Acute stress alters the 'default' brain processing.

Active adaptation to acute stress is essential for coping with daily life challenges. The stress hormone cortisol, as well as large scale re-allocations of brain resources have been implicated in this adaptation. Stress-induced shifts between large-scale brain networks, including salience (SN), central executive (CEN) and default mode networks (DMN), have however been demonstrated mainly under task-conditions. It remains unclear whether such network shifts also occur in the absence of ongoing task-demands, and most critically, whether these network shifts are predictive of individual variation in the magnitude of cortisol stress-responses. In a sample of 335 healthy participants, we investigated stress-induced functional connectivity changes (delta-FC) of the SN, CEN and DMN, using resting-state fMRI data acquired before and after a socially evaluated cold-pressor test and a mental arithmetic task. To investigate which network changes are associated with acute stress, we evaluated the association between cortisol increase and delta-FC of each network. Stress-induced cortisol increase was associated with increased connectivity within the SN, but with decreased coupling of DMN at both local (within network) and global (synchronization with brain regions also outside the network) levels. These findings indicate that acute stress prompts immediate connectivity changes in large-scale resting-state networks, including the SN and DMN in the absence of explicit ongoing task-demands. Most interestingly, this brain reorganization is coupled with individuals' cortisol stress-responsiveness. These results suggest that the observed stress-induced network reorganization might function as a neural mechanism determining individual stress reactivity and, therefore, it could serve as a promising marker for future studies on stress resilience and vulnerability.

High Endogenous Testosterone Levels Are Associated With Diminished Neural Emotional Control in Aggressive Police Recruits.

Although police officers are carefully selected for their high emotion-regulation abilities, excessive aggression in police officers has been reported, particularly in socially challenging situations known to elicit high state testosterone levels. Adequate regulation of emotional actions depends on the prefrontal cortex's control over the amygdala. We investigated the effects of trait aggression and endogenous testosterone on this emotional-control neurocircuitry in 275 healthy, high-functioning police recruits using a functional MRI social-emotional task eliciting impulsive and controlled approach-and-avoidance actions. Higher levels of aggression were counteracted by increased anterior prefrontal cortex (aPFC) control over the amygdala when control over automatic emotional actions was required. Crucially, testosterone had a detrimental effect on this aggression-dependent aPFC recruitment: Police recruits with relatively high trait aggression and high state testosterone showed reduced aPFC control over the amygdala during emotion regulation. This provides a mechanistic explanation for inadequate behavioral control during socially challenging situations in otherwise well-functioning individuals.

Neural correlates of emotional action control in anger-prone women with borderline personality disorder.

BACKGROUND: Difficulty in controlling emotional impulses is a crucial component of borderline personality disorder (BPD) that often leads to destructive, impulsive behaviours against others. In line with recent findings in aggressive individuals, deficits in prefrontal amygdala coupling during emotional action control may account for these symptoms. METHODS: To study the neurobiological correlates of altered emotional action control in individuals with BPD, we asked medication-free, anger-prone, female patients with BPD and age- and intelligence-matched healthy women to take part in an approach-avoidance task while lying in an MRI scanner. The task required controlling fast behavioural tendencies to approach happy and avoid angry faces. Additionally, before the task we collected saliva testosterone and self-reported information on tendencies to act out anger and correlated this with behavioural and functional MRI (fMRI) data. RESULTS: We included 30 patients and 28 controls in our analysis. Patients with BPD reported increased tendencies to act out anger and were faster in approaching than avoiding angry faces than with healthy women, suggesting deficits in emotional action control in women with BPD. On a neural level, controlling fast emotional action tendencies was associated with enhanced activation in the antero- and dorsolateral prefrontal cortex across groups. Healthy women showed a negative coupling between the left dorsolateral prefrontal cortex and right amygdala, whereas this was absent in patients with BPD. LIMITATIONS: Specificity of results to BPD and sex differences remain unknown owing to the lack of clinical control groups and male participants. CONCLUSION: The results indicate reduced lateral prefrontal-amygdala communication during emotional action control in anger-prone women with BPD. The findings provide a possible neural mechanism underlying difficulties with controlling emotional impulses in patients with BPD.

