Overview of empathy The process by which one’s affective experience is shared by another person is known as empathy. In order to understand empathy using the scientific method it is imperative to first define empathy. There are a wide range of definitions of empathy in the literature. 1) The capacity to understand and respond to the unique affective experiences of another person, 2) Similarity between one’s own feelings and those of another person, and 3) Interaction between 2 individuals with one experiencing and sharing the feelings of the other (Decety and Jackson 2006). Within these definitions there are three underlying components; 1) an affective response to the other person, 2) cognitive capacity to take the perspective of another person, and 3) emotional regulation. Emotional regulation is thought to avoid confusion between the self and the person who is the target of the empathy. As theorised by Goldman, (Goldman 2006) behaviour may be simulated  by activation of the same neural resources for action and perception, so called ‘simulation theory’. A recent study on empathy for pain (Singer, Seymore et al. 2004) showed that empathy for pain activates the affective, but not sensory components of the ‘pain matrix’. If simulation theory holds true for a mechanism for empathy in humans, then completely taking the perspective of another person may result in emotional conflict and distress (Decety and Jackson 2006). In light of this, emotional regulation serves to prevent complete singularity between the self, and the other person. In this essay, I will first describe some studies that have investigated the neural substrate for empathy in the human brain using pain as the experimental tool, and link these ideas with recent discovery of mirror neurons. Since anterior cingulate cortex and anterior insula activation is common across all empathy related studies these areas will be the main focus of this essay. Then, using experimental evidence I will argue that empathy can be thought of as a ‘mystical experience’; the idea being that a third person ‘persona’ (whether material or immaterial) is imprinted onto oneself. Finally I will look at some pathology that result in an alteration of empathy and how this gives insights into its neural mechanisms.

 Many ‘empathy’ studies use pain as the experimental tool. Does this confuse empathy with compassion? For example, one study has shown that “empathy for pain in others  activates the affective components of the pain matrix but not the sensory components”(Singer, Seymore et al. 2004). In this study, couples were recruited, and were required to observe their spouse in a painful condition whilst undergoing fMRI scanning. It was found that specifically during the observation of pain in one’s spouse and the experience of pain in oneself activation was seen in right anterior insula (rAI), and anterior cingulate cortex (ACC) (Singer, Seymore et al. 2004). Another study has investigated the neural activation whilst observing a painful stimuli and also while experiencing a painful stimuli (in the form of a painful thermal stimulation). Brain regions that were active were ACC, and bilateral AI, and these were activated at greater levels during the actual experience of pain than the observation of pain (Botvinick, Jha et al. 2005). This finding is to be expected, since pain that is physically felt activates not only the affective regions of the pain matrix (Singer, Seymore et al. 2004), but also the sensory regions. The experience of pain is also key in generating empathy. If one experiences pain in the form of a simple pinprick to the finger, then observes a third person experiencing the same stimulus, the right dorsal ACC is active (Morrison, Lloyd et al. 2004). This finding highlights the importance of personal experience in empathy. In order to experience the affective aspects of (in this case) pain, one must have a physical experience of pain, i.e. feel pain for themselves. It is interesting also that the right dorsal ACC was active preferentially in both felt and seen pain. In another study, it was found that the amount of ACC activation was due to the amount of perceived pain in another individual (Jackson, Meltzoff et al. 2005). It is important to note that in this study no pain was afflicted onto subjects. Notwithstanding the fact that it is likely that the participants (mean age= 22 years) have experienced pain throughout their lives, in this study participants were required to imagine the experience of pain in another individual without a direct reference to themselves. In the imagery of others’ pain the ACC and AI were active bilaterally (Jackson, Meltzoff et al. 2005) It is important to note in pain-related empathy