The thalamus and hypothalamus have traditionally been thought of as a simple relay system and the master control over the pituitary gland, respectively. But as our understanding of the functions of these areas of the neuraxis grows so too does the variety of functions these areas contribute to human function. The thalamus is now thought to play a vital role in the innate stimulatory patterns of wide areas of cortex that allow consciousness. We can record this activity with an electroencephalogram. The hypothalamus seems to be the control centre for certain aspects of the sympathetic nervous system and is also involved in certain types of learning and memory.

In this chapter we will explore the anatomy and neurological functional circuits of these interesting and clinically relevant areas of the neuraxis.

The diencephalon encloses the third ventricle and includes the thalamus with its lateral and medial geniculate bodies, the subthalamus, the epithalamus, and the hypothalamus. Each cerebral hemisphere contains a thalamus, which is a large egg-shaped mass of grey matter, in the dorsal portion of the diencephalon (Fig. 10.1). The thalamus is an important link between sensory receptors and cerebral cortex for all modalities except olfaction.

Figure 10.1 A cross-sectional view of the anatomical relationships of the diencephalon.

The rostral end of the thalamus, also known as the anterior tubercle, is narrower than the posterior portion of the thalamus, which contains a medial enlargement referred to as the pulvinar and a lateral enlargement referred to as the lateral geniculate body. The medial surface of the thalamus forms the lateral wall of the third ventricle and forms a connection to the medial surface of the opposite thalamus through a short communicating projection of grey matter called the massa intermedia or the central thalamic adhesion (Chusid 1982). The thalamus receives extensive projections from all of the main subcortical areas of the nervous system including spinal cord, hypothalamus, cerebellum, and the basal ganglia and forms reciprocal projections with the majority of the cerebral cortex. The connections to and from the cortex, also known as the thalamic radiations, are carried in four fibre tracts referred to as peduncles or stalks. These projections form a considerable portion of the internal capsule (Fig. 10.2). The anterior thalamic peduncle carries projection fibres from the anterior and medial thalamic nuclei to all areas of the frontal cortex. The superior peduncle carries projection fibres to and from the ventral and lateral thalamic nuclei to the pre- and postcentral gyri and premotor and presensory areas of the cortex. The posterior peduncle caries projection fibres to and from the posterior and lateral thalamic areas including the lateral geniculate body and the pulvinar to the posterior and occipital cortical areas. The inferior thalamic peduncle connects the posterior thalamic areas including the medial geniculate body to the temporal areas of cortex (Williams & Warwick 1984). The external medullary laminae are layers of myelinated fibres on the lateral surface of the thalamus immediately adjacent to the internal capsule (Fig. 10.3). The internal medullary lamina is a vertical sheet of white matter deep in the substance of the thalamus that bifurcates in the anterior portion of the thalamus to divide the substance of the thalamus into lateral, medial, and anterior segments (Fig. 10.3). The thalamus has seven groups of nuclei organised with respect to the internal medullary lamina. These include the anterior nuclear group located rostrally, the nuclei of the midline, the medial nuclei, the ventral nuclei, lateral nuclear mass which expands posteriorly to include the pulvinar, the intralaminar nuclear group, and the reticular nuclei (Fig. 10.3). Several nuclei of the thalamus are considered to be areas of singularity dependent on neural activation from the cortex to survive. These nuclei show marked transneural degeneration if the areas of cortex that project to them are damaged, understimulated, or subject to excessive inhibition (Williams & Warwick 1984). This process is an example of diaschisis, where reduced output from one area of the neuraxis results in degeneration of the downstream neuron pools.

Figure 10.2 The relationship of the thalamus to the internal capsule, the globus pallidus, putamen, and the caudate nucleus, and the location in the internal capsule of a variety of efferent and afferent pathways.

Figure 10.3 The thalamic nuclei and their main projections to the cortex.

The anterior nuclear group receives input from the ipsilateral mammillary nuclei of the hypothalamus via the mammillothalamic tract and from the presubiculum of the hippocampal formation (Fig. 10.4). Neurons in the anterior thalamic group project to regions of the cingulate and frontal cortices, mainly areas 23, 24, and 32. The anterior group of nuclei is a principal limbic component in linking the hippocampus and the hypothalamus and is involved with the modulation of memory and emotion.

Figure 10.4 The formation of the thalamic fasciculus from the ansa lenticularis and the fasciculus lenticularis. Note that the anterior nuclear group receives input from the ipsilateral mammillary nuclei of the hypothalamus via the mammillothalamic tract and from the presubiculum of the hippocampal formation.

