**4. A model for the regulation of pleasure and happiness**

### **4.1. Cortical regulation of behaviour**

Behaviour can be considered a mechanism where the brain manages input to create a specific output, which enables the organism to adapt to changed circumstances within the biosphere. In humans, input from the senses is primarily translated within the cerebral cortex into a specific behavioural output. Sensory information is processed within the posterior cerebral cortex in a stepwise fashion [25, 67]. Specific information is integrated with other sensory information and transmitted from the primary sensory cortex to the secondary sensory cortex, from there to the association cortex and so on. Within the anterior cerebral cortex, a similar now diverging flow of information occurs, which leads to the activation of specific brain regions, e.g. the motor cortex. Apart from this stepwise analysis, other fibres connect to more distant regions that run in parallel. Every neural connection is capable of learning, due to the characteristics of glutamatergic transmission, which can increase or decrease the sensitivity of connecting synapses by inducing long-term potentiation (LTP) or long-term depression (LTD). Therefore, the cortex can 'learn' to transmit specific sensory information to a specific output unit via a 'preferred' cortical tract. Accordingly, the cerebral cortex learns to interpret sensory information and produce a specific behavioural response.

#### **4.2. Subcortical regulation of behaviour**

Although this process is expedient, it can be expected to be highly sensitive to dysregulation, both in routine functions and in learning. Therefore, a parallel circuit has evolved, which includes subcortical structures. All processing units in the cerebral cortex also send information to the basal ganglia [68]. The route through the basal ganglia and thalamus leads to corresponding processing units in the anterior cortex [69]. This parallel circuit has stimulatory and inhibitory pathways, and its glutamatergic synapses can also induce LTP and LTD. Therefore, this parallel route through the basal ganglia enables the brain to correct serially transmitted information, when it arrives at the 'final' destination. Moreover, the connection through the basal ganglia is convergent [69]. Hence, the processing units in the posterior and anterior cortices and their outputs converge within this subcortical circuit to the same output unit. Again, the 'learning' ability of glutamatergic synapses within this framework makes it possible to process a constantly varying input and produce very complex, sophisticated output patterns, in a reproducible, precise fashion.

In addition, the amygdala affects the activity of the ventral tegmental area through a pathway including the lateral habenula. We want to suggest that anteromedial division of the bed nucleus of the stria terminalis contains the human limbic equivalent of the lamprey habenula-projecting globus pallidus (GPh). This area receives input from GABAergic projection neurons originating within the central amygdaloid nucleus [40] and gives output to medial and caudal regions of the lateral habenula [41, 42]. When this limbic GPh is functioning similar to lamprey GPh, the amygdala can inhibit reward-seeking behaviour by stimulating the pathway, which runs from corticoid amygdala, through central amygdala, anteromedial bed nucleus of the stria terminalis, lateral habenula and rostromedial tegmental nucleus to ventral

In conclusion, the amygdaloid complex plays an essential role in fear and anger control, perception and attention to relevant sensory input (including, e.g. facial expression in order to allow adequate social functioning), by validating this input with respect to their significance for reward-seeking and misery-fleeing behaviour. The activity of this emotional response is regulated through a pathway including the habenula, in which two routes can be distinguished: one including the hippocampus, septal nuclei and medial habenula and the other

Behaviour can be considered a mechanism where the brain manages input to create a specific output, which enables the organism to adapt to changed circumstances within the biosphere. In humans, input from the senses is primarily translated within the cerebral cortex into a specific behavioural output. Sensory information is processed within the posterior cerebral cortex in a stepwise fashion [25, 67]. Specific information is integrated with other sensory information and transmitted from the primary sensory cortex to the secondary sensory cortex, from there to the association cortex and so on. Within the anterior cerebral cortex, a similar now diverging flow of information occurs, which leads to the activation of specific brain regions, e.g. the motor cortex. Apart from this stepwise analysis, other fibres connect to more distant regions that run in parallel. Every neural connection is capable of learning, due to the characteristics of glutamatergic transmission, which can increase or decrease the sensitivity of connecting synapses by inducing long-term potentiation (LTP) or long-term depression (LTD). Therefore, the cortex can 'learn' to transmit specific sensory information to a specific output unit via a 'preferred' cortical tract. Accordingly, the cerebral cortex learns to interpret

Although this process is expedient, it can be expected to be highly sensitive to dysregulation, both in routine functions and in learning. Therefore, a parallel circuit has evolved, which includes subcortical structures. All processing units in the cerebral cortex also send information to the

including central amygdala, bed nucleus of the stria terminalis and lateral habenula.

**4. A model for the regulation of pleasure and happiness**

sensory information and produce a specific behavioural response.

tegmental area (**Figure 5**).

