Neurobiological research indicates that emotional processing takes place through the fornix.

Limbic System, Hypothalamus and Pituitary Gland

Following the isocortical mantle over the hemisphere to its medial edges, the structures of the limbic system are encountered. These include the amygdala, hippocampus, parahippocampal gyrus, cingulate gyrus, subcallosal gyri and associated structures.

Limbic structures are associated with memory processing, emotional responses, fight-or-flight responses, aggression and sexual response—in summary, with activities contributing to preservation of the individual and the continuation of the species. The limbic system is often somewhat misleadingly described as a phylogenetically ancient part of the brain: the hippocampus is unequivocally a mammalian innovation, whereas the isocortex itself has equally ancient antecedents.

The key limbic structures are located in the mesial temporal lobe and these are readily identified with MRI. The amygdala is the most anterior structure, separated from the hippocampal head by the uncal recess of the temporal horn (Fig. 53.10). The medial-lying uncus (hook) has anterior amygdaloid and posterior hippocampal components.

The hippocampal head, body and tail are well shown on coronal imaging along with the parahippocampal gyrus (Fig. 53.11).

The white matter connections of the hippocampus via the fimbria-fornix system are visualised on coronal and sagittal images. A thinned layer of grey matter called the indusium griseum arches over the corpus callosum to the hippocampi but is not visible on standard imaging.

The hypothalamus forms the floor of the third ventricle and its side walls anteriorly, following an oblique line inferiorly from the foramen of Monro to the midbrain aqueduct. It consists of a group of nuclei serving a number of autonomic, appetite-related and regulatory functions for the body, as well as controlling and producing hormonal output from the pituitary gland. The hypothalamus is intimately linked to other limbic structures and might be considered the output for the limbic system.

The pituitary infundibulum (or stalk), a hollow conical structure, extends inferiorly from the hypothalamus to the pituitary gland. The pituitary gland varies considerably in size, with sometimes only a thin rim of glandular tissue visible at the floor of the pituitary fossa. In young females, the gland may fill the fossa with a convex upper border. Anterior and posterior lobes of the pituitary gland can be distinguished on MRI, the posterior lobe normally returning high signal on T1 weighted images due to neurosecretory granules in the neurohypophysis (the pituitary ‘bright spot’). Both gland and stalk show strong contrast enhancement.

Publisher Summary

The limbic system plays an important role in human communication of all types. This chapter focuses on the role of limbic system in social and communicative behavior. The limbic system is responsible for the bulk of nonpropositional human communication. This forebrain network of cortical and subcortical structures has been thought of only in relation to its regulation of emotion and motivation, but in fact its range of functional responsibilities is large and includes major segments of social and communicative behavior. It is known that humans share these structures homologously with other mammals, and for nonhuman primates, the limbic system comprises the level of neural activity that controls species-wide communication interactions. The chapter discusses the evolution of the limbic system in human species, its development in human ontogeny, and several human clinical syndromes that have limbic etiologies. It also provides an overview of the relationship between limbic and linguistic communication. Moreover, limbic information processing is of interest not only as a nonverbal fringe to language but also because it lies at the heart of many theoretical issues currently under discussion in linguistics and psycholinguistics.

Functional Anatomy of the Limbic System—Key Position of the Hypothalamus

Figure 59-4 shows the anatomical structures of the limbic system, demonstrating that they are an interconnected complex of basal brain elements. Located in the middle of all these structures is the extremely smallhypothalamus, which from a physiological point of view is one of the central elements of the limbic system.Figure 59-5 illustrates schematically this key position of the hypothalamus in the limbic system and shows other subcortical structures of the limbic system surrounding it, including theseptum, paraolfactory area, anterior nucleus of the thalamus, portions of the basal ganglia, hippocampus, andamygdala.

Surrounding the subcortical limbic areas is thelimbic cortex, composed of a ring of cerebral cortex on each side of the brain—(1) beginning in theorbitofrontal area on the ventral surface of the frontal lobes, (2) extending upward into thesubcallosal gyrus, (3) then over the top of the corpus callosum onto the medial aspect of the cerebral hemisphere in thecingulate gyrus, and finally (4) passing behind the corpus callosum and downward onto the ventromedial surface of the temporal lobe to theparahippocampal gyrus anduncus.

