Cancer Cells Employ Nuclear Caspase-8 to Overcome the p53-Dependent G2/M Checkpoint through Cleavage of USP28.

Cytosolic caspase-8 is a mediator of death receptor signaling. While caspase-8 expression is lost in some tumors, it is increased in others, indicating a conditional pro-survival function of caspase-8 in cancer. Here, we show that tumor cells employ DNA-damage-induced nuclear caspase-8 to override the p53-dependent G2/M cell-cycle checkpoint. Caspase-8 is upregulated and localized to the nucleus in multiple human cancers, correlating with treatment resistance and poor clinical outcome. Depletion of caspase-8 causes G2/M arrest, stabilization of p53, and induction of p53-dependent intrinsic apoptosis in tumor cells. In the nucleus, caspase-8 cleaves and inactivates the ubiquitin-specific peptidase 28 (USP28), preventing USP28 from de-ubiquitinating and stabilizing wild-type p53. This results in de facto p53 protein loss, switching cell fate from apoptosis toward mitosis. In summary, our work identifies a non-canonical role of caspase-8 exploited by cancer cells to override the p53-dependent G2/M cell-cycle checkpoint.

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.

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.

Top-Down Modulation of Early Visual Processing in V1: Dissociable Neurophysiological Effects of Spatial Attention, Attentional Load and Task-Relevance.

Until today, there is an ongoing discussion if attention processes interact with the information processing stream already at the level of the C1, the earliest visual electrophysiological response of the cortex. We used two highly powered experiments (each N = 52) and examined the effects of task relevance, spatial attention, and attentional load on individual C1 amplitudes for the upper or lower visual hemifield. Bayesian models revealed evidence for the absence of load effects but substantial modulations by task-relevance and spatial attention. When the C1-eliciting stimulus was a task-irrelevant, interfering distracter, we observed increased C1 amplitudes for spatially unattended stimuli. For spatially attended stimuli, different effects of task-relevance for the two experiments were found. Follow-up exploratory single-trial analyses revealed that subtle but systematic deviations from the eye-gaze position at stimulus onset between conditions substantially influenced the effects of attention and task relevance on C1 amplitudes, especially for the upper visual field. For the subsequent P1 component, attentional modulations were clearly expressed and remained unaffected by these deviations. Collectively, these results suggest that spatial attention, unlike load or task relevance, can exert dissociable top-down modulatory effects at the C1 and P1 levels.

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.

Right medial temporal lobe structures particularly impact early stages of affective picture processing.

Human vision prioritizes emotional stimuli. This is reflected in stronger electrocortical activation in response to emotional than neutral stimuli, measurable on the surface of the head. Feedback projections from brain structures deep within the medial temporal lobes (mTLs), in particular the amygdala, are thought to give rise to this phenomenon, although causal evidence is rare. Given the many pathways involved in visual processing, the influence of mTL structures could be restricted to specific time windows. Therefore, we delineate the temporal dynamics of the impact of right mTL structures on affective picture processing, investigating event-related potentials (ERPs) in 19 patients (10 female) with right mTL resections and 19 individually matched healthy participants, while they viewed negative and neutral scenes. Groups differed significantly at early- and mid-latency processing stages. Patients with right mTL resection, unlike controls, showed no (P1: 90-140 ms) or marginal (N1: 170-220 ms) emotion modulation. At mid-latency (early posterior negativity: 220-370 ms), emotion modulation over the ipsi-resectional right hemisphere was smaller in patients than in controls, but groups did not differ over the left hemisphere. During late parietal positivities (400-650 ms and 650-900 ms), both groups had similar emotion modulation. Our results demonstrate that right mTL structures attenuate particularly early processing of affectively negative scenes. This is theoretically consistent with an initial amygdala-dependent feedforward sweep in visual emotion processing whose absence is successively compensated. Findings specify the impact of right mTL structures on emotional picture processing and highlight the value of time-resolved measures in affective neuroscience.

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.

