Prediction and action in cortical pain processing.

Predicting that a stimulus is painful facilitates action to avoid harm. But how distinct are the neural processes underlying the prediction of upcoming painful events vis-à-vis those taking action to avoid them? Here, we investigated brain activity as a function of current and predicted painful or nonpainful thermal stimulation, as well as the ability of voluntary action to affect the duration of upcoming stimulation. Participants performed a task which involved the administration of a painful or nonpainful stimulus (S1), which predicted an immediately subsequent very painful or nonpainful stimulus (S2). Pressing a response button within a specified time window during S1 either reduced or did not reduce the duration of the upcoming stimulation. Predicted pain increased activation in several regions, including anterior cingulate cortex (ACC), midcingulate cortex (MCC), and insula; however, activation in ACC and MCC depended on whether a meaningful action was performed, with MCC activation showing a direct relationship with motor output. Insula's responses for predicted pain were also modulated by potential action consequences, albeit without a direct relationship with motor output. These findings suggest that cortical pain processing is not specifically tied to the sensory stimulus, but instead, depends on the consequences of that stimulus for sensorimotor control of behavior.

Nav1.7 is required for normal C-low threshold mechanoreceptor function in humans and mice.

Patients with bi-allelic loss of function mutations in the voltage-gated sodium channel Nav1.7 present with congenital insensitivity to pain (CIP), whilst low threshold mechanosensation is reportedly normal. Using psychophysics (n = 6 CIP participants and n = 86 healthy controls) and facial electromyography (n = 3 CIP participants and n = 8 healthy controls), we found that these patients also have abnormalities in the encoding of affective touch, which is mediated by the specialized afferents C-low threshold mechanoreceptors (C-LTMRs). In the mouse, we found that C-LTMRs express high levels of Nav1.7. Genetic loss or selective pharmacological inhibition of Nav1.7 in C-LTMRs resulted in a significant reduction in the total sodium current density, an increased mechanical threshold and reduced sensitivity to non-noxious cooling. The behavioural consequence of loss of Nav1.7 in C-LTMRs in mice was an elevation in the von Frey mechanical threshold and less sensitivity to cooling on a thermal gradient. Nav1.7 is therefore not only essential for normal pain perception but also for normal C-LTMR function, cool sensitivity and affective touch.

Genetic risk-factors for anxiety in healthy individuals: polymorphisms in genes important for the HPA axis.

BACKGROUND: Two important aspects for the development of anxiety disorders are genetic predisposition and alterations in the hypothalamic-pituitary-adrenal (HPA) axis. In order to identify genetic risk-factors for anxiety, the aim of this exploratory study was to investigate possible relationships between genetic polymorphisms in genes important for the regulation and activity of the HPA axis and self-assessed anxiety in healthy individuals. METHODS: DNA from 72 healthy participants, 37 women and 35 men, were included in the analyses. Their DNA was extracted and analysed for the following Single Nucleotide Polymorphisms (SNP)s: rs41423247 in the NR3C1 gene, rs1360780 in the FKBP5 gene, rs53576 in the OXTR gene, 5-HTTLPR in SLC6A4 gene and rs6295 in the HTR1A gene. Self-assessed anxiety was measured by the State and Trait Anxiety Inventory (STAI) questionnaire. RESULTS: Self-assessed measure of both STAI-S and STAI-T were significantly higher in female than in male participants (p = 0.030 and p = 0.036, respectively). For SNP rs41423247 in the NR3C1 gene, there was a significant difference in females in the score for STAI-S, where carriers of the G allele had higher scores compared to the females that were homozygous for the C allele (p < 0.01). For the SNP rs53576 in the OXTR gene, there was a significant difference in males, where carriers of the A allele had higher scores in STAI-T compared to the males that were homozygous for the G allele (p < 0.01). CONCLUSION: This study shows that SNP rs41423247 in the NR3C1 gene and SNP rs53576 in the OXTR gene are associated with self-assessed anxiety in healthy individuals in a gender-specific manner. This suggests that these SNP candidates are possible genetic risk-factors for anxiety.

Rare human nerve growth factor-ß mutation reveals relationship between C-afferent density and acute pain evaluation.

