Empathic neural responses to others' pain are modulated by emotional contexts

Recent brain imaging studies indicate that empathy for pain relies upon both the affective and/or the sensorimotor nodes of the pain matrix, and empathic neural responses are modulated by stimulus reality, personal experience, and affective link with others. The current work investigated whether and how empathic neural responses are modulated by emotional contexts in which painful stimulations are perceived. Using functional magnetic resonance imaging (fMRI), we first showed that perceiving a painful stimulation (needle penetration) applied to a face with neutral expression induced activation in the anterior cingulate cortex (ACC) relative to nonpainful stimulation (Q‐tip touch). However, when observation of the painful stimuli delivered to a neutral face was intermixed with observation of painful or happy faces, the ACC activity decreased while the activity in the face area of the secondary somatosensory cortex increased to the painful stimulation. Moreover, the secondary somatosensory activity associated with the painful stimulation decreased when the painful stimulation was applied to faces with happy and painful expressions. The findings suggest that observing painful stimuli in an emotional context weakens affective responses but increases sensory responses to perceived pain and implies possible interactions between the affective and sensory components of the pain matrix during empathy for pain. Hum Brain Mapp 2009. © 2009 Wiley‐Liss, Inc.     

Mindfulness meditation regulates anterior insula activity during empathy for social pain

Mindfulness has been shown to reduce stress, promote health, and well‐being, as well as to increase compassionate behavior toward others. It reduces distress to one's own painful experiences, going along with altered neural responses, by enhancing self‐regulatory processes and decreasing emotional reactivity. In order to investigate if mindfulness similarly reduces distress and neural activations associated with empathy for others' socially painful experiences, which might in the following more strongly motivate prosocial behavior, the present study compared trait, and state effects of long‐term mindfulness meditation (LTM) practice. To do so we acquired behavioral data and neural activity measures using functional magnetic resonance imaging (fMRI) during an empathy for social pain task while manipulating the meditation state between two groups of LTM practitioners that were matched with a control group. The results show increased activations of the anterior insula (AI) and anterior cingulate cortex (ACC) as well as the medial prefrontal cortex and temporal pole when sharing others' social suffering, both in LTM practitioners and controls. However, in LTM practitioners, who practiced mindfulness meditation just prior to observing others' social pain, left AI activation was lower and the strength of AI activation following the mindfulness meditation was negatively associated with trait compassion in LTM practitioners. The findings suggest that current mindfulness meditation could provide an adaptive mechanism in coping with distress due to the empathic sharing of others' suffering, thereby possibly enabling compassionate behavior. Hum Brain Mapp 38:4034–4046, 2017. © 2017 Wiley Periodicals, Inc.     

Emotional priming with facial exposures in euthymic patients with bipolar disorder

People with bipolar disorder have abnormal emotional processing. We investigated the automatic and controlled emotional processing via a priming paradigm with subliminal and supraliminal facial exposure. We compared 20 euthymic bipolar patients and 20 healthy subjects on their performance in subliminal and supraliminal tasks. Priming tasks consisted of three different primes according to facial emotions (happy, sad, and neutral) followed by a neutral face as a target stimulus. The prime stimuli were presented subliminally (17 msec) or supraliminally (1000 msec). In subliminal tasks, both patients and controls judged the neutral target face as significantly more unpleasant (negative judgment shift) when presented with negative emotion primes compared with positive primes. In supraliminal tasks, bipolar subjects showed significant negative judgment shift, whereas healthy subjects did not. There was a significant group × emotion interaction for the judgment rate in supraliminal tasks. Our finding of persistent affective priming even at conscious awareness may suggest that bipolar patients have impaired cognitive control on emotional processing rather than automatically spreading activation of emotion.     

Brain activation to briefly presented emotional words: Effects of stimulus awareness

It is unknown to what extent briefly presented emotional words can be processed without awareness. By means of two independent functional magnetic resonance imaging studies, using either a block or an event‐related design, we investigated brain activation to very briefly presented threat related and neutral words during two backward masking conditions (with and without gap between target and mask). In both experiments, emotional words were perceived during the supraliminal “with gap” condition, but they were not recognized during the subliminal “without gap” condition, as indicated by signal detection theory analysis. Imaging results of both experiments showed increased activation of the amygdala, the medial prefrontal cortex and language‐processing cortical areas to negative versus neutral words during supraliminal but not subliminal conditions. These results suggest that even very briefly presented emotional words are capable of triggering increased cortical and subcortical processing; however, only when awareness of these stimuli is given. Hum Brain Mapp 36:655–665, 2015. © 2014 Wiley Periodicals, Inc .     

