Empathy—the ability to share and understand the emotions of others—is a cornerstone of human social interactions. When we witness someone in pain, we often experience a mirrored emotional response, a phenomenon known as affect sharing. While this ability is essential for social bonding and survival, the precise neural mechanisms behind empathy remain largely unknown.

A research team led by Dr. KEUM Sehoon at the Center for Cognition and Sociality (CCS) within the Institute for Basic Science (IBS) in South Korea has uncovered key insights into how the brain processes others’ distress. Using miniature endoscopic calcium imaging, the researchers identified specific neural ensembles in the anterior cingulate cortex (ACC) that encode empathic freezing, a behavioral response in which an observer reacts with fear when witnessing distress in others.

To investigate this phenomenon, the team conducted a series of real-time brain imaging experiments in mice, tracking individual neurons as they observed another mouse experiencing mild foot shocks. The results showed that specific ACC neurons were activated both when the observer experienced pain firsthand and when they witnessed another in pain, reinforcing the idea that observing distress triggers a neural response similar to direct pain experience.

The study further revealed that ACC population activity during empathic freezing closely resembles the neural representation of affective—rather than sensory—aspects of direct pain experiences. This suggests that witnessing another’s pain triggers activation in the ACC as if the observer were experiencing pain themselves, highlighting the ACC’s specialized role in processing the emotional aspects of pain.

Further analysis revealed that ACC neurons projecting to the periaqueductal gray (PAG), a brain region involved in fear and pain regulation, selectively conveyed emotional pain information. The researchers used optogenetics, a technique that enables precise control of neural activity with light, to manipulate this pathway. When they inhibited the ACC-to-PAG circuit, empathic freezing, and pain avoidance behaviors were significantly reduced. This confirms that this pathway transforms perceived distress into behavioral responses, reinforcing its crucial role in affective empathy.

Unlike previous studies that focused on animals with prior pain experience, this study used naïve observer mice with no previous exposure to pain, allowing the researchers to examine pure emotional contagion without the influence of past experiences. This approach provides new insights into the fundamental neural mechanisms of affective empathy.

Understanding how the brain encodes empathy could have major implications for mental health research. Conditions such as autism spectrum disorder (ASD), antisocial personality disorder, PTSD, and schizophrenia often involve difficulties in processing social and emotional cues. By identifying the specific brain circuits involved in affect sharing, scientists may develop new strategies for treating these disorders.

Dr. Keum stated, "Our findings pinpoint the specific brain circuits involved in processing others’ pain emotionally, offering a foundation for new approaches to studying empathy-related neuropsychiatric disorders."

This study was published online on February 25 in the journal Nature Communications.

Figure 1. Experimental setup for observational fear testing and calcium imaging in observer mice. The observer mouse witnesses the demonstrator mouse receiving electric shocks, enabling the assessment of observational fear. During the experiment, miniature endoscopic calcium imaging is used to monitor neuronal activity in the observer's anterior cingulate cortex (ACC). Green-labeled neurons indicate cells expressing calcium indicators (GCamp6f), while white-labeled neurons represent activated cells observed through calcium imaging (Raw). The observed behaviors in the observational fear experiment include observer freezing (OB-freezing; pink), demonstrator pain response (DM-reaction; blue), and demonstrator freezing (DM-freezing; yellow). Lastly, examples of GCamp6f signals from neurons associated with each behavior are presented.