Fearful face scrambles increase early visual sensory processing in the absence of face information.

Emotional facial expressions elicit distinct increased early electrophysiological responses. Many studies report even emotional modulations of very early sensory processing at about 80 and 100 ms after stimulus presentation, indexed by the P1. These early effects are often interpreted to index differential responses to biologically relevant expressions. Since specific spatial frequencies differ between fearful and neutral expressions, it has recently been suggested that these early modulations are substantially driven by such low-level visual differences. However, it remains unclear whether similar P1 effects are also observed in experiments in which no recognizable face information is presented at all. This study investigated this question and explored also whether any effects depend on colour information and attentional conditions. Participants (N = 20) performed a continuous perceptual task of low or high difficultly and were presented with task-irrelevant black/white and colour images of fearful and neutral faces, rendered unrecognizable by doing Fourier phase transformation. ERP findings revealed increased P1 amplitudes for fearful scrambles regardless of experimental conditions. Taken together, our findings show early emotional effects in the absence of any facial expression. Specific low-level frequency information seems to increase P1 amplitudes which thus might have implications for the interpretation of very early sensory emotional expression effects.

Electrophysiological responses to negative evaluative person-knowledge: Effects of individual differences.

Faces transmit rich information about a unique personal identity. Recent studies examined how negative evaluative information affects event-related potentials (ERPs), the relevance of individual differences, such as trait anxiety, neuroticism, or agreeableness, for these effects is unclear. In this preregistered study, participants (N = 80) were presented with neutral faces, either associated with highly negative or neutral biographical information. Faces were shown under three different task conditions that varied the attentional focus on face-unrelated features, perceptual face information, or emotional information. Results showed a task-independent increase of the N170 component for faces associated with negative information, while interactions occurred for the Early Posterior Negativity (EPN) and the Late Positive Potential (LPP), showing ERP differences only when paying attention to the evaluative information. Trait anxiety and neuroticism did not influence ERP differences. Low agreeableness increased EPN differences during perceptual distraction. Thus, we observed that low agreeableness leads to early increased processing of potentially hostile faces, although participants were required to attend to a face-unrelated feature.

"She finds you abhorrent" - The impact of emotional context information on the cortical processing of neutral faces in depression.

Depression is associated with abnormalities in patterns of information processing, particularly in the context of processing of interpersonal information. The present study was designed to investigate the differences in depressive individuals in cortical processing of facial stimuli when neutral faces were presented in a context that involved information about emotional valence as well as self-reference. In 21 depressive patients and 20 healthy controls, event-related potentials (ERPs) were recorded during the presentation of neutral facial expressions, which were accompanied by affective context information that was either self- or other-related. Across conditions, depressive patients showed larger mean P100 amplitudes than healthy controls. Furthermore, mean late positive potential (LPP) amplitudes of depressive patients were larger in response to faces in self-related than in other-related context. In addition, irrespective of self-reference, mean LPP responses of depressive patients to faces presented after socially threatening sentences were larger compared with faces presented after neutral sentences. Results regarding self-reference supported results of previous studies indicating larger mean amplitudes in self-related conditions. Findings suggest a general heightened initial responsiveness to emotional cues and a sustained emotion processing of socially threatening information in depressive patients.

Let's Talk About Each Other: Neural Responses to Dissenting Personality Evaluations Based on Real Dyadic Interactions.

Dyadic interactions are associated with the exchange of personality-related messages, which can be congruent or incongruent with one's self-view. In the current preregistered study (N = 52), we investigated event-related potentials (ERPs) toward real social evaluations in order to uncover the neural mechanisms underlying the processing of congruent and incongruent evaluative feedback. Participants interacted first, and then during an electroencephalogram (EEG) session, they received evaluations from their interaction partner that were either congruent or incongruent with their own ratings. Findings show potentiated processing of self-related incongruent negative evaluations at early time points (N1) followed by increased processing of both incongruent negative and positive evaluations at midlatency time windows (early posterior negativity) and a prioritized processing of self-related incongruent positive evaluations at late time points (feedback-related P3, late positive potential). These findings reveal that, after real social interactions, evaluative feedback about oneself that violates one's self-view modulates all processing stages with an early negativity and a late positivity bias.

