Psychological Resilience Factors and Their Association With Weekly Stressor Reactivity During the COVID-19 Outbreak in Europe: Prospective Longitudinal Study.

BACKGROUND: Cross-sectional relationships between psychosocial resilience factors (RFs) and resilience, operationalized as the outcome of low mental health reactivity to stressor exposure (low "stressor reactivity" [SR]), were reported during the first wave of the COVID-19 pandemic in 2020. OBJECTIVE: Extending these findings, we here examined prospective relationships and weekly dynamics between the same RFs and SR in a longitudinal sample during the aftermath of the first wave in several European countries. METHODS: Over 5 weeks of app-based assessments, participants reported weekly stressor exposure, mental health problems, RFs, and demographic data in 1 of 6 different languages. As (partly) preregistered, hypotheses were tested cross-sectionally at baseline (N=558), and longitudinally (n=200), using mixed effects models and mediation analyses. RESULTS: RFs at baseline, including positive appraisal style (PAS), optimism (OPT), general self-efficacy (GSE), perceived good stress recovery (REC), and perceived social support (PSS), were negatively associated with SR scores, not only cross-sectionally (baseline SR scores; all P<.001) but also prospectively (average SR scores across subsequent weeks; positive appraisal (PA), P=.008; OPT, P<.001; GSE, P=.01; REC, P<.001; and PSS, P=.002). In both associations, PAS mediated the effects of PSS on SR (cross-sectionally: 95% CI -0.064 to -0.013; prospectively: 95% CI -0.074 to -0.0008). In the analyses of weekly RF-SR dynamics, the RFs PA of stressors generally and specifically related to the COVID-19 pandemic, and GSE were negatively associated with SR in a contemporaneous fashion (PA, P<.001; PAC,P=.03; and GSE, P<.001), but not in a lagged fashion (PA, P=.36; PAC, P=.52; and GSE, P=.06). CONCLUSIONS: We identified psychological RFs that prospectively predict resilience and cofluctuate with weekly SR within individuals. These prospective results endorse that the previously reported RF-SR associations do not exclusively reflect mood congruency or other temporal bias effects. We further confirm the important role of PA in resilience.

Dynamic Modelling of Mental Resilience in Young Adults: Protocol for a Longitudinal Observational Study (DynaM-OBS).

BACKGROUND: Stress-related mental disorders are highly prevalent and pose a substantial burden on individuals and society. Improving strategies for the prevention and treatment of mental disorders requires a better understanding of their risk and resilience factors. This multicenter study aims to contribute to this endeavor by investigating psychological resilience in healthy but susceptible young adults over 9 months. Resilience is conceptualized in this study as the maintenance of mental health or quick recovery from mental health perturbations upon exposure to stressors, assessed longitudinally via frequent monitoring of stressors and mental health. OBJECTIVE: This study aims to investigate the factors predicting mental resilience and adaptive processes and mechanisms contributing to mental resilience and to provide a methodological and evidence-based framework for later intervention studies. METHODS: In a multicenter setting, across 5 research sites, a sample with a total target size of 250 young male and female adults was assessed longitudinally over 9 months. Participants were included if they reported at least 3 past stressful life events and an elevated level of (internalizing) mental health problems but were not presently affected by any mental disorder other than mild depression. At baseline, sociodemographic, psychological, neuropsychological, structural, and functional brain imaging; salivary cortisol and α-amylase levels; and cardiovascular data were acquired. In a 6-month longitudinal phase 1, stressor exposure, mental health problems, and perceived positive appraisal were monitored biweekly in a web-based environment, while ecological momentary assessments and ecological physiological assessments took place once per month for 1 week, using mobile phones and wristbands. In a subsequent 3-month longitudinal phase 2, web-based monitoring was reduced to once a month, and psychological resilience and risk factors were assessed again at the end of the 9-month period. In addition, samples for genetic, epigenetic, and microbiome analyses were collected at baseline and at months 3 and 6. As an approximation of resilience, an individual stressor reactivity score will be calculated. Using regularized regression methods, network modeling, ordinary differential equations, landmarking methods, and neural net-based methods for imputation and dimension reduction, we will identify the predictors and mechanisms of stressor reactivity and thus be able to identify resilience factors and mechanisms that facilitate adaptation to stressors. RESULTS: Participant inclusion began in October 2020, and data acquisition was completed in June 2022. A total of 249 participants were assessed at baseline, 209 finished longitudinal phase 1, and 153 finished longitudinal phase 2. CONCLUSIONS: The Dynamic Modelling of Resilience-Observational Study provides a methodological framework and data set to identify predictors and mechanisms of mental resilience, which are intended to serve as an empirical foundation for future intervention studies. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39817.

Mild early-life stress exaggerates the impact of acute stress on corticolimbic resting-state functional connectivity.

