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The neurovisceral integration model proposes that information flows bidirectionally between the brain and the heart via the vagus nerve, indexed by vagally mediated heart rate variability (vmHRV). Voluntary reduction in breathing rate (slow-paced breathing, SPB, 5.5 Breathing Per Minute (BPM)) can enhance vmHRV. Additionally, prefrontal transcranial direct current stimulation (tDCS) can modulate the excitability of the prefrontal region and influence the vagus nerve. However, research on the combination of SPB and prefrontal tDCS to increase vmHRV and other cardiac (heart rate (HR) and blood pressure) and peripheral (skin conductance) indices is scarce. We hypothesized that the combination of 20 min of SPB and prefrontal tDCS would have a greater effect than each intervention in isolation. Hence, 200 participants were divided into four groups: active tDCS with SPB, active tDCS with 15 BPM breathing, sham tDCS with SPB, and sham tDCS with 15 BPM breathing. Regardless of the tDCS condition, the 5.5 BPM group showed a significant increase in vmHRV over 20 minutes and significant decreases in HR at the first and second 5-min epochs of the intervention. Regardless of breathing condition, the active tDCS group exhibited higher HR at the fourth 5-min epoch of the intervention than the sham tDCS group. No other effects were observed. Overall, SPB is a robust technique for increasing vmHRV, whereas prefrontal tDCS may produce effects that counteract those of SPB. More research is necessary to test whether and how SPB and neuromodulation approaches can be combined to improve cardiac vagal tone., (© 2024 Society for Psychophysiological Research.)

The tendency to ruminate (i.e., repetitive, self-referential, negative thoughts) is a maladaptive form of emotional regulation and represents a transdiagnostic vulnerability factor for stress-related psychopathology. Vagally-mediated heart rate variability (vmHRV) provides a non-invasive, surrogate measure of vagal modulation of the heart, and higher HRV is considered an indicator of susceptibility, or ability to respond to stress. Past research has suggested a link between trait rumination and vmHRV; however, inconsistent results exist in healthy individuals. In this study, we investigated the association between the tendency to ruminate, brooding, and reflection (using the Ruminative Response Scale) with vmHRV measured at baseline in a healthy population using a large cross-sectional dataset (N = 1189, 88% female; mean age = 21.55, ranging from 17 to 48 years old), which was obtained by combining samples of healthy individuals from different studies from our laboratory. The results showed no cross-sectional correlation between vmHRV and trait rumination (confirmed by Bayesian analysis), even after controlling for important confounders such as gender, age, and depressive symptoms. Also, a non-linear relationship was rejected. In summary, based on our results in a large sample of healthy individuals, vmHRV is not a marker of trait rumination (as measured by the Ruminative Response Scale)., (© 2023 Society for Psychophysiological Research.)

Acute psychosocial stress effects on inhibition have been investigated in young adults, but little is known about these effects in older adults. The present study investigated effects of the Trier Social Stress Test on cognitive inhibition (i.e., ability to ignore distracting information) using a cross-over (stress vs. control) design in healthy young (N = 50; 18-30 years; M age  = 23.06) versus older adults (N = 50; 65-84 years; M age  = 71.12). Cognitive inhibition was measured by a letter flanker task and psychophysiological measures (cortisol, heart rate, subjective stress) validated the stress induction. The results showed that while stress impaired overall accuracy across age groups and sessions, stress (vs. control) made older adults' faster in session 1 and slower in session 2. Given that session 2 effects were likely confounded by practice effects, these results suggest that acute psychosocial stress improved older adults' RTs on a novel flanker task but impaired RTs on a practiced flanker task. That is, the interaction between stress and learning effects might negatively affect response execution when testing older adults on flanker tasks. If confirmed by future research, these results might have important implications especially in settings where repeated cognitive testing is performed under acute stress., (© 2023. Springer Nature Limited.)

