Diencephalon

Published on 13/06/2015 by admin

Filed under Basic Science

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 0 (0 votes)

This article have been viewed 2593 times

Chapter 15 Diencephalon

The diencephalon is part of the prosencephalon (forebrain), which develops from the foremost primary cerebral vesicle and differentiates into a caudal diencephalon and rostral telencephalon. The cerebral hemispheres develop from the sides of the telencephalon, each containing a lateral ventricle. The sites of evagination become the interventricular foramina, through which the two lateral ventricles and midline third ventricle communicate. The diencephalon corresponds largely to the structures that develop lateral to the third ventricle.

The lateral walls of the diencephalon form the epithalamus most superiorly, the thalamus centrally and the subthalamus and hypothalamus most inferiorly. The epithalamus in the mature brain contains the anterior and posterior paraventricular nuclei, the medial and lateral habenular nuclei, the stria medullaris thalami and the pineal gland. The thalamus undergoes proliferation to form numerous nuclear masses that have extensive reciprocal connections with the cerebral cortex. The subthalamic region consists of the subthalamic nucleus, zona incerta and fields of Forel. The subthalamic nucleus is closely related to the basal ganglia and is considered with them in Chapter 14. The hypothalamic rudiment gives rise to most of the subdivisions of the adult hypothalamus.

Thalamus

The thalamus is an ovoid nuclear mass, approximately 4 cm long, that borders the dorsal part of the third ventricle (Figs 15.115.3; see also Fig. 1.10). The narrow anterior pole lies close to the midline and forms the posterior boundary of the interventricular foramen. Posteriorly, an expansion, the pulvinar, extends beyond the third ventricle to overhang the superior colliculus (Fig. 15.4). The brachium of the superior colliculus (superior quadrigeminal brachium) separates the pulvinar above from the medial geniculate body below. A small oval elevation, the lateral geniculate body, lies lateral to the medial geniculate.

image

Fig. 15.4 Oblique view of the dorsal aspect of the brain stem and thalamus.

(Photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

The superior (dorsal) surface of the thalamus (see Fig. 15.2) is covered by a thin layer of white matter, the stratum zonale. It extends laterally from the line of reflection of the ependyma (taenia thalami) and forms the roof of the third ventricle. This curved surface is separated from the overlying body of the fornix by the choroid fissure, with the tela choroidea within it. More laterally, it forms part of the floor of the lateral ventricle. The lateral border of the superior surface of the thalamus is marked by the stria terminalis and the overlying thalamostriate vein, which separate the thalamus from the body of the caudate nucleus. Laterally, a slender sheet of white matter, the external medullary lamina, separates the main body of the thalamus from the reticular nucleus. Lateral to this, the thick posterior limb of the internal capsule lies between the thalamus and the lentiform complex.

The medial surface of the thalamus is the superior (dorsal) part of the lateral wall of the third ventricle (see Fig. 5.8). It is usually connected to the contralateral thalamus by an interthalamic adhesion behind the interventricular foramina. The boundary with the hypothalamus is marked by an indistinct hypothalamic sulcus, which curves from the upper end of the cerebral aqueduct to the interventricular foramen. The thalamus is continuous with the midbrain tegmentum, the subthalamus and the hypothalamus.

Internally, the thalamus is divided into anterior, medial and lateral nuclear groups by a vertical Y-shaped sheet of white matter, the internal medullary lamina (Figs 15.5, 15.6). In addition, intralaminar nuclei lie embedded within, and surrounded by, the internal medullary lamina. Midline nuclei either abut the ependyma of the lateral walls of the third ventricle medially or lie adjacent to, and to some extent within, the interthalamic adhesion. Reticular nuclei lie lateral to the main nuclear mass, separated from it by the external medullary lamina.

In general, thalamic nuclei both project to and receive fibres from the cerebral cortex (see Fig. 15.6). The whole cerebral cortex, not only the neocortex but also the phylogenetically older palaeocortex of the piriform lobe and archicortex of the hippocampal formation, are reciprocally connected with the thalamus. The thalamus is the major route by which subcortical neuronal activity influences the cerebral cortex, and the greatest input to most thalamic nuclei comes from the cerebral cortex.

The projection to the thalamus from the cortex is precisely reciprocal; each cortical area projects in a topographically organized manner to all sites in the thalamus from which it receives an input. Corticothalamic fibres that reciprocate ‘specific’ thalamocortical pathways arise from modified pyramidal cells of layer VI, whereas those reciprocating ‘non-specific’ inputs arise from typical pyramidal cells of layer V and may in part be axon collaterals of other cortical–subcortical pathways.

It is customary to consider thalamic nuclei as either ‘specific’ nuclei, which mediate finely organized and precisely transmitted sensory information to discrete cortical sensory areas, or ‘non-specific’ nuclei, which are part of a general arousal system. The specific nuclei are further subdivided into relay nuclei and association nuclei. However, many nuclei classified as specific may also send non-specific projections to widespread cortical areas. Similarly, the division of thalamic nuclei into relay and association groups rests on the assumption that relay nuclei receive a major subcortical pathway, whereas association nuclei receive their principal non-cortical input from other thalamic nuclei. There is little evidence of significant intrathalamic connectivity but there are increasing indications of non-cortical afferent pathways linked to so-called association nuclei.

Anterior Group of Thalamic Nuclei

The anterior group of nuclei are enclosed between the arms of the Y-shaped internal medullary lamina and underlie the anterior thalamic tubercle (see Fig. 15.2, 15.6). Three subdivisions are recognized. The largest is the anteroventral nucleus; the others are the anteromedial and anterodorsal nuclei.

The anterior nuclei are the principal recipients of the mammillothalamic tract, which arises from the mammillary nuclei of the hypothalamus. The mammillary nuclei receive fibres from the hippocampal formation via the fornix. The medial mammillary nucleus projects to the ipsilateral anteroventral and anteromedial thalamic nuclei, and the lateral mammillary nucleus projects bilaterally to the anterodorsal nuclei. The nuclei of the anterior group also receive a prominent cholinergic input from the basal forebrain and the brain stem.

The cortical targets of efferent fibres from the anterior nuclei of the thalamus lie largely on the medial surface of the hemisphere (see Fig. 15.6). They include the anterior limbic area (in front of and inferior to the corpus callosum), the cingulate gyrus and the parahippocampal gyrus (including the medial entorhinal cortex and the pre- and para-subiculum). These thalamocortical pathways are reciprocal. There also appear to be minor connections between the anterior nuclei and the dorsolateral prefrontal and posterior areas of the neocortex. The anterior thalamic nuclei are believed to be involved in the regulation of alertness and attention and in the acquisition of memory.

Medial Group of Thalamic Nuclei

The single component of this thalamic region is the mediodorsal or dorsomedial nucleus, which is particularly large in humans. Laterally, it is limited by the internal medullary lamina and intralaminar nuclei (see Figs. 15.5, 15.6). Medially, it abuts the midline parataenial and reuniens (medioventral) nuclei. It can be divided into anteromedial magnocellular and posterolateral parvocellular parts.

The small magnocellular division receives olfactory input from the piriform and adjacent cortex, the ventral pallidum and the amygdala. The mediobasal amygdaloid nucleus projects to the dorsal part of the anteromedial magnocellular nucleus, and the lateral nuclei project to the more central and anteroventral regions. The anteromedial magnocellular nucleus projects to the anterior and medial prefrontal cortex, notably to the lateral posterior and central posterior olfactory areas on the orbital surface of the frontal lobe. In addition, fibres pass to the ventromedial cingulate cortex, and a few pass to the inferior parietal cortex and anterior insula. These cortical connections are reciprocal.

The larger posterolateral parvocellular division connects reciprocally with the dorsolateral and dorsomedial prefrontal cortex, the anterior cingulate gyrus and the supplementary motor area. In addition, efferent fibres pass to the posterior parietal cortex.

The mediodorsal nucleus appears to be involved in a wide variety of higher functions. Damage may lead to a decrease in anxiety, tension, aggression or obsessive thinking. There may also be transient amnesia, with confusion developing over time. Much of the neuropsychology of medial nuclear damage reflects defects in functions similar to those performed by the prefrontal cortex, with which it is closely linked. The effects of ablation of the mediodorsal nuclei parallel, in part, the results of prefrontal lobotomy.

Lateral Group of Thalamic Nuclei

The lateral nuclear complex, lying lateral to the internal medullary lamina, is the largest major division of the thalamus (see Fig. 15.6). It is divided into dorsal and ventral tiers of nuclei. The lateral dorsal nucleus, lateral posterior nucleus and pulvinar all lie dorsally. The lateral and medial geniculate nuclei lie inferior to the pulvinar, near the posterior pole of the thalamus. The ventral tier nuclei are the ventral anterior, ventral lateral and ventral posterior nuclei.

Ventral Lateral Nucleus

The ventral lateral (VL) thalamus consists of two major divisions with distinctly different connections and functions. The anterior division, or pars oralis (VLo), receives topographically organized fibres from the internal segment of the ipsilateral globus pallidus. The posterior division, or pars caudalis (VLc), receives topographically organized fibres from the contralateral deep cerebellar nuclei. Additional subcortical projections have been reported from the spinothalamic tract and the vestibular nuclei. Numerous cortical afferents to both VLo and VLc originate from precentral motor cortical areas, including areas 4 and 6.

The VLo nucleus sends efferent fibres to the supplementary motor cortex on the medial surface of the hemisphere and to the lateral premotor cortex. The VLc nucleus projects efferent fibres to the primary motor cortex, where they end in a topographically arranged fashion. The head region of area 4 receives fibres from the medial part of VLc, and the leg region receives fibres from lateral VLc.

