Induction of Empathy by the Smell of Anxiety

The communication of stress/anxiety between conspecifics through chemosensory signals has been documented in many vertebrates and invertebrates. Here, we investigate how chemosensory anxiety signals conveyed by the sweat of humans (N = 49) awaiting an academic examination are processed by the human brain, as compared to chemosensory control signals obtained from the same sweat donors in a sport condition. The chemosensory stimuli were pooled according to the donation condition and administered to 28 participants (14 males) synchronously to breathing via an olfactometer. The stimuli were perceived with a low intensity and accordingly only about half of the odor presentations were detected by the participants. The fMRI results (event-related design) show that chemosensory anxiety signals activate brain areas involved in the processing of social emotional stimuli (fusiform gyrus), and in the regulation of empathic feelings (insula, precuneus, cingulate cortex). In addition, neuronal activity within attentional (thalamus, dorsomedial prefrontal cortex) and emotional (cerebellum, vermis) control systems were observed. The chemosensory perception of human anxiety seems to automatically recruit empathy-related resources. Even though the participants could not attentively differentiate the chemosensory stimuli, emotional contagion seems to be effectively mediated by the olfactory system.     

Human Gender Differences in the Perception of Conspecific Alarm Chemosensory Cues

It has previously been established that, in threatening situations, animals use alarm pheromones to communicate danger. There is emerging evidence of analogous chemosensory “stress” cues in humans. For this study, we collected alarm and exercise sweat from “donors,” extracted it, pooled it and presented it to 16 unrelated “detector” subjects undergoing fMRI. The fMRI protocol consisted of four stimulus runs, with each combination of stimulus condition and donor gender represented four times. Because olfactory stimuli do not follow the canonical hemodynamic response, we used a model-free approach. We performed minimal preprocessing and worked directly with block-average time series and step-function estimates. We found that, while male stress sweat produced a comparably strong emotional response in both detector genders, female stress sweat produced a markedly stronger arousal in female than in male detectors. Our statistical tests pinpointed this gender-specificity to the right amygdala (strongest in the superficial nuclei). When comparing the olfactory bulb responses to the corresponding stimuli, we found no significant differences between male and female detectors. These imaging results complement existing behavioral evidence, by identifying whether gender differences in response to alarm chemosignals are initiated at the perceptual versus emotional level. Since we found no significant differences in the olfactory bulb (primary processing site for chemosensory signals in mammals), we infer that the specificity in responding to female fear is likely based on processing meaning, rather than strength, of chemosensory cues from each gender.     

The Roles of Noradrenergic and Glucocorticoid Activation in the Development of Intrusive Memories

Intrusive memories are a common feature of many psychological disorders. Recent evidence has potentially extended cognitive models of intrusions by identifying the role of biological markers of arousal at the time of consolidation in subsequent memory for emotional events. This study investigated the role of arousal during consolidation in the development of intrusive memories. Seventy-eight university students (37 men and 41 women) viewed 20 negative and 20 neutral images. Half the participants then underwent a cold pressor test (High Stress), immersing their hand in ice water, while the remaining participants immersed their hand in warm water (Low Stress). Samples of salivary alpha-amylase (sAA) and cortisol were collected from participants at baseline and following the stressor challenge. Participants completed a delayed free recall test and intrusion questionnaires two days later. Participants in the High Stress condition reported more intrusions of negative images than participants in the Low Stress condition. An interaction variable in a linear regression of increased noradrenergic and cortisol values predicted intrusive memories of emotional stimuli for men but not women. These findings are consistent with recent evidence of the combined effects of noradrenaline and corticoid responses to stress on emotional memories, and also with increasing evidence of gender differences in how stress hormones influence formation of emotional memories. These findings point to possible mechanisms by which development of intrusions may be prevented after consolidation of traumatic experiences.     

Intensified Neuronal Investment in the Processing of Chemosensory Anxiety Signals in Non-Socially Anxious and Socially Anxious Individuals

Background

The ability to communicate anxiety through chemosensory signals has been documented in humans by behavioral, perceptual and brain imaging studies. Here, we investigate in a time-sensitive manner how chemosensory anxiety signals, donated by humans awaiting an academic examination, are processed by the human brain, by analyzing chemosensory event-related potentials (CSERPs, 64-channel recording with current source density analysis).