The prefrontal cortex plays a crucial role in cognitive processes, both during anticipatory and reactive modes of cognitive control. Transcranial Direct Current Stimulation (tDCS) can modulate these cognitive resources. However, there is a lack of research exploring the impact of tDCS on emotional material processing in the prefrontal cortex, particularly in regard to proactive and reactive modes of cognitive control. In this study, 35 healthy volunteers underwent both real and sham tDCS applied to the right prefrontal cortex in a counterbalanced order, and then completed the Cued Emotion Control Task (CECT). Pupil dilation, a measure of cognitive resource allocation, and behavioral outcomes, such as reaction time and accuracy, were collected. The results indicate that, as compared to sham stimulation, active right-sided tDCS reduced performance and resource allocation in both proactive and reactive modes of cognitive control. These findings highlight the importance of further research on the effects of tDCS applied to the right prefrontal cortex on cognitive engagement, particularly for clinical trials utilizing the present electrode montage in combination with cognitive interventions., (© 2023 The Author(s).)

Previous research has shown that patients with anorexia nervosa (AN) show an attentional bias to food. However, due to different conceptualizations of attentional bias and the use of various paradigms, results are inconclusive and more precise insights into the exact nature of this attentional bias are needed. Therefore, an eye-tracking paradigm with food (low and high caloric) and non-food (objects) pictures was used to investigate biases in AN patients (n = 25) compared to healthy controls (n = 22). Several indices of visual attention were examined, both during free (initial orientation, fixation frequency, fixation time) and explicitly instructed (engagement, disengagement) viewing. Our results during the free viewing phase indicated that AN patients (as compared to healthy matched controls) looked less frequently and spent less time fixating on food stimuli, compared to the comparison group. No differences between both groups (n = 47) in initial orientation could be observed. Interestingly, during the instructed viewing phase, no differences between the patient and the comparison group were observed in engagement or disengagement to food stimuli. These results suggest an (initial) attentional avoidance of food in AN patients when closely investigating spontaneous attentional processes, while this could not be observed during gaze behaviour when receiving clear instructions. Hence, future research should look into how attentional bias during spontaneous gaze patterns could serve as a potential marker of AN, and how targeting this bias could be applied in treatment interventions., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Age-related differences in the psychophysiology of the acute stress response are poorly understood given the limited number of studies and the high heterogeneity of findings. The present study contributes by investigating age differences in both the psychological and physiological responses to acute stress in a sample of healthy younger (N = 50; 18-30; M age = 23.06; SD = 2.90) and older adults (N = 50; 65-84; M age = 71.12; SD = 5.02). Specifically, the effects of psychosocial stress (i.e., age-adapted Trier Social Stress Test) were investigated at numerous timepoints throughout the stress response phases (i.e., baseline, anticipation, reactivity, recovery) on cortisol, heart rate, subjective stress, and anticipatory appraisal of the stressful situation. The study was conducted in a between-subject (younger vs. older) cross-over (stress vs. control) design. Results revealed age-related differences in both physiological and psychological variables: older adults had overall lower salivary cortisol levels in the stress and control conditions and lower stress-induced cortisol increase (i.e., AUCi). In addition, older adults' cortisol reactivity was delayed compared to younger adults. Older adults showed a lower heart rate response in the stress condition while no age differences were observed in the control condition. Finally, older adults reported less subjective stress and a less negative stress appraisal during the anticipation phase than younger adults, which could potentially explain lower physiological reactivity in this age group. Results are discussed in relation to the existing literature, potential underlying mechanisms, and future directions for the field., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The use of speech as a digital biomarker to detect stress levels is increasingly gaining attention. Yet, heterogeneous effects of stress on specific acoustic speech features have been observed, possibly due to previous studies' use of different stress labels/categories and the lack of solid stress induction paradigms or validation of experienced stress. Here, we deployed a controlled, within-subject psychosocial stress induction experiment in which participants received both neutral (control condition) and negative (negative condition) comparative feedback after solving a challenging cognitive task. This study is the first to use a (non-actor) within-participant design that verifies a successful stress induction using both self-report (i.e., decreased reported valence) and physiological measures (i.e., increased heart rate acceleration using event-related cardiac responses during feedback exposure). Analyses of acoustic speech features showed a significant increase in Fundamental Frequency (F0) and Harmonics-to-Noise Ratio (HNR), and a significant decrease in shimmer during the negative feedback condition. Our results using read-out-loud speech comply with earlier research, yet we are the first to validate these results in a well-controlled but ecologically-valid setting to guarantee the generalization of our findings to real-life settings. Further research should aim to replicate these results in a free speech setting to test the robustness of our findings for real-world settings and should include semantics to also take into account what you say and not only how you say it., (© 2022. The Author(s).)