Thus, on the medial and ventral surfaces of each cerebral hemisphere is a ring of mostlypaleocortex that surrounds a group of deep structures intimately associated with overall behavior and emotions. In turn, this ring of limbic cortex functions as a two-way communication and association linkage between theneocortex and the lower limbic structures.

Many of the behavioral functions elicited from the hypothalamus and other limbic structures are also mediated through the reticular nuclei in the brain stem and their associated nuclei. We pointed out inChapter 56, as well as earlier in this chapter, that stimulation of the excitatory portion of this reticular formation can cause high degrees of cerebral excitability while also increasing the excitability of much of the spinal cord synapses. InChapter 61, we see that most of the hypothalamic signals for controlling the autonomic nervous system are also transmitted through synaptic nuclei located in the brain stem.

An important route of communication between the limbic system and the brain stem is themedial forebrain bundle, which extends from the septal and orbitofrontal regions of the cerebral cortex downward through the middle of the hypothalamus to the brain stem reticular formation. This bundle carries fibers in both directions, forming a trunk line communication system. A second route of communication is through short pathways among the reticular formation of the brain stem, thalamus, hypothalamus, and most other contiguous areas of the basal brain.

Mini-dictionary of terms

Limbic system: Set of brain regions recognized to participate in emotion, memories, and arousal. Its activation can modulate reinforcing behaviors and lead to autonomic or endocrine responses.

Neuronal ensembles: A population of neurons, closely grouped or diffusely distributed, capable of firing together to participate in a particular neural computation.

Neuronal plasticity: Activity-dependent functional and/or morphological modifications of neuronal properties and synaptic connections.

Optogenetics: Technique that combines genetic engineering to express light-sensitive ion channels in cells with the use of light stimuli to manipulate the activity of neurons.

Calcium imaging: Microscopy technique using fluorescent molecules that change their fluorescence properties when binding Ca2 + ions. In individual neurons, changes in the level of fluorescence correlate with firing activity.

Topographical anatomy of the hypothalamus

The hypothalamus is the most ventral part of the diencephalon, lying beneath the thalamus and ventromedial to the subthalamus (Fig. 16.1; see alsoFigs 12.1–12.3Fig. 12.1Fig. 12.2Fig. 12.3). It forms the floor and the lower part of the lateral wall of the third ventricle, below the hypothalamic sulcus (seeFig. 12.2). On the base of the brain, parts of the hypothalamus can be seen occupying the small area circumscribed by the crura cerebri, optic chiasm and optic tracts (seeFig. 12.1). Between the rostral limits of the two crura cerebri, on either side of the midline, lie two distinct, rounded eminences, themammillary bodies, which contain the hypothalamicmammillary nuclei. In the midline, immediately caudal to the optic chiasm, lies a small elevated area known as thetuber cinereum, from the apex of which extends the thininfundibulum (infundibular process), orpituitary stalk. This is attached to thepituitary gland (hypophysis), a pea-sized structure which lies within the hypophyseal fossa (sella turcica) of the sphenoid bone (seeFigs 5.1,5.4). The pituitary gland consists of two major, cytologically distinct, parts: the posterior pituitary orneurohypophysis and the anterior pituitary oradenohypophysis (Figs 16.2,16.3). The posterior pituitary is a neuronal structure, being an expansion of the distal part of the infundibulum. The anterior pituitary is not neural in origin. The two parts are, however, closely linked by thepituitary (hypophyseal)portal system of vessels (Fig. 16.3), which are derived from the superior hypophyseal artery. Releasing factors, which are synthesised in the hypothalamus, pass to the adenohypophysis through these vessels to control the release of anterior pituitary hormones.

The hypothalamus is able to integrate interoceptive signals from internal organs and fluid-filled cavities and make appropriate adjustments to the internal environment by virtue of its input and output systems.

