Neurobiology and neuropharmacology of emotion






Philippe FOSSATI,MD, PhD
GH Pitié Salpétrière
Service de Psychiatrie d’Adultes & CNRS USR 3246
AP-HP, CR-ICM
Université Pierre & Marie
Paris-VI, Paris – FRANCE

Neurobiology and neuropharmacology of emotion


by P. Fossati, France



This review focuses on the links between the emotional brain and the social brain through analysis of the role of the amygdala. The amygdala is believed to have a key role in detection of salient and personally relevant stimuli in concert with other regions of the emotional brain. Among salient stimuli, social signals are potent sources of emotion as they indicate self-relevant information in the environment. We describe the role of main neurotransmitters— serotonin, norepinephrine, and dopamine—on amygdala activity and we emphasize the role of oxytocin in social function. Evidence from brain imaging studies show that oxytocin may regulate the salience of social signals through modulation of amygdala activity.

Medicographia. 2013;35:344-348 (see French abstract on page 348)



Emotions are defined as episodic and synchronized changes in physiological, behavioral, and cognitive responses of the organism, reflecting the identification of salient stimuli in the environment. Emotional episodes are critical to survival and have a strong and persistent influence on cognitive processes such as perception, attention, memory, and decision-making. Accordingly, with this persistent relationship between cognitive and emotional processes and the putative dysfunction of these processes in psychiatric disorders, there is a growing interest in the study of the neurobiology of emotion. In this paper, we will focus on findings about the neuroimaging and neurochemistry of emotion with a special emphasis on the links between emotion, social behaviors, and the amygdala.

Emotional brain and social brain
Animal studies, brain lesions in human, and more recently, neuroimaging studies have contributed to the definition of the so-called “emotional brain.” The emotional brain is a highly distributed set of cortical, subcortical, and limbic regions organized into several subsystem networks (Figure 1).1,2

The emotional perception network is composed of cortical and subcortical structures, including sensory cortices, and the amygdala, anterior cingulate cortex, insula, basal ganglia, and orbitofrontal cortex. This system is associated with the detection and evaluation of emotional stimuli.

The emotional regulation network comprises the ventro- and dorsolateral prefrontal cortex, the rostral anterior cingulate cortex, the dorsomedial prefrontal cortex, the posterior cingulate cortex, the precuneus, and the hippocampus. These regions are involved in contextualization of emotion and emotional regulation, the ability to dampen or increase response to emotional stimuli. A subset of these regions (ie, medial prefrontal cortex, hippocampus, posterior cingulate cortex, precuneus) constitutes the default-mode network (DMN). The DMN has been related to prospection, autobiographical memory, self-referential processing, and theory of mind, a common set of cognitive processes devoted to projecting oneself into worlds that differ mentally, temporally, or physically from one’s current experience.

Several stimuli can activate the emotional brain. Among these stimuli, social stimuli such as faces, persons, or social feedback (ie, social criticism or approbation) are major sources of emotion. It is now well admitted that there is a large overlap between the emotional brain and the social brain.3

The amygdala and processing of self-relevant stimuli

Major evidence for such overlap between the emotional and the social brain comes from studies on the amygdala. The amygdala is a major component of the emotional perception network and it receives input from the sensory cortices and thalamus. The amygdala has strong reciprocal connections with other regions of the emotional brain, such as the ventromedial prefrontal cortex and the orbitofrontal cortex. Moreover, the amygdala has widespread projections to the basal forebrain, striatum, nucleus accumbens, hippocampus, and sensory cortices.4

The amygdala is usually associated with fear processing and is involved in threat detection and fear learning.5,6 Brain imaging studies have challenged the specific role of the amygdala in fear processing by showing that both negative emotion and positive emotion activate the amygdaloid complex.7

The amygdala is also sensitive to social signals, such as faces, gaze direction, intention, and trustworthiness.8 Consistent with a putative role of the amygdala in social processes, patients with amygdala lesions showed not only abnormal fear response, but also impaired social behaviors. Amygdala lesions are associated with increased social approach and difficulties to monitor interpersonal distance.9 Likewise, mental disorders with major social impairment such as autism and schizophrenia show abnormal functioning of the amygdala, characterized by increased reactivity in response to social stimuli.





Figure 1
Figure 1. Emotional brain organized into perception and regulation
networks.

The emotional brain is a highly distributed set of cortical and subcortical regions
organized into two main networks: a ventral perception network involved
in the detection and evaluation of emotional stimuli, and a dorsal regulation network
involved in self-regulatory processes and cognitive regulation of emotion.