Responses can be recorded in the VL thalamus during both passive and active movement of the contralateral body. The topography of its connections and recordings made within the nucleus suggest that VLc contains a body representation comparable with that in the ventral posterior nucleus. Stereotaxic surgery of the VL nucleus is sometimes used in the treatment of essential tremor. In the past, thalamotomy was used extensively for the treatment of Parkinson’s disease; however, the internal segment of the globus pallidus and the subthalamic nucleus are now the preferred neurosurgical targets for Parkinson’s disease.

Ventral Posterior Nucleus

The ventral posterior (VP) nucleus is the principal thalamic relay for the somatosensory pathways. It is thought to consist of two major divisions, the ventral posterolateral (VPl) and ventral posteromedial (VPm) nuclei. The VPl nucleus receives the medial lemniscal and spinothalamic pathways, and the VPm nucleus receives the trigeminothalamic pathway. Connections from the vestibular nuclei and lemniscal fibres terminate along the ventral surface of the VP nucleus.

There is a well-ordered topographical representation of the body in the VP nucleus. The VPl is organized so that sacral segments are represented laterally and cervical segments medially. The latter abut the face area of representation (trigeminal territory) in VPm. Taste fibres synapse anteriorly and ventromedially within the VPl nucleus.

At a more detailed level, single body regions are represented as curved lamellae of neurones, parallel to the lateral border of the VP nucleus, such that there is a continuous overlapping progression of adjacent receptive fields from dorsolateral to ventromedial. Considerably less change in location of receptive field on the body is seen when passing anteroposteriorly through the nucleus. Although not precisely dermatomal in nature, these curvilinear lamellae of cells probably derive from afferents related to a few adjacent spinal segments. There is considerable distortion of the body map within the nucleus, reflecting the differences in the density of peripheral innervation in different body regions; for example, many more neurones respond to stimulation of the hand than of the trunk. Within a single lamella, neurones in the anterodorsal part of the nucleus respond to deep stimuli, including movement of joints, tendon stretch and manipulation of muscles. Most ventrally, neurones once again respond to deep stimuli, particularly tapping. Intervening cells within a single lamella respond only to cutaneous stimuli. This organization has been confirmed by recordings made in the human VP nucleus.

Single lemniscal axons have an extended anteroposterior terminal zone within the nucleus. Rods of cells running the length of the anteroposterior, dorsoventrally oriented lamellae respond with closely similar receptive field properties and locations, derived from a small bundle of lemniscal afferents. It appears, therefore, that each lamella contains the complete representation of a single body part (e.g. a finger). Lamellae consist of multiple narrow rods of neurones, oriented anteroposteriorly, each of which receives input from the same small region of the body represented within the lamella and from the same type of receptors. These thalamic ‘rods’ form the basis for both place- and modality-specific input to columns of cells in the somatic sensory cortex. Spinothalamic tract afferents to the VPl nucleus terminate throughout the nucleus. The neurones from which these axons originate appear to be mainly of the ‘wide dynamic range’ class, with responses to both low-threshold mechanoreceptors and high-threshold nociceptors. A smaller proportion are solely high-threshold nociceptors. Some neurones respond to temperature changes. There is evidence that spinothalamic tract neurones carrying nociceptive and thermal information terminate in a distinct nuclear area, identified as the posterior part of the ventral medial nucleus (VMpo).

The VP nucleus projects to the primary somatic sensory cortex of the postcentral gyrus and to the second somatic sensory area in the parietal operculum. VMpo projects to the insular cortex. Within the primary sensory cortex, the central cutaneous core of the VP nucleus projects solely to area 3b; dorsal and ventral to this, a narrow band of cells projects to both area 3b and area 1. The most dorsal and ventral deep stimulus receptive cells project to areas 3a and 2. The whole nucleus projects to the second somatic sensory area.

Medial Geniculate Nucleus

The medial geniculate nucleus, which is a part of the auditory pathway (Ch. 12), is located within the medial geniculate body, a rounded elevation situated posteriorly on the ventrolateral surface of the thalamus and separated from the pulvinar by the superior quadrigeminal brachium. It receives fibres travelling in the inferior quadrigeminal brachium. Three major subnuclei—medial, ventral and dorsal—are recognized within it. The inferior brachium separates the medial (magnocellular) nucleus, which consists of sparse, deeply staining neurones, from the lateral nucleus, which is made up of medium-sized, densely packed and darkly staining cells. The dorsal nucleus overlies the ventral nucleus and expands posteriorly; therefore, it is sometimes known as the posterior nucleus of the medial geniculate. It contains small to medium-sized, pale-staining cells, which are less densely packed than those of the lateral nucleus. The ventral nucleus receives fibres from the central nucleus of the ipsilateral inferior colliculus via the inferior quadrigeminal brachium and also from the contralateral inferior colliculus. The nucleus contains a complete tonotopic representation. Low-pitched sounds are represented laterally, and progressively higher-pitched sounds are encountered as the nucleus is traversed from lateral to medial. The dorsal nucleus receives afferents from the pericentral nucleus of the inferior colliculus and from other brain stem nuclei of the auditory pathway. A tonotopic representation has not been described in this subdivision, and cells within the dorsal nucleus respond to a broad range of frequencies. The magnocellular medial nucleus receives fibres from the inferior colliculus and from the deep layers of the superior colliculus. Neurones within the magnocellular subdivision may respond to modalities other than sound. However, many cells respond to auditory stimuli, usually to a wider range of frequencies than do neurones in the ventral nucleus. Many units show evidence of binaural interaction, with the leading effect arising from stimuli in the contralateral cochlea. The ventral nucleus projects primarily to the primary auditory cortex. The dorsal nucleus projects to auditory areas surrounding the primary auditory cortex. The magnocellular division projects diffusely to auditory areas of the cortex and to adjacent insular and opercular fields.

Lateral Geniculate Nucleus

The lateral geniculate body, which is part of the visual pathway (Ch. 12), is a small ovoid ventral projection from the posterior thalamus (Fig. 15.7). The superior quadrigeminal brachium enters the posteromedial part of the lateral geniculate body dorsally, lying between the medial geniculate body and the pulvinar.

image

Fig. 15.7 Coronal section through the brain showing the lateral geniculate nucleus.

(Photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

The lateral geniculate nucleus is an inverted, somewhat flattened U-shaped nucleus and is laminated. Its internal organization is usually described on the basis of six laminae, although seven or eight may be present. The laminae are numbered 1 to 6, from the innermost ventral to the outermost dorsal (Fig. 15.8). Laminae 1 and 2 consist of large cells, the magnocellular layers, whereas layers 4 to 6 have smaller neurones, the parvocellular laminae. The apparent gaps between laminae are called the interlaminar zones. Most ventrally, an additional superficial, or S, lamina is recognized.

The lateral geniculate nucleus receives a major afferent input from the retina. The contralateral nasal retina projects to laminae 1, 4 and 6, whereas the ipsilateral temporal retina projects to laminae 2, 3 and 5. The parvocellular laminae receive axons predominantly of X-type retinal ganglion cells, which are slowly conducting cells with sustained responses to visual stimuli. The faster conducting, rapidly adapting Y-type retinal ganglion cells project mainly to magnocellular laminae 1 and 2 and give off axonal branches to the superior colliculus. A third type of retinal ganglion cell—the W cell, which has large receptive fields and slow responses—projects to both the superior colliculus and the lateral geniculate nucleus and terminates particularly in the interlaminar zones and in the S lamina.

The lateral geniculate nucleus is organized in a visuotopic manner and contains a precise map of the contralateral visual field. The vertical meridian is represented posteriorly, the peripheral anteriorly, the upper field laterally, and the lower field medially (Ch. 12). Similar precise point-to-point representation is also found in the projection of the lateral geniculate nucleus to the visual cortex. Radially arranged inverted pyramids of neurones in all laminae respond to a single small area of the contralateral visual field and project to a circumscribed area of cortex. The termination of geniculocortical axons in the visual cortex is considered in detail in Chapter 16.

Aside from retinal afferents, the lateral geniculate nucleus receives a major corticothalamic projection, the axons of which ramify densely in the interlaminar zones. The major part of this projection arises from the primary visual cortex, Brodmann’s area 17, but smaller projections from extrastriate visual areas pass to the magnocellular and S laminae. Other afferents include fibres from the superficial layer of the superior colliculus (which terminate in the interlaminar zone between laminae 1 and 2 or 2 and 3 and around lamina S), noradrenergic fibres from the locus coeruleus, serotoninergic afferents from the midbrain raphe nuclei and cholinergic fibres from the pontine and mesencephalic reticular formation.

The efferent fibres of the lateral geniculate nucleus pass principally to the primary visual cortex (area 17) in the banks of the calcarine sulcus. It is possible that additional small projections pass to extrastriate visual areas in the occipital lobe, possibly arising primarily in the interlaminar zones.

Pulvinar

The pulvinar corresponds to the posterior expansion of the thalamus, which overhangs the superior colliculus. It has three major subdivisions: the medial, lateral and inferior pulvinar nuclei. The medial pulvinar nucleus is dorsomedial and consists of compact, evenly spaced neurones. The inferior pulvinar nucleus lies laterally and inferiorly and is traversed by bundles of axons in the mediolateral plane, an arrangement that confers a fragmented appearance of horizontal cords or sheets of cells separated by fibre bundles. The inferior pulvinar nucleus lies most inferiorly and laterally and is a more homogeneous collection of cells.

The subcortical afferents to the pulvinar are uncertain. Medial and lateral pulvinar nuclei may receive fibres from the superior colliculus. It has been suggested that the inferior pulvinar nucleus receives fibres both from the superior colliculus and directly from the retina and that it contains a complete retinotopic representation.

