Topographically selective motor inhibition under threat of pain.

ABSTRACT: Pain-related motor adaptations may be enacted predictively at the mere threat of pain, before pain occurrence. Yet, in humans, the neurophysiological mechanisms underlying motor adaptations in anticipation of pain remain poorly understood. We tracked the evolution of changes in corticospinal excitability (CSE) as healthy adults learned to anticipate the occurrence of lateralized, muscle-specific pain to the upper limb. Using a Pavlovian threat conditioning task, different visual stimuli predicted pain to the right or left forearm (experiment 1) or hand (experiment 2). During stimuli presentation before pain occurrence, single-pulse transcranial magnetic stimulation was applied over the left primary motor cortex to probe CSE and elicit motor evoked potentials from target right forearm and hand muscles. The correlation between participants' trait anxiety and CSE was also assessed. Results showed that threat of pain triggered corticospinal inhibition specifically in the limb where pain was expected. In addition, corticospinal inhibition was modulated relative to the threatened muscle, with threat of pain to the forearm inhibiting the forearm and hand muscles, whereas threat of pain to the hand inhibited the hand muscle only. Finally, stronger corticospinal inhibition correlated with greater trait anxiety. These results advance the mechanistic understanding of pain processes showing that pain-related motor adaptations are enacted at the mere threat of pain, as sets of anticipatory, topographically organized motor changes that are associated with the expected pain and are shaped by individual anxiety levels. Including such anticipatory motor changes into models of pain may lead to new treatments for pain-related disorders.

Changes in brain rhythms and connectivity tracking fear acquisition and reversal.

Fear conditioning is used to investigate the neural bases of threat and anxiety, and to understand their flexible modifications when the environment changes. This study aims to examine the temporal evolution of brain rhythms using electroencephalographic signals recorded in healthy volunteers during a protocol of Pavlovian fear conditioning and reversal. Power changes and Granger connectivity in theta, alpha, and gamma bands are investigated from neuroelectrical activity reconstructed on the cortex. Results show a significant increase in theta power in the left (contralateral to electrical shock) portion of the midcingulate cortex during fear acquisition, and a significant decrease in alpha power in a broad network over the left posterior-frontal and parietal cortex. These changes occur since the initial trials for theta power, but require more trials (3/4) to develop for alpha, and are also present during reversal, despite being less pronounced. In both bands, relevant changes in connectivity are mainly evident in the last block of reversal, just when power differences attenuate. No significant changes in the gamma band were detected. We conclude that the increased theta rhythm in the cingulate cortex subserves fear acquisition and is transmitted to other cortical regions via increased functional connectivity allowing a fast theta synchronization, whereas the decrease in alpha power can represent a partial activation of motor and somatosensory areas contralateral to the shock side in the presence of a dangerous stimulus. In addition, connectivity changes at the end of reversal may reflect long-term alterations in synapses necessary to reverse the previously acquired contingencies.

Theta and alpha power track the acquisition and reversal of threat predictions and correlate with skin conductance response.

The ability to flexibly adjust one's threat predictions to meet the current environmental contingencies is crucial to survival. Nevertheless, its neural oscillatory correlates remain elusive in humans. Here, we tested whether changes in theta and alpha brain oscillations mark the updating of threat predictions and correlate with response of the peripheral nervous system. To this end, electroencephalogram and electrodermal activity were recorded in a group of healthy adults, who completed a Pavlovian threat conditioning task that included an acquisition and a reversal phase. Both theta and alpha power discriminated between threat and safety, with each frequency band showing unique patterns of modulations during acquisition and reversal. While changes in midcingulate theta power may learn the timing of an upcoming danger, alpha power may reflect the preparation of the somato-motor system. Additionally, ventromedial prefrontal cortex theta may play a role in the inhibition of previously acquired threat responses, when they are no longer appropriate. Finally, theta and alpha power correlated with skin conductance response, establishing a direct relationship between activation of the central and peripheral nervous systems. Taken together these results highlight the existence of multiple oscillatory systems that flexibly regulate their activity for the successful expression of threat responses in an ever-changing environment.

