Investigating two mobile just-in-time adaptive interventions to foster psychological resilience: research protocol of the DynaM-INT study.

BACKGROUND: Stress-related disorders such as anxiety and depression are highly prevalent and cause a tremendous burden for affected individuals and society. In order to improve prevention strategies, knowledge regarding resilience mechanisms and ways to boost them is highly needed. In the Dynamic Modelling of Resilience - interventional multicenter study (DynaM-INT), we will conduct a large-scale feasibility and preliminary efficacy test for two mobile- and wearable-based just-in-time adaptive interventions (JITAIs), designed to target putative resilience mechanisms. Deep participant phenotyping at baseline serves to identify individual predictors for intervention success in terms of target engagement and stress resilience. METHODS: DynaM-INT aims to recruit N = 250 healthy but vulnerable young adults in the transition phase between adolescence and adulthood (18-27 years) across five research sites (Berlin, Mainz, Nijmegen, Tel Aviv, and Warsaw). Participants are included if they report at least three negative burdensome past life events and show increased levels of internalizing symptoms while not being affected by any major mental disorder. Participants are characterized in a multimodal baseline phase, which includes neuropsychological tests, neuroimaging, bio-samples, sociodemographic and psychological questionnaires, a video-recorded interview, as well as ecological momentary assessments (EMA) and ecological physiological assessments (EPA). Subsequently, participants are randomly assigned to one of two ecological momentary interventions (EMIs), targeting either positive cognitive reappraisal or reward sensitivity. During the following intervention phase, participants' stress responses are tracked using EMA and EPA, and JITAIs are triggered if an individually calibrated stress threshold is crossed. In a three-month-long follow-up phase, parts of the baseline characterization phase are repeated. Throughout the entire study, stressor exposure and mental health are regularly monitored to calculate stressor reactivity as a proxy for outcome resilience. The online monitoring questionnaires and the repetition of the baseline questionnaires also serve to assess target engagement. DISCUSSION: The DynaM-INT study intends to advance the field of resilience research by feasibility-testing two new mechanistically targeted JITAIs that aim at increasing individual stress resilience and identifying predictors for successful intervention response. Determining these predictors is an important step toward future randomized controlled trials to establish the efficacy of these interventions.

The STRESS-NL database: A resource for human acute stress studies across the Netherlands.

Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ±â€¯16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts.

The functional role of cardiac activity in perception and action.

SKORA, L.I., J.J.A. LIVERMORE and K. Roelofs. The functional role of cardiac activity in perception and action. NEUROSCI BIOBEHAV REV X(X) XXX-XXX, 2022. Patterns of cardiac activity continuously vary with environmental demands, accelerating or decelerating depending on circumstances. Simultaneously, cardiac cycle affects a host of higher-order processes, where systolic baroreceptor activation largely impairs processing. However, a unified functional perspective on the role of cardiac signal in perception and action has been lacking. Here, we combine the existing strands of literature and use threat-, anticipation-, and error-related cardiac deceleration to show that deceleration is an adaptive mechanism dynamically attenuating the baroreceptor signal associated with each heartbeat to minimise its impact on exteroceptive processing. This mechanism allows to enhance attention afforded to external signal and prepare an appropriate course of action. Conversely, acceleration is associated with a reduced need to attend externally, enhanced action tendencies and behavioural readjustment. This novel account demonstrates that dynamic adjustments in heart rate serve the purpose of regulating the level of precision afforded to internal versus external evidence in order to optimise perception and action. This highlights that the importance of cardiac signal in adaptive behaviour lies in its dynamic regulation.

Endogenous testosterone levels are predictive of symptom reduction with exposure therapy in social anxiety disorder.

