Triggered by your heart: Effects of cardioafferent traffic and stress on automatic responses in a Simon task.

Variations in cardioafferent traffic are relayed to the brain via arterial baroreceptors and have been shown to modulate perceptual processing. However, less is known about the cognitive-behavioral consequences of these effects and their role during stress. Here, we investigated in how far automatic responses during the Simon task were modulated by exposure to a laboratory stressor and the different phases of the cardiac cycle. In this study, 30 participants performed three blocks of a combined horizontal and vertical Simon task, which is characterized by either sensorimotor or cognitive response conflicts, respectively. Before each block, subjects were exposed to both the cold pressor test (CPT) and a control condition according to a within-subjects design. Target stimuli were presented during either systole or diastole. Behavioral and EEG-correlates of task processing were assessed along with subjective, cardiovascular, and endocrine measures of stress. The stress induction was successful yielding significant increases in all these measures compared to control. Moreover, we found the expected Simon effects: in incompatible compared to compatible trials performance was decreased and LRP latency as well as anterior N2 area increased. Importantly, accuracy was improved in compatible but reduced in incompatible trials during systole vs. diastole but only in the horizontal Simon condition. Stress dampened N2 area, however, no interactions with cardiac cycle were evident. These results indicate a faciliatory effect of cardioafferent traffic on automated sensorimotor processes.

Stress from early life to adulthood: Is there a protective role of cognitive control?

Early life events can have long-lasting effects that may impact the quality of life into adulthood. The link between childhood adversities and adult mental and physical health is well documented, however, the underlying mechanisms remain poorly understood. Executive functions are assumed to be a key factor in successfully dealing with cognitive-emotional challenges thereby contributing to stress resilience and mental health across the lifespan. Here, we examined whether cognitive control moderates the link between early life adversity and depression. Data was available from a sample of 424 participants aged 20-70 years (Clinicaltrials.gov: NCT05155397). They performed in the Stroop task and behavior as well as frontal theta power were recorded. Negative childhood experiences were assessed with the Childhood Trauma Questionnaire (CTQ), chronic stress was measured with the Trier Inventory for Chronic Stress (TICS) and depression symptoms with Beck's Depression Inventory (BDI). The CTQ predicted symptoms of chronic stress and depression. Regression models pointed to the TICS as a crucial mediator in the relationship between CTQ and BDI. However, parameters of cognitive control demonstrated a rather weak effect as moderators. These results indicate that chronic stress is an important mediator linking childhood trauma to depression but suggest only a limited role for cognitive control.

Immediate and Delayed Salivary Cytokine Responses during Repeated Exposures to Cold Pressor Stress.

INTRODUCTION: Excessive stress is increasingly recognized as an important trigger of many diseases prevalent in modern societies, and monitoring such stress-related effects could aid prevention. The measurement of salivary markers of inflammation is emerging as a promising tool to non-invasively quantify stress' effects on immune processes in everyday life and thereby detect early aberrations before the manifestation of serious health problems. However, more laboratory-controlled research is needed in order to establish the timescale and determinants of salivary cytokine responses to acute stress. METHODS: We repeatedly exposed participants to Cold Pressor Stress Test (CPT) or a control procedure and measured a wide array of salivary cytokines as well as subjective, cardiovascular, and cortisol stress reactions. CPT exposure was repeated every 15 min, 3 times in total, with a duration of 3 min each. Saliva was sampled immediately after the first two exposures as well as in 15-min intervals until 60 min after the onset of the first intervention. RESULTS: We found that many cytokines were detectable in saliva. Specific stress effects were limited to IL-8 and IL-6, however, which decreased immediately or 15 min after stress onset, respectively. Moreover, IL-8 was negatively correlated to cortisol output in the stress but not in the control group. Significant increases were also observed in salivary TNFα and IFNγ; however, these effects were similar under both stress and control conditions. DISCUSSION: Our results show that particular salivary cytokines may be sensitive to immediate effects of acute CPT-induced stress and also highlight the importance of employing control procedures to discern stress effects from unrelated variations in salivary cytokines.

Stress exposure, hand preference, and hand skill: A deep phenotyping approach.