The cortical targets of efferent fibres from the pulvinar are widespread. In essence, the medial pulvinar nucleus projects to association areas of the parietotemporal cortex, whereas lateral and inferior pulvinar nuclei project to visual areas in the occipital and posterior temporal lobes. Thus, the inferior pulvinar nucleus connects with the striate and extrastriate cortex in the occipital lobe and with visual association areas in the posterior part of the temporal lobe. The lateral pulvinar nucleus connects with extrastriate areas of the occipital cortex, posterior parts of the temporal association cortex and the parietal cortex. The medial pulvinar nucleus connects with the inferior parietal cortex, the posterior cingulate gyrus and widespread areas of the temporal lobe, including the posterior parahippocampal gyrus and the perirhinal and entorhinal cortices. It also has extensive connections with prefrontal and orbitofrontal cortices. Similarly, the lateral pulvinar nucleus may also connect with the rostromedial prefrontal cortex.

Little is known of the functions of the pulvinar. The inferior pulvinar nucleus contains a complete retinotopic representation, and lateral and medial pulvinar nuclei also contain visually responsive cells. However, the latter nucleus, at least, is not purely visual; other modality responses can be recorded, and some cells may be polysensory. Given the complex functions of the association areas to which they project, particularly in the temporal lobe (e.g. perception, cognition, memory), it is likely that the role of the pulvinar in modulating these functions is equally complex.

Anteriorly, the major subdivisions of the pulvinar blend into a poorly differentiated region within which several nuclear components have been recognized, including the anterior or oral pulvinar, the suprageniculate limitans and the posterior nuclei. The connectivity of this complex is not well understood. It is recognized that different components receive subcortical afferents from the spinothalamic tract and the superior and inferior colliculi. Cortical connections centre primarily on the insula and adjacent parts of the parietal operculum posteriorly. Stimulation of this region has been reported to elicit pain, and large lesions may alleviate painful conditions. Similarly, excision of its cortical target in the parietal operculum, or small infarcts in this cortical region, may result in hypoalgesia.

Intralaminar Nuclei

The intralaminar nuclei are collections of neurones within the internal medullary lamina of the thalamus. Two groups of nuclei are recognized. The anterior (rostral) group is subdivided into central medial, paracentral and central lateral nuclei. The posterior (caudal) intralaminar group consists of the centromedian and parafascicular nuclei. The designations central medial and centromedian can lead to confusion, but they are an accepted part of the terminology of thalamic nuclei in common usage. The centromedian nucleus is much larger, is considerably expanded in humans in comparison with other species and is importantly related to the globus pallidus, deep cerebellar nuclei and motor cortex. Anteriorly, the internal medullary lamina separates the mediodorsal nucleus from the ventral lateral complex. It is occupied by the paracentral nucleus laterally and the central medial nucleus ventromedially, as the two laminae converge toward the midline. A little more posteriorly, the central lateral nucleus appears dorsally in the lamina as the latter splits to enclose the lateral dorsal nucleus. More posteriorly, at the level of the ventral posterior nucleus, the lamina splits to enclose the ovoid centromedian nucleus. The smaller parafascicular nucleus lies more medially.

The anterior intralaminar nuclei (i.e. central medial, paracentral and central lateral) have reciprocal connections with widespread cortical areas. There is some evidence of areal preference. Thus, the central lateral nucleus projects mainly to parietal and temporal association areas, the paracentral nucleus to the occipitotemporal and prefrontal cortex and the central medial nucleus to the orbitofrontal and prefrontal cortex and to the cortex on the medial surface. In contrast, the posterior nuclei (i.e. centromedian and parafascicular) have more restricted connections, principally with the motor, premotor and supplementary motor areas. Both anterior and posterior intralaminar nuclei also project to the striatum. Many cells throughout the anterior nuclei have branched axons, which pass to both the cortex and the striatum. Dual projections are less frequent in the posterior nuclei. The thalamostriate projection is topographically organized. The posterior intralaminar nuclei receive a major input from the internal segment of the globus pallidus. Additional afferents come from the pars reticulata of the substantia nigra, the deep cerebellar nuclei, the pedunculopontine nucleus of the midbrain and possibly the spinothalamic tract. The anterior nuclei have widespread subcortical afferents. The central lateral nucleus receives afferents from the spinothalamic tract, and all component nuclei receive fibres from the brain stem reticular formation, the superior colliculus and several pretectal nuclei. Afferents to all intralaminar nuclei from the brain stem reticular formation include a prominent cholinergic pathway.

The precise functional role of the intralaminar nuclei is unclear. They appear to mediate cortical activation from the brain stem reticular formation and play a part in sensorimotor integration. Damage to the intralaminar nuclei may contribute to thalamic neglect—that is, the unilateral neglect of stimuli originating from the contralateral body or extrapersonal space. This may arise particularly from unilateral damage to the centromedian–parafascicular complex. The latter has been targeted in humans for the neurosurgical control of pain and epilepsy. Bilateral injury to the posterior intralaminar nuclei leads to akinetic mutism, with apathy and loss of motivation. A second syndrome associated with damage involving the intralaminar nuclei is that of unilateral motor neglect, in which there is contralateral paucity of spontaneous movement and motor activity.

Reticular Nucleus

The reticular nucleus is a curved lamella of large, deeply staining fusiform cells that wraps around the lateral margin of the thalamus, separated from it by the external medullary lamina. Anteriorly, it curves around the rostral pole of the thalamus to lie between it and the prethalamic nuclei, notably the bed nucleus of the stria terminalis. The nucleus is so named because it is crisscrossed by bundles of fibres that, as they pass between the thalamus and cortex, produce a reticular appearance.

The nucleus is thought to receive collateral branches of corticothalamic, thalamocortical and probably thalamostriatal and pallidothalamic fibres as they traverse it. It receives an additional, probably cholinergic, afferent pathway from the nucleus cuneiformis of the midbrain. Broadly speaking, the afferents from the cortex and thalamus are topographically arranged. The reticular nucleus contains visual, somatic and auditory regions, each with a crude topographical representation of the sensorium concerned. Cells within these regions respond to visual, somatic or auditory stimuli with a latency, suggesting that these properties arise from activation by thalamocortical axon collaterals. Only in areas where representations abut do cells show modality convergence.

The efferent fibres from the reticular nucleus pass into the body of the thalamus and are GABAergic. The projections into the main thalamic nuclei broadly, but not entirely, reciprocate the thalamoreticular connections. There may also be projections to the contralateral dorsal thalamus. The reticular nucleus is believed to function in gating information relayed through the thalamus.

Hypothalamus

The hypothalamus consists of only 4 cubic centimetres of neural tissue, or 0.3% of the total brain. Nevertheless, it contains the integrative systems that, via the autonomic and endocrine effector systems, control fluid and electrolyte balance, food ingestion and energy balance, reproduction, thermoregulation and immune and many emotional responses.

The hypothalamus extends from the lamina terminalis to a vertical plane posterior to the mammillary bodies, and from the hypothalamic sulcus to the base of the brain beneath the third ventricle. It lies beneath the thalamus and anterior to the tegmental part of the subthalamus and the mesencephalic tegmentum (see Figs 15.5, 5.8, 15.10). Laterally, it is bordered by the anterior part of the subthalamus, internal capsule and optic tract. Structures in the floor of the third ventricle reach the pial surface in the interpeduncular fossa (Fig. 15.9). From anterior to posterior, they are the optic chiasma, tuber cinereum, tuberal eminences and infundibular stalk, mammillary bodies and posterior perforated substance. The last lies in the interval between the diverging crura cerebri, pierced by small central branches of posterior cerebral arteries. Within it is the small interpeduncular nucleus, which receives terminals of the fasciculus retroflexus of both sides and has other connections with the mesencephalic reticular formation and mammillary bodies.

image

Fig. 15.9 Interpeduncular fossa and surrounding structures.

(Photograph by Kevin Fitzpatrick on behalf of GKT School of Medicine, London.)

The mammillary bodies are smooth, hemispherical, pea-sized eminences lying side by side, anterior to the posterior perforated substance. Each has nuclei enclosed in white fascicles derived largely from the fornix. The tuber cinereum, between the mammillary bodies and the optic chiasma, is a convex mass of grey matter. From it, the median, conical, hollow infundibulum becomes continuous ventrally with the posterior lobe of the pituitary. Around the base of the infundibulum is the median eminence, which is demarcated by a shallow tubero-infundibular sulcus.

Hypothalamic lesions have long been linked with widespread and bizarre endocrine syndromes and with metabolic, visceral, motor and emotional disturbances. The hypothalamus has major interactions with the neuroendocrine system and the autonomic nervous system, integrating responses to both internal and external afferent stimuli with the complex analysis of the world provided by the cerebral cortex.

The hypothalamus controls the endocrine system in a variety of ways: through magnocellular neurosecretory projections to the posterior pituitary, through parvocellular neurosecretory projections to the median eminence (these control the endocrine output of the anterior pituitary and thereby the peripheral endocrine organs) and via the autonomic nervous system. The posterior pituitary neurohormones vasopressin and oxytocin are primarily involved in the control of osmotic homeostasis and various aspects of reproductive function, respectively. Through its effects on the anterior pituitary, the hypothalamus influences the thyroid gland (thyroid-stimulating hormone [TSH]), suprarenal cortex (adrenocorticotropic hormone [ACTH]), gonads (luteinizing hormone [LH], follicle-stimulating hormone [FSH], prolactin), mammary gland (prolactin) and the processes of growth and metabolic homeostasis (growth hormone [GH]).

The hypothalamus influences both parasympathetic and sympathetic divisions of the autonomic nervous system. In general, parasympathetic effects predominate when the anterior hypothalamus is stimulated; sympathetic effects depend more on the posterior hypothalamus.

