Diencephalon
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The suprachiasmatic nucleus also influences the activity of upper
spinal preganglionic sympathetic neurones. These neurones in turn
project to superior cervical ganglion neurones, which project to the
pineal gland. Circadian variation in this 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 devel-
opment, and administration of melatonin has been advocated to allevi-
ate jet-lag.
Parvocellular neurosecretory neurones lie within the periventricular
zone: in particular, in the medial parvocellular part of the paraven-
tricular nucleus, and the arcuate nucleus. The arcuate nucleus is
median in the post-infundibular part of the tuber cinereum; it extends
forwards into the median eminence and almost encircles the infundib-
ular 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 ventri-
cle. Circadian variation in the secretion of all anterior pituitary hor-
mones 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
5-HT (5-hydroxytryptamine, serotonin) and noradrenaline (norepine-
phrine) from the brainstem influence the output of most anterior pitu-
itary 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.


DiEnCEPHAlon
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noiTCES
ventromedial and dorsomedial nuclei; the mammillary body; and
tuberomammillary nuclei. Magnocellular neurosecretory neurones are
found in the supraoptic nucleus and paraventricular nucleus, and as
Se OVLT isolated clusters of cells between them.
MeP
Supraoptic and paraventricular nuclei
Nac
DBB SCh AV
PVpo The supraoptic nucleus, curved over the lateral part of the optic chiasma,
MP
BST III contains a uniform population of large neurones. Behind the chiasma,
F a thin plate of cells in the floor of the brain forms the retrochiasmatic
AHA part.
PVH
PVa LHA Supraoptic neurones synthesize vasopressin and they all appear to
MFB project to the neurohypophysis. The magnocellular vasopressin neu-
rones detect as little as 1% increase in the osmotic pressure of the
VM Arc DM blood and stimulate release of vasopressin from the posterior pituitary.
OT
A fall in blood volume or blood pressure of greater than 5–10% stimu-
PM lates the release of vasopressin and the urge to drink. These responses
IC MTT are mediated via volume receptors in the walls of the great veins and
PVp atria and baroreceptors in the carotid sinus, which all project via the
MM TM
vagus and glossopharyngeal nerves to the nucleus tractus solitarius and
thence to the magnocellular nuclei. A biochemical defect in vaso-
PHA
T pressin production, or interruption of the supraopticohypophysial
CP
pathway (e.g. due to a head injury), can cause cranial diabetes
SNc insipidus.
PAG The paraventricular nucleus extends from the hypothalamic sulcus
SNr
downwards across the medial aspect of the column of the fornix, its
ventrolateral angle reaching towards the supraoptic nucleus. Its neu-
rones are more diverse. Magnocellular neurones, which project to the
Fig. 23.9 A horizontal section showing the major cell groups and tracts in
neurohypophysis, tend to lie laterally; parvocellular neurones, which


and around the hypothalamus. Abbreviations: III, third ventricle; AHA,
project to the median eminence and infundibulum, lie more medially;
anterior hypothalamic area; Arc, arcuate nucleus; AV, anteroventral
and intermediate-sized neurones, which may project caudally, lie pos-
preoptic nucleus; BST, bed nucleus of stria terminalis; DBB, nucleus of
teriorly. The axons of the paraventricular magnocellular neurones pass
diagonal band; DM, dorsomedial nucleus; LHA, lateral hypothalamic area;
towards the supraoptic nucleus (paraventriculohypophysial tract),
MeP, median preoptic nucleus; MM, mammillary body (mainly medial
mammillary nucleus); MP, medial preoptic nucleus; Nac, nucleus where they join axons of supraoptic neurones to form a supraoptico-
accumbens; OVLT, vascular organ of the lamina terminalis; PAG, hypophysial tract. This runs down the infundibulum, superficially, and
periaqueductal grey matter; PHA, posterior hypothalamic area; PM, into the neural lobe, where the axons are distended and branch repeat-
posteromedial nucleus in the chiasmatic/tuberal region of the edly around the capillaries. Vasopressin and oxytocin are produced by
hypothalamus; PV, periventricular nucleus (PVa, anterior part; PVp, separate neurones; vasopressin neurones tend to cluster in the ventro-
posterior part; PVpo, preoptic part); PVH, paraventricular (hypothalamic) lateral part of the paraventricular nucleus and the oxytocin neurones
nucleus; SCh, suprachiasmatic nucleus; Se, septal cortex; SNc, lie around them.
substantia nigra pars compacta; SNr, substantia nigra pars reticularis; The hypothalamus is essential for the control of pituitary oxytocin,
T, midbrain tegmentum; TM, tuberomammillary nucleus; VM, ventromedial gonadotrophin and prolactin secretion. The release of oxytocin from


nucleus. Fibre tracts: CP, cerebral peduncle; F, fornix; IC, internal neurosecretory nerve terminals in the neurohypophysis induces con-
capsule; MFB, medial forebrain bundle; MTT, mammillothalamic tract; traction of the uterus and of the myoepithelial cells that surround the
OT, optic tract. (Modified with permission from Elsevier. Progress in Brain mammary gland alveoli. Two neuroendocrine reflexes are involved.
Research, vol 87, Swanson LW, Biochemical switching in hypothalamic
Stretching of the cervix of the uterus during childbirth stimulates a
circuits mediating responses to stress, pp. 181–200, 1991.)
multisynaptic afferent pathway that passes via the pelvic plexus, antero-
lateral column and brainstem to the magnocellular oxytocin neurones
(the Ferguson reflex). This is a positive feedback mechanism, which is
Table 23.3 Main hypothalamic nuclei and their function
terminated by the birth of the child. The milk ejection reflex is evoked
Region Nucleus Hormone secreted Function by suckling of the nipple, which activates intercostal nerves and, thereby,
an afferent connection to the hypothalamus. The reflex can be both
Chiasmatic Medial Median preoptic GnRH
Periventricular GnRH, somatostatin, conditioned to a baby’s cry and inhibited by stress.
CRH, TRH At the tuberal level, the ventromedial nucleus is well defined by a
Suprachiasmatic ‘Master’ clock surrounding neurone-poor zone but the dorsomedial nucleus above it
Intermediate Supraoptic Vasopressin
is much less distinct. The ventromedial nucleus contains neurones
Paraventricular Vasopressin, oxytocin
receptive to plasma levels of glucose and other nutrients, and receives
Tuberal Medial Dorsomedial TRH, ANP
visceral somatic afferents via the nucleus tractus solitarius. The lateral
Ventromedial TRH Satiety centre
Arcuate GHRH, dopamine Secrete to portal hypothalamus receives olfactory afferents, which act as important food
system signals. Both areas receive extensive inputs from limbic structures. Stim-


Lateral Lateral Feeding centre ulation and lesion experiments, together with human case studies,
Posterior Medial Mammillary body Memory suggest that the ventromedial nuclei act together as a ‘satiety centre’.
Bilateral ventromedial nucleus damage promotes overeating (hyper-
Abbreviations: ANP, atrial natriuretic peptide; CRH, corticotrophin-releasing hormone; GHRH, growth phagia), and restricting food intake may provoke rage-like outbursts.
hormone-releasing hormone; GnRH, gonadotrophin-releasing hormone; TRH, thyrotrophin-releasing The resultant obesity is usually coupled with hyposexuality (Fröhlich
hormone.
syndrome). Interestingly, in infants, ventromedial damage can lead to
emaciation despite apparently normal feeding. Experimental lesions in
the lateral hypothalamus promote hypophagia or aphagia, while stimu-
In addition to these peptide-containing cells, dopamine neurones lation can prolong feeding, supporting the concept of a lateral hypotha-
in the arcuate nucleus (A12 group) have terminals in the median emi- lamic ‘feeding centre’.
nence and infundibulum. Dopamine acts as the principal prolactin The ventromedial nucleus, lateral hypothalamic area and paraven-
release-inhibiting hormone, and also inhibits secretion of TSH (like- tricular nucleus also influence intermediate metabolism through the
wise, TSH acts as a prolactin-releasing hormone). Noradrenergic termi- autonomic and endocrine systems. These appear to complement the
nals are found in the median eminence, where they may act largely in effects on feeding behaviour. Thus, ventromedial stimulation facilitates
a paracrine manner. glucagon release and increases glycogenolysis, gluconeogenesis and
The intermediate zone of the hypothalamus contains the best- lipolysis, whereas lateral hypothalamic stimulation causes insulin
differentiated nuclei. These are: the paraventricular and supraoptic release and the opposite metabolic effects. Lesions of the ventromedial
nuclei; ‘intermediate’ nuclear groups, which show sexual dimorphism; nucleus also cause increased vagal and decreased sympathetic tone.