ABSTRACTStress exposure and reactivity may show differential associations with handedness, but shallow phenotyping may influence the current knowledge. Importantly, different handedness measures do not necessarily show high correlations with each other and should not be used interchangeably as they may reflect different dimensions of laterality. Here, data on handedness from 599 participants in the population-based, longitudinal Dortmund Vital Study was used to determine various asymmetry indices. Hand preference was assessed with the Edinburgh Handedness Inventory (EHI) and the lateral preference inventory (LPI) measuring handedness, footedness, earedness, and eyedness. Hand performance was determined using the pegboard test. In addition, data on several dimensions of stress exposure and reactivity, including hair cortisol, and mental well-being was analysed to determine associations with handedness. All handedness measures correlated significantly with each other, with the strongest correlation between the EHI and the LPI handedness score. The EHI and LPI hand measures resulted in the highest effect sizes and most consistent correlations with stress or mental well-being. In contrast, the pegboard test only showed very little association with the stress and mental well-being measures. This highlights the importance of handedness phenotyping. Including preference measures is recommended to disentangle the link between handedness and mental health.

Stress effects on the top-down control of visuospatial attention: Evidence from cue-dependent alpha oscillations.

Stress is assumed to inhibit the top-down control of attention and to facilitate bottom-up processing. Evidence from human experiments, however, remains scarce. Previous studies have addressed how stress affects the interplay of bottom-up and top-down mechanisms of attention. A key open question is in how far such effects can actually be attributed to a stress-induced modulation of top-down attention control. We sought to isolate top-down from bottom-up effects by assessing stress effects on anticipatory changes in alpha oscillations that precede stimulus processing. Participants performed in a cued target detection task in which a cue prompted them to covertly shift their attention to left or right screen positions, 20 min after being exposed to the bilateral feet cold pressor test or a warm water control procedure. The stressor led to a substantial increase in cortisol, peaking 20 min post stressor, along with rises in heart rate, blood pressure, and subjective ratings of stress and arousal. As expected, cued attention deployment led to higher alpha power over posterior electrodes contralateral versus ipsilateral to the attended hemifield during the cue-target interval. Importantly, this purely endogenous effect was potentiated by stress, however, significant differences were restricted to the middle of the cue-target interval and thus temporally separated from the appearance of the target. These results indicate that stress does not impair top-down attentional control per se but may introduce a qualitative change modulating the way attention is deployed to meet action goals.

Promoter haplotypes of the corticotropin-releasing hormone encoding gene modulate the physiological stress response in vitro and in vivo.

The corticotropin-releasing hormone (CRH) is a neuropeptide mediating stress responses. CRH exerts effects via the hypothalamus pituitary adrenal axis as well as immediate effects on the sympathetic-adrenal-medullary system. Genetic variants of the CRH promoter were previously found to be associated with altered CRH promoter activity and physiological reactions. Functional characterization of three CRH promoter haplotypes have been performed in vitro using a reporter gene assay under different stimulation conditions. Furthermore, 232 healthy subjects were genotyped and the influence of CRH haplotypes on basal parameters such as post-awakening cortisol and blood pressure as well as on stress reactivity measured after socially evaluated cold pressor test (SeCPT) was investigated. In vitro, CRH haplotype 2 showed the highest promoter activity under baseline conditions and after forskolin stimulation compared with other haplotypes. Forskolin treatment resulted in a two fold increase of haplotype 2 promoter activity compared with the baseline condition. Cell line-dependent promoter activation was found after hydrocortisone treatment. In vivo, CRH haplotype 2 carriers showed significant higher baseline blood pressure (p = .002) and blood pressure after SeCPT (p < .001), but did not differ in cortisol levels. This study provides converging evidence for the importance of CRH promoter variants on physiological stress response parameters.

Stress and selective attention: Immediate and delayed stress effects on inhibition of return.

The relationship between attention and stress is far from understood. In fact, some studies reported better attentional selection during and after stress, some studies reported worse attentional selection, and some studies reported no effects of stress on attentional selection at all. We argue that given the complexity of both concepts more data are needed as to ultimately understand this relationship. Here we use an established attentional task that yields the inhibition of return (IOR) effect which is assumed to tap attentional control of oculomotor behavior. Participants were stressed with a Cold Pressor Test (CPT) and immediate and delayed effects of stress on hypothalamus-pituitary-adrenal (HPA) axis activation and IOR were analyzed. IOR was neither by immediate nor by delayed after-effects of the CPT stress procedure modulated, instead, we observed reliable and significant IOR in all experimental conditions. Attentional control of oculomotor behavior is therefore not altered after CPT stress, nor related to the post-stress activity of the HPA axis.