The rare nerve growth factor-ß (NGFB) mutation R221W causes a selective loss of thinly myelinated fibers and especially unmyelinated C-fibers. Carriers of this mutation show altered pain sensation. A subset presents with arthropathic symptoms, with the homozygous most severely affected. The aim of the present study was to investigate the relationship between peripheral afferent loss and pain evaluation by performing a quantification of small-fiber density in the cornea of the carriers, relating density to pain evaluation measures. In vivo corneal confocal microscopy (CCM) was used to quantify C-fiber loss in the cornea of 19 R221W mutation carriers (3 homozygous) and 19 age-matched healthy control subjects. Pain evaluation data via the Situational Pain Questionnaire (SPQ) and the severity of neuropathy based on the Neuropathy Disability Score (NDS) were assessed. Homozygotes, heterozygotes, and control groups differed significantly in corneal C-nerve fiber density, with the homozygotes showing a significant afferent reduction. Importantly, peripheral C-fiber loss correlated negatively with pain evaluation, as revealed by SPQ scores. This study is the first to investigate the contribution of small-fiber density to the perceptual evaluation of pain. It demonstrates that the lower the peripheral small-fiber density, the lower the degree of reported pain intensity, indicating a functional relationship between small-fiber density and higher level pain experience.

ALE meta-analysis reveals dissociable networks for affective and discriminative aspects of touch.

Emotionally-laden tactile stimulation-such as a caress on the skin or the feel of velvet-may represent a functionally distinct domain of touch, underpinned by specific cortical pathways. In order to determine whether, and to what extent, cortical functional neuroanatomy supports a distinction between affective and discriminative touch, an activation likelihood estimate (ALE) meta-analysis was performed. This meta-analysis statistically mapped reported functional magnetic resonance imaging (fMRI) activations from 17 published affective touch studies in which tactile stimulation was associated with positive subjective evaluation (n = 291, 34 experimental contrasts). A separate ALE meta-analysis mapped regions most likely to be activated by tactile stimulation during detection and discrimination tasks (n = 1,075, 91 experimental contrasts). These meta-analyses revealed dissociable regions for affective and discriminative touch, with posterior insula (PI) more likely to be activated for affective touch, and primary somatosensory cortices (SI) more likely to be activated for discriminative touch. Secondary somatosensory cortex had a high likelihood of engagement by both affective and discriminative touch. Further, meta-analytic connectivity (MCAM) analyses investigated network-level co-activation likelihoods independent of task or stimulus, across a range of domains and paradigms. Affective-related PI and discriminative-related SI regions co-activated with different networks, implicated in dissociable functions, but sharing somatosensory co-activations. Taken together, these meta-analytic findings suggest that affective and discriminative touch are dissociable both on the regional and network levels. However, their degree of shared activation likelihood in somatosensory cortices indicates that this dissociation reflects functional biases within tactile processing networks, rather than functionally and anatomically distinct pathways.

Where pain meets action in the human brain.

Pain's complex influence on behavior implies that it involves an action component, although little is known about how the human brain adaptively translates painful sensations into actions. The consistent activation of premotor and motor-related regions during pain, including the midcingulate cortex (MCC), raises the question of whether these areas contribute to an action component. In this fMRI experiment, we controlled for voluntary action-related processing during pain by introducing a motor task during painful or nonpainful stimulation. The MCC (particularly the caudal cingulate motor zone [CCZ]), motor cortex, thalamus, and cerebellum responded during action regardless of pain. Crucially, however, these regions did not respond to pain unless an action was performed. Reaction times were fastest during painful stimulation and correlated with CCZ activation. These findings are consistent with the results of an activation likelihood estimate meta-analysis in which activation across experiments involving pain, action execution, or action preparation (with a total of 4929 subjects) converged in a similar network. These findings suggest that specific motor-related areas, including the CCZ, play a vital role in the control and execution of context-sensitive behavioral responses to pain. In contrast, bilateral insular cortex responded to pain stimulation regardless of action.

"Feeling" others' painful actions: the sensorimotor integration of pain and action information.

Sensorimotor regions of the brain have been implicated in simulation processes such as action understanding and empathy, but their functional role in these processes remains unspecified. We used functional magnetic resonance imaging (fMRI) to demonstrate that postcentral sensorimotor cortex integrates action and object information to derive the sensory outcomes of observed hand-object interactions. When subjects viewed others' hands grasping or withdrawing from objects that were either painful or nonpainful, distinct sensorimotor subregions emerged as showing preferential responses to different aspects of the stimuli: object information (noxious vs. innocuous), action information (grasps vs. withdrawals), and painful action outcomes (painful grasps vs. all other conditions). Activation in the latter region correlated with subjects' ratings of how painful each object would be to touch and their previous experience with the object. Viewing others' painful grasps also biased behavioral responses to actual tactile stimulation, a novel effect not seen for auditory control stimuli. Somatosensory cortices, including primary somatosensory areas 1/3b and 2 and parietal area PF, may therefore subserve somatomotor simulation processes by integrating action and object information to anticipate the sensory consequences of observed hand-object interactions.