Pituitary gland
359
32
RETPAHC
The medial mammillary nuclei, which form the bulk of the mam- lamus. Visual afferents leave the optic chiasma and pass dorsally into
millary bodies, are very prominent. The distinct existence of a lateral the suprachiasmatic nucleus. No auditory connections have been iden-
mammillary nucleus is controversial, though a group of larger cells does tified, though it is clear that such stimuli influence hypothalamic activ-
occur along the lateral border of the medial mammillary nucleus. ity. However, many hypothalamic neurones respond best to complex
Lateral to this is the tuberomammillary nucleus, which gives rise to sensory stimuli, suggesting that sensory information reaching the neo-
widespread axons that diffusely innervate the entire cerebral cortex, cortex has converged and been processed by the amygdala, hippocam-
hypothalamus and brainstem. pus and neocortex. Neocortical corticohypothalamic afferents to the
The lateral zone of the hypothalamus forms a continuum that runs hypothalamus are poorly defined, but probably arise from frontal and
from the preoptic nucleus through the lateral hypothalamic area to the insular cortices. Some may relay in the mediodorsal thalamic nucleus
posterior hypothalamus. In the tuberal region, the lateral tuberal nuclei and project into the hypothalamus via the periventricular route. Other
are large and well defined, and surrounded by fine fibres. direct corticohypothalamic fibres may end in lateral, dorsomedial,
mammillary and posterior hypothalamic nuclei, but all these connec-
tions are questioned.
CONNECTIONS OF THE HYPOTHALAMUS
Like the rest of the forebrain, the hypothalamus also receives diffuse
aminergic inputs from the locus coeruleus and raphe nuclei. In addi-
The hypothalamus has reciprocal interaction with the rest of the body tion, it receives input from the ventral tegmental ascending cholinergic
via two (possibly three) quite distinct routes: neural connections, the pathway: a noradrenergic input to dorsomedial, periventricular, para-
bloodstream and (probably) the cerebrospinal fluid. ventricular, supraoptic and lateral hypothalamic nuclei from the ventral


Some hypothalamic neurones have specific receptors that sense the tegmental noradrenergic bundle, and fibres from the mesolimbic
temperature, osmolarity, glucose, free fatty acid and hormone content dopaminergic system. Group A11 innervates the medial hypothalamic
of the blood. Neurosecretory neurones secrete neurohormones into the nuclei, and groups A13 and A14 supply the dorsal and rostral hypotha-
blood. These control the anterior pituitary and act on organs such as lamic nuclei. Many of these fibres also run in the medial forebrain
the kidney, breast, uterus and blood vessels. Some of the neural con- bundle.
nections, especially those to the mammillary bodies, form discrete The medial forebrain bundle is a loose grouping of fibre pathways
myelinated fascicles, but most are diffuse and unmyelinated, and their that mostly run longitudinally through the lateral hypothalamus (see
origin and termination are uncertain. Most pathways are multisynaptic Fig. 23.9). It connects forebrain autonomic and limbic structures with
and many of the synapses on hypothalamic neurones are derived from the hypothalamus and brainstem, receiving and giving small fascicles
intrinsic interneurones. throughout its course. It contains descending hypothalamic afferents
Broadly, neural inputs to the hypothalamus are derived from the from the septal area and orbitofrontal cortex, ascending afferents from
ascending visceral and somatic sensory systems, the visual and olfactory the brainstem, and efferents from the hypothalamus.
systems, and numerous tracts from the brainstem, thalamus, ‘limbic’
structures and neocortex. Efferent neural projections are reciprocal to
Efferent connections
most of these and, 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 con- Hypothalamic efferents include reciprocal paths to the limbic system,
nections to the telencephalon. descending polysynaptic paths to autonomic and somatic motor neu-
rones, and neural and neurovascular links with the pituitary.
Afferent connections Septal areas and the amygdaloid complex have reciprocal hypotha-
lamic connections along the paths described above. The medial preoptic


and anterior hypothalamic areas give short projections to nearby hy-
The hypothalamus receives visceral, gustatory and somatic sensory
pothalamic groups. The ventromedial nucleus has more extensive pro-
information from the spinal cord and brainstem. It receives largely
jections that pass via the medial forebrain bundle to the bed nucleus of
polysynaptic projections from the nucleus tractus solitarius, probably
the stria terminalis, nucleus basalis (basal nucleus of Meynert), central
directly and indirectly via the parabrachial nucleus and medullary
nucleus of the amygdala, and midbrain reticular formation. The poste-
noradrenergic cell groups (ventral noradrenergic bundle); collaterals of
rior hypothalamus projects largely to the midbrain central grey matter.
lemniscal somatic afferents (to the lateral hypothalamus); and projec-
Some tuberal and posterior lateral hypothalamic neurones project di-
tions from the dorsal longitudinal reticular formation. Many enter via
rectly to the entire neocortex and appear to be essential for maintaining
the medial forebrain bundle (see Fig. 23.9) and periventricular fibre
cortical arousal, but the topography of these projections is unclear.
system. Others converge in the midbrain tegmentum, forming the
Hypothalamic neurones projecting to autonomic neurones are
mammillary peduncle to the mammillary body.
found in the paraventricular nucleus (oxytocin and vasopressin
The major forebrain inputs to the hypothalamus are derived from
neurones), perifornical and dorsomedial nuclei (atrial natriuretic
structures in the limbic system, including the hippocampal formation,
peptide neurones), lateral hypothalamic area (α-melanocyte-stimulating
amygdala and septum, and from the piriform lobe and adjacent
hormone; α-MSH neurones) and zona incerta (dopamine neurones).
neocortex. These connections, which are reciprocal, form prominent
These fibres run through the medial forebrain bundle into the tegmen-
fibre systems, i.e. the fornix, stria terminalis and ventral amygdalofugal
tum, ventrolateral medulla and dorsal lateral funiculus of the spinal
tracts.


cord. In the brainstem, fibres innervate the parabrachial nucleus,
The hippocampal formation – in particular, the subiculum and CA1
nucleus ambiguus, nucleus of the solitary tract and dorsal motor
– is reciprocally connected to the hypothalamus by the fornix, a complex
nucleus of the vagus. In the spinal cord, they end on sympathetic and
tract that also contains commissural connections. As the fornix curves
parasympathetic preganglionic neurones in the intermediolateral
ventrally towards the anterior commissure, it is joined by fascicles from
column. Both oxytocin- and vasopressin-containing fibres can be traced
the cingulate gyrus, indusium griseum and the septal area. It divides
to the most caudal spinal autonomic neurones.
around the anterior commissure into pre- and postcommissural parts.
The medial mammillary nucleus gives rise to a large ascending fibre
The precommissural fornix is distributed to the septum and preoptic
bundle, which diverges into the mammillothalamic and mammilloteg-
hypothalamus, and the septum in turn sends numerous fibres to the
mental tracts (see Fig. 23.9). The mammillothalamic tract ascends
hypothalamus. The postcommissural fornix passes ventrally and poste-
through the lateral hypothalamus to reach the anterior thalamic nuclei,
riorly through the hypothalamus to the medial mammillary nucleus.
whence massive projections radiate to the cingulate gyrus. The mam-
In its course it gives off many fibres to the medial and lateral hypotha-
millotegmental tract curves inferiorly into the midbrain ventral to the
lamic nuclei.
medial longitudinal fasciculus, and is distributed to tegmental reticular
The amygdala innervates most hypothalamic nuclei anterior to the
nuclei.
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 hypotha-
PITUITARY GLAND
lamus by two routes. The short ventral amygdalofugal path passes medi-


ally over the optic tract, beneath the lentiform complex, to reach the
hypothalamus. The long curved stria terminalis runs parallel to the The pituitary gland, or hypophysis cerebri (Fig. 23.10; see Fig. 18.10),
fornix, separated from it by the lateral ventricle, passes through the bed is a reddish-grey, ovoid body, about 12 mm in transverse and 8 mm in
nucleus of the stria terminalis, and is then distributed to the anterior anteroposterior diameter, and with an average adult weight of 500 mg.
hypothalamus via the medial forebrain bundle. It is continuous with the infundibulum, a hollow, conical, inferior
Olfactory afferents reach the hypothalamus largely via the nucleus process from the tuber cinereum of the hypothalamus. It lies within the
accumbens and septal nuclei, and most terminate in the lateral hypotha- pituitary fossa of the sphenoid bone, where it is covered superiorly by