Pavlovian threat learning shapes the kinematics of action.

Prompt response to environmental threats is critical to survival. Previous research has revealed mechanisms underlying threat-conditioned physiological responses, but little is known about how threats shape action. Here we tested if threat learning shapes the kinematics of reaching in human adults. In two different experiments conducted on independent samples of participants, after Pavlovian threat learning, in which a stimulus anticipated the delivery of an aversive shock, whereas another did not, the peak velocity and acceleration of reaching increased for the shocked-paired stimulus, relative to the unpaired one. These kinematic changes appeared as a direct consequence of learning, emerging even in absence of an actual threat to body integrity, as no shock occurred during reaching. Additionally, they correlated with the strength of sympathetic response during threat learning, establishing a direct relationship between previous learning and subsequent changes in action. The increase in velocity and acceleration of action following threat learning may be adaptive to facilitate the implementation of defensive responses. Enhanced action invigoration may be maladaptive, however, when defensive responses are inappropriately enacted in safe contexts, as exemplified in a number of anxiety-related disorders.

General Pavlovian-to-instrumental transfer in humans: Evidence from Bayesian inference.

When repeatedly paired with rewarding outcomes (i.e., Pavlovian conditioning), environmental cues may acquire predictive and motivational significance and later enhance instrumental responding for the same (i.e., outcome-specific transfer) or motivationally similar (i.e., general transfer) outcomes. Although outcome-specific and general Pavlovian-to-Instrumental Transfer (PIT) are characterized by different neural substrates and behavioral mechanisms, general transfer has never been studied in isolation from outcome-specific transfer in humans. The first aim of the present study was to test whether the general transfer effect could emerge in isolation and independently of outcome-specific transfer. Our results showed that general transfer can be elicited without the concurrent presence of outcome-specific transfer, supporting the idea that outcome-specific and general transfer can be studied independently of each other. The second aim of the present study was to clarify whether the affordance-like properties of the outcomes can affect the general transfer. In fact, a critical difference in current studies on general transfer concerns the use of cues associated with outcomes for which an action was previously learned (or not) during the instrumental training. This apparently minor difference affects the affordance-like properties of the outcome and may also be transferred to the cue, in turn impacting general transfer. Results revealed a general transfer of the same magnitude regardless of whether cues were associated with reward earned or not during instrumental conditioning. These findings increase the current knowledge on the incentive motivational mechanism behind general transfer, indicating that it is independent of the motor features of the outcome.

Interaction effect: Are you doing the right thing?

How to correctly interpret interaction effects has been largely discussed in scientific literature. Nevertheless, misinterpretations are still frequently observed, and neuroscience is not exempt from this trend. We reviewed 645 papers published from 2019 to 2020 and found that, in the 93.2% of studies reporting a statistically significant interaction effect (N = 221), post-hoc pairwise comparisons were the designated method adopted to interpret its results. Given the widespread use of this approach, we aim to: (1) highlight its limitations and how it can lead to misinterpretations of the interaction effect; (2) discuss more effective and powerful ways to correctly interpret interaction effects, including both explorative and model selection procedures. The paper provides practical examples and freely accessible online materials to reproduce all analyses.

The Cost of Imagined Actions in a Reward-Valuation Task.

Growing evidence suggests that humans and other animals assign value to a stimulus based not only on its inherent rewarding properties, but also on the costs of the action required to obtain it, such as the cost of time. Here, we examined whether such cost also occurs for mentally simulated actions. Healthy volunteers indicated their subjective value for snack foods while the time to imagine performing the action to obtain the different stimuli was manipulated. In each trial, the picture of one food item and a home position connected through a path were displayed on a computer screen. The path could be either large or thin. Participants first rated the stimulus, and then imagined moving the mouse cursor along the path from the starting position to the food location. They reported the onset and offset of the imagined movements with a button press. Two main results emerged. First, imagery times were significantly longer for the thin than the large path. Second, participants liked significantly less the snack foods associated with the thin path (i.e., with longer imagery time), possibly because the passage of time strictly associated with action imagery discounts the value of the reward. Importantly, such effects were absent in a control group of participants who performed an identical valuation task, except that no action imagery was required. Our findings hint at the idea that imagined actions, like real actions, carry a cost that affects deeply how people assign value to the stimuli in their environment.

