Phylogenetically, the limbic system comprises the oldest parts of the telencephalon and the subcortical structures that derive from it. In a simplified view, brain function can be considered the product of the neocortex and the limbic system, which complement each other to generate human behavior with purpose and objective [1]. In this process of complementation, the neocortex mainly regulates precise spatiotemporal communication with the environment and executes cognitive and stereognostic functions, producing precise motor outputs (Fig. 6.1).

The limbic system has a primordial link with emotionality and motivation for action (reinforcement/reward system) and with the process of learning and memory (involving a high affective content, remembering only what we are interested in emotionally) [2]. The limbic system gives the information derived from the inner and outer world its particular emotional meaning [3]. Hence, its role as a last level in the autonomic motor hierarchy.

Another aspect to consider is the role of the limbic system as a selective inhibitor of impulses and basic needs, immediately related to survival. The selective inhibition of certain circuits of a nontopographic character, but relative to memories loaded with internal meaning can prevent the activation of (too many) lateral ways and thus allows the exclusive creation of relevant temporospatial associations (emotional learning). A lateral dispersion in these highly-interconnected circuits would lead to phenomena of resonance, overabundance, and/or blockade (obsessive ideas, epileptic seizures, anxiety, etc.). From a physiological perspective, the limbic system is able to carry out tasks of this type, as it repeats the basic scheme, present in many other brain structures, that different sources of information, complementary and/or opposite, are confronted in the same structure or nodal point, through intermixed circuits [4].

A cortical portion and a subcortical portion are distinguished in the limbic system:

James Papez’s ideas about the limbic system, enunciated in the 1930s, have been confirmed by recent neuroimaging studies of brain locations [5]. For Papez, the limbic system is part of the circuit of emotional expression. As it was known that the hypothalamus was fundamental for the expression of emotional reaction programs, Papez postulated that the way in which the cerebral cortex modifies, and where these programs become conscious, is through corticohypothalamic connections via the cingulate gyrus and the hippocampus [6]. According to Papez’s hypothesis, the hippocampus processes emotional information and projects to the mammillary bodies through the fornix. The hypothalamus, in turn, provides information to thalamic nuclei (through the mammillothalamic tract) and from these to the cingulate gyrus [7]. Subsequently, MacLean extended this scheme to include in the limbic system hypothalamic areas, the septal area, the nucleus accumbens , neocortical areas (orbitofrontal cortex), and the amygdala. The circuit of Papez, and the most recent modifications to it, are summarized in Fig. 6.5.

The afferent and efferent connections of the limbic system are extremely complex [8]. As we have mentioned, the most outstanding fact is a massive reciprocal connection with the hypothalamus. The hypothalamus communicates with the hippocampus and the septum through the fornix, with the amygdala through the stria terminalis and ventral amygdalofugal pathway, and with the portions of the olfactory brain through the central forebrain bundle.

Although there is no complete agreement about the anatomical composition of the limbic system , it is accepted that a set of structures located in the medial portion of the telencephalon, highly interconnected with each other, share direct projections to the hypothalamus, thus regulating the neuroendocrine, autonomic, and behavioral processes associated with this portion of the diencephalon [5].

The hippocampus is a portion of the cerebral cortex that forms a kind of horn along the curvature of the lateral ventricle (Fig. 6.6). It is subdivided into the hippocampus proper, or Ammon’s horn, the dentate gyrus, and the subicular complex. The connections to hippocampal formation come from the entorhinal cortex, contralateral hippocampus, subcortical structures such as the medial septum, certain raphe nuclei, and the locus coeruleus (LC) from the brainstem. The hippocampus projects back to the subicular region and the hippocampus, in turn, extends over other cortical areas, the anterolateral thalamus, the mammillary bodies, the ventromedial and anterior nuclei of the hypothalamus, and the lateral septum. Through the fornix, the hippocampus projects over the lateral septum (Fig. 6.5) [2, 4].

Thus, the limbic system presents multiple excitation circuits, neuronal substrates of importance for both emotionality and memory. As we describe later, the fixation of memory engrams depends on the simultaneous activation of limbic system pathways [3].

At the end of the nineteenth century, Jackson proposed that a function is often represented at various levels of the nervous system. The higher levels, having appeared later, mediate the function in a more precise form than the lower levels. In addition, they are more easily excited and usually have an inhibitory action on lower levels. Therefore, a lesion of the higher levels releases the inferior levels of inhibition and allows behavioral expression [6].

