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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.

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.

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.

Understanding transient dynamics of the autonomic nervous system during fear learning remains a critical step to translate basic research into treatment of fear-related disorders. In humans, it has been demonstrated that fear learning typically elicits transient heart rate deceleration. However, classical analyses of heart rate variability (HRV) fail to disentangle the contribution of parasympathetic and sympathetic systems, and crucially, they are not able to capture phasic changes during fear learning. Here, to gain deeper insight into the physiological underpinnings of fear learning, a novel frequency-domain analysis of heart rate was performed using a short-time Fourier transform, and instantaneous spectral estimates extracted from a point-process modeling algorithm. We tested whether spectral transient components of HRV, used as a noninvasive probe of sympathetic and parasympathetic mechanisms, can dissociate between fear conditioned and neutral stimuli. We found that learned fear elicited a transient heart rate deceleration in anticipation of noxious stimuli. Crucially, results revealed a significant increase in spectral power in the high frequency band when facing the conditioned stimulus, indicating increased parasympathetic (vagal) activity, which distinguished conditioned and neutral stimuli during fear learning. Our findings provide a proximal measure of the involvement of cardiac vagal dynamics into the psychophysiology of fear learning and extinction, thus offering new insights for the characterization of fear in mental health and illness.

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 STATEMENTPavlovian 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.

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.

Predictive coding theory suggests that prior knowledge assists human behavior, from simple perceptual formation to complex decision-making processes. Here, we manipulate prior knowledge by inducing uninformative vs. informative (low and high) target probability expectation in a perceptual decision-making task while simultaneously recording EEG. We found that priors did not impact sensitivity (d') but did shape response criterion (c), being more liberal for high expected trials and more conservative for low expected trials. Importantly, we mapped the neural signature of this criterion shift, with liberal and conservative trials characterized by low and high posterior alpha amplitude, respectively. Moreover, we demonstrated that inter-areas communication along the fronto-parietal-occipital pathway is linked to the strategic tuning of sensory areas. Specifically, whereas parieto-occipital alpha synchronization facilitates the exploitation of expectancy-type information by shaping pre-stimulus alpha amplitude in a prior-dependent fashion, fronto-parietal theta coupling mediates a supervisory process on the predictive machinery, attenuating the impact of prior on sensory processing. These findings aided us in tracing the neurofunctional mechanisms underlying the differences in predictive styles existing in the general population. Crucially, an imbalance between alpha and theta synchronization leads to interindividual differences favoring priors overweighting (believers) vs. prioritization of sensory input (empiricist) strategy, respectively.

Research in neuroscience reveals that the brain constructs multiple representations of space. Here, we primarily focus on interpersonal representation—i.e. the region of space immediately surrounding our body, in which we interact with other people, in individuals with a deficit of social interaction, such as autism. We review results from several studies, revealing that autism affects the interpersonal space regulation, influencing both its size (permeability) and its changes depending on social interaction (plasticity). Indeed, individuals with autism prefer larger or shorter interpersonal space compared to healthy controls, thereby indicating a deficit of interpersonal space permeability. Furthermore, individuals with autism fail to modify their interpersonal space following a brief cooperative interaction with an unfamiliar adult, suggesting a deficit in interpersonal space plasticity. Interestingly, the deficit observed in interpersonal space plasticity depends on the person’s perspective and reflects the severity of social impairment. Finally, the link between social competence, action, and space is addressed, showing that autism affects social-interpersonal space, but not action-peripersonal space.

Specific phobia (SP) is the most prevalent anxiety disorder, with especially high prevalence in women (6-12%). SP is characterized by an excessive, irrational fear of a specific object or situation, which is either avoided at all cost, or endured with great distress, interfering with work and quality of life. The combination of psychotherapy and pharmacotherapy are generally regarded as first-line treatment. However, about 25% of patients respond poorly to treatment and show a high risk of chronicity, or experience a return of fear. Estimates of direct and indirect annual costs for SP are high (Bajbouj and Padberg, 2014). Therefore, developing and implementing new effective treatments for such a highly debilitating disorder is urgently needed. Increasing evidence suggests that targeted modulation of neural networks by non-invasive brain stimulation (NIBS) might represent a further treatment option (Bajbouj and Padberg, 2014). However, very few studies have tested the efficacy of NIBS in the treatment of SP.