studies two brain regions are always reported to be active- ACC and AI. Where specifically in these regions the activation is found differs, e.g. some studies specify right ACC (Morrison, Lloyd et al. 2004) whereas other studies find activation bilaterally in ACC (Jackson, Meltzoff et al. 2005). The important difference between these studies is the fact that one uses actual pain as a reference (Morrison, Lloyd et al. 2004) whereas the other requires the participants to imagine and project the response to pain without a direct reference point (Jackson, Meltzoff et al. 2005). The latter may be ascribed to participants experiencing a quasi-mystical experience as will be discussed later. One study has conducted fMRI on a Buddhist monk whilst performing a special form of meditation that generates feeling of love and compassion. When comparing the meditation condition with baseline (no meditation) several brain regions were activated. These were left medial prefrontal cortex, anterior cingulate gyrus, the caudate nucleus, right insula, left midbrain, and left post-central gyrus. It is important to note the overlap between these studies, two areas of note are anterior cingulate gyrus and right insula cortex (Singer, Seymore et al. 2004; Engström and Söderfeldt 2010). Since these two regions are active in almost every empathy study to date (Preston and de Waal 2002), it may be suggested that what may be being studied is not empathy, but compassion or sympathy for others in pain. If one observes pain in a member of a different racial group, activation in ACC is significantly decreased with respect to observation of pain in a member of the same racial group as the observer (Xu, Zuo et al. 2009). This finding brings to the forefront an evolutionary point of view. We would be most likely to feel sympathy or compassion for a member of our own group since evolutionarily in social species such as the human, survival of the group is the ‘goal’. The group with which we identify with may be thought of as one single entity, therefore if one member experiences a painful situation, other members may also experience this, in order that if given the opportunity, they may alleviate the suffering of that individual. This idea would explain the findings of Singer (Singer, Seymour et al. 2004) in that people in a romantic relationship with each other experience the affective components of the pain matrix whilst watching their partner experience pain. In concluding this section I am putting forth the idea that studies that use pain as a tool for understanding empathy may be measuring sympathy or compassion instead (Engström and Söderfeldt 2010). Empathy itself may be a process that is not dissimilar to a mystical experience, where in pain studies; the ‘affective component’ seen in observers may be a representation of emotions such as sympathy or compassion or both. In many of these studies, there is often overlap between brain areas activated whilst watching other in a painful situation and actual experience of the pain itself. A theory to explain this has been generated and termed the Perception-Action Model (PAM) (Preston and de Waal 2002). In this model, the central idea is that mere perception of an emotion in another individual activates the brain areas that both generate that emotion and prepare for the emotion to be experienced by the ‘self’ in order so that the emotion may “resonate within the individual” (Preston and de Waal 2002). It is important to note however that the original source of this is from a third person- the individual with whom we are empathizing with. Since empathy involves the mapping of the emotions of others onto the neural framework of oneself (Decety and Jackson 2006), this idea appears similar to a mystical experience. A definition of a mystical experience has been suggested consisting of two main criteria: It is a transient experience, it is a passive experience (James 1902). It is well accepted within current theories of empathy that the emotions of others are mapped onto the brain of oneself, but this is not long-lasting or permanent (Preston and de Waal 2002; Decety and Jackson 2006). Empathy has also been suggested to be a passive, or involuntary experience that has an innate, built-in origin (Hoffman 1981). Therefore, empathy may be thought of as a mystical experience. One study has used fMRI to study brain activity during a religious/mystical experience. Nuns were scanned in an fMRI machine whilst in a subjectively reported ‘state of union with God’ or mystical experience and the following brain regions were active; Right medial orbitofrontal cortex, right middle temporal cortex, right inferior and superior parietal lobe, right caudate, left