Cortical Lamination and Cortical Connections

The cortical laminae represent, to some extent, horizontal aggregations of neurones with common connections. This is most clearly seen in the lamination of cortical efferent (pyramidal) cells. The internal pyramidal lamina, layer V, gives rise to corticosubcortical fibres, notably corticostriate, corticobulbar, corticopontine and corticospinal axons. In addition, a significant proportion of feedback corticocortical axons arise from cells in this layer, as do some corticothalamic fibres. Layer VI, the multiform lamina, is the major source of corticothalamic fibres. Supragranular pyramidal cells—predominantly in layer III, but also in layer II—give rise primarily to both ipsilateral (association) and contralateral (commissural) corticocortical pathways. Short corticocortical fibres arise more superficially, and long corticocortical (both association and commissural) axons come from cells in the deeper parts of layer III. Major afferents to a cortical area tend to terminate in layers I, IV and VI. Quantitatively, fewer projections end either in the intervening laminae II, III and V or sparsely throughout the depth of the cortex. Numerically, the major single input to a cortical area tends to have its main termination field in layer IV. This pattern of termination is seen in the major thalamic input to visual cortex and somatosensory cortex. In general, non-thalamic subcortical afferents to the neocortex, which are shared by widespread areas, tend to terminate throughout all cortical layers, but the laminar pattern of their endings still varies considerably from area to area.

Columns and Modules

Experimental physiological and connectional studies have demonstrated the internal organization of the cortex, which is at right angles to the pial surface, with vertical columns or modules running through the depth of the cortex. The term ‘column’ refers to the observation that all cells encountered by a microelectrode penetrating and passing perpendicularly through the cortex respond to a single peripheral stimulus, a phenomenon first identified in the somatosensory cortex. In the visual cortex, narrow (50 µm) vertical strips of neurones respond to a bar stimulus of the same orientation (orientation columns), and wider strips (500 µm) respond preferentially to stimuli detected by one eye (ocular dominance columns). Adjacent orientation columns aggregate within an ocular dominance column to form a hypercolumn, responding to all orientations of stimulus for both eyes for one point in the visual field. Similar functional columnar organization has been described in widespread areas of neocortex, including the motor cortex and so-called association areas.

Primary Motor Cortex

The primary motor cortex (MI) corresponds to the precentral gyrus (area 4). It is the area of cortex with the lowest threshold for eliciting contralateral muscle contraction by electrical stimulation. The primary motor cortex contains a detailed, topographically organized map (motor homunculus) of the opposite body half, with the head represented most laterally and the legs and feet represented on the medial surface of the hemisphere in the paracentral lobule (Fig. 16.13). A striking feature is the disproportionate representation of body parts in relation to their physical size. Thus, large areas represent the muscles of the hand and face, which are capable of finely controlled or fractionated movements.

Fig. 16.13 A, The motor homunculus showing proportional somatotopic representation in the main motor area. B, The sensory homunculus showing proportional somatotopic representation in the somaesthetic cortex.

(After Penfield, W., Rasmussen, T., 1950. The Cerebral Cortex of Man. Macmillan, New York.)

The cortex of area 4 is agranular, and layers II and IV are difficult to identify. The most characteristic feature is the presence in lamina V of some extremely large pyramidal cell bodies, Betz cells, which may approach 80 µm in diameter. The axons of these neurones project into the corticospinal and corticobulbar tracts.

The major thalamic connections of area 4 are with the ventral posterolateral nucleus, which in turn receives afferents from the deep cerebellar nuclei. The ventral posterolateral nucleus also contains a topographical representation of the contralateral body, which is preserved in its point-to-point projection to area 4, where it terminates largely in lamina IV. Other thalamic connections of area 4 are with the centromedian and parafascicular nuclei. These seem to provide the only route through which output from the basal ganglia, via the thalamus, reaches the motor cortex; this appears to be the case, because the projection of the internal segment of the globus pallidus to the ventrolateral nucleus of the thalamus is confined to the anterior division, and there is no overlap with cerebellothalamic territory. The anterior part of the ventrolateral nucleus projects to the premotor and supplementary motor areas of cortex, with no projection to area 4.

The ipsilateral somatosensory cortex (SI) projects in a topographically organized way to area 4, and the connection is reciprocal. The projection to the motor cortex arises in areas 1 and 2, with little or no contribution from area 3b. Fibres from SI terminate in layers II and III of area 4, where they contact mainly pyramidal neurones. Evidence suggests that neurones activated monosynaptically by fibres from SI, as well as those activated polysynaptically, make contact with layer V pyramidal cells, which give rise to corticospinal fibres, including Betz cells. Movement-related neurones in the motor cortex that can be activated from SI tend to have a late onset of activity, mainly during the execution of movement. It has been suggested that this pathway plays a role primarily in the making of motor adjustments during a movement. Additional ipsilateral corticocortical fibres to area 4 from behind the central sulcus come from the second somatosensory area (SII).

Neurones in area 4 are responsive to peripheral stimulation and have receptive fields similar to those in the primary sensory cortex. Cells located posteriorly in the motor cortex have cutaneous receptive fields, whereas more anteriorly situated neurones respond to stimulation of deep tissues.

The motor cortex receives major frontal lobe association fibres from the premotor cortex and the supplementary motor area, as well as fibres from the insula. It is probable that these pathways modulate motor cortical activity in relation to the preparation, guidance and temporal organization of movements. Area 4 sends fibres to, and receives fibres from, its contralateral counterpart and also projects to the contralateral supplementary motor cortex.

Apart from its contribution to the corticospinal tract, the motor cortex has diverse subcortical projections. The connections to the striatum and pontine nuclei are heavy. It also projects to the subthalamic nucleus. The motor cortex sends projections to all nuclei in the brain stem, which are themselves the origin of descending pathways to the spinal cord—namely, the reticular formation, red nucleus, superior colliculus, vestibular nuclei and inferior olivary nucleus.

Premotor Cortex

Immediately in front of the primary motor cortex lies Brodmann’s area 6 (Fig. 16.14). Area 6 extends onto the medial surface, where it becomes contiguous with area 24 in the cingulate gyrus, anterior and inferior to the paracentral lobule. A number of functional motor areas are contained in this cortical region. Lateral area 6, the area over most of the lateral surface of the hemisphere, corresponds to the premotor cortex. The premotor cortex is divided into dorsal and ventral areas on functional grounds and on the basis of ipsilateral corticocortical association connections.

Fig. 16.14 Lateral (A) and medial (B) surfaces of the left cerebral hemisphere showing the approximate correspondence of Brodmann’s areas to the primary motor cortex (area 4), premotor areas (areas 6 and 8) and motor speech areas (areas 44 and 45).

The major thalamic connections of the premotor cortex are with the anterior division of the ventrolateral nucleus and with the centromedian, parafascicular and centrolateral components of the intralaminar nuclei. Subcortical projections to the striatum and pontine nuclei are prominent, and this area also projects to the superior colliculus and the reticular formation. Both dorsal and ventral areas contribute to the corticospinal tract. Commissural connections are with the contralateral premotor, motor and superior parietal (area 5) cortices. Ipsilateral corticocortical (association) connections with area 5 in the superior parietal cortex and inferior parietal area 7b are common to both dorsal and ventral subdivisions of the premotor cortex, and both send a major projection to the primary motor cortex. The dorsal premotor area also receives fibres from the posterior superior temporal cortex and projects to the supplementary motor cortex. The frontal eye field (area 8) projects to the dorsal subdivision. Perhaps the greatest functionally significant difference in connectivity between the two premotor area subdivisions is that the dorsal premotor area receives from the dorsolateral prefrontal cortex, whereas the ventral subdivision receives from the ventrolateral prefrontal cortex. All these association connections are either likely or known to be reciprocal.

Neuronal activity in the premotor cortex in relation to both preparation for movement and movement itself has been extensively studied experimentally. Direction selectivity for movement is a common feature of many neurones. In behavioural tasks, neurones in the dorsal premotor cortex show anticipatory activity and task-related discharge as well as direction selectivity, but little or no stimulus-related changes. The dorsal premotor cortex is probably important in establishing a motor set or intention, contributing to motor preparation in relation to internally guided movement. In contrast, ventral premotor cortex is related more to the execution of externally (especially visually) guided movements in relation to a specific external stimulus.