Testosterone during Puberty Shifts Emotional Control from Pulvinar to Anterior Prefrontal Cortex.

UNLABELLED: Increased limbic and striatal activation in adolescence has been attributed to a relative delay in the maturation of prefrontal areas, resulting in the increase of impulsive reward-seeking behaviors that are often observed during puberty. However, it remains unclear whether and how this general developmental pattern applies to the control of social emotional actions, a fundamental adult skill refined during adolescence. This domain of control pertains to decisions involving emotional responses. When faced with a social emotional challenge (e.g., an angry face), we can follow automatic response tendencies and avoid the challenge or exert control over those tendencies by selecting an alternative action. Using an fMRI-adapted social approach-avoidance task, this study identifies how the neural regulation of emotional action control changes as a function of human pubertal development in 14-year-old adolescents (n = 47). Pubertal maturation, indexed by testosterone levels, shifted neural regulation of emotional actions from the pulvinar nucleus of the thalamus and the amygdala to the anterior prefrontal cortex (aPFC). Adolescents with more advanced pubertal maturation showed greater aPFC activity when controlling their emotional action tendencies, reproducing the same pattern consistently observed in adults. In contrast, adolescents of the same age, but with less advanced pubertal maturation, showed greater pulvinar and amygdala activity when exerting similarly effective emotional control. These findings qualify how, in the domain of social emotional actions, executive control shifts from subcortical to prefrontal structures during pubertal development. The pulvinar and the amygdala are suggested as the ontogenetic precursors of the mature control system centered on the anterior prefrontal cortex. SIGNIFICANCE STATEMENT: Adolescents can show distinct behavioral problems when emotionally aroused. This could be related to later development of frontal regions compared with deeper brain structures. This study found that when the control of emotional actions needs to be exerted, more mature adolescents, similar to adults, recruit the anterior prefrontal cortex (aPFC). Less mature adolescents recruit specific subcortical regions, namely the pulvinar and amygdala. These findings identify the subcortical pulvino-amygdalar pathway as a relevant precursor of a mature aPFC emotional control system, opening the way for a neurobiological understanding of how emotion control-related disorders emerge during puberty.

Reduced serotonin transporter availability decreases prefrontal control of the amygdala.

After a threatening event, the risk of developing social psychopathologies is increased in short-allele (s) carriers of the serotonin transporter gene. The amygdala becomes overresponsive to emotional stimuli, an effect that could be driven by local hypersensitivity or by reduced prefrontal regulation. This study distinguishes between these two hypotheses by using dynamic causal modeling of fMRI data acquired in a preselected cohort of human s-carriers and homozygous long-allele carriers. Increased amygdala activity in s-carriers originates from reduced prefrontal inhibitory regulation when social emotional behavior needs to be controlled, suggesting a mechanism for increased vulnerability to psychopathologies.

A poly(amidoamine)-based polymeric nanoparticle platform for efficient in vivo delivery of mRNA.

The successful use of mRNA vaccines enabled and accelerated the development of several new vaccine candidates and therapeutics based on the delivery of mRNA. In this study, we developed bioreducible poly(amidoamine)-based polymeric nanoparticles (PAA PNPs) for the delivery of mRNA with improved transfection efficiency. The polymers were functionalized with chloroquinoline (Q) moieties for improved endosomal escape and further stabilization of the mRNA-polymer construct. Moreover, these PAAQ polymers were covalently assembled around a core of multi-armed ethylenediamine (Mw 800, 2 % w/w) to form a pre-organized polymeric scaffolded PAAQ (ps-PAAQ) as a precursor for the formation of the mRNA-loaded nanoparticles. Transfection of mammalian cell lines with EGFP mRNA loaded into these PNPs showed a favorable effect of the Q incorporation on GFP protein expression. Additionally, these ps-PAAQ NPs were co-formulated with PEG-polymer coatings to shield the positive surface charge for increased stability and better in vivo applicability. The ps-PAAQ NPs coated with PEG-polymer displayed smaller particle size, electroneutral surface charge, and higher thermal stability. Importantly, these nanoparticles with both Q and PEG-polymer coating induced significantly higher luciferase activity in mice muscle than uncoated ps-PAAQ NPs, following intramuscular injection of PNPs loaded with luciferase mRNA. The developed technology is broadly applicable and holds promise for the development of new nucleotide-based vaccines and therapeutics in a range of infectious and chronic diseases.

