Investigating adverse daily life effects following a psychosocial laboratory stress task, and the moderating role of Psychopathology.

Laboratory stress tasks are necessary to closely investigate the stress response in a controlled environment. However, to our knowledge, no study has tested whether participating in such tasks can pose any daily life adverse effect. Fifty-three healthy participants (46 women) took part in a laboratory session where stress was induced using a typical psychosocial stressor: the repeated Montreal Imaging Stress Task (rMIST). Average levels of negative affect (NA), heart rate (HR), root mean square of successive differences (RMSSD), and skin conductance level (SCL), as well as reactivity across all these parameters as measured with the experience sampling method (ESM) in the four days prior to the laboratory session were compared with the four days following the session. We also assessed whether vulnerability to psychopathology moderated these associations. Findings showed that the task did not pose any significant adverse effect on participants. However, there was an unexpected increase in average RMSSD and a decrease in average SCL pre- to post- task. In addition, more vulnerable individuals were more likely to experience an increase in average levels of NA in the days following the task compared to the days preceding it. Our findings suggest that laboratory stress tasks may pose a significant risk to more vulnerable individuals.

Exploring the role of OXTR gene methylation in attachment development: A longitudinal study.

The current study explored longitudinally whether oxytocin receptor gene methylation (OXTRm) changes moderated the association between parental sensitivity changes and children's attachment changes over three waves. Six hundred six Flemish children (10-12 years, 42.8%-44.8% boys) completed attachment measures and provided salivary OXTRm data on seven CpG sites. Their parents reported their sensitive parenting. Results suggest that OXTRm changes hardly link to attachment (in)security changes after the age of 10. Some support was found for interaction effects between parental sensitivity changes and OXTRm changes on attachment changes over time. Effects suggest that for children with increased OXTRm in the promotor region and decreased methylation in the inhibitor region over time, increased parental sensitivity was associated with increased secure attachment and decreased insecure attachment over time.

Chronic oxytocin administration stimulates the oxytocinergic system in children with autism.

Clinical efficacy of intranasal administration of oxytocin is increasingly explored in autism spectrum disorder, but to date, the biological effects of chronic administration regimes on endogenous oxytocinergic function are largely unknown. Here exploratory biological assessments from a completed randomized, placebo-controlled trial showed that children with autism (n = 79, 16 females) receiving intranasal oxytocin for four weeks (12 IU, twice daily) displayed significantly higher salivary oxytocin levels 24 hours after the last oxytocin nasal spray administration, but no longer at a four-week follow up session. Regarding salivary oxytocin receptor gene (OXTR) epigenetics (DNA-methylation), oxytocin-induced reductions in OXTR DNA-methylation were observed, suggesting a facilitation of oxytocin receptor expression in the oxytocin compared to the placebo group. Notably, heightened oxytocin levels post-treatment were significantly associated with reduced OXTR DNA-methylation and improved feelings of secure attachment. These findings indicate that four weeks of chronic oxytocin administration stimulated the endogenous oxytocinergic system in children with autism.

At the Head and Heart of Oxytocin's Stress-Regulatory Neural and Cardiac Effects: A Chronic Administration RCT in Children with Autism.

INTRODUCTION: Intranasal administration of oxytocin presents a promising new approach to reduce disability associated with an autism spectrum disorder diagnosis. Previous investigations have emphasized the amygdala as the neural foundation for oxytocin's acute effects. However, to fully understand oxytocin's therapeutic potential, it is crucial to gain insight into the neuroplastic changes in amygdala circuitry induced from chronic oxytocin administrations, particularly in pediatric populations. OBJECTIVE: We aimed to examine the impact of a 4-week course of intranasal oxytocin on amygdala functional connectivity in children with autism, compared to placebo. Additionally, we investigated whether oxytocin improves cardiac autonomic arousal, as indexed by high-frequency heart rate variability. METHODS: Fifty-seven children with autism aged 8-12 years (45 boys, 12 girls) participated in a double-blind, randomized pharmaco-neuroimaging trial involving twice-daily administrations of intranasal oxytocin or placebo. Resting-state fMRI scans and simultaneous, in-scanner heart rate recordings were obtained before, immediately after, and 4 weeks after the nasal spray administration period. RESULTS: Significant reductions in intrinsic amygdala-orbitofrontal connectivity were observed, particularly at the 4-week follow-up session. These reductions were correlated with improved social symptoms and lower cardiac autonomic arousal. Further, oxytocin's neural and cardiac autonomic effects were modulated by epigenetic modifications of the oxytocin receptor gene. The effects were more pronounced in children with reduced epigenetic methylation, signifying heightened expression of the oxytocin receptor. CONCLUSION: These findings underscore that a 4-week oxytocin administration course decreases amygdala connectivity and improves cardiac autonomic balance. Epigenetic modulators may explain inter-individual variation in responses to oxytocin.