Frontal Eye Field

The frontal eye field lies predominantly within Brodmann’s area 8, anterior to the superior premotor cortex (Fig. 16.15). It receives its major thalamic projection from the parvocellular mediodorsal nucleus, with additional afferents from the medial pulvinar, the ventral anterior nucleus and the suprageniculate–limitans complex. It connects with the paracentral nucleus of the intralaminar group. The thalamocortical pathways to the frontal eye field form part of a pathway from the superior colliculus, the substantia nigra and the dentate nucleus of the cerebellum. The frontal eye field has extensive ipsilateral corticocortical connections, receiving fibres from several visual areas in the occipital, parietal and temporal lobes, including the medial temporal area (V5) and area 7a. There is also a projection from the superior temporal gyrus, which is auditory rather than visual in function. From within the frontal lobe, the frontal eye field receives fibres from the ventrolateral and dorsolateral prefrontal cortices. It projects to the dorsal and ventral premotor cortices and to the medial motor area, probably to the supplementary eye field adjacent to the supplementary motor area proper. It projects prominently to the superior colliculus, the pontine gaze centre within the pontine reticular formation and other oculomotor-related nuclei in the brain stem. As its name implies, it is important in the control of eye movements. Destructive lesions of the frontal eye field cause ipsilateral conjugate deviation of the eyes, whereas stimulation, such as with an epileptic discharge, induces contralateral deviation.

Fig. 16.15 Lateral surface of the left cerebral hemisphere showing the frontal eye field, corresponding to parts of Brodmann’s areas 6, 8 and 9. The perimeter of this area is delineated by an interrupted line to indicate the uncertainty of its precise extent.

Supplementary Motor Cortex

The supplementary motor area (MII) lies medial to area 6 and extends from the most superolateral part to the medial surface of the hemisphere. Area 24 in the cingulate gyrus adjacent to area 6 contains several motor areas, which are termed cingulate motor areas. An additional functional subdivision, the pre–supplementary motor area, lies anterior to the supplementary motor area on the medial surface of the cortex. For purposes of this discussion, these additional medial motor areas are included with the supplementary motor cortex.

The supplementary motor area receives its major thalamic input from the anterior part of the ventral lateral nucleus, which in turn is the major recipient of fibres from the internal segment of the globus pallidus. Additional thalamic afferents are from the ventral anterior nucleus; the intralaminar nuclei, notably the centrolateral and centromedial nuclei; and the mediodorsal nucleus. The connections with the thalamus are reciprocal. The supplementary motor cortex receives connections from widespread regions of the ipsilateral frontal lobe, including the primary motor cortex; the dorsal premotor area; the dorsolateral and ventrolateral prefrontal, medial prefrontal and orbitofrontal cortex; and the frontal eye field. These connections are reciprocal, but the major ipsilateral efferent pathway is to the motor cortex. Parietal lobe connections of the supplementary motor cortex are with superior parietal area 5 and possibly inferior parietal area 7b. Contralateral connections are with the supplementary motor area and motor and premotor cortices of the contralateral hemisphere. Subcortical connections, other than with the thalamus, pass to the striatum, subthalamic nucleus, pontine nuclei, brain stem reticular formation and inferior olivary nucleus. The supplementary motor area makes a substantial contribution to the corticospinal tract, contributing as much as 40% of the fibres from the frontal lobe.

The supplementary motor area contains a representation of the body in which the leg is posterior and the face anterior, with the upper limb between them. Its role in the control of movement involves primarily complex tasks, which require temporal organization of sequential movements and retrieval of motor memory. The consequences of damage to the supplementary motor area bear some striking similarities to the effects of basal ganglia dysfunction; akinesia is common, and there may be problems with the performance of sequential, complex movements. Stimulation of the supplementary motor area in conscious patients has been reported to elicit the sensation of an urge to move or the feeling that a movement is about to occur. A region anterior to the supplementary motor area for face representation is important in vocalization and speech production.

Prefrontal Cortex

The prefrontal cortex on the lateral surface of the hemisphere comprises predominantly Brodmann’s areas 9, 46 and 45 (see Figs 16.12, 16.14, 16.15). In non-human primates, two subdivisions of the lateral prefrontal cortex are recognized: a dorsal area equivalent to area 9 and perhaps including the superior part of area 46, and a ventral area consisting of the inferior part of area 46 and area 45. Areas 44 and 45 are particularly notable in humans because, in the dominant hemisphere, they constitute the motor speech area (Broca’s area; see Case 12). Both the dorsolateral and ventrolateral prefrontal areas receive their major thalamic afferents from the mediodorsal nucleus, and there are additional contributions from the medial pulvinar, the ventral anterior nucleus and the paracentral nucleus of the anterior intralaminar group. The dorsolateral area receives long association fibres from the posterior and middle superior temporal gyrus, including auditory association areas; from parietal area 7a; and from much of the middle temporal cortex. From within the frontal lobe it also receives projections from the frontal pole (area 10) and from the medial prefrontal cortex (area 32) on the medial surface of the hemisphere. It projects to the supplementary motor area, the dorsal premotor cortex and the frontal eye field. All these thalamic and corticocortical connections are reciprocal. Commissural connections are with the homologous area and with the contralateral inferior parietal cortex. The ventrolateral prefrontal area receives long association fibres from areas 7a and 7b of the parietal lobe, auditory association areas of the temporal operculum, the insula and the anterior part of the lower bank of the superior temporal sulcus. From within the frontal lobe it receives fibres from the anterior orbitofrontal cortex and projects to the frontal eye field and the ventral premotor cortex. It connects with the contralateral homologous area via the corpus callosum. These connections are probably all reciprocal.

The cortex of the frontal pole (area 10) receives thalamic input from the mediodorsal nucleus, the medial pulvinar and the paracentral nucleus. It is reciprocally connected with the cortex of the temporal pole, the anterior orbitofrontal cortex and the dorsolateral prefrontal cortex. The orbitofrontal cortex connects with the mediodorsal, anteromedial, ventral anterior, medial pulvinar, paracentral and midline nuclei of the thalamus. Cortical association pathways come from the inferotemporal cortex, the anterior superior temporal gyrus and the temporal pole. Within the frontal lobe, it has connections with the medial prefrontal cortex, the ventrolateral prefrontal cortex and medial motor areas. Commissural and other connections follow the general pattern for all neocortical areas.

The medial prefrontal cortex is connected with the mediodorsal, ventral anterior, anterior medial pulvinar, paracentral, midline and suprageniculate–limitans nuclei of the thalamus. It receives fibres from the anterior cortex of the superior temporal gyrus. Within the frontal lobe, it has connections with the orbitofrontal cortex and the medial motor areas of the dorsolateral prefrontal cortex.

Information on the detailed functions of the subregions of the prefrontal cortex is sparse. The dorsolateral prefrontal cortex is important for spatial processing of afferent information and for the organization of self-ordered working memory tasks, including verbal working memory. The ventrolateral prefrontal cortex is concerned with the mnemonic processing of objects.

Evidence from surgical lesions (prefrontal lobotomy) or pathological damage suggests a role for the prefrontal cortex in the appreciation or understanding of time, the normal expression of emotions (affect) and the ability to predict the consequences of actions. Both hemispheres interact in these functions, so deficits following unilateral damage may be relatively slight. The medial prefrontal cortex as a whole is important in auditory and visual associations, and widespread changes in prefrontal activation are associated with calculating, thinking and decision making.

Somatosensory Cortex

The postcentral gyrus corresponds to the primary somtosensory cortex (SI; Brodmann’s areas 3a, 3b, 1 and 2). Area 3a lies most anteriorly, apposing area 4, the primary motor cortex of the frontal lobe; area 3b is buried in the posterior wall of the central sulcus; area 1 lies along the posterior lip of the central sulcus; and area 2 occupies the crown of the postcentral gyrus.

The primary somatosensory cortex contains within it a topographical map of the contralateral half of the body. The face, tongue and lips are represented inferiorly; the trunk and upper limbs are represented on the superolateral aspect and the lower limbs on the medial aspect of the hemisphere, giving rise to the familiar ‘homunculus’ map (see Fig. 16.13).