medial prefrontal cortex, left anterior cingulate cortex, left inferior parietal lobe, left insula, left caudate, and left brainstem. Of particular relevance to empathy are left ACC and left insula because in all empathy studies ACC and insula are active, either bilaterally or with right lateralization. According to the Bible, prayer, or union with the will of God is thought to impart knowledge on to the person. When empathizing, union occurs between two individuals involuntarily (Hoffman 1981). The main idea here is that in all empathy studies, no matter what the experimental tool, AI and ACC are activated (Preston and de Waal 2002). Since these are also active during compassionate meditation and in mystical experience, this suggests that empathy, because it involves representing a third ‘person’ entity on the neural background of the ‘self’, empathy may be thought of as a mystical experience in which the other is ‘transposed’ onto the self in a fashion not dissimilar to mystical experience. (In mystical experience it is left ACC and AI activated) Right AI and ACC may be due to the recognition that the third person entity is ‘real’ as opposed to mystical experience, in which the third entity is not material. In the empathy study described above (Jackson, Meltzoff et al. 2005) where there was no direct reference point for pain the activation in left ACC that was reported may be ascribed to the generation of a quasi-mystical experience, in which participants ‘invented’ the third person, then used the ‘made-up’ third persons’ perception as that which was transposed onto their own neural architecture. This idea would be concordant with the fMRI data during mystical experience in which left insula and left ACC were found to be active, but not right insula or right ACC (Beauregard and Paquette 2006). In the Singer study (Singer, Seymour et al. 2004), participants observed the hand of their loved one through a mirror i.e. they could not directly see their loved one. If the mystical experience hypothesis is true, then the activation in bilateral ACC and AI can be explained. Since they could not see the faces of their loved one (only the hand) it may have been necessary to ‘make up’ the owner of the hand as their loved one. This would make the loved one a quasi-imagined being, since they could not directly see them and would explain the ACC and AI activation in left hemisphere that has been shown to be active in mystical experience (Beauregard and Paquette 2006). In contrast, one study used a person in a video as the target for empathy (Morrison, Lloyd et al. 2004). In this study, when the third person received a painful stimulus there was no activation seen in either left ACC or left AI in the observer. The mystical experience hypothesis may also explain this finding. Since the observer could see the face of the target, it was unnecessary to have to ‘invent’ the target. Since left ACC and AI are active in the ‘invention’ or a third entity e.g. God (Beauregard and Paquette 2006) it is not surprising that no left ACC or AI was observed in Morrison’s study (Morrison, Lloyd et al. 2004). Therefore, in concluding this section, the left ACC activation found in some empathy studies may be explained by the ‘invention’ of a third person character, in the absence of a direct perception of the identity of the third person from which to draw the required information from that is used in the generation of empathy. Mirror NeuronsMirror neurons are specialized neurons that fire action potentials when an individual performs an action, but also when observing that same action performed by another similar individual (Gallese, Fadiga et al. 1996; Rizzolatti, Fadiga et al. 1996). Mirror neurons have been suggested previously (Carr, Iacoboni et al. 2003) to be the neural substrate for the process of empathy by way of the ‘simulation theory’ (Goldman 2006) by coding the mental state of another individual . One study used fMRI to generate a ‘map’ of brain areas active when both observing a facial expression and imitating that facial expression. In the human, left inferior frontal gyrus (IFG) (Brocas area 44) and the right anterior parietal cortex are thought to contain mirror neurons due to their activation during ‘self’ and ‘other’ movements (Preston and de Waal 2002). One study has shown that activity in IFG causally activates anterior insula (Jabbi and Keysers 2008). Interestingly however in the empathy studies described here that use pain as an experimental tool, no activity in IFG was observed. IFG has been shown to be preferentially active during the perception of both an action and the intention of the action (Iacoboni, Molnar-Szakacs et al. 2005) i.e. an action and the reason