Methodology/Principal Findings

In the first study cerebral stimulus processing was recorded from 28 non-socially anxious participants and in the second study from 16 socially anxious individuals. Each individual participated in two sessions, smelling sweat samples donated from either female or male donors (88 sessions; balanced session order). Most of the participants of both studies were unable to detect the stimuli olfactorily. In non-socially anxious females, CSERPs demonstrate an increased magnitude of the P3 component in response to chemosensory anxiety signals. The source of this P3 activity was allocated to medial frontal brain areas. In socially anxious females chemosensory anxiety signals require more neuronal resources during early pre-attentive stimulus processing (N1). The neocortical sources of this activity were located within medial and lateral frontal brain areas. In general, the event-related neuronal brain activity in males was much weaker than in females. However, socially anxious males processed chemosensory anxiety signals earlier (N1 latency) than the control stimuli collected during an ergometer training.

Conclusions/Significance

It is concluded that the processing of chemosensory anxiety signals requires enhanced neuronal energy. Socially anxious individuals show an early processing bias towards social fear signals, resulting in a repression of late attentional stimulus processing.     

Effects of reproductive status on behavioral and endocrine responses to acute stress in a biparental rodent, the California mouse (Peromyscus californicus)

In several mammalian species, lactating females show blunted neural, hormonal, and behavioral responses to stressors. It is not known whether new fathers also show stress hyporesponsiveness in species in which males provide infant care. To test this possibility, we determined the effects of male and female reproductive status on stress responsiveness in the biparental, monogamous California mouse (Peromyscus californicus). Breeding (N = 8 females, 8 males), nonbreeding (N = 10 females, 10 males) and virgin mice (N = 12 females, 9 males) were exposed to a 5-min predator-urine stressor at two time points, corresponding to the early postpartum (5-7 days postpartum) and mid/late postpartum (19-21 days postpartum) phases, and blood samples were collected immediately afterwards. Baseline blood samples were obtained 2 days prior to each stress test. Baseline plasma corticosterone (CORT) concentrations did not differ among male or female groups. CORT responses to the stressor did not differ among female reproductive groups, and all three groups showed distinct behavioral responses to predator urine. Virgin males tended to increase their CORT response from the first to the second stress test, while breeding and nonbreeding males did not. Moreover, virgin and nonbreeding males showed significant behavioral changes in response to predator urine, whereas breeding males did not. These results suggest that adrenocortical responses to a repeated stressor in male California mice may be modulated by cohabitation with a female, whereas behavioral responses to stress may be blunted by parental status.     

Social Environment Affects Peripheral Oxytocin and Cortisol during Stress Responses in Guinea-Pigs

Numerous studies have demonstrated interactions between oxytocin (OT) secretion, adrenal activity, an animal's social environment, and stress responses. In the present study, we hypothesized that partner preference and pair bonding cause increased peripheral OT, which down‐regulates the adrenal and behavioral response in stress. In addition, we tested whether these interactions depended on sex, the social environment of the individual, or the type of stressor. Experiments were carried out on guinea‐pigs held in sexual‐pairs or stressed by isolation. Among the paired individuals choice tests were carried out to document partner preference. Female preference for a male was expressed by spatial cohesion. Stress responses to abiotic stimuli were examined and compared between isolated and cohabited animals with or without preference. Results show that OT of cohabited animals was significantly higher than during isolation. OT levels were further increased in males preferred by females. Cortisol (CORT) levels were elevated in isolated animals. There were no significant differences between pairs with and without female preference. Behaviorally, partner preferences were expressed by high amounts of tactile contact. The stress‐induced behavioral immobility response after exposure to a noise stressor was significantly reduced in preferred males and to a lesser extent in their female partners. Only females with preferences showed an endocrine stress response. Their levels of OT increased. There was no consistent post‐stressor release of CORT. The data indicate that the social environment of an individual, here expressed as preference or isolation, influences peripheral OT secretion. Behavioral stress responses were similarly affected by social factors without a clear involvement of peripheral CORT or OT.     