The somatosensory properties of SI depend on its thalamic input from the ventral posterior nucleus of the thalamus, which in turn receives the medial lemniscal, spinothalamic and trigeminothalamic pathways. The nucleus is divided into a ventral posterolateral part, which receives information from the trunk and limbs, and a ventral posteromedial part, in which the head is represented. Within the ventral posterior nucleus, neurones in the central core respond to cutaneous stimuli, and those in the most dorsal anterior and posterior parts, which arch as a ‘shell’ over this central core, respond to deep stimuli. This is reflected in the differential projections to SI: the cutaneous central core projects to 3b, the deep tissue–responsive neurones send fibres to areas 3a and 2 and an intervening zone projects to area 1. Within the ventral posterior nucleus, anteroposterior rods of cells respond with similar modality and somatotopic properties. They appear to project to restricted focal patches in SI of approximately 0.5 mm, which form narrow strips mediolaterally along SI. The laminar termination of thalamocortical axons from the ventral posterior nucleus is different in the separate cytoarchitectonic subdivisions of SI. In areas 3a and 3b these axons terminate mainly in layer IV and the adjacent deep part of layer III, whereas in areas 1 and 2 they end in the deeper half of layer III, avoiding lamina IV. Additional thalamocortical fibres to SI arise from the intralaminar system, notably the centrolateral nucleus.

There is a complex internal connectivity within SI. An apparently stepwise hierarchical progression of information processing occurs from area 3b through area 1 to area 2. Outside the postcentral gyrus, SI has ipsilateral corticocortical association connections with a second somatosensory area (SII); area 5 in the superior parietal lobe; area 4, the motor cortex, in the precentral gyrus; and the supplementary motor cortex in the medial part of area 6 of the frontal lobe.

SI has reciprocal commissural connections with its contralateral homologue, with the exception that the cortices containing the representation of the distal extremities are relatively devoid of such connections. Callosal fibres in SI arise mainly from the deep part of layer III and terminate in layers I to IV. Callosally projecting pyramidal cells receive monosynaptic thalamic and commissural connections.

SI has reciprocal subcortical connections with the thalamus and claustrum and receives afferents from the basal nucleus of Meynert, the locus coeruleus and the midbrain raphe. It has other prominent subcortical projections. Corticostriatal fibres, arising in layer V, pass mainly to the putamen of the same side. Corticopontine and corticotectal fibres from SI arise in layer V. SI projects to the main pontine nuclei and to the pontine tegmental reticular nucleus. In addition, axons arising in SI pass to the dorsal column nuclei and the spinal cord. Corticospinal pyramidal cells are found in layer V of SI. The topographical representation in the cortex is preserved in terms of the spinal segments to which different parts of the postcentral gyrus project. Thus, the arm representation projects to the cervical enlargement, the leg representation to the lumbosacral enlargement and so on. Within the grey matter of the spinal cord, fibres from SI terminate in the dorsal horn, Rexed’s laminae III to V. Fibres from areas 3b and 1 end more dorsally, and those from area 2 more ventrally.

The second somatosensory area (SII) lies along the upper bank of the lateral fissure, posterior to the central sulcus. SII contains a somatotopic representation of the body, with the head and face most anteriorly, adjacent to SI, and the sacral regions most posteriorly. SII is reciprocally connected with the ventral posterior nucleus of the thalamus in a topographically organized fashion. Some thalamic neurones probably project to both SI and SII via axon collaterals. Other thalamic connections of SII are with the posterior group of nuclei and with the intralaminar central lateral nucleus. SII also projects to laminae IV to VII of the dorsal horn of the cervical and thoracic spinal cord, the dorsal column nuclei, the principal trigeminal nucleus and the periaqueductal grey matter of the midbrain.

Within the cortex, SII is reciprocally connected with SI in a topographically organized manner and projects to the primary motor cortex. SII also projects in a topographically organized way to the lateral part of area 7 (area 7b) in the superior parietal lobe, and it makes connections with the posterior cingulate gyrus. Across the corpus callosum, both right and left SII areas are interconnected, although distal limb representations are probably excluded. There are additional callosal projections to SI and area 7b.

Experimental studies show that neurones in SII respond particularly to transient cutaneous stimuli, such as brush strokes or tapping, which are characteristic of the responses of Pacinian corpuscles in the periphery. They show little response to maintained stimuli.

Superior and Inferior Parietal Lobules

Posterior to the postcentral gyrus, the superior part of the parietal lobe is composed of areas 5, 7a and 7b (see Fig. 16.12; Fig. 16.16). Area 5 receives a dense feed-forward projection from all cytoarchitectonic areas of SI in a topographically organized manner. The thalamic afferents to this area come from the lateral posterior nucleus and from the central lateral nucleus of the intralaminar group. Ipsilateral corticocortical fibres from area 5 go to area 7, the premotor and supplementary motor cortices, the posterior cingulate gyrus and the insular granular cortex. Commissural connections between area 5 on both sides tend to avoid the areas of representation of the distal limbs. The response properties of cells in area 5 are more complex than in SI, with larger receptive fields and evidence of submodality convergence. Area 5 contributes to the corticospinal tract.

Fig. 16.16 Lateral surface of the left hemisphere showing the motor speech areas (44 and 45) and areas 5, 7a and 7b. Wernicke’s area is variously depicted by different authorities and is tentatively indicated here by the large parietotemporal area enclosed by the dotted line and including areas 39 and 40. Some consider areas 22 and 37 to be auditory and visuo-auditory areas, respectively, associated with speech and language.

In non-human primates, the inferior parietal lobe is area 7. In humans, this area is more superior, and areas 39 and 40 intervene inferiorly. The counterparts of the latter areas in monkeys are unclear, and there is little experimental evidence of their connections and functions. Their role in human cerebral processing is discussed later. In the monkey, area 7b receives somatosensory inputs from area 5 and SII. Connections pass to the posterior cingulate gyrus (area 23), insula and temporal cortex. Area 7b is reciprocally connected with area 46 in the prefrontal cortex and the lateral part of the premotor cortex. Commissural connections of area 7b are connected with the contralateral homologous area and with SII, the insular granular cortex and area 5. Thalamic connections are with the medial pulvinar nucleus and the intralaminar paracentral nucleus.

In monkeys, area 7a is not related to the cortical pathways for somatosensory processing; instead, it forms part of a dorsal cortical pathway for spatial vision. The major ipsilateral corticocortical connections to area 7a are derived from visual areas in the occipital and temporal lobes. In the ipsilateral hemisphere, area 7a has connections with the posterior cingulate cortex (area 24) and with areas 8 and 46 of the frontal lobe. Commissural connections are with its contralateral homologue. Area 7a is connected with the medial pulvinar and intralaminar paracentral nuclei of the thalamus. In experimental studies, neurones within area 7a are visually responsive. They relate largely to peripheral vision, respond to stimulus movement and are modulated by eye movement.

Injury of the superior parietal cortex in humans can lead to the inability to recognize the shapes of objects by touch (astereognosis) and a variety of disorders reflecting breakdown of the body scheme or body image, such as difficulty assimilating spatial perception of the body (amorphosynthesis) and sensory neglect of the contralateral body (asomatognosia), which causes a variety of syndromes, including so-called dressing apraxia (see Case 3). More complex perceptional disturbances follow damage of the inferior parietal cortex, including areas 39 and 40. These include difficulties with language, because Wernicke’s speech area includes parts of the inferior parietal lobe of the dominant hemisphere (see Fig. 16.16 and Case 12), and dyscalculia if the dominant hemisphere is involved. Contralateral sensory neglect extends to the extracorporeal space and includes the visual appreciation of the world, such as the omission of one side (usually the left) of a drawing when a patient is asked to copy a sketch of a clock face. Difficulties with complex orientation in space, such as map reading, are also seen.

Auditory Cortex

The temporal operculum houses the primary auditory cortex, AI (Fig. 16.18). This is coextensive with granular area 41 in the transverse temporal gyri. Surrounding areas constitute auditory association cortex. The primary auditory cortex is reciprocally connected with all subdivisions of the medial geniculate nucleus and may receive additional thalamocortical projections from the medial pulvinar. The geniculocortical fibres terminate densely in layer IV. AI contains a tonotopic representation of the cochlea in which high frequencies are represented posteriorly and low frequencies anteriorly. Single-cell responses are to single tones of a narrow frequency band. Cells in single vertical electrode penetrations share an optimal frequency response.

Fig. 16.18 Lateral aspect of the left cerebral hemisphere. The opercula have been cut away to expose the insula and the adjoining anterior and posterior transverse temporal gyri and their continuity with the superior temporal gyrus.