Input to the hypothalamus is both circulatory and neural in origin (Fig. 16.4). The circulating blood provides physical (temperature, osmolality), chemical (blood glucose, acid–base state) and hormonal signals of the state of the body, its growth and development and its readiness for action. (e.g. sex, suckling, defence, escape, etc.). Neural signals come from a number of sources. The largest input originates from limbic structures, the hippocampus and the amygdala. Fibres of hippocampal origin constitute the fornix, a large component of which terminates in the medial mammillary nucleus within the mammillary body (Figs 16.5–16.7). Fibres from the amygdala to the hypothalamus run in the stria terminalis (seeFig. 12.3). The nucleus solitarius of the medulla projects to the hypothalamus, conveying information collected by the autonomic nervous system concerning the pressure within the smooth-muscled walls of organs (baroreceptors) and the chemical constituents of the fluid-filled cavities (chemoreceptors). The state of arousal is communicated by connections that originate in the brainstem. Monoaminergic projections ascend in the medial forebrain bundle (seeFig. 9.14) and the reticular formation provides input both directly and indirectly via the thalamus.

Abstract

The limbic system is one of the most complicated structures in the brain. It is involved in homeostasis, memory, emotions, olfaction, and many other psychologic functions. This system includes the amygdala, septal nuclei, cingulate cortex, and many other structures that reach the forebrain, midbrain, lower brainstem, and the spinal cord. The limbic system is highly complex, since it connects with the neocortex and central nuclei and utilizes many different neurotransmitters. The olfactory system utilizes olfactory (receptor) cells, sustentacular (supporting) cells, and basal cells. It sends information through cranial nerve I to the brain, and handles the sense of smell. Olfactory receptors can respond to many different odorants. The sense of smell is crucial in order for the sense of taste to function properly. There are many different conditions that affect the limbic, olfactory, and gustatory systems, which will be discussed in detail in this chapter.

Limbic system

The limbic system is a complex neural network (see Fig. 1.12). It handles emotions, homeostasis, memory, motivations, unconscious drives, and olfaction. Its complexity makes the study of this system clinically difficult. Improvements in behavioral studies, deep-brain stimulation, functional magnetic resonance imaging (MRI), and perfusion have allowed for better understanding of the limbic system. The limbic lobe contains the structures of this system, which include:

Amygdala (amygdaloid nuclear complex)—fear and emotion center;

Various hypothalamic nuclei—homeostasis, hunger, satiety, sleep onset, and thermoregulation;

Olfactory cortex—sense of smell;

Septal nuclei—below the rostrum of the corpus callosum, they are essential in generating the theta rhythm of the hippocampus, and play a role in reward and reinforcement, along with the nucleus accumbens;

Nucleus accumbens—a region in the basal forebrain, rostral to the preoptic area of the hypothalamus, playing an important role in processing rewarding stimuli and reinforcing stimuli; these include exercise, sex, and drugs;

Hippocampal formation—mainly involved in memory, and believed to play a role in spatial navigation and control of attention;

Cingulate cortex—in the medial aspect of the cerebral cortex, involved with emotion formation and processing, learning, and memory;

Areas of the basal ganglia—at the base of the forebrain and top of the midbrain, involved in reward learning, cognition, and frontal lobe functioning;

Ventral tegmental area—close to the midline, on the floor of the midbrain, involved in drug and natural reward circuitry in the brain;

Limbic midbrain areas—including the periaqueductal gray matter, play critical roles in autonomic function, motivated behavior, and behavioral responses to threatening stimuli.

The limbic brain includes these structures and their projections, which reach the forebrain, midbrain, lower brain stem, and the spinal cord limbic systems. The spinal cord limbic systems are reached primarily via the fornix, stria terminalis, ventral amygdalofugal pathway, and mammillothalamic tract.