Representation of perceived sound valence in the human brain

Perceived emotional valence of sensory stimuli influences their processing in various cortical and subcortical structures. Recent evidence suggests that negative and positive valences are processed separately, not along a single linear continuum. Here, we examined how brain is activated when subjects are listening to auditory stimuli varying parametrically in perceived valence (very unpleasant-neutral-very pleasant). Seventeen healthy volunteers were scanned in 3 Tesla while listening to International Affective Digital Sounds (IADS-2) in a block design paradigm. We found a strong quadratic U-shaped relationship between valence and blood oxygen level dependent (BOLD) signal strength in the medial prefrontal cortex, auditory cortex, and amygdala. Signals were the weakest for neutral stimuli and increased progressively for more unpleasant or pleasant stimuli. The results strengthen the view that valence is a crucial factor in neural processing of emotions. An alternative explanation is salience, which increases with both negative and positive valences.     

Ketamine administration reduces amygdalo‐hippocampal reactivity to emotional stimulation

Increased amygdala reactivity might lead to negative bias during emotional processing that can be reversed by antidepressant drug treatment. However, little is known on how N‐methyl‐d ‐aspartate (NMDA) receptor antagonism with ketamine as a novel antidepressant drug target might modulate amygdala reactivity to emotional stimulation. Using functional magnetic resonance imaging (fMRI) and resting‐state fMRI (rsfMRI), we assessed amygdalo‐hippocampal reactivity at baseline and during pharmacological stimulation with ketamine (intravenous bolus of 0.12 mg/kg, followed by a continuous infusion of 0.25 mg/kg/h) in 23 healthy subjects that were presented with stimuli from the International Affective Picture System (IAPS). We found that ketamine reduced neural reactivity in the bilateral amygdalo‐hippocampal complex during emotional stimulation. Reduced amygdala reactivity to negative pictures was correlated to resting‐state connectivity to the pregenual anterior cingulate cortex. Interestingly, subjects experienced intensity of psychedelic alterations of consciousness during ketamine infusion predicted the reduction in neural responsivity to negative but not to positive or neutral stimuli. Our findings suggest that the pharmacological modulation of glutamate‐responsive cerebral circuits, which is associated with a shift in emotional bias and a reduction of amygdalo‐hippocampal reactivity to emotional stimuli, represents an early biomechanism to restore parts of the disrupted neurobehavioral homeostasis in MDD patients. Hum Brain Mapp 37:1941–1952, 2016. © 2016 Wiley Periodicals, Inc .     

Enhanced Olfactory Sensory Perception of Threat in Anxiety: An Event-Related fMRI Study

The current conceptualization of threat processing in anxiety emphasizes emotional hyper-reactivity, which mediates various debilitating symptoms and derangements in anxiety disorders. Here, we investigated olfactory sensory perception of threat as an alternative causal mechanism of anxiety. Combining an event-related functional magnetic resonance imaging paradigm with an olfactory discrimination task, we examined how anxiety modulates basic perception of olfactory threats at behavioral and neural levels. In spite of subthreshold presentation of negative and neutral odors, a positive systematic association emerged between negative odor discrimination accuracy and anxiety levels. In parallel, the right olfactory primary (piriform) cortex indicated augmented response to subthreshold negative (vs. neutral) odors as a function of individual differences in anxiety. Using a psychophysiological interaction analysis, we further demonstrated amplified functional connectivity between the piriform cortex and emotion-related regions (amygdala and hippocampus) in response to negative odor, particularly in anxiety. Finally, anxiety also intensified skin conductance response to negative (vs. neutral) odor, indicative of potentiated emotional arousal to subliminal olfactory threat in anxiety. Together, these findings elucidate exaggerated processing of olfactory threat in anxiety across behavioral, autonomic physiological, and neural domains. Critically, our data emphasized anxiety-related hyper-sensitivity of the primary olfactory cortex and basic olfactory perception in response to threat, highlighting neurosensory mechanisms that may underlie the deleterious symptoms of anxiety.     

