Ergothioneine boosts mitochondrial respiration and exercise performance via direct activation of MPST.

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

How and when social evaluative feedback is processed in the brain: A systematic review on ERP studies.

Social evaluative feedback informs the receiver of the other's views, which may contain judgments of personality-related traits and/or the level of likability. Such kinds of social evaluative feedback are of particular importance to humans. Event-related potentials (ERPs) can directly measure where in the processing stream feedback valence, expectancy, or contextual relevance modulate information processing. This review provides an overview and systematization of studies and early, mid-latency, and late ERP effects. Early effects were inconsistently reported for all factors. Feedback valence effects are more consistently reported for specific mid-latency ERPs (Reward Positivity, RewP, and Early Posterior Negativity, EPN) and late positivities (P3 and Late Positive Potential, LPP). Unexpected feedback consistently increased the Feedback Related Negativity (FRN) and, less consistently, decreased P3 amplitudes. Contextual relevance of the sender (e.g., human vs computer sender) or self-relatedness increased mid-latency to late ERPs. Interactions between valence and other factors were less often found, arising during mid-latency stages, where most consistent interactions showed larger EPN and P3 amplitude differences for valent feedback in a more relevant context. The ERP findings highlight that social evaluative feedback is consistently differentiated during mid-latency processing stages. The review discusses the relevance of findings, possible shortcomings of different experimental designs, and open questions. Furthermore, we suggest concrete venues for future research.

Amygdala and cortical gamma-band responses to emotional faces are modulated by attention to valence.

The amygdala might support an attentional bias for emotional faces. However, whether and how selective attention toward a specific valence modulates this bias is not fully understood. Likewise, it is unclear whether amygdala and cortical signals respond to emotion and attention in a similar way. We recorded gamma-band activity (GBA, > 30 Hz) intracranially in the amygdalae of 11 patients with epilepsy and collected scalp recordings from 19 healthy participants. We presented angry, neutral, and happy faces randomly, and we denoted one valence as the target. Participants detected happy targets most quickly and accurately. In the amygdala, during attention to negative faces, low gamma-band activity (LGBA, < 90 Hz) increased for angry compared with happy faces from 160 ms. From 220 ms onward, amygdala high gamma-band activity (HGBA, > 90 Hz) was higher for angry and neutral faces than for happy ones. Monitoring neutral faces increased amygdala HGBA for emotions compared with neutral faces from 40 ms. Expressions were not differentiated in GBA while monitoring positive faces. On the scalp, only threat monitoring resulted in expression differentiation. Here, posterior LGBA was increased selectively for angry targets from 60 ms. The data show that GBA differentiation of emotional expressions is modulated by attention to valence: Top-down-controlled threat vigilance coordinates widespread GBA in favor of angry faces. Stimulus-driven emotion differentiation in amygdala GBA occurs during a neutral attentional focus. These findings align with a multi-pathway model of emotion processing and specify the role of GBA in this process.

Effects of emotion on auditory ERPs are independent of manipulated target relevance.

Emotional attention describes the prioritized processing of emotional information to help humans quickly detect biologically salient stimuli and initiate appropriate reactions. Humans can also voluntarily attend to specific stimulus features that are target-relevant. Electrophysiological studies have shown specific temporal interactions between voluntary and emotional attention, while no such studies exist for natural sounds (e.g., explosions, running water, applause). In two experiments (N = 40, each), we examined event-related potentials (ERPs) toward target relevant or irrelevant negative, neutral, or positive sounds. Target relevance was induced by the instruction to respond blockwise to either negative, neutral, or positive sounds. Emotional sounds elicited increased fronto-central N1 and P2 amplitudes and a larger late positive potential (LPP), with more sustained effects for negative sounds. Target relevance increased amplitudes during an early LPP interval (400-900 ms) but did not interact with the valence of the sounds. These results show early and late ERP modulations for natural sounds, which do not interact with the target relevance of the sound valence, in contrast to findings from the visual domain. Thus, findings indicate little temporal overlap between emotional processes and target relevance effects in the auditory domain. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

A cytosolic mutp53(E285K) variant confers chemoresistance of malignant melanoma.