Hippocampal formation

The hippocampal formation includes the dentate gyrus, hippocampus, and subicular complex (see Fig. 1.13). The subicular complex includes the subiculum, presubiculum, and parasubiculum. The neocortex of the parahippocampal gyrus passes medially from the collateral sulcus, and joins the transitional juxtallocortex of the subiculum. This structure is curved superomedially to the inferior surface of the dentate gyrus, and then curves laterally to the laminae of the hippocampus. The curve is continued superiorly and then medially, above the dentate gyrus. It ends while pointing to the center of the superior surface of the dentate gyrus. Three pathways in the hippocampal formation are believed to utilize glutamate, aspartate, or both as the major excitatory neurotransmitter.

Figure 1.13. Hippocampal formation.

A circuit within in the limbic system that was first described by the anatomist named James Papez back in 1937, was initially believed to play a large role in emotions. Today, the Papez circuit is known to play a major role in memory formation and processing, and has many other functions. The circuit is very complex, with structures include the following:

•

Hippocampus;

•

Mammillary body;

•

Anterior nucleus of the thalamus;

•

Cingulate gyrus.

The Papez circuit (see Fig. 1.14) begins at the hippocampus, connecting to the mammillary body via the fornix. The connection between the mammillary body and anterior nucleus of the thalamus is through mammillothalamic fibers. The connection between the anterior nucleus and the cingulate gyrus is via the cingulate bundle, entorhinal cortex, and subiculum, then back to the hippocampal formation to complete the circuit. This circuit may be the most well described circuit out of the many circuits of the limbic system.

Figure 1.14. The Papez circuit.

Functions of the limbic system

The limbic system has close reciprocal links with the hypothalamus, thalamus and cortex and it functions as part of an integrated complex. Phylogenetically ancient, it is concerned with the preservation of the individual and the species. Individual responses to a challenging situation may involve offensive or defensive reactions, anger, fear, acceleration of heart and respiration. Species preservation includes sexual responses, mating and the care of offspring.

The limbic system participates in a memory retention mechanism. Lesions of the hippocampus or any interruption of the Papez circuit will depress memorization of recent events, although long-established memories are unaffected. Localized lesions of the hippocampus can sometimes be demonstrated by magnetic resonance imaging (Press et al., 1989). As noted previously, the anterior and dorsal medial thalamic nuclei are involved in memorization. The nature of long-term memory storage is imperfectly understood.

There are so-called ‘pleasure centres’ in the limbic system. Thus, if a human septal area is stimulated by an electrode under local anaesthesia, the patient becomes much less inhibited and even euphoric. Less significantly, there are also ‘aversion centres’. The balance of activity in these centres represents reward or punishment and is a neural substrate in motivation and in the emotional equilibrium between euphoria and depression. The anterior and dorsal medial thalamic nuclei are involved in this (p. 168). The local concentration of monoamine neurotransmitters is sometimes abnormal in psychological disorders and, as described below, this can be improved therapeutically.

Limbic System

The limbic system has been postulated long ago to play a primordial part in the behavioural and anticonvulsant actions of benzodiazepines. One electrophysiological approach has been the study of evoked potentials in the hippocampus elicited by stimulation of other limbic areas or extralimbic structures. A most intensively studied connection is that between the basolateral nucleus of the amygdaloid complex and the ventral hippocampus. In an earlier study we found that benzodiazepines are most potent in depressing the amplitude of the amygdalo-hippocampal evoked potential and in increasing its latency (Jalfre, Monachon and Haefely, 1971). Tsuchiya (1977) obtained similar findings on the amygdalo-hippocampal potential and, in addition, a depressant effect on the hippocampal response to stimulation of the central gray matter.

Other techniques used in the study of limbic activity are the so-called after-discharges; repetitive stimulation of a structure above a certain intensity induces paroxysmal activity in the stimulated structure as well as in distant areas, which outlasts the period of stimulation. Benzodiazepines were found to be most potent in raising the threshold for the induction of after-discharges and in shortening the duration and reducing the amplitude of after-discharges (Schallek, Zabransky and Kuehn, 1964). The structures found to be most sensitive to the action of benzodiazepines are those in the limbic system and parts of the thalamus.