DiEnCEPHAlon
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noiTCES
Fig. 23.10 A median section through the
hypophysis cerebri.
Anterior commissure
Infundibular recess Anterior cerebral artery
Tuber cinereum
Arachnoid mater Lamina terminalis
Posterior communicating artery Optic recess
Posterior cerebral artery Optic chiasma
Oculomotor nerve
Trochlear nerve
Optic nerve
Superior cerebellar artery Hypophysis cerebri,
anterior lobe
Hypophysis cerebri,
posterior lobe
Sphenoidal sinus
Basilar artery
a circular diaphragma sellae of dura mater. The latter is pierced centrally Adenohypophysis
by an aperture for the infundibulum and separates the anterior superior
aspect of the pituitary from the optic chiasma. Inferiorly, the pituitary
The adenohypophysis is highly vascular. It consists of epithelial cells of
is separated from the floor of the fossa by a venous sinus that com-
varying size and shape arranged in cords or irregular follicles, between
municates with the circular sinus. The meninges blend with the pitui-
which lie thin-walled vascular sinusoids supported by a delicate reticu-
tary capsule and are not separate layers.
lar connective tissue (Fig. 23.12). Most of the hormones synthesized
The pituitary (Sam and Frohman 2008) has two major parts, the
by the adenohypophysis are trophic (see Table 23.4 for a summary of
neurohypophysis and adenohypophysis, which differ in their origin,
pituitary hormones). They include the peptides GH, involved in the
structure and function. The neurohypophysis is a diencephalic down-
control of body growth, and prolactin, which stimulates both growth
growth connected with the hypothalamus. The adenohypophysis is an
of breast tissue and milk secretion. Glycoprotein trophic hormones are
ectodermal derivative of the stomatodeum. Both include parts of the
the large pro-opiomelanocortin precursor of ACTH, which controls the
infundibulum (whereas the older terms ‘anterior lobe’ and ‘posterior
secretion of certain suprarenal cortical hormones; TSH; FSH, which


lobe’ do not). The infundibulum has a central infundibular stem, which
stimulates growth and secretion of oestrogens in ovarian follicles and
contains neural hypophysial connections and is continuous with the
spermatogenesis (acting on testicular Sertoli cells); and LH, which
median eminence of the tuber cinereum. Thus, the term neurohypo-
induces progesterone secretion by the corpus luteum and testosterone
physis includes the median eminence, infundibular stem and neural
synthesis by Leydig cells in the testis. Pro-opiomelanocortin is cleaved
lobe or pars posterior. Surrounding the infundibular stem is the pars
into a number of different molecules, including ACTH. Beta-lipotropin
tuberalis, a component of the adenohypophysis. The main mass of the
is released from the pituitary but its lipolytic function in humans is
adenohypophysis may be divided into the pars anterior (pars distalis)
uncertain. Beta-endorphin is another cleavage product released from
and the pars intermedia, which are separated in fetal and early postnatal
the pituitary.
life by the hypophysial cleft, a vestige of Rathke’s pouch, from which it
Neurones that secrete the peptides and amines that control the
develops.
anterior lobe are widely distributed within the hypothalamus. They are
The neurohypophysis includes the pars posterior (pars nervosa, pos-
situated mainly in the medial zone, in the arcuate nucleus, medial
terior or neural lobe), infundibular stem and median eminence. The
parvocellular part of the paraventricular nucleus, and periventricular
adenohypophysis includes the pars anterior (pars distalis or glandula-
nucleus.
ris), pars intermedia and pars tuberalis.
Arteries and veins of the pituitary gland
Neurohypophysis
The arteries of the pituitary arise from the internal carotid arteries via
In early fetal life, the neurohypophysis contains a cavity continuous a single inferior and several superior hypophysial arteries on each side
with the third ventricle. Axons arising from groups of hypothalamic (Page 1982). The former come from the cavernous part of the internal


neurones (e.g. the magnocellular neurones of the supraoptic and para- carotid artery, the latter from its supraclinoid part and from the anterior
ventricular nuclei) terminate in the neurohypophysis. The long magno- and posterior cerebral arteries. The inferior hypophysial arteries divide
cellular axons pass to the main mass of the neurohypophysis. They form into medial and lateral branches, which anastomose across the midline
the neurosecretory hypothalamohypophysial tract and terminate near and form an arterial ring around the infundibulum. Fine branches from
the sinusoids of the posterior lobe. Some smaller parvocellular neu- this circular anastomosis enter the neurohypophysis to supply its capil-
rones in the periventricular zone have shorter axons, and end in the lary bed. The superior hypophysial arteries supply the median emi-
median eminence and infundibular stem among the superior capillary nence, upper infundibulum and, via the artery of the trabecula, the
beds of the venous portal circulation. These small neurones produce lower infundibulum. (The trabecula is a compact band of connective
releasing and inhibitory hormones, which control the secretory activi- tissue and blood vessels lying within the pars distalis on either side of
ties of the adenohypophysis via its portal blood supply. the midline; it forms a prominent fibrovascular tuft close to the junction
The neurohormones stored in the main part of the neurohypophysis of the central and lateral parts of the pars distalis; Xuereb et al (1954).)
are vasopressin (antidiuretic hormone; ADH), which controls reabsorp- A confluent capillary net, extending through the neurohypophysis, is
tion of water by renal tubules, and oxytocin, which promotes the con- supplied by both sets of hypophysial vessels. Reversal of flow can occur
traction of uterine smooth muscle in childbirth and the ejection of milk in cerebral capillary beds lying between the two supplies.
from the breast during lactation (pituitary hormones are summarized The arteries of the median eminence and infundibulum end in char-


in Table 23.4). Storage granules containing active hormone polypep- acteristic sprays of capillaries, which are most complex in the upper
tides bound to a transport glycoprotein, neurophysin, pass down axons infundibulum. In the median eminence, these form an external or
from their site of synthesis in the neuronal somata (Fig. 23.11). ‘mantle’ plexus and an internal or ‘deep’ plexus. The external plexus, fed


Diencephalon
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RETPAHC
Usually obliterated in childhood, remnants may persist in the form Table 23.4 Pituitary hormones
of cystic cavities, often present near the adenoneurohypophysial fron-
Hormone Cell type Function / effector Releasing Inhibitor
tier, which sometimes invade the neural lobe. The human pars inter-
site factor
media is rudimentary. It may be partially displaced into the neural lobe,
and has been included in the anterior and posterior parts by different ACTH Corticotrophs Suprarenal cortex CRH
(basophils)
observers. Apart from this equivocation, which is of little significance,
the pars anterior and pars posterior may be equated with the anterior TSH Thyrotrophs Thyroid gland TRH Somatostatin
(basophils)
and posterior lobes. When the associated infundibular parts continuous
LH, FSH Gonadotrophs Gonads GnRH GnIH
with these lobes are included, the names adenohypophysis and neuro-
(basophils) (pulsatile)
hypophysis become appropriate.
GH Somatotrophs Body growth and GHRH Somatostatin
The thin, unmyelinated axons of the neurohypophysis are ensheathed
(acidophils) metabolism
by typical astrocytes in the infundibulum (see Fig. 23.12). Near the
Prolactin Lactotrophs Mammary gland Dopamine
posterior lobe, astrocytes are replaced by pituicytes. These are dendritic (acidophils)
neuroglial cells of variable appearance, often with long processes
Vasopressin Magnocellular Water absorption in
running parallel to adjacent axons; they constitute most of the non- (ADH) hypothalamic neurons distal renal tubule
excitable tissue in the neurohypophysis. Typically, their cytoplasmic Oxytocin Magnocellular Contraction of uterine
processes end on the walls of capillaries and sinusoids between nerve hypothalamic neurons smooth muscle and
terminals. Axons also end in perivascular spaces; they lie close to the ejection of breast milk
walls of sinusoids but remain separated from them by two basal