Human endogenous oxytocin and its neural correlates show adaptive responses to social touch based on recent social context.

Both oxytocin (OT) and touch are key mediators of social attachment. In rodents, tactile stimulation elicits the endogenous release of OT, potentially facilitating attachment and other forms of prosocial behavior, yet the relationship between endogenous OT and neural modulation remains unexplored in humans. Using a serial sampling of plasma hormone levels during functional neuroimaging across two successive social interactions, we show that contextual circumstances of social touch influence not only current hormonal and brain responses but also later responses. Namely, touch from a male to his female romantic partner enhanced her subsequent OT release for touch from an unfamiliar stranger, yet females' OT responses to partner touch were dampened following stranger touch. Hypothalamus and dorsal raphe activation reflected plasma OT changes during the initial social interaction. In the subsequent interaction, precuneus and parietal-temporal cortex pathways tracked time- and context-dependent variables in an OT-dependent manner. This OT-dependent cortical modulation included a region of the medial prefrontal cortex that also covaried with plasma cortisol, suggesting an influence on stress responses. These findings demonstrate that modulation between hormones and the brain during human social interactions can flexibly adapt to features of social context over time.

Vicarious responses to social touch in posterior insular cortex are tuned to pleasant caressing speeds.

BACKGROUND: Affective touch carries strong significance for social mammals, including humans. Gentle, dynamic touch of a kind that occurs during social interactions is preferentially encoded by a distinct neural pathway involving tactile C (CT) afferents, a type of unmyelinated afferent nerve found exclusively in hairy skin. CT afferents increase firing when the skin is stroked at a pleasant, caress-like speed of ∼3 cm/s, and their discharge frequency correlates with the subjective hedonic experience of the caress. In humans, the posterior insula is a cortical target for CT afferents. Since the potential social relevance of affective touch extends to the touch interactions of others, we postulated that information from CT afferents in posterior insular cortex provides a basis for encoding observed caresses. RESULTS: In two experiments, we exploited CT afferents' functionally unique tuning curve for stroking speed, demonstrating that a speed optimal for eliciting CT discharge (3 cm/s) also gives rise to higher BOLD responses in posterior insula than a nonoptimal speed (30 cm/s). When participants viewed videos of others' arms being stroked at CT-optimal versus -nonoptimal speeds, the posterior insula showed a similar response as to directly felt touch. Further, this region's response was specific for social interactions, showing no CT-related modulation for nonsocial dynamic-touch videos. CONCLUSIONS: These findings provide direct evidence for a functional relationship between CT signaling and processing in posterior insular cortex. Such selective tuning for CT-optimal signals in insula may allow recognition of the hedonic relevance of a merely observed caress.

Reduced C-afferent fibre density affects perceived pleasantness and empathy for touch.

We examined patients with a heritable disorder associated with a mutation affecting the nerve growth factor beta gene. Their condition has been classified as hereditary sensory and autonomic neuropathy type V. Carriers of the mutation show a reduction in density of thin and unmyelinated nerve fibres, including C afferents. A distinct type of unmyelinated, low-threshold mechanoreceptive C fibre, the C-tactile afferent, is present in hairy but not glabrous skin of humans and other mammals. They have been implicated in the coding of pleasant, hedonic touch of the kind that occurs in affiliative social interactions. We addressed the relationship between C fibre function and pleasant touch perception in 10 individuals from a unique population of mutation carriers in Sweden. We also investigated the effect of reduced C-fibre density on patients' evaluation of observed interpersonal touch (empathy). Results showed that patients perceived gentle, slow arm stroking, optimal for eliciting C-tactile afferent responses (1-10 cm/s), as less pleasant than did matched controls and also differed in their rating patterns across stimulation velocities. Further, patients' blood-oxygen-level-dependent responses in posterior insular cortex--a target for C afferents--were not modulated by stimulation optimal for activating C-tactile afferents. Hence, perception of the hedonic aspect of dynamic touch likely depends on C-tactile afferent density. Closely similar patterns between individuals' ratings of felt and seen touch suggest that appraisal of others' touch is anchored in one's own perceptual experience, whether typical or atypical.

Hedonic Responses to Touch are Modulated by the Perceived Attractiveness of the Caresser.

