Mitral cell axons run centrally in the olfactory tract (Figure 34.2). The tract divides in front of the anterior perforated substance into medial and lateral olfactory striae.

Figure 34.2 Brain viewed from below, showing cortical olfactory areas.

The medial stria contains axons from the anterior olfactory nucleus, which consists of multipolar neurons scattered within the olfactory tract. Some of these axons travel to the septal area via the diagonal band (see later, under Limbic system). Others cross the midline in the anterior commissure and inhibit mitral cell activity in the contralateral bulb (by exciting granule cells there). The result is a relative enhancement of the more active bulb, providing a directional cue to the source of olfactory stimulation.

The lateral olfactory stria terminates in the piriform lobe of the anterior temporal cortex. The human piriform lobe includes the cortical part of the amygdala, the uncus, and the anterior end of the parahippocampal gyrus. The highest center for olfactory discrimination is the posterior part of the orbitofrontal cortex, which receives connections from the piriform lobe via the mediodorsal nucleus of the thalamus.

The medial forebrain bundle links the olfactory cortical areas with the hypothalamus and brainstem. These linkages trigger autonomic responses such as salivation and gastric contraction, and arousal responses through the reticular formation.

Points of clinical interest are mentioned in Clinical Panel 34.1.

Clinical Panel 34.1 Olfactory disturbance

A routine test of olfactory function is to ask the patient to identify strong-smelling substances such as coffee and chocolate through each nostril in turn. Loss of smell, or anosmia, may not be detected by the patient without testing if it is unilateral. If it is bilateral, the complaint may be one of loss of taste because the flavor of foodstuffs depends on the olfactory qualities of volatile elements; in such cases, the four primary taste sensations (sweet, sour, salty, bitter) are preserved. Unilateral anosmia may be caused by a meningioma compressing the olfactory bulb or tract, or by a head injury with fracture of the anterior cranial fossa. Anosmia may be a clue to a fracture, and should prompt tests for leakage of cerebrospinal fluid into the nasal cavity.

Olfactory auras are a typical prodromal feature of uncinate epilepsy (see Clinical Panel 34.3).

Limbic System

The limbic system comprises the limbic cortex (so-called limbic lobe) and related subcortical nuclei. The term ‘limbic’ (Broca, 1878) originally referred to a limbus or rim of cortex immediately adjacent to the corpus callosum and diencephalon. The limbic cortex is now taken to include the three-layered allocortex of the hippocampal formation and septal area, together with transitional mesocortex in the parahippocampal gyrus, cingulate gyrus, and insula. The principal subcortical component of the limbic system is the amygdala, which merges with the cortex on the medial side of the temporal pole. Closely related subcortical areas are the hypothalamus, reticular formation, and the nucleus accumbens. Cortical areas closely related to the limbic system are the orbitofrontal cortex and the temporal pole (Figure 34.3).

Figure 34.3 Medial view of cortical and subcortical limbic areas. MDN, mediodorsal nucleus of thalamus.

Figure 34.4 is a graphic reconstruction of mainly subcortical limbic areas.

Figure 34.4 Three-dimensional computerized reconstruction of postmortem brain showing components of the limbic system in relation to the ventricular system.

(Excerpt of figure from Kretschmann and Weinrich, 1998, with kind permission of the authors and the publisher.)

Parahippocampal gyrus

The parahippocampal gyrus is a major junctional region between the cerebral neocortex and the allocortex of the hippocampal formation. Its anterior part is the entorhinal cortex (area 28 of Brodmann), which is six-layered but has certain peculiar features. The entorhinal cortex can be said to face in two directions. Its neocortical face exchanges massive numbers of afferent and efferent connections with all four association areas of the neocortex. Its allocortical face exchanges abundant connections with the hippocampal formation. In the broadest terms, the entorhinal cortex receives a constant stream of cognitive and sensory information from the association areas, transmits it to the hippocampal formation for consolidation (see later), retrieves it in consolidated form, and returns it to the association areas where it is encoded in the form of memory traces. The fornix and its connections form a second, circuitous pathway from hippocampus to neocortex.

