The limbic system was traditionally thought of as the integration system for olfaction and hence the old term rhinencephalon. It is now clear that the limbic structures are involved in a variety of functions that define us as human. The limbic system is involved in the complex integration of multimodal information concerning olfactory, visceral, and somatic input that emerges in the form of emotional and behavioural responses. This involves such behaviours as seeking and capturing prey, courtship, mating, raising children, the socialisation of aggression, and the maintenance of human relationships. The limbic system also plays a role in the development of emotional drives and the establishment of memory.

The exact components of the limbic system remain open for debate. For our purposes in this text the following structures will be considered as components of the limbic system (Figs 12.1 and 12.2):

Figure 12.1 The limbic system from a variety of views.

Figure 12.2 Three-dimensional representation of the limbic system.

The olfactory bulb, tract, and cortex

The olfactory bulb and tract develop from ectodermal extensions of the anteromedial part of the primitive cerebral hemisphere. The bulb is radial in structure with six defined layers, which include, from the surface to the central core (Fig. 12.3):

1. The olfactory nerve fibre layer;

2. The area of synaptic glomeruli;

3. The molecular and external granule layers;

4. The mitral cell layer;

5. The internal granule layer; and

6. The fibres of the olfactory tract.

Figure 12.3 The olfactory bulb and tract.

The olfactory nerves (CN I) emerge as the axons of the olfactory cells of the nasal mucosa. These axons are then collected into complex intercrossing bundles, which gather into about 20 nerve axon bundles that traverse the cribriform plate of the ethmoid bone to synapse in the glomeruli of the olfactory bulb (Fig. 12.4). The olfactory epithelium is bathed in lipid substance produced by Bowman’s glands that dissolves particles in the air and makes them accessible to the receptors of the olfactory nerves.

Figure 12.4 The olfactory nerves.

The glomeruli of the olfactory bulb are composed of a complex of axons, dendrites, and neurons including the dendrites of external granule, mitral and tuft cells, and axons from the contralateral olfactory bulb and corticofugal fibres supplying descending modulation. The axons of the mitral and tuft cells course centrally through the olfactory tract to the anterior olfactory nucleus where some axons synapse and others project collaterals but continue with the postganglionic axons to form the olfactory stria. The axons continue posteriorly and divide into the medial and lateral olfactory stria at the junction of the anterior perforated substance, circumventing the olfactory tubercle. The lateral olfactory stria project to the anterior perforated substance, the piriform lobe of the cerebrum, the lateral olfactory gyrus, and the corticomedial group of amygdaloid nuclei. This group of structures is referred to as the primary olfactory cortex (Fig. 12.5). The medial olfactory stria give collaterals to the anterior perforated substance. Some fibres cross the midline via the anterior commissure and synapse in the contralateral anterior olfactory nucleus. These fibres are the only sensory fibres known to reach the cortex without synapsing in one of the thalamic nuclei. The entorhinal area of the parahippocampal gyrus, which forms the caudal area of the piriform lobe, is considered the secondary olfactory cortex. The secondary olfactory cortex mediates emotional and autonomic reflexes associated with smell, along with the hypothalamus. The primary and secondary olfactory cortical areas are responsible for the human perception of smell.

Figure 12.5 Anatomical structures and locations of the primary and secondary olfactory cortices.

The hippocampal formation

The hippocampal formation is composed of a curved column of phylogenically ancient brain called the archipallium (Fig. 12.6). The hippocampal formation includes the hippocampus proper, the subiculum, and the dentate gyrus. Following the structure of the archipallium from a central point in the dentate gyrus in a radial clockwise fashion, the archipallium can be divided into three zones: the dentate gyrus, the cornu ammonis, and the subiculum (Fig. 12.7). The dentate gyrus and cornu ammonis display the three-layered cortical structure of the ancient cortices; the subiculum demonstrates a gradual shift from four layers to six layers through its length (Fig. 12.8). The hippocampal formation includes the following structures:

• The indusium griseum;

• The longitudinal stria;

• The dentate gyrus;

• The cornu ammonis (Ammon’s horn);

• The subiculum; and

• Parts of the uncus.

Figure 12.6 The complex embryological folding that occurs during the development of the hippocampus, subiculum, dentate gyrus, and parahippocampal gyrus.

Figure 12.7 The components of the hippocampal formation includes the hippocampus proper, the subiculum, and the dentate gyrus.

Figure 12.8 The components of the hippocampal formation.

The hippocampus consists of the complex interfolding of the dentate gyrus and the cornu ammonis and remains superior to the subiculum and the parahippocampal gyrus throughout its length.