Previous research has shown that a specific type of C fiber, the C tactile afferents, are involved in detecting gentle, dynamic tactile stimuli on the skin, giving rise to affective responses in the central nervous system. Despite building on such bottom-up information flow, the hedonic perception and the physiological consequences of affective touch are influenced by various sources of top-down information. In the present study we investigated how perception of affective touch is influenced by the attractiveness of hypothetical caressers. Participants were stroked on the arm and the palm while looking at photos of high attractive and low attractive opposite-gender faces, and were instructed to imagine those people as the caressers. In a control condition no photo was paired with the touch. The stroking stimulation was delivered with a soft brush either on the forearm or on the palm, and either with a slower or faster speed. Participants rated the pleasantness of each stimulation, while electrocardiographic recordings were made to extract heart rate variability data. Results showed that participants preferred touch stimuli paired with high attractive faces; they also preferred palm stroking and slower stroking speed. Like subjective pleasantness ratings, heart rate variability responses to affective touch (slow) were higher for high attractive than for low attractive caressers, but were not selective for arm or palm stroking. Overall, the present study confirms that contextual social information plays a major role in affective touch experiences, influencing not only the hedonic quality of the experience but also the physiological state of the body.

The skin as a social organ.

In general, social neuroscience research tends to focus on visual and auditory channels as routes for social information. However, because the skin is the site of events and processes crucial to the way we think about, feel about, and interact with one another, touch can mediate social perceptions in various ways. This review situates cutaneous perception within a social neuroscience framework by discussing evidence for considering touch (and to some extent pain) as a channel for social information. Social information conveys features of individuals or their interactions that have potential bearing on future interactions, and attendant mental and emotional states. Here, we discuss evidence for an affective dimension of touch and explore its wider implications for the exchange of social information. We consider three important roles for this affective dimension of the cutaneous senses in the transmission and processing of social information: first, through affiliative behavior and communication; second, via affective processing in skin-brain pathways; and third, as a basis for intersubjective representation.

Bodily sensations in social scenarios: Where in the body?

Bodily states are fundamental to emotions' emergence and are believed to constitute the first step in the chain of events that culminate in emotional awareness. Recent works have shown that distinct topographical maps can be derived to describe how basic and more complex emotions are represented in the body. However, it is still unclear whether these bodily maps can also extend to emotions experienced specifically within social interactions and how these representations relate to basic emotions. To address this issue, we used the emBODY tool to obtain high-resolution bodily maps that describe the body activation and deactivation experienced by healthy participants when presented with social scenarios depicting establishment or loss of social bonds. We observed patterns of activation/deactivation for each single social scenario depending on the valence, but also a common activation of head, chest and deactivation of limbs for positive and negative social scenarios, respectively. Furthermore, we show that these maps are comparable to those obtained when taking the perspective of a third person, suggesting the existence of common body representation of social emotions for the self and other person evaluation. Finally, we showed that maps related to complex social scenarios are strongly correlated with bodily states experienced in basic emotions, suggesting that the patterns of body activation/deactivation observed for social scenarios might arise from a complex interaction of the basic emotions that these experiences elicit.

Using Facial Electromyography to Assess Facial Muscle Reactions to Experienced and Observed Affective Touch in Humans.

"Affective" touch is believed to be processed in a manner distinct from discriminatory touch and to involve activation of C-tactile (CT) afferent fibers. Touch that optimally activates CT fibers is consistently rated as hedonically pleasant. Patient groups with impaired social-emotional functioning also show disordered affective touch ratings. However, relying on self-reported ratings of touch has many limitations, including recall bias and communication barriers. Here, we describe a methodological approach to study affective responses to touch via facial electromyography (EMG) that circumvents the reliance on self-report ratings. Facial EMG is an objective, quantitative, and non-invasive method to measure facial muscle activity indicative of affective responses. Responses can be assessed across healthy and patient populations without the need for verbal communication. Here, we provide two separate datasets demonstrating that CT-optimal and non-optimal touch elicit distinct facial muscle reactions. Moreover, facial EMG responses are consistent across stimulus modalities, e.g. tactile (experienced touch) and visual (observed touch). Finally, the temporal resolution of facial EMG can detect responses on timescales that supersede that of verbal reporting. Together, our data suggest that facial EMG is a suitable methodology for use in affective tactile research that can be used to supplement, or in some cases, supplant, existing measures.

Putting a good face on touch: Facial expression reflects the affective valence of caress-like touch across modalities.

