The Neuroendocrinology of Empathy
The Neuroendocrinology of Empathy
- James BurkettJames BurkettUniversity of Toledo, Neurosciences Department
- and Farzaneh NaghaviFarzaneh NaghaviUniversity of Toledo, Neurosciences Department
“Empathy” is an umbrella term for any type of process in which one is affected by the emotional state of others, and it is of great importance for daily social interaction. Empathic processes are thought to have evolved in the context of parental care to motivate caregivers to respond to helpless neonates’ needs, but over time may have been generalized outside the rearing context to make a wider social network and help shape social behaviors. It is becoming more apparent that in several psychiatric disorders, such as major depressive disorder, autism spectrum disorder, and antisocial personality disorder, impaired empathic behaviors are correlated with the severity of the disease and a reduced quality of life. Therefore, developing scientific avenues for the study of empathy, its mechanisms, and origins is important for human health and understanding the human condition.
- Neuroendocrine and Autonomic Systems
History of Terminology
In 1851, philosopher Auguste Comte coined the term “altruism” to describe the social behavior that derives from unselfish motives, while contemporary philosophers and psychologists were deeply divided on the issue of whether prosocial behavior, in any degree, is ultimately motivated by self-benefit (Batson, 1987). Observations of apparent altruism in nature, including in the behavior of bees, ants, and other animals, have led to a definition of altruism in evolutionary biology as a type of helping behavior to promote the welfare of others regardless of motivation (Mayr, 1961; Nowak et al., 2010). This has prompted a debate in evolutionary biology and social psychology over how a mechanism can evolve that benefits others at a cost to the self (Batson, 1987; Cialdini et al., 1987; Mayr, 1961; Nowak et al., 2010; Preston & de Waal, 2002). More recently, this has been explained using a distinction between ultimate and proximate mechanisms (Mayr, 1961). The proximate explanation is concerned with the “how,” or the mechanisms of the immediate presentation of behavior. By contrast, the ultimate explanation is related to “why,” or explanations of why a behavior evolved over time. These levels of explanation need not correspond, as the motivation for performing a behavior can be autonomous from the benefit the behavior provides. This distinction has been used to propose that empathy is a proximate mechanism that motivates altruistic behavior and that evolved to promote gene proliferation through group selection (Batson, 1987; de Waal, 2008; Nowak et al., 2010; Wilson, 2012).
The term Einfühlung in 1873 was derived from the Greek word empathea, meaning “feeling into,” to describe how art could convey emotion (Aldouby, 2020). Later, in 1903, Lipps applied the term to describe the ability of individuals to project themselves into another’s situation. This aesthetic description was translated into the English language as “empathy” by Edward Titchener, a British-born psychologist, although the meaning of the term has changed in contemporary psychology (Batson, 2002). Until recently, empathy was defined in social psychology as a cognitive state rather than an emotional one (Hojat, 2009), where perspective taking (or “theory of mind”) and perceiving others as in need are the two primary elements (Batson, 2002). In this view, empathy is a high-level, cognitive phenomenon that is typically reserved for humans (de Waal & Preston, 2017; Preston & de Waal, 2002).
Nonetheless, it is clear from numerous studies that nonhuman animals become distressed by the distress of conspecific, and there is evidence that at least several species will act pro-socially to terminate the conspecific’s distress, a behavior referred to as consolation (de Waal, 2008; de Waal & Preston, 2017; Preston & de Waal, 2002). More recent studies have identified similar behaviors in laboratory rodents (Bartal et al., 2014; Burkett et al., 2016; Cezar et al., 2020; Sato et al., 2015). Therefore, empathy appears to be a phylogenetically continuous phenomenon that has varied presentations across a wide range of species. However, there is no consensus on the definition of the term “empathy” in the literature, and the annals of empathy are rife with disagreements and discrepancies. Many different concepts have been used to define empathy, focusing on state matching, emotional contagion, sympathy, compassion, motor mimicry, and perspective taking, though each concept refers to a different phenomenon (Batson, 2009; Yalçın & DiPaola, 2019). There are also different theoretical models of empathy, among which the Russian Doll model (de Waal, 2007), the perception-action model of empathy (de Waal & Preston, 2017; Preston & de Waal, 2002), and the top-down and bottom-up theories (de Waal & Ferrari, 2010) have received eminent attention.