Testosterone inhibits trust but promotes reciprocity.

The steroid hormone testosterone has been associated with behavior intended to obtain or maintain high social status. Although such behavior is typically characterized as aggressive and competitive, it is clear that high social status is achieved and maintained not only through antisocial behavior but also through prosocial behavior. In the present experiment, we investigated the impact of testosterone administration on trust and reciprocity using a double-blind randomized control design. We found that a single dose of 0.5 mg of testosterone decreased trust but increased generosity when repaying trust. These findings suggest that testosterone may mediate different types of status-seeking behavior. It may increase competitive, potentially aggressive, and antisocial behavior when social challenges and threats (i.e., abuse of trust and betrayal) need to be considered; however, it may promote prosocial behavior in the absence of these threats, when high status and good reputation may be best served by prosocial behavior.

Basal hypercortisolism and trauma in patients with psychogenic nonepileptic seizures.

PURPOSE: Several studies have indicated that psychogenic nonepileptic seizures (PNES) are associated with psychological trauma, but only a few studies have examined the associations with neurobiologic stress systems, such as the hypothalamus-pituitary-adrenal (HPA) axis and its end-product cortisol. We tested several relevant HPA-axis functions in patients with PNES and related them to trauma history. METHODS: Cortisol awakening curve, basal diurnal cortisol, and negative cortisol feedback (using a 1 mg dexamethasone suppression test) were examined in 18 patients with PNES and 19 matched healthy controls (HCs) using saliva cortisol sampling on two consecutive days at 19 time points. Concomitant sympathetic nervous system (SNS) activity was assessed by analyzing saliva alpha-amylase (sAA). RESULTS: Patients with PNES showed significantly increased basal diurnal cortisol levels compared to HCs. This effect was driven mainly by patients reporting sexual trauma who showed a trend toward higher cortisol levels as compared to patients without a sexual trauma report. Importantly, the increased basal diurnal cortisol levels in patients were not explained by depression, medication, or smoking, or by current seizures or group differences in SNS activity. DISCUSSION: This is the first study showing that basal hypercortisolism in patients with PNES is independent of the acute occurrence of seizures. In addition, basal hypercortisolism was more pronounced in traumatized patients with PNES as compared to nontraumatized patients with PNES. These findings suggest that HPA-axis activity provides a significant neurobiologic marker for PNES.

The effect of stress induction on working memory in patients with psychogenic nonepileptic seizures.

Although psychogenic nonepileptic seizures (PNES) are considered a stress-induced paroxysmal disintegration of cognitive functions, it remains unknown whether stress indeed impairs cognitive integrative functions, such as working memory (WM), in patients with PNES. An N-back task with emotional distracters (angry, happy, and neutral faces) was administered at baseline and after stress induction (Cold Pressor Test) to 19 patients with PNES and 20 matched healthy controls. At baseline, patients displayed increased WM interference for the facial distracters. After stress induction, group differences generalized to the no-distracter condition. Within patients, high cortisol stress responses were associated with larger stress-induced WM impairments in the no-distracter condition. These findings demonstrate that patients' cognitive integrative functions are impaired by social distracters and stress induction. Moreover, the stress- and cortisol-related generalization of the relative WM impairments offers a promising experimental model for the characteristic paroxysmal disintegration of attentional and mnemonic functions in patients with PNES associated with stress.

Trauma, stress, and preconscious threat processing in patients with psychogenic nonepileptic seizures.