With this hierarchical notion in mind, MacLean proposed in the 1950s, that the brain of modern mammals is the sum of three superimposed brains, acquired during evolution (Fig. 6.7). For MacLean, to the visceral and appetitive of the primitive reptiles, an emotional brain was added, whose functions would be assumed, finally, by the limbic system of birds and, mainly, mammals [6]. There would be:

However, it would be naive to take this functional division as absolute. In fact, the SNC operates with a unique behavior resulting from the function of the three hypothetical levels [1].

The limbic system determines the appearance of an inner world, a concept that is superimposed in part, but not equivalent, to that of internal environment. The internal world is not based on the presence of interoceptors or the development of homeostatic mechanisms, but on the development of internal signals of identity. For example, being able to inhibit certain desires (avoiding a food source in the presence of a predator) is the behavioral expression of the existence of internal circuits capable of generating states in which information from extero- and interoceptors is subjected to a scrutiny of memories or plans not merely contingent or immediate. In this sense, the limbic system is a powerful inhibitor of desires and needs related to the survival of the individual, depending on the conditions of the internal environment and the external environment (physical and social) [9].

The amygdala plays a major role in the limbic function [2, 10]. It is a subcortical structure located at the tip of the temporal lobe and continuous with the uncus of the parahippocampal gyrus (Fig. 6.8). The amygdala is composed of several nuclei, reciprocally connected with the hypothalamus, hippocampus, neocortex, and thalamus (Fig. 6.9). Despite the important olfactory input it receives, the amygdala is not essential for olfactory discrimination [3].

In 1939, Klüver and Bucy described the bilateral lesion of the amygdala nuclei and part of the anterior pole of the temporal lobe as producing a behavioral syndrome in monkeys characterized by: (a) psychic blindness; (b) exaggerated oral exploratory behavior; (c) temerity or loss of fear, because, for example, they play with snakes, which they normally fear; (d) excessive indiscriminate eating behavior (hyperbulimia); (e) increased sexual behavior (self, homo-, and heterosexual); (f) hypermetamorphosis, or a tendency to react to any visual stimulus. This clinical picture suggests that, under normal conditions, the amygdala functions as an inhibitory center, preventing reckless or inappropriate behaviors in relation to feeding, sex, and exploration of the environment [11].

Given the diversity of the afferents received by the amygdala from the limbic cortex and the rest of the association cortex, in addition to its dense projection on the hypothalamus nuclei, it is easy to accept the guiding role of the amygdala for the correct structuring of most available sensory information. Thus, the pioneering study by Klüver and Bucy showed the involvement of the amygdala in numerous emotional processes, in which a complex elaboration and association of stimuli from different sensorial sources are carried out.

The electrical stimulation of the amygdala produces effects on the ANS similar to those induced by stimulation of the hypothalamus [7]. Primarily, stimulation of the central amygdala produces changes in BP and heart rate, motility, and gastrointestinal secretions, mydriasis, piloerection, etc. Stimulation of the corticomedial amygdala produces an increase in the secretion of ACTH and gonadotrophins, whereas the stimulation of the basolateral portion in some cases inhibits it. Stimulation of the amygdala also induces motor phenomena such as contralateral head spin, masticatory and swallowing movements, or clonic and rhythmic movements that may become convulsive if the stimulus is prolonged [12].

It is characteristic that the effects of stimulation of the amygdala depend on the functional status of the animal, its environment, and the levels of endocrine, metabolic, and autonomic variables. The same stimulus can increase ACTH levels if they are low, but decrease them if they were previously increased. This indicates the important role of context evaluation in emotional response.

The stimulation of the amygdala in humans produces auras with emotional and polysensorial content (“déjà vu,” hallucinations, etc.). In animals, the selective lesion of the amygdala decreases the performance in passive avoidance tests, mainly because of the loss of fear. Animals with a lesioned amygdala show poor affective behavior, with loss of hierarchical rank [3].

Functionally, three groups of nuclei are distinguished in the amygdala (Fig. 6.9) [2]:

Thus, the corticomedial amygdala participates in endocrine and behavioral functions related to sexual activity, the central amygdala modulates brainstem nuclei with somatic and autonomic motor responses, and the basolateral amygdala participates in processes of sensorial and behavioral association. Through the amygdala, affective behaviors that have proven to be appropriate on previous occasions are induced.