Positive emotional priming of facial affect perception in females is diminished by chemosensory anxiety signals

Chemosensory communication of anxiety is a common phenomenon in vertebrates and improves perceptual and responsive behaviour in the perceiver in order to optimize ontogenetic survival. A few rating studies reported a similar phenomenon in humans. Here, we investigated whether subliminal face perception changes in the context of chemosensory anxiety signals. Axillary sweat samples were taken from 12 males while they were waiting for an academic examination and while exercising ergometric training some days later. 16 subjects (eight females) participated in an emotional priming study, using happy, fearful and sad facial expressions as primes (11.7 ms) and neutral faces as targets (47 ms). The pooled chemosensory samples were presented before and during picture presentation (920 ms). In the context of chemosensory stimuli derived from sweat samples taken during the sport condition, subjects judged the targets significantly more positive when they were primed by a happy face than when they were primed by the negative facial expressions (P = 0.02). In the context of the chemosensory anxiety signals, the priming effect of the happy faces was diminished in females (P = 0.02), but not in males. It is discussed whether, in socially relevant ambiguous perceptual conditions, chemosensory signals have a processing advantage and dominate visual signals or whether fear signals in general have a stronger behavioural impact than positive signals.     

Emotional voice and emotional body postures influence each other independently of visual awareness

Multisensory integration may occur independently of visual attention as previously shown with compound face-voice stimuli. We investigated in two experiments whether the perception of whole body expressions and the perception of voices influence each other when observers are not aware of seeing the bodily expression. In the first experiment participants categorized masked happy and angry bodily expressions while ignoring congruent or incongruent emotional voices. The onset between target and mask varied from -50 to +133 ms. Results show that the congruency between the emotion in the voice and the bodily expressions influences audiovisual perception independently of the visibility of the stimuli. In the second experiment participants categorized the emotional voices combined with masked bodily expressions as fearful or happy. This experiment showed that bodily expressions presented outside visual awareness still influence prosody perception. Our experiments show that audiovisual integration between bodily expressions and affective prosody can take place outside and independent of visual awareness.     

Bitter substances suppress afferent responses to an appetitive mixture: evidence for peripheral integration of chemosensory stimuli.

The processes that lead from detection of chemicals, transduction, and coding with the appropriate message to initiate ingestion of a palatable meal or to reject a potentially noxious substance are poorly understood in vertebrates owing to the complex organization of the taste system. As a first step in elucidating the cellular basis of the behavioral differences elicited by appetitive stimuli and bitter compounds, we recorded from the afferent nerves conveying peripheral chemosensory information to the CNS in the head of the leech, Hirudo medicinalis. Superfusion of the chemosensory region of the lip of Hirudo with a mixture of NaCl (150 mM) and arginine (1 mM), an appetitive solution that elicits ingestion, increased the neuronal activity in the afferent cephalic nerves, for example (Zhang X, Wilson RJ, Li Y, Kleinhaus AL. 2000. Chemical and thermal stimuli have short-lived effects on the Retzius cell in the medicinal leech. J Neurobiol 43:304-311.). In the present paper we show that superfusing the lip with quinine or denatonium reduced the basal neural activity in the afferents. Furthermore, these bitter substances in the appetitive solution counteracted the increased activity the appetitive solution evoked in the cephalic nerves. Thus, the neural activity evoked by the application of appetitive and aversive stimuli to the chemosensory area of the lip paralleled the opposite behavioral responses to the same chemicals. The results suggest that individual leech taste cells possess receptors for both types of stimuli. Therefore, the leech may be a good model system in which to study peripheral taste events in cells that may possess multiple receptors and transduction mechanisms that interact to integrate information.     

Stress impairs new but not established relationships in seasonally social voles

Affiliative social relationships are impacted by stressors and can shape responses to stress. However, the effects of stress on social relationships in different contexts are not well understood. Meadow voles provide an opportunity to study these effects on peer relationships outside of a reproductive context. In winter months, female meadow voles cohabit with peers of both sexes, and social huddling is facilitated by exposure to short, winter-like day lengths in the lab. We investigated the role of stress and corticosterone (cort) levels in social behavior in short day-housed female meadow voles. A brief forced swim elevated cort levels, and we assessed the effects of this stressor on new and established relationships between females. In pairs formed following exposure to swim stress, the stressor significantly reduced the fraction of huddling time subjects spent with a familiar partner. Swim stress did not affect partner preferences in pairs established prior to the stressor. Finally, we examined fecal glucocorticoid metabolite levels via immunoassay in voles housed under short day (10 h light) versus long day (14 h light) conditions and detected higher glucocorticoid levels in long day-housed voles. These findings support a role for stress regulation in the formation of social relationships in female meadow voles, and are consistent with a potential role for seasonal variation in cort in the behavioral transition from solitary to social. Together they highlight the importance of stress and possibly glucocorticoid signaling for social behavior.     