The hippocampal complex (or hippocampal formation) comprises the subiculum, the hippocampus proper, and the dentate gyrus (Figure 34.5). All three are composed of temporal lobe allocortex which has tucked itself into an S-shaped scroll along the floor of the lateral ventricle. The band-like origin of the fornix from the subiculum and hippocampus is the fimbria. The hippocampus is also known as Ammon’s horn (after an Egyptian deity with a ram’s head). For research purposes, it is divided into four cornu ammonis (CA) zones (Fig. 34.6A).

Figure 34.5 Hippocampal formation. (A) View from above. (B) Enlargement from (A) showing the entorhinal cortex and the three component parts of the hippocampal formation.

The principal cells of the subiculum and hippocampus are pyramidal cells; those of the dentate gyrus are granule cells. The dendrites of both granule and pyramidal cells are studded with dendritic spines. The hippocampal complex is also rich in inhibitory (GABA) internuncial neurons.

It should be mentioned that in general discussions related to memory, it is customary to use the term ‘hippocampus’ as synonymous with ‘hippocampal complex’.

Connections

Afferents

The largest afferent connection of the hippocampal complex is the perforant path, which projects from the entorhinal cortex onto the dendrites of dentate granule cells (Figure 34.6B). The subiculum gives rise to a second, alvear path which contributes to a sheet of fibers on the ventricular surface of the hippocampus, the alveus.

The axons of the granule cells are called mossy fibers; they synapse upon pyramidal cells in the CA3 sector. The axons of the CA3 pyramidal cells project into the fimbria; before doing so they give off Schaffer collaterals, which run a recurrent course from CA3 to CA1. CA1 projects into the entorhinal cortex.

Auditory information enters the hippocampus from the association cortex of the superior and middle temporal gyri. The supramarginal gyrus (area 40) transmits coded information about personal space (the body schema described in Ch. 32) and extrapersonal (visual) space. From the occipito-temporal region on the inferior surface, information concerning object shape and color, and facial recognition, is projected to cortex called perirhinal, or transrhinal, immediately lateral to the entorhinal cortex. From here, it enters the hippocampus. A return projection from entorhinal to perirhinal cortex is linked to the temporal polar and prefrontal cortex.

In addition to the discrete afferent connections mentioned above, the hippocampus is diffusely innervated from several sources, mainly by way of the fornix:

• A dense cholinergic innervation, of particular significance in relation to memory, is received from the septal nucleus.

• A noradrenergic innervation is received from the cerulean nucleus.

• A serotonergic innervation enters from the raphe nuclei of the midbrain. The linkage between serotonin depletion and major depression is mentioned in Chapter 26.

• A dopaminergic innervation enters from the ventral tegmental area of the midbrain. The linkage between dopamine and schizophrenia is discussed in Clinical Panel 34.2.

Clinical Panel 34.2 Schizophrenia

Schizophrenia occurs in about 1% of the population in all countries where the prevalence has been studied. It is a heritable illness with around a 10% risk of occurrence if a person’s first-degree relative is affected, and as much as 50% risk of occurrence if both parents or an identical co-twin is affected. Although the onset of illness is typically in early adulthood, there is substantial evidence for neurodevelopmental disturbance in the illness, with increased rates of birth complications, early developmental insults, and childhood social, motor, and academic underperformance in those who later develop schizophrenia. Cognitive dysfunction is present in the illness, but relatively stable throughout life, unlike the progressive dementias.

MRI studies reveal enlargement of lateral ventricles and regionally specific atrophy predominantly affecting frontal and temporal parts of the cortex, the medial temporal lobe, and thalamus. There is a reduction or even a reversal of the usual left–right difference in the size of the temporal plane on the upper surface of the superior temporal gyrus. There is some progression of these neuroimaging abnormalities in the early years of the illness which then plateau. Postmortem studies indicate that the atrophy identified by imaging studies is related to loss of neuropil and reduced neuronal size rather than neuronal loss. No evidence of astrogliosis or of neurodegenerative disease pathology has been identified. Consistent with neurodevelopmental disturbance, underlying the illness are findings of aberrantly located neurons, for example in the entorhinal cortex and in white matter.