The Hypothalamus-Pituitary-Gonadal (HPG)-axis, and testosterone in particular, play an important role in social motivational behavior. Socially avoidant behavior, characteristic of social anxiety disorder (SAD), has been linked to low endogenous testosterone levels, and can be alleviated by testosterone administration in SAD. Although these beneficial effects of testosterone may translate to exposure therapy, it remains unknown whether testosterone increases prior to exposure improve therapy outcomes. In this proof-of-principle study, we tested whether pre-exposure (reactive and baseline) endogenous testosterone levels were predictive of exposure outcome in SAD. Seventy-three participants (52 females) with a principal SAD diagnosis performed four speech exposures: three during one standardized exposure therapy session and one at post-assessment one week later. Subjective fear levels were assessed before and after each speech exposure and social anxiety symptoms were assessed at pre- and post-treatment. Pre-treatment testosterone levels were assessed before (baseline) and in response to a pre-exposure instruction session (reactive). Pre-treatment testosterone levels were not related to fear levels during exposure therapy, but predicted pre- to post-treatment reductions in social anxiety symptom severity. Specifically, low baseline and high reactive pre-treatment testosterone levels were associated with larger reductions in social anxiety symptom severity. These findings support the role of HPG-axis in social fear reduction. Specifically, our finding that high reactive testosterone as well as low baseline testosterone predicted exposure outcome in SAD, suggests that good reactivity of the HPG-axis is a promising marker for the symptom-reducing effects of exposure therapy.

Stress matters: Randomized controlled trial on the effect of probiotics on neurocognition.

Probiotics are microorganisms that provide health benefits when consumed. In animals, probiotics reverse gut microbiome-related alterations in depression-like symptoms, in cognition, and in hormonal stress response. However, in humans, a causal understanding of the gut-brain link in emotion and cognition is lacking. Additionally, whether the effects of probiotics on neurocognition are visible only in presence of stress, remains unclear. We investigated the effects of a multispecies probiotic (Ecologic®Barrier) on specific neurocognitive measures of emotion reactivity, emotion regulation, and cognitive control using fMRI. Critically, we also tested whether probiotics can buffer against the detrimental effects of acute stress on working memory. In a double blind, randomized, placebo-controlled, between-subjects intervention study, 58 healthy participants were tested once before and once after a 28-day intervention. Without stress induction, probiotics did not affect brain, behavioral, or related self-report measures. However, relative to placebo, the probiotics group did show a significant stress-related increase in working memory performance after supplementation. This change was associated with intervention-related neural changes in frontal cortex during cognitive control exclusively in the probiotics group. Overall, our results show neurocognitive effects of a multispecies probiotic in healthy women only under challenging situations, buffering against the detrimental effects of stress on cognition.

Testosterone in human studies: Modest associations between plasma and salivary measurements.

Testosterone is involved in many processes like aggression and mood disorders. As it may easily diffuse from blood into saliva, salivary testosterone is thought to reflect plasma free testosterone level. If so, it would provide a welcome noninvasive and less stressful alternative to blood sampling. Past research did not reveal consensus regarding the strength of the association, but sample sizes were small. This study aimed to analyse the association in a large cohort. In total, 2,048 participants (age range 18-65 years; 696 males and 1,352 females) were included and saliva (using cotton Salivettes) and plasma were collected for testosterone measurements. Levels were determined by enzyme-linked immunosorbent assay and radioimmunoassay respectively. Free testosterone was calculated by the Vermeulen algorithm. Associations were determined using linear regression analyses. Plasma total and free testosterone showed a significant association with salivary testosterone in men (adjusted ß = .09, p = .01; and ß = .15, p < .001, respectively) and in women (adjusted ß = .08, p = .004; and crude ß = .09, p = .002 respectively). The modest associations indicate that there are many influencing factors of both technical and biological origin.

Stress, childhood trauma, and cognitive functions in functional neurologic disorders.

Conversion disorder (CD) has traditionally been ascribed to psychologic factors such as trauma, stress, or emotional conflict. Although reference to the psychologic origin of CD has been removed from the criteria list in DSM-5, many theories still incorporate CD as originating from adverse events. This chapter provides a critical review of the literature on stressful life events in CD and discusses current cognitive and neurobiologic models linking psychologic stressors with conversion symptomatology. In addition, we propose a neurobiologic stress model integrating those cognitive models with neuroendocrine stress research and propose that stress and stress-induced changes in hypothalamus-pituitary-adrenal (HPA) axis function may result in cognitive alterations, that in turn contribute to experiencing conversion symptoms. Experimental studies indeed suggest that basal as well as stress-induced changes in HPA axis responding lead to alterations in attentional processing in CD. Although those changes are stronger in traumatized patients, similar patterns have been observed in patients who do not report a history of traumatic events. We conclude that, whereas adverse events may play an important role in many cases of CD, a substantial proportion of patients do not report a history of traumatization or recent stressful events. Studies integrating effects of stress on cognitive functioning in CD are scarce. We propose that, instead of focusing research on defining etiologic events in terms of symptom-eliciting events, future research should work towards an integrated mechanistic account, assessing alterations in cognitive and biologic stress systems in an integrated manner in patients with CD. Such an account may not only serve early symptom detection, it might also provide a starting point for better-targeted interventions.