Charged With a Crime: The Neuronal Signature of Processing Negatively Evaluated Faces Under Different Attentional Conditions.

Our brains rapidly respond to human faces and can differentiate between many identities, retrieving rich semantic emotional-knowledge information. Studies provide a mixed picture of how such information affects event-related potentials (ERPs). We systematically examined the effect of feature-based attention on ERP modulations to briefly presented faces of individuals associated with a crime. The tasks required participants (N = 40 adults) to discriminate the orientation of lines overlaid onto the face, the age of the face, or emotional information associated with the face. Negative faces amplified the N170 ERP component during all tasks, whereas the early posterior negativity (EPN) and late positive potential (LPP) components were increased only when the emotional information was attended to. These findings suggest that during early configural analyses (N170), evaluative information potentiates face processing regardless of feature-based attention. During intermediate, only partially resource-dependent, processing stages (EPN) and late stages of elaborate stimulus processing (LPP), attention to the acquired emotional information is necessary for amplified processing of negatively evaluated faces.

Attributed social context and emotional content recruit frontal and limbic brain regions during virtual feedback processing.

In communication, who is communicating can be just as important as what is said. However, sender identity in virtual communication is often inferred rather than perceived. Therefore, the present research investigates the brain structures activated by sender identity attributions and evaluative feedback processing during virtual communication. In a functional magnetic resonance imaging (fMRI) study, 32 participants were told that they would receive personality feedback, either sent from another human participant or from a randomly acting computer. In reality, both conditions contained random but counterbalanced feedback, automatically delivered by approving or denying negative, neutral, or positive adjectives. Although physically identical, feedback attributed to the "human" sender activated multiple regions within a "social brain" network, including the superior frontal, medial prefrontal, and orbitofrontal cortex, anterior and posterior parts of the cingulate cortex, and the bilateral insula. Regardless of attributed sender, positive feedback increased responses in the striatum and bilateral amygdalae, while negative compared to neutral feedback elicited stronger insula and somatosensory responses. These results reveal the recruitment of an extensive mentalizing and social brain network by mere sender attributions and the activation of brain structures related to reward and punishment by verbal feedback, demonstrating its embodied processing.

Perceived communicative context and emotional content amplify visual word processing in the fusiform gyrus.

The personal significance of a language statement depends on its communicative context. However, this is rarely taken into account in neuroscience studies. Here, we investigate how the implied source of single word statements alters their cortical processing. Participants' brain event-related potentials were recorded in response to identical word streams consisting of positive, negative, and neutral trait adjectives stated to either represent personal trait feedback from a human or to be randomly generated by a computer. Results showed a strong impact of perceived sender. Regardless of content, the notion of receiving feedback from a human enhanced all components, starting with the P2 and encompassing early posterior negativity (EPN), P3, and the late positive potential (LPP). Moreover, negative feedback by the "human sender" elicited a larger EPN, whereas positive feedback generally induced a larger LPP. Source estimations revealed differences between "senders" in visual areas, particularly the bilateral fusiform gyri. Likewise, emotional content enhanced activity in these areas. These results specify how even implied sender identity changes the processing of single words in seemingly realistic communicative settings, amplifying their processing in the visual brain. This suggests that the concept of motivated attention extends from stimulus significance to simultaneous appraisal of contextual relevance. Finally, consistent with distinct stages of emotional processing, at least in contexts perceived as social, humans are initially alerted to negative content, but later process what is perceived as positive feedback more intensely.

Phasic Dopamine Modifies Sensory-Driven Output of Striatal Neurons through Synaptic Plasticity.