The clinical presentation is quite variable but the symptoms and behavioral changes can be categorized into two broad spectra – positive symptoms and negative symptoms.

• Positive psychotic symptoms include hallucinations, delusions, and disorganized thoughts and behavior. Hallucinations are typically auditory (the patient hears voices, which are commonly derogatory in nature and refer to the patient in the third person). Delusions often take a paranoid form, with a belief that the patient is being monitored or the subject of a conspiracy. Other typical delusions include a belief that one’s thoughts and actions are being controlled by an outside agency and that thoughts are not private, but are somehow accessible by other people. Thought processes frequently become disorganized with the normal flow and logic of speech breaking down and in severe cases becoming incoherent. Disorganized behavior includes disinhibited, socially inappropriate behaviour or in some cases physical aggression in response to hallucinations or delusions. Although positive symptoms cause great distress to patients and their families, they are much more responsive to antipsychotic medication treatment than the negative ones, which in the long term are more disabling.

• Negative (deficit) psychotic symptoms refer to an inability to engage in normal emotional and social interactions with people and frequently lead to impaired capacity to self-care. The patient lacks motivation, has little to say, and in conversation rambles from one inconsequential theme to another. There is a loss of emotional responsiveness (flattening of affect), including inability to experience pleasure (anhedonia). Personal hygiene and ability to live independently and manage affairs are often impaired. The negative symptoms appear to be associated with ‘hypofrontality,’ i.e. diminished prefrontal function. Functional imaging studies using fMRI and PET support this idea by demonstrating failure of the normal response of the dorsolateral prefrontal cortex to standard tests of cognitive function.

Medications used to treat psychotic disorders such as schizophrenia are called antipsychotics, neuroleptics or major tranquillizers. All such antipsychotic medications block dopamine D₂ receptors to some extent (e.g. haloperidol or olanzapine). In the normal brain, the D₂ receptors are on spiny (excitatory) stellate cells in the mesocortical projection territory of the ventral tegmental nucleus. D₂ receptors are inhibitory, for one or more of three possible reasons noted in Chapter 8. Interestingly, symptoms closely resembling the positive psychotic ones of schizophrenia may be induced by consuming excessive amounts of dopamine-stimulating drugs such as cocaine or amphetamine (’speed’). Amphetamine is known to increase the amount of dopamine in the forebrain extracellular space (Clinical Panel 34.5). In schizophrenia, dopaminergic overactivity seems not to be a matter of overproduction but of greater effectiveness through an increased number of postsynaptic dopamine receptors on the spiny stellate neurons. (The assistance of Professor Colm McDonald, Department of Psychiatry, NUI, Galway, Ireland is gratefully appreciated.)

References

Harrison PJ, Weinberger DR. Schizophrenia genes, gene expression, and neuropathology: on the matter of their convergence. Mol Psychiatry. 2005;10:40-68.

Leonard BE. Drug treatment of schizophrenia and the psychoses. In: Fundamentals of psychopharmacology. Chichester: Wiley; 2003:255-294.

Picchioni MM, Murray RM. Schizophrenia. BMJ. 2007;335:91-95.

Efferents

The largest efferent connection is a massive projection via the entorhinal cortex to the association areas of the neocortex. A second, forward projection is the fornix (Figure 34.5A). The fornix is a direct continuation of the fimbria, which receives axons from the subiculum and hippocampus proper. The crus of the fornix arches up beneath the corpus callosum, where it joins its fellow to form the trunk and links with its opposite number through a small hippocampal commissure. Anteriorly, the trunk divides into two pillars. Each pillar splits around the anterior commissure, sending precommissural fibers to the septal area and postcommissural fibers to the anterior hypothalamus, mammillary body, and medial forebrain bundle. The mammillary body projects into the anterior nucleus of thalamus, which projects in turn to the cingulate cortex, completing the Papez circuit from cingulate cortex to hippocampus, with return to cingulate cortex via fornix, mammillary body, and anterior thalamic nucleus (Figure 34.7).