Abundant evidence shows that early-life stress (ELS) predisposes for the development of stress-related psychopathology when exposed to stressors later in life, but the underlying mechanisms remain unclear. To study predisposing effects of mild ELS on stress sensitivity, we examined in a healthy human population the impact of a history of ELS on acute stress-related changes in corticolimbic circuits involved in emotional processing (i.e., amygdala, hippocampus and ventromedial prefrontal cortex [vmPFC]). Healthy young male participants (n = 120) underwent resting-state functional magnetic resonance imaging (fMRI) in two separate sessions (stress induction vs. control). The Childhood Trauma Questionnaire (CTQ) was administered to index self-reported ELS, and stress induction was verified using salivary cortisol, blood pressure, heart rate and subjective affect. Our findings show that self-reported ELS was negatively associated with baseline cortisol, but not with the acute stress-induced cortisol response. Critically, individuals with more self-reported ELS exhibited an exaggerated reduction of functional connectivity in corticolimbic circuits under acute stress. A mediation analysis showed that the association between ELS and stress-induced changes in amygdala-hippocampal connectivity became stronger when controlling for basal cortisol. Our findings show, in a healthy sample, that the effects of mild ELS on functioning of corticolimbic circuits only become apparent when exposed to an acute stressor and may be buffered by adaptations in hypothalamic-pituitary-adrenal axis function. Overall, our findings might reveal a potential mechanism whereby even mild ELS might confer vulnerability to exposure to stressors later in adulthood.

Molecular characterization of the stress network in individuals at risk for schizophrenia.

The biological mechanisms underlying inter-individual differences in human stress reactivity remain poorly understood. We aimed to identify the molecular underpinning of aberrant neural stress sensitivity in individuals at risk for schizophrenia. Linking mRNA expression data from the Allen Human Brain Atlas to task-based fMRI revealed 201 differentially expressed genes in cortex-specific brain regions differentially activated by stress in individuals with low (healthy siblings of schizophrenia patients) or high (healthy controls) stress sensitivity. These genes are associated with stress-related psychiatric disorders (e.g. schizophrenia and anxiety) and include markers for specific neuronal populations (e.g. ADCYAP1, GABRB1, SSTR1, and TNFRSF12A), neurotransmitter receptors (e.g. GRIN3A, SSTR1, GABRB1, and HTR1E), and signaling factors that interact with the corticosteroid receptor and hypothalamic-pituitary-adrenal axis (e.g. ADCYAP1, IGSF11, and PKIA). Overall, the identified genes potentially underlie altered stress reactivity in individuals at risk for schizophrenia and other psychiatric disorders and play a role in mounting an adaptive stress response in at-risk individuals, making them potentially druggable targets for stress-related diseases.

The Role of Stress in Bipolar Disorder.

Stress is a major risk factor for bipolar disorder. Even though we do not completely understand how stress increases the risk for the onset and poorer course of bipolar disorder, knowledge of stress physiology is rapidly evolving. Following stress, stress hormones - including (nor)adrenaline and corticosteroid - reach the brain and change neuronal function in a time-, region-, and receptor-dependent manner. Stress has direct consequences for a range of cognitive functions which are time-dependent. Directly after stress, emotional processing is increased at the cost of higher brain functions. In the aftermath of stress, the reverse is seen, i.e., increased executive function and contextualization of information. In bipolar disorder, basal corticosteroid levels (under non-stressed conditions) are generally found to be increased with blunted responses in response to experimental stress. Moreover, patients who have bipolar disorder generally show impaired brain function, including reward processing. There is some evidence for a causal role of (dysfunction of) the stress system in the etiology of bipolar disorder and their effects on brain system functionality. However, longitudinal studies investigating the functionality of the stress systems in conjunction with detailed information on the development and course of bipolar disorder are vital to understand in detail how stress increases the risk for bipolar disorder.

Disrupted upregulation of salience network connectivity during acute stress in siblings of schizophrenia patients.

BACKGROUND: An adaptive neural stress response is essential to adequately cope with a changing environment. It was previously argued that sympathetic/noradrenergic activity during acute stress increases salience network (SN) connectivity and reduces executive control network (ECN) connectivity in healthy controls, with opposing effects in the late aftermath of stress. Altered temporal dynamics of these networks in response to stress are thought to play a role in the development of psychopathology in vulnerable individuals. METHODS: We exposed male healthy controls (n = 40, mean age = 33.9) and unaffected siblings of schizophrenia patients (n = 39, mean age = 33.2) to the stress or control condition of the trier social stress test and subsequently investigated resting state functional connectivity of the SN and ECN directly after and 1.5 h after stress. RESULTS: Acute stress resulted in increased functional connectivity within the SN in healthy controls, but not in siblings (group × stress interaction pfwe < 0.05). In the late aftermath of stress, stress reduced functional connectivity within the SN in both groups. Moreover, we found increased functional connectivity between the ECN and the cerebellum in the aftermath of stress in both healthy controls and siblings of schizophrenia patients. CONCLUSIONS: The results show profound differences between siblings of schizophrenia patients and controls during acute stress. Siblings lacked the upregulation of neural resources necessary to quickly and adequately cope with a stressor. This points to a reduced dynamic range in the sympathetic response, and may constitute a vulnerability factor for the development of psychopathology in this at-risk group.

Reward-Related Striatal Responses Following Stress in Healthy Individuals and Patients With Bipolar Disorder.