The auditory cortex interconnects with prefrontal cortex, although the projections from AI are small. In general, posterior parts of the operculum project to areas 8 and 9. Central parts project to areas 8, 9 and 46. More anterior regions project to areas 9 and 46, to area 12 on the orbital surface of the hemisphere and to the anterior cingulate gyrus on the medial surface. Contralateral corticocortical connections are with the same and adjacent regions in the other hemisphere. Onward connections of the auditory association pathway converge with those of the other sensory association pathways in cortical regions within the superior temporal sulcus.

Injury of the auditory cortex in humans produces a variety of manifestations, including cortical deafness, verbal auditory agnosia and non-verbal auditory agnosia. The markedly bilateral nature of the auditory pathway means that noticeable deficits occur only when there is bilateral damage. Damage of the temporoparietal junction has effects on auditory selective attention.

Evidence suggests that area 21 in humans, the middle temporal cortex, is polysensory and that it connects with auditory, somatosensory and visual cortical association pathways. The auditory association areas of the superior temporal gyrus project in a complex, ordered fashion to the middle temporal gyrus, as does the parietal cortex. The middle temporal gyrus connects with the frontal lobe—the most posterior parts project to the posterior prefrontal cortex, areas 8 and 9, and the intermediate regions connect more anteriorly with areas 19 and 46. Farther forward, the middle temporal region has connections with anterior prefrontal areas 10 and 46 and with anterior orbitofrontal areas 11 and 14. The most anterior middle temporal cortex is connected with the posterior orbitofrontal cortex, area 12, and with the medial surface of the frontal pole. Farther forward, this middle temporal region projects to the temporal pole and the entorhinal cortex. Thalamic connections are with the pulvinar nuclei and the intralaminar group. Other subcortical connections follow the general pattern for all cortical areas. Some projections (e.g. to the pons), particularly from anteriorly in the temporal lobe, are minimal. Physiological responses of cells in this middle temporal region show a convergence of different sensory modalities, and some of these neurones are involved in facial recognition. In line with this complexity, lesions of the temporal lobe in humans can lead to considerable disturbance of intellectual function, particularly when the dominant hemisphere is involved. These disturbances can include visuospatial difficulties, prosopagnosia, hemiagnosia and severe sensory dysphasia.

The inferior temporal cortex, area 20, is a higher visual association area. The posterior inferior temporal cortex receives major ipsilateral corticocortical fibres from occipitotemporal visual areas, notably V4. It contains a coarse retinotopic representation of the contralateral visual field and sends a major feed-forward pathway to the anterior part of the inferior temporal cortex. The anterior inferior temporal cortex projects onto the temporal pole and to paralimbic areas on the medial surface of the temporal lobe. Additional ipsilateral association connections of the inferior temporal cortex are with the anterior middle temporal cortex, in the walls of the superior temporal gyrus and with visual areas of the parietotemporal cortex. Frontal lobe connections are with area 46 in the dorsolateral prefrontal cortex (posterior inferior temporal) and with the orbitofrontal cortex (anterior inferior temporal). The posterior area also connects with the frontal eye fields. Reciprocal thalamic connections are with the pulvinar nuclei; the posterior part is related mainly to the inferior and lateral nuclei, and the anterior part to the medial and adjacent lateral pulvinar. Intralaminar connections are with the paracentral and central medial nuclei. Other subcortical connections conform to the general pattern of all cortical regions. Callosal connections are between corresponding areas and the adjacent visual association areas of each hemisphere.

The cortex of the temporal pole receives feed-forward projections from widespread areas of temporal association cortex that are immediately posterior to it. The dorsal part receives predominantly auditory input from the anterior part of the superior temporal gyrus. The inferior part receives visual input from the anterior area of the inferior temporal cortex. Other ipsilateral connections are with the anterior insular, posterior and medial orbitofrontal and medial prefrontal cortices. The temporal pole projects onward into limbic and paralimbic areas. Thalamic connections are mainly with the medial pulvinar nucleus and with intralaminar and midline nuclei. Other subcortical connections are the same as for the cortex in general, although some projections, such as to the pontine nuclei, are very small. Physiological responses of cells here and in more medial temporal cortex correspond particularly to behavioural performance and to the recognition of high-level aspects of social stimuli.

Nuclei of the amygdala (see later) project to, and receive fibres from, neocortical areas, predominantly of the temporal lobe and possibly the inferior parietal cortex. The density of these pathways increases toward the temporal pole.

Claustrum

The claustrum (see Figs 16.35, 16.42) is a thin sheet of grey matter lying deep to the insula. It is approximately coextensive with the insula, from which it is separated by the extreme capsule. Medially, the claustrum is separated from the putamen by the external capsule. It is thickest anteriorly and inferiorly, where it becomes continuous with the anterior perforated substance, amygdala and prepiriform cortex. In animals, it has reciprocal, topographically organized connections with many regions of the neocortex. Little is known about the connections and functional significance of the claustrum in the human brain.

Olfactory Pathways

The olfactory pathways include the olfactory nerves, olfactory bulb and olfactory tract, together with its central connections in the frontal and temporal lobes. These are primarily described in Chapter 12. The close association of these structures with limbic regions is shown in Figure 16.7.

Hippocampal Formation

The hippocampal formation includes the dentate gyrus, hippocampus, subicular complex and entorhinal cortex.

The hippocampus lies above the subiculum and medial parahippocampal gyrus, forming a curved elevation, approximately 5 cm long, along the floor of the inferior horn of the lateral ventricle (Fig. 16.25). Its anterior end is expanded, and its margin there may have two or three shallow grooves that give it a paw-like appearance, the pes hippocampi. The ventricular aspect is convex. It is covered by ependyma, beneath which fibres of the alveus converge medially on a longitudinal bundle of fibres, the fimbria of the fornix (Fig. 16.26). Passing medially from the collateral sulcus, the neocortex of the parahippocampal gyrus merges with the transitional juxtallocortex of the subiculum. The latter curves superomedially to the inferior surface of the dentate gyrus, then laterally to the laminae of the hippocampus. The curvature continues, first superiorly, then medially above the dentate gyrus, and ends pointing toward the centre of the superior surface of the dentate gyrus. The dentate gyrus is a crenated strip of cortex related inferiorly to the subiculum, laterally to the hippocampus and, more medially, to the fimbria of the fornix (Figs 16.26, 16.27). The form of the fimbria is quite variable, but medially, it is separated from the crenated medial margin of the dentate gyrus by the fimbriodentate sulcus (Fig. 16.28). The hippocampal sulcus, of variable depth, lies between the dentate gyrus and the subicular extension of the parahippocampal gyrus. Posteriorly, the dentate gyrus is continuous with the gyrus fasciolaris and thus with the indusium griseum. Anteriorly, it continues into the notch of the uncus, turning medially across its inferior surface, as the tail of the dentate gyrus (band of Giacomini) and vanishes on the medial aspect of the uncus (see Fig. 16.27). The tail separates the inferior surface of the uncus into an anterior uncinate gyrus and posterior intralimbic gyrus.

Fig. 16.25 Dissection of the left cerebral hemisphere demonstrating structures of the limbic system. The body of the corpus callosum has been divided sagitally. The frontal, temporal and occipital lobes have been sectioned horizontally, and their superior parts removed. The left lentiform complex and thalamus have been removed, and the floor of the inferior horn of the lateral ventricle opened.

(Dissection by A. M. Seal; photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

Fig. 16.26 A–C, Coronal sections of the temporal lobe and inferior horn of the lateral ventricle illustrating the hippocampus and related structures. This series of diagrams is intended to assist in understanding the relative positions of the dentate gyrus, cornu ammonis, subiculum and parahippocampal gyrus in the floor of the inferior horn.

Fig. 16.27 Basal aspect of the brain dissected to display the dentate gyrus, uncus and fimbria on the left.

Fig. 16.28 Coronal, thionin-stained section of the human hippocampal formation. a, molecular layer of the dentate gyrus; b, granule cell layer of the dentate gyrus; c, plexiform layer of the dentate gyrus; CA1–CA3, fields of the hippocampus; d, stratum oriens layer of the hippocampus; DG, dentate gyrus; e, pyramidal cell layer of the hippocampus; EC, entorhinal cortex; f, stratum radiatum of the hippocampus; fim, fimbria; g, stratum lacunosum-molecular of the hippocampus; PaS, parasubiculum; PRC, perirhinal cortex; PrS, presubiculum; S, subiculum.

(Photomicrograph courtesy of David Amaral.)