Reminders of mortality decrease midcingulate activity in response to others’ suffering

Reminders of mortality influence human social cognition, but whether and how reminders of mortality affect brain activity underlying social cognition remains unclear. To test whether increasing mortality salience modulates neural responses to others’ suffering, we scanned healthy adults who viewed video clips showing others in pain using functional magnetic resonance imaging. One group of participants were primed to increase mortality salience and another group were primed with negative affect in terms of fear/anxiety. We found that perceiving painful vs non-painful stimuli in the pre-priming session activated the midcingulate/dorsal medial prefrontal cortex (MCC/dMPFC), bilateral anterior insula/inferior frontal cortex, bilateral secondary somatosensory cortex and left middle temporal gyrus. However, MCC/dMPFC activity in response to perceived pain in others was significantly decreased in the post-priming session by the mortality salience priming, but was not influenced by the negative affect priming. Moreover, subjective fear of death induced by the priming procedures mediated the change in MCC/dMPFC activity across the priming procedures. Subjective fear of death also moderated the co-variation of MCC/dMPFC and left insular activity during perception of others in pain. Our findings indicate that reminders of mortality decrease neural responses to others’ suffering and this effect is mediated by the subjective fear of death.     

Emotion self-regulation and empathy depend upon longer stimulus exposure

Observation of others in pain induces positive elevation (pain effect) in late event-related potentials (ERP). This effect is associated with top-down attention regulating processes. It has previously been shown that stimulus exposure duration can affect top-down attentional modulation of response to threat-related stimuli. We investigated the effect of exposure duration on ERP response to others in pain. Two late ERP components, P3 and late positive potentials (LPP), from 18 healthy people were measured while they viewed pictures of hands in painful or neutral situations for either 200 or 500 ms, during two task conditions (pain judgment and counting hands). P3 and LPP pain effects during the pain judgment condition were significantly greater with 500 ms than 200 ms stimulus presentation. Ours is the first study to suggest that engagement of empathy-related self-regulatory processes reflected in late potentials requires longer exposure to the pain-related stimulus. Although this is important information about the relationship between early sensory and subsequent brain processing, and about engagement of self-regulatory processes, the neural basis of this time-dependence remains unclear. It might be important to investigate the relationship between stimulus duration and empathic response in clinical populations where issues of self-regulation, empathic response and speed of information processing exist.     

Spatiotemporal dynamics of affective picture processing revealed by intracranial high‐gamma modulations

Our comprehension of the neural mechanisms underlying emotional information processing has largely benefited from noninvasive electrophysiological and functional neuroimaging techniques in recent years. However, the spatiotemporal dynamics of the neural events occurring during emotional processing remain imprecise due to the limited combination of spatial and temporal resolution provided by these techniques. This study examines the modulations of high‐frequency activity of intracranial electroencephalography recordings associated with affective picture valence, in epileptic patients awaiting neurosurgery. Recordings were obtained from subdural grids and depth electrodes in eight patients while they viewed a series of unpleasant, pleasant and neutral pictures from the International Affective Picture System. Broadband high‐gamma (70–150 Hz) power was computed for separate 100‐ms time windows and compared according to ratings of emotional valence. Compared to emotionally neutral or pleasant pictures, unpleasant stimuli were associated with an early and long‐lasting (≈200–1,000 ms) bilateral increase in high‐gamma activity in visual areas of the occipital and temporal lobes, together with a late and transient (≈500–800 ms) decrease found bilaterally in the lateral prefrontal cortex (PFC). Pleasant pictures were associated with increased gamma activity in the occipital cortex, compared to the emotionally neutral stimuli. Consistent with previous studies, our results provide direct evidence of emotion‐related modulations in the visual ventral pathway during picture processing. Results in the lateral PFC also shed light on the neural mechanisms underlying its role in negative emotions processing. This study demonstrates the utility of intracranial high‐gamma modulations to study emotional process with a high spatiotemporal precision. Hum Brain Mapp, 36:16–28, 2015.. © 2014 Wiley Periodicals, Inc.     