Theoretical Models of Empathy
The perception-action model proposes empathy as a process rather than a capacity, by which a subject comes to share representations of another’s state (physical or emotional) through observation, and as such is concerned primarily with proximate mechanisms (de Waal & Preston, 2017; Preston & de Waal, 2002). When the observed state is an emotional state, the shared representation is an emotional state, reflecting emotional contagion. However, the perception-action model is flexible and can also be used to explain physical states or motor actions, encompassing such capacities as motor mimicry, facial mimicry, accent imitation, and social learning (Preston, 2007; Singer & Lamm, 2009). In this model, the subject accesses the subjective state of the other through the subject’s own neuronal and bodily representations, which therefore also encompasses concepts such as mirror neurons and mirror systems (de Waal & Preston, 2017; Preston & de Waal, 2002). These shared representations are proposed to serve as the core mechanism for both affective and cognitive components of empathy and can therefore motivate actions ranging from instinctual prosocial behaviors to explicit situational helping. This model is compatible with the Russian Doll, which places perception-action mechanisms in its innermost layer (de Waal, 2007).
In the Russian Doll model, empathy refers to any type of process in which one is affected by the emotional state of another, adopts another’s perspective, or assesses the reason for another’s state (de Waal & Preston, 2017; Preston & de Waal, 2002). This model proposes three evolutionary steps that build on each other, making the different layers of the Russian Doll; and as such, principally addresses ultimate mechanisms (de Waal, 2007). The innermost layer is “emotional contagion,” which is an automatic and reflexive emotional matching between the subject and the other, which may be followed by physiological state matching, self–other differentiation, and prosocial behavior. The Russian Doll model proposes that the next evolutionary step is the capacity for sympathetic concern, or the capacity to assess another’s situation and needs, which can lead to feelings of sorrow or concern for a distressed other and an explicit motivation to help. This middle layer builds on existing capacities for emotional contagion but combines both emotional and cognitive elements and is not automatic or reflexive. Consolation, or comforting contact directed to the other that provides a calming effect, is the most-given example for sympathetic concern in the literature; however, the observation of consolation in laboratory rodents suggests that this behavior may not require complex cognition or an understanding of situations or needs, but rather can be an expression of instinctive caring behaviors motivated by emotional empathy (Burkett et al., 2016). The outermost layer of the Russian Doll model is perspective taking, or theory of mind. Perspective taking is an ability to imagine the thoughts and feelings of others in their specific situation, which can take into account knowledge, desire, belief, and goal (Decety & Ickes, 2011), and it has been reported in apes, birds, and mammals (de Waal & Preston, 2017). Empathetic perspective taking refers specifically to the application of this capacity toward imagining the emotions of another in their specific situation. By extension, the Russian Doll model proposes that these layers may be independently observed in different animals, with emotional contagion being a common core element that is likely to be phylogenetically continuous.
The top-down and bottom-up approach was proposed as a modification to the perception-action model (de Waal & Ferrari, 2010). This model relies on a distinction between “bottom-up” emotional empathy, which largely consists of automatic and reflexive aspects of empathy such as emotional contagion, and “top-down” cognitive empathy, which represents the application of cognitive capacities toward the understanding of the emotions and situations of others, and encompasses capacities such as theory of mind, empathetic perspective taking, and explicit situational helping (de Waal, 2008). In bottom-up emotional empathy, when the subject is exposed directly to the other, the individual-specific, shared neural representations are activated. The activation of these distributed personal representations, such as physiological states, semantic concepts, associated memories, facial expressions, and body postures, is required for the automatic spreading of emotions. If the pattern of activation passes a threshold, it can lead to the activation of relevant motor areas to generate a behavioral response. However, humans and some other animals are also capable of conscious, cognitive evaluation to consider information that is not directly observable, such as imagining or reasoning about the other’s internal state. This “top-down” cognitive empathy adds to the subject’s representations of the other and the situation. These top-down processes recruit neural regions that support working memory, executive function, emotion regulation, and visuospatial perception. The activation of top-down cognitive empathy can feed back into bottom-up emotional empathy, even in the absence of an observable other, leading to representations at the emotional level.