Malignant melanoma (MM) is known to be intrinsically chemoresistant, even though only ~20% of MM carry mutations of the tumor suppressor p53. Despite improvement of systemic therapy the mortality rate of patients suffering from metastatic MM is still ~70%, highlighting the need for alternative treatment options or for the re-establishment of conventional therapeutic approaches, including chemotherapy. Screening the p53 mutation status in a cohort of 19 patient-derived melanoma samples, we identified one rarely described missense mutation of p53 leading to E285K amino acid exchange (mutp53(E285K)). Employing structural and computational analysis we revealed a major role of E285 residue in maintaining stable conformation of wild-type p53 (wtp53). E285K mutation was predicted to cause interruption of a salt-bridge network affecting the conformation of the C-terminal helix of the DNA-binding domain (DBD) thereby preventing DNA interaction. In this context, a cluster of frequently mutated amino acid residues in cancer was identified to putatively lead to similar structural effects as E285K substitution (E285 cluster). Functional analysis, including knockdown of endogenous p53 and reconstitution with diverse p53 missense mutants confirmed mutp53(E285K) to have lost transcriptional activity, to be localized in the cytosol of cancer cells, by both means conferring chemoresistance. Re-sensitization to cisplatin-induced cell death was achieved using clinically approved compounds aiming to restore p53 wild-type function (PRIMA1-Met), or inhibition of AKT-driven MAPK survival pathways (afuresertib), in both cases being partially due to ferroptosis induction. Consequently, active ferroptosis induction using the GPX4 inhibitor RSL3 proved superior in tumorselectively fighting MM cells. Due to high prevalence of the E285-cluster mutations in MM as well as in a variety of other tumor types, we conclude this cluster to serve an important function in tumor development and therapy and suggest new implications for ferroptosis induction in therapeutic applications fighting MM in particular and cancer in general.

Dissociating different temporal stages of emotional word processing by feature-based attention.

Negative emotional content is prioritized across different stages of information processing as reflected by different components of the event-related potential (ERP). In this preregistered study (N = 40), we investigated how varying the attentional focus allows us to dissociate the involvement of specific ERP components in the processing of negative and neutral words. Participants had to discriminate the orientation of lines overlaid onto the words, the word type (adjective/noun), or the emotional content (negative/neutral). Thus, attention was either not focused on words (distraction task), non-emotional aspects, or the emotional relevance of words. Regardless of the task, there were no significant differences between negative and neutral words for the P1, N1, or P2 components. In contrast, interactions between emotion and task were observed for the early posterior negativity (EPN) and late positive potential (LPP). EPN differences were absent during the distraction task but were present in the other two tasks. LPP emotion differences were found only when attention was directed to the emotional content of words. Our study adds to the evidence that early ERP components do not reliably separate negative and neutral words. However, results show that mid-latency and late stages of emotion processing are separable by different attention tasks. The EPN represents a stage of attentional enhancement of negative words given sufficient attentional resources. Differential activations during the LPP stage are associated with more elaborative processing of the emotional meaning of words.

Beyond facial expressions: A systematic review on effects of emotional relevance of faces on the N170.

The N170 is the most prominent electrophysiological signature of face processing. While facial expressions reliably modulate the N170, there is considerable variance in N170 modulations by other sources of emotional relevance. Therefore, we systematically review and discuss this research area using different methods to manipulate the emotional relevance of inherently neutral faces. These methods were categorized into (1) existing pre-experimental affective person knowledge (e.g., negative attitudes towards outgroup faces), (2) experimentally instructed affective person knowledge (e.g., negative person information), (3) contingency-based affective learning (e.g., fear-conditioning), or (4) the immediate affective context (e.g., emotional information directly preceding the face presentation). For all categories except the immediate affective context category, the majority of studies reported significantly increased N170 amplitudes depending on the emotional relevance of faces. Furthermore, the potentiated N170 was observed across different attention conditions, supporting the role of the emotional relevance of faces on the early prioritized processing of configural facial information, regardless of low-level differences. However, we identified several open research questions and suggest venues for further research.

The effects of visual perceptual load on detection performance and event-related potentials to auditory stimuli.

Load Theory states that perceptual load prevents, or at least reduces, the processing of task-unrelated stimuli. This study systematically examined the detection and neural processing of auditory stimuli unrelated to a visual foreground task. The visual task was designed to create continuous perceptual load, alternated between low and high load, and contained performance feedback to motivate participants to focus on the visual task instead of the auditory stimuli presented in the background. The auditory stimuli varied in intensity, and participants signaled their subjective perception of these stimuli without receiving feedback. Depending on stimulus intensity, we observed load effects on detection performance and P3 amplitudes of the event-related potential (ERP). N1 amplitudes were unaffected by perceptual load, as tested by Bayesian statistics. Findings suggest that visual perceptual load affects the processing of auditory stimuli in a late time window, which is associated with a lower probability of reported awareness of these stimuli.

Potentiated early neural responses to fearful faces are not driven by specific face parts.