PURPOSE: Psychogenic nonepileptic seizures (PNES) have long been considered as paroxysmal dissociative symptoms characterized by an alteration of attentional functions caused by severe stress or trauma. Although interpersonal trauma is common in PNES, the proposed relation between trauma and attentional functions remains under explored. We examined the attentional processing of social threat in PNES in relation to interpersonal trauma and acute psychological stress. METHODS: A masked emotional Stroop test, comparing color-naming latencies for backwardly masked angry, neutral, and happy faces, was administered to 19 unmedicated patients with PNES and 20 matched healthy controls, at baseline and in a stress condition. Stress was induced by means of the Trier Social Stress Test and physiologic stress parameters, such as heart rate variability (HRV) and cortisol, were measured throughout the experiment. RESULTS: No group differences related to the acute stress induction were found. Compared to controls, however, patients displayed a positive attentional bias for masked angry faces at baseline, which was correlated to self-reported sexual trauma. Moreover, patients showed lower HRV at baseline and during recovery. DISCUSSION: These findings are suggestive of a state of hypervigilance in patients with PNES. The relation with self-reported trauma, moreover, offers the first evidence linking psychological risk factors to altered information processing in PNES.

Basal cortisol is positively correlated to threat vigilance in patients with psychogenic nonepileptic seizures.

Previous studies have provided evidence for a vigilant attentional bias toward threat stimuli and increased basal diurnal cortisol levels in patients with psychogenic nonepileptic seizures (PNES). Because cortisol levels may be predictive of threat vigilance, we reanalyzed previous data on threat vigilance in 19 unmedicated patients with PNES and found a positive correlation between baseline cortisol levels and attentional bias scores for threat stimuli (r=0.49, P=0.035). There was no such relationship in healthy matched controls (n=20) or in patients with epileptic seizures (n=17). These findings provide the first evidence linking an endocrine stress marker to increased threat sensitivity in PNES and support new integrated psychoneurobiological models of PNES.

Diminished cortisol responses to psychosocial stress associated with lifetime adverse events a study among healthy young subjects.

BACKGROUND: Animal and human studies have found that prior stressful events can result in an altered reactivity in the HPA axis. The aim of the present study was to investigate the role of adverse events in childhood on cortisol reactivity to psychosocial stress in young healthy subjects (n=80). METHODS: Salivary cortisol levels were measured before, during and after exposure to a psychosocial stress task in healthy men and women with high (n=33) and low (n=47) exposure to adverse childhood events. RESULTS: A significant blunted cortisol response was found in individuals with a history of adverse events compared to individuals with no adverse life events, with no differences in baseline cortisol levels. This finding appeared to be primarily driven by men. The groups did not differ on any other physiological or subjective stress measure, including heart rate, blood pressure, and subjective tension. CONCLUSIONS: These findings suggest that, at least in healthy young males, adverse childhood events are associated with changes in HPA-axis functioning. Longitudinal studies are needed to investigate whether the blunted cortisol response is a risk factor in the etiology of psychiatric disorders or rather reflects resiliency with regard to the development of psychopathology.

Cortisol administration enhances the coupling of midfrontal delta and beta oscillations.

There is increasing evidence that the strength of the relation between slow (SW) and fast (FW) wave activity in the EEG is associated with specific motivational states and their corresponding neuroendocrine patterns. Enhanced correlations between SW and FW have been related to anxiety, behavioral inhibition and high basal cortisol levels. However, the direct effects of cortisol on SW-FW coupling have not been experimentally studied yet. The present study investigated whether cortisol administration increases SW-FW coupling. Resting state EEG recordings were obtained from 40 right-handed healthy male subjects with extreme low or high scores on a behavioral inhibition scale, after placebo and cortisol (50 mg) administration. As expected, cortisol resulted in a significant increase in correlation between SW (delta) and FW (beta) activity compared to placebo. In addition, delta-beta correlation was significantly higher in high compared to low behaviorally inhibited subjects in both conditions. These results suggest that cortisol can modify brain activity, increasing a pattern associated with anxiety and behavioral inhibition. This is in line with findings associating cortisol with behavioral inhibition and anxiety.

The effects of cortisol administration on approach-avoidance behavior: an event-related potential study.

We investigated the effects of cortisol administration (50 mg) on approach and avoidance tendencies in low and high trait avoidant healthy young men. Event-related brain potentials (ERPs) were measured during a reaction time task, in which participants evaluated the emotional expression of photographs of happy and angry faces by making an approaching (flexion) or avoiding (extension) arm movement. The task consisted of an affect-congruent (approach happy faces and avoid angry faces) and an affect-incongruent (reversed instruction) condition. Behavioral and ERP analyses showed that cortisol enhanced congruency effects for angry faces in highly avoidant individuals only. The ERP effects involved an increase of both early (P150) and late (P3) positive amplitudes, indicative of increased processing of the angry faces in high avoidant subjects after cortisol administration. Together, these results suggest a context-specific effect of cortisol on processing of, and adaptive responses to, motivationally significant threat stimuli, particularly in participants highly sensitive to threat signals.