The trilaminar cortex of the dentate gyrus is the least complex of the hippocampal fields. Its major cell type is the granule cell, found in the dense granule cell layer. Granule cells (approximately 9 × 10⁶ in the human dentate gyrus) have unipolar dendrites that extend into the overlying molecular layer, which receives most of the afferent projections to the dentate gyrus (primarily from the entorhinal cortex). The granule cell and molecular layers are sometimes referred to as the fascia dentata. The polymorphic layer, or hilus of the dentate gyrus, contains cells that give rise primarily to ipsilateral association fibres. They remain within the dentate gyrus and do not extend into other hippocampal fields.

The hippocampus is trilaminar archicortex. It consists of a single pyramidal cell layer, with plexiform layers above and below it. It can be divided into three distinct fields: CA1, CA2 and CA3 (Figs 16.28, 16.29). Field CA3 borders the hilus of the dentate gyrus at one end, and field CA2 at the other. Field CA3 pyramidal cells are the largest in the hippocampus, and the whole pyramidal cell layer in this field is about 10 cells thick. The most important feature of pyramidal cells in CA3 is that they receive the mossy fibre input from dentate granule cells on their proximal dendrites. The border between CA3 and CA2 is not well marked because the pyramidal cells of the former appear to extend under the border of the latter for some distance. The CA2 field has the most compact layer of pyramidal cells. It completely lacks a mossy fibre input from dentate granule cells and receives a major input from the supramammillary region of the hypothalamus. Field CA1 is usually described as the most complex of the hippocampal subdivisions, and its appearance varies along its transverse and rostrocaudal axes. The CA1–CA2 border is not sharp, and at its other end, CA1 overlaps the subiculum for some distance. The thickness of the pyramidal cell layer varies from 10 to more than 30 cells. Approximately 10% of neurones in this field are interneurones.

Fig. 16.29 Hippocampal formation, showing the disposition of the various cell fields. Dentate gyrus, pink; hippocampus proper (cornu ammonis), yellow; areas of the subicular complex, green; entorhinal cortex, blue. CA1–CA3, hippocampal cell fields.

It is common to describe several strata within the layers of the hippocampus (see Figs 16.28, 16.29). Starting from the ventricular aspect, these are the alveus (containing subicular and hippocampal pyramidal cell axons converging on the fimbria of the fornix), stratum oriens (mainly the basal dendrites of pyramidal cells and some interneurones), stratum pyramidalis, stratum lucidum (containing mossy fibres that make contact with the proximal dendrites of pyramidal cells in field CA3), stratum radiatum and stratum lacunosum-moleculare. The stratum lucidum is not as prominent in humans as it is in other primates, and it is not present in fields CA1 and CA2.

In the stratum radiatum and stratum oriens, CA3 and CA2 cells receive associational connections from other rostrocaudal levels of the hippocampus, as well as afferents from subcortical structures such as the septal nuclei and supramammillary region. The projections from pyramidal cells of fields CA3 and CA2 to CA1, often called Schaffer collaterals, also terminate in the stratum radiatum and stratum oriens. The projections from the entorhinal cortex to the dentate gyrus (the perforant pathway) travel in the stratum lacunosum-moleculare, where they make synaptic contact en passant with the distal apical dendrites of hippocampal pyramidal cells.

The subicular complex is generally subdivided into the subiculum, presubiculum and parasubiculum (see Figs 16.28, 16.29). The major subcortical projections of the hippocampal formation (to the septal nuclei, mammillary nuclei, nucleus accumbens and anterior thalamus), and those to the entorhinal cortex, all arise from pyramidal neurones of the subicular complex. The subiculum consists of a superficial molecular layer containing apical dendrites of subicular pyramidal cells, a pyramidal cell layer that is approximately 30 cells thick and a deep polymorphic layer. The presubiculum is medial to the subiculum and is distinguished by a densely packed superficial layer of pyramidal cells. There is a plexiform layer superficial to this dense cell layer. Cells deep to it are regarded as either a medial extension of the subiculum or a lateral extension of the deep layers of the entorhinal cortex. The parasubiculum also has a superficial plexiform layer and a primary cell layer. It forms the boundary between the subicular complex as a whole and the entorhinal cortex. The cell layers deep to the parasubiculum are indistinguishable from the deep layers of the entorhinal cortex.

The entorhinal cortex (Brodmann’s area 28; see Figs 16.7, 16.28, 16.29) extends rostrally to the anterior limit of the amygdala. Caudally, it overlaps a portion of the hippocampal fields. The more primitive levels of the entorhinal cortex (below the amygdala) receive projections from the olfactory bulb. More caudal regions do not generally receive primary olfactory inputs.

The entorhinal cortex is divisible into six layers and is quite distinct from other neocortical regions. Layer I is acellular and plexiform. Layer II is a narrow cellular layer that consists of islands of large pyramidal and stellate cells. These cell islands are a distinguishing feature of the entorhinal cortex. They form small bumps on the surface of the brain that can be seen by the naked eye (verrucae hippocampae) and indicate the boundaries of the entorhinal cortex. Layer III consists of medium-sized pyramidal cells. There is no internal granular layer (another classic feature of entorhinal cortex); in its place is an acellular region of dense fibres called the lamina dissecans, which is sometimes called layer IV. Layers III and V are apposed in regions where the lamina dissecans is absent. Layer V consists of large pyramidal cells five or six deep. Layer VI is readily distinguishable from layer V only close to the border with the perirhinal cortex. Its cells continue around the angular bundle (subcortical white matter deep to the subicular complex, made up largely of perforant path axons) to lie beneath the pre- and parasubiculum.

Glutamate or aspartate appears to be the major excitatory transmitter in three pathways in the hippocampal formation—namely, the perforant pathway, which arises in the entorhinal cortex and terminates primarily in the dentate gyrus; the mossy fibres, which run from the dentate granule cells to the pyramidal cells of the CA3 field; and the Schaffer collaterals of CA3 pyramidal cells, which terminate on CA1 pyramidal cells.

GABAergic neurones are found in the deep portions of the granule cell layer in the dentate gyrus (basket cells). The highest concentration of GABA receptors is found in the molecular layer of the dentate gyrus. In the hippocampus proper, GABAergic cells are found mostly in the stratum oriens but also in the pyramidal cell layer and stratum radiatum.

There are many peptide-containing neurones in the hippocampal formation. Granule cells in the dentate gyrus appear to contain the opioid peptide dynorphin, which is also present in mossy fibres running to the CA3 field. Enkephalin, or a related peptide, may be present in fibres arising in the entorhinal cortex. There is a dense plexus of somatostatin-immunoreactive fibres in the molecular layer of the dentate gyrus and also in the stratum lacunosum-moleculare of the hippocampus. The polymorphic layer of the dentate gyrus, stratum oriens of the hippocampus and deep layers of the entorhinal cortex all contain somatostatin-immunoreactive neurones. VIP-immunoreactive neurones are plentiful in many hippocampal fields, especially in the superficial layers of the entorhinal cortex. Cells containing cholecystokinin (CCK) immunoreactivity are found in the hilar region of the dentate gyrus; in all layers of the hippocampus, especially in the pyramidal cell layer; and throughout the subicular complex and entorhinal cortex. There are also substantial plexuses of CCK-immunoreactive fibres in the stratum lacunosum-moleculare, subicular complex and entorhinal cortex. Hippocampal CCK-immunoreactive cells may give rise to extrinsic projections (e.g. to the lateral septum and medial mammillary nucleus), because CCK-immunoreactive fibres are found in the fimbria or fornix.

The dentate gyrus is the point of entry into the hippocampal circuitry. It receives fibres via the perforant path projections from layers II and III of the entorhinal cortex. The axons terminate in the outer two thirds of the molecular layer of the dentate gyrus, on the dendritic spines of granule cells. These cells project heavily via their mossy fibres onto the proximal dendrites of CA3 pyramidal cells. The latter give rise, via the so-called Schaffer collaterals, to a projection that terminates mainly in the stratum radiatum of the CA1 hippocampal field. The CA1 field projects heavily to the subicular complex, which projects to the entorhinal cortex.

The subiculum, rather than the hippocampus, projects to the mammillary complex, whereas the hippocampus gives rise principally to efferents destined for the septal complex. Summaries of hippocampal circuitry and connections are shown schematically in Figure 16.30.