for the action. Areas involved in empathy display mirror neuron-like properties Though mirror neurons have not yet been directly demonstrated in humans some empathy-related brains areas display mirror-neuron characteristics. E.g. the same brain regions (in the affective part of the pain matrix) are active in both the experience and the observation of pain, namely ACC and AI. For example, in the Morrison study (Morrison, Lloyd et al. 2004) right ACC was preferentially active during both the experience of pain and the observation of pain in a third person. This is analogous to the mirror neurons described by Rizzolatti in area F5 of the monkey (Rizzolatti, Fadiga et al. 1996). ACC may be the ‘emotional equivalent’ of area F5 in the monkey and IFG in the human for motor actions. On the contrary, there are reasons to suspect that mirror neurons are not the neural substrate that underlies empathy in humans. 1) Mirror neurons have not yet been directly demonstrated in humans, 2) phenotypic mirror neurons are about 6% of the total number of neurons recorded in area F5 of the monkey, this means that in human studies where IFG is active in a observation/experience task, it may not be exclusively ‘mirror neurons’ that are active, and 3) the mirror neuron hypothesis may be too simple to explain empathy in humans (Perkins, Stokes et al. 2010). Empathy in pathological cases One way to test the contribution of a particular brain region to a neural process is to introduce pathology, or, in the case of humans, look at the brains of individuals who are afflicted with neuro/psycho-pathology. One example of a pathology that appears to affect the process of empathy is Conduct Disorder (CD) (Sterzer, Stadler et al. 2007). CD is a disorder characterized by verbal and physical aggression, cruel behaviour toward pets and other people and general destructive behaviour. In one study, grey matter volume in ‘emotion-related’ areas of the brain was measured in CD patients and age/intelligence matched healthy controls. Grey matter volume was reduced in the amygdala and bilateral ACC. Furthermore, the volume of grey matter in bilateral ACC was positively correlated with scores on empathy questionnaires (Sterzer, Stadler et al. 2007). This finding suggests that bilateral ACC is part of a ‘core matrix’ for empathy (Fan, Duncan et al. 2010), since its reduction also reduces empathy in individuals with CD.  An alternative explanation however, is that over time individuals with CD have learned to ‘ignore’ the pain of others. This may mean that when they observe the pain of others and ignore it, ACC is not activated and therefore may not develop as in healthy subjects. Since the causality of the ACC reduction is unknown, both of the following hypotheses are viable; reduced ACC volume contributes to the reduced empathy, or, reduced empathy during childhood development contributes to the non-development of ACC. Another pathology in which the process of empathy is perturbed is the Autism Spectrum Disorders (ASDs). There are three main classifications of ASDs; Autism, Asperger syndrome, and Pervasive Developmental Disorder Not Otherwise Specified. Generally, these disorders are classified by impaired social interaction and communication deficits (Baron-Cohen, Leslie et al. 1985). In one study, autistic children were asked to take the perspective of a third person and report the belief of that third party. The ability to perform this task has been termed Theory of Mind (Premack and Woodruff 1978) and empathy is thought to be a process that allows this. Children with autism are unable to report the beliefs of a third person in a simple paradigm. Two dolls were used; one doll placed a marble in a particular location then ‘left’ the scene. Whilst away the marble was moved to a different location by the other doll. The first doll was returned to the scene and participants were asked where the first doll will look for its marble.Healthy children answered that the doll would look in the last place that it was left (demonstration of theory of mind for the first doll), however children with autism were unable to do so (Baron-Cohen, Leslie et al. 1985), instead they pointed to where the marbleactuallywas. The inability to correctly perform this task was attributed by the authors to a lack of empathy. Lesions of ACC are known to result in a lack of social judgement and inability to interpret social cues (Devinsky, Morrell et al. 1995). It is imperative to measure the volume of ACC in individuals with autism and compare these with ACC volumes of healthy controls. To date, it is known that there are alterations in ACC, in the form of less GABAAreceptors present (Oblak, Gibbs et al. 2009). In concluding this