Animals are facing a complex sensory world in which only few stimuli are relevant to guide behavior. Value has to be assigned to relevant stimuli such as odors to select them over concurring information. Phasic dopamine is involved in the value assignment to stimuli in the ventral striatum. The underlying cellular mechanisms are incompletely understood. In striatal projection neurons of the ventral striatum in adult mice, we therefore examined the features and dynamics of phasic dopamine-induced synaptic plasticity and how this plasticity may modify the striatal output. Phasic dopamine is predicted to tag inputs that occur in temporal proximity. Indeed, we observed D1 receptor-dependent synaptic potentiation only when odor-like bursts and optogenetically evoked phasic dopamine release were paired within a time window of <1 s. Compatible with predictions of dynamic value assignment, the synaptic potentiation persisted after the phasic dopamine signal had ceased, but gradually reversed when odor-like bursts continued to be presented. The synaptic plasticity depended on the sensory input rate and was input specific. Importantly, synaptic plasticity amplified the firing response to a given olfactory input as the dendritic integration and the firing threshold remained unchanged during synaptic potentiation. Thus, phasic dopamine-induced synaptic plasticity can change information transfer through dynamic increases of the output of striatal projection neurons to specific sensory inputs. This plasticity may provide a neural substrate for dynamic value assignment in the striatum.

People matter: Perceived sender identity modulates cerebral processing of socio-emotional language feedback.

How do human brains integrate content with social context in communication? Recent research demonstrates that the perceived communicative embedding of perceptually identical language messages alters their cortical processing. When emotional trait-adjectives are perceived as human-generated personality feedback, event-related brain potentials are considerably larger than when the same adjectives are perceived as random computer-generated feedback. Here, we investigate the unique role of ascribed sender humanness for the underlying neural mechanisms. Participants were told that they were going to receive written positive, negative, or neutral feedback from an unknown stranger or from a socially intelligent computer system while high-density EEG was recorded. In the event-related potential (ERP), feedback from the 'human sender' elicited larger P2, Early Posterior Negativity (EPN), P3, and Late Positive Potential (LPP) components. The sources of this activity were localized in extended visual cortex, but also in the right superior frontal gyri, related to mentalizing about others, and the bilateral postcentral gyri implicated in embodied language processing. For emotional feedback, larger EPN, P3 and LPP amplitudes were also observed, resulting from enhanced activity in visual and temporal regions. Finally, for the EPN an interaction between sender and emotion was found, showing substantially increased visual processing of human-generated emotional feedback. These data confirm visual amplification effects induced by motivated attention but crucially also reveal distinct effects of perceiving a communication partner as human that activate 'social brain' structures. Obviously who is perceived as saying something can be as relevant as what is said and induce specific brain activity.

Selective visual attention to emotional words: Early parallel frontal and visual activations followed by interactive effects in visual cortex.

Human brains spontaneously differentiate between various emotional and neutral stimuli, including written words whose emotional quality is symbolic. In the electroencephalogram (EEG), emotional-neutral processing differences are typically reflected in the early posterior negativity (EPN, 200-300 ms) and the late positive potential (LPP, 400-700 ms). These components are also enlarged by task-driven visual attention, supporting the assumption that emotional content naturally drives attention. Still, the spatio-temporal dynamics of interactions between emotional stimulus content and task-driven attention remain to be specified. Here, we examine this issue in visual word processing. Participants attended to negative, neutral, or positive nouns while high-density EEG was recorded. Emotional content and top-down attention both amplified the EPN component in parallel. On the LPP, by contrast, emotion and attention interacted: Explicit attention to emotional words led to a substantially larger amplitude increase than did explicit attention to neutral words. Source analysis revealed early parallel effects of emotion and attention in bilateral visual cortex and a later interaction of both in right visual cortex. Distinct effects of attention were found in inferior, middle and superior frontal, paracentral, and parietal areas, as well as in the anterior cingulate cortex (ACC). Results specify separate and shared mechanisms of emotion and attention at distinct processing stages. Hum Brain Mapp 37:3575-3587, 2016. © 2016 Wiley Periodicals, Inc.