Previous research supports the distinction between proactive and reactive control. Although the dorsolateral prefrontal cortex (DLPFC) has been consistently related to these processes, lateralization of proactive and reactive control is still under debate. We manipulated brain activity to investigate the role of the left and right DLPFC in proactive and reactive cognitive control. Using a single-blind, sham-controlled crossover within-subjects design, 25 young healthy females performed the 'AX' Continuous Performance Task after receiving sham vs active high-frequency repetitive transcranial magnetic stimulation (HF-rTMS) to increase left and right DLPFC activity. Reaction times (RTs) and pupillometry were used to assess patterns of proactive and reactive cognitive control and task-related resource allocation, respectively. We observed that, compared to sham, HF-rTMS over the left DLPFC increased proactive control. After right DLPFC HF-rTMS, participants showed slower RTs on AX trials, suggesting more reactive control. However, this latter result was not supported by RTs on BX trials (i.e. the trial that specifically assess reactive control). Pupil measures showed a sustained increase in resource allocation after both active left and right HF-rTMS. Our results with RT data provide evidence on the role of the left DLPFC in proactive control and suggest that the right DLPFC is implicated in reactive control., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The left dorsolateral prefrontal cortex (lDLPFC) is implicated in anticipatory (i.e. during anticipation of emotional stimuli) and online (i.e. during confrontation with emotional stimuli) emotion regulatory processes. However, research that investigates the causal role of the lDLPFC in these processes is lacking. In this study, 74 participants received active or sham transcranial direct current stimulation (tDCS) over the lDLPFC. Participants were told strangers evaluated them. These (rigged) social evaluations were presented, and in 50% of the trials, participants could anticipate the valence (positive or negative) of the upcoming social feedback. Pupil dilation (a marker of cognitive resource allocation) and skin conductance responses (a marker of arousal) were measured. The results indicate that active (compared to sham) tDCS reduced arousal during the confrontation with anticipated feedback but only marginally during the confrontation with unanticipated feedback. When participants were given the opportunity to anticipate the social feedback, tDCS reduced arousal, irrespective of whether one was anticipating or being confronted with the anticipated feedback. Moreover, tDCS reduced cognitive resource allocation during anticipation, which was associated with resource allocation increases during the subsequent confrontation. Altogether, results suggest that the lDLPFC is causally implicated in the interplay between anticipatory and online emotion regulatory processes., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Social-evaluative threat (SET) - a situation in which one could be negatively evaluated by others - elicits profound (psycho)physiological reactivity which, if chronically present and not adaptively regulated, has deleterious effects on mental and physical health. Decreased self-awareness and increased other-awareness are understood to be an adaptive response to SET. Attentional deployment - the process of selectively attending to certain aspects of emotional stimuli to modulate emotional reactivity - is supported by fronto-parietal and fronto-limbic networks, with the dorsolateral prefrontal cortex being a central hub. The primary aim of the current study was to investigate the effects of active (versus sham) prefrontal transcranial direct current stimulation (tDCS) on self and other-attentional deployment during the exposure to a SET context. Seventy-four female participants received active or sham tDCS and were subsequently exposed to a rigged social feedback paradigm. In this paradigm a series of social evaluations were presented together with a photograph of the supposed evaluator and a self- photograph of the participant, while gaze behavior (time to first fixation, total fixation time) and skin conductance responses (SCRs; a marker of emotional reactivity) were measured. For half of the evaluations, participants could anticipate the valence (negative or positive) of the evaluation a priori . Analyses showed that participants receiving active tDCS were (a) slower to fixate on their self-photograph, (b) spent less time fixating on their self-photograph, and (c) spent more time fixating on the evaluator photograph. During unanticipated evaluations, active tDCS was associated with less time spent fixating on the evaluation. Furthermore, among those receiving active tDCS, SCRs were attenuated as a function of slower times to fixate on the self-photograph. Taken together, these results suggest that in a context of SET, prefrontal tDCS decreases self-attention while increasing other-attention, and that attenuated self-referential attention specifically may be a neurocognitive mechanism through which tDCS reduces emotional reactivity. Moreover, the results suggest that tDCS reduces vigilance toward stimuli that possibly convey threatening information, corroborating past research in this area., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Allaert, Erdogan, Sanchez-Lopez, Baeken, De Raedt and Vanderhasselt.)