Enhanced stress response by a bilateral feet compared to a unilateral hand Cold Pressor Test.

The Cold Pressor Test (CPT) is a frequently employed laboratory stress protocol. However, with many experimental designs the application in its classic form (immersion of the dominant hand into ice-water) is problematic as unilateral stimulation may need to be avoided and/or hands are required for further measurements. Here, we describe a simple modification of the classic CPT in which both feet are immersed into ice-water and compare the evoked neuroendocrine stress response to the classic CPT in a within-subjects design. Twenty-four healthy participants were exposed to each of both CPT versions on two subsequent days in randomized order. Heart rate, blood pressure, salivary alpha-amylase and cortisol were measured at baseline and during or after CPT exposition, respectively, along with subjective ratings of pain and stress. The bilateral feet CPT induced marked increases in all measured stress parameters. Moreover, with the exception of blood pressure, autonomic and endocrine responses were enhanced compared to the classic CPT. The bilateral feet CPT thus is a valid and simple modification and may be useful when the application of the classic CPT is unfeasible or a stronger neuroendocrine stress response is of interest.

Intranasal insulin increases regional cerebral blood flow in the insular cortex in men independently of cortisol manipulation.

Insulin and cortisol play a key role in the regulation of energy homeostasis, appetite, and satiety. Little is known about the action and interaction of both hormones in brain structures controlling food intake and the processing of neurovisceral signals from the gastrointestinal tract. In this study, we assessed the impact of single and combined application of insulin and cortisol on resting regional cerebral blood flow (rCBF) in the insular cortex. After standardized periods of food restriction, 48 male volunteers were randomly assigned to receive either 40 IU intranasal insulin, 30 mg oral cortisol, both, or neither (placebo). Continuous arterial spin labeling (CASL) sequences were acquired before and after pharmacological treatment. We observed a bilateral, locally distinct rCBF increase after insulin administration in the insular cortex and the putamen. Insulin effects on rCBF were present regardless of whether participants had received cortisol or not. Our results indicate that insulin, but not cortisol, affects blood flow in human brain structures involved in the regulation of eating behavior.

Heart rate response to post-learning stress predicts memory consolidation.

Stressful experiences are often well remembered, an effect that has been explained by beta-adrenergic influences on memory consolidation. Here, we studied the impact of stress induced heart rate (HR) responses on memory consolidation in a post-learning stress paradigm. 206 male and female participants saw 52 happy and angry faces immediately before being exposed to the Cold Pressor Test or a non-stressful control procedure. Memory for the faces and their respective expression was tested twice, after 30 min and on the next day. High HR responders (in comparison to low HR responders as well as to the non-stressful control group) showed enhanced recognition memory one day after learning. Our results show that beta-adrenergic activation elicited shortly after learning enhances memory consolidation and that the stress induced HR response is a predictor for this effect.

Removing the cardiac field artifact from the EEG using neural network regression.

When EEG recordings are used to reveal interactions between central-nervous and cardiovascular processes, the cardiac field artifact (CFA) poses a major challenge. Because the electric field generated by cardiac activity is also captured by scalp electrodes, the CFA arises as a heavy contaminant whenever EEG data are analyzed time-locked to cardio-electric events. A typical example is measuring stimulus-evoked potentials elicited at different phases of the cardiac cycle. Here, we present a nonlinear regression method deploying neural networks that allows to remove the CFA from the EEG signal in such scenarios. We train neural network models to predict R-peak centered EEG episodes based on the ECG and additional CFA-related information. In a second step, these trained models are used to predict and consequently remove the CFA in EEG episodes containing visual stimulation occurring time-locked to the ECG. We show that removing these predictions from the signal effectively removes the CFA without affecting the intertrial phase coherence of stimulus-evoked activity. In addition, we provide the results of an extensive grid search suggesting a set of appropriate model hyperparameters. The proposed method offers a replicable way of removing the CFA on the single-trial level, without affecting stimulus-related variance occurring time-locked to cardiac events. Disentangling the cardiac field artifact (CFA) from the EEG signal is a major challenge when investigating the neurocognitive impact of cardioafferent traffic by means of the EEG. When stimuli are presented time-locked to the cardiac cycle, both sources of variance are systematically confounded. Here, we propose a regression-based approach deploying neural network models to remove the CFA from the EEG. This approach effectively removes the CFA on a single-trial level and is purely data-driven, providing replicable results.

