Written by Jaak Panksepp, neuroscientist and psychobiologist

The Greek philosopher Zeno of Citium (356 to 264 B.C.), the founder of Stoicism, considered pain to be one of nine forms of grief. We often speak about the loss of a loved one in terms of painful feelings, but it is still not clear to what extent such metaphors reflect what is actually happening in the human brain? Enter Eisenberger and colleagues (1) on page 290 of this issue with a bold neuroimaging experiment that seeks to discover whether the metaphor for the psychological pain of social loss is reflected in the neural circuitry of the human brain. Using functional magnetic resonance imaging (fMRI), they show that certain human brain areas that “light up” during physical pain are also distress as indicated by substantial blood-flow changes in two key brain areas.

One of these areas, the anterior cingulate cortex, has been implicated in generating the aversive experience of physical pain. Eisenberger and colleagues demonstrate that the greater the feeling of social distress, the more this brain area becomes activated. The other brain region, in the prefrontal cortex, showed an opposite pattern of activity, becoming more active when the distress was least. In other words, the two brain areas involved in the distressing feelings of social exclusion responded in opposite ways to the degree of social pain experienced. This suggests that the anterior cingulate is more important for elaborating feelings of emotional distress, whereas the prefrontal cortex, already implicated in emotional regulation (3), counteracts the painful feeling of being shunned.

These results are consistent with the idea that aversive feelings of social exclusion and physical pain arise, in part, from the same brain regions. They dovetail nicely with what we know about separation distress in other animals. In our work a quarter of a century ago, we examined the neurochemistry of social attachments in animals (4, 5). We found that the same neurochemicals that regulate physical pain also control the psychological pain of social loss. Indeed, plant opioids (such as morphine) as well as endogenous brain opioids (especially endorphins)—known to alleviate physical pain—also alleviated separation distress (as measured by isolation cries) in dogs, guinea pigs, chicks, rats, and primates (6).

How can we further elucidate the neural mechanisms that underlie the emotional pain induced by social exclusion? Two strategies might help. If the participants in the Eisenberger et al. study were to be given opioids, one would predict that they would feel less distress at being shunned, and that the brain areas implicated in elaborating such feelings would not be as profoundly activated. The administration of opioid receptor antagonists should intensify both effects. Other brain chemicals, such as oxytocin and prolactin (6) that are also powerful regulators of separation distress in animals, may have effects similar to those of opioids but they are too difficult to manipulate experimentally in humans.

Brain imaging has yielded a plethora of neural correlates of affective states (3) including the response to breathlessness (7), the craving for chocolate (8), winning the lottery (9), the sex-specific appeal of pretty faces (10), the ecstasy of peak musical experiences (11), human sympathy (12), male sexual arousal (13), and even rectal distension (14). The human brain areas implicated by Eisenberger et al. in feelings of social pain have many other functions. The cingulate gyrus (a long ribbon of tissue at the brain’s midline) contains two distinct “emotional” zones: The far anterior region elaborates negative feelings, whereas posterior regions elaborate positive feelings.

The antidepressant effects of mood-elevating drugs and placebos both depend on reducing the activity of the (subgenual) anterior cingulate and increasing the activity of the posterior cingulate (15). The most profound effects observed by Eisenberger et al. seem to be centered in the central cingulate region that is known to integrate emotion and cognition. This region is activated during male sexual arousal (12) and during stressful cognitive tasks requiring attention (16).

The feelings induced by experimental games in the laboratory, such as “CyberBall” in the Eisenberger et al. study, are a pale shadow of the real-life feelings that humans and other animals experience in response to the sudden loss of social support. It will be interesting to study more intense emotional states arising from profound personal loss with fMRI, which should allow us to probe even deeper into the regions of the mammalian brain that control separation distress (6). A step in this direction is the visualization by positron emission tomography of regions of the human brain activated during sadness (17). These regions correspond to some of the deeper brain areas activated during separation distress in animals. Localized electrical stimulation of many subcortical brain sites provokes separation cries in mammals (6, 18, 19). These sites include not only the anterior cingulate, but also the bed nucleus of the stria terminalis, the ventral septal and dorsal preoptic areas, the dorsomedial thalamus, and the periaqueductal central gray area of the brain stem.

The latter two areas are known to control feelings of physical pain. Psychological pain in humans, especially grief and intense loneliness, may share some of the same neural pathways that elaborate physical pain. Given the dependence of mammalian young on their caregivers, it is not hard to comprehend the strong survival value conferred by common neural pathways that elaborate both social attachment and the affective qualities of physical pain.