Fig. 16.30 Neuronal organization and connections of the dentate gyrus, hippocampus (cornu ammonis), subiculum and parahippocampal gyrus. Cell somata, dendrites and axons of the pyramidal neurones of the cornu ammonis are yellow; the axons form the efferent hippocampal fibres of the alveus and fimbria. Afferent fibres to the cornu ammonis from the fimbria are purple; afferents from the entorhinal cortex via the perforant path are blue; basket neurones are black; neurones of the dentate gyrus and their axons, which form the mossy fibres of the hippocampus, are magenta; and subicular efferents to the fornix via the alveus are green.

The medial septal complex and the supramammillary area of the posterior hypothalamus are the two major sources of subcortical afferents to the hippocampal formation. There are also projections from the amygdaloid complex and claustrum (to the subicular complex and entorhinal cortex), as well as monoaminergic projections from the ventral tegmental area, the mesencephalic raphe nuclei and the locus coeruleus. The noradrenergic and serotoninergic projections reach all hippocampal fields but are especially dense in the dentate gyrus.

The projections from the septal complex arise in the medial septal and vertical limb nuclei of the diagonal band. They travel via the dorsal fornix, fimbria, and supracallosal striae and take a ventral route through the amygdaloid complex. These projections reach all hippocampal fields, but the most prominent terminations are in the dentate gyrus, field CA3, presubiculum, parasubiculum and entorhinal cortex. Many of these medial septal or diagonal band neurones are GABAergic or cholinergic, and they form part of the topographically organized basal forebrain cholinergic system (cell groups Ch1 and Ch2).

Neurones in the supramammillary area also provide significant innervation of the hippocampal formation. They arrive partly through the fornix and partly through a ventral route, and they terminate most heavily in the dentate gyrus and fields CA2 and CA3 of the cornu ammonis.

All divisions of the anterior thalamic nuclear complex and the associated lateral dorsal nucleus project to the hippocampal formation and are directed predominantly to the subicular complex. Some midline thalamic nuclei, particularly the parataenial, central medial and reuniens nuclei, also project to the hippocampal formation, especially to the entorhinal cortex.

In humans, the fornix contains approximately 1.2 million fibres. Cells in the CA3 field project bilaterally to the lateral nucleus of the septal complex, via the precommissural fornix. They give rise to the Schaffer collaterals to CA1 cells and to the commissural projections to the contralateral hippocampus. Neurones in the subicular complex and entorhinal cortex give rise to projections to the nucleus accumbens and to parts of the caudate nucleus and putamen. The subicular complex gives rise to the major postcommissural fibre system of the fornix. The presubiculum, in particular, projects to the anterior thalamic nuclear complex (anteromedial, anteroventral and laterodorsal nuclei). Both the subiculum and the presubiculum provide the major extrinsic input to the mammillary complex. Both the lateral and the medial mammillary nuclei receive afferents from the subicular complex.

Several fields in the temporal lobe neocortex, especially TF and TH of the parahippocampal gyrus, the dorsal bank of the superior temporal gyrus, the perirhinal cortex (Brodmann’s area 35) and the temporal polar cortex, together with the agranular insular cortex and posterior orbitofrontal cortex, all project to the entorhinal cortex. Projections to the entorhinal cortex also arise from the dorsolateral prefrontal cortex (Brodmann’s areas 9, 10, 46), the medial frontal cortex (Brodmann’s areas 25, 32), the cingulate cortex (Brodmann’s areas 23, 24) and the retrosplenial cortex. The subicular complex receives direct cortical inputs, such as from the temporal polar cortex, perirhinal cortex, parahippocampal gyrus, superior temporal gyrus and dorsolateral prefrontal cortex. The entorhinal cortex projects to the perirhinal cortex as well as to the temporal polar cortex and caudal parahippocampal and cingulate gyri. In monkeys, the subicular complex also projects to a number of cortical areas, including the perirhinal cortex, parahippocampal gyrus, caudal cingulate gyrus, and medial frontal and medial orbitofrontal cortices.

CASE 11 Alzheimer’s Disease

A 64-year-old man is brought for evaluation by his family because of impaired memory noted in the past 6 months. He has been unable to keep up with the demands of his business, has made a number of unfortunate decisions reflecting faulty judgment and has found it necessary to turn control of the family finances over to his wife. He has become increasingly apathetic and withdrawn, removing himself from his customary active social life.

On examination, he appears apathetic, with little spontaneous speech. He responds to direct questions and challenges slowly and incompletely. He has impaired memory for both recent and remote events, can no longer carry out simple arithmetic calculations, has a shortened attention span and is unable to explain proverbs or similarities in an abstract manner. He becomes intermittently agitated and is often delusional. With the exception of a mild, predominantly dysnomic form of aphasia and the occasional appearance of Parkinsonian signs, such as bradykinesia and rigidity, the remainder of the neurological examination is normal. A reversion to primitive reflex levels (e.g. forced grasping) may be evident.

Discussion: This man demonstrates the typical devastating, progressive clinical abnormalities of Alzheimer’s disease, probably the most common dementing illness of middle and later life (to be distinguished from diffuse Lewy body disease, vascular dementia, and normal-pressure hydrocephalus, for example). Ultimately, much of the cerebral grey matter is involved, with typical neuropathological alterations and neurofibrillary changes reflecting intracellular accumulation of the protein tau, amyloid-containing senile plaques, deposition of amyloid in small vessel walls and neuronal vacuolization and loss. The earliest morphological changes are found in the medial temporal lobe and in the basal nucleus (of Meynert), with secondary loss of acetylcholine transferase, especially in the neocortex, reflecting the degeneration of cholinergic projections from the basal nucleus (Fig. 16.31).

Fig. 16.31 Alzheimer’s disease, demonstrating marked cortical atrophy with enlargement of the lateral ventricles (hydrocephalus ex vacuo) and gaping of the Sylvian fissures.

(Courtesy of John S. Woodard, MD.)

Septum

The septum is a midline and paramedian structure (see Figs 14.6, 16.22). Its upper portion corresponds largely to the bilateral laminae of fibres, sparse grey matter and neuroglia known as the septum pellucidum, which separates the lateral ventricles. Below this, the septal region is made up of four main nuclear groups: dorsal, ventral, medial and caudal. The dorsal group is essentially the dorsal septal nucleus, the ventral group consists of the lateral septal nucleus, the medial group contains the medial septal nucleus and the nucleus of the diagonal band of Broca and the caudal group contains the fimbrial and triangular septal nuclei.

The major afferents to the region terminate primarily in the lateral septal nucleus. They include fibres carried in the fornix that arise from hippocampal fields CA3 and CA1 and the subiculum. There are also afferents arising from the preoptic area; anterior, paraventricular and ventromedial hypothalamic nuclei; and lateral hypothalamic area. The lateral septum receives a rich monoaminergic innervation, including noradrenergic afferents from the locus coeruleus and medullary cell groups (A1, A2), serotoninergic afferents from the midbrain raphe nuclei and dopaminergic afferents from the ventral tegmental area (A10).

Projections from the lateral septum run to the medial and lateral preoptic areas, anterior hypothalamus, and supramammillary and midbrain ventral tegmental area via the medial forebrain bundle. There is also a projection to the medial habenular nucleus and to some midline thalamic nuclei via the stria medullaris thalami, which runs on the dorsomedial wall of the third ventricle. The projections from the habenula via the fasciculus retroflexus to the interpeduncular nucleus and adjacent ventral tegmental area in the midbrain provide a route through which forebrain limbic structures can influence midbrain nuclear groups.

A large proportion of the medial septal or diagonal band neurones are cholinergic or GABAergic. They project to the hippocampal formation and cingulate cortex.

Amygdala

The amygdaloid nuclear complex is made up of lateral, central and basal nuclei that lie in the dorsomedial temporal pole, anterior to the hippocampus, and close to the tail of the caudate nucleus (see Fig. 16.22). Collectively, the nuclei form the ventral, superior and medial walls of the tip of the inferior horn of the lateral ventricle. The amygdala is partly continuous above with the inferomedial margin of the claustrum. Fibres of the external capsule and substriatal grey matter, including the cholinergic magnocellular nucleus basalis (of Meynert), incompletely separate it from the putamen and globus pallidus. Laterally, it is close to the optic tract. It is partly deep to the gyrus semilunaris, gyrus ambiens and uncinate gyrus (see Fig. 16.7).