The term medial temporal lobe is clinically inclusive of the hippocampal complex, parahippocampal gyrus, and amygdala. The term is most often used in relation to seizures (Clinical Panel 34.3).

Clinical Panel 34.3 Temporal lobe epilepsy

Complex focal (partial) seizures are synonymous with temporal lobe epilepsy. The initial event, or aura, may be a simple partial seizure whose electrical activity escapes into the temporal lobe. Many originate in a focus of runaway neural activity within the temporal lobe and spread over the general cortex within seconds to trigger a secondarily generalized tonic–clonic seizure (Figure CP 34.3.1) as mentioned in Chapter 30. Types of temporal lobe auras include well-formed visual or auditory hallucinations (scenes, sound sequences), a sense of familiarity with the surrounding scene (’déjà vu’), a sense of strangeness (‘jamais vu’) or a sense of fear. Attacks originating in the uncus are ushered in by unpleasant olfactory or gustatory auras. Bizzare psychic auras can occur, where the patient has an ‘out of body experience’ in the form of a sensation of floating in the air and looking down at themselves and any others present.

Following accurate localization of the ictal (seizure) focus by means of recording electrodes inserted into the exposed temporal lobe, a tissue block including the focus may be removed, with abolition of seizures in four out of five cases. Histological examination of the surgical biopsy typically reveals hippocampal sclerosis: the picture is one of glial scarring, with extensive neuronal loss in CA2 and CA3 sectors. The granule cells of the dentate gyrus are relatively well preserved. Loss of inhibitory, GABA internuncials has been blamed in the past but these cells have recently been shown to persist. Instead, the granule cells appear to be disinhibited, because of loss of minute, inhibitory basket cells from among their dendrites.

Because 30% of sufferers from temporal lobe epilepsy have first-degree relatives similarly afflicted, often from childhood, a genetic influence must be significant. One possibility could be ‘faulty wiring’ of the hippocampus during mid-fetal life. Histological preparations show areas of congenital misplacement of hippocampal pyramidal cells, some lying on their sides or even in the subjacent white matter.

The sclerosis is regarded as a typical CNS healing process following extensive loss of neurons. The neuronal loss in turn seems to be inflicted by glutamate toxicity – a known effect of excessively high rates of discharge of pyramidal cells in any part of the cerebral cortex. Dentate granule cells are the main source of burst-firing, which is no surprise in view of their natural role in long-term potentiation and kindling (see main text).

References

Emerson RG, Pedley TA. EEG and evoked potentials. In: Bradley WG, Daroff RB, Finichel GM, Jankovic J, editors. Neurology in clinical practice: principles of diagnosis and management. Philadelphia: Elsevier; 2004:465-490.

Bernasconi N, Bernasconi A, Caramanos Z, et al. Mesial temporal damage in temporal lobe epilepsy: a volumetric MRI study of the hippocampus, amygdala and parahippocampal region. Brain. 2003;126:462-469.

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Figure CP 34.3.1 Complex focal seizure. The ictal focus (arrow) occupies the middle–posterior junctional zone of the right temporal lobe (cf. electrode positions in Figure 30.2). Within a second the entire cortex exhibits a secondarily generalized seizure (to the right of the dashed line).

LTP is described as an associative phenomenon, because the required expulsion of the magnesium plug from the NMDA receptor (Figure 34.8) is facilitated when the powerful depolarizing stimulus is coupled with a weaker stimulus to the depolarized neuron from another source. Norepinephrine and dopamine are suitable associative candidates, one or both being released during elevation of the attentional or motivational state at the appropriate time.