Endogenous oxytocin levels in children with autism: Associations with cortisol levels and oxytocin receptor gene methylation.

Alterations in the brain's oxytocinergic system have been suggested to play an important role in the pathophysiology of autism spectrum disorder (ASD), but insights from pediatric populations are sparse. Here, salivary oxytocin was examined in the morning (AM) and afternoon (PM) in school-aged children with (n = 80) and without (n = 40) ASD (boys/girls 4/1), and also characterizations of DNA methylation (DNAm) of the oxytocin receptor gene (OXTR) were obtained. Further, cortisol levels were assessed to examine links between the oxytocinergic system and hypothalamic-pituitary-adrenal (HPA) axis signaling. Children with ASD displayed altered (diminished) oxytocin levels in the morning, but not in the afternoon, after a mildly stress-inducing social interaction session. Notably, in the control group, higher oxytocin levels at AM were associated with lower stress-induced cortisol at PM, likely reflective of a protective stress-regulatory mechanism for buffering HPA stress activity. In children with ASD, on the other hand, a significant rise in oxytocin levels from the morning to the afternoon was associated with a higher stress-induced cortisol release in the afternoon, likely reflective of a more reactive stress regulatory release of oxytocin for reactively coping with heightened HPA activity. Regarding epigenetic modifications, no overall pattern of OXTR hypo- or hypermethylation was evident in ASD. In control children, a notable association between OXTR methylation and levels of cortisol at PM was evident, likely indicative of a compensatory downregulation of OXTR methylation (higher oxytocin receptor expression) in children with heightened HPA axis activity. Together, these observations bear important insights into altered oxytocinergic signaling in ASD, which may aid in establishing relevant biomarkers for diagnostic and/or treatment evaluation purposes targeting the oxytocinergic system in ASD.

Differential effect of panic on the DNA methylation of the glucocorticoid receptor gene exon 1F in chronic subjective tinnitus with distress.

OBJECTIVE: Tinnitus can be regarded as a chronic stressor, leading to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis. There is important comorbidity with anxiety, particularly panic, potentially associated with differences in HPA axis functioning and methylation patterns of HPA axis-related genes. This study examines DNA methylation of the glucocorticoid receptor gene ( NR3C1 ) exon 1F in adults with chronic subjective tinnitus and the possible differential effect of panic. METHODS: In a well characterized tinnitus sample ( n  = 22, half of which had co-occurring panic attacks), and unaffected controls ( n  = 31) methylation patterns of the CpG sites were determined using pyrosequencing and compared between groups through linear mixed models. Gene expression was determined using quantitative PCR on mRNA. RESULTS: Comparing the combined tinnitus groups to the control group, no DNA methylation differences were observed; however, the tinnitus group with panic attacks showed consistently higher mean methylation values across all CpGs compared to the tinnitus-only and the control group ( P  = 0.03 following Tukey correction), which became even more pronounced when accounting for childhood trauma ( P  = 0.012). Moreover, a significant positive correlation was found between methylation of the CpG7 site and the Beck Anxiety Inventory total score ( P  = 0.001) in the total population. NR3C1 -1F expression was not significantly different between the three groups. CONCLUSION: Panic is associated with higher DNA methylation of the NR3C1 exon 1F in adults with chronic subjective tinnitus, consistent with the reduced negative glucocorticoid feedback and HPA axis hyperfunction observed in individuals with panic disorder.

Mild daily stress, in interaction with NR3C1 DNA methylation levels, is linked to alterations in the HPA axis and ANS response to acute stress in early adolescents.