The lateral nucleus has dorsomedial and ventrolateral subnuclei. The central nucleus has medial and lateral subdivisions. The basal nucleus is commonly divided into a dorsal magnocellular basal nucleus, an intermediate parvocellular basal nucleus and a ventral band of darkly staining cells usually referred to as the paralaminar basal nucleus because it borders the white matter ventral to the amygdaloid complex. The accessory basal nucleus lies medial to the basal nuclear divisions. It is usually divided into dorsal magnocellular and ventral parvocellular parts. The lateral and basal nuclei are often referred to collectively as the basolateral area (nuclear group) of the amygdaloid complex.

It has been suggested that the basolateral complex of nuclei (lateral, basal, accessory basal) shares several characteristics with the cortex and that it may be considered a quasi-cortical structure. Although it lacks a laminar structure, it has direct, often reciprocal, connections with adjacent temporal and other areas of cortex, and it projects to the motor or premotor cortex. It receives a direct cholinergic and non-cholinergic input from the magnocellular corticopetal system in the basal forebrain and has reciprocal connections with the mediodorsal thalamus. The distribution of small peptidergic neurones in the basolateral nuclear complex (e.g. those containing neuropeptide Y, somatostatin and CCK) are also similar in form and density to those found in the adjacent temporal lobe cortex. Projection neurones from this part of the amygdala appear to utilize, at least in part, the excitatory amino acids glutamate and aspartate as transmitters. Moreover, they project to the ventral striatum rather than to hypothalamic and brain stem sites. Thus, it may be appropriate to consider this part of the amygdaloid complex as a polymodal cortex-like area that is separated from the cerebral cortex by fibres of the external capsule.

The central nucleus is present through the caudal half of the amygdaloid complex, lying dorsomedial to the basal nucleus. It is divided into medial and lateral parts. The medial part, which contains larger cells than the lateral part, resembles the adjacent putamen. The medial and central nuclei appear to have an extension across the basal forebrain, as well as within the stria terminalis, which merges with the bed nucleus of the stria terminalis. This extensive nuclear complex, sometimes referred to as the ‘extended amygdala,’ is illustrated in Figure 16.32. It can be considered a macrostructure formed by the centromedial amygdaloid complex (medial nucleus, medial and lateral parts of the central nucleus), the medial bed nucleus of the stria terminalis and the cell columns that traverse the sublenticular substantia innominata, which lies between them. It has been suggested that portions of the medial nucleus accumbens may be included in the extended amygdala.

Fig. 16.32 Coronal section through the basal forebrain and temporal pole, illustrating the relationship among the striatum (yellow), globus pallidus (dorsal globus pallidus, GP; ventral pallidum, VP), extended amygdala (blue) and magnocellular corticopetal basal forebrain system (magenta). Note that the medial part of the nucleus accumbens–olfactory tubercle area (green) may be a mixed zone of the ventral striatopallidal system and the extended amygdala.

A consistent feature of the intrinsic connections among amygdaloid nuclei is that they arise primarily in lateral and basal nuclei and terminate in central and medial nuclei, which suggests a largely unidirectional flow of information. In brief, the lateral nucleus projects to all divisions of the basal nucleus, accessory basal nucleus, and paralaminar and anterior cortical nuclei and less heavily to the central nucleus. The lateral nucleus receives few afferents from other nuclei. The magnocellular, parvocellular and intermediate parts of the basal nucleus project to the accessory basal, central (especially the medial part) and medial nuclei, as well as to the periamygdaloid cortex and the amygdalohippocampal area. The accessory basal nucleus projects densely to the central nucleus, especially its medial division, as well as to the medial and cortical nuclei. Its major intra-amygdaloid afferents arise from the lateral nucleus. The medial nucleus projects to the accessory basal, anterior cortical and central nuclei, as well as to the periamygdaloid cortex and amygdalohippocampal area; afferents arise especially from the lateral nucleus. The intrinsic connections of the cortical nucleus are not well understood. The posterior part of the cortical nucleus projects to the medial nucleus, but it has been difficult to differentiate this projection from that arising in the amygdalohippocampal area. The central nucleus projects to the anterior cortical nucleus and the various cortical transition zones. It forms an important focus for afferents from many of the amygdaloid nuclei, especially the basal and accessory basal nuclei, and it has major extrinsic connections.

The organization of the extensive subcortical and cortical interconnections and connections of the amygdala are consistent with a role in emotional behaviour. It receives highly processed unimodal and multimodal sensory information from the thalamus and sensory and association cortices, olfactory information from the bulb and piriform cortex and visceral and gustatory information relayed via brain stem structures and the thalamus. Its projections reach widespread areas of the brain, including the endocrine and autonomic domains of the hypothalamus and brain stem. In a functional sense, the limbic–amygdala complex is strategically placed between the cerebral cortex and hypothalamus, serving to effectively modulate an organism’s response to changes within the environment via hypothalamic and neuroendocrine mechanisms, as well as motor responses via the brain stem.

Corpus Callosum

The corpus callosum is the largest fibre pathway of the brain (Figs. 16.2, 16.4, 16.35, 16.36). It links the cerebral cortex of the two cerebral hemispheres, and it roofs much of the lateral ventricles. It forms an arch approximately 10 cm long, with an anterior end approximately 4 cm from the frontal poles and a posterior end approximately 6 cm from the occipital poles. Its anterior portion is known as the genu. This recurves posteroinferiorly in front of the septum pellucidum, then diminishes rapidly in thickness and is prolonged to the upper end of the lamina terminalis as the rostrum. The trunk of the corpus callosum arches back and is convex above. It ends posteriorly in the expanded splenium, which is its thickest part.

Fig. 16.35 Oblique coronal section of the brain.

(Dissection by E. L. Rees; photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

Fig. 16.36 Superior aspect of the corpus callosum revealed by partial removal of the cerebral hemispheres.

The median region of the trunk of the corpus callosum forms the floor of the great longitudinal fissure. There, it lies close to the anterior cerebral vessels and the lower border of the falx cerebri, which may contact it from behind. On each side, the trunk is overlapped by the cingulate gyrus, separated from it by the callosal sulcus. The inferior surface of the corpus callosum is concave in its long axis. The septum pellucidum is attached to it anteriorly. Posteriorly, it is fused with the fornix and its commissure.

The superior surface of the callosal trunk (see Fig. 16.35) is covered by a thin layer of grey matter, the indusium griseum. This extends anteriorly around the genu; then, on the inferior aspect of the rostrum, it continues into the paraterminal gyrus. It contains narrow longitudinal bundles of fibres on each side, the medial and lateral longitudinal striae. Posteriorly, the indusium griseum is continuous with the dentate gyrus and hippocampus through the gyrus fasciolaris (Fig. 16.37).

Fig. 16.37 Anterior aspect of a coronal section of the cerebrum. The posterior parts of the thalami have been removed to reveal the splenium of the corpus callosum.

The splenium of the corpus callosum overhangs the posterior ends of the thalami, the pineal gland and the tectum but is separated from them by several structures. On each side, the crus of the fornix and gyrus fasciolaris curve up to the splenium. The crus continues forward on the inferior surface of the callosal trunk, but the gyrus fasciolaris skirts above the splenium, then rapidly diminishes into the indusium griseum. The tela choroidea of the third ventricle advances below the splenium through the transverse fissure, and the internal cerebral veins emerge between its two layers to form the great cerebral vein. Posteriorly, the splenium is near the tentorium cerebelli, great cerebral vein and beginning of the straight sinus.

Nerve fibres of the corpus callosum radiate into the white matter core of each hemisphere, thereafter dispersing to the cerebral cortex. Commissural fibres forming the rostrum extend laterally, below the anterior horn of the lateral ventricle, connecting the orbital surfaces of the frontal lobes. Fibres in the genu curve forward, as the forceps minor, to connect the lateral and medial surfaces of the frontal lobes. Fibres of the trunk pass laterally, intersecting with the projection fibres of the corona radiata to connect wide neocortical areas of the hemispheres (Figs 16.38, 16.39). Fibres of the trunk and splenium, which form the roof and lateral wall of the posterior horn and the lateral wall of the inferior horn of the lateral ventricle, constitute the tapetum. The remaining fibres of the splenium curve back into the occipital lobes as the forceps major.

Fig. 16.38 Left cerebral hemisphere dissected from its medial aspect to display the fibre bundles of the corona radiata and internal capsule.

(Dissection by A. M. Seal; photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

Fig. 16.39 Lateral aspect of the left side of the brain showing the convergence of cortical projection fibres through the corona radiata into the cerebral peduncles and pons.