120 Schizophrenia Treatment - The New Facets

**4.1. Cortical regulation of behaviour**

**4.2. Subcortical regulation of behaviour**

This organisation of connections is well known as the extrapyramidal system, which regulates cognition and movements [70]. In our mental function model, we suggest that a similar organisation can be distinguished within the limbic cortex, although here, the structure is more complex and less modular, due to the ancient origins of these structures. To simplify, we propose the corticoid regions of the amygdala to represent the primary limbic cortex. These corticoid regions are connected with many other cortical areas. The superficial (cortical) and deep (basolateral) corticoid regions of the amygdaloid complex can be considered input areas, and the centromedial (ganglionic or nuclear) region can be considered the output area of the amygdaloid complex [46]. In the earliest vertebrate ancestors, the striatum directly manages autonomic and motor control centres in lower diencephalon and brainstem [2]. In the lamprey very limited connectivity exists between pallial (cortex) areas and diencephalic and brainstem control centres. This is also true within the corresponding system in mammals: only light connectivity has been found between corticoid amygdalar areas and the hypothalamus or brainstem [45]. The stria terminalis connects the 'striatal' centromedial amygdala with its corresponding pallidum (bed nucleus of the stria terminalis) and also directly with the hypothalamus and brainstem [45]. Although the majority of output from the limbic basal ganglia flows to the brainstem, also connectivity exists with the (dorsal) thalamus and cerebral cortex. This is true for the output of the bed nucleus of the stria terminalis [40, 49] and for the output of the hypothalamus, which is probably related to affect the motor output of higher vertebrates, including humans, by inducing the drive to seek food, warmth, comfort, etc., or to escape from pain, thirst, misery, etc. [55]. This finally results in a limbic cortical-subcortical circuit that is more complex, but nevertheless essentially similar, to the well-known extrapyramidal system, provided that one realises that the cerebral neocortex was included within the circuit on a later evolutionary moment (**Figure 6**).

Hence, two types of cortical-subcortical circuits may be distinguished: extrapyramidal and limbic circuits. These systems have different ganglionic relay stations: the extrapyramidal circuit includes the dorsal and ventral striatum, and the limbic circuit includes the extended amygdala (as defined in Ref. [34]). These circuits are linked to each other by means of the nucleus accumbens, which serves as an interface between the two circuits [71]. The core part belongs to the extrapyramidal and the shell parts more to the limbic circuit. The extrapyramidal circuit regulates rational, cognitively constructed, skilled behaviour, which is often goal oriented and includes decision-making. The limbic circuit regulates emotional (instinctive and automatic) behaviours, which are often defensive, and this regulation includes (attentive)

**Figure 6.** Limbic cortical-subcortical regulatory circuit. BST, bed nucleus of the stria terminalis; CM, centromedial amygdala; orange, extended amygdala; dark yellow, diencephalon and brainstem; and light yellow, corticoid amygdala and neocortex.

salience. The two systems influence each other in a reciprocal (yin-and-yang-like) fashion; moreover, both systems can inhibit or activate, as the situation demands. It is generally accepted that the prefrontal cortex (PFC) is in control of selecting the appropriate response [72, 73]. The dorsolateral PFC is particularly important for controlling rational responses, and the medial PFC controls emotional responses. Within the medial PFC, the orbitofrontal cortex (OFC) plays a particularly noteworthy role, because it is essential for regulating the direction of motivation [74].

#### **4.3. Motivation to reward-seeking and misery-fleeing behaviour**

Behaviour can be a reaction to an influence in the environment, or it can also be generated by the individual. To enable this proactive instead of reactive behaviour, motivation comes into play [73, 75]. Three stages of behavioural motivation can be distinguished: general motivation, initiative and selective precedence conveying (via inhibition). The OFC plays a significant role in regulating these processes by delivering input to the ventral striatum, the anterior cingulate cortex and the amygdala [74].

Although the extrapyramidal and limbic circuits regulate two different types of behaviour (constructed/rational and instinctive/intuitive, respectively), the individual must be highly motivated to express these conducts. This motivation requires the involvement of two specific structures: the NAcbC and the NAcbS (**Figure 7**) [71, 76, 77]. The NAcbC motivates the individual to show behaviour that may lead to a feeling of reward. The NAcbS motivates the individual to show behaviour that may lead to escape from adversity [6]. When high stimulation of these motivations suddenly ceases as its goal is obtained, the individual experiences feelings of pleasure (NAcbC) or feelings of happiness (NAcbS). Therefore, we disCircuits Regulating Pleasure and Happiness in Schizophrenia: The Neurobiological Mechanism of Delusions http://dx.doi.org/10.5772/66412 123

**Figure 7.** Stimulation of the core and shell of the nucleus accumbens (adapted from Ref. [76] with permission of the author). VTA, ventral tegmental area; LC, locus coeruleus. Red arrows, glutamatergic; blue arrows, GABAergic; grey arrows, dopaminergic; and green arrow, adrenergic.

tinguish between circuits that regulate pleasure and circuits that regulate happiness [6]. We have hypothesised that the best candidate for the perception of feelings of pleasure (reward) and happiness (euphoria) would be the insular cortex [7]. The posterior part of the insula contains areas for gustation, thermo-sensation, pain, somato-sensation and viscera-sensation [15]. Indeed, the insular cortex has been demonstrated to be involved in processing emotions like anger, fear, happiness, sadness or disgust and has been shown to display treatmentresponsive changes of activity in different mood disorders [78].