essay, there are two key brain regions that contribute to empathy for pain in humans ACC and AI. Whether or not these regions are also involved in compassion and this is the explanation for the observed ‘empathy’ is unknown. Empathy may be thought of as a mystical experience, in which the left ACC may indicate the ‘invention’ of the third person in the absence of sufficient information of exactly what or who the ‘other individual’ is, and the right ACC being active when the participant is fully aware and can perceive the identity of the other individual. Secondly, the jury is still out on whether or not mirror neurons, or human homologues underlie the process of empathy. Finally, studies from pathological studies highlights the importance of ACC in the process of empathy, as evidenced by a lack of empathy in individuals with CD, and the fact that lesions of ACC result in a lack of social perception and interaction. References Baron-Cohen, S., A. M. Leslie, et al. (1985). “Does the autistic child have a “theory of mind” ?”Cognition21(1): 37-46.   Beauregard, M. and V. Paquette (2006). “Neural correlates of a mystical experience in Carmelite nuns.”Neuroscience Letters405(3): 186-190.   Botvinick, M., A. P. Jha, et al. (2005). “Viewing facial expressions of pain engages cortical areas involved in the direct experience of pain.”NeuroImage25(1): 312-319.   Carr, L., M. Iacoboni, et al. (2003). “Neural mechanisms of empathy in humans: A relay from neural systems for imitation to limbic areas.”Proceedings of the National Academy of Sciences of the United States of America100(9): 5497-5502.   Decety, J. and P. Jackson (2006). “A Social-Neuroscience Perspective on Empathy.”Current Directions in Psychological Science15: 54-58.   Devinsky, O., M. J. Morrell, et al. (1995). “Contributions of anterior cingulate cortex to behavior.”Brain118(1): 279-306.   Engström, M. and B. Söderfeldt (2010). “Brain Activation During Compassion Meditation: A Case Study.”The Journal of Alternative and Complementary Medicine16(5): 597-599.   Fan, Y., N. W. Duncan, et al. (2010). “Is there a core neural network in empathy? An fMRI based quantitative meta-analysis.”Neuroscience & Biobehavioral ReviewsIn Press, Uncorrected Proof.   Gallese, V.,L. Fadiga, et al. (1996). “Action recognition in the premotor cortex.”Brain119(2):593-609. Goldman, A. (2006).Simulating minds: The philosophy, psychology, and neuroscience of mindreading. New york, Oxford University Press.   Hoffman, M. (1981). “Is altrusim part of human nature?”Journal of Personality and Social Psychology40: 121-137.   Iacoboni, M., I. Molnar-Szakacs, et al. (2005). “Grasping the Intentions of Others with One’s Own Mirror Neuron System.”PLoS Biol3(3): e79.   Jabbi, M. and C. Keysers (2008). “Inferior Frontal Gyrus Activity Triggers Anterior Insula Response to Emotional FAcial Expressions.”Emotion8(6): 775-780.   Jackson, P. L., A. N. Meltzoff, et al. (2005). “How do we perceive the pain of others? A window into the neural processes involved in empathy.”NeuroImage24(3): 771-779.   James, W. (1902).The Varieties of Religious Experience: A study in Human Nature, Longmans, Green and Co.   Morrison, I., D. Lloyd, et al. (2004). “Vicarious responses to pain in anterior cingulate cortex: Is empathy a multisensory issue?”Cognitive, Affective, & Behavioral Neuroscience4(2): 270-278.   Oblak, A., T. Gibbs, et al. (2009). “Decreased GABA-A receptors and benzodiazepine binding sites in the anterior cingulate cortex in autism.”Autism Research2(4): 205-219.   Perkins, T., M. Stokes, et al. (2010). “Mirror neuron dysfunction in autism spectrum disorders.”Journal of Clinical Neuroscience17(10): 1239-1243.   Premack, D. and G. Woodruff (1978). “Does the chimpamzee have a theory of mind?”Behavioral Brain Sciences1: 555-557.   Preston, S. and F. de Waal (2002). “Empathy: Its ultimate and proximate bases.”Behavioral and Brain Sciences25: 1-72.   Rizzolatti, G., L. Fadiga, et al. (1996). “Premotor cortex and the recognition of motor actions.”Cognitive Brain Research3(2): 131-141.   Singer, T., B. Seymore, et al. (2004). “Empathy for Pain Involves the Affective but not Sensory Components of Pain.”Science303: 1157-1162.   Singer, T., B. Seymour, et al. (2004). “Empathy for Pain Involves the Affective but not Sensory Components of Pain.”Science303(5661): 1157-1162.   Sterzer, P., C. Stadler, et al. (2007). “A structural neural deficit in adolescents with conduct disorder and its association with lack of empathy.”NeuroImage37(1): 335-342.   Xu, X., X. Zuo, et al. (2009). “Do You Feel My Pain? Racial Group Membership Modulates Empathic Neural Responses.”J. Neurosci.29(26): 8525-8529.   image used from: http://www.fid-gesundheitswissen.de/neurologie/gehirn/