laminae, one around the nerve endings and the other underlying the Abbreviations: ACTH, adrenocorticotrophic hormone; ADH, antidiuretic hormone; CRH, corticotrophin-
fenestrated endothelial cells. The spaces between the basal laminae are releasing hormone; FSH, follicle-stimulating hormone; GH, growth hormone; GHRH, growth hormone-
releasing hormone; GnIH, gonadotrophin-inhibitory hormone; GnRH, gonadotrophin-releasing hormone;
occupied by fine collagen fibrils.
LH, luteinizing hormone; TRH, thyrotrophin-releasing hormone; TSH, thyroid-stimulating hormone.
The epithelial endocrine cells, which secrete the different adenohy-
pophysial hormones, may be distinguished in part by their differing
affinities for acidic and basic dyes. Cells staining strongly are described
as chromophils, while those with low affinity for dyes are chromo- A small collection of adenohypophysial tissue lies in the mucoperio-
phobes. Acidophils stain strongly with acidic dyes, whereas basophils, steum of the human nasopharyngeal roof. By 28 weeks in utero it is well
which are more prevalent in the central part of the gland, stain strongly vascularized and capable of secretion, receiving blood from the systemic
with basic dyes. Cells may also be classified according to the hormones vessels of the nasopharyngeal roof. At this stage, it is covered posteriorly
they synthesize into somatotrophs (GH-secreting acidophils, the most by fibrous tissue. This is replaced in the second half of fetal life by
numerous chromophil type); lactotrophs (prolactin-secreting acido- venous sinuses, and a trans-sphenoidal portal venous system develops,
phils, which are dominant in pregnancy and hypertrophy during bringing the nasopharyngeal tissue under the same hypothalamic
lactation); gonadotrophs (FSH- and LH-secreting basophils); thyro- control as the cranial adenohypophysial tissue. The peripheral vascular-


trophs (TH-secreting basophils); and corticotrophs (ACTH-secreting ity of the pharyngeal hypophysis persists until about the fifth year. The
basophils). Chromophobes are thought to be quiescent or degranulated organ is then reinvested by fibrous tissue and presumed to be controlled
chromophils, or immature precursor cells, and constitute up to half of once more by factors present in systemic blood. Though it does not
the cells of the adenohypophysis. change in size after birth in males, in females it becomes smaller, return-
The pars intermedia contains follicles of chromophobe cells that ing to natal volume during the fifth decade, when once again it may be
surround cyst-like structures lined by epithelium and are filled, to controlled via a trans-sphenoidal extension of the hypothalamo-
varying degrees, with glycosylated colloidal material. Secretory products hypophysial portal venous system. The human pharyngeal hypophysis
of this region may include cleavage products of pro-opiomelanocortin may be a reserve of potential adenohypophysial tissue, which may be
but their functional significance is uncertain. The pars tuberalis contains stimulated, particularly in females, to synthesize and secrete adenohy-
a large number of blood vessels, between which are cords or clusters of pophysial hormones in middle age, when intracranial adenohypophy-
gonadotrophs and undifferentiated cells. sial tissue is beginning to fail.


Subthalamus
361
32
RETPAHC
Hypothalamic nuclei
respond to emotional and
exteroceptive stimuli Paraventricular nucleus
Supraoptic nucleus
Mammillary body
Optic chiasma
Superior hypophysial artery
Primary capillary plexus in the upper
infundibulum receives releasing and
Artery of the trabecula inhibitory neuroendocrine factors from
hypothalamic nuclei axon terminals
Hypothalamohypophysial
Portal veins carry neuroendocrine portal system
factors to the adenohypophysis
Inferior hypophysial artery
Secondary capillary plexus
Axon terminal
Capillary plexus of Acidophil
the posterior lobe Basophil
Chromophobe
Hypophysial vein (to dural sinuses) Hypophysial vein (to dural sinuses)
Posterior or neural lobe Anterior lobe
Fig. 23.11 The main systems controlling the endocrine secretory activities of the pituitary gland.
RP
Neurohypophysis
PI
A B
Fig. 23.12 The pituitary gland (trichrome-stained). A, The endocrine cells of the adenohypophysis. Chromophils can be distinguished as acidophils
(yellow) and basophils (pink). Chromophobes are pale-staining cells. A network of sinusoids is seen between clusters of secretory cells. B, The
neurohypophysis (right), with nerve fibres and pituicytes. To the left is the pars intermedia (PI) with scattered, deeper-staining secretory cells and a cyst
containing colloid (top left), representing the remnants of Rathke’s pouch (RP).
by the superior hypophysial arteries, is continuous with the infundibular gland to their targets and also facilitates feedback control of secretion.
plexus and is drained by long portal vessels, which descend to the pars However, venous drainage of the adenohypophysis appears restricted:
anterior. The internal plexus lies within and is supplied by the external few vessels connect it directly to the systemic veins and so the routes
plexus. It is continuous posteriorly with the infundibular capillary bed by which blood leaves remain obscure.
and, like the external plexus, is drained by long portal vessels. Short


portal vessels run from the lower infundibulum to the pars anterior.
SUBTHALAMUS
Both types of portal vessel 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 The subthalamus is a complex region of nuclear groups and fibre tracts
hormone-releasing factors, probably elaborated in parvocellular groups (see Fig. 24.12). The main nuclear groups are the subthalamic nucleus,
of hypothalamic neurones, and these control the secretory cycles of cells the reticular nucleus, the zona incerta, the fields of Forel and the pre-
in the pars anterior. The pars intermedia appears to be avascular. geniculate nucleus. The rostral poles of the red nucleus and substantia
There are three possible routes for venous drainage of the neurohy- nigra also extend into this area.
pophysis: to the adenohypophysis, via long and short portal vessels; The main subthalamic tracts are: the upper parts of the medial,
into the dural venous sinuses, via the large inferior hypophysial veins; spinal and trigeminal lemnisci and the solitariothalamic tract,
and to the hypothalamus, via capillaries passing to the median emi- all approaching their terminations in the thalamic nuclei; the denta-
nence. The venous drainage carries hypophysial hormones from the tothalamic tract from the contralateral superior cerebellar peduncle


DiEnCEPHAlon
362
3
noiTCES
accompanied by ipsilateral rubrothalamic fibres; the fasciculus retro- traverses the superomedial region of the red nucleus to reach the
flexus; the fasciculus lenticularis; the fasciculus subthalamicus; the ansa interpeduncular nucleus. The habenular nuclear complex is limited
lenticularis; fascicles from the prerubral field (H field of Forel); the laterally by a fibrous lamina, which enters the fasciculus retroflexus.
continuation of the fasciculus lenticularis (in the H field of Forel); and Posteriorly, the nuclei of the two sides and the internal medullary
2
the fasciculus thalamicus (the H field of Forel). laminae are linked across the midline by the habenular commissure.
1
The tela choroidea of the third ventricle usually arises from the epend-
yma at the superolateral corner of the medial habenular nucleus.
SUBTHALAMIC NUCLEUS
Afferent fibres to the habenular nuclei travel in the stria medullaris
from the prepiriform cortex bilaterally, the nucleus basalis (of Meynert)
The subthalamic nucleus is structurally and functionally related to the
and the hypothalamus. Afferents from the internal pallidum ascend
basal ganglia and is therefore considered with them on page 369.
through the thalamus and may be collaterals of pallidothalamic axons.
Additional inputs come from the pars compacta of the substantia nigra,
ZONA INCERTA AND FIELDS OF FOREL the midbrain raphe nuclei and the lateral dorsal tegmental nucleus. The
afferent pathways mostly end in the lateral habenular nucleus. The only
The zona incerta is an aggregation of small cells that lies between the identified afferent fibres to the medial habenular nucleus come from
ventral part of the external medullary lamina of the thalamus and the the septofimbrial nucleus.
cerebral peduncle. It is linked to the reticular nucleus dorsolaterally. The medial habenular nucleus sends efferent fibres to the interpe-