BACKGROUND: Daily Hassles (DH) or daily stress - is a mild type of stressor with unique contributions to psychological distress. Yet, most prior studies that investigate the effects of stressful life experiences focus on childhood trauma or on early life stress and little is known about the effects of DH on epigenetic changes in stress system related genes and on the physiological response to social stressors. METHODS: In the present study, conducted among 101 early adolescents (mean age = 11.61; SD = 0.64), we investigated whether Autonomic Nervous System (ANS) (namely heart rate and heart rate variability) and Hypothalamic-Pituitary-Adrenal (HPA) axis functioning (measured as cortisol stress reactivity and recovery) are associated with DNA methylation (DNAm) in the glucocorticoid receptor gene (NR3C1), the level of DH and their interaction. To assess the stress system functioning the TSST protocol was used. RESULTS: Our findings show that higher NR3C1 DNAm in interaction with higher levels of daily hassles, is associated with blunted HPA axis reactivity to psychosocial stress. In addition, higher levels of DH are associated with extended HPA axis stress recovery. In addition, participants with higher NR3C1 DNAm had lower ANS adaptability to stress, specifically lower parasympathetic withdrawal; for heart rate variability this effect was strongest for participants with higher level of DH. CONCLUSIONS: The observation that interaction effects between NR3C1 DNAm levels and daily stress on the functioning of the stress-systems, are already detectable in young adolescents, highlights the importance of early interventions, not only in the case of trauma, but also daily stress. This might help to prevent stress-induced mental and physical disorders later in life.

Short bursts of transcutaneous auricular vagus nerve stimulation enhance evoked pupil dilation as a function of stimulation parameters.

Transcutaneous auricular vagus nerve stimulation (taVNS) is a neurostimulatory technique hypothesised to enhance central noradrenaline. Currently, there is scarce evidence in support of a noradrenergic mechanism of taVNS and limited knowledge on its stimulation parameters (i.e., intensity and pulse width). Therefore, the present study aimed to test whether taVNS enhances pupil dilation, a noradrenergic biomarker, as a function of stimulation parameters. Forty-nine participants received sham (i.e., left ear earlobe) and taVNS (i.e., left ear cymba concha) stimulation in two separate sessions, in a counterbalanced order. We administered short bursts (5s) of seven stimulation settings varying as a function of pulse width and intensity and measured pupil size in parallel. Each stimulation setting was administered sixteen times in separate blocks. We expected short bursts of stimulation to elicit phasic noradrenergic activity as indexed by event-related pupil dilation and event-related temporal derivative. We hypothesised higher stimulation settings, quantified as the total charge per pulse (pulse width x intensity), to drive greater event-related pupil dilation and temporal derivative in the taVNS compared to sham condition. Specifically, we expected stimulation settings in the taVNS condition to be associated with a linear increase in event-related pupil dilation and temporal derivative. We found stimulation settings to linearly increase both pupil measures. In line with our hypothesis, the observed dose-dependent effect was stronger in the taVNS condition. We also found taVNS to elicit more intense and unpleasant sensations than sham stimulation. These results support the hypothesis of a noradrenergic mechanism of taVNS. However, future studies should disentangle whether stimulation elicited sensations mediate the effect of taVNS on evoked pupil dilation.

Is daily-life stress reactivity a measure of stress recovery? An investigation of laboratory and daily-life stress.

Typical measures of laboratory reactivity (i.e. difference between control and stress) and recovery (i.e. difference between stress and post-stress) were compared with a conventional measure of daily-life reactivity, best known as event-related stress. Fifty-three healthy individuals between 19 and 35 years of age took part in a laboratory session where stress was induced using the repeated Montreal Imaging Stress Task and 8 days of experience sampling method. Measures of negative affect, heart rate (HR), HR variability, and skin conductance level were collected. Findings show no strong associations between laboratory and daily life measures with the exception of laboratory affective recovery and daily life reactivity. Findings and their implications are discussed.

The cumulative effect of chronic stress and depressive symptoms affects heart rate in a working population.

