Chapter Summary
Study guidelines
Olfactory System
In most vertebrates the olfactory system is altogether more important than it is in humans. While damage to the olfactory pathway on one side is associated with anosmia on that side, olfactory deficits are often found in neurodegenerative disorders.
Limbic System
Cortical and subcortical limbic areas are prominent features of the brain in primitive mammals where they are intimately concerned with mechanisms of attack and defence, procreation, and feeding. The principal effector elements of the limbic system are the hypothalamus and the reticular formation.
The elements, pathways, and transmitters of the human limbic system provide the bedrock on which most of psychiatry and clinical psychology are built.
Olfactory system
The olfactory system is remarkable in four respects:
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The somas of the primary afferent neurons occupy a surface epithelium.
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The axons of the primary afferents enter the cerebral cortex directly; second-order afferents are not interposed.
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The primary afferent neurons undergo continuous turnover, being replaced from basal stem cells.
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The pathway to the cortical centres in the frontal lobe is entirely ipsilateral.
The olfactory system consists of the olfactory epithelium and olfactory nerves, the olfactory bulb and tract, and several areas of the olfactory cortex.
Olfactory epithelium
The olfactory epithelium occupies the upper one fifth of the lateral and septal walls of the nasal cavity. The epithelium contains three cell types ( Figure 34.1 ):
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Olfactory neurons . These are bipolar neurons each with a dendrite extending to the epithelial surface and an unmyelinated axon contributing to the olfactory nerve. The dendrites are capped by immotile cilia containing molecular receptor sites. The axons run upward through the cribriform (‘sieve-like’) plate of the ethmoid bone and enter the olfactory bulb. The axons (some 3 million on each side) are grouped into fila (bundles) by investing Schwann cells. The collective fila constitute the olfactory nerve .
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Sustentacular cells are interspersed among the bipolar neurons.
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Basal stem cells lie between the other two cell types. Olfactory bipolar neurons are unique in that they undergo a continuous cycle of growth, degeneration, and replacement. The basal cells transform into fresh bipolar olfactory neurons, which survive for about a month. Replacement declines over time accounting for the general reduction in olfactory sensitivity with age.
Olfactory bulb ( Figure 34.1 )
The olfactory bulb consists of three-layered allocortex surrounding the commencement of the olfactory tract. The chief cortical neurons are some 50,000 mitral (or tufted) cells , which receive the olfactory nerve fibres and give rise to the olfactory tract.
Contact between olfactory fibres and mitral cell dendrites takes place in some 2000 glomeruli , which are sites of innumerable synapses and have a glial investment, but each receives its input from sensory neurons that respond to the same stimulus ( odourant ). Glomeruli that are ‘on-line’ (active) inhibit neighbouring, ‘off-line’ glomeruli through the mediation of γ-aminobutyric acid (GABA)ergic periglomerular cells (cf. the horizontal cells of the retina), representing an initial stage of signal (specific odour) processing. Mitral cell activity is also sharpened at a deeper level by granule cells that are devoid of axons (cf. the amacrine cells of the retina), representing the next stage of signal processing and contrast enhancement between mitral cells. The granule cells receive excitatory dendrodendritic contacts from active mitral cells, and they suppress neighbouring mitral cells through inhibitory (GABA) dendrodendritic contacts.
Central connections
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 .
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 centre for olfactory discrimination is the posterior part of the orbitofrontal cortex, which receives connections from the piriform lobe via the dorsal medial 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 .
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. If it is unilateral, loss of smell, or anosmia , may not be detected by the patient without testing. If it is bilateral, the complaint may be one of loss of taste because the flavour 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/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 term ‘limbic system’ is most useful when defined as the limbic cortex (further defined below) 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 complex 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, the 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 34.4 is a graphic reconstruction of mainly subcortical limbic areas.
Parahippocampal gyrus
The parahippocampal gyrus is a major junctional region between the cerebral neocortex and the allocortex of the hippocampal complex. 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 complex. In the broadest terms the entorhinal cortex receives a constant stream of cognitive and sensory information from the association areas of the neocortex, transmits it to the hippocampal complex 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 the hippocampus to neocortex.