Altered cortical-amygdala coupling in social anxiety disorder during the anticipation of giving a public speech.

BACKGROUND: Severe stress in social situations is a core symptom of social anxiety disorder (SAD). Connectivity between the amygdala and cortical regions is thought to be important for emotion regulation, a function that is compromised in SAD. However, it has never been tested if and how this connectivity pattern changes under conditions of stress-inducing social evaluative threat. Here we investigate changes in cortical-amygdala coupling in SAD during the anticipation of giving a public speech. METHOD: Twenty individuals with SAD and age-, gender- and education-matched controls (n = 20) participated in this study. During the functional magnetic resonance imaging (fMRI) session, participants underwent three 'resting-state' fMRI scans: one before, one during, and one after the anticipation of giving a public speech. Functional connectivity between cortical emotion regulation regions and the amygdala was investigated. RESULTS: Compared to controls, SAD participants showed reduced functional integration between cortical emotion regulation regions and the amygdala during the public speech anticipation. Moreover, in SAD participants cortical-amygdala connectivity changes correlated with social anxiety symptom severity. CONCLUSIONS: The distinctive pattern of cortical-amygdala connectivity suggests less effective cortical-subcortical communication during social stress-provoking situations in SAD.

Plasminogen activator-1 overexpression decreases experimental postthrombotic vein wall fibrosis by a non-vitronectin-dependent mechanism.

BACKGROUND: Factors associated with postthrombotic syndrome are known clinically, but the underlying cellular processes at the vein wall are not well delineated. Prior work suggests that vein wall damage does not correlate with thrombus resolution but rather with plasminogen activator-1 (PAI-1) and matrix metalloproteinase (MMP) activity. OBJECTIVE: We hypothesized that PAI-1 would confer post venous thrombosis (VT) vein wall protection via a vitronectin (Vn)-dependent mechanism. METHODS: A stasis model of VT was used with harvest over 2 weeks, in wild-type, Vn(-/-) , and PAI-1-overexpressing mice (PAI-1 Tg). RESULTS: PAI-1 Tg mice had larger VT at 6 and 14 days, compared to controls, but Vn(-/-) mice had no alteration of VT resolution. Gene deletion of Vn resulted in an increase in, rather than the expected decrease in, circulating PAI-1 activity. While both Vn(-/-) and PAI-1 Tg had attenuated intimal fibrosis, PAI-1 Tg had significantly less vein wall collagen and a compensatory increase in collagen III gene expression. Both Vn(-/-) and PAI-1 Tg vein wall had less monocyte chemotactic factor-1 and fewer macrophages (F4/80), with significantly less MMP-2 activity and decreased TIMP-1 antigen. Ex vivo assessment of transforming growth factor ß-mediated fibrotic response showed that PAI-1 Tg vein walls had increased profibrotic gene expression (collagens I and III, MMP-2, and α-smooth muscle actin) compared with controls, opposite of the in vivo response. CONCLUSIONS: The absence of Vn increases circulating PAI-1, which positively modulates vein wall fibrosis in a dose-dependent manner. Translationally, PAI-1 elevation may decrease vein wall damage after deep vein thrombosis, perhaps by decreasing macrophage-mediated activities.

Amygdala activation and its functional connectivity during perception of emotional faces in social phobia and panic disorder.