Throughout history poets have written about the pain of a broken heart. It seems that such poetic insights into the human condition are now supported by neurophysiological findings. Will the opposite also prove to be the case—that socially supportive and loving feelings reduce the sting of pain (20, 21). A reasonable working hypothesis is that social feelings such as love are constructed partly from brain neural circuits that alleviate the feelings of social isolation. Will we eventually discover that the feeling of a broken heart arises from the rich autonomic circuits of the brain’s limbic system that control cardiac neurodynamics? Will we find that people we consider “cold” or “warm” influence different thermoregulatory neural pathways in our brains?

As exemplified by the Eisenberger et al. study, such poetic insights garner some support from neurophysiological research, adding a humanistic touch to the mind-brain sciences. Feelings of love and loneliness, and the thoughts they provoke, are constructed in part from neural pathways in the brain that regulate core emotional responses, such as playfulness, sexuality, and friendship, as well as separation distress in our fellow creatures (6).

Of course, scientists should continue to be skeptical about such hypotheses until they are supported by solid research such as that carried out by Eisenberger and co-workers. Although there are many species differences in the emotional systems that we share as ancestral gifts with other animals (6, 22, 23), the field of neuroscience will be more productive if it remains open to the similar nature of human and animal affective experiences.

The emotional pain of social loss.
There are remarkable similarities between regions of the guinea pig brain that when activated provoke separation distress and areas of the human brain that are activated during feelings of sadness. During separation distress in guinea pigs, the most responsive brain areas are the anterior cingulate (AC), the ventral septal (VS) and dorsal preoptic areas (dPOA), the bed nucleus of the stria terminalis
(BN), the dorsomedial thalamus (DMT), and the periaqueductal central gray area of the brain stem (PAG) (18, 19). In humans experiencing sadness (17), it is the anterior cingulate that is most responsive, but other areas that are also activated include the DMT, PAG, and insula. The correspondence between the brain regions activated during human sadness and those activated during animal separation distress suggests that human feelings may arise from the instinctual emotional action systems of ancient regions of the mammalian brain. OB, olfactory bulb; CC, corpus callosum; CB, cerebellum.

References and Notes
1.↵ N. I. Eisenberger, M. D. Lieberman, K. D. Williams, Science 302, 290 (2003). Abstract/
2.↵ To visualize the game, see http://www.psy.mq.edu.au/staff/kip/cyberball.htm.
3.↵ K. L. Phan et al., NeuroImage 16, 331 (2002).
4.↵ J. Panksepp et al., Neurosci. Biobehav. Rev. 4, 473 (1980).
5.↵ J. Panksepp, in Progress in Theory in Psychopharmacology, S. J. Cooper, Ed. (Academic Press, London,1981),pp.149-175.
6.↵ J. Panksepp, Affective Neuroscience (Oxford Univ. Press,NewYork,1998).
7.↵ M. Liotti et al., Proc. Natl. Acad. Sci. U.S.A. 98, 2035 (2001).
8.↵ D. M. Small et al., Brain 124, 1720 (2001).
9.↵ B. Knutson et al., J. Neurosci. 21, RC159 (2001).
10.↵ I. Aharon et al., Neuron 32, 537 (2001).
11.↵ A. J. Blood et al., Proc. Natl. Acad. Sci. U.S.A. 98,
12.↵ J. Decety, T. Chaminade, Neuropsychologia 41, 127 (2003). 13.↵ J. Redoute et al., Hum. Brain Mapp. 11, 162 (2000).
14.↵ M. K. Kern et al., Am. J Physiol. 281, G1512 (2001).
15.↵ H. S. Mayberg et al., Am. J. Psychiatry 159, 728 (2002).
16.↵ C. S. Carter et al., Proc. Natl. Acad. Sci. U.S.A. 97, 1944 (2000).
17.↵ A. R. Damasio et al., Nature Neurosci. 3, 1049 (2000).
18.↵ B. H. Herman, J. Panksepp, Science 211, 1060 (1981).
19.↵ J. Panksepp et al., in The Physiological Control of Mammalian Vocalizations, J. D. Newman, Ed. (Plenum, New York,1988),pp.263-299.
20.↵ J. Panksepp, Psychopharmacology 72, 111 (1980).
21.↵ A. Miller, A Road Beyond Loss (Memorial Foundation for Lost Children, Bowling Green, OH, 1995) When I lost my daughter 12 years ago in a horrendous traffic accident, among her papers I found a poem that is now carved on her tombstone. The last stanza is particularly pertinent to the question of whether love can reduce the emotional pain of loss. When your days are full of pain, And you don’t know what to do, Recall these words I tell you now –I will always care for you.
22. J. Panksepp, Psychol. Rev. 110, 376 (2003).
23. J. Panksepp, Consciousness & Emotion 1, 17 (2000).

Keywords; Pain, social loss, emotional distress, neurochemistry, brain chemicals, breathlessness

Published in Science 10 Oct 2003: Vol. 302, Issue 5643, pp. 237-239 DOI: 10.1126/science.1091062