Afferent projections received by the hippocampus include (Fig. 12.9):

• Cingulate gyrus;

• Septal nuclei;

• Entorhinal cortex;

• Indusium griseum;

• Commissural fibres from the opposite hippocampal formation; and

• Aminergic fibres from the brainstem reticular formation.

Figure 12.9 The afferent and efferent projections to the hippocampal formation.

The efferent outflow from the hippocampus courses through the fornix, which is mainly composed of the axons from pyramidal neurons in Ammon’s horn and the dentate gyrus. These fibres terminate in the following structures:

• The cingulate gyrus;

• The septum pellucidum;

• Preoptic and anterior hypothalamic nuclei;

• Anterior thalamus;

• Mammillary nucleus;

• Reticular formation of the brainstem; and

• Tegmentum of the mesencephalon.

The hippocampus has several important functions including a primary role in the acquisition of associative behaviour. It is also involved in the identification of contiguity between spatial and temporal events through memory recall mechanisms (McIntosh & Gonzalez-Lima 1998).

The limbic system is involved in the complex integration of multimodal information concerning olfactory, visceral, and somatic input that emerges in the form of emotional and behavioural responses. This involves such behaviours as seeking and capturing prey, courtship, mating, raising children, the socialisation of aggression, and the maintenance of human relationships. The limbic system also plays a role in the development of emotional drives and the establishment of memory. In the process of integrating the perceptions generated by the sensory systems, the amygdala is recruited to colour those perceptions with emotion. The hippocampus is called upon to store aspects of those perceptions in long-term memory.

The medial circuit or archicortical division of the temporolimbic system mediates important aspects of learning, memory, and attentional control, as well as information related to internal states. The lateral or basolateral circuit, which has extensive connections with dorsolateral prefrontal cortex and posterior parietal association cortex, processes information concerning the external world, the implicit integration of affect, drives, and social–personal interactions.

Disorders of the limbic system produce a wide variety of bizarre behavioural syndromes, disorders of memory, and aggressive behaviours.

The hypothalamus, amygdala, and prefrontal cortex are the critical neural structures implicated in the expression of aggression (Weiger & Bear 1988). The ventromedial hypothalamic area, in particular, mediated primarily via cholinergic neurotransmission, has been associated with predatory-type aggression. Bilateral lesions in this area may lead to aggressive outbursts referred to as hypothalamic rage that are provoked by frustrated attempts to satisfy basic drives such as hunger, thirst, and sexual need. Hypothalamic rage typically involves outbursts of simple behaviours such as kicking, biting, scratching, or throwing objects and is usually a wild, lashing out response not directed against specific targets (Reeves & Plum 1969). After the event, patients may express remorse and exhibit some insight about their uncontrolled impulses. Aggressive behaviour is also the hallmark of intermittent explosive disorder, which likely involves frontotemporolimbic circuitry. Patients with this disorder present with impulsive loss of behavioural control episodes, in response to minimal provocation which often leads to serious violence. The prefrontal cortex is intimately connected with the hypothalamus and the amygdala and is essential in the hierarchy of aggression control. Orbitofrontal lesions frequently lead to affective disinhibition, most commonly irritability with angry outbursts but also including silliness, euphoria, loud behaviour, and interpersonal and social disinhibition (Lichter & Cummings 2001). The actions of individuals that exhibit aggressive behaviour and violent criminal activity resulting from disinhibited frontal lobe syndromes are usually impulsive, and lack elaborate planning and consideration of consequences. The actions are usually simple in nature and committed without remorse. Abnormalities in prefrontal and subcortical circuitry may also underlie the aggressive and violent acts seen in patients with antisocial personality disorder. Aggressive behaviour has also been linked to disturbed neurotransmission involving specific neural circuitry in the limbic system. Serotonergic, noradrenergic, dopaminergic, and GABA-ergic circuits have all been identified as playing a role in modulating behaviours including aggressive behaviour. The most consistent findings relate to the serotonergic system. Both high and low concentrations of serotonin levels have been implicated in abnormal behaviours. For example, low serotonin levels have been found in the cerebrospinal fluid of people who have attempted suicide and of those who have successfully completed suicide (Virkkunen et al. 1995).