The central nucleus is closely related anatomically and functionally to the lateral hypothalamus and to various structures of the brainstem, such as NTS and PBN, which, in turn, participate in gustatory, cardiorespiratory, and visceral functions. The corticomedial portion and the periamygdala cortex receive afferents from the main and accessory olfactory bulb and project to the olfactory cortex. The basolateral portion , which is more phylogenetically modern, receives afferences from the association cortex, especially of the inferior (visual) temporal gyrus, upper temporal (acoustic), and lobe of the insula (somatosensory). It is also closely related to the prefrontal orbitomedial cortex and to the dorsomedial nucleus of the thalamus. Altogether, the amygdala nuclei project, through the stria terminalis and the ventral pathway, to various areas of the hypothalamus, apart from other cortical and subcortical structures (Fig. 6.10).

The concept of “extended amygdala ” defines the mesolimbic and mesocortical circuits involved in the hedonic response (pleasure) [13]. The neurons of the amygdala respond preferentially to sensory stimuli loaded with an emotional tone, i.e., related to situations of reward or punishment.

The amygdala participates in the learning process, particularly when it comes to the association of a stimulus with an emotional response. This function is so important that we recognize today an “emotional memory ,” with mechanisms different from the “cognitive memory ” (Figs. 6.11 and 6.12) [3]. The most conclusive contemporary evidence for the involvement of the amygdala and other limbic structures in emotional behavior has been given by PET and fMRI in individuals with affective diseases and in normal individuals in situations of anxiety [14].

The human amygdala mediates interaction between the body and the brain during affective processing. The amygdala supports the perception of fear signals and threat and its activity correlates with the emotional intensity rating of affective pictures including facial expressions. Outputs from the amygdala innervate hypothalamic and brainstem autonomic circuits to trigger autonomic arousal responses to emotional challenges, particularly threats [7]. Amygdala-induced autonomic arousal is expressed as increased sympathetic activity and/or decreased heart rate variability. The amygdala is also sensitive to feedback from the periphery regarding the state of bodily arousal.

By means of various procedures (electrophysiological, autoradiographic, immunohistochemical, functional neuroimaging), the connections through which the limbic system, via the amygdala, regulate the expression of anxiety, have been schematized as follows:

Because it controls emotional behavior, the limbic system controls motivation. Thus, the limbic system determines the appearance of an internal world that integrates the homeostatic functions based on the presence of interoceptors with an elaboration of internal signals of identity [5].

The avoidance of a food source in the presence of a predator is the behavioral expression of the existence of internal circuits capable of generating states in which the information coming from extero- and interoceptors is subjected to verification of the opportunity to execute it or not. It corresponds, as we discussed in Chap. 5, to an allostatic response in which physiological systems fluctuate to meet the demands of external forces. The limbic system is a powerful inhibitor of desires and needs related to the survival of the individual, depending on the conditions of the internal environment and the outside world, and therefore the main regulator of allostatic responses [2].

During emotion regulation, prefrontal control systems modulate emotion generative systems, such as the amygdala, which is responsible for the detection of affectively arousing stimuli. More specifically, these prefrontal structures include dorsal regions of the lateral prefrontal cortex that have been implicated in selective attention and working memory ; ventral parts of the prefrontal cortex implicated in response inhibition; the anterior cingulate cortex, which is involved in monitoring control processes; and the dorsomedial prefrontal cortex, which is implicated in monitoring the affective state [15]. A typical pattern detected when individuals deliberately regulate affective responses (as in mindfulness meditation) is increased activation within the prefrontal cortex and decreased activation in the amygdala, suggesting that prefrontal cortex projections to the amygdala exert an inhibitory top–down influence [16].

Although it seems difficult to reach an agreement to define what is understood by “emotion,” it is unanimously accepted that in situations that are tense or committed for the individual (for example, the startle that happens before the sudden presence of a predator), a nonspecific activation of the vegetative system (tachycardia, cold sweat, etc.) and the skeletal motor system (expression of terror, fight/flight) occurs, together with a greater or lesser knowledge of the cause of the shock [17].

Faced with an emotion, we can consider the internal, personal nature, which in humans also has a cognitive character. We can also consider an external, behavioral aspect, which serves as a key signal for members of the same species or related species [18].

Of course, the external expression of emotion s is a consequence of the internal aspects. The conflict that arises before the unexpected evolution of a situation, such as the presence of a predator in an unexpected place, is resolved by the activation of certain autonomic and somatic motor manifestations that imply a reevaluation of available sensory data. These motor acts, mediated by both the somatic system and the ANS, are expressive of the state of the inner world [3].

Poor emotional and social adaptation to an environment in constant change characterize limbic system lesions. Without limbic connections and with an intact hypothalamus, cats or monkeys trigger complex behaviors lacking in objective or normal content, for example, the “false rabies,” hyperphagia, and hypersexuality (Klüver-Bucy syndrome) mentioned above.