#### **4.4. Brainstem regulation of behaviour**

salience. The two systems influence each other in a reciprocal (yin-and-yang-like) fashion; moreover, both systems can inhibit or activate, as the situation demands. It is generally accepted that the prefrontal cortex (PFC) is in control of selecting the appropriate response [72, 73]. The dorsolateral PFC is particularly important for controlling rational responses, and the medial PFC controls emotional responses. Within the medial PFC, the orbitofrontal cortex (OFC) plays a particularly noteworthy role, because it is essential for regulating the direction

**Figure 6.** Limbic cortical-subcortical regulatory circuit. BST, bed nucleus of the stria terminalis; CM, centromedial amygdala; orange, extended amygdala; dark yellow, diencephalon and brainstem; and light yellow, corticoid amygdala

Behaviour can be a reaction to an influence in the environment, or it can also be generated by the individual. To enable this proactive instead of reactive behaviour, motivation comes into play [73, 75]. Three stages of behavioural motivation can be distinguished: general motivation, initiative and selective precedence conveying (via inhibition). The OFC plays a significant role in regulating these processes by delivering input to the ventral striatum,

Although the extrapyramidal and limbic circuits regulate two different types of behaviour (constructed/rational and instinctive/intuitive, respectively), the individual must be highly motivated to express these conducts. This motivation requires the involvement of two specific structures: the NAcbC and the NAcbS (**Figure 7**) [71, 76, 77]. The NAcbC motivates the individual to show behaviour that may lead to a feeling of reward. The NAcbS motivates the individual to show behaviour that may lead to escape from adversity [6]. When high stimulation of these motivations suddenly ceases as its goal is obtained, the individual experiences feelings of pleasure (NAcbC) or feelings of happiness (NAcbS). Therefore, we dis-

**4.3. Motivation to reward-seeking and misery-fleeing behaviour**

the anterior cingulate cortex and the amygdala [74].

of motivation [74].

and neocortex.

122 Schizophrenia Treatment - The New Facets

The activities of the NAcbC and NAcbS, in turn, are regulated by monoaminergic nuclei within the midbrain. These nuclei transmit signals through dopaminergic (ventral tegmental area), adrenergic (norepinephrine, locus coeruleus) and serotonergic (raphe nuclei) tracts. In addition to their direct regulation of the NAcbC and/or NAcbS [6, 7], these monoaminergic nuclei regulate the activity of other, first relay station, basal ganglia and important parts of other areas in the forebrain. Therefore, it may be concluded that behavioural output is controlled at three levels within the brain. The highest level is the cerebral cortex (isocortex, limbic cortex, corticoid (cortical, basolateral) amygdala and hippocampal complex). The second level is the subcortical forebrain (dorsal striatum, ventral striatum, extended amygdala). The third level of control is the midbrain (monoaminergic regulation centres).

#### **4.5. Habenular regulation of behaviour**

As part of our model, we suggest that a fourth regulatory system exists, the habenula, which connects the cerebral cortex and midbrain systems (**Figure 8**) [6, 7]. Based on the regulation of appetitive behaviour in lampreys, we suggest the lateral habenula also to have an important regulatory function in humans [6]. In the lamprey, when a behaviour is particularly rewarding, the lateral habenula promotes this behaviour by intensifying stimulation of the phylogenetic homologue of the ventral tegmental area. However, when the reward is smaller than expected or absent, the behaviour is inhibited by affecting the ventral tegmental area equivalent of the lamprey. The medial habenula appears to play a similar role with respect to misery-fleeing behaviour as the lateral habenula with respect to reward-seeking activities.