Defensive freezing links Hypothalamic-Pituitary-Adrenal-axis activity and internalizing symptoms in humans.

The Hypothalamic-Pituitary-Adrenal (HPA)-axis plays an important role in the expression of defensive freezing. Adaptive freezing reactivity, characterized by an immediate increase in acute stress and timely termination upon threat offset or need to act, is essential for adequate stress coping. Blunted HPA-axis activity in animals is associated with blunted freezing reactivity and internalizing symptoms. Despite their potential relevance, it remains unknown whether these mechanisms apply to humans and human psychopathology. Using a well-established method combining electrocardiography and posturography, we assessed freezing before, immediately after, and one hour after a stress induction in 92 human adolescents. In line with animal models, human adolescents showed stress-induced freezing, as quantified by relative reductions in heart rate and body sway after, as compared to before, stress. Moreover, relatively lower basal cortisol was associated with reduced stress-induced freezing reactivity (i.e., less immediate freezing and less recovery). Path analyses showed that decreased freezing recovery in individuals with reduced cortisol levels was associated with increased levels of internalizing symptoms. These findings suggest that reduced freezing recovery may be a promising marker for the etiology of internalizing symptoms.

A randomized controlled study of power posing before public speaking exposure for social anxiety disorder: No evidence for augmentative effects.

This manuscript details a randomized controlled study designed to test the efficacy of power posing (i.e., briefly holding postures associated with dominance and power) as an augmentative strategy for exposure therapy for social anxiety disorder (SAD). Seventy-three individuals diagnosed with SAD were assigned to one of three conditions: power posing, submissive posing, or rest (no posing) prior to participating in an exposure therapy session. Participants were assessed for between-group differences in pre- and post-manipulation salivary hormone levels, within-session subjective experiences of fear, and pre- and 1-week post-treatment SAD severity outcome measures. Though the intervention resulted in decreased SAD symptom severity one week later, analyses revealed no significant between-group differences on any tested variables. Accordingly, this study provides no evidence to suggest that power posing impacts hormone levels or exposure therapy outcomes.

The effects of stress-induced cortisol responses on approach-avoidance behavior.

High glucocorticoid stress-responses are associated with prolonged freezing reactions and decreased active approach and avoidance behavior in animals. The present study was designed to investigate the effects of cortisol responses and trait avoidance on approach-avoidance behavior in humans. Twenty individuals were administered a computerized approach-avoidance (AA)-task before and after stress-induction (Trier Social Stress Test). The AA-task involved a reaction time (RT) task, in which participants made affect congruent and affect incongruent arm movements towards positive and threatening social stimuli. Affect congruent responses involved arm extension (avoidance) in response to angry faces and arm flexion (approach) in response to happy faces. Reversed responses were made in affect incongruent instruction conditions. As expected, participants with high cortisol responses showed significantly decreased RT congruency-effects in a context of social stress. Low trait avoidance was also associated with diminished congruency-effects during stress. However, the latter effect disappeared after controlling for the effects of cortisol. In sum, in agreement with animal research, these data suggest that high cortisol responses are associated with a decrease in active approach-avoidance behavior during stress. These findings may have important implications for the study of freezing and avoidance reactions in patients with anxiety disorders, such as social phobia and post-traumatic stress disorder.

Exogenous testosterone in women enhances and inhibits competitive decision-making depending on victory-defeat experience and trait dominance.