Uninstructed BIAT faking when ego depleted or in normal state: differential effect on brain and behavior.

BACKGROUND: Deception can distort psychological tests on socially sensitive topics. Understanding the cerebral processes that are involved in such faking can be useful in detection and prevention of deception. Previous research shows that faking a brief implicit association test (BIAT) evokes a characteristic ERP response. It is not yet known whether temporarily available self-control resources moderate this response. We randomly assigned 22 participants (15 females, 24.23 ± 2.91 years old) to a counterbalanced repeated-measurements design. Participants first completed a Brief-IAT (BIAT) on doping attitudes as a baseline measure and were then instructed to fake a negative doping attitude both when self-control resources were depleted and non-depleted. Cerebral activity during BIAT performance was assessed using high-density EEG. RESULTS: Compared to the baseline BIAT, event-related potentials showed a first interaction at the parietal P1, while significant post hoc differences were found only at the later occurring late positive potential. Here, significantly decreased amplitudes were recorded for 'normal' faking, but not in the depletion condition. In source space, enhanced activity was found for 'normal' faking in the bilateral temporoparietal junction. Behaviorally, participants were successful in faking the BIAT successfully in both conditions. CONCLUSIONS: Results indicate that temporarily available self-control resources do not affect overt faking success on a BIAT. However, differences were found on an electrophysiological level. This indicates that while on a phenotypical level self-control resources play a negligible role in deliberate test faking the underlying cerebral processes are markedly different.

Higher, faster, worse? An event-related potentials study of affective picture processing in migraine.

BACKGROUND: Migraine is a disorder of periodic disabling headache. Facilitated cortical responsivity has been suggested as one predisposing factor. Although the underlying mechanisms of migraine attack onsets are not fully understood, facilitated cortical responsivity has been suggested as one predisposing factor. Here, we investigate if enhanced cortical responsivity is reflected in altered event-related potentials during processing of complex pictures. METHOD: Altogether, 16 migraine patients and 16 healthy volunteers participated in this study. Each patient had a diagnosed migraine and was headache- and medication-free for the study. Participants watched positive, negative and neutral pictures from the international affective picture system. An electroencephalogram was recorded during picture presentation. Afterwards, participants were asked to rate the pictures for valence and arousal. RESULTS: Migraine patients showed significantly more negative-going early event-related potential components from 100 ms to 180 ms to all picture categories over occipital regions as well as more positive-going late potentials over central regions. Patients and controls did not differ in valence and arousal ratings for the international-affective picture system. DISCUSSION: Patients with migraine seem to react cortically more intensely to all kinds of pictorial stimuli, regardless of emotional content. This facilitated processing may be related to the high cortical responsivity shown in various other event-related potential studies and might contribute to the recurring intense headache attacks.

Shaping memory accuracy by left prefrontal transcranial direct current stimulation.

Human memory is dynamic and flexible but is also susceptible to distortions arising from adaptive as well as pathological processes. Both accurate and false memory formation require executive control that is critically mediated by the left prefrontal cortex (PFC). Transcranial direct current stimulation (tDCS) enables noninvasive modulation of cortical activity and associated behavior. The present study reports that tDCS applied to the left dorsolateral PFC (dlPFC) shaped accuracy of episodic memory via polaritiy-specific modulation of false recognition. When applied during encoding of pictures, anodal tDCS increased whereas cathodal stimulation reduced the number of false alarms to lure pictures in subsequent recognition memory testing. These data suggest that the enhancement of excitability in the dlPFC by anodal tDCS can be associated with blurred detail memory. In contrast, activity-reducing cathodal tDCS apparently acted as a noise filter inhibiting the development of imprecise memory traces and reducing the false memory rate. Consistently, the largest effect was found in the most active condition (i.e., for stimuli cued to be remembered). This first evidence for a polarity-specific, activity-dependent effect of tDCS on false memory opens new vistas for the understanding and potential treatment of disturbed memory control.