Social phobia (SP) and panic disorder (PD) have been associated with aberrant amygdala responses to threat-related stimuli. The aim of the present study was to examine amygdala function and its connectivity with medial prefrontal cortex (mPFC) during emotional face perception in PD and SP, and the role of illness severity. Blood oxygen level dependent responses while perceiving emotional facial expressions were compared in 14 patients with PD, 17 patients with SP, 8 patients with comorbid PD and SP, and 16 healthy controls. We found that PD, but not SP, was associated with amygdala and lingual gyrus hypoactivation during perception of angry, fearful, happy and neutral faces, compared to healthy participants. No significant effect of PD and SP diagnoses was found on amygdala-mPFC connectivity. A positive correlation of anxiety symptom severity was found on amygdala-dorsal anterior cingulate and dorsal mPFC connectivity during perception of fearful faces. Amygdala hypoactivation suggests reduced responsiveness to positive and negative emotional faces in PD. Symptom severity, but not the presence of PD and SP diagnosis per se, explains most of the abnormalities in amygdala-mPFC connectivity during perception of fearful faces.

Dopamine transporter polymorphisms affect social approach-avoidance tendencies.

There is increasing interest in the role of striatal dopaminergic activity in social approach-avoidance motivation. The 9-repeat allele of the dopamine transporter (DAT) gene, associated with increased striatal dopamine levels, has been found to be related to increased sensitivity to reward. However, it remains unexplored whether this polymorphism influences automatic action tendencies in the social domain. We set out to test experimentally whether human carriers of the 9-repeat allele show increased approach-avoidance tendencies compared to non-9-repeat carriers. One hundred and one healthy adults, genotyped for the DAT gene, performed the social Approach-Avoidance Task, a reaction time task requiring participants to approach or avoid visually presented emotional (happy and angry) faces, by pulling a joystick towards them or pushing the joystick away from themselves, respectively. In accordance with expectations, 9-repeat carriers showed stronger approach-avoidance effects compared to non-9-repeat carriers. These results suggest a role for striatal dopaminergic polymorphisms in motivational responses to social-emotional cues. Our findings may be relevant in the selection of candidate genes in future studies involving social behavior.

Positive and negative life events and personality traits in predicting course of depression and anxiety.

OBJECTIVE: To examine the prognostic value of personality dimensions and negative and positive life events for diagnostic and symptom course trajectories in depressive and anxiety disorder. METHOD: A total of 1209 subjects (18-65 years) with depressive and/or anxiety disorder were recruited in primary and specialized mental health care. Personality dimensions at baseline were assessed with the NEO-FFI and incidence and date of life events retrospectively with a structured interview at 2-year follow-up. DSM-IV-based diagnostic interviews as well as life chart assessments allowed course assessment at both the diagnostic and symptom trajectory level over 2 years. RESULTS: Life events were significantly related to diagnostic and symptom course trajectories of depression and anxiety also after correcting for sociodemographic and clinical characteristics. Only negative life events prospectively predicted longer time to remission of depressive disorder. Prospective associations of neuroticism and extraversion with prognosis of anxiety and depression were greatly reduced after correcting for baseline severity and duration of index disorder. Personality traits did not moderate the effect of life events on 2-year course indicators. CONCLUSIONS: Negative life events have an independent effect on diagnostic and symptom course trajectories of depression and to a lesser extent anxiety unconfounded by sociodemographic, clinical, and personality characteristics.

The Stanford Hypnotic Susceptibility Scale, Form C: normative data of a Dutch student sample.

Norms for the Dutch language version of the Standford Hypnotic Susceptibility Scale, Form C (SHSS:C; Weitzenhoffer & Hilgard, 1962) are presented. These norms are based upon a sample of 135 students at a Dutch university. Generally, the psychometric properties of the Dutch version of the SHSS:C are similar to other language versions. However, the mean score was somewhat lower than that found in the original norming studies at Stanford University.

The question of symptom lateralization in conversion disorder.

OBJECTIVE: The purpose of this study was to determine whether or not conversion symptoms are lateralized. Studies have shown a predominant left-oriented manifestation of symptoms for most somatoform disorders. The reports in the literature on the lateralization of conversion symptoms, however, are rather conflicting. They show left-sided, right-sided, or no symptom lateralization in conversion disorders. METHODS: One hundred fourteen patients with conversion disorder were screened for symptom lateralization. RESULTS: Those patients with unilateral symptoms (32.5%) showed no significant bias toward left or right symptom presentation. CONCLUSION: Based on these results, and the conflicting findings from previous studies, we conclude that there is insufficient support for lateralization theories in conversion disorder.