Prioritized processing of fearful compared to neutral faces is reflected in increased amplitudes of components of the event-related potential (ERP). It is unknown whether specific face parts drive these modulations. Here, we investigated the contributions of face parts on ERPs to task-irrelevant fearful and neutral faces using an ERP-dependent facial decoding technique and a large sample of participants (N = 83). Classical ERP analyses showed typical and robust increases of N170 and EPN amplitudes by fearful relative to neutral faces. Facial decoding further showed that the absolute amplitude of these components, as well as the P1, was driven by the low-frequency contrast of specific face parts. However, the difference between fearful and neutral faces was not driven by any specific face part, as supported by Bayesian statistics. Furthermore, there were no correlations between trait anxiety and main effects or interactions. These results suggest that increased N170 and EPN amplitudes to task-irrelevant fearful compared to neutral faces are not driven by specific facial regions but represent a holistic face processing effect.

The effects of visual working memory load on detection and neural processing of task-unrelated auditory stimuli.

While perceptual load has been proposed to reduce the processing of task-unrelated stimuli, theoretical arguments and empirical findings for other forms of task load are inconclusive. Here, we systematically investigated the detection and neural processing of auditory stimuli varying in stimulus intensity during a stimuli-unrelated visual working memory task alternating between low and high load. We found, depending on stimulus strength, decreased stimulus detection and reduced P3, but unaffected N1 amplitudes of the event-related potential to auditory stimuli under high as compared to low load. In contrast, load independent awareness effects were observed during both early (N1) and late (P3) time windows. Findings suggest a late neural effect of visual working memory load on auditory stimuli leading to lower probability of reported awareness of these stimuli.

Testing stimulus exposure time as the critical factor of increased EPN and LPP amplitudes for fearful faces during perceptual distraction tasks.

Fearful facial expressions are prioritized across different information processing stages, as evident in early, intermediate, and late components of event-related brain potentials (ERPs). Recent studies showed that, in contrast to early N170 modulations, mid-latency (Early Posterior Negativity, EPN) and late (Late Positive Potential, LPP) emotional modulations depend on the attended perceptual feature. Nevertheless, several studies reported significant differences between emotional and neutral faces for the EPN or LPP components during distraction tasks. One cause for these conflicting findings might be that when faces are presented sufficiently long, participants attend to task-irrelevant features of the faces. In this registered report, we tested whether the presentation duration of faces is the critical factor for differences between reported emotional modulations during perceptual distraction tasks. To this end, 48 participants were required to discriminate the orientation of lines overlaid onto fearful or neutral faces, while face presentation varied (100 msec, 300 msec, 1,000 msec, 2,000 msec). While participants did not need to pay attention to the faces, we observed main effects of emotion for the EPN and LPP, but no interaction between emotion and presentation duration. Of note, unregistered exploratory tests per presentation duration showed no significant EPN and LPP emotion differences during short durations (100 and 300 msec) but significant differences with longer durations. While the presentation duration seems not to be a critical factor for EPN and LPP emotion effects, future studies are needed to investigate the role of threshold effects and the applied analytic designs to explain conflicting findings in the literature.

Early neural potentiation to centrally and peripherally presented fear-conditioned faces.

For humans, it is vitally important to rapidly detect and process threatening signals regardless of whether stimuli occur at fixation or in the periphery. However, it is unknown whether eccentricity affects early neuronal electrophysiological responses to fear-conditioned stimuli. We examined early event-related potentials (ERPs) of the electroencephalogram (EEG) to fear-conditioned faces to address this question. Participants (N = 80) were presented with faces, either paired with an aversive (CS+) or neutral sound (CS-), at central or peripheral positions. We ensured constant central fixation using online eye-tracking but directed attention to either centrally or peripherally presented faces. Manipulation checks showed successful fear-conditioning (i.e., on average lower ratings in valence and higher ratings in arousal and perceived threat) and successful shifts of visuospatial attention indexed by high task performance and pre-stimulus alpha lateralization of the EEG spectra. We observed a generally increased P1 to fear-conditioned faces regardless of presentation location. An N170 difference between fear-conditioned and neutral stimuli was found but was restricted to the central location and depended on the effectivity of fear-conditioning. A similar effect was observed for the early posterior negativity (EPN). Trait anxiety was not related to differential ERP responses to CS+ versus CS- faces for any ERP component. These findings suggest that the P1 indexes early responses to centrally and peripherally presented fear-conditioned faces. Subsequent stages are modulated by the spatial location of the stimuli. This suggests different stages of neural processing of fear-conditioned faces depending on their spatial location. Finally, our results question the hypothesis that trait anxiety in healthy participants is related to altered visual processing of fear-conditioned faces.

Fearful faces straight ahead or in the periphery: Early neuronal responses independently of trait anxiety.