Stimulation of the anterior hypothalamus and paraventricular nucleus can cause decreased blood pressure and decreased heart rate. Stimulation in the anterior hypothalamus induces sweating and vasodilatation (and thus heat loss) via projections that pass through the medial forebrain bundle to autonomic centres in the brain stem and cord. Damage to the anterior hypothalamus (e.g. during surgery for suprasellar extensions of pituitary tumours) can result in an uncontrollable rise in body temperature. Projections to the ventromedial hypothalamus conjointly regulate food intake. Stimulation in the posterior part of the hypothalamus induces sympathetic arousal with vasoconstriction, piloerection, shivering and increased metabolic heat production. Circuitry mediating shivering is located in the dorsomedial posterior hypothalamus. This does not imply the existence of discrete parasympathetic and sympathetic ‘centres.’ Stimuli in many different parts of the hypothalamus can cause profound changes in heart rate, cardiac output, vasomotor tone, peripheral resistance, differential bloodflow in organs and limbs, frequency and depth of respiration, motility and secretion in the alimentary tract, erection and ejaculation.

Hypothalamic Nuclei

The hypothalamus contains a number of neuronal groups that have been classified on phylogenetic, developmental, cytoarchitectonic, synaptic and histochemical grounds into named nuclei, many of which are not clearly delineated, especially in the adult. Although it contains a few large myelinated tracts, many of the connections are diffuse and unmyelinated, and the precise paths of many afferent, efferent, and intrinsic connections are uncertain.

The hypothalamus can be divided anteroposteriorly into chiasmatic (supraoptic), tuberal (infundibulo-tuberal) and posterior (mammillary) regions and mediolaterally into periventricular, intermediate (medial) and lateral zones. Between the intermediate and lateral zones is a paramedian plane that contains the prominent myelinated fibres of the column of the fornix, the mammillothalamic tract and the fasciculus retroflexus. For this reason, some authors group the periventricular and intermediate zones as a single medial zone. These divisions are artificial, and functional systems cross them. The main nuclear groups and myelinated tracts are illustrated in Figures 15.10 and 15.11.

The periventricular zone of the hypothalamus borders the third ventricle. In the anterior wall of the ventricle is the vascular organ of the lamina terminalis (organum vasculosum), which is continuous dorsally with the median preoptic nucleus and subfornical organ. On each side in the chiasmatic region are part of the preoptic nucleus; the small, sexually dimorphic suprachiasmatic nucleus; and periventricular neurones, which are medial to and blend with the paraventricular nucleus. In the tuberal region, the periventricular cell group expands around the base of the third ventricle to form the arcuate nucleus, which overlies the median eminence. In the posterior region, the narrow periventricular zone is continuous laterally with the posterior hypothalamic area and behind that with midbrain periaqueductal grey matter. The periventricular zone also contains a prominent periventricular fibre system.

CASE 2 Wernicke’s Encephalopathy

A 62-year-old man, a chronically undernourished alcoholic, complains of double vision. During the following week, unsteadiness of gait and mild mental confusion appear. Progression of these symptoms prompts hospitalization. Examination demonstrates a confused and disoriented man who exhibits bilateral sixth nerve palsies, coarse nystagmus on gaze to either side and a striking ataxia of gait. A diagnosis of acute Wernicke’s encephalopathy is made, and he is treated with parenteral thiamine. During the next week, the ophthalmoparesis disappears, and the nystagmus, though lingering, is much reduced in amplitude. His gait slowly improves, but he is left with residual ataxia. As his sensorium clears under treatment, a profound disorder of memory becomes evident, characterized primarily by a striking inability to form new memories. Mental tasks that are not memory dependent are, for the most part, intact.

Discussion: This man exhibits a classic Wernicke-Korsakoff syndrome due to thiamine deficiency. Anatomically, the ophthalmoparesis reflects reversible lesions involving the brain stem oculomotor complex bilaterally in the midbrain or pons, and the nystagmus is due to lesions involving the vestibular nuclei. The truncal ataxia is related to observed lesions involving the superior vermis of the cerebellum. The anatomical substrate of the memory defect, the Korsakoff component of the disorder, in all likelihood reflects bilateral subtotal tissue necrosis, which may be haemorrhagic, involving the mammillary bodies or thalamus (Fig. 15.12). Despite vigorous therapy with thiamine, the memory problem may persist indefinitely, posing a major functional disability.

Suprachiasmatic Nucleus

Although it contains only a few thousand neurones, the suprachiasmatic nucleus is a remarkable structure. It appears to be the neural substrate for day–night cycles in motor activity, body temperature, plasma concentration of many hormones, renal secretion, sleeping and waking and many other variables. Lesions of the suprachiasmatic region lead to a disordered sleep–wake cycle.

The suprachiasmatic nucleus has two principal subdivisions. Retinal fibres terminate in a ventrolateral subdivision, characterized by neurones immunoreactive for vasoactive intestinal polypeptide (VIP). This appears to be a general input zone, which also receives afferents from the midbrain raphe and parts of the lateral geniculate nucleus of the thalamus. The dorsomedial subdivision has relatively sparse afferent innervation and characteristically contains parvocellular neurones immunoreactive for arginine vasopressin. Neurones within the suprachiasmatic nuclei that receive direct retinal input do not respond to pattern, movement or colour. Instead, they operate as luminance detectors, responding to the onset and offset of light, and their firing rates vary in proportion to light intensity, thereby synchronizing to the light–dark cycle.

The nucleus receives glutamatergic afferents from retinal ganglion cells that entrain the rhythm to the light–dark cycle, but these are not essential for the production of the rhythm, which persists in the blind. The suprachiasmatic nucleus contains many different neurotransmitters, including vasopressin, VIP, neuropeptide Y and neurotensin. Axons from the suprachiasmatic nuclei pass to many other hypothalamic nuclei, including the paraventricular, ventromedial, dorsomedial and arcuate nuclei.

The suprachiasmatic nucleus also influences the activity of preganglionic sympathetic neurones at the C8–T1 level. These project to superior cervical ganglion neurones, which in turn project to the pineal gland. In the pineal gland, which contains modified photoreceptors, circadian variation in the postganglionic sympathetic input causes parallel variation in pineal N-acetyltransferase activity and thus pineal melatonin production. The role of the pineal gland in humans is uncertain. Pineal tumours can influence reproductive development, and the administration of melatonin has been advocated to alleviate jet lag.

Parvocellular neurosecretory neurones lie within the periventricular zone, in particular the medial parvocellular part of the paraventricular nucleus and the arcuate nucleus. The arcuate nucleus is median in the postinfundibular part of the tuber cinereum. It extends forward into the median eminence and almost encircles the infundibular base but does not meet anteriorly, where the infundibulum adjoins the median part of the optic chiasma. Its numerous neurones are all small and round in coronal section, and oval or fusiform in sagittal section. No glial layer intervenes between the nucleus and the ependymal tanycytes lining the infundibular recess of the third ventricle. Circadian variation in the secretion of all anterior pituitary hormones suggests that projections from the suprachiasmatic nucleus must reach parvocellular neurosecretory neurones. Afferents from the limbic system probably mediate the widespread effects of stress, and serotonin and noradrenaline from the brain stem influence the output of most anterior pituitary hormones. The axons of parvocellular neurones converge on the infundibulum, forming a tubero-infundibular tract, which ends on the capillary loops that form the hypophysial portal vessels.

Neurones producing growth hormone–releasing hormone (GHRH) are largely restricted to the arcuate nucleus. Some extend dorsally into the periventricular nucleus and laterally into the retrochiasmatic area. Their fibres run through the periventricular region to the neurovascular zone of the median eminence. The neurones receive afferent information from glucose receptors in the ventromedial nucleus. Inputs from the hippocampal–amygdala–septal complex could explain the release of GH during stress. In humans, midline defects such as septo-optic dysplasia are associated with defective GH secretion. Dopamine has a stimulatory effect.

Neurones producing somatostatin (GH release-inhibiting hormone) are located in the periventricular nucleus. GHRH and somatostatin are secreted in intermittent (3- to 5-hour) reciprocal pulses, but the origin of the pulses is unclear. A large pulse of GH is secreted at the onset of slow-wave sleep. Somatostatin also inhibits the release of pituitary TSH.

Neurones producing GHRH and projecting to the median eminence are also located in the periventricular and arcuate nuclei. Other GHRH-producing neurones are found in the periventricular preoptic area, but these appear to project to the vascular organ of the lamina terminalis. LH and FSH are secreted in circhoral (hourly) pulses, which are stimulated by GHRH, and are influenced by central monoamine and γ-aminobutyric acid (GABA), by oestrogen and progesterone acting indirectly through other neurones, by corticotropin-releasing factor and by endogenous opioids.

Corticotropin-releasing hormone neurones are located primarily in parvocellular paraventricular neurones. They are profoundly stimulated by neurogenic (limbic input) and hypoglycaemic (ventromedial nucleus) stress and are also controlled by negative feedback by cortisol.

Thyrotropin-releasing hormone (TRH) neurones are more widely distributed in the periventricular, ventromedial and dorsomedial nuclei. TRH release is influenced by core temperature, sensed in the anterior hypothalamus, and by negative feedback of thyroid hormones. It stimulates the release of pituitary TSH and also acts to excite cold-sensitive and inhibit warm-sensitive neurones in the preoptic area.

Other tubero-infundibular arcuate neurones contain neuropeptide Y and neurotensin. Arcuate neurones containing pro-opiomelanocortin peptides project to the periventricular nucleus rather than to the median eminence.