The impact of acute psychosocial stress on magnetoencephalographic correlates of emotional attention and exogenous visual attention

Stress-induced acute activation of the cerebral catecholaminergic systems has often been found in rodents. However, little is known regarding the consequences of this activation on higher cognitive functions in humans. Theoretical inferences would suggest increased distractibility in the sense of increased exogenous attention and emotional attention. The present study investigated the influence of acute stress responses on magnetoencephalographic (MEG) correlates of visual attention. Healthy male subjects were presented emotional and neutral pictures in three subsequent MEG recording sessions after being exposed to a TSST-like social stressor, intended to trigger a HPA-response. The subjects anticipation of another follow-up stressor was designed to sustain the short-lived central catecholaminergic stress reactions throughout the ongoing MEG recordings. The heart rate indicates a stable level of anticipatory stress during this time span, subsequent cortisol concentrations and self-report measures of stress were increased. With regard to the MEG correlates of attentional functions, we found that the N1m amplitude remained constantly elevated during stressor anticipation. The magnetic early posterior negativity (EPNm) was present but, surprisingly, was not at all modulated during stressor anticipation. This suggests that a general increase of the influence of exogenous attention but no specific effect regarding emotional attention in this time interval. Regarding the time course of the effects, an influence of the HPA on these MEG correlates of attention seems less likely. An influence of cerebral catecholaminergic systems is plausible, but not definite.     

Effects of low-spatial frequency components of fearful faces on fusiform cortex activity

Emotive faces elicit neural responses even when they are not consciously perceived. We used faces hybridized from spatial frequency-filtered individual stimuli to study processing of facial emotion. Employing event-related functional magnetic resonance imaging (fMRI), we show enhanced fusiform cortex responses to hybrid faces containing fearful expressions when such emotional cues are present in the low-spatial frequency (LSF) range. Critically, this effect is independent of whether subjects use LSF or high-spatial frequency (HSF) information to make gender judgments on the hybridized faces. The magnitude of this fusiform enhancement predicts behavioral slowing in response times when participants report HSF information of the hybrid stimulus in the presence of fear in the unreported LSF components. Thus, emotional modulation of a face-responsive region of fusiform is driven by the low-frequency components of the stimulus, an effect independent of subjects' reported perception but evident in an incidental measure of behavioral performance.     

Stressor-Like Effects of c-Jun N-Terminal Kinase (JNK) Inhibition

There is an urgent need for novel treatment strategies for stressor related disorders, particularly depression and anxiety disorders. Indeed, existing drug treatments are only clinically successful in a subset of patients and relapse is common. This likely stems from the fact that stressor disorders are heterogeneous with multiple biological pathways being affected. To this end, the present investigation sought to assess in mice the contribution of the c-Jun N terminal kinase (JNK) pathway to the behavioral, hormonal and neurochemical effects of an acute stressor. Indeed, although JNK has been shown to modulate glucocorticoid receptors in vitro, virtually nothing is known of the role for JNK in affecting stressor induced pathology. We presently found that the JNK antagonist, SP600125, (but not the p38 antagonist, SB203580) increased plasma corticosterone levels under resting conditions and in the context of an acute stressor (wet bedding + restraint). SP600125 also reduced exploration in an open field arena, but prevented the stressor induced increase in open arm exploration in an elevated plus maze. Finally, SP600125 affected noradrenergic activity in the central amygdala and locus coruleus under resting condition, but prevented the noradrenergic effects within the paraventricular nucleus of the hypothalamus that were induced by the acute stressor exposure. These data suggest inhibiting endogenous JNK can have stressor-like corticoid, behavioral and central monoamine effects under basal conditions, but can actually reverse some behavioral and neurochemical effects of an acute stressor. Thus, endogenous JNK appears to affect stress relevant processes in a context-dependent manner.     