The limbic system acts through the programs contained in the hypothalamus, as demonstrated by electrophysiological experiments [19]. The electrical stimulation of the amygdala in the experimental animal triggers effects such as those observed after hypothalamic stimulation. Such effects include homeostatic responses and complex autonomic, endocrine, and somatic behaviors.

Bilateral ablation of the amygdala in monkeys eliminates the possibility of social functioning of the animal [20]. They cannot recognize the social meaning of the exteroceptive cues that regulate group behavior, and appear anxious and insecure. This picture is due to the interruption of the flow of information between the parietal–temporal–occipital association cortex and the hypothalamus, which occurs through the limbic system (in this case, the amygdala). The result of this alteration is the suppression of a correct evaluation of the sensorial information in the context of the affective state. Selective lesioning of the amygdaloid nuclei decreases performance in passive-type avoidance tests, probably because of the loss of fear. It should be remembered that in the basolateral amygdala there are numerous receptors for opiate and GABA, the destruction of which causes a change in the thresholds for physical pain and affective reactions. In fact, amygdala-lesioned animals present very poor affective behavior, losing their hierarchical rank in their group, and finally being rejected by it [20].

The close link among the parietal–temporal–occipital association cortex , the hypothalamus, and the limbic system is indicated by the following experiments: (a) amygdala neurons can be activated by stimulation of sensory neocortical areas; (b) temporal lobe epilepsy in humans is accompanied by various emotional, autonomic, and sensorimotor signs. Both functional neuroimaging and clinical observations in humans indicate that the connection: “parietal-temporal–occipital association cortex–amygdala” contains important neuronal substrates of motivated behaviors and emotions. That is, through this system, the sensory information is compared with the contents of memory and thus becomes significant.

Expression of emotions is primarily based on neurovegetative reactions, which are, in part, inherited and typical of the species, and partly acquired during early postnatal age. Innate emotional reactions serve as signals to the congeners and to members of other species, and are therefore of very important adaptive and evolutionary value (Fig. 6.13).

In parallel with this innate element of emotional behavior, an acquired component is identified, resulting from the first stages of contact of the newborn with his mother and the environment that surrounds him. It is through this process that the particularization of emotional responses occurs, and therefore, it influences the type of pathological condition that, if it occurs, is observed in everyone (Fig. 5.​14).

The limbic cortex of a newborn child fixes engrams, depending on the type of emotional stimulation it receives in the early stages of development. Clearly, this is an active interface between neuroscience and psychology. The production of emotions is associated with the cognitive capacity of the species, and therefore with the perception and evaluation of sensorial stimuli in relation to the memory of the lived experience.

The initial works in experimental psychology carried out by Wundt at the end of nineteenth century, led to the description of the relationship between the intensity of the sensorial stimulus and the pleasure or not of the perception. Near the threshold, the stimulus is perceived as neutral, at higher intensities as pleasurable, and at even greater intensities, as unpleasant. That is, the sensorial and hedonic intensity of a given stimulus, for example, a certain taste, are not linearly related [1].

To this hedonic theory of emotion, cognitive factors were later added. According to this interpretation, the intensity of the emotion depends on the level of adaptation of the subject that perceives and its expectation before the stimulus. A relative discrepancy between these elements generates the opposite effect. Studies based on the analysis of facial expression indicated a three-dimensional aspect for emotion: pleasant–unpleasant, attention–inattention, and intensity [21].

One of the most persistent influences on the concept of emotion was that of Charles Darwin, who emphasized its genetic components. Darwin suggested that emotional expressions are evolutionary remnants of previously adaptive behaviors that persist, albeit of no use, in a moderate form (e.g., grinding teeth as a sign of aggression; Fig. 6.14).

William James was the first to propose that emotion consists of bodily changes originating in the perception of the stimulus (Fig. 6.15) [22]. This theory was called James–Lange, because of the contribution made independently by a Danish physician, Carl Lange, to its formulation. According to the James–Lange theory, emotional quality is the result of perceived changes in bodily activity triggered because of sensory perception.

The elucidation of the structure and function of the ANS marked a fundamental milestone in the study of the visceral correlates of emotion. It was Walter Cannon who first established the direct link between emotional activity and sympathetic function. In what Cannon called an “emerging theory of emotion,” he described the sympathetic division of the ANS as the mediator of the reaction to stress. For Cannon, it is the CNS that triggers the emotions and not the bodily changes (Fig. 6.15) [23]. More recently, a cognitive view developed that combines both positions: there is a central effect of production of the emotional by the limbic system, which is fed by body correlates of the emotions (Fig. 6.15) [17]. Improved anatomical and functional description of bidirectional interactions between body and brain has advanced our understanding of emotional and, for some emotions, there is good evidence for specific coupling with autonomically mediated changes in peripheral physiology [24].