In addition to these peptide-containing cells, dopamine neurones in the arcuate nucleus (A12 group) have terminals in the median eminence and infundibulum. Dopamine acts as the principal prolactin–release inhibiting hormone and also inhibits the secretion of TSH (likewise, TSH acts as a prolactin-releasing hormone). Noradrenergic terminals are found in the median eminence, where they may act largely in a paracrine manner.

The intermediate zone of the hypothalamus contains the best differentiated nuclei. These are the paraventricular and supraoptic nuclei; ‘intermediate’ nuclear groups, which show sexual dimorphism; ventromedial and dorsomedial nuclei; mammillary body; and tuberomammillary nuclei. Magnocellular neurosecretory neurones are found in the supraoptic and paraventricular nuclei and as isolated clusters of cells between them.

Supraoptic and Paraventricular Nuclei

The supraoptic nucleus, curved over the lateral part of the optic chiasma, contains a uniform population of large neurones. Behind the chiasma, a thin plate of cells in the floor of the brain forms the retrochiasmatic part.

Supraoptic neurones synthesize vasopressin, and they all appear to project to the neurohypophysis. The magnocellular vasopressin neurones can detect as little as 1% increase in the osmotic pressure of the blood and stimulate the release of vasopressin from the posterior pituitary. A fall in blood volume or blood pressure of greater than 5% to 10% stimulates the release of vasopressin and the urge to drink via volume receptors in the walls of the great veins and atria and baroreceptors in the carotid sinus. These project via the vagus and glossopharyngeal nerves to the nucleus tractus solitarius and thence to the magnocellular nuclei. A biochemical defect in vasopressin production, or interruption of the supraoptico-hypophysial pathway (e.g. due to a head injury), can cause cranial diabetes insipidus.

The paraventricular nucleus extends from the hypothalamic sulcus downward across the medial aspect of the column of the fornix, its ventrolateral angle reaching toward the supraoptic nucleus. Its neurones are more diverse. Magnocellular neurones, which project to the neurohypophysis, tend to lie laterally; parvocellular neurones, which project to the median eminence and infundibulum, lie more medially; and intermediate-sized neurones, which may project caudally, lie posteriorly. The axons of the paraventricular magnocellular neurones pass toward the supraoptic nucleus (paraventriculo-hypophysial tract), where they join axons of supraoptic neurones to form a supraoptico-hypophysial tract. This runs down the infundibulum, superficially, and into the neural lobe, where the axons are distended and branch repeatedly around the capillaries. Vasopressin and oxytocin are produced by separate neurones. Vasopressin neurones tend to cluster in the ventrolateral part of the paraventricular nucleus, and oxytocin cells lie around them.

The hypothalamus is essential for the control of pituitary oxytocin, gonadotropin and prolactin secretion. The release of oxytocin from neurosecretory nerve terminals in the neurohypophysis induces contraction of both the uterus, at term, and the myoepithelial cells that surround the mammary gland alveoli. Two neuroendocrine reflexes are involved. Stretching of the cervix of the uterus during childbirth stimulates a multisynaptic afferent pathway that passes via the pelvic plexus, anterolateral column and brain stem to the magnocellular oxytocin neurones (the Ferguson reflex). This is a positive feedback mechanism that is terminated by the birth of the child. The milk ejection reflex involves stimulation (by suckling) of the intercostal nerves, which innervate the nipples, and a similar central pathway. It can be both conditioned to a baby’s cry and inhibited by stress.

At the tuberal level, the ventromedial nucleus is well defined by a surrounding neurone-poor zone, but the dorsomedial nucleus above it is much less distinct. The ventromedial nucleus contains neurones receptive to plasma levels of glucose and other nutrients and receives visceral somatic afferents via the nucleus tractus solitarius. The lateral hypothalamus receives olfactory afferents, which act as important food signals. Both areas receive extensive inputs from limbic structures. Stimulation and lesion experiments, together with human case studies, suggest that the ventromedial nuclei act together as a ‘satiety centre.’ Bilateral ventromedial nucleus damage promotes overeating (hyperphagia), and restricting food intake may provoke rage-like outbursts. The resultant obesity is usually coupled with hyposexuality (Fröhlich’s syndrome). Interestingly, in infants, ventromedial damage can lead to emaciation despite apparent normal feeding. Experimental lesions in the lateral hypothalamus promote hypophagia or aphagia, whereas stimulation can prolong feeding, supporting the concept of a lateral hypothalamic ‘feeding centre.’

The ventromedial nucleus, lateral hypothalamic area and paraventricular nucleus also influence intermediate metabolism through the autonomic and endocrine systems. These appear to complement the effects on feeding behaviour. Thus, ventromedial stimulation facilitates glucagon release and increases glycogenolysis, gluconeogenesis and lipolysis, whereas lateral hypothalamic stimulation causes insulin release and opposite metabolic effects. Lesions of the ventromedial nucleus also cause increased vagal and decreased sympathetic tone.

The medial mammillary nuclei, which form the bulk of the mammillary bodies, are very prominent. The composition of a lateral mammillary nucleus is controversial, although a group of larger cells can be distinguished along the lateral border of the medial mammillary nucleus. Lateral to this lies the tuberomammillary nucleus, which gives rise to widespread axons that diffusely innervate the entire cerebral cortex, hypothalamus and brain stem.

The lateral zone of the hypothalamus forms a continuum that runs from the preoptic nucleus through the lateral hypothalamic area to the posterior hypothalamus. In the tuberal region, the lateral tuberal nuclei are large and well defined and surrounded by fine fibres.

Connections of the Hypothalamus

The hypothalamus has afferent and efferent connections with the rest of the body via two (possibly three) distinct routes: neural connections, the blood stream and (probably) the cerebrospinal fluid.

Some hypothalamic neurones have specific receptors that sense the temperature, osmolarity, glucose, free fatty acid and hormone content of the blood. Neurosecretory neurones secrete neurohormones into the blood. These control the anterior pituitary and act on organs such as the kidney, breast, uterus and blood vessels. Some of these neural connections, especially those to the mammillary bodies, form discrete myelinated fascicles; most, however, are diffuse and unmyelinated, and their origin and termination are uncertain. Most pathways are multisynaptic, which means that the majority of synapses on any hypothalamic neurone are derived from hypothalamic interneurones.

Broadly, neural inputs to the hypothalamus are derived from the ascending visceral and somatic sensory systems, the visual and olfactory systems and numerous tracts from the brain stem, thalamus, ‘limbic’ structures and neocortex. Efferent neural projections are reciprocal to most of these sources; in particular, they impinge on and control the central origins of autonomic nerve fibres. The hypothalamus therefore exerts control via the autonomic and endocrine systems and through its connections to the telencephalon.

CASE 3 Narcolepsy

A 25-year-old graduate student presents with the complaint of excessive daytime fatigue, interfering with social and occupational function, beginning at age 17. She also reports difficulties with memory, concentration and attention and diffuse headaches in association with sleepiness. Colleagues and teachers have reported that she repeatedly falls asleep in class. The patient confirms a long-standing history of momentary ‘blackout spells’ while sedentary, not usually preceded by a premonitory subjective sense of sleepiness; these spells have also occurred while driving, resulting in a few episodes of veering into the adjoining lane. In addition, she reports automatisms, wherein she types illegibly on the computer as she falls asleep. Upon questioning, she reports vivid dreams during sleep, usually with a threatening content and associated with an inability to move to extricate herself from the imagined danger. She also recalls rare episodes of cataplexy—the sudden onset of weakness in her facial muscles after laughter or anger. On one occasion, she collapsed in a store when she lost all motor ability in both legs for a few minutes; she was rushed to the emergency room and released within a few hours, with no positive findings. She maintains regular bedtimes, obtaining 8 hours of sleep each night. She naps for 2 hours a day on weekends, finding naps to be refreshing; naps are associated with dreams.

Past medical and psychiatric histories are negative, and she takes no medications. She consumes two caffeinated beverages in the morning, which allows her to function at a nominal cognitive level in the morning. Serum laboratory tests, including TSH, are within normal limits. The Epworth Sleepiness Scale (ESS) score is 19, which is elevated. Polysomnography reveals high proportions of stages 1 and 2 sleep; diminished proportions of slow-wave sleep; multiple awakenings and arousals, most prominently during rapid eye movement (REM) sleep; and a short REM latency of 67 minutes. The apnoea-hypopnoea index is within normal limits at 1.2. Multiple sleep latency testing performed during the day following the nocturnal polysomnogram reveals a mean sleep latency of 2.5 minutes and three sleep-onset REM episodes.

Discussion: This case illustrates narcolepsy with cataplexy. Consistent with the diagnosis are the symptoms of excessive daytime somnolence with consequent sleep attacks, a high ESS score, cataplexy, hypnagogic hallucinations and sleep paralysis. The mean sleep latency score of less than 8 minutes in conjunction with two or more sleep-onset REM episodes, in the context of no other sleep, medical, or neurological pathology, confirms the diagnosis of narcolepsy.

Although the cause of human narcolepsy is unknown, recent studies have demonstrated an enhanced pattern of gliosis, as visualized through glial fibrillary acidic protein–labelled astrocytes in the hypothalamus and, to a lesser extent, the thalamus of narcoleptic brains compared with those of controls. Gliosis is thought to be the basis of the destruction of hypocretin or orexin neurones in the perifornical area of the posterior hypothalamus; under normal conditions, these neurones have widespread projections throughout the human central nervous system, with dense innervations of the hypothalamus, histaminergic tuberomammillary nucleus, noradrenergic locus coeruleus, serotoninergic raphe nuclei, dopaminergic ventral tegmental area, midline thalamus and nucleus of the diagonal band–nucleus basalis complex of the forebrain. This pattern of projections from the hypocretin neurones is thought to play an important role in arousal and maintenance of the awake state. The cause of the destruction of hypocretin neurones is unknown, but a high association between the human leukocyte antigen (HLA) allele DQB1*0602 and narcolepsy suggests a common genetic pathophysiological mechanism for the disorder. Because most other HLA-associated disorders are autoimmune in nature (e.g. multiple sclerosis, myasthenia gravis, systemic lupus erythematosus), narcolepsy may be an autoimmune disorder as well.