Recent advances in our understanding of this area of the neuraxis have led to the conclusion that an intact and normally functioning hippocampal-fornical-mammillo-thalamic-limbo-cortical pathway is essential for the establishment of recent memory. The medial nuclei are composed of a number of small nuclei including the parafascicular, submedius, paracentralis, and paralateralis. However, the medial nuclei are dominated by the nucleus medius dorsalis. The medial nuclei form reciprocal projections from the hypothalamus, the frontal cortex, the amygdaloid complex, the corpus striatum, and the brainstem reticular formation. These nuclei also form reciprocal projections with all other thalamic nuclei. Dysfunction of the medial nuclei in humans results in complex changes in motivational drive, in problem-solving ability, and in emotional stability.

The ventral nuclear group is composed of three nuclei, the ventral anterior (VA), the ventral posterior (VP), and the ventral intermedius (VI). The ventral posterior nucleus is further divided into the functionally important ventral posterior lateral (VPL) and ventral posterior medial (VPM) nuclei. The vast majority of the fibres reaching the ventral group are from the afferent fibres of the sensory system of humans. The VPL receives projections from the contralateral cuneate and gracile nuclei via the medial lemniscal pathway and both contralateral and ipsilateral spinothalamic projections via the anterolateral system. The VPM receives projections from the trigeminal and gustatory lemnisci. These nuclei project reciprocally via the posterior limb of the internal capsule to the somatosensory areas including areas 1, 2, and 3 of cortex (see Fig. 10.2). The VI nuclei receive extensive projections from the dentate and interpositus nuclei of the cerebellum and from the basal ganglia. The VI projects to other thalamic nuclei and to the motor areas of cortex, namely areas 4 and 6. The VA nucleus receives extensive projections from the globus pallidus via the thalamic fasciculus and from the dentate nucleus of the cerebellum. The VA nucleus is therefore very important in the integration or modulation of projections from the basal ganglia and the cerebellum on the cortical areas of motor function.

The midline nuclei are composed of the paraventricular, parataenial, and reuniens nuclei. The afferent and efferent projections of these nuclei are very difficult to elucidate but they, along with the intralaminar nuclei, most probably mediate cortical arousal.

The lateral nuclear group is composed of the lateral dorsal (LD) nucleus, the lateral posterior (LP) nucleus, and the pulvinar, which on its own occupies approximately 25% of the whole caudal thalamic area. The pulvinar is relatively late in phylogeny and only occurs in higher primates and humans. The pulvinar is thought to receive projections from the lateral and medial geniculate bodies as well as direct projections from retinal cells of the optic tracts. The pulvinar reciprocally projects to the temporal, occipital, and parietal cortices. The LD nucleus reciprocally projects to the inferior parietal and posterior cingulate cortices. The LP nucleus reciprocally projects to the parietal and postcentral gyri areas of cortex.

The reticular nuclei form an outer shell around the lateral aspects of the thalamus. All afferent and efferent projection fibres, to and from the thalamus, pass through this reticular nuclear area. The neurons of this nucleus are predominantly GABA-ergic in nature, while other thalamic nuclei are mainly excitatory and glutaminergic. The reticular nuclei appear not to have direct projections to the cortex but only to other nuclei of the thalamus (Destexhe & Sejnowski 2003).

The intralaminar nuclei include several small clusters of neurons contained within the substance of the internal medullary laminae. These nuclei include paracentralis, centralis lateralis and centralis limitans, and the much larger central medial nucleus. The function of these nuclei is still not clear.

The nuclei of the midline are small islands of neurons usually in the area of the interthalamic adhesion. These nuclei receive a predominance of their projections from the reticular formation of the brainstem and project to the corpus striatum and cerebellum. The functional significance of these nuclei remains a mystery.

The lateral geniculate nucleus (LGN) appears as a swelling on the rostral surface of the pulvinar and receives afferent input from the axons of the retinal ganglion cells of the temporal half of the ipsilateral eye and the nasal half of the contralateral eye. The LGN neurons then project axons to the ipsilateral primary visual cortex via the optic radiations. The nucleus consists of six layers of nerve cells and is the terminus of about 90% of the fibres of the optic tract. The remaining 10% of fibres terminate in the pretectal areas of the mesencephalon, the superior colliculus of the tectum of the mesencephalon, and some fibres synapse directly on neurons in the hypothalamus (Snell 2001). Only 10–20% of the projections arriving in the LGN are derived directly from the retina. The remaining projections arise from the brainstem reticular formation, the pulvinar, and reciprocal projections from the striate cortex. These projections between the LGN and the striate cortex are important for a number of reasons but may play a major role in the process of physiological completion or ‘fill-in’ that occurs during visual processing in the cortex.