BACKGROUND: Stress has a major impact on the onset and recurrence of mood episodes in bipolar disorder (BD), but the underlying mechanisms remain unknown. Previous studies have shown distinct time-dependent effects of stress on reward processing in healthy individuals. Impaired reward processing is a core characteristic of BD, and altered reward processing during recovery from stress could influence the development and course of bipolar disorder. METHODS: We investigated brain responses during reward processing 50 minutes after stress using functional magnetic resonance imaging in 40 healthy control subjects and 40 patients with euthymic BD assigned to either an acute stress test (Trier Social Stress Test) or a no-stress condition. RESULTS: Acute stress increased cortisol levels in both healthy control subjects and patients with BD. Ventral striatal responses to reward outcome were increased in healthy control subjects during stress recovery but not in patients with BD. For anticipation, no differences were found between the groups following stress. CONCLUSIONS: For the first time, we show altered reward processing in patients with BD during the recovery phase of stress. These data suggest reduced neural flexibility of hedonic signaling in response to environmental challenges. This may increase the susceptibility to stressful life events in the future and play a role in the development of further psychopathology in the longer term.

Glucocorticoid receptor exon 1F methylation and the cortisol stress response in health and disease.

Childhood trauma has been proposed to increase vulnerability to develop psychopathology in part through an altered cortisol stress response. Research in rats has suggested that this effect is mediated by methylation in the glucocorticoid receptor 17 region (GR-17 or GR-1F in humans), with higher methylation after poor maternal care leading to an increased cortisol stress response in adulthood. In humans, the associations between childhood trauma and GR-1F methylation or the cortisol stress response are equivocal. Remarkably, evidence for the relation between GR-1F methylation and the cortisol stress response has been conflicting as well. To further explore this, we investigated the associations of peripheral GR-1F methylation (52 CpGs) with the cortisol stress response (Trier Social Stress Test) and with childhood trauma in three independent studies (total N = 241) including healthy controls, patients with schizophrenia and bipolar disorder and unaffected siblings of patients with one of these disorders. We did not find any significant association between GR-1F methylation and the cortisol stress response (areas under the curve) or childhood trauma, nor did we observe any group differences between patients, siblings and healthy controls. Our findings do not support GR-1F methylation as a proxy for the cortisol stress response, nor its link with childhood trauma or psychopathology. These results suggest that multifactorial models for stress-related psychopathology are needed. Alternatively, future longitudinal studies may reveal GR-1F methylation to be a useful parameter at an individual level.

Divergent influences of anterior cingulate cortex GABA concentrations on the emotion circuitry.

Neuroimaging research has revealed that emotion processing recruits a widespread neural network including the dorsal anterior cingulate cortex (dACC), hippocampus, and amygdala. Recent studies have started to investigate the role of the primary inhibitory neurotransmitter γ-aminobutyric acid (GABA) on brain function, but little is known about the influences of GABA on this emotion circuitry. Using magnetic resonance spectroscopy, we investigated the role of GABA levels in the dACC on emotion processing by presenting emotional and neutral pictures to 68 healthy male participants during functional magnetic resonance imaging. Results revealed opposing associations of dACC GABA levels and neural activity. GABA levels were positively correlated with blood oxygen level dependent (BOLD) responses to emotional stimuli in the amygdala and to emotional and neutral stimuli in the hippocampus. In contrast, GABA levels were negatively correlated with BOLD responses for the comparison between positive and negative stimuli in the dACC. Our results suggest positive influences of dACC GABA on BOLD responses in the hippocampus and amygdala, and negative influences on BOLD responses in the dACC that are dependent on emotional valence.

GABA Concentrations in the Anterior Cingulate Cortex Are Associated with Fear Network Function and Fear Recovery in Humans.

Relapse of fear after successful treatment is a common phenomenon in patients with anxiety disorders. Animal research suggests that the inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays a key role in the maintenance of extinguished fear. Here, we combined magnetic resonance spectroscopy and functional magnetic resonance imaging to investigate the role of GABA in fear recovery in 70 healthy male participants. We associated baseline GABA levels in the dorsal anterior cingulate cortex (dACC) to indices of fear recovery as defined by changes in skin conductance responses (SCRs), blood oxygen level dependent responses, and functional connectivity from fear extinction to fear retrieval. The results showed that high GABA levels were associated with increased SCRs, enhanced activation of the right amygdala, and reduced amygdala-ventromedial prefrontal cortex connectivity during fear recovery. Follow-up analyses exclusively for the extinction phase showed that high GABA levels were associated with reduced amygdala activation and enhanced amygdala-ventromedial prefrontal cortex connectivity, despite the absence of correlations between GABA and physiological responses. Follow-up analyses for the retrieval phase did not show any significant associations with GABA. Together, the association between GABA and increases in SCRs from extinction to retrieval, without associations during both phases separately, suggests that dACC GABA primarily inhibits the consolidation of fear extinction. In addition, the opposite effects of GABA on amygdala activity and connectivity during fear extinction compared to fear recovery suggest that dACC GABA may initially facilitate extinction learning.