More medially there is a scattered group of cells in a matrix of fibres duncular nucleus of the midbrain. The lateral habenular nucleus sends
known as the H field of Forel (see Fig. 24.11). Field H of Forel consists fibres to the raphe nuclei and the adjacent reticular formation of the
1
of the thalamic fasciculus, which lies dorsal to the zona incerta. Field midbrain, the pars compacta of the substantia nigra and the ventral
H of Forel contains the fasciculus lenticularis and lies ventrally, between tegmental area, and to the hypothalamus and basal forebrain.
2
the zona incerta and the subthalamic nucleus (see Figs 24.6, 24.12). The main habenular outflow reaches the interpeduncular nucleus,
The zona incerta receives fibres from the sensorimotor cortex, the mediodorsal thalamic nucleus, mesencephalic tectum and reticular for-
pregeniculate nucleus, the deep cerebellar nuclei, the trigeminal nuclear mation, the largest component constituting the fasciculus retroflexus to
complex and the spinal cord. It projects to the spinal cord and the the interpeduncular nucleus. The latter provides relays to the midbrain
pretectal region. Its functions are unknown. reticular formation, from which tectotegmentospinal tracts and dorsal
The neurones of the H field of Forel receive afferents from the spinal longitudinal fasciculi connect with autonomic preganglionic neurones
cord, the reticular formation of the brainstem and, possibly, the internal controlling salivation, gastric and intestinal secretory activity and motil-
pallidum. They may project to the spinal cord. Like the zona incerta, ity, and motor nuclei for mastication and deglutition.
their functions are unknown. The stria medullaris crosses the superomedial thalamic aspect, skirts
In addition to terminal parts of the lemniscal, dentatothalamic and medial to the habenular trigone and sends many fibres into the ipsilat-
rubrothalamic tracts, the subthalamus contains massive fibre tracts eral habenula. Other fibres cross in the anterior pineal lamina and


derived from the globus pallidus. The fasciculus lenticularis is the dorsal decussate, as the habenular commissure, to reach the contralateral
component of pallidofugal fibres that traverse the internal capsule. It habenula. Some fibres are really commissural and interconnect the
turns medially near the medial aspect of the capsule, partly intermin- amygdaloid complexes and hippocampal cortices. They are accompa-
gled with the dorsal zone of the subthalamic nucleus and the ventral nied by crossed tectohabenular fibres. Serotonin-containing fibres from
part of the zona incerta, where the fasciculus traverses the H field of the ventral ascending tegmental serotoninergic bundle, which join the
2
Forel. Reaching the medial border of the zona incerta, the fasciculus fasciculus retroflexus to reach the nuclei, may control neurones of the
intermingles with fibres of the ansa lenticularis, scattered elements of habenulopineal tract, and thus influence innervation of pinealocytes.
the prerubral nucleus, and dentatothalamic and rubrothalamic fibres. Similarly, habenular nuclear afferents from the dorsal ascending teg-
This merging of diverse pathways and associated cell groups is variously mental noradrenergic bundle may influence pinealocytes.
called the prerubral, tegmental or H field of Forel. Little is known of the physiological functions of the habenular
The ansa lenticularis has a complex origin from both parts of the nuclei. It has been suggested that they may be involved in the control
globus pallidus and possibly other adjacent structures. It curves medi- of sleep mechanisms. Though the human habenula is relatively small,
ally round the ventral border of the internal capsule, and continues it is a focus of integration of diverse olfactory, visceral and somatic
dorsomedially to mingle with other fibres in the prerubral field. Some afferent paths. Lesions that include this area of the medial diencephalon
fibres in the fasciculus lenticularis and ansa lenticularis synapse in the indicate that it plays a role in the regulation of visceral and neuroen-
subthalamic nucleus, prerubral field and zona incerta. The remainder docrine functions. Ablation of the habenula causes extensive changes


continue laterally, with other fascicles, into the thalamic nuclei, particu- in metabolism and in endocrine and thermal regulation.
larly the ventral anterior, ventral lateral and centromedian nuclei.
The thalamic fasciculus extends from the prerubral field, and its ter-
POSTERIOR COMMISSURE
ritory is termed the H field of Forel. It lies dorsal to, and also partly
1
traverses, the zona incerta, and is related dorsally to the ventral thalamic
nuclei. It contains continuations of the fasciculus lenticularis and ansa The posterior commissure, which is of unknown constitution in
lenticularis, and dentatothalamic, rubrothalamic and thalamostriate humans, is a small fasciculus that decussates in the inferior pineal
fibres. lamina. Various small nuclei are associated with it. Among these are the
The subthalamic fasciculus connects the subthalamic nucleus with interstitial nuclei of the posterior commissure, the nucleus of Dark-
the globus pallidus. It contains an abundant two-way array of fibres that schewitsch in the periaqueductal grey matter, and the interstitial nucleus
traverse the internal capsule, interweaving with it at right angles. of Cajal near the upper end of the oculomotor complex, closely linked
with the medial longitudinal fasciculus. Fibres from all these nuclei and
the fasciculus cross in the posterior commissure. It also contains fibres
EPITHALAMUS from thalamic and pretectal nuclei and the superior colliculi, together
with fibres that connect the tectal and habenular nuclei. The destina-
The epithalamus consists of the anterior and posterior paraventricular tions and functions of many of these fibres are obscure.
nuclei, the medial and lateral habenular nuclei, the stria medullaris
thalami, posterior commissure and the pineal body.
PINEAL GLAND
HABENULAR NUCLEI AND STRIA
The pineal gland or epiphysis cerebri (see Figs 18.10, 25.48B) is a small,
MEDULLARIS THALAMI reddish-grey organ, occupying a depression between the superior col-


liculi. It is inferior to the splenium of the corpus callosum, from which
The habenular nuclei lie posteriorly at the dorsomedial aspect of the it is separated by the tela choroidea of the third ventricle and the con-
thalamus, immediately deep to the ependyma of the third ventricle, tained cerebral veins. It is enveloped by the lower layer of the tela, which
with the stria medullaris thalami above and laterally. The medial is reflected from the gland to the tectum. The pineal is about 8 mm
habenular nucleus is a densely packed, deeply staining mass of cholin- long. Its base, directed anteriorly, is attached by a peduncle, which
ergic neurones, whereas the lateral nucleus is more dispersed and paler- divides into inferior and superior laminae, separated by the pineal
staining. The fasciculus retroflexus (habenulo-interpeduncular tract) recess of the third ventricle, and containing the posterior and habenular
emerges from the ventral margin of the nuclei and courses ventrally, commissures respectively. Aberrant commissural fibres may invade the
skirts the inferior zone of the thalamic mediodorsal nucleus, and gland but do not terminate near parenchymal cells.


363
32
RETPAHC
Key references
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 themselves 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 and/or into the great
cerebral vein.
Postganglionic adrenergic sympathetic axons (derived from neu- Pineal calcification
rones in the superior cervical ganglion) enter the dorsolateral aspect of
the gland from the region of the tentorium cerebelli as the nervus
Calcified choroid plexus within
conarii, which may be single or paired. The nerve lies deep to the (lateral) temporal horn of left
endothelium of the wall of the straight sinus and is associated with lateral ventricle.
blood vessels and parenchymal cells within the pineal.
The pineal gland contains cords and clusters of pinealocytes, associ-
ated with astrocyte-like neuroglia. Neuroglia are the main cellular com-
ponent of the pineal stalk. Pinealocytes are highly modified neurones. Fig. 23.13 An axial CT image showing calcification of the pineal gland
They contain multiple synaptic ribbons, randomly distributed between and choroid plexus.
adjacent cells, and are coupled by gap junctions. Two or more processes
extend from each cell body and end in bulbous expansions near capil-
oscillator in the suprachiasmatic nucleus of the hypothalamus governs
laries or, less frequently, on ependymal cells of the pineal recess. These
cyclical pineal behaviour (see above).
terminal expansions contain rough endoplasmic reticulum, mitochon-
From the second decade, calcareous deposits accumulate in pineal
dria and dense-cored vesicles that store melatonin. Melatonin, and its
extracellular matrix, where they are deposited concentrically as corpora