Frontal and parietal EEG alpha asymmetry: a large-scale investigation of short-term reliability on distinct EEG systems.

EEG resting-state alpha asymmetry is one of the most widely investigated forms of functional hemispheric asymmetries in both basic and clinical neuroscience. However, studies yield inconsistent results. One crucial prerequisite to obtain reproducible results is the reliability of the index of interest. There is a body of research suggesting a moderate-to-good reliability of EEG resting-state alpha asymmetry, but unfortunately sample sizes in these studies are typically small. This study presents the first large-scale short-term reliability study of frontal and parietal EEG resting-state alpha asymmetry. We used the Dortmund Vital Study data set containing 370 participants. In each participant, EEG resting state was recorded eight times, twice with their eyes opened, twice with their eyes-closed, each on two different EEG systems. We found good reliability of EEG alpha power and alpha asymmetry on both systems for electrode pairs. We also found that alpha power asymmetry reliability is higher in the eyes-closed condition than in the eyes-open condition. The frontomedial electrode pair showed weaker reliability than the frontolateral and parietal electrode pairs. Interestingly, we found no population-level alpha asymmetry in frontal electrodes, one of the most investigated electrode sites in alpha asymmetry research. In conclusion, our results suggest that while EEG alpha asymmetry is an overall reliable measure, frontal alpha asymmetry should be assessed using multiple electrode pairs.

Combining mental and physical stress: Synergy or interference?

Both cognitive stressors (such as mental arithmetic tasks) and physical stressors (such as the cold pressor test, CP) are among the most widely employed tools in acute stress research, and there is growing evidence for a high degree of stimulus-response specificity, rather than uniformity, in the human stress response. However, little is known about potential synergistic or interfering effects during concurrent administration. While cognitive tasks have been hypothesized to attenuate pain perception during CP, they are also thought to enhance physiological reactivity. Conversely, physical stress might interfere with effective stress induction by cognitive challenges. To address these questions, 56 participants underwent either the CP (3-min ice-water immersion of feet) or a warm-water control condition. In half of the sample, the Paced Auditory Serial Addition Task (PASAT) was performed simultaneously (fully crossed interventions). Salivary cortisol, cardiovascular parameters, and subjective ratings as well as voice pitch (F0) were assessed. Results show that cortisol responses, self-reported pain and subjective arousal were mainly driven by cold exposure, which also led to increased F0. The PASAT incrementally enhanced cardiovascular reactions, but did not affect pain ratings nor cortisol responses to the CP. However, intra-individual concordance between elevated blood pressure and other reactivity measures was enhanced by PASAT administration during the CP. Importantly, performance decrements in the mental-arithmetic task were not associated with diminished stress responses. In conclusion, our results speak against any strong interference when administering cognitive and painful physical stressors simultaneously, pointing rather to specific additive effects, particularly regarding cardiovascular reactivity.

Low self-reported stress despite immune-physiological changes in paramedics during rescue operations.

Despite the high stress levels, paramedics seem to ignore or even negate the stress. This can be detrimental and lead to stress-related diseases. Therefore, we investigated the divergence between physiological and psychological stress responses of paramedics. Participants were 16 paramedics and 17 white-collar workers. We assessed psychological stress parameters, cortisol awakening response (CAR), and quantified immune parameters. In paramedics, electrocardiogram (ECG) was measured during one complete 24-hour shift. Our results revealed that CAR was higher in paramedics compared to controls. An alteration of immune parameters was observed even during days of free time. Also, ECG recordings showed acute stress in paramedics during rescue situations. Questionnaires revealed that rescue-service specific stressors affect psychological outcomes. However, paramedics reported significantly less mental stress and higher levels of depersonalization than controls. Taken together, our results suggest higher stress in paramedics compared to controls. However, paramedics negate their daily stress. Our findings underline therefore the importance to develop stress-management interventions for paramedics including sensitization for their stress reactions.