Background: Chronic stress and depressive symptoms have both been linked to increased heart rate (HR) and reduced HR variability. However, up to date, it is not clear whether chronic stress, the mechanisms intrinsic to depression or a combination of both cause these alterations. Subclinical cases may help to answer these questions. In a healthy working population, we aimed to investigate whether the effect of chronic stress on HR circadian rhythm depends on the presence of depressive symptoms and whether chronic stress and depressive symptoms have differential effects on HR reactivity to an acute stressor. Methods: 1,002 individuals of the SWEET study completed baseline questionnaires, including psychological information, and 5 days of electrocardiogram (ECG) measurements. Complete datasets were available for 516 individuals. In addition, a subset (n = 194) of these participants completed a stress task on a mobile device. Participants were grouped according to their scores for the Depression Anxiety Stress Scale (DASS) and Perceived Stress Scale (PSS). We explored the resulting groups for differences in HR circadian rhythm and stress reactivity using linear mixed effect models. Additionally, we explored the effect of stress and depressive symptoms on night-time HR variability [root mean square of successive differences (RMSSD)]. Results: High and extreme stress alone did not alter HR circadian rhythm, apart from a limited increase in basal HR. Yet, if depressive symptoms were present, extreme chronic stress levels did lead to a blunted circadian rhythm and a lower basal HR. Furthermore, blunted stress reactivity was associated with depressive symptoms, but not chronic stress. Night-time RMSSD data was not influenced by chronic stress, depressive symptoms or their interaction. Conclusion: The combination of stress and depressive symptoms, but not chronic stress by itself leads to a blunted HR circadian rhythm. Furthermore, blunted HR reactivity is associated with depressive symptoms and not chronic stress.

A Comparative Study Measuring the Difference of Healthcare Workers Reactions Among Those Involved in a Patent Safety Incident and Healthcare Professionals While Working During COVID-19.

OBJECTIVES: This study aimed to describe the differences and similarities in the reaction of the healthcare worker involved in a patient safety incident or during the COVID-19 pandemic. We also compared the differences in support they need. METHODS: A secondary data analysis was performed based on 2 cross-sectional survey studies. One study evaluated the impact of patient safety incidents on healthcare professionals, and the other evaluated the impact of COVID-19. Measurements on mental health reactions and an evaluation of the experienced support system were compared between 883 doctors and 1970 nurses working in different hospitals. RESULTS: Anxiety, difficulties concentrating, doubting knowledge and skills, feeling on their own, feeling unhappy and dejected, feeling uncertain in team, flashbacks, hypervigilance, sleep deprivation, stress and wanting to quit profession were statistically higher in the COVID-19-related groups. Second victims tend to speak about it with their own/close colleagues, whereas healthcare workers working during the COVID-19 pandemic talk more often to their partner and friends. Only a small number talked to a psychologist, but the number who needed to talk to a psychologist but did not is higher than the number who did talk to a psychologist or used professional support in all 5 groups. CONCLUSIONS: The impact of the COVID-19 pandemic on the mental health of healthcare workers is larger than after being involved in a patient safety incident. There is the need for an adequate support system, and the mental health of all healthcare workers needs to be considered. Partners and friend play a more important role in the support experienced during the COVID-19 pandemic, and there is an important need for professional help.

Exhausted Heart Rate Responses to Repeated Psychological Stress in Women With Major Depressive Disorder.

Past research links depression and blunted cardiac vagal reactivity to chronic stress. Yet, to our knowledge no experiment investigates heart rate (variability) responses to a repeated laboratory stressor in patients with depression. Repeated exposure may provide valuable information on stress reactivity in depression. Fifty-nine women (30 inpatients diagnosed with depression and 29 matched controls) underwent two consecutive runs of a mental arithmetic stress paradigm consisting of one baseline and two exposures to control, stress, and recovery phases of 5 min each, in a case-control design. Subjective stress and electrocardiography were recorded. Variance of heart rate (HR) and root mean square of successive RR interval differences (RMSSD) were analyzed using linear mixed models. Overall, physiological parameters (HR and RMSSD) and subjective stress showed a strong group effect (all p < 0.001). In both groups, subjective stress and HR increased in response to stress, but the subjective stress levels of patients with depression did not return to baseline levels after the first stressor and for the remainder of the experiment (all p < 0.004 compared to baseline). Patients' HR reactivity responded oppositely: while HR recovered after the first stress exposure, no reactivity was observed in response to the second exposure. These findings may suggest that the often-reported blunted HR/HRV response to stressors results from exhaustion rather than an incapacity to react to stress. The altered HR reactivity could indicate allostatic (over-) load in depression.