precursor 5-HT (serotonin), are synthesized from tryptophan by the
arenacea or ‘brain sand’ (Fig. 23.13). Pineal gland and choroid plexus
pinealocytes, and secreted into the surrounding network of fenestrated
calcifications are the most frequent sites of intracranial calcifications
capillaries.
incidentally discovered among head computed tomography examina-
The pineal is an endocrine gland of major regulatory importance
tions; calcification can provide a useful indicator of a space-occupying
(Macchi and Bruce 2004). It modifies the activity of the adenohypophy-
lesion if the gland is significantly displaced from the midline.
sis, neurohypophysis, endocrine pancreas, parathyroids, suprarenal
cortex, suprarenal medulla and gonads. Its effects are largely inhibitory.
Indoleamine and polypeptide hormones secreted by pinealocytes are
believed to reduce the synthesis and release of hormones by the pars Bonus e-book images and table
anterior, either by direct action on its secretory cells or indirectly by
inhibiting production of hypothalamic releasing factors. Pineal secre-
tions may reach their target cells via the cerebrospinal fluid or the blood Fig. 23.5 Magnetic resonance images from four different patients
stream. Some pineal indoleamines, including melatonin and enzymes with neurological or psychiatric disorders, showing the position of
for their biosynthesis (e.g. 5-HT, N-acetyltransferase), show circadian deep brain-stimulating electrodes.
rhythms in concentration. The level rises during darkness, and falls
during the day, when secretion may be inhibited by sympathetic activity. Table 23.4 Pituitary hormones.
It is thought that the intrinsic rhythmicity of an endogenous circadian
KEY REFERENCES
Benabid AL, Pollak P, Gervason C et al 1991 Long-term suppression of Macchi MM, Bruce JN 2004 Human pineal physiology and functional sig-
tremor by chronic stimulation of the ventral intermediate thalamic nificance of melatonin. Front Neuroendocrinol 25:177–95.
nucleus. Lancet 337:403–6. A review of the neuroanatomy and physiology of the pineal gland, including


The first description of deep brain stimulation of the ventral intermediate its rhythmic output functions, particularly the regulation of melatonin
(Vim) nucleus of the thalamus for tremor reduction. synthesis.
Hodaie M, Wennberg RA, Dostrovsky JO et al 2002 Chronic anterior thala- Nieuwenhuys R 1985 Chemoarchitecture of the Brain. Berlin: Springer.
mus stimulation for intractable epilepsy. Epilepsia 43:603–8. A description of the connections and neurochemistry of the hypothalamus.
A description of the use of deep brain stimulation for seizure reduction in
Page RB 1982 Pituitary blood flow. Am J Physiol 243:E427–42.
intractable epilepsy.
A detailed description of the pituitary portal system.
Jones EG 1985 The Thalamus. New York: Plenum, pp. 403–11.
Sam S, Frohman LA 2008 Normal physiology of hypothalamic pituitary
A description of the nomenclature and connections of thalamic nuclei.
regulation. Endocrinol Metab Clin North Am 37:1–22, vii.
Lozano AM, Lipsman N 2013 Probing and regulating dysfunctional circuits A description of the normal physiology of the hypothalamic–pituitary axis.
using deep brain stimulation. Neuron 77:406–24.
Tasker RR, Doorly T, Yamashiro K 1988 Thalamotomy in generalized dysto-
A review of recent advances in the field of deep brain stimulation.
nia. Adv Neurol 50:615–31.
Macchi G, Jones EG 1997 Toward an agreement on terminology of nuclear A description of the effect of thalamotomy on different aspects of dystonia.
and subnuclear divisions of the motor thalamus. J Neurosurg 86:
670–85.
A comparison of the different nomenclatures for motor thalamic nuclei in
humans and monkeys and a proposal for a common terminology.


Diencephalon
363.e1
32
RETPAHC
REFERENCES
Benabid AL, Pollak P, Gervason C et al 1991 Long-term suppression of Macchi G, Jones EG 1997 Toward an agreement on terminology of nuclear
tremor by chronic stimulation of the ventral intermediate thalamic and subnuclear divisions of the motor thalamus. J Neurosurg 86:
nucleus. Lancet 337:403–6. 670–85.
The first description of deep brain stimulation of the ventral intermediate A comparison of the different nomenclatures for motor thalamic nuclei in
(Vim) nucleus of the thalamus for tremor reduction. humans and monkeys and a proposal for a common terminology.
Boccard SG, Pereira EA, Moir L et al 2013 Long-term outcomes of deep brain Macchi MM, Bruce JN 2004 Human pineal physiology and functional sig-
stimulation for neuropathic pain. Neurosurgery 72:221–30. nificance of melatonin. Front Neuroendocrinol 25:177–95.
Casagrande V, Ichida J 2011 Processing in the lateral geniculate nucleus A review of the neuroanatomy and physiology of the pineal gland, including
(LGN). In: Levin LA, Nilsson SFE, Ver Hoeve J et al (eds) Adler’s Phy- its rhythmic output functions, particularly the regulation of melatonin
siology of the Eye, 11th ed. Philadelphia: Elsevier, Saunders; Ch. 29, synthesis.
pp. 574–85. Mohawk JA, Takahashi JS 2011 Cell autonomy and synchrony of suprachi-
Cooper IS 1976 20-year followup study of the neurosurgical treatment of asmatic nucleus circadian oscillators. Trends Neurosci 34:349–58.
dystonia musculorum deformans. Adv Neurol 14:423–52. Nieuwenhuys R 1985 Chemoarchitecture of the Brain. Berlin: Springer.
Giacino J, Fins JJ, Machado A et al 2012 Central thalamic deep brain stimula- A description of the connections and neurochemistry of the hypothalamus.
tion to promote recovery from chronic posttraumatic minimally con-
Page RB 1982 Pituitary blood flow. Am J Physiol 243:E427–42.


scious state: challenges and opportunities. Neuromodulation 15:
A detailed description of the pituitary portal system.
339–49.
Gruber D, Kühn AA, Schoenecker T et al 2010 Pallidal and thalamic Piedad JCP, Rickards HE, Cavanna AE 2012 What patients with Gilles de la
deep brain stimulation in myoclonus-dystonia. Mov Disord 25: Tourette syndrome should be treated with deep brain stimulation and
1733–43. what is the best target? Neurosurgery 71:173–92.
Hodaie M, Wennberg RA, Dostrovsky JO et al 2002 Chronic anterior thala- Sam S, Frohman LA 2008 Normal physiology of hypothalamic pituitary
mus stimulation for intractable epilepsy. Epilepsia 43:603–8. regulation. Endocrinol Metab Clin North Am 37:1–22, vii.
A description of the use of deep brain stimulation for seizure reduction in A description of the normal physiology of the hypothalamic–pituitary axis.
intractable epilepsy.
Tasker RR, Doorly T, Yamashiro K 1988 Thalamotomy in generalized dysto-
Hubble JP, Busenbark KL, Wilkinson S et al 1996 Deep brain stimulation nia. Adv Neurol 50:615–31.
for essential tremor. Neurology 46:1150–3. A description of the effect of thalamotomy on different aspects of dystonia.
Jiménez F, Nicolini H, Lozano AM et al 2013 Electrical stimulation of the Xuereb GP, Prichard MM, Daniel PM 1954 The arterial supply and venous
inferior thalamic peduncle in the treatment of major depression and drainage of the human hypophysis cerebri. Q J Exp Physiol Cogn Med
obsessive compulsive disorders. World Neurosurg 80:S30.e17–25. Sci 39:199–217.
Jones EG 1985 The Thalamus. New York: Plenum, pp. 403–11.
A description of the nomenclature and connections of thalamic nuclei.
Lozano AM, Lipsman N 2013 Probing and regulating dysfunctional circuits
using deep brain stimulation. Neuron 77:406–24.
A review of recent advances in the field of deep brain stimulation.