For humans, it is vitally important to rapidly detect potentially threatening stimuli such as fearful faces in the periphery. Trait anxiety has been related to biased responses to threatening faces, which might be more pronounced for peripheral stimuli. We examined the impact of spatial location and trait anxiety on event-related potentials to fearful faces (ERPs) in a large sample (N = 80). Using a face-unrelated oddball detection task and online eye-tracking, we ensured central fixation but sustained attention to the location of fearful and neutral faces at central or peripheral locations (12° left or right). Manipulation checks showed high task performance and successful shifts of visuospatial attention indexed by prestimulus alpha lateralization of the EEG spectra. Concerning ERPs, we observed increased P1 amplitudes for fearful compared to neutral faces, independent of the spatial location. In contrast, the N170 to fearful faces was only potentiated for centrally presented faces. Finally, fearful and neutral faces did not differ during the EPN window at any spatial location. Trait anxiety was unrelated to fearful-neutral ERP differences for each examined location. Our findings show that differential P1 responses are less constrained by the stimulus location, possibly due to coarse low-level stimulus information processing. However, the relative N170 increase for fearful faces depends on the central stimulus location. Furthermore, findings support the view that differential processing at the stage of the EPN depends on attentional conditions. Finally, our results question the hypothesis that trait anxiety differences correlate with mandatorily altered processing of threatening stimuli. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Neural correlates of consciousness in an attentional blink paradigm with uncertain target relevance.

Several event-related potentials (ERPs) have been proposed as neural correlates of consciousness (NCC), most prominently the early visual awareness negativity (VAN) and the late P3b component. Highly influential support for the P3b comes from studies utilizing the attentional blink (AB), where conscious perception of a first visual target (T1) impairs reporting a second target (T2) presented shortly afterwards. Recent no-report studies using other paradigms suggest that the P3b component may reflect post-perceptual processes associated with decision-making rather than awareness. However, no-report studies are limited in their awareness assessment, and their conclusions have not been tested in an AB paradigm. The present study (N = 38) addressed these issues using a novel AB paradigm, which reduced decision-making processes by omitting a discrimination task on T2 stimuli and rendering their relevance uncertain. Nevertheless, awareness was assessed trial by trial. Comparing ERPs in response to seen versus unseen T2 stimuli revealed a VAN but no enhanced P3b regardless of whether they were marked as distinct from distractor stimuli or not. Our results corroborate the VAN and challenge the P3b as NCC despite rigorous trial-by-trial assessment of conscious perception. Thus, they support the idea that awareness emerges during early sensory processing.

Emotion and attention in face processing: Complementary evidence from surface event-related potentials and intracranial amygdala recordings.

Face processing is biased by emotional and voluntarily directed attention, both of which modulate processing in distributed cortical areas. The amygdala is assumed to contribute to an attentional bias for emotional faces, although its interaction with directed attention awaits further clarification. Here, we studied the interaction of emotion and attention during face processing via scalp EEG potentials of healthy participants and intracranial EEG (iEEG) recordings of the right amygdala in one patient. Three randomized blocks consisting of angry, neutral, and happy facial expressions were presented, and one expression was denoted as the target category in each block. Happy targets were detected fastest and most accurately both in the group study and by the iEEG patient. Occipital scalp potentials revealed emotion differentiation for happy faces in the early posterior negativity (EPN) around 300 ms after stimulus onset regardless of the target condition. A similar response to happy faces occurred in the amygdala only for happy targets. On the scalp, a late positive potential (LPP, around 600 ms) enhancement for targets occurred for all target conditions alike. A simultaneous late signal in the amygdala was largest for emotional targets. No late signal enhancements were found for neutral targets in the amygdala. Cortical modulations, by contrast, showed both attention-independent effects of emotion and emotion-independent effects of attention. These results demonstrate an attention-dependence of amygdala activity during the processing of facial expressions and partly independent cortical mechanisms.

Effects of task load, spatial attention, and trait anxiety on neuronal responses to fearful and neutral faces.

There is an ongoing debate on how different components of the event-related potential (ERP) to threat-related facial expressions are modulated by attentional conditions and interindividual differences in trait anxiety. In the current study (N = 80), we examined ERPs to centrally presented, task-irrelevant fearful and neutral faces, while participants had to solve a face-unrelated visual task, which differed in difficulty and spatial position. Critically, we used a fixation-controlled experimental design and ensured the spatial attention manipulation by spectral analysis of the EEG. Besides the factors emotion, spatial attention, and perceptual load, we also investigated correlations between trait anxiety and ERPs. While P1 emotion effects were insignificant, the N170 was increased to fearful faces regardless of load and spatial attention conditions. During the EPN time window, a significantly increased negativity for fearful faces was observed only during low load and spatial attention to the face. We found no significant relationship between ERPs and trait anxiety, questioning the hypothesis of a general hypersensitivity toward fearful expressions in anxious individuals. These results show a high resistance of the N170 amplitude increase for fearful faces to spatial attention and task load manipulations. By contrast, the EPN modulation by fearful faces index a resource-dependent stage of the ERP, requiring both spatial attention at the location of faces and low load of the face-irrelevant task.