The spontaneous activity of single neurones in the hippocampus was found to be consistently depressed by benzodiazepines in studies of Olds and Olds (1969) in freely moving rats. In immobilized cats, Chou and Wang (1977) observed a strong depression of the spontaneous firing rate of neurones in the amygdala and the hippocampus by benzodiazepines. About half of the neurones tested were responsive to the drugs, but could not be characterized in relation to the non-responsive units. Most interestingly, morphine, which produces fear and rage reactions in the cat very similar to those obtained by electrical stimulation of either the amygdala or the hippocampus, increased the firing rate of amygdala and hippocampal neurones. The activating effect of morphine was potently antagonized by benzodiazepines.

Considering the prominent facilitatory effect of benzodiazepines on recurrent GABA ergic inhibition in the hippocampus, it appears reasonable to assume that a more effective recurrent inhibition of principal output cells in the hippocampus, and perhaps also in the amygdala and the septum, are the basis of the drug effects on the multiple electrical phenomena in limbic structures.

16.5.3.1 Hippocampus

The limbic system is primarily responsible for our emotional life and participates in various higher order mental functions such as learning, motivation, and memory formation. The hippocampus belongs to the limbic system and plays an important role in the formation, consolidation, and retention of memories, spatial navigation, and the regulation of stress. Traumatic stress is associated with aberrations in hippocampal volumes.

In a longitudinal brain-imaging study, Whittle et al. (2016) investigated the impact of childhood maltreatment on the volume of hippocampal subregions during adolescence, an important period of plasticity. Using structural MRI, 166 (85 male) adolescent participants took part in three assessments during adolescence (12, 16, and 19 years). Participants were given a self-report of childhood maltreatment and assessed using the Diagnostic and Statistical Manual of Mental Disorders Axis I psychopathology index. Researchers observed that childhood maltreatment was significantly correlated with the development of psychopathologies later in life. Further, both child maltreatment and early onset psychiatric disorder impact the development of different hippocampal subregions. Although researchers observed a significant correlation between early maltreatment and psychopathologies, they could not confirm that hippocampal volume alterations mediated this correlation.

Rinne-Albers et al. (2013) conducted a review of imaging studies looking at traumatized juveniles and young adults. They found that structural MRI studies of hippocampal volume observed in children are inconsistent and do not correlate with the decrease in volume that is detected in adults with childhood trauma-induced PTSD. Researchers hypothesized that hippocampal volume decreases observed in adulthood appeared over time and therefore could not be detected during childhood. Furthermore, Rinne-Albers et al. postulate that a consequence of childhood-trauma induced PTSD results in hippocampal atrophy, or alternatively, a smaller hippocampus may make one more sensitive to early perturbations thereby increasing vulnerability for development of PTSD.

Childhood maltreatment is correlated with significantly increased rates of major depressive disorder (MDD) and is a risk factor for substance abuse and psychopathologies later in life (Kaufman & Charney, 2001; Teicher, Anderson, & Polcari, 2012). Likely the most frequently reported neuroimaging discovery correlated with MDD is the structural finding of reduced hippocampal volumes. Although subjects impacted by childhood maltreatment frequently present with reduced hippocampal volumetric measures, it is unclear whether the observed reduction is a consequence of MDD or a possible risk factor.

Opel et al. (2014) sought to differentiate the diagnostic influence of MDD from the impact of childhood maltreatment on hippocampal morphology. Using a structural MRI and the Childhood Trauma Questionnaire, 85 depressed patients and 85 sex and age matched healthy controls were examined. Results indicate that there was a robust correlation between the level of previous maltreatment and the degree of hippocampal atrophy in depressed patients. Researchers suggest that rather than a diagnosis of MDD, hippocampal loss in MDD patients could be a result of early adverse experiences. Data from this study suggest that early maltreatment may generate hippocampal atrophy that may create a trait-like risk factor, a “limbic scar” for acquiring MDD later in life. Correlations between hippocampal atrophy, childhood maltreatment, and MDD have been observed and reported in several other imaging studies (Teicher et al., 2012; Vythilingam et al., 2002). Despite differences in research parameters and results, it is evident that early adverse life events alter hippocampal volumetric measures, and increase the risk of psychopathologies later in life.