Hippocampal complex
The hippocampal complex (or hippocampal formation) consists of the subiculum , hippocampus proper , and 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 fornix originates from the subiculum and hippocampus as a band-like structure called the fimbria. The early neuroanatomists called the hippocampus ‘Ammon’s horn’ (or cornu ammonis), because it looked to them like a ram’s horn. They further divided the hippocampus into four regions known as cornu ammonis (CA) 1 to 4 ( Fig. 34.6A ).
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Afferent from the sensory association cortex.
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Entorhinal cortex projecting perforant path fibres to the dentate gyrus.
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Dentate granule cell projecting to CA3.
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CA3 principal neuron projecting into the fimbria and CA1.
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CA1 principal cell projecting to the subiculum.
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Subicular principal cell projecting into the fimbria.
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Subicular principal cell projecting into the entorhinal cortex.
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Entorhinal pyramidal cell projecting to the sensory association cortex.
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) interneurons.
Connections
Afferents
The largest source of afferents to 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 afferent path, the alvear path , which contributes to a sheet of fibres on the ventricular surface of the hippocampus, the alveus .
The axons of the granule cells are called mossy fibres ; 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 Chapter 32 ) and extrapersonal (visual) space. From the occipitotemporal region on the inferior surface, information concerning object shape and colour, 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 the 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:
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A dense cholinergic innervation, of particular significance in relation to memory, is received from the septal nucleus.
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A noradrenergic innervation is received from the locus ceruleus.
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A serotonergic innervation enters from the raphe nuclei of the midbrain. The linkage between serotonin depletion and major depression is mentioned in Chapter 26 .
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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 about a 10% risk of occurrence if a person’s first-degree relative is affected and as much as a 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.
Magnetic resonance imaging (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 behavioural changes can be categorised into two broad spectra—positive symptoms and negative symptoms.
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Positive psychotic symptoms include hallucinations, delusions, and disorganised thoughts and behaviour. Hallucinations are typically auditory (the patient hears voices that 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 disorganised with the normal flow and logic of speech breaking down and in severe cases becoming incoherent. Disorganised behaviour 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.
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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 rambles from one inconsequential theme to another in conversation. There is a loss of emotional responsiveness ( flattening of affec t), 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,’ that is, diminished prefrontal function. Functional imaging studies using functional MRI (fMRI) and positron emission tomography (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 tranquillisers. All such antipsychotic medications block dopamine D 2 receptors to some extent (e.g. haloperidol or olanzapine). In the normal brain the D 2 receptors are on spiny (excitatory) stellate cells in the mesocortical projection territory of the ventral tegmental nucleus. D 2 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.)
Suggested references
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- Carter C.S., Bullmore E.T., Harrison P.: Is there a flame in the brain in psychosis?. Biol Psychiat 2014; 75: pp. 258-259.
- Citrome L.: Unmet needs in the treatment of schizophrenia: new targets to help different symptom domains. J Clin Psychiat 2014; 75: pp. 21-26.
- Correll C.U., Kane J.M.: Schizophrenia: mechanism of action of current and novel treatments. J Clin Psychiat 2014; 75: pp. 347-348.
- Niculescu A.B.: Schizophrenia: from genetics to biology to predictive medicine. J Clin Psychiat 2014; 75: pp. 4-7.
- van den Heuvel M.P., Fornito A.: Brain networks in schizophrenia. Neuropsychol Rev 2014; 24: pp. 32-48.
Efferents
The largest efferent connection from the hippocampal complex is a massive projection via the entorhinal cortex to the association areas of the neocortex. A second 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 fibres to the septal area and postcommissural fibres to the anterior hypothalamus, mammillary body, and medial forebrain bundle. The mammillary body projects into the anterior nucleus of the thalamus, which projects in turn to the cingulate cortex, completing the Papez circuit from the cingulate cortex to the hippocampus with return to the cingulate cortex via the fornix, mammillary body, and anterior thalamic nucleus ( Figure 34.7 ).