Individual differences in environmental sensitivity at physiological and phenotypic level: Two sides of the same coin?

Young adolescents are hypothesized to differ in their environmental sensitivity, at both phenotypic (i.e., Sensory Processing Sensitivity [SPS]) and physiological (i.e., biological stress response) level. This is the first study that investigated whether individual differences in environmental sensitivity at physiological level could be predicted by individual differences at phenotypic level, as measured with the HSC scale. A total of 101 adolescents (Mage = 11.61, SDage = 0.64) participated in a standardized social stress task (i.e., Trier Social Stress Task-Modified version for children and adolescents (TSST-M)). From baseline to the end of recovery, eight cortisol samples were collected, as well as a continuous measure of Autonomic Nervous System activity. Adolescents reported on SPS and on perceived stress before, during, and after TSST-M. As a follow-up analysis, the quality of the environment, the possible overlap with Neuroticism, and several covariates were considered. Multilevel models were used to investigate within- and between-person differences in stress reactivity across different systems. Results indicate significant individual differences in heart rate, heart rate variability, skin conductance, cortisol, and perceived stress in response to the TSST-M. Only for perceived stress significant differences in SPS were observed, with more sensitive individuals perceiving more negative and less positive affect. For environmental quality and the interaction between SPS and Neuroticism results showed higher recovery rates of heart rate in high quality environments and stronger cortisol responses for adolescents scoring high on both SPS and Neuroticism. Potential explanations for these findings and implications for current theorizing on environmental sensitivity are discussed.

No evidence for a modulating effect of continuous transcutaneous auricular vagus nerve stimulation on markers of noradrenergic activity.

Although transcutaneous auricular vagus nerve stimulation (taVNS) is thought to increase central noradrenergic activity, findings supporting such mechanism are scarce and inconsistent. This study aimed to investigate whether taVNS modulates indirect markers of phasic and tonic noradrenergic activity. Sixty-six healthy participants performed a novelty auditory oddball task twice on separate days: once while receiving taVNS (left cymba concha), once during sham (left earlobe) stimulation. To maximize potential effects, the stimulation was delivered continuously (frequency: 25 Hz; width: 250 µs) at an intensity individually calibrated to the maximal level below pain threshold. The stimulation was administered 10 min before the oddball task and maintained throughout the session. Event-related pupil dilation (ERPD) to target stimuli and pre-stimulus baseline pupil size were assessed during the oddball task as markers of phasic and tonic noradrenergic activity, respectively. Prior to and at the end of stimulation, tonic pupil size at rest, cortisol, and salivary alpha-amylase were assessed as markers of tonic noradrenergic activity. Finally, we explored the effect of taVNS on cardiac vagal activity, respiratory rate, and salivary flow rate. Results showed a greater ERPD to both target and novelty compared to standard stimuli in the oddball task. In contrast to our hypotheses, taVNS did not impact any of the tested markers. Our findings strongly suggest that continuous stimulation of the cymba concha with the tested stimulation parameters is ineffective to increase noradrenergic activity via a vagal pathway.

Blood brain barrier permeability increases with age in individuals with 22q11.2 deletion syndrome.

22q11.2 deletion syndrome (22q11.2DS) is characterised by high rates of psychotic disorders and immune abnormalities. Blood-brain barrier (BBB) permeability is known to be a risk factor for schizophrenia and immune aberrations. OBJECTIVE: To evaluate the relationship between psychosis and BBB permeability in this population. METHODS: We examined two biomarkers for BBB permeability, s100ß and neuron-specific enolase (NSE), in 22q11.2DS individuals with/without psychosis. The first cohort of this Israeli-Belgium study was comprised of 20 22q11.2DS adults (30.58 ± 9.42 years) afflicted with a psychotic disorder, another group of 69 non-psychotic 22q11.2DS adults (23.42 ± 8.36 years), and 58 healthy controls (26.39 ± 7.77 years). A second cohort was comprised of 18 non-psychotic 22q11.2DS Israeli children (5.83 ± 1.55 years) and 14 healthy controls (5.34 ± 1.43 years). NSE and s100ß serum levels were detected in all participants. RESULTS: Both factors were elevated in adults with 22q11.2DS compared to healthy controls, specifically in the non-psychotic sub-group. In contrast, there were no significant differences in their levels between the two groups of the paediatric cohort. CONCLUSIONS: Increased BBB permeability seems to be a trait of 22q11.2DS that evolves sometime in early adulthood. Our findings are in line with previous reports on non-syndromic schizophrenia, and suggest potential novel neural pathways to psychosis in 22q11.2DS.