CHAPTER
24
Basal ganglia
The term basal ganglia is used to denote a number of subcortical therapeutic strategies for both medical and neurosurgical treatments of
nuclear masses that lie in the inferior part of the cerebral hemisphere, movement disorders.
in close relationship with the internal capsule (Fig. 24.1; see Fig. 25.43).
The traditional definition of the basal ganglia included the corpus
CORPUS STRIATUM
striatum, claustrum and amygdaloid complex. The term has now been
restricted to the corpus striatum and, according to some authorities,
other nuclei in the diencephalon and midbrain (principally the subtha- The corpus striatum consists of the caudate nucleus, putamen and
lamic nucleus, substantia nigra, pedunculopontine nucleus) that col- globus pallidus (Fig. 24.2). Because of their close proximity, the
lectively form a functional complex involved in the control of movement putamen and globus pallidus were once considered as an entity, the
and motivational aspects of behaviour (Jankovic 2012). The function lentiform (lenticular) complex or nucleus. However, although the name
of the claustrum is unknown; the amygdala is more closely related to has been retained in gross anatomical terminology and in some com-
the limbic system and is, therefore, described in that context. pound names (e.g. sublenticular, retrolenticular), the putamen and
Disorders of the basal ganglia are principally characterized by abnor- globus pallidus have quite different connections. Rather, it is now
malities of movement, muscle tone and posture. There is a wide spec- known that the putamen and caudate nucleus share a common chemo-
trum of clinical presentations ranging from poverty of movement and cytoarchitecture and connections, and they are referred to jointly as the
hypertonia at one extreme (typified by Parkinson’s disease) to abnormal neostriatum, or simply the striatum.
involuntary movements (dyskinesias) at the other. The underlying The striatum is considered to be the principal ‘input’ structure of the
pathophysiological mechanisms that mediate these disorders have been basal ganglia since it receives the majority of afferents from other parts


much studied in recent years and are better understood than for any of the neuraxis. Its principal efferent connections are to the globus pal-
other type of complex neurological dysfunction (Penney and Young lidus and pars reticularis of the substantia nigra. The globus pallidus
1986, Jankovic 2012). This has led to the introduction of new rational and, more particularly, its medial segment, together with the pars reticu-
laris of the substantia nigra, is regarded as the main ‘output’ structure
because it is the source of basal ganglia efferent fibre projections, mostly
directed to the thalamus.
LENTIFORM COMPLEX
Head of The lentiform complex (see Figs 16.7, 24.1; Fig. 24.3) lies deep to the
External caudate nucleus insular cortex, with which it is roughly coextensive, although they are
capsule Anterior limb of separated by a thin layer of white matter and by the claustrum. The
Putamen internal capsule latter splits the insular subcortical white matter to create the extreme
Globus pallidus
Thalamus
Basal ganglia
Insula
Corpus striatum Amygdala
A
Anterior horn of
the lateral Neostriatum (striatum) Paleostriatum
ventricle
Head of
Anterior limb of
caudate
the internal
nucleus
capsule
Globus
pallidus Claustrum
Caudate nucleus Putamen Globus pallidus
Putamen
Insula
B
Lentiform nucleus
Fig. 24.1 Axial (A) and coronal (B) magnetic resonance images of the
brain showing the basal ganglia, thalamus and internal capsule. (Courtesy Fig. 24.2 Terminology and relationships of structures forming the basal
364 of Alan Jackson.) ganglia.


Striatum
365
42
RETPAHC
and external capsules; the external capsule separates the claustrum from dorsal striatum. A smaller inferomedial part of the rostral striatum is
the putamen. The internal capsule separates the lentiform complex referred to as the ventral striatum, and includes the nucleus accumbens.
from the caudate nucleus. The caudate and putamen are traversed by numerous small bundles of
The lentiform complex consists of the laterally placed putamen and thinly myelinated, or unmyelinated, small-diameter axons, which are
the more medially placed globus pallidus (pallidum), which are sepa- mostly striatal afferents and efferents. They radiate through the striatal
rated by a thin layer of fibres, the external medullary lamina. The globus tissue as though converging on, or radiating from, the globus pallidus.
pallidus is itself divided into two segments, a lateral (external) segment The bundles are occasionally referred to by the archaic term ‘Wilson’s
and a medial (internal) segment, separated by an internal medullary pencils’ and they account for the striated appearance of the corpus
lamina. The two segments have distinct afferent and efferent connec- striatum.
tions. Inferiorly, a little behind the fundus striati, the lentiform complex
is grooved by the anterior commissure, which connects inferior parts of
the temporal lobes and the anterior olfactory cortex of the two sides CAUDATE NUCLEUS
(see Fig. 24.6). The area above the commissure is referred to as the
dorsal pallidum, and that below it as the ventral pallidum. The caudate nucleus is a curved, tadpole-shaped mass. It has a large
anterior head, which tapers to a body, and a down-curving tail (Fig.
24.4). The head is covered with ependyma and lies in the floor and
STRIATUM
lateral wall of the anterior horn of the lateral ventricle, in front of the
interventricular foramen. The tapering body is in the floor of the body


The striatum consists of the caudate nucleus, putamen and ventral of the ventricle, and the narrow tail follows the curve of the inferior
striatum, which are all highly cellular and well vascularized. The vast horn, and so lies in the ventricular roof, in the temporal lobe. Medially,
bulk of the caudate nucleus and putamen are often referred to as the the greater part of the caudate nucleus abuts the thalamus, along a
junction that is marked by a groove, the sulcus terminalis. The sulcus
contains the stria terminalis, lying deep to the ependyma (Fig. 24.5).
Anterior limb of Body of caudate
internal capsule nucleus
Posterior limb of
internal capsule
Head of caudate
Caudate nucleus nucleus
Thalamostriate vein External capsule Thalamus
Fornix
Extreme capsule
Thalamus, anterior part
Thalamus, lateral part Putamen
Thalamus, medial part Internal capsule ANTERIOR POSTERIOR
Internal medullary
lamina Globus pallidus
Subthalamic Optic tract
nucleus
Pes hippocampi
Substantia nigra
Putamen Tail of caudate
Crus cerebri nucleus
Collateral sulcus
Amygdala
Fig. 24.4 The striatum within the left cerebral hemisphere. (With
Fig. 24.3 The anterior aspect of a coronal section through the left permission from Crossman AR, Neary D 2010 Neuroanatomy, 4th edn.
cerebral hemisphere. Edinburgh: Churchill Livingstone.)
Dorsomedial Choroid Corpus Cingulate Thalamostriate vein Fig. 24.5 An oblique section through the
Body of lateral ventricle Subcallosal
thalamic plexus collosum gyrus and stria terminalis diencephalon and basal ganglia. Abbreviations:
fasciculus
PVe on stt era ril
o
n ru lic mle bu s
o
fof thalamus nucleus F far so cn it co u- lo uc scipital
B cao ud dy a o tef nucleus
I fiC eV ld, si n ot fe r Fn oa rl
e


c l.e rebral veins; H, H 1, H 2, subthalamic
internal capsule
Superior
External capsule
longitudinal
fasciculus
Putamen
Thalamic
reticular
Insula nucleus
External ICV
medullary Globus pallidus
lamina (lateral segment)
Claustrum Globus pallidus
(medial segment)
Extreme
capsule
H
Internal 1
medullary H
lamina H 2
Subthalamic
nucleus Third ventricle
Zona incerta Centromedian nucleus of thalamus
Substantia pars reticularis
nigra pars compacta (A9) Crus cerebri
Red nucleus
Retrorubral area (A8)
Paranigral nucleus (A10)


BASAl gAngliA
366
3
nOiTCES
A Corpus callosum B Fig. 24.6 Coronal sections through the corpus
Subcallosal Anterior horn of Subcallosal Anterior horn of striatum and anterior perforated substance. A is
fasciculus lateral ventricle fasciculus lateral ventricle anterior to B.
Fronto-occipital Head of Corpus
bundle caudate nucleus callosum
Head of caudate Anterior limb
nucleus of internal
Anterior limb of capsule
internal capsule
External Septal nuclei
External
capsule
capsule Septal Bed nucleus of
Extreme nuclei Extreme stria terminalis
capsule
capsule Diagonal Claustum Anterior
Claustrum band (Broca) commissure
Preoptic
Nucleus accumbens hypothalamus
Putamen
Paraolfactory Optic
Lateral olfactory stria (tract) area Putamen chiasma
Olfactory tubercle of Fundus striati Olfactory tubercle Nucleus basalis (of Meynert)
anterior perforated substance Globus pallidus, lateral segment Globus pallidus, medial segment
Ventral pallidum
Anterior horn of Septum nucleus accumbens (see Fig. 24.6), which abuts the nuclei of the
lateral ventricle pellucidum Corpus callosum Caudate nucleus septum, close by the paraolfactory area, diagonal band of Broca and the
fornix.
The nucleus accumbens receives a dopaminergic innervation from
the midbrain ventral tegmental area (cell group A10). It is believed to
represent the neural substrate for the rewarding effects of several classes
of drugs of abuse and is, therefore, a major determinant of their addic-
tive potential. The experimental observation that the locomotor activat-
ing effects of psychomotor stimulant drugs such as amphetamine and
cocaine (which act presynaptically on dopaminergic neurones to
enhance dopamine release or block its reuptake, respectively) are
dependent on dopamine transmission in the nucleus accumbens, led
to the hypothesis that the reinforcing or rewarding properties of these
Anterior drugs are mediated by the mesolimbic dopamine system.
limb of
internal
capsule STRIATAL CONNECTIVITY