Afferent Connections

The hypothalamus receives visceral, gustatory and somatic sensory information from the spinal cord and brain stem. It receives largely polysynaptic projections from the nucleus tractus solitarius, probably directly and indirectly via the parabrachial nucleus and medullary noradrenergic cell groups (ventral noradrenergic bundle); collaterals of lemniscal somatic afferents (to the lateral hypothalamus); and projections from the dorsal longitudinal reticular formation. Many enter via the medial forebrain bundle (see Fig. 15.11) and periventricular fibre system. Others converge in the midbrain tegmentum, forming the mammillary peduncle to the mammillary body.

The major forebrain inputs to the hypothalamus are derived from structures in the limbic system, including the hippocampal formation, amygdala and septum, and from the piriform lobe and adjacent neocortex. These connections, which are reciprocal, form prominent fibre systems: the fornix, stria terminalis and ventral amygdalofugal tracts.

The hippocampal formation, in particular the subiculum and CA1, is reciprocally connected to the hypothalamus by the fornix, a complex tract that also contains commissural connections. As the fornix curves ventrally toward the anterior commissure, it is joined by fascicles from the cingulate gyrus, indusium griseum and septal areas. It divides around the anterior commissure into pre- and postcommissural parts. The precommissural fornix is distributed to the septum and preoptic hypothalamus, and the septum in turn sends numerous fibres to the hypothalamus. The postcommissural fornix passes ventrally and posteriorly through the hypothalamus to the medial mammillary nucleus. In its course, it gives off many fibres to the medial and lateral hypothalamic nuclei.

The amygdala innervates most hypothalamic nuclei anterior to the mammillary bodies. Its corticomedial nucleus innervates preoptic and anterior hypothalamic areas and the ventromedial nucleus. The central nuclei project to the lateral hypothalamus. The fibres reach the hypothalamus by two routes. The short ventral amygdalofugal path passes medially over the optic tract, beneath the lentiform complex, to reach the hypothalamus. The long, curved stria terminalis runs parallel to the fornix, separated from it by the lateral ventricle; it passes through the bed nucleus of the stria terminalis and is then distributed to the anterior hypothalamus via the medial forebrain bundle.

Olfactory afferents reach the hypothalamus largely via the nucleus accumbens and septal nuclei, and most terminate in the lateral hypothalamus. Visual afferents leave the optic chiasma and pass dorsally into the suprachiasmatic nucleus. No auditory connections have been identified, although it is clear that such stimuli influence hypothalamic activity. However, many hypothalamic neurones respond best to complex sensory stimuli, suggesting that sensory information reaching the neocortex has converged and been processed by the amygdala, hippocampus and neocortex. Neocortical corticohypothalamic afferents to the hypothalamus are poorly defined but probably arise from frontal and insular cortices. Some may relay in the mediodorsal thalamic nucleus and project into the hypothalamus via the periventricular route. Other direct corticohypothalamic fibres may end in lateral, dorsomedial, mammillary and posterior hypothalamic nuclei, but all these connections are questionable.

Like the rest of the forebrain, the hypothalamus also receives diffuse aminergic inputs from the locus coeruleus (noradrenaline, or norepinephrine) and the raphe nuclei (serotonin, or 5-hydroxytryptamine [5-HT]). In addition, it receives a cholinergic input from the ventral tegmental ascending cholinergic pathway; a noradrenergic input to dorsomedial, periventricular, paraventricular, supraoptic and lateral hypothalamic nuclei from the ventral tegmental noradrenergic bundle; and dopamine fibres from the mesolimbic dopaminergic system. Group A11 innervates the medial hypothalamic nuclei, and groups A13 and A14 supply the dorsal and rostral hypothalamic nuclei. Many of these fibres also run in the medial forebrain bundle.

The medial forebrain bundle is a loose grouping of fibre pathways that mostly run longitudinally through the lateral hypothalamus (see Fig. 15.11). It connects forebrain autonomic and limbic structures with the hypothalamus and brain stem, receiving and giving small fascicles throughout its course. It contains descending hypothalamic afferents from the septal area and orbitofrontal cortex, ascending afferents from the brain stem and efferents from the hypothalamus.

Efferent Connections

Hypothalamic efferents include reciprocal paths to the limbic system, descending polysynaptic paths to autonomic and somatic motor neurones and neural and neurovascular links with the pituitary.

Septal areas and the amygdaloid complex have reciprocal hypothalamic connections along the paths described earlier. The medial preoptic and anterior hypothalamic areas give short projections to nearby hypothalamic groups. The ventromedial nucleus has more extensive projections that pass via the medial forebrain bundle to the bed nucleus of the stria terminalis, basal nucleus of Meynert, central nucleus of the amygdala and midbrain reticular formation. The posterior hypothalamus projects largely to midbrain central grey matter. Some tuberal and posterior lateral hypothalamic neurones project directly to the entire neocortex and appear to be essential for maintaining cortical arousal, but the topography of these projections is unclear.

Hypothalamic neurones projecting to autonomic neurones are found in the paraventricular nucleus (oxytocin and vasopressin neurones), perifornical and dorsomedial nuclei (atrial natriuretic peptide neurones), lateral hypothalamic area (α-melanocyte-stimulating hormone neurones) and zona incerta (dopamine neurones). These fibres run through the medial forebrain bundle into the tegmentum, ventrolateral medulla and dorsal lateral funiculus of the spinal cord. In the brain stem, fibres innervate the parabrachial nucleus, nucleus ambiguus, nucleus of the solitary tract and dorsal motor nucleus of the vagus. In the spinal cord, they end on sympathetic and parasympathetic preganglionic neurones in the intermediolateral column. Both oxytocin- and vasopressin-containing fibres can be traced to the most caudal spinal autonomic neurones.

The medial mammillary nucleus gives rise to a large ascending fibre bundle that diverges into mammillothalamic and mammillotegmental tracts (see Fig. 15.11). The mammillothalamic tract ascends through the lateral hypothalamus to reach the anterior thalamic nuclei, where massive projections radiate to the cingulate gyrus. The mammillotegmental tract curves inferiorly into the midbrain, ventral to the medial longitudinal fasciculus, and is distributed to the tegmental reticular nuclei.

Pituitary Gland

The pituitary gland, or hypophysis cerebri, is a reddish grey ovoid body approximately 12 mm in transverse diameter and 8 mm in anteroposterior diameter, weighing approximately 500 mg (see Fig. 5.8; Fig. 15.13). It is continuous with the infundibulum, a hollow, conical inferior process from the tuber cinereum of the hypothalamus. It lies within the pituitary fossa of the sphenoid bone, where it is covered superiorly by a circular diaphragma sellae of dura mater. The latter is pierced centrally by an aperture for the infundibulum and separates the anterior superior aspect of the pituitary from the optic chiasma. The pituitary is flanked by the cavernous sinuses and their contents. Inferiorly, it is separated from the floor of the pituitary fossa by a venous sinus that communicates with the circular sinus. The meninges blend with the pituitary capsule and are not separate layers.

The pituitary has two major parts—neurohypophysis and adenohypophysis—which differ in their origin, structure and function. The neurohypophysis is a diencephalic downgrowth connected with the hypothalamus. The adenohypophysis is an ectodermal derivative of the stomatodeum. Both include parts of the infundibulum (whereas the older terms ‘anterior lobe’ and ‘posterior lobe’ do not). The infundibulum has a central infundibular stem that contains neural hypophysial connections and is continuous with the median eminence of the tuber cinereum. Thus, the neurohypophysis includes the median eminence, infundibular stem and neural lobe or pars posterior. Surrounding the infundibular stem is the pars tuberalis, a component of the adenohypophysis. The main mass of the adenohypophysis can be divided into the pars anterior (pars distalis) and the pars intermedia, which are separated in fetal and early postnatal life by the hypophysial cleft, a vestige of Rathke’s pouch, from which it develops. Although usually obliterated in childhood, remnants may persist in the form of cystic cavities near the adenoneurohypophysial frontier, sometimes invading the neural lobe. The human pars intermedia is rudimentary. It may be partially displaced into the neural lobe, so it has been included in the anterior and posterior parts by different observers. Apart from this equivocation, which is of little significance in view of the exiguous status of the human pars intermedia, the pars anterior and pars posterior can be equated with the anterior and posterior lobes. When the associated infundibular parts continuous with these lobes are included, the names adenohypophysis and neurohypophysis become appropriate and are used here as follows: neurohypophysis includes the pars posterior (pars nervosa, posterior or neural lobe), infundibular stem and median eminence; adenohypophysis includes the pars anterior (pars distalis or glandularis), pars intermedia and pars tuberalis.

Neurohypophysis

In early fetal life, the neurohypophysis contains a cavity continuous with the third ventricle. Axons arising from groups of hypothalamic neurones (e.g. magnocellular neurones of the supraoptic and paraventricular nuclei) terminate in the neurohypophysis. The long magnocellular axons pass to the main mass of the neurohypophysis. They form the neurosecretory hypothalamohypophysial tract and terminate near the sinusoids of the posterior lobe. Some smaller parvocellular neurones in the periventricular zone have shorter axons and end in the median eminence and infundibular stem among the superior capillary beds of the venous portal circulation. These small neurones produce releasing and inhibitory hormones, which control the secretory activities of the adenohypophysis via its portal blood supply.