Unifying Evidence on Delay Discounting: Open Task, Analysis Tutorial, and Normative Data from an Italian Sample.

Despite the widespread use of the delay discounting task in clinical and non-clinical contexts, several task versions are available in the literature, making it hard to compare results across studies. Moreover, normative data are not available to evaluate individual performances. The present study aims to propose a unified version of the delay discounting task based on monetary rewards and it provides normative values built on an Italian sample of 357 healthy participants. The most used parameters in the literature to assess the delay discount rate were compared to find the most valid index to discriminate between normative data and a clinical population who typically present impulsivity issues, i.e., patients with a lesion to the medial orbitofrontal cortex (mOFC). In line with our hypothesis, mOFC patients showed higher delay discounting scores than the normative sample and the normative group. Based on this evidence, we propose that the task and indexes here provided can be used to identify extremely high (above the 90th percentile for hyperbolic k or below the 10th percentile for AUC) or low (below the 10th percentile for hyperbolic k or above the 90th percentile for AUC) delay discounting performances. The complete dataset, the R code used to perform all analyses, a free and modifiable version of the delay discounting task, as well as the R code that can be used to extract all indexes from such tasks and compare subjective performances with the normative data here presented are available as online materials.

Fearful faces modulate spatial processing in peripersonal space: An ERP study.

Peripersonal space (PPS) represents the region of space surrounding the body. A pivotal function of PPS is to coordinate defensive responses to threat. We have previously shown that a centrally-presented, looming fearful face, signalling a potential threat in one's surroundings, modulates spatial processing by promoting a redirection of sensory resources away from the face towards the periphery, where the threat may be expected - but only when the face is presented in near, rather than far space. Here, we use electrophysiological measures to investigate the neural mechanism underlying this effect. Participants made simple responses to tactile stimuli delivered on the cheeks, while watching task-irrelevant neutral or fearful avatar faces, looming towards them either in near or far space. Simultaneously with the tactile stimulation, a ball with a checkerboard pattern (probe) appeared to the left or right of the avatar face. Crucially, this probe could either be close to the avatar face, and thus more central in the participant's vision, or further away from the avatar face, and thus more peripheral in the participant's vision. Electroencephalography was continuously recorded. Behavioural results confirmed that in near space only, and for fearful relative to neutral faces, tactile processing was facilitated by the peripheral compared to the central probe. This behavioural effect was accompanied by a reduction of the N1 mean amplitude elicited by the peripheral probe for fearful relative to neutral faces. Moreover, the faster the participants responded to tactile stimuli with the peripheral probe, relative to the central, the smaller was their N1. Together these results, suggest that fearful faces intruding into PPS may increase expectation of a visual event occurring in the periphery. This fear-induced effect would enhance the defensive function of PPS when it is most needed, i.e., when the source of threat is nearby, but its location remains unknown.

Modulation of cue-guided choices by transcranial direct current stimulation.

Environmental cues may anticipate the availability of rewards, thus acting as a guide towards a specific choice (i.e., cue-guided choices). Despite the lateral prefrontal cortex having a critical role in using past learning and flexibly selecting relevant information to guide behavior, the literature on the neural basis of human cue-guided choice mainly focused on the subcortical brain structures implicated, while the specific role of cortical areas remained unclear. The present study aimed to provide causal evidence for the involvement of the lateral prefrontal cortex in two forms of human cue-guided choice, namely outcome-specific and general. To do this, 2 mA cathodal, anodal or sham transcranial direct current stimulation was applied over the lateral prefrontal cortex (with the posterior parietal cortex serving as control region) in three separate groups performing a Pavlovian-to-Instrumental Transfer task. Results showed, for the first time, a dissociation in the cortical structures involved in human cue-guided choice. Cathodal stimulation of the lateral prefrontal cortex reduced the outcome-specific transfer. In striking contrast, there was no influence on the general transfer. These results argue in favor of the presence of at least two possible neural pathways underlying cue-guided choices.