The Biological Study of Empathy
Scientific study of empathy in the laboratory was slow to develop because of the difficulties of bringing the multidimensional psychological phenomenon into a well-controlled and reproducible environment. The discovery of mirror neurons in macaques in 1992 provided one of the earliest means of studying the biological basis of the perception of the actions of others (Rizzolatti et al., 1988, 1990). Later, the discovery of mirror neurons in the frontal and parietal cortices in humans led to the proposal that mirror-like systems, wherein a single brain region or single neuron responds to action and to observation, can underlie both observational learning (Peeters et al., 2009) and social emotions (Gallese et al., 2004) like love, happiness, anger, sadness, fear, and disgust. Nonetheless, this idea that perception of emotion and experience of that emotion activates overlapping neural mechanisms, as suggested by the perception-action model, has also been criticized (Decety, 2010). Investigation of the mirror neuron homologue in humans has been done using different techniques, including functional magnetic resonance imaging (fMRI), positron emission tomography, electroencephalography, magnetoencephalography, and transcranial magnetic stimulation (Dinstein et al., 2008). Of these, the results of fMRI studies have consistently confirmed the activation of certain brain regions both by the personal experience of pain and by the observation of the pain of others, including most prominently the anterior cingulate cortex (ACC) and anterior insular cortex (INS) (Lamm et al., 2011; Yamada & Decety, 2009). Studies have also shown a broad overlap between cortical areas active in humans during action observation and areas showing mirroring properties in the macaque, including the inferior parietal lobule, inferior frontal gyrus, and the ventral premotor cortex (Molenberghs et al., 2012). Other brain regions, such as the paracingulate, the anterior and posterior cingulate gyrus and the amygdala also are suggested to be involved in emotion regulation and empathizing with the experiences of others (Völlm et al., 2006). More likely, the functional significance of mirror neurons varies based on their location in different brain regions. For example, the mirror neuron system in the INS and ACC might underlie the capacity to understand a specific emotion in others (Hutchison et al., 1999; Wicker et al., 2003), whereas the parieto-frontal mirror network encodes the goal of the observed motor acts and the intentions behind them (Gazzola et al., 2007). However, evidence for the existence of mirror neurons in humans is indirect and principally relies on functional neuroimaging studies that cannot yet unambiguously detect single neuron activity (Mukamel et al., 2010). Therefore, there is still a doubt as to whether these areas contain mirror neuron populations, or if mirror systems sufficiently explain all facets of action or emotion understanding in humans (Grafton, 2009; Kilner et al., 2009).
Empathy Paradigms in Rodents
Several behavioral paradigms for animals, from primates to rodents, have been developed to provide a well-controlled and reproducible environment for studying empathy-related phenomena (Keysers & Gazzola, 2016). These paradigms can be categorized into four general groups based on the type of behavior being assayed: emotional contagion, observational learning, social operant conditioning, and prosocial responding. Emotional contagion paradigms focus on the emotional responses of an observer exposed to a demonstrator in a particular emotional state, the most common of which is pain (Cezar et al., 2020; Kim et al., 2014; Langford et al., 2006). Outcome measures of these studies typically focus on anxiety and physiological stress. In observational learning paradigms, an observer learns to associate the affective state of another with the valence of a stimulus or context (Wrenn, 2004). Studies of this kind typically measure associative learning, most often fear conditioning. In social operant conditioning paradigms, the observer’s performance of a learned behavior is reinforced or punished by association with harm or reward to another (Masserman et al., 1964; Sato et al., 2015). Like observational learning, outcomes focus on operant learning or responding. In prosocial responding paradigms, an observer is exposed to a distressed other and has the opportunity to perform a prosocial behavior in response (Bartal et al., 2014; Burkett et al., 2016; Sato et al., 2015). These prosocial responses range from instinctual consoling to operant rescue behaviors and are often species specific.