To take into account both emotional and social roles of the amygdala, Sander et al10 suggested that the amygdala implements processes related to the detection and evaluation of the self-relevance of stimuli. According to this proposition, “the specificity and differentiation of emotion mostly relies upon the cognitive evaluation of the meaning and the consequences of a relevant external event within a specific context and relationship to one’s own goals.”10 Self-relevance relates here to goals, needs, and concerns. This could explain why the amygdala response is preferential for some stimuli over others in specific contexts, depending on the subject’s motivation. For instance, response to food stimuli in the amygdala would increase if participants are hungry.11

Social signals and self-relevance

The detection, monitoring, and evaluation of social signals are essential for individuals to navigate the social world and social signals may indicate the presence of self-relevant stimuli in the environment. For instance, negative social signals, such as social exclusion, are associated with intense emotional responses and behavioral changes. To be socially excluded is to be rejected, ignored, or devaluated by others. Social exclusion may result from several social situations including, for instance, forced separation from a loved one, loss of a job, or being ostracized or criticized. Most people have experienced episodes of social exclusion in their lives.

A seminal functional magnetic resonance imaging (fMRI) study has illustrated that social exclusion literally induces psychic pain with activation of the ventrolateral prefrontal cortex, anterior insula, and anterior cingulate cortex, regions classically involved in physical pain.12 In this study, the authors used a Cyberball paradigm, in which participants were led to believe that they were participating in a ball game with real individuals over the Internet, whereas the actions of the other two players were preprogrammed to exclude the participant after a few throws.13 Several studies have replicated these results on social exclusion and a recent meta-analysis by our group (Rotgé et al, in preparation) showed that social exclusion induced by the Cyberball task mainly activates the subgenual cingulate cortex, a region involved in the production of negative emotion and the pathophysiology of major depression.

Social exclusion has a profound psychological and physiological impact, as it threatens fundamental human needs, such as sense of self-esteem, sense of belonging, meaning of existence, and sense of control.14 On a cognitive level, social exclusion may dampen self-esteem, which, according to the sociometer theory, is a gauge that measures the quality of people’s relationships with others and alerts the individual to the possibility of social exclusion.15 Consistent with this formulation, in a recent fMRI study in which subjects received feedback from peers on how they were liked or disliked, Somerville et al16 showed that the level of self-esteem modulated reactivity of the ventromedial prefrontal cortex and amygdala to positive and negative social feedback. Decreased self-esteem induced by social exclusion may affect self-evaluation and increase self-focused attention (“Am I likable? Why don’t others like me?”). The by-product of self-evaluation may subsequently increase people’s need to pay more attention to others in order to detect self-relevant stimuli and to reconnect with others.

Overall, this emphasizes the importance of social inclusion and social acceptance for emotional well-being.

Neuropharmacology of emotion

The discovery of drugs such as imipramine and iproniazid, which elevate mood in patients with depression, revolutionized the treatment of mood disorders. Antidepressant drugs and their mechanisms of action on two principal neurotransmitters, ie, serotonin and norepinephrine, contribute to the development of research on the chemistry of mood and emotion.17

Beyond their abilities to correct depressive symptoms in patients with major depression, antidepressants modulate the processing of emotional stimuli in healthy subjects. In a seminal study, Harmer et al18 showed in healthy volunteers that a single dose of the selective serotonin reuptake inhibitor (SSRI) citalopram enhanced the recognition of happy and fearful faces. One-week administration of the same drug in healthy volunteers facilitated the processing of positive emotional information with a better memory for self-related positive personality traits. In this study, the authors used a memory task where subjects encoded positive and negative personality traits while making a self-referential judgment on these words. Citalopram also induced a decrease in recognition of negative facial expressions. The short-term emotional effects of citalopram occurred without any changes in mood. Several studies have replicated these findings with other SSRIs or using different antidepressant drugs with different mechanisms of action. For instance, reboxetine, a selective norepinephrine reuptake inhibitor, and venlafaxine, a serotonin-norepinephrine reuptake inhibitor showed slightly similar effects on emotion processing in healthy subjects.19 According to a recent review, serotoninergic agents may target negative emotion whereas noradrenergic agents target positive emotion.20

Harmer et al21 have suggested that pharmacological antidepressant interventions and manipulation of serotonin and/or norepinephrine may exert their therapeutic effects through the correction of emotional biases of depression. Two emotional biases have been described in major depression: (i) the tendency to prioritize the processing of negative emotional stimuli and (ii) increased self-focus, the tendency to relate to one’s self emotional or neutral stimuli. The early correction of these emotional biases and exposure to environmental stimulation would over time and experience reduce depressive symptoms.22 This effect of antidepressants, such as SSRIs, on the processing of emotion mirrors the effect of serotonin depletion on sadness.23

In both healthy and depressed patients, self-focus involves the medial prefrontal cortex, whereas the processing of negative information mainly involves the amygdala.24,25 SSRIs in healthy subjects modulate the medial prefrontal cortex and amygdala regions, an effect consistent with the distribution of serotoninergic receptors in limbic pathways.26