The mind and body are intrinsically and dynamically coupled. Perceptions, thoughts, and feelings change, and respond to, the state of the body [10]. Neuroimaging techniques are beginning to detail the neuronal substrates mediating these interactions between mental and physiological states, implicating cortical regions (specifically insular and cingulate cortices) alongside subcortical (amygdala) and brainstem (notably dorsal pons) in these mechanisms [10, 21]. For example, by combining fMRI with carotid stimulation in healthy participants, it was shown that manipulating afferent cardiovascular signals alters the central processing of emotional information (fearful and neutral facial expressions) [25]. Carotid stimulation attenuated activity across cortical and brainstem regions. Modulation of emotional processing was apparent as a significant expression-by-stimulation interaction within the left amygdala, where responses during appraisal of fearful faces were selectively reduced by carotid stimulation. Moreover, activity reductions within insula, amygdala, and hippocampus correlated with the degree of stimulation-evoked change in the explicit emotional ratings of fearful faces. Across participants, individual differences in autonomic state, as assessed by heart rate variability, predicted the extent to which carotid stimulation influenced neural (amygdala) responses during appraisal and subjective rating of fearful faces [25]. Thus, cortical locations of emotional function in man have begun to be defined using PET and fMRI [26–29]. This methodology is also employed to determine the sites and effects of pharmacological treatments [30].

For the physiological detection of emotion, a sensitive, non-invasive indicator is the electrical response of the skin, also known as the psychogalvanic reflex, or electrodermal reflex. The potential or electrical resistance (or conductance) of any part of the body can be quantified through electrodes on the skin. The skin conductance response is a remarkably powerful and informative psychophysiological index [31]. Because it is relatively easy to measure, and provides reliable indices of a wide variety of psychological states and processes, skin conductance response has been one of the most popular aspects of ANS activity used to study human cognition and emotion [31, 32]. The analysis of the variability of the heart rate also allows the evaluation of the sympathetic and parasympathetic response at the thoracic level before different emotional situations (Fig. 4.​13) [33].

Muscle tone is another general peripheral indicator for emotions such as anxiety or fear, particularly at the level of the face and neck muscles. The startle reflex is considered a phenomenon that is closely related to the emotional state of the individual. This reflex consists of an initial blink, with a latency close to 0.04 s. Then, contraction of the skeletal muscles ensues, with a latency of 0.1 s. Finally, after 1 s, more complex signs appear (changes in skin potential, increased BP and heart rate). This sequential motor program is an example of stereotyped reactivity of ANS and the somatic motor system [34].

It must be noted that the different physical and chemical indicators of emotionality used so far simply reflect an overall level of emotional tension and do not discriminate between types of emotions.

The main function of the basal ganglia is to select a particular movement or sequence of thoughts or an autonomic response that is most appropriate for the situation, suppressing any possible other ones [1]. Thus, the basal ganglia play an important role in limbic function.

There are five main components of the basal ganglia (Figs. 6.16 and 6.17): (a) three subcortical nuclei: caudate, putamen, and globus pallidus; (b) a diencephalic component: the subthalamic nucleus of Luys; (c) a mesencephalic component: the substantia nigra and the ventral tegmental area [35].

The caudate and putamen have the same embryological origin, identical cellular types and are fused by their anterior part (to form the striatum). The ventral part of the striatum (ventral striatum or nucleus accumbens) has a functional identity because of its connection with the limbic system. The striatum comprises the entry nuclei to the circuit of the basal ganglia.

The globus pallidus is a diencephalic structure divided into two segments, internal and external (or medial and lateral). The substantia nigra , which is the largest nucleus of the midbrain, comprises a compact dorsal portion (“pars compacta”) of pigmented dopaminergic cells, and a ventral, reticular portion (“pars reticulata”) of nonpigmented GABAergic neurons.

The substantia nigra pars reticulata and the medial (or internal) globus pallidus form a functional unit as the exit sector of the basal ganglia. In these connections, and in the functional relation with the limbic system (ventral striatum), another set of dopaminergic neurons (ventral tegmental area, VTA, or A10), adjacent to the substantia nigra, participates [35].

The main entry to the basal ganglia is at the level of the striated body (caudate–putamen) and the ventral striatum (accumbens; Figs. 6.17 and 6.18). Both the caudate and the putamen receive an important dopaminergic projection of the substantia nigra pars compacta (nigrostriatal pathway). The ventral striatum receives projections from the dopaminergic neurons of the VTA.