Disentangling sensorimotor and cognitive cardioafferent effects: A cardiac-cycle-time study on spatial stimulus-response compatibility.

Cardiac-cycle-time effects are attributed to variations in baroreceptor (BR) activity and have been shown to impinge on subcortical as well as cortical processes. However, cognitive and sensorimotor processes mediating voluntary responses seem to be differentially affected. We sought to disentangle cardiac-cycle-time effects on subcortical and cortical levels as well as sensorimotor and cognitive processes within a spatial stimulus-response-compatibility paradigm employing startling stimuli of different modalities. Air-puffs and white noise-bursts were presented unilaterally during either cardiac systole or diastole while bilateral startle EMG responses were recorded. Modality, laterality and cardiac-cycle-time were randomly varied within-subjects. Cognitive and sensorimotor stimulus-response-compatibility was orthogonally varied between-subjects: Participants (N = 80) responded to the stimuli via left/right button-push made with either the contra- or ipsilateral hand (sensorimotor compatibility) on either the ipsi- or contralateral button (cognitive compatibility). We found that sensorimotor compatible reactions were speeded during systole whereas sensorimotor incompatible ones were prolonged. This effect was independent of cognitive compatibility and restricted to auditory stimuli. Startle was inhibited during systole irrespective of modality or compatibility. Our results demonstrate how differential cardiac-cycle-time effects influence performance in conflict tasks and further suggest that stimulus-response-compatibility paradigms offer a viable method to uncover the complex interactions underlying behavioral BR effects.

Test-retest reproducibility of a combined physical and cognitive stressor.

When studying the factors which influence stress reactivity in within-subject designs, test-retest reproducibility data is needed to estimate power and sample size. We report such data regarding a new experimental stress protocol, based on simultaneous application of the socially evaluated, bilateral feet Cold Pressor Test (CPT) and the Paced Auditory Serial Addition Task (PASAT). Cardiovascular, neuroendocrine, and subjective (affective) stress responses of 32 healthy males were measured twice, at an interval of one week. The novel protocol induced substantial stress reactivity in all parameters at both test and retest. Cardiovascular reactivity remained unchanged, but cortisol and subjective responses were lower at second stress exposure, with high test-retest stability of neuroendocrine (r>.7) and cardiovascular measures (r = .5 to r = .9). PASAT performance improved. Response attenuation suggests habituation-like and/or learning effects. Data provided by our study demonstrate feasibility and power of this stress protocol for investigating changes in stress reactivity in repeated, within-subject designs.

The socially evaluated handgrip test: Introduction of a novel, time-efficient stress protocol.

Most widely-used stress-induction procedures (such as the TSST and the Cold Pressor Test) require considerable effort and overhead in terms of preparation, logistics, and staff recruitment. Moreover, while known to reliably induce HPA axis activation, especially when combined with social self-threat, most conventional laboratory stressors cannot be flexibly adapted to elicit either a mainly autonomic or an additional endocrine stress response. Being a promising alternative approach, a new version of the isometric handgrip test enriched by a social-evaluative component was evaluated in the present study. On two consecutive sessions, forty participants (20 women) performed a handgrip task at both 45% (stress) and 10% (control) of maximum voluntary isometric contraction lasting for 3min. During the stress test, continuous visual feedback on performance was given. Participants in the social-evaluative condition (50%) were observed and evaluated by a previously unknown person of the opposite sex, whereas in the standard condition feedback was provided via a computer monitor. Cardiovascular measures (heart rate, blood pressure) as well as additional indices of autonomic reactivity (skin conductance, heart-rate variability) were registered before, during, and after stress induction. Moreover, changes in salivary cortisol and in subjective well-being were assessed. Relative to control, significant increases in cardiovascular and sympathetic activity were found, irrespective of experimental group. Importantly, however, additional social evaluation resulted in elevated cortisol levels. Furthermore, evidence for reduced vagal tone during sustained socially evaluated handgrip emerged. In conclusion, the socially evaluated handgrip test represents a versatile, time-efficient method to induce stress in small laboratory settings.

Emotional stress regulation: The role of relative frontal alpha asymmetry in shaping the stress response.