The tendency to ruminate (i.e., repetitive negative self-referential thoughts that perpetuate depressive mood) is associated with (a) an elevated propensity to maladaptively experience counterfactual thinking (CFT) and regret, and (b) hypo-activity of the left dorsolateral prefrontal cortex (DLPFC). The goal of this study was to investigate whether anodal transcranial direct current stimulation (tDCS) over the left DLPFC, in function of self-critical rumination tendencies, momentarily reduces counterfactual thinking and regret (assessed via self-report and psychophysiological indices). Eighty healthy participants with different levels of self-critical rumination received either anodal or sham tDCS while performing a decision making task in which they were repeatedly confronted with optimal, suboptimal, and non-optimal choice outcomes. The results showed that among rumination-prone individuals, anodal (versus sham) tDCS was associated with decreased CFT and attenuated psychophysiological reactivity to the differential choice outcomes. Conversely, among low rumination-prone individuals, anodal (versus sham) tDCS was associated with increased CFT and regret, but in absence of any effects on psychophysiological reactivity. Potential working mechanisms for these differential tDCS effects are discussed. Taken together, these results provide initial converging evidence for the adaptive effects of left prefrontal tDCS on CFT and regret to personal choice outcomes among individuals prone to engage in self-critical rumination.

Even though the ventromedial neural network (reward pathway) has been well documented to be a mediator for increased craving, the prefrontal cortex is receiving ever more attention for craving monitoring. In the current study, we examined whether causal modulation of the prefrontal cortex, and its associated neural network, diminishes reward-triggered approach bias (due to increased cognitive control), alcohol craving and consumption. Using a double-blind within-subjects design in a subclinical group of forty-five heavy drinkers, a single sham controlled session of bilateral transcranial direct current stimulation (tDCS) was applied to the dorsolateral prefrontal cortex (DLPFC). Following real and sham tDCS placing the anode over the right and cathode over the left DLPFC, a rewarded Go/NoGo paradigm was administrated to provoke behavioral biases (irrespective of the task goal) After the cognitive paradigm, alcohol consumption was examined using a beer taste test. Bifrontal tDCS resulted in a reduced reward-triggered approach bias and reduced alcohol consumption, but not self-reported craving. Interestingly, reward-triggered approach bias and alcohol consumption were reliably associated in the sham condition, but not in the tDCS condition. Reward-trigged approach biases might be a cognitive mechanism associated with alcohol prone behavior, and the role of the prefrontal network may be significant., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background and Objectives: The Dorsolateral prefrontal cortex (DLPFC) is implicated in cognitive and emotional responses. Yet, research that investigates the causal role of the left versus right DLPFC during the processes of emotion appraisal is lacking. In the current study, transcranial direct current stimulation (tDCS) was used to disentangle the functional lateralization of the DLPFC on emotional processing in response to the anticipation of, and subsequent confrontation with emotional stimuli in healthy volunteers., Methods: Forty-eight subjects received both active and sham (on separate days) anodal tDCS over either the left (N = 24) or right (N = 24) DLPFC. Subjects' pupil dilation (PD, a physiological marker of cognitive resource allocation) was recorded while performing an appraisal task in which negative and positive emotion eliciting images were presented, each preceded by an informative cue indicating the valence of the upcoming stimulus., Results: As compared to sham stimulation, left DLPFC anodal tDCS resulted in increased PD when confronted with negative emotional images, whereas right DLPFC anodal tDCS resulted in decreased PD when confronted with emotional images, irrespective of valence., Limitations: The interpretation of pupil dilation in response to emotional stimuli is limited., Conclusion: These findings suggest inverse lateralized DLPFC effects on cognitive resource allocation (as measured by pupillary responses) when confronted with emotional stimuli. The current findings may shed some light on mechanisms that explain the antidepressant effects of non-invasive brain stimulation of the left DLPFC., Competing Interests: The authors have declared that no competing interests exist.