The medial geniculate nucleus (MGN) or body is the tonotopically organised auditory input to the superior temporal gyrus. It appears as a swelling on the posterior surface of the pulvinar. Afferent fibres arriving in the medial geniculate body from the inferior colliculus form the inferior brachium. The inferior colliculus receives projections from the lateral lemniscus. The MGN receives auditory information from both ears but predominantly from the contralateral ear. The efferent projection fibres of the MGN form the auditory radiations that terminate in the auditory cortex of the superior temporal gyrus (Snell 2001).

The visual image inverts and reverses as it passes through the lens of the eye and forms an image on the retina. Image from the upper visual field is projected onto the lower retina and that from the lower visual field onto the upper retina. The left visual field is projected to the right hemiretina of each eye in such a fashion that the right nasal hemiretina of the left eye and the temporal hemiretina of the right eye receive the image. The central image or focal point of the visual field falls on the fovea of the retina, which is the portion of the retina with the highest density of retinal cells and as such produces the highest visual acuity. The fovea receives the corresponding image of the central 1–2° of the total visual field but represents about 50% of the axons in the optic nerve and projects to about 50% of the neurons in the visual cortex. The macula comprises the space surrounding the fovea and also has a relatively high visual acuity. The optic disc is located about 15° medially or towards the nose on each retina and is the convergence point for the axons of retinal cells as they leave the retina and form the optic nerve. This area, although functionally important, has no photoreceptors. This creates a blind spot in each eye about 15° temporally from a central fixation point. When both eyes are functioning, open, and focused on a central fixation point, the blind spots do not overlap so all of the visual field is represented in the cortex and one is not aware of the blind spot in one’s visual experience. The area of the visual striate cortex, which is the primary visual area of the occipital lobe, representing the blind spot and the monocular crescent which are both in the temporal field, does not contain alternating independent ocular dominance columns. This means that these areas only receive information from one eye. If that eye is closed, the area representing the blind spot of the eye remaining open will not be activated because of the lack of receptor activation at the retina.

It is expected that when one eye is closed the visual field should now have an area not represented by visual input, and the absence of vision over the area of the blind spot should be apparent. However, this does not occur. The cortical neurons responsible for the area of the blind spot must receive stimulus from other neurons that create the illusion that the blind spot is not there. This is indeed the case and is accomplished by a series of horizontal projecting neurons located in the visual striate cortex that allow for neighbouring hypercolumns to activate one another. The horizontal connections between these hypercolumns allow for perceptual completion or ‘fill-in’ to occur (Gilbert & Wiesel 1989; McGuire et al. 1991).

The blind spot is therefore not strictly monocular, but it is dependent on the frequency of firing (FOF) of horizontal connections from neighbouring neurons. These may be activated via receptors and pathways from either eye.

Perceptual completion refers to the process whereby the brain fills in the region of the visual field that corresponds to a lack of visual receptors. This explains why one generally is not aware of the blind spot in everyday experience. The size and shape of the blind spots can be mapped utilising simple procedures as outlined in Chapter 4.

The size and shape of the blind spots are dependent to some extent on the central integrative state (CIS) of the horizontal neurons of the cortex that supply the stimulus for the act of completion to occur. The integrative state of the horizontal neurons is determined to some extent by the activity levels of the neurons in the striate cortex in general. Several factors can contribute to the CIS of striate cortical neurons; however, a major source of stimulus results from thalamocortical activation via the reciprocal thalamocortical optic radiation pathways. It is clear from the above that the majority of the projection fibres reaching the LGN are not from retinal cells. This strongly suggests that the LGN acts as a multimodal sensory integration convergence point that in turn activates neurons in the striate cortex appropriately. The level of activation of the LGN is temporally and spatially dependent on the activity levels of all the multimodal projections that it receives.

In 1997, Professor Frederick Carrick discovered that asymmetrically altering the afferent input to the thalamus resulted in an asymmetrical effect on the size of the blind spot in each eye. The blind spot was found to decrease on the side of increased afferent stimulus. This was attributed to an increase in brain function on the contralateral side because of changes in thalamocortical activation that occurred because of multimodal sensory integration in the thalamus.