Neural Substrates of Empathy
Investigation of the neural substrates of empathy in animals has focused primarily on the few brain regions identified in human research and their connections to task-relevant regions. The majority of these studies have focused on the ACC, with some few investigating the INS. In humans the ACC is involved in the affective experience of pain and the reward of pain relief (Fuchs et al., 2014). In rodent studies, the ACC also seems to play this dual role, and is consistently activated by the observation of pain or distress in another (Burkett et al., 2016; Hashemi et al., 2017; Jeon et al., 2010; Kim et al., 2014; Smith et al., 2021), which may be lateralized to the right hemisphere (Jeon et al., 2010; Kim et al., 2014). Studies have also consistently reported hyperalgesia in observers witnessing pain in others (Langford et al., 2006; Smith et al., 2017, 2021), which may involve mirror neurons in the ACC (Carrillo et al., 2019). Manipulations that inhibit neuronal activity in the ACC or that inhibit specific receptor systems, including those for oxytocin, serotonin, and dopamine, can inhibit emotional contagion, observational learning, and prosocial responses (Allsop et al., 2018; Burkett et al., 2016; Cezar et al., 2020; Jeon et al., 2010; Smith et al., 2017). At least some of these effects may be specific to interneurons in the ACC, which mediate observational fear in mice (Keum et al., 2018) and have expression patterns in ACC that are related to sociality (Hashemi et al., 2017; Robertson et al., 2016). Studies of connectivity between brain regions have suggested functional connections between ACC and thalamus or amygdala, which control emotional contagion for painful or fearful stimuli (Allsop et al., 2018; Jeon et al., 2010; Smith et al., 2021; Zheng et al., 2020), and intriguing new evidence suggests emotional contagion for reward is related to functional connections between ACC and the nucleus accumbens (Smith et al., 2021). Nonetheless, activation of functional connections between ACC and amygdala or thalamus can have contradictory effects (Allsop et al., 2018; Kim et al., 2014; Zheng et al., 2020). Only one study has examined the necessary role of the INS in empathy-related behaviors, and found it necessary for social approach toward distressed conspecifics (Rogers-Carter et al., 2018).
Neuroendocrinology of Empathy
The principle neurohormone that has been investigated for its role in empathy across species is oxytocin. Oxytocin is a neuropeptide that is largely conserved through mammalian evolution, and was originally studied for its role in childbirth and the ejection of milk during breastfeeding (Ross & Young, 2009). Oxytocin release in the brain as a neurohormone is now known to be involved in various social behaviors such as social attachment (Bosch & Young, 2018; Numan & Young, 2016; Young & Wang, 2004), approach (Crawley et al., 2007; Teng et al., 2013), recognition (Ferguson et al., 2001), buffering (Guzmán et al., 2014; Smith & Wang, 2014), reward (Dölen et al., 2013), and learning (Choe et al., 2015; Hurlemann et al., 2010). Oxytocin release has been measured in humans and dogs during social encounters, as well as in a wide range of animals, including humans, during sex (Johnson & Young, 2017; Young & Wang, 2004). In humans, genetic variation in the oxytocin receptor predicts trait empathy (Gong et al., 2017), and intranasal administration of oxytocin enhances emotional recognition (Shahrestani et al., 2013) and emotional empathy (Hurlemann et al., 2010). Intranasal oxytocin has been investigated for the potential to treat autism, and improves aspects of empathy and social functioning by engaging primary sensory regions of the brain (Andari & Rilling, 2021; Andari et al., 2010, 2016; Aoki et al., 2014).
Recent studies in rodents and monkeys have demonstrated the importance of oxytocin in emotional contagion, observational learning, and prosocial responses. Both acute and chronic intranasal administration of oxytocin in mice increase observational fear learning, and peripheral oxytocin antagonists can reduce observational fear (Pisansky et al., 2017; Sakaguchi et al., 2018). Chemogenetic activation of oxytocinergic neurons in the hypothalamic paraventricular nucleus (PVN) enhances observational fear learning (Sakaguchi et al., 2018), whereas inhibition of the projection from PVN to the amygdala impairs emotion discrimination (Ferretti et al., 2019). Observing a distressed conspecific enhances functional connectivity between ACC and amygdala, and functional connectivity in this circuit is directly enhanced by intranasal oxytocin (Ito et al., 2015; Sripada et al., 2013).
Regarding the effect of oxytocin on prosocial behavior, oxytocin knock-out prairie voles show diminished consolation toward distressed conspecifics (Kitano et al., 2020), and an oxytocin antagonist administered either centrally or only to the ACC similarly abolishes consolation in prairie voles (Burkett et al., 2016). In a social learning task involving rescuing behavior in rats, learned helping causes an activation in oxytocin receptor-containing neurons in the ACC and amygdala, and oxytocin inhibition in the ACC impairs learning the task (Yamagishi et al., 2020).
In the past two decades, empathy has gone from a concept debated primarily in psychology and philosophy to a nascent topic for scientific investigation. The neuroscience of empathy has progressed to the point where circuitry is beginning to be mapped and molecular substrates discovered, with oxytocin being the primary focus in many models. Even while progress on new paradigms pushes forward, there is still careful conceptual work being done that lays a foundation for understanding this new science in relation to fundamental psychological concepts. Over the next ten years, it can be expected that knowledge in this topic area will expand far beyond what is contained in this article.
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