Background: Attention to relevant emotional information in the environment is an important process related to vulnerability and resilience for mood and anxiety disorders. In the present study, the effects of left and right dorsolateral prefrontal cortex (i.e., DLPFC) stimulation on attentional mechanisms of emotional processing were tested and contrasted., Methods: A sample of 54 healthy participants received 20 min of active and sham anodal transcranial direct current stimulation (i.e., tDCS) either of the left (n = 27) or of the right DLPFC (n = 27) on two separate days. The anode electrode was placed over the left or the right DLPFC, the cathode over the corresponding contra lateral supraorbital area. After each neurostimulation session, participants completed an eye-tracking task assessing direct processes of attentional engagement towards and attentional disengagement away from emotional faces (happy, disgusted, and sad expressions)., Results: Compared to sham, active tDCS over the left DLPFC led to faster gaze disengagement, whereas active tDCS over the right DLPFC led to slower gaze disengagement from emotional faces. Between-group comparisons showed that such inverse change patterns were significantly different and generalized for all types of emotion., Conclusions: Our findings support a lateralized role of left and right DLPFC activity in enhancing/worsening the top-down regulation of emotional attention processing. These results support the rationale of new therapies for affective disorders aimed to increase the activation of the left over the right DLPFC in combination with attentional control training, and identify specific target attention mechanisms to be trained.

Background: In mitogen-stimulated lymphocyte responses (sLR), cytokines and cell-surface receptors in peripheral human blood lymphocytes (PBL) are sensitive to cyclosporine (CsA), and can predict its in vivo effect with pharmacodynamic (PD) modeling. This is not known for multiple-agent combinations., Methods: Twenty-five concentration mixtures of CsA (0-1200 ng/ml) plus sirolimus (SRL, 0-30 ng/ml) were added to whole blood from five normal human subjects (NHS) for effect on a limited array of six targets. Effect-concentration relationships were analyzed with E(max) PD equations, and expressed as the range of concentration mixtures associated with one-half of maximal inhibitory effect (EC(50)) on a model biomarker target. This predicted range was examined to see whether it contained representative concentration mixtures of these two drugs, which were associated with a stable post-transplant outcome in a logistic regression model of 1039 clinical trial patients., Results: PD analyses suggested that in NHS samples containing CsA+SRL (n=5), (1) PMA-Ionomycin-stimulated T-cell expression of intracellular IL-2, TNF-alpha, and IFN-gamma was inhibited by CsA, and minimally by SRL, and (2) the two agents inhibited pokeweed mitogen (PWM)-stimulated B-cell expression of CD54 and CD95, but not CD86 (ICAM-1, Fas antigen, and B7.2), synergistically. With CD54 as the model biomarker, contour plots also predicted a wide range of concentration mixtures of the two agents across which an EC(50) could be predicted for CsA+SRL in a population (e.g., CsA-72 ng/ml+SRL 15 ng/ml, n=5), as well as in the individual subject (e.g., CsA-0 ng/ml+SRL-13.75 ng/ml in NHS-D310). Logistic regression analysis of clinical outcomes in 1039 patients suggested that the concentration mixture of CsA congruent with 50-150 ng/ml+SRL congruent with 10 ng/ml was associated with a stable post-transplant course. The EC(50) contour plot for CD54 suggested a nearly identical CsA concentration of 120 ng/ml in the presence of 10 ng/ml of sirolimus., Conclusions: Our data suggest that pharmacodynamic evaluation of immunosuppressive agents with biomarkers may be an efficient process with which to characterize immunosuppressive effect of combination agents in individual patients and in patient populations.

With reference to a case of Hodgkin's granuloma of the frontal lobe, a review of the literature has enabled 8 similar cases of intra-cerebral localisation of this disease to be reclassified. Their mechanism is discussed on the basis of neuropathological data and in particular their development in situ. Excision of the lesion appears to be the treatment of choice.

Bismuth encephalopathy mainly affects chronic constipation sufferers. The case described, which is practically identical, should be considered (in the absence of constipation) within the context of resection for cancer. The responsibility of bismuth, suggested in five similar cases by Burns and colleagues, is here confirmed by the blood, C.S.F. and urine levels. The mechanism of encephalopathy and the possibility of a failure to eliminate bismuth affecting these levels are discussed.