The neurohormones stored in the main part of the neurohypophysis are vasopressin (antidiuretic hormone), which controls reabsorption of water by renal tubules, and oxytocin, which promotes the contraction of uterine smooth muscle in childbirth and the ejection of milk from the breast during lactation. Storage granules containing active hormone polypeptides bound to a transport glycoprotein, neurophysin, pass down axons from their site of synthesis in the neuronal somata. The granules are seen as swellings along the axons and at their terminals, which can reach the size of erythrocytes (Fig. 15.14).

The thin, non-myelinated axons of the neurohypophysis are ensheathed by typical astrocytes in the infundibulum (Figs 15.15, 15.16). Near the posterior lobe, astrocytes are replaced by pituicytes, which constitute most of the non-excitable tissue in the neurohypophysis. Pituicytes are dendritic neuroglial cells of variable appearance, often with long processes running parallel to adjacent axons. Typically, their cytoplasmic processes end on the walls of capillaries and sinusoids between nerve terminals. Axons also end in perivascular spaces. Although they are close to the walls of sinusoids, they remain separated from them by two basal laminae—one around the nerve endings, and the other underlying the fenestrated endothelial cells. Fine collagen fibrils occupy the spaces between basal laminae.

Adenohypophysis

The adenohypophysis is highly vascular. It consists of epithelial cells of varying size and shape arranged in cords or irregular follicles, between which lie thin-walled vascular sinusoids supported by a delicate reticular connective tissue (see Figs 15.1415.16). Most of the hormones synthesized by the adenohypophysis are trophic. They include the peptides; GH, involved in the control of body growth; and prolactin, which stimulates both the growth of breast tissue and milk secretion. Glycoprotein trophic hormones are the large pro-opiomelanocortin precursor of ACTH, which controls the secretion of certain suprarenal cortical hormones; TSH; FSH, which stimulates the growth and secretion of oestrogens in ovarian follicles and spermatogenesis (acting on testicular Sertoli cells); and LH, which induces progesterone secretion by the corpus luteum and testosterone synthesis by Leydig cells in the testis. Pro-opiomelanocortin is cleaved into a number of different molecules, including ACTH. β-Lipotropin is released from the pituitary, but its lipolytic function in humans is uncertain. β-Endorphin is another cleavage product released from the pituitary.

The epithelial endocrine cells, which secrete the different adenohypophysial hormones, are distinguished in part by their differing affinities for acidic and basic dyes. Cells staining strongly are described as chromophils, and those with low affinity for dyes are chromophobes. Chromophils that stain strongly with acidic dyes are classed as acidophils, whereas basophils stain strongly with basic dyes; the latter are more prevalent in the central part of the gland. Classification according to the hormones synthesized divides cells into somatotrophs (GH-secreting acidophils, the most numerous chromophil type), lactotrophs (prolactin-secreting acidophils, which are dominant in pregnancy and hypertrophic during lactation), gonadotrophs (FSH- and LH-secreting basophils), thyrotrophs (TSH-secreting basophils) and corticotrophs (ACTH-secreting basophils). Chromophobes are thought to be quiescent or degranulated chromophils or immature precursor cells; they constitute up to one half the cells of the adenohypophysis.

Neurones that secrete the peptides and amines that control the anterior lobe are widely distributed within the hypothalamus. They are situated mainly in the medial zone, arcuate nucleus, medial parvocellular part of the paraventricular nucleus and periventricular nucleus.

The pars intermedia contains follicles of chromophobe cells that surround cyst-like structures lined by epithelium and filled, to varying degrees, with glycosylated colloidal material. Secretory products of this region may include cleavage products of pro-opiomelanocortin, but their functional significance is uncertain. The pars tuberalis contains a large number of blood vessels, between which are cords or clusters of gonadotrophs and undifferentiated cells.

A small collection of adenohypophysial tissue lies in the mucoperiosteum of the human nasopharyngeal roof. By 28 weeks in utero, it is well vascularized and capable of secretion, receiving blood from the systemic vessels of the nasopharyngeal roof. At this stage, it is covered posteriorly by fibrous tissue. This is replaced in the second half of fetal life by venous sinuses, and a transsphenoidal portal venous system develops, bringing the nasopharyngeal tissue under the same hypothalamic control as the cranial adenohypophysial tissue. The peripheral vascularity of the pharyngeal hypophysis persists until about the fifth year. The organ is then reinvested by fibrous tissue and is presumed to be controlled again by factors present in systemic blood. Although it does not change in size after birth in males, in females it becomes smaller, returning to natal volume during the fifth decade, when it may once again be controlled by a transsphenoidal extension of the hypothalamohypophysial portal venous system. The human pharyngeal hypophysis may be a reserve of potential adenohypophysial tissue, which may be stimulated, particularly in females, to synthesize and secrete adenohypophysial hormones in middle age, when intracranial adenohypophysial tissue begins to fail.

Vessels of the Pituitary

The arteries of the pituitary arise from the internal carotid arteries via a single inferior and several superior hypophysial arteries on each side (Fig. 15.17). The former comes from the cavernous part of the internal carotid artery, and the latter come from its supraclinoid part and from the anterior and posterior cerebral arteries. The inferior hypophysial artery divides into medial and lateral branches, which anastomose across the midline and form an arterial ring around the infundibulum. Fine branches from this circular anastomosis enter the neurohypophysis to supply its capillary bed. The superior hypophysial arteries supply the median eminence, upper infundibulum and, via arteries of the trabeculae, lower infundibulum. A confluent capillary net, extending through the neurohypophysis, is supplied by both sets of hypophysial vessels. Reversal of flow can occur in cerebral capillary beds lying between the two supplies.

The arteries of the median eminence and infundibulum end in characteristic sprays of capillaries, which are most complex in the upper infundibulum. In the median eminence, these form an external or ‘mantle’ plexus and an internal or ‘deep’ plexus. The external plexus, fed by the superior hypophysial arteries, is continuous with the infundibular plexus and is drained by long portal vessels that descend to the pars anterior. The internal plexus lies within and is supplied by the external plexus. It is continuous posteriorly with the infundibular capillary bed and, like the external plexus, is drained by long portal vessels. Short portal vessels run from the lower infundibulum to the pars anterior. Both types of portal vessels open into vascular sinusoids, which lie between the secretory cords in the adenohypophysis and provide most of its blood. There is no direct arterial supply. The portal system carries hormone-releasing factors, probably elaborated in parvocellular groups of hypothalamic neurones, and these control the secretory cycles of cells in the pars anterior. The pars intermedia appears to be avascular.

There are three possible routes for venous drainage of the neurohypophysis: to the adenohypophysis, via long and short portal vessels; into the dural venous sinuses, via the large inferior hypophysial veins; and to the hypothalamus, via capillaries passing to the median eminence. The venous drainage carries hypophysial hormones from the gland to their targets and also facilitates feedback control of secretion. However, venous drainage of the adenohypophysis appears to be restricted. Few vessels connect it directly to the systemic veins, so the routes by which blood leaves remain obscure.

CASE 4 Pituitary Apoplexy

A 37-year-old woman, 1 week postpartum, develops the worst headache of her life, with associated nausea, vomiting, and double vision. Her examination is remarkable for a bilateral superior quadrantanopsia, mild disorientation and a stiff neck; her right eye is down and out with ptosis. Neuroimaging reveals a pituitary haemorrhage compressing the optic chiasm and extending into the right cavernous sinus. She is treated with corticosteroids, and over the course of a week her symptoms resolve.

Discussion: This patient suffers from postpartum pituitary apoplexy (Sheehan’s syndrome). Pituitary apoplexy occurs when there is rapid expansion of the pituitary from haemorrhage, infarction or acute enlargement of a pituitary adenoma. The presenting symptoms are typically headache, nausea, vomiting, oculomotor palsies and visual field deficits. Upward expansion of the pituitary causes compression of the optic nerve, leading to visual field and acuity changes. Lateral expansion into the cavernous sinus can lead to compression of the cranial nerves contained therein (III, IV, V and VI). Mental status changes and meningismus may occur with leakage of blood products into the cerebrospinal fluid or secondary to increased intracranial pressure.

Risk factors for pituitary apoplexy include pregnancy, head trauma and bromocriptine treatment. Immediate treatment for pituitary apoplexy is supportive medical care, monitoring of electrolytes and steroid replacement therapy. In severe cases, surgical decompression may be needed. Endocrinopathies (e.g. diabetes insipidus) or amenorrhea may result secondary to pituitary apoplexy because patients frequently develop hypopituitarism.

Subthalamus

The subthalamus is a complex region of nuclear groups and fibre tracts (Fig. 15.18). The main nuclear groups are the subthalamic nucleus, the reticular nucleus, the zona incerta, the fields of Forel and the pregeniculate nucleus. The rostral poles of the red nucleus and substantia nigra also extend into this area.

The main subthalamic tracts are the upper parts of the medial, spinal and trigeminal lemnisci and the solitariothalamic tract, all approaching their terminations in the thalamic nuclei; the dentatothalamic tract from the contralateral superior cerebellar peduncle, accompanied by ipsilateral rubrothalamic fibres; the fasciculus retroflexus; the fasciculus lenticularis; the fasciculus subthalamicus; the ansa lenticularis; fascicles from the prerubral field (H field of Forel); the continuation of the fasciculus lenticularis (in the H2 field of Forel); and the fasciculus thalamicus (H1 field of Forel).