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Backward-projecting neurons in the cingulate gyrus.
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Projection into the entorhinal cortex.
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Projection into the hippocampus.
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Fornix.
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Mammillothalamic tract.
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Projections from the anterior nucleus of the thalamus to the cingulate cortex.
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 ).
Complex focal (partial) seizures are synonymous with the older term of 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 generalised tonic–clonic seizure ( Figure 34.8 ) 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 (‘dé j à 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. Bizarre 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 localisation 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. Histologic 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 interneurons 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 midfoetal life. Histologic 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 central nervous system 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).
Suggested references
Memory function of the hippocampal complex
The evidence for a mnemonic (memory-related) function in the hippocampal complex is discussed at considerable length in psychology texts. Some insights are given below.
Glossary
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Short-term memory : Holding one or more items of new information briefly in mind (e.g. a new telephone number while pressing the buttons).
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Long-term (remote) memory : Stored information capable of retrieval at appropriate moments. Two kinds of long-term memory are recognised: explicit and implicit.
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Explicit memory has to do with recollections of facts and events of all kinds that can be explicitly stated—or declared; hence the term declarative memory . The term episodic memory is also used, in the autobiographical sense of recollection of episodes involving personal experience. Yet another term, semantic memory , was devised in the context of memory for the meaning of written and spoken words, but is now also used to include knowledge of facts and concepts.
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Implicit memory has to do with performance of learned motor procedures, such as riding a bicycle or assembling a jigsaw puzzle. The term procedural memory is commonly used.
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Working memory : Effortless brief simultaneous retrieval of several items from long-term memory stores for a task in hand, such as driving a car along a familiar route while making appropriate decisions based on previous experience.
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Consolidation : The process of storing new information in long-term memory. Novel factual information is relayed from the relevant sensory association areas to the hippocampal complex for encoding. Following a prolonged period of processing, the encoded information is relayed back to the same association areas and (with the exception of strongly autobiographical episodes) no longer depends on the hippocampal complex for retrieval.
Clinical and Experimental Observations
Bilateral damage or removal of the anterior part of the hippocampal complex is followed by anterograde amnesia , a term used to denote absence of conscious recall of newly acquired information for more than a few minutes. When asked to name a commonplace object, the patient will have no difficulty because access to long-term memories does not require the anterior hippocampus. However, when the same object is shown a few minutes later, the patient will not remember having seen it. There is loss of explicit/declarative memory.
Procedural (how-to-do) memory is preserved. If asked to assemble a jigsaw puzzle, the patient will do it in the normal way. When asked to repeat the exercise the next day, the patient will do it faster, although there will be no recollection of having seen the puzzle previously. The hippocampus is not required for procedural memory . We have previously noted that the basal ganglia are the storehouse of routine motor programs and that the cerebellum is the storehouse of motor adaptations to novel conditions.
Long-term potentiation (LTP) is uniquely powerful in the dentate gyrus and hippocampus. It is regarded as vital for preservation (consolidation) of memory traces. Under experimental conditions, LTP is most easily demonstrated in the perforant path–dentate granule cell connections and in the Schaffer collateral–CA1 connections. A strong, brief (milliseconds) stimulus to the perforant path or Schaffer collaterals induces the target cells to show long-lasting (hours) sensitivity to a fresh stimulus. LTP is associated with a cascade of biochemical events in the target neurons, following activation of appropriate glutamate receptors, as described in Chapter 8 in the context of pain sensitisation. Repetitive stimuli may cause cyclic adenosine 3′,5′-monophosphate (cAMP) to increase its normal rate of activation of protein kinases involved in phosphorylation of proteins that regulate gene transcription. The outcome is increased production of proteins (including enzymes) required for transmitter synthesis and of other proteins for construction of additional channels and synaptic cytoskeletons ( Figure 34.9 ).