Revaluing the Role of vmPFC in the Acquisition of Pavlovian Threat Conditioning in Humans.

The role of the ventromedial prefrontal cortex (vmPFC) in human pavlovian threat conditioning has been relegated largely to the extinction or reversal of previously acquired stimulus-outcome associations. However, recent neuroimaging evidence questions this view by also showing activity in the vmPFC during threat acquisition. Here we investigate the casual role of vmPFC in the acquisition of pavlovian threat conditioning by assessing skin conductance response (SCR) and declarative memory of stimulus-outcome contingencies during a differential pavlovian threat-conditioning paradigm in eight patients with a bilateral vmPFC lesion, 10 with a lesion outside PFC and 10 healthy participants (each group included both females and males). Results showed that patients with vmPFC lesion failed to produce a conditioned SCR during threat acquisition, despite no evidence of compromised SCR to unconditioned stimulus or compromised declarative memory for stimulus-outcome contingencies. These results suggest that the vmPFC plays a causal role in the acquisition of new learning and not just in the extinction or reversal of previously acquired learning, as previously thought. Given the role of the vmPFC in schema-related processing and latent structure learning, the vmPFC may be required to construct a detailed representation of the task, which is needed to produce a sustained conditioned physiological response in anticipation of the unconditioned stimulus during threat acquisition.SIGNIFICANCE STATEMENT Pavlovian threat conditioning is an adaptive mechanism through which organisms learn to avoid potential threats, thus increasing their chances of survival. Understanding what brain regions contribute to such a process is crucial to understand the mechanisms underlying adaptive as well as maladaptive learning, and has the potential to inform the treatment of anxiety disorders. Importantly, the role of the ventromedial prefrontal cortex (vmPFC) in the acquisition of pavlovian threat conditioning has been relegated largely to the inhibition of previously acquired learning. Here, we show that the vmPFC actually plays a causal role in the acquisition of pavlovian threat conditioning.

Subliminal determinants of cue-guided choice.

By anticipating potential rewards, external cues can guide behavior to achieve a goal. Whether the conscious elaboration of these cues is necessary to elicit cue-guided choices is still unknown. The goal of the present study is to test whether the subliminal presentation of a visual cue previously paired with a reward is sufficient to bias responses that can lead to the same or a similar reward. To this aim, three experiments compared the subliminal and supraliminal presentation of reward-associated cues during a Pavlovian-to-Instrumental Transfer task. In line with previous evidence, results showed that the supraliminal presentation of reward-associated Pavlovian cues biased participant's choice towards motivationally similar rewards (general transfer) as well as towards rewards sharing the precise sensory-specific properties of the cue (outcome-specific transfer). In striking contrast, subliminal cues biased choice only towards motivationally similar rewards (general transfer). Taken together, these findings suggest that cue-guided choices are modulated by the level of perceptual threshold (i.e., subliminal vs supraliminal) of reward-associated cues. Although conscious elaboration of the cue is necessary to guide choice towards a specific reward, subliminal processing is still sufficient to push towards choices sharing the motivational properties of the cue. Implications for everyday life, clinical conditions, and theoretical accounts of cue-guided choices are discussed.

The spatial logic of fear.