As outlined above, the amygdala receives sensory input from various cortical areas and projects to the hypothalamus and temporolimbic cortex via the ventral amygdalofugal pathway and stria terminalis (Othmer et al. 1998). This connectivity provides a neural mechanism whereby external stimuli receive emotional colouring. Hence, a limbic hyperconnection syndrome may account for the heightened emotional responsivity that is part of the rare and controversial behavioural syndrome, the Gastaut-Geschwind syndrome, which is characterised by dysfunction in three distinct areas of psychosocial interactions including heightened emotional responses, exaggerated behaviours, and lability in physiological drives. The altered emotional responses include periods of intense metaphysical preoccupation with hyperreligiosity, and exaggerated philosophic or moral concerns. They may also experience changes in affect such as depression, paranoia, or irritability. Their behavioural ’viscosity’ manifests as exaggerated verbal, motor, and writing behaviours, nonrational adherence to ideas, interpersonal adhesiveness with prolonged encounters, obsessive preoccupation with detail, excessive need to collect background information, and copious description of thoughts and feelings with a moral or religious twang (Trimble et al. 1997).

Finally, they experience prolonged and powerful alterations of physiological drives resulting in hyposexuality, aggression, and fear responses (Lichter & Cummings 2001).

Damage or dysfunction of the amygdala may result in alterations of perception of various learned emotional states. Sensory inflow for various learned emotional states, especially fear and anxiety, projects to the amygdala via the basolateral complex. Recall that this group of nuclei receives information directly from the thalamus and the cortex. Lesions of the lateral basal complex often result in placid, satiated, and neglectful responses to somatic, visual, and olfactory stimuli with no regard to the significance of the behaviour actually performed and the stimulus for performing it. It appears that lesions of the basolateral complex leave intact the learned association between conditional stimuli and non-rewarding aspects of the unconditional stimulus, but abolish the association between the conditional stimuli and rewarding aspects of the unconditional stimulus. This mechanism may explain the bizarre behaviour exhibited in the Kluver-Bucy syndrome. Classically, the person will try to put anything in their hand into their mouth. They often make attempts to have sexual intercourse with inappropriate species or objects. A classic example is of the unfortunate chap arrested whilst attempting to have sex with the pavement. Effectively, it is the ’what is this’ pathway that is damaged with regard to foodstuff and choice of sexual partners. Monkeys with surgically modified temporal lobes have great difficulty in knowing what prey is, what a mate is, what food is, and in general what the significance of any object might be.

Other symptoms of temporolimbic dysfunction may include inability to visually recognise objects, which is referred to as visual agnosia, the loss of normal fear and anger responses, memory loss, distractibility, seizures, and dementia. The disorder may be associated with other diseases or conditions that can result in brain damage such as herpes encephalitis or trauma. Similar symptomatology can be seen with lesions of the hypothalamus, as previously discussed.

The hippocampus and various other areas of the limbic system are known to play a role in the establishment of memory and learning. The memory process will be explored in an overview fashion here since memory problems are frequently observed in patients with other neurological dysfunctions, and a rudimentary understanding of memory is clinically relevant to their treatment.

Implicit memory, which is the memory we use to perform a previously learned task and does not require conscious recall, and includes various types of memory such as procedural, priming, associative, and nonassociative. Procedural memory is involved with recall of how to perform previously learned skills or habits. It is thought to rely heavily on areas of the striatum. Priming is a type of memory in which the recall of words or objects is enhanced with prior exposure to the words or objects. This type of memory utilises neocortical circuits. Associative learning or memory involves the association of two or more stimuli and includes classical conditioning and operant conditioning (Kandel et al. 2000).

Classical conditioning involves the presynaptic facilitation of synaptic transmission that is dependent on activity in both pre- and postsynaptic cells. The neuron circuit learns to associate one type of stimulus with another. When stimuli are paired in this manner the result is a greater and longer-lasting enhancement. For this form of activity-dependent facilitation to occur, the conditioned and unconditional stimuli must occur at closely spaced intervals in time. Influx of calcium in response to action potentials in the conditional stimulus pathway leads to potentiation of the stimulus by binding of activated calcium/calmodulin to adenylyl cyclase. This occurs in a fashion similar to sensitisation due to serotonin release described above. Adenylyl cyclase acts as a coincidence detector, recognising molecular response to both a conditioned stimulus and an unconditional stimulus present simultaneously or within a required space of time. The postsynaptic component of classical conditioning is a retrograde signal to the sensory neurons that potentiation of the stimulus has indeed occurred.

In a simple circuit subjected to classical conditioning, the neuron has both the NMDA-type and non-NMDA receptors. Only non-NMDA receptors are activated in habituation and sensitisation due to a magnesium plug in the NMDA receptor channel. In classical conditioning, as a result of pairing of stimuli the magnesium plug is expelled, opening the NMDA channel, which results in the influx of calcium, thereby activating signalling pathways in the neuron. This gives rise to activation of a variety of retrograde messenger systems that enhance the amount of neurotransmitter released.

Therefore, in classical conditioning three signals need to converge within a specific period of time for learning to occur. These signals include:

Long-term storage of implicit memory involving both sensitisation and classical conditioning involves the cyclic AMP (cAMP)–protein kinase A (PKA)–mitogen-activated protein kinase (MAPK)–cAMP response element-binding protein (CREB) pathway (see Chapter 3).