Zona Incerta and Fields of Forel

The zona incerta is an aggregation of small cells that lies between the ventral part of the external medullary lamina of the thalamus and the cerebral peduncle. It is linked to the reticular nucleus dorsolaterally. More medially is a scattered group of cells in a matrix of fibres known as the H field of Forel. Field H1 of Forel consists of the thalamic fasciculus, which lies dorsal to the zona incerta. Field H2 of Forel contains the fasciculus lenticularis and lies ventrally, between the zona incerta and the subthalamic nucleus (see Fig. 15.18).

The zona incerta receives fibres from the sensorimotor cortex, the pregeniculate nucleus, the deep cerebellar nuclei, the trigeminal nuclear complex and the spinal cord. It projects to the spinal cord and the pretectal region. Its functions are unknown.

The neurones of the H field of Forel receive afferents from the internal segment of the globus pallidus, the spinal cord and the reticular formation of the brain stem. They may project to the spinal cord. Like the zona incerta, their functions are unknown.

In addition to terminal parts of the lemniscal, dentatothalamic and rubrothalamic tracts, the subthalamus contains massive fibre tracts derived from the globus pallidus. The fasciculus lenticularis is the dorsal component of pallidofugal fibres that traverse the internal capsule. It turns medially near the medial aspect of the capsule, partly intermingled with the dorsal zone of the subthalamic nucleus and the ventral part of the zona incerta, where the fasciculus traverses the H2 field of Forel. Reaching the medial border of the zona incerta, the fasciculus intermingles with fibres of the ansa lenticularis, scattered elements of the prerubral nucleus and dentatothalamic and rubrothalamic fibres. This merging of diverse pathways and associated cell groups is variously called the prerubral, tegmental or H field of Forel.

The ansa lenticularis has a complex origin from both parts of the globus pallidus and possibly other adjacent structures. It curves medially around the ventral border of the internal capsule and continues dorsomedially to mingle with other fibres in the prerubral field. Some fibres in the fasciculus lenticularis and ansa lenticularis synapse in the subthalamic nucleus, prerubral field and zona incerta. The remainder continue laterally, with other fascicles, into the thalamic nuclei, particularly the ventral anterior, ventral lateral and centromedian nuclei.

The thalamic fasciculus extends from the prerubral field; its territory is sometimes termed the H1 field of Forel. It lies dorsal to, and also partly traverses, the zona incerta and is related dorsally to the ventral thalamic nuclei. It contains continuations of the fasciculus lenticularis and ansa lenticularis and dentatothalamic, rubrothalamic and thalamostriate fibres.

The subthalamic fasciculus connects the subthalamic nucleus with the globus pallidus. It contains an abundant two-way array of fibres that traverse the internal capsule, interweaving with it at right angles.

Epithalamus

The epithalamus consists of the anterior and posterior paraventricular nuclei, medial and lateral habenular nuclei, stria medullaris thalami, posterior commissure and pineal body.

Habenular Nuclei and Stria Medullaris

The habenular nuclei lie posteriorly at the dorsomedial corner of the thalamus, immediately deep to the ependyma of the third ventricle, with the stria medullaris thalami above and lateral. The medial habenular nucleus is a densely packed, deeply staining mass of cholinergic neurones, whereas the lateral nucleus is more dispersed and paler staining. The habenulo-interpenduncular tract, or fasciculus retroflexus, emerges from the ventral margin of the nuclei and courses ventrally, skirts the inferior zone of the thalamic mediodorsal nucleus and traverses the superomedial region of the red nucleus to reach the interpeduncular nucleus. The habenular nuclear complex is limited laterally by a fibrous lamina that enters the habenulo-interpeduncular tract. Posteriorly, the nuclei of the two sides and the internal medullary laminae are linked across the midline by the habenular commissure. The tela choroidea of the third ventricle usually arises from the ependyma at the superolateral corner of the medial habenular nucleus.

Afferent fibres to the habenular nuclei travel in the stria medullaris from the prepiriform cortex bilaterally, the basal nucleus of Meynert and the hypothalamus. Afferents from the internal segment of the globus pallidus ascend through the thalamus and may be collaterals of pallidothalamic axons. Additional inputs come from the pars compacta of the substantia nigra, the midbrain raphe nuclei and the lateral dorsal tegmental nucleus. The afferent pathways mostly end in the lateral habenular nucleus. The only identified afferent fibres to the medial habenular nucleus come from the septofimbrial nucleus.

The medial habenular nucleus sends efferent fibres to the interpeduncular nucleus of the midbrain. The lateral habenular nucleus sends fibres to the raphe nuclei and the adjacent reticular formation of the midbrain, to the pars compacta of the substantia nigra and the ventral tegmental area and to the hypothalamus and basal forebrain.

The main habenular outflow reaches the interpeduncular nucleus, mediodorsal thalamic nucleus, mesencephalic tectum and reticular formation, the largest component constituting the habenulo-interpeduncular tract to the interpeduncular nucleus. The latter provides relays to the midbrain reticular formation, from which tectotegmentospinal tracts and dorsal longitudinal fasciculi connect with autonomic preganglionic neurones controlling salivation and gastric and intestinal secretory activity and motility and with motor nuclei for mastication and deglutition.

The stria medullaris crosses the superomedial thalamic aspect, skirts medial to the habenular trigone and sends many fibres into the ipsilateral habenula. Other fibres cross in the anterior pineal lamina and decussate, as the habenular commissure, to reach the contralateral habenula. Some fibres are really commissural and interconnect the amygdaloid complexes and hippocampal cortices. They are accompanied by crossed tectohabenular fibres. Serotonin-containing fibres from the ventral ascending tegmental serotoninergic bundle, which join the habenulo-interpeduncular tract to reach the nuclei, may control neurones of the habenulopineal tract and thus influence innervation of pinealocytes. Similarly, habenular nuclear afferents from the dorsal ascending the tegmental noradrenergic bundle may influence pinealocytes.

Little is known of the physiological functions of the habenular nuclei. It has been suggested that they are involved in the control of sleep mechanisms. Although the human habenula is relatively small, it is a focus of integration of diverse olfactory, visceral and somatic afferent paths. Lesions that include this area of the medial diencephalon indicate that it plays a role in the regulation of visceral and neuroendocrine functions. Ablation of the habenula causes extensive changes in metabolism and in endocrine and thermal regulation.

Pineal Gland

The pineal gland, or epiphysis cerebri (see Fig. 5.8; Fig. 15.19), is a small, reddish grey organ occupying a depression between the superior colliculi. It is inferior to the splenium of the corpus callosum, from which it is separated by the tela choroidea of the third ventricle and the contained cerebral veins. It is enveloped by the lower layer of the tela, which is reflected from the gland to the tectum. The pineal is approximately 8 mm long. Its base, directed anteriorly, is attached by a peduncle, which divides into inferior and superior laminae that are separated by the pineal recess of the third ventricle and contain the posterior and habenular commissures, respectively. Aberrant commissural fibres may invade the gland but do not terminate near parenchymal cells.

Septa extend into the pineal gland from the surrounding pia mater. They divide the gland into lobules and carry blood vessels and fine unmyelinated sympathetic axons. The gland has a rich blood supply. The pineal arteries are branches of the medial posterior choroidal arteries, which are branches of the posterior cerebral artery. Within the gland, branches of the arteries supply fenestrated capillaries whose endothelial cells rest on a tenuous and sometimes incomplete basal lamina. The capillaries drain into numerous pineal veins, which open into the internal cerebral veins or the great cerebral vein.

Postganglionic adrenergic sympathetic axons (derived from the superior cervical ganglion) enter the dorsolateral aspect of the gland from the region of the tentorium cerebelli as the nervus conarii, which may be single or paired. The nerve lies deep to the endothelium of the wall of the straight sinus. It is associated with blood vessels and parenchymal cells within the pineal.

The pineal gland contains cords and clusters of pinealocytes, associated with astrocyte-like neuroglia. Neuroglia are the main cellular component of the pineal stalk. Pinealocytes are highly modified neurones. They contain multiple synaptic ribbons, randomly distributed between adjacent cells, and are coupled by gap junctions. Two or more processes extend from each cell body and end in bulbous expansions near capillaries or, less frequently, on ependymal cells of the pineal recess. These terminal expansions contain rough endoplasmic reticulum, mitochondria and dense-core vesicles that store melatonin. Melatonin and its precursor serotonin are synthesized from tryptophan by the pinealocytes and secreted into the surrounding network of fenestrated capillaries.

The pineal is an endocrine gland of major regulatory importance. It modifies the activity of the adenohypophysis, neurohypophysis, endocrine pancreas, parathyroids, adrenal cortex, adrenal medulla and gonads. Its effects are largely inhibitory. Indolamine and polypeptide hormones secreted by pinealocytes are believed to reduce the synthesis and release of hormones by the pars anterior, either by acting directly on its secretory cells or by indirectly inhibiting the production of hypothalamic releasing factors. Pineal secretions may reach their target cells via the cerebrospinal fluid or the blood stream. Some pineal indolamines, including melatonin and enzymes for their biosynthesis (e.g. serotonin, N-acetyltransferase), show circadian rhythms in concentration. The level rises during darkness and falls during the day, when secretion may be inhibited by sympathetic activity. It is thought that the intrinsic rhythmicity of an endogenous circadian oscillator in the suprachiasmatic nucleus of the hypothalamus governs cyclical pineal behaviour.

From the second decade, calcareous deposits accumulate in pineal extracellular matrix, where they are deposited concentrically as corpora arenacea or ‘brain sand’ (Fig. 15.20). Calcification is often detectable in skull radiographs, where it can be a useful indicator of a space-occupying lesion if the gland is significantly displaced from the midline.

image

Fig. 15.20 Computed tomogram of the head in the horizontal plane at the level of the pineal gland.

(Courtesy of Shaun Gallagher, GKT School of Medicine, London; photograph by Sarah-Jane Smith.)