Peripersonal space (PPS) refers to the space surrounding the body. PPS is characterised by distinctive patterns of multisensory integration and sensory-motor interaction. In addition, facial expressions have been shown to modulate PPS representation. In this study we tested whether fearful faces lead to a different distribution of spatial attention, compared to neutral and joyful faces. Participants responded to tactile stimuli on the cheeks, while watching looming neutral, joyful (Experiment 1) or fearful (Experiment 2) faces of an avatar, appearing in far or near space. To probe spatial attention, when the tactile stimulus was delivered, a static ball briefly appeared central or peripheral in participant's vision, respectively ≈1° or ≈10° to the left or right of the face. With neutral and joyful faces, simple reactions to tactile stimuli were facilitated in near rather than in far space, replicating classic PPS effects, and in the presence of central rather than peripheral ball, suggesting that attention may be focused in the immediate surrounding of the face. However, when the face was fearful, response to tactile stimuli was modulated not only by the distance of the face from the participant, but also by the position of the ball. Specifically, in near space only, response to tactile stimuli was additionally facilitated by the peripheral compared to the central ball. These results suggest that as fearful faces come closer to the body, they promote a redirection of attention towards the periphery. Given the sensory-motor functions of PPS, this fear-evoked redirection of attention would enhance the defensive function of PPS specifically when it is most needed, i.e. when the source of threat is nearby, but its location has not yet been identified.

Fear-specific enhancement of tactile perception is disrupted after amygdala lesion.

Tactile perception on one's own face is enhanced when viewing a fearful face being touched - as opposed to just approached - by fingers, compared to viewing other expressions, a phenomenon known as the emotional modulation of Visual Remapping of Touch (eVRT). This effect seems to be related to a preferential activation of the somatosensory system in response to threat. To test the contribution of the amygdala to this mechanism, a group of patients with unilateral lesions to the amygdala, a control group of patients with lesions in the extra-temporal regions, and a group of healthy participants completed an eVRT paradigm. They were required to detect bilateral tactile stimulation on their own cheeks, while viewing fearful, happy, or neutral faces being touched or just approached by fingers. Healthy participants and control patients confirmed that viewing a neutral face being touched - as opposed to just approached - by fingers increases tactile detection on one's own face (i.e., the typical VRT effect) and that this effect is enhanced for fearful faces, compared to neutral and happy faces. However, in patients with amygdala lesion, although the standard VRT effect was preserved for neutral faces, this was disrupted for fearful faces. This result indicates that the preferential activation of the somatosensory cortices in response to threat relies on structural integrity of the amygdala.

Aberrant reward prediction error during Pavlovian appetitive learning in alexithymia.

Extensive literature shows that alexithymia, a subclinical trait defined by difficulties in identifying and describing feelings, is characterized by multifaceted impairments in processing emotional stimuli. Nevertheless, its underlying mechanisms remain elusive. Here, we hypothesize that alexithymia may be characterized by an alteration in learning the emotional value of encountered stimuli and test this by assessing differences between individuals with low (LA) and high (HA) levels of alexithymia in the computation of reward prediction errors (RPEs) during Pavlovian appetitive conditioning. As a marker of RPE, the amplitude of the feedback-related negativity (FRN) event-related potential was assessed while participants were presented with two conditioned stimuli (CS) associated with expected or unexpected feedback, indicating delivery of reward or no-reward. No-reward (vs reward) feedback elicited the FRN both in LA and HA. However, unexpected (vs expected) feedback enhanced the FRN in LA but not in HA, indicating impaired computation of RPE in HA. Thus, although HA show preserved sensitivity to rewards, they cannot use this response to update the value of CS that predict them. This impairment may hinder the construction of internal representations of emotional stimuli, leaving individuals with alexithymia unable to effectively recognize, respond and regulate their response to emotional stimuli.

Intentionality attribution and emotion: The Knobe Effect in alexithymia.

