spatial compatibility effect was present from the earliest stages of movement preparation and throughout the different stages of movement execution, the affordance effect was restricted to the early stages of movement execution. Finally, we tested a small group of unilateral arm amputees using EMG, and found residual spatial compatibility but no affordance, suggesting that spatial compatibility effects do not necessarily rely on individuals’ available affordances. Our results show dissociation between affordance and spatial compatibility effects, and suggest that rather than evoking the specific motor action most suitable for interaction with the viewed object, graspable objects prompt the motor system in a general, body-part independent fashion

The lottery-panel task for bi-dimensional parameter-free elicitation of risk attitudes

We propose first, a simple task for the eliciting attitudes toward risky choice, the SGG lottery-panel task, which consists in a series of lotteries constructed to compensate riskier options with higher risk-return trade-offs. Using Principal Component Analysis technique, we show that the SGG lottery-panel task is capable of capturing two dimensions of individual risky decision making i.e. subjects’ average risk taking and their sensitivity towards variations in risk-return. From the results of a large experimental dataset, we confirm that the task systematically captures a number of regularities such as: A tendency to risk averse behavior (only around 10% of choices are compatible with risk neutrality); An attraction to certain payoffs compared to low risk lotteries, compatible with over-(under-) weighting of small (large) probabilities predicted in PT and; Gender differences, i.e. males being consistently less risk averse than females but both genders being similarly responsive to the increases in risk-premium. Another interesting result is that in hypothetical choices most individuals increase their risk taking responding to the increase in return to risk, as predicted by PT, while across panels with real rewards we see even more changes, but opposite to the expected pattern of riskier choices for higher risk-returns. Therefore, we conclude from our data that an “economic anomaly” emerges in the real reward choices opposite to the hypothetical choices. These findings are in line with Camerer's (1995) view that although in many domains, paid subjects probably do exert extra mental effort which improves their performance, choice over money gambles is not likely to be a domain in which effort will improve adherence to rational axioms (p. 635). Finally, we demonstrate that both dimensions of risk attitudes, average risk taking and sensitivity towards variations in the return to risk, are desirable not only to describe behavior under risk but also to explain behavior in other contexts, as illustrated by an example. In the second study, we propose three additional treatments intended to elicit risk attitudes under high stakes and mixed outcome (gains and losses) lotteries. Using a dataset obtained from a hypothetical implementation of the tasks we show that the new treatments are able to capture both dimensions of risk attitudes. This new dataset allows us to describe several regularities, both at the aggregate and within-subjects level. We find that in every treatment over 70% of choices show some degree of risk aversion and only between 0.6% and 15.3% of individuals are consistently risk neutral within the same treatment. We also confirm the existence of gender differences in the degree of risk taking, that is, in all treatments females prefer safer lotteries compared to males. Regarding our second dimension of risk attitudes we observe, in all treatments, an increase in risk taking in response to risk premium increases. Treatment comparisons reveal other regularities, such as a lower degree of risk taking in large stake treatments compared to low stake treatments and a lower degree of risk taking when losses are incorporated into the large stake lotteries. Results that are compatible with previous findings in the literature, for stake size effects (e.g., Binswanger, 1980; Antoni Bosch-Domènech & Silvestre, 1999; Hogarth & Einhorn, 1990; Holt & Laury, 2002; Kachelmeier & Shehata, 1992; Kühberger et al., 1999; B. J. Weber & Chapman, 2005; Wik et al., 2007) and domain effect (e.g., Brooks and Zank, 2005, Schoemaker, 1990, Wik et al., 2007). Whereas for small stake treatments, we find that the effect of incorporating losses into the outcomes is not so clear. At the aggregate level an increase in risk taking is observed, but also more dispersion in the choices, whilst at the within-subjects level the effect weakens. Finally, regarding responses to risk premium, we find that compared to only gains treatments sensitivity is lower in the mixed lotteries treatments (SL and LL). In general sensitivity to risk-return is more affected by the domain than the stake size. After having described the properties of risk attitudes as captured by the SGG risk elicitation task and its three new versions, it is important to recall that the danger of using unidimensional descriptions of risk attitudes goes beyond the incompatibility with modern economic theories like PT, CPT etc., all of which call for tests with multiple degrees of freedom. Being faithful to this recommendation, the contribution of this essay is an empirically and endogenously determined bi-dimensional specification of risk attitudes, useful to describe behavior under uncertainty and to explain behavior in other contexts. Hopefully, this will contribute to create large datasets containing a multidimensional description of individual risk attitudes, while at the same time allowing for a robust context, compatible with present and even future more complex descriptions of human attitudes towards risk.