Christian Keysers

3,4-methylenedioxymethamphetamine (MDMA) is widely described as an “empathogen”, yet empathy is not a unitary process. Here we review MDMA’s social effects by decomposing them into social perception and emotion discrimination, sociability and social reward, affective sharing, cognitive empathy and mentalizing, and prosocial behaviour. Available evidence gathered in humans and other mammals demonstrate that MDMA has distinct effects across these domains, although research coverage remains uneven across domains. We argue that MDMA is best understood not as a global empathy enhancer, but as a domain-specific modulator of social reward, threat perception, positive-valence affective sharing, and interpersonal appraisal. Moving beyond this simplified empathy enhancer concept is essential for understanding both the therapeutic promise and the interpersonal risks of MDMA.

Early-life adversity can alter emotional and social development and increase risk to later stress. We investigated how early adverse experiences (EAE), triggered using the limited bedding and nesting model, and later adverse experiences (LAE) triggered by footshocks affect adult emotional contagion (EC) responses in rats. Adult male and female rats then witnessed a conspecific receiving footshocks. Adolescence-footshock exposed observers showed cingulate cortex associated increased immobility, proximity, and attention toward distressed conspecifics during adulthood, compared to adult-exposed and sham animals. While EAE did altered maternal care, stress physiology, and pup weight, we found evidence that it did not alter immobility during EC. However, female demonstrators paired with EAE observers showed increased immobility, linked to a reduced rate and lower frequency of the observers’ 50 kHz vocalizations. Mediation analysis revealed that a shift towards lower-frequency 50 kHz vocalizations specifically mediated this effect, suggesting a sex-specific pathway by which early adversity shapes social behavior. Early and adolescent adversity influenced distinct aspects of emotional contagion: EAE mediated an observer-to-demonstrator emotional transfer during EC, while LAE impacted a demonstrator-to-observer transfer, with no evidence of additive effects. Our results highlight developmentally specific and sex-dependent mechanisms by which early and later adversity alter social-affective responses in adulthood.

Functional ultrasound imaging (fUSI) enables brain-wide mapping of hemodynamic activity in awake rodents, offering a powerful bridge between systems neuroscience in animals and human neuroimaging. However, extending fUSI beyond tightly controlled sensory paradigms to more naturalistic behaviors is limited by motion-related confounds arising from locomotion, physiological arousal, and movement-linked neural activity. Here, we introduce a behavior-informed modeling framework that explicitly incorporates continuous measurements of running speed and head motion into a general linear model to account for motion-related variance while preserving interpretable task-related signals. We validate this approach in two head-fixed paradigms with distinct motion profiles: a visual stimulation task with minimal stimulus-driven movement, and a noxious stimulation task in which locomotion and arousal are intrinsic to the behavioral response. In both cases, explicit behavioral modeling recovers neural response patterns that more closely resemble low-motion reference conditions than blind, model-free denoising approaches. Critically, during noxious stimulation, behavior-informed modeling preserves shock-intensity-dependent activity in the primary somatosensory cortex that is attenuated by global component removal. These findings demonstrate that explicit modeling of behavior enables reliable interpretation of brain-wide fUSI signals during naturalistic, high-motion conditions, opening the door to studying affective and cognitive processes that were previously difficult to access with functional ultrasound imaging.

Interpersonal motor interactions are central to social life, yet it remains unclear how social cues relevant to detecting engagement are encoded in the brain. Recent evidence suggests that regions traditionally associated with mentalizing, such as the dorsomedial prefrontal cortex (dmPFC) and temporo-parietal junction (TPJ), co-activate with nodes of the Action Observation Network (AON) during motor engagement with others, pointing to a synergistic role in the processing of action features during interaction. Using fMRI and Representational Similarity Analysis (RSA), we examined brain responses to reach-to-grasp actions varying in Goal (passing vs. placing), Perspective (2nd vs. 3rd person), and Gaze visibility, creating a gradient of perceived engagement. Our results show that the TPJ and premotor cortices, but not the dmPFC, displayed convergent neural geometry during action observation. Model- and cluster-based analyses further linked TPJ and AON regions in multiple representational spaces: left-hemisphere regions aligned with goal encoding, whereas right-hemisphere regions aligned with an Engagement model capturing first-person interaction. Critically, we demonstrate that the rTPJ and left premotor cortex share representational geometry for action perspective, directly coupling mentalizing and sensorimotor systems in the encoding of directional cues. By contrast, the dmPFC appeared representationally isolated from both TPJ and AON regions, with response patterns showing no similarity to Goal or Engagement models. This is consistent with accounts of its recruitment under richer interactive demands rather than selectivity for abstract action features. Together, these findings support a distributed, sensorimotor account of engagement encoding and reveal new functional links among key social cognition areas.

Functional neuroimaging studies suggest that a large-scale brain network transforms others’ pain into its vicarious representation in the observer, potentially modulating helping behavior. However, the neuromolecular basis of individual differences in vicarious pain and helping is poorly understood. We investigated the role of the endogenous μ-opioid receptor (MOR) system in altruistic costly helping. MOR density was measured using [¹¹C]carfentanil. In a separate fMRI experiment, participants could donate money to reduce a confederate’s pain from electric shocks. Participants were generally willing to help, and brain activity was observed in amygdala, anterior insula, anterior cingulate cortex (ACC), striatum, primary motor cortex, primary somatosensory cortex and thalamus when witnessing others’ pain. Haemodynamic responses were negatively associated with MOR availability in emotion circuits. However, MOR availability positively associated with the ACC and hippocampus during helping. These findings suggest that the endogenous MOR system modulates altruism in the human brain.

Empathy determines our emotional and social lives. Research has recognized the role of the right temporoparietal junction (rTPJ) in social cognition; however, there is less direct causal evidence for its involvement in empathic responses to pain, which is typically attributed to simulation mechanisms. Given the rTPJ’s role in processing false beliefs and contextual information during social scenarios, we hypothesized that empathic responses to another person’s pain depend on the rTPJ if participants are given information about people’s intentions, engaging mentalizing mechanisms alongside simulative ones. Participants viewed videos of an actress freely showing or suppressing pain caused by an electric shock while receiving 6 Hz repetitive transcranial magnetic stimulation (rTMS) over the rTPJ or sham vertex stimulation. Active rTMS had no significant effect on participants’ ratings depending on the pain expression, although participants rated the actress’s pain as lower during rTPJ perturbation. In contrast, rTMS accelerated response times for providing ratings during pain suppression. We also found that participants perceived the actress’s pain as more intense when they knew she would suppress it rather than show it. These results suggest an involvement of the rTPJ in attributing pain to others and provide new insights into people’s behavior in judging others’ pain when it is concealed.