Operant conditioning involves the association of a stimulus to a behaviour utilising rewards and punishments as reinforcement for the desired behaviour. Operant conditioning probably utilises a similar neurophysiological mechanism as described above for classical conditioning.

Nonassociative learning or memory occurs when a person or neuron is exposed to a novel stimulus either once or repeatedly. This type of learning or memory involves the neurophysiological processes of habituation and sensitisation of synaptic function, which are important processes in nonassociative learning and memory (Kandel et al. 2000).

The process of habituation involves the presynaptic depression of synaptic transmission that is dependent on the frequency of activation of the circuit. In the presence of certain types of long-term inactivation or long-term activation of synaptic transmission, the structure of the sensory neuron will adapt to the stimulus. This process predominantly occurs at sites in the neuraxis specific for learning and memory storage. If habituating stimuli are presented one after the other without rest between sessions, a robust short-term memory can be formed, but long-term memory is seriously compromised. Therefore, the main principle for stimulating long-term memory is that frequent but well-spaced training is usually much more effective than massed training. To say this in another way, ’cramming’ for an exam may work in the short term but for long-term memory retention frequent, spaced study sessions are much better.

The process of sensitisation involves presynaptic facilitation of synaptic transmission. This process is particularly effective when a stimulus is harmful to the neuron or perceived as harmful to the person. Sensitisation involves axoaxonic, serotonergic connections which activate the G protein, adenylyl cyclase, cAMP, PKA/PKC pathway, which increases release of transmitter from neurons through phosphorylation of several substrate proteins. The process of sensitisation can occur in a direct fashion which only involves the pre- and postsynaptic neurons, or in an indirect fashion which involves the participation of interneurons.

Memory can be classified into two distinct, but functionally related systems, based on how the information contained in the memory is stored and retrieved. These classifications include implicit and explicit memory.

Explicit memory, which is the factual recall of persons, places, and things and the understanding of the significance of these things, is more flexible than implicit memory and includes various classifications of memory which include:

For example, the statement ’Last year I attended the Rolling Stones concert with my sister’ is utilising episodic memory and the statement ‘Mercury is the planet closest to the sun’ is utilising semantic memory.

Explicit memory involves the process of long-term potentiation of synapses in the hippocampus. The entorhinal cortex acts as both the primary input and primary output of the hippocampus in this process. The unimodal and polymodal areas of association cortex project to the parahippocampal gyrus and the perirhinal cortex, which both project to the entorhinal cortex. Information then flows from the entorhinal cortex to the hippocampus in three possible pathways including the perforant, the mossy fibre, and the Schaffer collateral pathways (Kandel et al. 2000).

The perforant pathway projects from entorhinal cortex to granular cells of the dentate gyrus. This is the primary conduit for polymodal information from the association cortices to the hippocampus. The mossy fibre pathway, which contains axons of the granule cells and runs to the pyramidal cells in the CA3 region of hippocampus, is dependent on noradrenergic activation of beta-adrenergic receptors, which activate adenylyl cyclase. This pathway is nonassociative in nature and can be modified by serotonin. The Schaffer collateral pathway consists of excitatory collaterals of the pyramidal cells in the CA3 region and ends on the pyramidal cells in the CA1 region. Long-term potentiation in the Schaffer collateral and perforant pathways is associative in nature (Fig. 12.10).

Figure 12.10 Input and output pathways of the hippocampal formation.

Long-term memory of explicit nature occurs through multiple sensory components being processed separately in unimodal and multimodal association cortices of the parietal, temporal, and frontal lobes. This information then passes simultaneously to the parahippocampal and perirhinal cortices. The information then projects to the entorhinal cortex and via the perforant pathway to the dentate gyrus and the hippocampus. From the hippocampus, information flows back to the entorhinal cortices via the subiculum, then perirhinal and parahippocampal cortices, then polymodal association areas of the neocortex. The elements involved in long-term memory occur in the cortical association areas and appear to have an unlimited capacity for storage of memories.

The entorhinal cortex is the first site of pathological changes in Alzheimer’s disease; therefore, the first sign would be loss of or defective explicit memory.

Memory processing can be divided into four processes which include:

The prefrontal cortex is the attentional control system, also referred to as the central executive centre. The attentional control system regulates information flow to two rehearsal systems, the articulatory loop, which is involved with language, words, and numbers processing, and the visuospatial sketch pad, which is involved with vision and actions such as memorising data or recognising the face of a friend at a party. This system is important for both establishing new memories and recalling long-term memories.