The stimulus utilised by Professor Carrick in his study was a manipulation of the upper cervical spine, which is known to increase the FOF of multimodal neurons in areas of the thalamus and brainstem that project to the visual striate cortex. These reciprocal connections lower the threshold for activation of neurons in the visual cortex. By decreasing the threshold for firing of neurons in the visual cortex, the manipulation resulted in a smaller blind spot because the area surrounding the permanent geometric blind spot zone is more likely to reach threshold and respond to the receptor activation that occurs immediately adjacent to the optic disc on the contralateral side. The size and shape of the blind spot will also be associated with the degree of activation of neurons associated with receptors adjacent to the optic disc. The receptors surrounding the optic disc underlie the neurons that form the optic nerve exiting by way of the optic disc. The amplitude of receptor potentials adjacent to the optic disc may therefore also be decreased because of interference of light transmission through the overlying fibres even though they should have lost their myelin coating during development; otherwise, interference would be even greater. This interference results in decreased receptor amplitude, which in turn results in decreased FOF of the corresponding primary afferent nerve. This may result in a blind spot that is physiologically larger than the true anatomical size of the blind spot.

This led to the understanding that the size and shape of the blind spots could be used as a measure of the CIS of areas of the thalamus and cortex due to the fact that the amplitude of somatosensory receptor potentials received by the thalamus will influence the FOF of cerebello-thalamocortical loops that have been shown to maintain a CIS of cortex.

Therefore, muscle stretch and joint mechanoreceptor potentials will alter the FOF of primary afferents that may have an effect on visual neurons associated with the cortical receptive field of the blind spot when visual afferents are in a steady state of firing. Professor Carrick proposed that ‘A change in the frequency of firing of one receptor-based neural system should effect the central integration of neurons that share synaptic relationships between other environmental modalities, resulting in an increase or decrease of cortical neuronal expression that is generally associated with a single modality’ (Carrick 1997).

Care should be taken not to base too much clinical significance on the blind spot sizes until any pathological or other underlying cause that may have resulted in the changes in blind spot size are ruled out. The blind spot has been found to increase in size because of the following conditions:

An ophthalmoscopic examination is therefore an important component of the functional neurological examination. There are several other valuable ophthalmoscopic findings discussed in Chapter 4 that can assist with estimating the CIS of various neuronal pools.

The thalamus receives input from every afferent sensory modality with the exception of olfaction. Olfactory perception occurs in the primary and secondary olfactory areas of the cortex, thus bypassing the thalamus.

The hypothalamus lies below or ventral to the thalamus and forms the floor and lateral inferior walls of the third ventricle.

The hypothalamus is composed of a number of structures including the mammillary bodies, the tuber cinereum, the infundibulum which arises from the tuber cinereum and continues inferiorly as the pituitary stalk, the optic chiasm, and a number of nuclear groups of neurons (Chusid 1982). The nuclear groups of the hypothalamus are divided by the fornix and the mammillothalamic tract into medial and lateral zones. The medial zone contains eight distinct groups of nuclei including the preoptic nucleus, the anterior nucleus, a section of the suprachiasmatic nucleus, the paraventricular nucleus, the dorsal medial nucleus, the ventromedial nucleus, the infundibular or arcuate nucleus, and the posterior nucleus (Fig. 10.5).

Figure 10.5 The (A) medial and (B) lateral nuclear groups of the hypothalamus.

The lateral zone contains six distinct groups of nuclei including a section of the preoptic nucleus, a section of the suprachiasmatic nucleus, the supraoptic nucleus, the lateral nucleus, the tuberomammillary nucleus, and the lateral tuberal nuclei.

The hypothalamus receives information from the rest of the body in a variety of ways that include information from the nervous system, information from the blood stream, and information from the cerebrospinal fluid (Fig. 10.5).

Afferent projections to the hypothalamus can take two basic forms. Direct projections, which form fairly distinct anatomical pathways, and multisynaptic collateralised projections, which are known to exist but difficult to identify as distinct pathways. The hypothalamus receives collateralised and direct afferent projections from wide-ranging areas of the neuraxis including:

The hypothalamic nuclei receive projections from a variety of areas of the neuraxis known to contribute to functional aspects of the limbic system.

The fornix is a fibre bundle that projects from the hippocampal formation to the mammillary bodies. The fornix receives collateral contributions from the cingulate gyrus and many of the septal nuclei as it curves ventrally towards the anterior commissural area. The fornix divides into two columns or crura at the anterior commissural area (Fig. 10.6). The hippocampal commissure is a collection of transverse fibres connecting the two crura throughout most of the length of the fornix. Before the anterior commissure intersects with the crural fibres the fornix gives rise to precommissural projections to the preoptic regions of the hypothalamus. The postcommissural fornix gives rise to projections to the dorsal, lateral, and periventricular regions of the hypothalamus before terminating in the mammillary bodies of the hypothalamus.

Figure 10.6 The structure of the fornix.