Interpersonal space (IPS) is the area around the body that individuals maintain between themselves and others during social interactions. When others violate our IPS, feeling of discomfort rise up, urging us to move farther away and reinstate an appropriate interpersonal distance. Previous studies showed that when individuals are exposed to closeness of an unknown person (a confederate), the skin conductance response (SCR) increases. However, if the SCR is modulated according to participant’s preferred IPS is still an open question. To test this hypothesis, we recorded the SCR in healthy participants when a confederate stood in front of them at various distances simulating either an approach or withdrawal movement (Experiment 1). Then, the comfort-distance task was adopted to measure IPS: participants stop the confederate, who moved either toward or away from them, when they felt comfortable with other’s proximity (Experiment 2). We found higher SCR when the confederate stood closer to participants simulating an IPS intrusion, compared to when the confederate moved farther away. Crucially, we provide the first evidence that SCR, acting as a warning signal, contributes to interpersonal distance preference suggesting a functional link between behavioral components of IPS regulation and the underlying physiological processes.

Body schema, a sensorimotor representation of the body used for planning and executing movements, is plastic because it extends by using a tool to reach far objects. Modifications of peripersonal space, i.e., a functional representation of reach space, usually co-occur with body schema changes. Here, we hypothesized that such plastic changes depend on the experience of controlling the course of events in space trough one’s own actions, i.e., the sense of agency. In two experiments, body schema and peripersonal space were assessed before and after the participants’ sense of agency over a virtual hand was manipulated. Body schema and peripersonal space enlarged or contracted depending on whether the virtual hand was presented in far space, or closer to the participants’ body than the real hand. These findings suggest that body schema and peripersonal space are affected by the dynamic mapping between intentional body movements and expected consequences in space.

We investigated episodic future thinking (EFT) and future-based cognition and decision-making in patient SG, who developed a dense retrograde amnesia following hypoxia due to a cardiac arrest. Despite intact general cognitive and executive functioning, SG was unable to remember events from his entire lifetime. He had, however, relatively spared anterograde memory and general semantic knowledge. Voxel-based morphometry detected a reduction of gray matter in the thalamus, cerebellum and fusiform gyrus bilaterally, and, at a reduced threshold, in several regions of the autobiographical memory network, including the hippocampi. We show that SG is unable to imagine personal future events, but can imagine fictitious events not self-relevant and not located in subjective time. Despite severely impaired EFT, SG shows normal attitudes towards the future time, and normal delay discounting rates. These findings suggest that retrieval of autobiographical information from long-term memory is necessary for EFT. However, relatively spared anterograde memory and general semantic knowledge may be sufficient to allow construction of fictitious experiences. As well, EFT is not necessary to drive future-oriented cognition and choice. These findings highlight the relation between autobiographical memory and EFT, and the fractionation of human temporal consciousness. Moreover, they contribute to our understanding of retrograde amnesia as an impairment of memory as well as future thinking.

Summary Erasing maladaptive memories has been a challenge for years. A way to change fear memories is to target the process of reconsolidation, during which a retrieved memory transiently returns to a labile state, amenable to modification [ 1 , 2 ]. Disruption of human fear-memory reconsolidation has been classically attempted with pharmacological [ 3 ] or behavioral (e.g., extinction) [ 4 ] treatments that, however, do not clarify the underlying brain mechanism. To address this issue, in 84 healthy humans submitted to six experiments, here, we combined a differential fear conditioning paradigm with repetitive transcranial magnetic stimulation (rTMS) administered in a state-dependent manner. In a critical condition, we stimulated the dorsolateral prefrontal cortex (dlPFC) 10 min after a reminder cue that reactivated a fear memory acquired 1 day before. At testing, 24 h after rTMS, participants exhibited decreased physiological expression of fear, as shown by their skin conductance response. Similar reductions were observed when targeting the left and the right dlPFC. In contrast, no decrease was observed in participants tested immediately after dlPFC-rTMS or in participants receiving either control rTMS (i.e., active control site and sham stimulations) or dlPFC-rTMS without preceding fear-memory reactivation, thus showing both the site and time specificity and state dependency of our rTMS intervention. Expression of fear was indeed reduced only when dlPFC-rTMS was administered within the reconsolidation time window. Moreover, dlPFC-rTMS prevented subsequent return of fear after extinction training. These findings highlight the causal role of dlPFC in fear-memory reconsolidation and suggest that rTMS can be used in humans to prevent the return of fear.