The association between self-reported stress and cardiovascular measures in daily life: A systematic review.

BACKGROUND: Stress plays an important role in the development of mental illness, and an increasing number of studies is trying to detect moments of perceived stress in everyday life based on physiological data gathered using ambulatory devices. However, based on laboratory studies, there is only modest evidence for a relationship between self-reported stress and physiological ambulatory measures. This descriptive systematic review evaluates the evidence for studies investigating an association between self-reported stress and physiological measures under daily life conditions. METHODS: Three databases were searched for articles assessing an association between self-reported stress and cardiovascular and skin conductance measures simultaneously over the course of at least a day. RESULTS: We reviewed findings of 36 studies investigating an association between self-reported stress and cardiovascular measures with overall 135 analyses of associations between self-reported stress and cardiovascular measures. Overall, 35% of all analyses showed a significant or marginally significant association in the expected direction. The most consistent results were found for perceived stress, high-arousal negative affect scales, and event-related self-reported stress measures, and for frequency-domain heart rate variability physiological measures. There was much heterogeneity in measures and methods. CONCLUSION: These findings confirm that daily-life stress-dynamics are complex and require a better understanding. Choices in design and measurement seem to play a role. We provide some guidance for future studies.

Role of NR3C1 and SLC6A4 methylation in the HPA axis regulation in burnout.

BACKGROUND: Work-related stress and burnout have become major occupational health concerns. Dysregulation of HPA axis is considered one of the central mechanisms and is potentially moderated through epigenetics. In the present study, we aim to investigate epigenetic regulation of the HPA axis in burnout, by focusing on salivary cortisol and cortisone and DNA methylation of the glucocorticoid receptor gene (NR3C1) and the serotonin transporter gene (SLC6A4). METHODS: We conducted a cross-sectional study with 59 subjects with burnout and 70 healthy controls recruited from the general population. All participants underwent a clinical interview and psychological assessment. Saliva samples were collected at 0, 30 and 60 min after awakening and were used to quantify cortisol and cortisone. Pyrosequencing was performed on whole blood-derived DNA to assess DNA methylation. RESULTS: There were no between-group differences in cortisol levels, whereas burnout participants had higher levels of cortisone. Job stress was associated with increased cortisol and cortisone. We observed both increased and decreased NR3C1 and SLC6A4 methylation in the burnout group compared to the control group. Some of these methylation changes correlated with burnout symptoms dimensionally. Increased methylation in a specific CpG in the SLC6A4 promoter region moderated the association between job stress and burnout. DNA methylation in this CpG was also associated with increased cortisol. In addition, average methylation of NR3C1 was negatively associated with cortisone levels. LIMITATIONS: This is a cross-sectional study and therefore no conclusions on causality could be made. CONCLUSIONS: We provide first evidence of changes in DNA methylation of NR3C1 and SLC6A4 in burnout, which were further associated with cortisol and cortisone. Further, increased cortisol and cortisone seemed to reflect job stress rather than burnout itself.

Twenty-Four-Hour Heart Rate Is a Trait but Not State Marker for Depression in a Pilot Randomized Controlled Trial With a Single Infusion of Ketamine.