Touch plays a central role in interpersonal behavior, especially in its capacity to convey-and induce- changes in affect. Previous research has established that slow, caress-like stroking over the skin elicits positive subjective affective responses, with higher ratings of "pleasantness" compared to a faster-moving touch stimulus. Ratings of pleasantness are associated with increased activity of a distinct class of nerve fibers: C-tactile (CT) afferents. Here, we used facial electromyography (EMG) to determine if touch that optimally activates CT afferents also influences facial muscle activity believed to reflect changes in affect. We found that less pleasant, fast-moving stroking (30 cm/s) elicited robustly negative facial EMG responses, as indexed by stronger contraction of the corrugator muscle. In contrast, pleasant, slow-moving stroking (3 cm/s) that optimally activates CT afferents resulted in decreased negative facial affective responses, manifested as significant corrugator relaxation compared to fast stroking. Moreover, the facial tracking of affective valence during touch was supra-modal, with similar effects during both directly-experienced touch and viewing of touch videos. The results of this EMG study imply that touch that fails to optimally activate CT afferent produces a negative affective response, whereas pleasant, caress-like touch has not only subjective but expressive correlates, reflected in net positive affective changes in facial expression.

Response-specific effects of pain observation on motor behavior.

How does seeing a painful event happening to someone else influence the observer's own motor system? To address this question, we measured simple reaction times following videos showing noxious or innocuous implements contacting corporeal or noncorporeal objects. Key releases in a go/nogo task were speeded, and key presses slowed, after subjects saw a video of a needle pricking a fingertip. No such effect was seen when the observed hand was replaced by a sponge, nor when the needle was replaced by a cotton bud. These findings demonstrate that pain observation modulates the motor system by speeding withdrawal movements and slowing approach movements of the finger. This illustrates a basic mechanism by which visual information about pain is used to facilitate appropriate behavioral responses.

How Accurate Appraisal of Behavioral Costs and Benefits Guides Adaptive Pain Coping.

Coping with pain is a complex phenomenon encompassing a variety of behavioral responses and a large network of underlying neural circuits. Whether pain coping is adaptive or maladaptive depends on the type of pain (e.g., escapable or inescapable), personal factors (e.g., individual experiences with coping strategies in the past), and situational circumstances. Keeping these factors in mind, costs and benefits of different strategies have to be appraised and will guide behavioral decisions in the face of pain. In this review we present pain coping as an unconscious decision-making process during which accurately evaluated costs and benefits lead to adaptive pain coping behavior. We emphasize the importance of passive coping as an adaptive strategy when dealing with ongoing pain and thus go beyond the common view of passivity as a default state of helplessness. In combination with passive pain coping, we highlight the role of the reward system in reestablishing affective homeostasis and discuss existing evidence on a behavioral and neural level. We further present neural circuits involved in the decision-making process of pain coping when circumstances are ambiguous and, therefore, costs and benefits are difficult to anticipate. Finally, we address the wider implications of this topic by discussing its relevance for chronic pain patients.

The effect of acute pain on risky and intertemporal choice.

Pain is a highly salient and attention-demanding experience that motivates people to act. We investigated the effect of pain on decision making by delivering acute thermal pain to participants' forearm while they made risky and intertemporal choices involving money. Participants (n = 107) were more risk seeking under pain than in a no-pain control condition when decisions involved gains but not when they involved equivalent losses. Pain also resulted in greater preference for immediate (smaller) over future (larger) monetary rewards. We interpret these results as a motivation to offset the aversive, pain-induced state, where monetary rewards become more appealing under pain than under no pain and when delivered sooner rather than later. Our findings add to the long-standing debate regarding the role of intuition and reflection in decision making.

The (Null) Effect of Affective Touch on Betrayal Aversion, Altruism, and Risk Taking.

Pleasant touch is thought to increase the release of oxytocin. Oxytocin, in turn, has been extensively studied with regards to its effects on trust and prosocial behavior, but results remain inconsistent. The purpose of this study was to investigate the effect of touch on economic decision making. Participants (n = 120) were stroked on their left arm using a soft brush (touch condition) or not at all (control condition; varied within subjects), while they performed a series of decision tasks assessing betrayal aversion (the Betrayal Aversion Elicitation Task), altruism (donating money to a charitable organization), and risk taking (the Balloon Analog Risk Task). We found no significant effect of touch on any of the outcome measures, neither within nor between subjects. Furthermore, effects were not moderated by gender or attachment. However, attachment avoidance had a significant effect on altruism in that those who were high in avoidance donated less money. Our findings contribute to the understanding of affective touch-and, by extension, oxytocin-in social behavior, and decision making by showing that touch does not directly influence performance in tasks involving risk and prosocial decisions. Specifically, our work casts further doubt on the validity of oxytocin research in humans.