Slow frequency repetitive transcranial magnetic stimulation affects reaction times, but not priming effects, in a masked prime task.

OBJECTIVE: Slow frequency repetitive transcranial magnetic stimulation (rTMS) reduces motor cortex excitability, but it is unclear whether this has behavioural consequences in healthy subjects. METHODS: We examined the effects of 1 Hz rTMS (train of 20 min; stimulus intensity 80% of active motor threshold) over left motor or left premotor cortex on performance in a visually cued choice reaction time task, using a 'masked prime' paradigm to assess whether rTMS might affect more automatic motor processes. Twelve healthy volunteers participated. RESULTS: Motor cortex rTMS and, to a lesser extent, premotor cortex rTMS resulted in a slowing of right (stimulated) hand responses, but not of left (unstimulated) hand responses. In a control experiment, rTMS of the left somatosensory cortex did not lead to slower right hand responses. DISCUSSION: We conclude that long trains of low intensity 1 Hz rTMS over the motor or premotor cortex can have subtle behavioural consequences outlasting the stimulation. rTMS did not affect the modulation of reaction times by subliminal primes, suggesting that priming effects triggered by subliminal primes are not generated at the level of motor or pre-motor cortex.     

Neural basis of pleasant and unpleasant emotions induced by social reputation

We used positron emission tomography to identify brain regions involved in the processing of emotions induced by social reputation from others. During positron emission tomographic scanning, individuals were presented with either a positive or a negative social reputation combined with face photographs of persons whom the individuals either liked or disliked. Behavioral results revealed that a positive reputation led to a higher pleasantness score than a negative reputation. Imaging data demonstrated that the orbitofrontal cortex was activated with positive reputations relative to negative reputations, and that the amygdala was activated with negative reputations relative to positive reputations. These findings suggest that pleasant and unpleasant emotions induced by positive and negative social reputations from others are associated with activity in different brain regions.     

The acquired capability for suicide: A comparison of suicide attempters,suicide ideators,and non‐suicidal controls

Background: The Interpersonal Theory of Suicide states that to make a serious or lethal suicide attempt, a person must experience reductions in fear and pain sensitivity sufficient to overcome self preservation reflexes (i.e., the acquired capability for suicide). The purpose of this study was to examine the fearlessness component of the acquired capability for suicide using self‐report assessment instruments and an objective measure of aversion (the affectively modulated startle reflex task). Methods: Depressed suicide ideators (n=15), depressed suicide attempters (n=15), and a group of control participants (n=14) were compared on their self‐report of acquired capability and painful and provocative life events, and completed the affectively modulated startle reflex task. This task compared electromyography recordings of participants' eye‐blink response to a startle probe while viewing pictures of varying hedonic valence (neutral, positive, negative, and suicide‐related). Results: Suicide attempters reported the highest levels of fearlessness and pain insensitivity and a greater history of painful and provocative life events. Although no group differences were found on the psychophysiology data, participants reacted to suicide‐related images with less aversion compared to neutral images with no differences between suicide‐related and positive images. Conclusions: Self‐reported fearlessness and pain insensitivity can differentiate suicide attempters and suicide ideators. Results suggest that one's self‐perception (i.e., cognitions regarding fear and pain tolerance) are more functionally related to suicide attempts than psychophysiological reactivity to suicide‐related stimuli. Depression and Anxiety, 2010. © 2010 Wiley‐Liss, Inc.     

Pain influences hedonic assessment of visual inputs

It is acknowledged that the emotional state created by visual inputs can modulate the way we feel pain; however, little is known about how acute pain influences the emotional assessment of what we see. In this study healthy subjects scored affective images while receiving painful or innocuous electrical shocks. Painful stimuli did not make unpleasant images more unpleasant, but rendered pleasant pictures significantly less pleasant. Brain responses to visual inputs (64-channels electroencephalogram) mirrored behavioural results, showing pain-induced effects in the orbitofrontal cortex, the subgenual portion of the cingulate gyrus, the anterior prefrontal and the temporal cortices, exclusively during presentation of pleasant images. In addition to this specific effect on pleasant pictures, pain also produced non-specific effects upon all categories of images, engaging cerebral areas associated with attention, alertness and motor preparation (middle-cingulate, supplemental motor, prefrontal cortex). Thus, pain appears to have a dual influence on visual processing: a non-specific effect related to orienting phenomena; and a more specific action exerted on supra-modal limbic areas involved in the production of affective states. The latter correlated with changes in the subjective appraisal of visual stimuli, and may underlie not only the change in their subjective assessment but also reactive processes aimed at coping with unpleasant contexts.     