Background: Abnormalities of heart rate (HR) and its variability are characteristic of major depressive disorder (MDD). However, circadian rhythm is rarely taken into account when statistically exploring state or trait markers for depression. Methods: A 4-day electrocardiogram was recorded for 16 treatment-resistant patients with MDD and 16 age- and sex-matched controls before, and for the patient group only, after a single treatment with the rapid-acting antidepressant ketamine or placebo (clinical trial registration available on https://www.clinicaltrialsregister.eu/ with EUDRACT number 2016-001715-21). Circadian rhythm differences of HR and the root mean square of successive differences (RMSSD) were compared between groups and were explored for classification purposes. Baseline HR/RMSSD were tested as predictors for treatment response, and physiological measures were assessed as state markers. Results: Patients showed higher HR and lower RMSSD alongside marked reductions in HR amplitude and RMSSD variation throughout the day. Excellent classification accuracy was achieved using HR during the night, particularly between 2 and 3 a.m. (90.6%). A positive association between baseline HR and treatment response (r = 0.55, p = 0.046) pointed toward better treatment outcome in patients with higher HR. Heart rate also decreased significantly following treatment but was not associated with improved mood after a single infusion of ketamine. Limitations: Our study had a limited sample size, and patients were treated with concomitant antidepressant medication. Conclusion: Patients with depression show a markedly reduced amplitude for HR and dysregulated RMSSD fluctuation. Higher HR and lower RMSSD in depression remain intact throughout a 24-h day, with the highest classification accuracy during the night. Baseline HR levels show potential for treatment response prediction but did not show potential as state markers in this study. Clinical trial registration: EUDRACT number 2016-001715-21.

Monocyte mitochondrial dysfunction, inflammaging, and inflammatory pyroptosis in major depression.

BACKGROUND: The macrophage theory of depression states that macrophages play an important role in Major Depressive Disorder (MDD). METHODS: MDD patients (N = 140) and healthy controls (N = 120) participated in a cross-sectional study investigating the expression of apoptosis/growth and lipid/cholesterol pathway genes (BAX, BCL10, EGR1, EGR2, HB-EGF, NR1H3, ABCA1, ABCG1, MVK, CD163, HMOX1) in monocytes (macrophage/microglia precursors). Gene expressions were correlated to a set of previously determined and reported inflammation-regulating genes and analyzed with respect to various clinical parameters. RESULTS: MDD monocytes showed an overexpression of the apoptosis/growth/cholesterol and the TNF genes forming an inter-correlating gene cluster (cluster 3) separate from the previously described inflammation-related gene clusters (containing IL1 and IL6). While upregulation of monocyte gene cluster 3 was a hallmark of monocytes of all MDD patients, upregulation of the inflammation-related clusters was confirmed to be found only in the monocytes of patients with childhood adversity. The latter group also showed a downregulation of the cholesterol metabolism gene MVK, which is known to play an important role in trained immunity and proneness to inflammation. CONCLUSIONS: The upregulation of cluster 3 genes in monocytes of all MDD patients suggests a premature aging of the cells, i.e. mitochondrial apoptotic dysfunction and TNF "inflammaging", as a general feature of MDD. The overexpression of the IL-1/IL-6 containing inflammation clusters and the downregulation of MVK in monocytes of patients with childhood adversity indicates a shift in this condition to a more severe inflammation form (pyroptosis) of the cells, additional to the signs of premature aging and inflammaging.

The repeated Montreal Imaging Stress Test (rMIST): Testing habituation, sensitization, and anticipation effects to repeated stress induction.

BACKGROUND: A psychosocial task that can induce comparable levels of stress repeatedly is fundamental to effectively study changes in stress reactivity over time or as a result of an intervention. However, existing tasks have struggled to provide consistent stress responses across repeated trials. AIM: The goal was to assess the efficacy of two different designs of the repeated Montreal Imaging Stress Test (rMIST) in reproducing the same pattern of reactivity over two separate sessions. METHODS: In two different studies, stress was induced using the rMIST on two separate sessions, one week apart. Each study used a different task design. In the first study (53 participants [45 women]; mean age=24.16 [SD=3.29]), the rMIST consisted of a single-longer stress exposure, while the second study (30 participants [27 women]; mean age=21.81 [SD=2.09]) consisted of several shorter stress exposures per session. Self-reported (i.e perceived stress [PS] and negative affect [NA]), physiological (i.e heart rate [HR], root mean square of successive differences [RMSSD]) and hormonal (i.e. salivary cortisol) measures of stress were used. RESULTS: Stress reactivity was comparable across the two repeated stress sessions in both studies. However, baseline HR in the second session increased relative to the first session in the first study, and there was no cortisol response. Additionally, there was a decrease in HR and HRV reactivity within the session on the second study, suggesting a habituation effect not between but within the session itself. CONCLUSION: The rMIST overcomes some of the challenges associated with repeated stress induction. However, an anticipation effect and a lack of cortisol response indicate that further adjustments to the task are necessary. Finally, task design is important for repeated stress reactivity.