There is renewing interest in the effects of antidepressants on anhedonia, a loss of positive emotion and a core feature of depression.27 It is now well established that dopamine is associated with reward processing and learning. Long-term treatment with nearly all antidepressants increases responsiveness to dopaminergic stimulation, perhaps due to enhanced signaling through dopamine D2 or D3 receptors.28 However, it has been suggested that long-term treatment (ie, more than two months) with an SSRI may induce a blunted response to positive and negative emotional stimuli, likely explained by dopamine depletion.29

Agomelatine is a new antidepressant and a potent agonist of melatonergic receptors MT1 and MT2 and an antagonist of the serotonin 2C (5-HT2C) receptor.30 This antagonistic action on 5-HT2C receptors facilitates dopamine release in the prefrontal cortex, without effect on extracellular levels of serotonin, indicating that agomelatine may show selective effects on positive emotion. It has also been demonstrated recently that the melatonergic part of agomelatine is necessary for the enhancement of dopamine neurotransmission.31 In healthy volunteers, Harmer et al32 showed that 7 days’ administration of agomelatine improved memory for self-encoded positive emotional words. These results are consistent with clinical studies indicating beneficial effects of agomelatine in anhedonia during treatment of major depression.33

The hedonic component of reward at the time of delivery of rewarding stimuli involves endogenous opioids. Endogenous opioids are a family of neuropeptides including endorphins, enkephalins, dynorphins, and orphanin FG, as well as their various receptor subtypes.34 Endogenous opioid receptors are distributed in cortical and subcortical regions, including the dorsal anterior cingulate cortex, the ventromedial prefrontal cortex, the orbitofrontal cortex, and the amygdala. Opioid peptides are major players in the experience of pleasure and positive emotion. Moreover, drugs derived from morphine are sometimes prescribed for treating psychic pain in severe depressed patients with melancholic features. It is noteworthy that genetic polymorphisms of opioid receptors modulate psychic pain and brain responses to social exclusion, suggesting that morphine might be used for remediation of distress induced by social separation.35

Oxytocin and social behaviors

We have emphasized that basic social stimuli (ie, gaze) or more complex social stimuli (ie, social approbation or criticism) are potent sources of emotion and that these stimuli signal self-relevant information in the environment. Can we modulate with pharmacological agents the tight relationships between social stimuli processing and emotional responses?

It is well known that oxytocin (OT) is a hormone with a unique role in parturition, milk letdown, and protection against intruders. Recent findings have emphasized the OT effect on the brain and its major role in social cognition.36 fMRI studies combining cognitive or emotional tasks with intranasal administration of OT demonstrate that OT exerts its effect on social function through the modulation of amygdala response to social and emotional stimuli. For instance, Domes et al37 demonstrated that intranasal OT reduced the right amygdala’s activation in response to angry, happy, or fearful facial expression. Moreover, OT has been shown to dampen amygdala activity when faces display a more socially salient (and self-relevant) signal, such as direct gaze compared with averted gaze.38 Likewise, OT increases gaze to the eye region of human faces, an essential feature to detect and identify emotion. Finally, OT improves memory for faces, with a bias for happy faces, which facilitates the establishment of social memory and links.39

Faces are a special category of visual stimuli that induces social approach or social withdrawal. By attenuating amygdala activity in response to negative facial expression, OT may allow more accurate appraisal of social signals and promote social approach. This is consistent with results from studies with neuroeconomic paradigms and economic games demonstrating that intranasal OT increases trust and abnormal acceptance of betrayal behavior.40 It is beyond the scope of this review to discuss evidence on the unique role of OT in social affiliation and attachment. However, we want to mention here that OT influences emotional responses and behaviors following social rejection. Thus, in two studies with the Cyberball task, subjects receiving intranasal OT had normal emotional responses to social exclusion, but showed an increased desire to reconnect with others and demonstrated increased helping behaviors.41,42 Overall, the prosocial and positive emotional biases induced by OT put emphasis on the therapeutic potential of this neuropeptide in mental disorders marked by emotional and social impairment.

Conclusion

The emotional brain has evolved to process salient stimuli in the environment. Within the emotional brain, the amygdala structure plays a major role in the detection of social stimuli that signal self-relevant and important information in the environment. Many antidepressants regulate the activity of the amygdala through modulation of the neurotransmitters norepinephrine, serotonin, and dopamine. We have discussed the role of neuropeptides such as OT in social behavior. OT, by regulating the response of the amygdala to social signals, induces positive emotional bias and promotes prosocial behaviors. OT activity is associated with activity of dopamine neurotransmitters, suggesting the complex interplay between neuropeptides and neurotransmitters for regulation of emotion. The studies of chemistry and neuroanatomy of emotion will contribute to unravel the functional architecture of the social and emotional brain. These studies will highlight the role of new pathophysiological pathways in mental disorders and will help to define new treatments. _


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Keywords: amygdala; emotional brain; neuropharmacology; oxytocin; self-relevance; social brain; social signals