The present experiment tested the causal impact of testosterone on human competitive decision-making. According to prevailing theories about testosterone's role in social behavior, testosterone should directly boost competitive decisions. But recent correlational evidence suggests that testosterone's behavioral effects may depend on specific aspects of the context and person relevant to social status (win-lose context and trait dominance). We tested the causal influence of testosterone on competitive decisions by combining hormone administration with measures of trait dominance and a newly developed social competition task in which the victory-defeat context was experimentally manipulated, in a sample of 54 female participants. Consistent with the hypothesis that testosterone has context- and person-dependent effects on competitive behavior, testosterone increased competitive decisions after victory only among high-dominant individuals but testosterone decreased competitive decisions after defeat across all participants. These results suggest that testosterone flexibly modulates competitive decision-making depending on prior social experience and dominance motivation in the service of enhancing social status.

Poly(amido amine)-based multilayered thin films on 2D and 3D supports for surface-mediated cell transfection.

Two linear poly(amido amine)s, pCABOL and pCHIS, prepared by polyaddition of cystamine bisacrylamide (C) with 4-aminobutanol (ABOL) or histamine (HIS), were explored to form alternating multilayer thin films with DNA to obtain functionalized materials with transfection capacity in 2D and 3D. Therefore, COS-7 cells were cultured on top of multilayer films formed by layer-by-layer dipcoating of these polymers with GFP-encoded pDNA, and the effect of the number of layers and cell seeding density on the transfection efficiency was evaluated. Multilayer films with pCABOL were found to be superior to pCHIS in facilitating transfection, which was attributed to higher incorporation of pDNA and release of the transfection agent. High amounts of transfected cells were obtained on pCABOL films, correlating proportionally over a wide range with seeding density. Optimal transfection efficiency was obtained with pCABOL films composed of 10 bilayers. Further increase in the number of bilayers only marginally increased transfection efficiency. Using the optimal multilayer and cell seeding conditions, pCABOL multilayers were fabricated on poly(ε-caprolactone) (PCL), heparinized PCL (PCL-HEP), and poly(lactic acid) (PLA) disks as examples of common biomedical supports. The multilayers were found to completely mask the properties of the original substrates, with significant improvement in cell adhesion, which is especially pronounced for PCL and PLA disks. With all these substrates, transfection efficiency was found to be in the range of 25-50% transfected cells. The pCABOL/pDNA multilayer films can also conveniently add transfection capability to 3D scaffolds. Significant improvement in cell adhesion was observed after multilayer coating of 3D-plotted fibers of PCL (with and without an additional covalent heparin layer), especially for the PCL scaffold without heparin layer and transfection was observed on both 3D PCL and PCL-HEP scaffolds. These results show that layer-by-layer dip-coating of pCABOL with functional DNA is an easy and inexpensive method to introduce transfection capability to biomaterials of any nature and shape, which can be beneficially used in various biomedical and tissue engineering applications.

Salivary testosterone: associations with depression, anxiety disorders, and antidepressant use in a large cohort study.

OBJECTIVE: Low circulating levels of testosterone have been associated with major depression, but there is more limited evidence for differences in patients with anxiety disorders. The use of selective serotonin reuptake inhibitors (SSRIs) and other antidepressants is associated with sexual side effects, warranting testing for interactions with testosterone. METHODS: Data are from 722 male and 1380 female participants of The Netherlands Study of Depression and Anxiety (NESDA), who were recruited from the community, general practice care, and specialized mental health care. Depressive and anxiety diagnoses were assessed using the DSM-IV Composite International Diagnostic Interview. To smooth the episodic secretion, the four morning saliva samples per participant and the two evening samples were pooled before testosterone analysis. RESULTS: Morning median testosterone levels were 25.2 pg/ml in men and 16.2 pg/ml in women, with lower evening levels of 18.2 and 14.1 pg/ml, respectively. Significant determinants of testosterone levels were sex, age, time of the day, use of contraceptives, and smoking status. Female patients with a current (1-month) depressive disorder (effect size 0.29; P=0.002), generalized anxiety disorder (0.25; P=0.01), social phobia (0.30; P<0.001), and agoraphobia without panic disorder (0.30; P=0.02) had lower salivary testosterone levels than female controls. Higher testosterone levels were found in male and female participants using SSRIs than in non-users (effect size 0.26; P<0.001). CONCLUSION: Salivary testosterone levels are lower in female patients with a depressive disorder, generalized anxiety disorder, social phobia, and agoraphobia as compared to female controls. SSRIs may increase salivary testosterone in men and women.