Processing of subliminal facial expressions of emotion: A behavioral and fMRI study

The recognition of emotional facial expressions is an important means to adjust behavior in social interactions. As facial expressions widely differ in their duration and degree of expressiveness, they often manifest with short and transient expressions below the level of awareness. In this combined behavioral and fMRI study, we aimed at examining whether or not consciously accessible (subliminal) emotional facial expressions influence empathic judgments and which brain activations are related to it. We hypothesized that subliminal facial expressions of emotions masked with neutral expressions of the same faces induce an empathic processing similar to consciously accessible (supraliminal) facial expressions. Our behavioral data in 23 healthy subjects showed that subliminal emotional facial expressions of 40 ms duration affect the judgments of the subsequent neutral facial expressions. In the fMRI study in 12 healthy subjects it was found that both, supra- and subliminal emotional facial expressions shared a widespread network of brain areas including the fusiform gyrus, the temporo-parietal junction, and the inferior, dorsolateral, and medial frontal cortex. Compared with subliminal facial expressions, supraliminal facial expressions led to a greater activation of left occipital and fusiform face areas. We conclude that masked subliminal emotional information is suited to trigger processing in brain areas which have been implicated in empathy and, thereby in social encounters     

Emotion in psychogenic nonepileptic seizures: responses to affective pictures

We examined emotional responses to standard affective pictures in 18 psychogenic nonepileptic seizure (PNES) patients. Given reports of trauma and posttraumatic stress symptoms (PTS) in many PNES patients, comparison groups were seizure-free individuals high and low in PTS (PTS-high, PTS-low; n=18 per group). Patients with psychogenic nonepileptic seizures (1) reported more emotional intensity to neutral and pleasant pictures than PTS-low and more intensity to neutral pictures than PTS-high, and (2) showed less positive emotional behavior to pleasant pictures than PTS-high. Groups did not differ in pleasantness/unpleasantness ratings, negative emotional behavior, cardiac interbeat interval, or respiratory sinus arrhythmia (RSA) reactivity to the pictures. Patients with psychogenic nonepileptic seizures reported more general emotion regulation difficulties and showed lower baseline RSA than PTS-low but not PTS-high. In sum, intense emotional experience and diminished positive emotional behavior characterized PNES patients' emotional responses.     

Amygdala-prefrontal dissociation of subliminal and supraliminal fear

Facial expressions of fear are universally recognized signals of potential threat. Humans may have evolved specialized neural systems for responding to fear in the absence of conscious stimulus detection. We used functional neuroimaging to establish whether the amygdala and the medial prefrontal regions to which it projects are engaged by subliminal fearful faces and whether responses to subliminal fear are distinguished from those to supraliminal fear. We also examined the time course of amygdala-medial prefrontal responses to supraliminal and subliminal fear. Stimuli were fearful and neutral baseline faces, presented under subliminal (16.7 ms and masked) or supraliminal (500 ms) conditions. Skin conductance responses (SCRs) were recorded simultaneously as an objective index of fear perception. SPM2 was used to undertake search region-of-interest (ROI) analyses for the amygdala and medial prefrontal (including anterior cingulate) cortex, and complementary whole-brain analyses. Time series data were extracted from ROIs to examine activity across early versus late phases of the experiment. SCRs and amygdala activity were enhanced in response to both subliminal and supraliminal fear perception. Time series analysis showed a trend toward greater right amygdala responses to subliminal fear, but left-sided responses to supraliminal fear. Cortically, subliminal fear was distinguished by right ventral anterior cingulate activity and supraliminal fear by dorsal anterior cingulate and medial prefrontal activity. Although subcortical amygdala activity was relatively persistent for subliminal fear, supraliminal fear showed more sustained cortical activity. The findings suggest that preverbal processing of fear may occur via a direct rostral-ventral amygdala pathway without the need for conscious surveillance, whereas elaboration of consciously attended signals of fear may rely on higher-order processing within a dorsal cortico-amygdala pathway.     