Frontal EEG asymmetry has been proposed as an index of emotional regulation, reflecting both state and trait components, and there is evidence that these factors influence the cortisol response to stress. Here, we asked whether cold pressor stress modulates frontal asymmetry and whether this is predictive of the neuroendocrine stress response. Twenty-four male participants underwent an automatized bilateral feet cold pressor test (bfCPT) and a warm water control procedure in counterbalanced order on two separate days, one week apart. EEG, heart rate and blood pressure were assessed at baseline as well as during and after the bfCPT. Salivary cortisol and subjective ratings of stress and arousal were assessed before and after the bfCPT. The bfCPT led to a significant increase in cortisol, cardiovascular parameters and in subjective ratings of stress and arousal that was absent in the control condition. Furthermore, analysis of relative frontal alpha-band asymmetry revealed a stronger relative right frontal activation during the bfCPT compared to the control condition at electrode pairs F7/8 but not F3/4. However, frontal asymmetry scores during the bfCPT were not predictive for neither physiological responses nor subjective ratings. Moreover, an association between physiological responses and frontal asymmetry assessed during rest at baseline could be observed at electrode pairs F3/F4, with stronger responses being associated with stronger relative right frontal activation. Our results show that cold pressor stress leads to an alteration of emotional processes as reflected in frontal EEG asymmetry at F7/F8. Moreover, physiological responses to the CPT seem to be differentially moderated by trait and state components present in frontal asymmetry.

Validation of an automated bilateral feet cold pressor test.

The Cold Pressor Test (CPT) is often used in psychobiological research. However, the classical CPT version (unilateral hand immersion into ice-water) involves some disadvantages: hands may be needed for further applications, attentional drift towards the affected sensory hemi-field and/or physiological activation of the contralateral hemisphere may produce a laterality bias. Furthermore, instruction-induced motor activity may bias physiologic reactivity. To avoid these problems, a fully automated bilateral feet CPT was developed and tested for validity and feasibility. The test procedure is based on computerized control of water influx and efflux. This allows for maximal standardization and precise timing. Furthermore, water is kept in permanent flow to prohibit formation of stable temperature layers in skin proximity. Laterality bias, instructions effects and motor responses (e.g. lifting feet out of a water basin) are avoided. In a counterbalanced within-subject design, 28 healthy male students were exposed to the CPT and to a warm water control (CNT) condition twice, one week apart. Cardiovascular parameters, salivary cortisol and subjective ratings (stress, arousal and pain) were assessed before, during, and after interventions. The CPT profoundly affected physiology as well as subjective ratings. Expectation effects (immediately before testing) were small. Furthermore, post-CPT (presumably compensatory/counter-regulatory) effects on heart rate and stroke volume were found. In conclusion, the automated bilateral feet CPT is a valid and feasible stress test modification. Hemodynamic, subjective and endocrine stress responses are substantial, suggesting that this test version represents an advanced and suitable tool in human stress research.

Blunted endocrine response to a combined physical-cognitive stressor in adults with early life adversity.

The negative health effects of early life adversity (ELA) continue long into adulthood. Changes in the physiological response to psychosocial stressors have been proposed to mediate this effect. However, many previous studies have come to contradicting conclusions as to whether ELA induces a long-term increase or decrease in stress reactivity. Therefore, we tested the association of ELA exposure and adult stress reactivity in a sample of early life adoptees and controls. Two previously validated stressful elements (bilateral feet CPT and the Paced Auditory Serial Addition Task (PASAT)) were combined in an extended Cold Pressor Test (CPT). This test was performed on 22 participants who had experienced severe ELA (separation from biological parents, institutionalization, and adoption in early childhood), and in 22 age-matched control participants. A prior history of ELA was associated with blunted reactivity of the hypothalamic-pituitary-adrenal (HPA) axis (Cohen´s d = 0.680). Cardiovascular reactivity remained unchanged, and affective reactivity (self-report ratings) were increased in participants exposed to ELA compared to the control group (range Cohen´s d: 0.642-0.879). Our results suggest that the activity of the HPA axis reactivity was inhibited in ELA participants. Importantly, cardiovascular stress responsiveness was not affected by ELA. This separation of the HPA axis and cardiovascular stress responses may best be explained by ELA selectively enhancing central feedback-sensitivity to glucocorticoids, but preserving cardiovascular/ autonomic stress reactivity.