Feature-based attention interacts with emotional picture content during mid-latency and late ERP processing stages.

Several components of the event-related potential (ERP) are amplified by emotional compared to neutral pictures. This study (N = 80) investigated systematically how attention to specific stimulus features influences ERPs to briefly presented (100 ms) negative and neutral pictures. Participants had to discriminate either (i) the orientation of overlaid lines, (ii) if the picture content was animate or inanimate, or (iii) if the emotional content was negative or neutral. ERP results showed interactions between the attention task and emotion processing for the early posterior negativity (EPN) and the late positive potential (LPP). For the EPN, attention to distracting perceptual information reduced emotional differences, while at the level of the LPP, emotion effects were selectively amplified when participants attended to the emotional content. These findings reveal the time-dependent effects of feature-based attention tasks on ERPs to emotional pictures.

Encoding in a social feedback context enhances and biases behavioral and electrophysiological correlates of long-term recognition memory.

Encoding often occurs in social contexts, yet research has hardly addressed their role in verbal memory. In three experiments, we investigated the behavioral and neural effects of encoding context on memory for positive, negative, and neutral adjectives, contrasting a social-feedback group (N = 24) with an explicit verbal-learning (N = 24) and a levels-of-processing group (N = 24). Participants in the social-feedback group were not aware of a recognition session one week later, but their memory was better than the explicit learning or the levels-of-processing groups'. However, they also exhibited the strongest response bias, particularly for positive words. Brain event-related potentials (ERPs) revealed largest early negativities (EPN) and late positivities (LPP) in the social-feedback group. Only in the subsequent slow-wave did the explicit learning group show higher amplitudes than the other two groups, suggesting reliance on strategic rather than automatic processes. Still, context-driven incidental encoding outweighed explicit instructions, specifying a decisive role of social factors in memory.

No trait anxiety influences on early and late differential neuronal responses to aversively conditioned faces across three different tasks.

The human brain's ability to quickly detect dangerous stimuli is crucial in selecting appropriate responses to possible threats. Trait anxiety has been suggested to moderate these processes on certain processing stages. To dissociate such different information-processing stages, research using classical conditioning has begun to examine event-related potentials (ERPs) in response to fear-conditioned (CS +) faces. However, the impact of trait anxiety on ERPs to fear-conditioned faces depending on specific task conditions is unknown. In this preregistered study, we measured ERPs to faces paired with aversive loud screams (CS +) or neutral sounds (CS -) in a large sample (N = 80) under three different task conditions. Participants had to discriminate face-irrelevant perceptual information, the gender of the faces, or the CS category. Results showed larger amplitudes in response to aversively conditioned faces for all examined ERPs, whereas interactions with the attended feature occurred for the P1 and the early posterior negativity (EPN). For the P1, larger CS + effects were observed during the perceptual distraction task, while the EPN was increased for CS + faces when deciding about the CS association. Remarkably, we found no significant correlations between ERPs and trait anxiety. Thus, fear-conditioning potentiates all ERP amplitudes, some processing stages being further modulated by the task. However, the finding that these ERP differences were not affected by individual differences in trait anxiety does not support theoretical accounts assuming increased threat processing or reduced threat discrimination depending on trait anxiety.

Effects of perceptual and working memory load on brain responses to task-irrelevant stimuli: Review and implications for future research.

Load Theory assumes that the extent of processing of task-irrelevant information depends on the level (high vs. low load) and type (perceptual vs. working memory) of task load. In this review, we address the neuroscientific perspective on Load Theory by a systematic evaluation of neuroimaging and electrophysiological studies, which manipulated perceptual or working memory load and reported brain responses to task-irrelevant unimodal and crossmodal stimuli. Studies show: (1) Load effects can be observed across the whole processing stream from subcortical areas to higher cortical areas, (2) both higher perceptual and working memory load lead to decreased distractor processing, (3) event-related potential studies suggest that load effects occur more reliably the later the ERP component and (4) load effects occur both within and across modalities. Thus, findings are at least partially consistent with assumptions of Load Theory. Based on the reviewed studies and theoretical and methodological considerations, we provide several suggestions, which might help to improve future research in the field.