Not all interhemispheric connections through the corpus callosum represent a simple linking of loci in one hemisphere with the same loci in the other. In areas containing a clear representation of a contralateral sensorium (e.g. body surface, visual field), only those areas that are functionally related to midline representation are linked to the contralateral hemisphere. This is seen most clearly for the visual areas, where the cortex containing the representation of each midline retinal zone is linked to its counterpart on the contralateral side. A similar arrangement is seen in somatic areas, where the trunk representation is callosally linked, but the peripheral limb areas (hands and feet) are not.

Connections that link the same or similar areas on each side are termed homotopic connections. The corpus callosum also interconnects heterogeneous cortical areas on the two sides (heterotopic connections). These may serve to connect functionally similar but anatomically different loci in the two hemispheres or to connect functional areas in one hemisphere with regions that are specialized for a unilaterally confined function in the other.

Congenital absence of the corpus callosum is rare. When it occurs, the clinical history usually lacks diagnostic features. This is perhaps not surprising, because apparently little disturbance of function occurs when large parts, and in some cases all, of the corpus callosum are surgically divided for the control of intractable epilepsy. The studies of Sperry (1974, 1984) on the effects of dividing the human corpus callosum revealed its function in the transfer of information (including memorized data) across the midline of the cerebrum and confirmed a long-suspected asymmetry of function, leading to the concept of ‘dominance,’ usually by the left hemisphere.

CASE 13 Glioma of the Corpus Callosum

A 45-year-old woman, previously well, complains of increasing headache and mild memory impairment. Over several months, she becomes increasingly indifferent and apathetic, with lack of interest in her surroundings and loss of normal emotional responses to external stimuli. She exhibits little spontaneous speech. She is described by family members as depressed and mentally ‘slow.’ On examination, she appears mildly demented and frankly abulic. Both plantar responses are extensor; there are no other focal neurological signs. Enhanced CT studies demonstrate an aggressive glioma involving the genu of the corpus callosum, with spread into the white matter of both frontal lobes (‘butterfly’ glioma).

Discussion: Glioma of the corpus callosum, particularly early in its course, must be distinguished from Alzheimer’s disease, multi-infarct dementia, frontotemporal dementia, Parkinson’s disease, and late-onset depression, as well as a host of systemic disorders. Neuroimaging is clearly diagnostic in these circumstances (Fig. 16.40). The tumour may be found in the genu, body, or splenum of the corpus callosum.

Fig. 16.40 Glioma of the corpus callosum. Post-contrast T1-weighted MRI demonstrates a glioma in the splenium of the corpus callosum.

CASE 14 Marchiafava–Bignami Disease

An elderly alcoholic becomes confused, exhibiting a progressive dementing illness with occasional seizures and a mixture of multifocal (pyramidal and extrapyramidal) clinical signs. The disorder evolves over several months, with occasional complete or incomplete remissions marking its overall course. Necrosis of the mesial portion of the corpus callosum is observed with MRI, amply confirmed on postmortem examination. The lesion in the corpus callosum involves especially its anterior part, and frank cavitation can be seen. The anterior commissure and occasionally other commissural bundles may be similarly involved, and lesions may spread from the corpus callosum into the centrum semiovale bilaterally (Fig. 16.41).

Fig. 16.41 Marchiafava-Bignami disease. Myelin sheath stain demonstrating symmetric demyelination in the corpus callosum (solid arrow) and anterior commissure (dashed arrow).

Discussion: The pathological changes are typical of Marchiafava-Bignami disease. Despite the highly characteristic pathological changes, there is no typical clinical syndrome associated with the anatomical lesions. The precise cause of the disease is not known. Originally thought to be caused by an undetermined toxin (e.g. a contaminant in red wine), it is more likely of nutritional origin.

Anterior Commissure

The anterior commissure is a compact bundle of myelinated nerve fibres that crosses anterior to the columns of the fornix and is embedded in the lamina terminalis, where it is part of the anterior wall of the third ventricle (see Fig. 16.22). In sagittal section it is oval; its long (vertical) diameter is approximately 1.5 mm. Laterally, it splits into two bundles. The smaller anterior bundle curves forward on each side to the anterior perforated substance and olfactory tract. The posterior bundle curves posterolaterally on each side in a deep groove on the anteroinferior aspect of the lentiform complex and subsequently fans out into the anterior part of the temporal lobe, including the parahippocampal gyrus. Areas thought to be connected via commissural fibres include the olfactory bulb and anterior olfactory nucleus; the anterior perforated substance, olfactory tubercle and diagonal band of Broca; the prepiriform cortex; the entorhinal area and adjacent parts of the parahippocampal gyrus; part of the amygdaloid complex, especially the nucleus of the lateral olfactory stria; the bed nucleus of the stria terminalis and the nucleus accumbens; and the anterior regions of the middle and inferior temporal gyri.

Internal Capsule

In horizontal cerebral sections, the internal capsule appears as a broad white band, with a lateral concavity, that accommodates the lentiform complex (see Figs 16.35, 16.38; Figs 16.42–16.44). It has an anterior limb, genu, posterior limb, and retrolenticular (retrolentiform) and sublenticular (sublentiform) parts. Both anterior and posterior limbs are medial to the lentiform complex. The head of the caudate nucleus is medial to the anterior limb, and the thalamus is medial to the posterior limb. Cortical efferent fibres of the internal capsule continue to converge as they descend. Fibres derived from the frontal lobe tend to pass posteromedially, whereas temporal and occipital fibres pass anterolaterally. Many, but not all, corticofugal fibres pass into the crus cerebri of the ventral midbrain. There, corticospinal and corticobulbar fibres are located in the middle half of the crus. Frontopontine fibres are located medially, whereas corticopontine fibres from temporal, parietal and occipital cortices are found laterally.

Fig. 16.42 Superior aspect of a horizontal section through the left cerebral hemisphere.

Fig. 16.43 Horizontal section of the brain through the frontal and occipital poles of the cerebral hemispheres.

(Dissection by E. L. Rees; photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

Fig. 16.44 Horizontal section through the internal capsule illustrating its main fibre components. Descending motor fibres, yellow; corticofugal fibres to the thalamus and pons, red; ascending fibres, blue.

(From Truex, R.C. [Ed.], Strong and Elwyn’s Human Neuroanatomy, 4th ed. London: Baillière Tindall and Cox, London; and Kretschmann, H.-J., 1998. Localization of the corticospinal fibres in the internal capsule in man. J. Anat. [Lond.] 160, 219–225.)

The anterior limb of the internal capsule contains frontopontine fibres, which arise from the cortex in the frontal lobe. They synapse with cells in the pontine nuclei. Axons of these cells enter the opposite cerebellar hemisphere through the middle cerebellar peduncle. Anterior thalamic radiations interconnect the medial and anterior thalamic nuclei and various hypothalamic nuclei and limbic structures with the frontal cortex.

The genu of the internal capsule is usually regarded as containing corticonuclear (corticobulbar) fibres, which are derived mainly from area 4 and terminate mostly in the contralateral motor nuclei of cranial nerves. Anterior fibres of the superior thalamic radiation, between the thalamus and cortex, also extend into the genu.

The posterior limb of the internal capsule includes the corticospinal tract. The fibres concerned with the upper limb are anterior. More posterior regions contain fibres representing the trunk and lower limbs. Other descending axons include frontopontine fibres, particularly from areas 4 and 6, and corticorubral fibres, which connect the frontal lobe to the red nucleus. Most of the posterior limb also contains fibres of the superior thalamic radiation (somaesthetic radiation) ascending to the postcentral gyrus.

The retrolenticular part of the internal capsule contains parietopontine, occipitopontine and occipitotectal fibres. It also includes the posterior thalamic radiation and optic radiation and interconnections between the occipital and parietal lobes and caudal parts of the thalamus, especially the pulvinar.

The optic radiation arises in the lateral geniculate body. It sweeps backward, intimately related to the superolateral aspect of the inferior horn and the lateral aspect of the posterior horn of the lateral ventricle, from which it is separated by the tapetum.

The sublenticular part of the internal capsule contains temporopontine and some parietopontine fibres, the acoustic (auditory) radiation from the medial geniculate body to the superior temporal and transverse temporal gyri (areas 41 and 42) and a few fibres that connect the thalamus with the temporal lobe and insula. Fibres of the acoustic radiation sweep anterolaterally below and behind the lentiform complex to reach the cortex.