The amygdaloid complex projects to the preoptic regions and to a variety of other hypothalamic nuclei via the amygdalohypothalamic fibres that arise from two different pathways, the stria terminalis and the ventral amygdalofugal tract (Fig. 10.7).

Figure 10.7 The structure of the amygdaloid complex and the medial forebrain bundle.

The medial forebrain bundle constitutes the main longitudinal pathway of the hypothalamus and contains both afferent and efferent fibres. Fibres from the septal nuclei, the olfactory cortex, and orbitofrontal cortex descend in this tract to the hypothalamic nuclei. Fibres from the pontomedullary reticular formation, the ventral tegmental cholinergic and noradrenergic projection systems, and mesolimbic dopamine projection system ascend in the medial forebrain bundle (Fig. 10.7).

The three major efferent projection systems of the hypothalamus include:

The hypothalamus functions to modulate a diverse array of bodily functions including autonomic, limbic, homeostatic, and endocrine activities.

Hypothalamic projections that originate mainly from the paraventricular and dorsal medial nuclei influence both parasympathetic and sympathetic divisions of the autonomic nervous system. These descending fibres initially travel in the medial forebrain bundle and then divide to travel in both the periaqueductal grey areas and the dorsal lateral areas of the brainstem and spinal cord. They finally terminate on the neurons of the parasympathetic preganglionic nuclei of the brainstem, the neurons in the intermediate grey areas of the sacral spinal cord usually beginning below the L2 spinal cord level, and the neurons in the intermediolateral cell column of the thoracolumbar spinal cord which usually habitate the spinal cord between the levels of T1 and L2. Descending autonomic modulatory pathways also arise from the nucleus solitarius, noradrenergic nuclei of the locus ceruleus, raphe nuclei, and the pontomedullary reticular formation.

The hypothalamus may play an important function in the emotional modulation of autonomic pathways and immune system function through influences of the limbic system projections it receives (Beck 2005).

A variety of homeostatic functions are also modulated by the hypothalamus. The suprachiasmatic nucleus regulates circadian rhythms; the lateral hypothalamus regulates appetite and body weight set points; the ventromedial nucleus inhibits appetite, where dysfunctions in this nucleus can result in obesity; the anterior regions of the hypothalamus regulate thirst, and both anterior and posterior hypothalamic regions are involved in thermoregulation. Sexual desire and other complex emotional states are also modulated by hypothalamic nuclei. Neuroendocrine control mechanisms operate mainly through the pituitary. Parvocellular neurons project to the median eminence to control the anterior pituitary gland. The hypothalamus does this indirectly via release of neurotransmitters and peptides into the highly fenestrated portal venous system and promotes the release of ‘releasing hormones’ and ‘release-inhibiting hormones’. Magnocellular neurons continue down the stalk to the posterior pituitary gland, directly into its general circulation. The hypothalamus promotes the release of oxytocin and vasopressin (Figs 10.8 and 10.9). The intimate relationship between the hypothalamus, the pituitary gland, and the adrenal gland, which is modulated by hormones released by the pituitary gland, is referred to as the hypothalamus–pituitary–adrenal axis. This system is responsible for numerous homeostatic responses of the neuraxis and has been implicated in the negative aspects of the stress response. When a disturbance in the homeostatic state is detected, both the sympathetic nervous system and the hypothalamus–pituitary–adrenal axial system become activated in the attempt to restore homeostasis via the resulting increase in both systemic (adrenal) and peripheral (postganglionic activation) levels of catecholamines and glucocorticoids. In the 1930s, Hans Selye described this series of events or reactions as the general adaptation syndrome or generalised stress response (Selye 1936). Centrally, two principal mechanisms are involved in this general stress response; these are the production and release of corticotrophin-releasing hormone produced in the paraventricular nucleus of the hypothalamus and increased norepinephrine release from the locus ceruleus norepinephrine-releasing system in the brainstem. Functionally, these two systems cause mutual activation of each other through reciprocal innervation pathways (Chrousos & Gold 1992). Activation of the locus ceruleus results in an increased release of catecholamines, of which the majority is norepinephrine, to wide areas of cerebral cortex and subthalamic and hypothalamic areas. The activation of these areas results in an increased release of catecholamines from the postganglionic sympathetic fibres as well as from the adrenal medulla.

Figure 10.8 Anatomical structure of the hypothalamic/pituitary system.

Figure 10.9 A diagrammatic summary of pituitary hormone actions.

This results in a number of catecholamine-mediated responses such as increased heart rate, increased blood pressure, and increased glucose release into the blood (see Chapter 8 for a more complete list of responses).