The left dorsolateral prefrontal cortex and caudate pathway: New evidence for cue‐induced craving of smokers

Although the activation of the prefrontal cortex (PFC) and the striatum had been found in smoking cue induced craving task, whether and how the functional interactions and white matter integrity between these brain regions contribute to craving processing during smoking cue exposure remains unknown. Twenty‐five young male smokers and 26 age‐ and gender‐matched nonsmokers participated in the smoking cue‐reactivity task. Craving related brain activation was extracted and psychophysiological interactions (PPI) analysis was used to specify the PFC‐efferent pathways contributed to smoking cue‐induced craving. Diffusion tensor imaging (DTI) and probabilistic tractography was used to explore whether the fiber connectivity strength facilitated functional coupling of the circuit with the smoking cue‐induced craving. The PPI analysis revealed the negative functional coupling of the left dorsolateral prefrontal cortex (DLPFC) and the caudate during smoking cue induced craving task, which positively correlated with the craving score. Neither significant activation nor functional connectivity in smoking cue exposure task was detected in nonsmokers. DTI analyses revealed that fiber tract integrity negatively correlated with functional coupling in the DLPFC‐caudate pathway and activation of the caudate induced by smoking cue in smokers. Moreover, the relationship between the fiber connectivity integrity of the left DLPFC‐caudate and smoking cue induced caudate activation can be fully mediated by functional coupling strength of this circuit in smokers. The present study highlighted the left DLPFC‐caudate pathway in smoking cue‐induced craving in smokers, which may reflect top‐down prefrontal modulation of striatal reward processing in smoking cue induced craving processing. Hum Brain Mapp 38:4644–4656, 2017. © 2017 Wiley Periodicals, Inc.     

Selective numbing and hyperarousal in male and female Bosnian refugees with PTSD

Emotional numbing is an important symptom of PTSD, but it is not clear whether it affects both positive and negative affect equally or not. To address this question we administered Lang's Looking at Pictures test, in which a series of pictures are rated for valence (pleasant-unpleasant) and arousal (high-low), to 10 male and 11 female Bosnian refugees suffering from PTSD (DSM-IV criteria) and to control groups of 11 male and 10 female Bosnian refugees with similar trauma exposure but without PTSD or any other major mental illness. The mean valence ratings for unpleasant, neutral, and pleasant pictures of both PTSD and control males and females were similar to normal ratings. Likewise, the mean arousal ratings for unpleasant, neutral, and pleasant pictures of both male and female controls were similar to normals, with both unpleasant and pleasant pictures rated more arousing than neutral pictures. In contrast, in both males and females with PTSD pleasant pictures were rated as almost completely non-arousing. Thus, in Bosnian refugees affective numbing is seen primarily with pleasant or positive stimuli.     

Neural correlates of the self‐concept in adolescence—A focus on the significance of friends

The formation of a coherent and unified self‐concept represents a key developmental stage during adolescence. Imaging studies on self‐referential processing in adolescents are rare, and it is not clear whether neural structures involved in self‐reflection are also involved in reflections of familiar others. In the current study, 41 adolescents were asked to make judgments about trait adjectives during functional magnetic resonance imaging (fMRI): they had to indicate whether the word describes themselves, their friends, their teachers or politicians. Findings indicate a greater overlap in neural networks for responses to self‐ and friend‐related judgments compared to teachers and politicians. In particular, classic self‐reference structures such as the ventromedial prefrontal cortex and medial posterior parietal cortex also exhibited higher activation to judgments about friends. In contrast, brain responses towards judgments of teachers (familiar others) compared to politicians (unfamiliar others) did not significantly differ. Results support behavioral findings of a greater relevance of friends for the development of a self‐concept during adolescence and indicate underlying functional brain processes. Hum Brain Mapp 38:987–996, 2017. © 2016 Wiley Periodicals, Inc.