The capacity to distinguish between intentional and unintentional actions is a crucial aspect of moral competence. Therefore, the processes shaping intentionality attribution, as well as their dysfunction, are object of intense inquiry. The 'Knobe effect' refers to the intriguing finding that people are more likely to judge as intentional actions leading to negative as opposed to positive side effects, which has been attributed to the emotional response elicited by negative (vs. positive) outcomes. Whether and how emotion drives the Knobe effect, however, is currently debated. Here, individuals with low (LA) and high (HA) levels of alexithymia, a personality trait characterized by difficulties in emotional processing, judged the intentionality of actions with side effects that varied in valence (positive/negative) and salience (low/high), while their subjective emotional response and skin conductance level were assessed. LA individuals attributed more intentionality to actions leading to negative (vs. positive) side effects, and to high (vs. low) salience side effects, and this related to their subjective emotional response to negative side effects. In the context of a generally reduced physiological activation to emotional stimuli, HA (compared to LA) individuals attributed less intentionality to actions leading to negative side effects, especially those with low salience, showing a reduced Knobe effect, which was accompanied by a reduced subjective emotional response to negative side effects. These results confirm the crucial role of emotion on intentionality attribution. Moreover, they contribute to qualifying the emotional processing difficulties associated with alexithymia, and their impact on moral cognition.

Threat learning promotes generalization of episodic memory.

The ability to generalize from and distinguish between aversive memories and novel experiences is critical to survival. Previous research has revealed mechanisms underlying generalization of threat-conditioned defensive responses, but little is known about generalization of episodic memory for threatening events. Here we tested if aversive learning influences generalization of episodic memory for threatening events in human adults. Subjects underwent Pavlovian threat-conditioning in which objects from one category were paired with a shock and objects from a different category were unpaired. The next day, subjects underwent a recognition memory test that included old, highly similar, and entirely novel items from the shock-paired and shock-unpaired object categories. Results showed that items highly similar to those from the object category previously paired with shock were mistaken for old items more often than items from the shock-unpaired category. This finding indicates that threat learning promotes generalization of episodic memory, and is consistent with the idea that threat generalization is an active process that may be adaptive for avoiding a myriad of potential threats following an emotional experience. Enhanced generalization of aversive episodic memories may be maladaptive, however, when old threat memories are inappropriately reactivated in harmless situations, exemplified in a number of stress- and anxiety-related disorders. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Alexithymia Is Related to the Need for More Emotional Intensity to Identify Static Fearful Facial Expressions.

Individuals with high levels of alexithymia, a personality trait marked by difficulties in identifying and describing feelings and an externally oriented style of thinking, appear to require more time to accurately recognize intense emotional facial expressions (EFEs). However, in everyday life, EFEs are displayed at different levels of intensity and individuals with high alexithymia may also need more emotional intensity to identify EFEs. Nevertheless, the impact of alexithymia on the identification of EFEs, which vary in emotional intensity, has largely been neglected. To address this, two experiments were conducted in which participants with low (LA) and high (HA) levels of alexithymia were assessed in their ability to identify static (Experiment 1) and dynamic (Experiment 2) morphed faces ranging from neutral to intense EFEs. Results showed that HA needed more emotional intensity than LA to identify static fearful - but not happy or disgusted - faces. On the contrary, no evidence was found that alexithymia affected the identification of dynamic EFEs. These results extend current literature suggesting that alexithymia is related to the need for more perceptual information to identify static fearful EFEs.

Alexithymia and the Reduced Ability to Represent the Value of Aversively Motivated Actions.

Alexithymia is a subclinical trait defined by difficulties in identifying and describing feelings and a cognitive style avoidant of introspection. Extensive literature shows that alexithymia is characterized by multifaceted impairments in processing emotional stimuli. Nevertheless, the mechanisms that may account for such impairments remain elusive. Here, we hypothesize that alexithymia may be understood as impairment in learning the emotional value of one's own actions and test this comparing performance of participants with high (HA) and low (LA) levels of alexithymia on a probabilistic selection task. Results show that, compared to LA, HA need more time to learn the value of individual stimuli and associated actions as difference in reinforcement rate between stimuli decreases. In addition, HA appear less able to generalize the value of previously learned actions that lead to a negative outcome, to make adaptive choices in a new context, requiring more time to avoid the most negative stimulus between two negative stimuli. Together, the results indicate that individuals with alexithymia show impaired learning of the value of aversively motivated actions. We argue that this impairment may hinder the construction of internal representations of emotional stimuli and actions and represent a mechanism that may account for the difficulties of alexithymia in processing emotional stimuli.