We commonly label moral violations in terms of ‘disgust’, yet it remains unclear whether metaphorical expressions linking disgust and morality are genuinely shared at the cognitive/neural level. Using transcranial magnetic stimulation (TMS), we provide new insights into this debate by measuring motor-evoked potentials (MEPs) from the tongue generated by TMS over the tongue primary motor area (tM1) in a small group of healthy participants presented with vignettes of moral transgressions and non-moral vignettes. We tested whether moral indignation, felt while evaluating moral vignettes, affected tM1 excitability. Vignettes exerted a variable influence on MEPs with no net effect of the moral category. However, in accordance with our recent study documenting reduced tM1 excitability during exposure to pictures of disgusting foods or facial expressions of distaste, we found that the vignettes of highly disapproved moral violations reduced tM1 excitability. Moreover, tM1 excitability and moral indignation were linearly correlated: the higher the moral indignation, the lower the tM1 excitability. Respective changes in MEPs were not observed in a non-oral control muscle, suggesting a selective decrease of tM1 excitability. These preliminary findings provide neurophysiological evidence supporting the hypothesis that morality might have originated from the more primitive experience of oral distaste.

The space around the body has been defined as action space ( peripersonal space) and a social space ( interpersonal space). Within the current debate about the characteristics of these spaces, here we investigated the functional properties and plasticity of action and social space in developmental age. To these aims, children with typical development and autism spectrum disorders were submitted to Reaching- and Comfort-distance tasks, to assess peripersonal and interpersonal space, respectively. Participants approached a person (confederate) or an object and stopped when they thought they could reach the stimulus (Reaching-distance task), or they felt comfortable with stimulus’ proximity (Comfort-distance task). Both tasks were performed before and after a cooperative tool-use training, in which participant and confederate actively cooperated to reach tokens by using either a long (Experiment 1) or a short (Experiment 2) tool. Results showed that in both groups, peripersonal space extended following long-tool-use but not short-tool-use training. Conversely, in typical development, but not in autism spectrum disorders children, interpersonal space toward confederate reduced following the cooperative tool-use training. These findings reveal that action and social spaces are functionally dissociable both in typical and atypical development, and that action but not social space regulation is intact in children with autism.

Individuals learn by comparing the outcome of chosen and unchosen actions. A negative counterfactual value signal is generated when this comparison is unfavorable. This can happen in private as well as in social settings—where the foregone outcome results from the choice of another person. We hypothesized that, despite sharing similar features such as supporting learning, these two counterfactual signals might implicate distinct brain networks. We conducted a neuropsychological study on the role of private and social counterfactual value signals in risky decision-making. Patients with lesions in the ventromedial prefrontal cortex (vmPFC), lesion controls, and healthy controls repeatedly chose between lotteries. In private trials, participants could observe the outcomes of their choices and the outcomes of the unselected lotteries. In social trials, participants could also see the other player's choices and outcome. At the time of outcome, vmPFC patients were insensitive to private counterfactual value signals, whereas their responses to social comparison were similar to those of control participants. At the time of choice, intact vmPFC was necessary to integrate counterfactual signals in decisions, although amelioration was observed during the course of the task, possibly driven by social trials. We conclude that if the vmPFC is critical in processing private counterfactual signals and in integrating those signals in decision-making, then distinct brain areas might support the processing of social counterfactual signals.

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.