Differential interaction between stressors and chronic amphetamine or phencyclidine upon operant behavior in the rat

Three types of stress were examined for their effects upon fixed-ratio 15 (FR-15) operant behavior in Sprague-Dawley rats before and after chronic dextroamphetamine to determine if cumulated drug could interact with stress to produce a state of behavioral toxicity. Six daily s.c. injections of saline were given to rats following 30-min behavioral sessions. Thirty minutes of exposure to a cold environment (7°C) or to electric footshock (2mA for 0.5 sec, 1 shock/min) had no significant effect upon FR-15 behavior beginning 15 min afterward. Five daily s.c. injections of 2.5 mg dextroamphetamine/kg after behavioral sessions suppressed behavior during the following days an average of 12%. Rats were again stressed twenty-two hours after the sixth injection. Footshock further suppressed behavior to 26% of the unstressed, chronic amphetamine-treated control group. Cold exposure failed to suppress behavior significantly below control levels. A similar experiment employing cold water exposure (15°C for 2 min) as the stressor showed that, although this stressor suppressed FR-15 behavior to 53% of the previous day's rates and reduced body temperature 2.1°C, chronic amphetamine failed to interact with the cold water stress to suppress behavior further. In a third experiment, 4.5 mg phencyclidine/kg, s.c., given after 30-min FR-15 sessions for six days, failed to interact with the footshock stress to cause behavioral suppression different from control treatment. While stress can interact with chronic treatment with lipophilic drugs, the quality of the stress, and the physical and pharmacologic properties of the drug are important determinants of the outcome upon conditioned behavior.     

Dissociation between Emotional Remapping of Fear and Disgust in Alexithymia

There is growing evidence that individuals are able to understand others’ emotions because they “embody” them, i.e., re-experience them by activating a representation of the observed emotion within their own body. One way to study emotion embodiment is provided by a multisensory stimulation paradigm called emotional visual remapping of touch (eVRT), in which the degree of embodiment/remapping of emotions is measured as enhanced detection of near-threshold tactile stimuli on one’s own face while viewing different emotional facial expressions. Here, we measured remapping of fear and disgust in participants with low (LA) and high (HA) levels of alexithymia, a personality trait characterized by a difficulty in recognizing emotions. The results showed that fear is remapped in LA but not in HA participants, while disgust is remapped in HA but not in LA participants. To investigate the hypothesis that HA might exhibit increased responses to emotional stimuli producing a heightened physical and visceral sensations, i.e., disgust, in a second experiment we investigated participants’ interoceptive abilities and the link between interoception and emotional modulations of VRT. The results showed that participants’ disgust modulations of VRT correlated with their ability to perceive bodily signals. We suggest that the emotional profile of HA individuals on the eVRT task could be related to their abnormal tendency to be focalized on their internal bodily signals, and to experience emotions in a “physical” way. Finally, we speculated that these results in HA could be due to a enhancement of insular activity during the perception of disgusted faces.     

How Psychological Stress Affects Emotional Prosody

We explored how experimentally induced psychological stress affects the production and recognition of vocal emotions. In Study 1a, we demonstrate that sentences spoken by stressed speakers are judged by naïve listeners as sounding more stressed than sentences uttered by non-stressed speakers. In Study 1b, negative emotions produced by stressed speakers are generally less well recognized than the same emotions produced by non-stressed speakers. Multiple mediation analyses suggest this poorer recognition of negative stimuli was due to a mismatch between the variation of volume voiced by speakers and the range of volume expected by listeners. Together, this suggests that the stress level of the speaker affects judgments made by the receiver. In Study 2, we demonstrate that participants who were induced with a feeling of stress before carrying out an emotional prosody recognition task performed worse than non-stressed participants. Overall, findings suggest detrimental effects of induced stress on interpersonal sensitivity.     

Chemosignals of fear enhance cognitive performance in humans

It is well documented across phyla that animals experiencing stress and fear produce chemical warning signals that can lead to behavioral, endocrinological, and immunological changes in the recipient animals of the same species. Humans distinguish between fear and other emotional chemosignals based on olfactory cues. Here, we study the effect of human fear chemosignals on the speed and accuracy of cognitive performance. In a double-blind experiment, female participants performed a word-association task while smelling one of the three types of olfactory stimuli: fear sweat, neutral sweat, and control odor carrier. We found that the participants exposed to the fear condition performed more accurately and yet with no sacrifice for speed on meaningful word conditions than those under either the neutral or the control condition. At the same time, they performed slower on tasks that contained ambiguous content. Possible factors that could introduce bias, such as individual differences due to anxiety, verbal skills, and perceived qualities of the smells, were ruled out. Our results demonstrate that human fear chemosignals enhance cognitive performances in the recipient. We suggest that this effect originates from learned associations, including greater cautiousness and concomitant changes in cognitive strategies.     