The habenula belongs to the epithalamus, which also harbours the pineal gland and the stria medullaris. The habenula's projections to the midbrain were very well conserved during vertebrate evolution [7, 79], but its input structures are not so easily to be traced back from the anatomy of earlier vertebrates. The septum, particularly the medial septum and the adjacent nucleus of the diagonal band of Broca, is the main input structure of the medial habenula [5, 62, 63]. We suggest that by means of this pathway the corticoid amygdala (cortical and basolateral areas of the amygdaloid complex) gives input to the medial habenula (via hippocampal complex and fornix) (**Figure 5**). Although probably an important part of the functional

**Figure 8.** Simplified representation of the connectivity through the epithalamus (adapted with permission from Ref. [79]). GPh, habenula-projecting globus pallidus; IPN, interpeduncular nucleus; RMTg, rostromedial tegmental nucleus; SNc, substantia nigra, pars compacta; and VTA, ventral tegmental area. GPh depends upon the cortical-subcortical circuit being considered. GPh is localised within the bed nucleus of the stria terminalis in the limbic circuit, within the ventral pallidum concerning the motivational circuit and within the globus pallidus (border region, GPb) within the extrapyramidal circuit.

input to the lateral habenula has not yet been elucidated, this nucleus is known to receive excitatory input from the preoptic area, lateral hypothalamus and globus pallidus and from anterior cingulate and the medial prefrontal cortex [5, 80, 81]. Moreover, the lateral habenula also receives strong GABAergic innervations from various brain regions [82]. In addition, the medial habenula is directly giving input to the lateral habenula [83]. The striatopallidal (extended) amygdala is heavily (directly and indirectly) connected to the lateral hypothalamus. We suggest that the activity of the lateral habenula is modulated by this pathway. In addition, the bed nucleus of the stria terminalis contains the human equivalent of lamprey habenula-projecting globus pallidus, as we have argued above.

The corticoid amygdaloid complex is in a perfect position to increase the magnitude of misery-fleeing (happiness) over reward-seeking (pleasure) behaviour. This limbic cortex regulates the activity of monoaminergic centres within the midbrain by affecting the medial and lateral habenula. In addition, the amygdaloid complex regulates instinctive motivation to gain certain essential prerequisites to maintain life (such as food, water, warmth, etc.) by affecting the lateral hypothalamus.

#### **4.6. Model for the regulation of behaviour**

**4.5. Habenular regulation of behaviour**

124 Schizophrenia Treatment - The New Facets

extrapyramidal circuit.

As part of our model, we suggest that a fourth regulatory system exists, the habenula, which connects the cerebral cortex and midbrain systems (**Figure 8**) [6, 7]. Based on the regulation of appetitive behaviour in lampreys, we suggest the lateral habenula also to have an important regulatory function in humans [6]. In the lamprey, when a behaviour is particularly rewarding, the lateral habenula promotes this behaviour by intensifying stimulation of the phylogenetic homologue of the ventral tegmental area. However, when the reward is smaller than expected or absent, the behaviour is inhibited by affecting the ventral tegmental area equivalent of the lamprey. The medial habenula appears to play a similar role with respect to misery-fleeing behaviour as the lateral habenula with respect to reward-seeking activities. The habenula belongs to the epithalamus, which also harbours the pineal gland and the stria medullaris. The habenula's projections to the midbrain were very well conserved during vertebrate evolution [7, 79], but its input structures are not so easily to be traced back from the anatomy of earlier vertebrates. The septum, particularly the medial septum and the adjacent nucleus of the diagonal band of Broca, is the main input structure of the medial habenula [5, 62, 63]. We suggest that by means of this pathway the corticoid amygdala (cortical and basolateral areas of the amygdaloid complex) gives input to the medial habenula (via hippocampal complex and fornix) (**Figure 5**). Although probably an important part of the functional

**Figure 8.** Simplified representation of the connectivity through the epithalamus (adapted with permission from Ref. [79]). GPh, habenula-projecting globus pallidus; IPN, interpeduncular nucleus; RMTg, rostromedial tegmental nucleus; SNc, substantia nigra, pars compacta; and VTA, ventral tegmental area. GPh depends upon the cortical-subcortical circuit being considered. GPh is localised within the bed nucleus of the stria terminalis in the limbic circuit, within the ventral pallidum concerning the motivational circuit and within the globus pallidus (border region, GPb) within the In conclusion, the extrapyramidal and limbic cortical systems regulate cognitive (rational) and instinctive behaviours, respectively. The intensity of behaviour that ultimately leads to reward is controlled by the cortico-striato-thalamo-cortical (CSTC) circuit that includes the NAcbC. The intensity of behaviour that ultimately leads to safety is controlled by the CSTC circuit that includes the NAcbS. On the temporal side of the brain, the amygdala determines

**Figure 9.** Overview of model for the regulation of behaviour.

the appropriateness of flight, fight, or appetitive responses. Based on attentive salience, it initiates the proper emotional component of behaviour. On the dorsal side of the brain, the caudate nucleus determines the suitability of the available repertoire of skilled behaviours; it selects the proper motor response to achieve the intended goals. The motivation to express these behaviours is regulated by monoaminergic centres within the midbrain. In turn, these monoaminergic centres are regulated by old and new parts of the cerebral cortex through a dorsal connection that travels through the medial and lateral habenula. Of note, the monoaminergic centres are also regulated by the medial prefrontal cortex via a direct ventral connection, which possibly travels through the medial forebrain bundle [7] (**Figure 9**).