Stress-induced reductions of sensory reactivity in female rats depend on ovarian hormones and the application of a painful stressor

The current experiments occurred in the context of disputes in the literature concerning whether inescapable stress causes differential changes in sensory reactivity, which could lead to differences in many learning procedures. We tested rats for differences in sensitivity and responsivity to acoustic stimuli through the use of the acoustic startle response (ASR) 2 h after stressor exposure and ambulatory activity 24 h later in the open field. Stressed females showed reduced responsivity to acoustic stimuli with no apparent shift in stimulus sensitivity. Males did not show differences in either reactivity index following stressor exposure. Reduced responsivity did not occur if females had been OVX (OVX alone did not effect stimulus responsivity or sensitivity). All groups that experienced tailshock stress also had reduced open field activity 24 h later. Restraint for 2 h did not reduce stimulus responsivity in the ASR or open field activity in female rats. Acute reductions in ASRs after a painful stressor appear to be a feature specific to females, with an apparent role of ovarian hormones as a modulator of the effect. Possible hormone and/or immunological mechanisms of these sex-specific effects are discussed. Understanding the mechanisms of this stressor-induced reduction in sensory reactivity could advance our knowledge of how individual differences in ovarian hormone levels influence the physical and psychological processes by which females acutely respond and later recover from traumatic events.     

Long-term behavioral and neuroendocrine alterations following chronic social stress in mice: implications for stress-related disorders

The period of adolescence is characterized by a high vulnerability to stress and trauma, which might result in long-lasting consequences and an increased risk to develop psychiatric disorders. Using a recently developed mouse model for chronic social stress during adolescence, we studied persistent neuroendocrine and behavioral effects of chronic social stress obtained 12 months after cessation of the stressor. As a reference, we investigated immediate effects of chronic stress exposure obtained at the end of the chronic stress period. Immediately after the 7 week chronic stress period stressed animals show significantly increased adrenal weights, decreased thymus weight, increased basal corticosterone secretion and a flattened circadian rhythm. Furthermore, stressed animals display an increased anxiety-like behavior in the elevated plus maze and the novelty-induced suppression of feeding test. Hippocampal mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) mRNA levels were significantly decreased. To investigate persistent consequences of this early stressful experience, the same parameters were assessed in aged mice 12 months after the cessation of the stressor. Interestingly, we still found differences between formerly stressed and control mice in important stress-related parameters. MR expression levels were significantly lower in stressed animals, suggesting lasting, possibly epigenetic alterations in gene expression regulation. Furthermore, we observed long-term behavioral alterations in animals stressed during adolescence. Thus, we could demonstrate that chronic stress exposure during a crucial developmental time period results in long-term, persistent effects on physiological and behavioral parameters throughout life, which may contribute to an enhanced vulnerability to stress-induced diseases.     

Effects of AKAP5 Pro100Leu Genotype on Working Memory for Emotional Stimuli

Recent investigations addressing the role of the synaptic multiadaptor molecule AKAP5 in human emotion and behavior suggest that the AKAP5 Pro100Leu polymorphism (rs2230491) contributes to individual differences in affective control. Carriers of the less common Leu allele show a higher control of anger as indicated by behavioral measures and dACC brain response on emotional distracters when compared to Pro homozygotes. In the current fMRI study we used an emotional working memory task according to the n-back scheme with neutral and negative emotional faces as target stimuli. Pro homozygotes showed a performance advantage at the behavioral level and exhibited enhanced activation of the amygdala and fusiform face area during working memory for emotional faces. On the other hand, Leu carriers exhibited increased activation of the dACC during performance of the 2-back condition. Our results suggest that AKAP5 Pro100Leu effects on emotion processing might be task-dependent with Pro homozygotes showing lower control of emotional interference, but more efficient processing of task-relevant emotional stimuli.