Neurones of both dorsal and ventral striatum are mainly medium-sized
multipolar cells. They have round, triangular or fusiform somata, mixed
with a smaller number of large multipolar cells. The ratio of medium
to large cells is at least 20 : 1. The large neurones have extensive spherical
or ovoid dendritic trees up to 60 µm across. The medium-sized neu-
Olfactory tract Putamen Claustrum Insula rones also have spherical dendritic trees, approximately 20 µm across,
Fig. 24.7 The posterior aspect of a coronal section through the anterior which receive the synaptic terminals of many striatal afferents. The
horn of the lateral ventricles. dendrites of both medium and large striatal cells may be either spiny
or non-spiny. The most common neurone (approximately 75% of the
total) is a medium-sized cell with spiny dendrites (so-called medium
The sulcus terminalis is especially prominent anterosuperiorly (because spiny neurones). These cells utilize γ-aminobutyric acid (GABA) as their
of the large size of the head and body of the caudate nucleus relative transmitter and also express the genes coding for either enkephalin or
to the tail), and here the stria terminalis is accompanied by the thala- substance P/dynorphin, depending on their efferent connections.
mostriate vein. Enkephalinergic neurones express D2 dopamine receptors. Substance
The corpus callosum lies above the head and body of the caudate P/dynorphin neurones express D1 receptors. These neurones are the
nucleus. The two are separated laterally by the fronto-occipital fascicu- major, and perhaps exclusive, source of striatal efferents to the pallidum
lus, and medially by the subcallosal fasciculus, which caps the nucleus and substantia nigra pars reticularis. The other medium-sized striatal
(see Fig. 24.5; Fig. 24.6). The caudate nucleus is largely separated from neurones are aspiny, and are intrinsic cells that contain acetylcholinester-


the lentiform complex by the anterior limb of the internal capsule (see ase (AChE), choline acetyltransferase (CAT) and somatostatin. Large
Figs 24.1, 24.6; Fig. 24.7). However, the inferior part of the head of the neurones with spiny dendrites contain AChE and CAT; most, perhaps
caudate becomes continuous with the most inferior part of the putamen all, are intrinsic neurones. Aspiny large neurones are all intrinsic
immediately above the anterior perforated substance; this junctional neurones.
region is sometimes known as the fundus striati (see Fig. 24.6). Variable Intrinsic synapses are probably largely asymmetric (type II), while
bridges of cells connect the putamen to the caudate nucleus for most those derived from external sources are symmetric (type I). The amin-
of its length. They are most prominent anteriorly, in the region of the ergic afferents from the substantia nigra, raphe and locus coeruleus all
fundus striati and the head and body of the caudate nucleus, where end as profusely branching axons with varicosities, which contain
they penetrate the anterior limb of the internal capsule (see Fig. 24.7). dense-core vesicles (the presumed store of amine transmitters). Many
In the temporal lobe, the anterior part of the tail of the caudate nucleus of these varicosities have no conventional synaptic membrane speciali-
becomes continuous with the posteroinferior part of the putamen. zations, and may release transmitter in a way analogous to that found
in peripheral postsynaptic sympathetic axons.
Neuroactive chemicals, whether intrinsic or derived from afferents,
VENTRAL STRIATUM are not distributed uniformly in the striatum. For example, 5-HT
(5-hydroxytryptamine, serotonin) and glutamic acid decarboxylase
The ventral striatum consists of the nucleus accumbens and the olfac- (GAD) concentrations are highest caudally, while substance P, acetyl-
tory tubercle. In front of the anterior commissure, much of the choline (ACh) and dopamine are highest rostrally. However, there is a


grey matter of the anterior perforated substance, and especially the finer-grain neurochemical organization showing that the striatum con-
olfactory tubercle, is indistinguishable from, and continuous with, sists of a mosaic of islands or striosomes (sometimes referred to as
the fundus striati, in terms of cellular composition, histochemistry and patches), each 0.5–1.5 mm across, packed into a background matrix.
interconnections. The caudate nucleus is continuous medially with the Striosomes contain substance P and enkephalin. During development,


Striatum
367
42
RETPAHC
the first dopamine terminals from the substantia nigra are found in suggested that some of the cells of origin lie in the supragranular ‘corti-
striosomes. Although this exclusivity does not persist after birth, strio- cal association’ layers II and III. The projection is organized topographi-
somes in the adult caudate nucleus still contain a higher concentration cally. The greater part of the input from the cerebral cortex to the dorsal
of dopamine than the matrix. The latter contains ACh and somatosta- striatum is derived from the frontal and parietal lobes, with that from
tin, and is the target of thalamostriatal axons. Receptors for at least some the occipitotemporal cortex being relatively small. Thus, the orbitofron-
neurotransmitters are also differentially distributed. For example, opiate tal association cortex projects to the inferior part of the head of the
receptors are found almost exclusively within striosomes, and mus- caudate nucleus, which lies next to the ventral striatum. The dorsola-
carinic receptors predominantly so. Moreover, the distribution of neu- teral frontal association cortex and frontal eye fields project to the rest
roactive substances within the striosomes is not uniform. In humans, of the head of the caudate nucleus, and much of the parietal lobe
the striosome/matrix patchwork is more evident in the caudate than the projects to the body of the nucleus. The somatosensory and motor
putamen, the latter consisting predominantly of matrix. cortices project predominantly to the putamen. Their terminals estab-
All afferents to the striatum terminate in a mosaic manner. The size lish a somatotopic pattern, in which the lower body is represented later-
of a cluster of terminals is usually 100–200 µm across. Some afferent ally and the upper body is represented medially. The motor cortex is
terminal clusters are not arranged in register with the clear striosome/ unique in also sending axons through the corpus callosum to the oppo-
matrix distributions seen in nigrostriatal and thalamostriatal axons. In site putamen, where they end with the same spatial ordering. The


general, afferents from the neocortex end in striatal matrix and those occipital and temporal cortices project to the tail of the caudate nucleus
from the allocortex end in striosomes. However, the distinction is not and to the inferior putamen.
absolute: although afferents from the neocortex arise in layers V and VI, The striatum receives afferents from the polysensory intralaminar
those from the superficial part of layer V end predominantly in striatal thalamus and these are more crudely organized spatially. The nucleus
matrix, whereas those from deeper neocortex project to striosomes. centralis lateralis, which receives a cerebellar input, projects to the
Striatal cell bodies that are the sources of efferents also form clusters anterior striatum (especially the caudate nucleus), while the centrome-
but, again, are not uniformly related to striosomes. For example, the dian nucleus, which receives input from both the cerebellum and inter-
cell bodies of some striatopallidal and striatonigral axons lie clustered nal (medial) globus pallidus, projects to the putamen.
within striosomes, but others lie outside them, still in clusters. The The aminergic inputs to the caudate and putamen are derived from
neurones and neuropil of the ventral striatum are essentially similar to the substantia nigra pars compacta (dopaminergic group A9; see Fig.
those of the dorsal striatum, but the striosomal/matrix organization is 21.17), the retrorubral nucleus (dopaminergic group A8), the dorsal
less well defined and seems to consist predominantly of striosomes. raphe nucleus (serotoninergic group B7) and the locus coeruleus
The major connections of the striatum are summarized in Figure (noradrenergic group A6). The nigrostriatal input is sometimes referred
24.8. Although the connections of the dorsal and ventral divisions to as the ‘mesostriatal’ dopamine pathway. It reaches the striatum by
overlap, the generalization can be made that the dorsal striatum is traversing the H fields (of Forel) in the subthalamus and running in


predominantly connected with motor and associative areas of the cer- the medial forebrain bundle. These aminergic inputs appear to modu-
ebral cortex, whilst the ventral striatum is connected with the limbic late the responses of the striatum to cortical and thalamic afferent
system and orbitofrontal and temporal cortices. For both dorsal and influences.
ventral striatum, the pallidum and substantia nigra pars reticularis are Efferents from the striatum pass to both segments of the globus pal-
key efferent structures. The fundamental arrangement is the same for lidus and to the substantia nigra pars reticularis, where they end in a
both divisions. The cerebral cortex projects to the striatum, which in topically ordered fashion. Fibres ending in either the external or inter-
turn projects to the pallidum and substantia nigra pars reticularis. Effer- nal pallidum originate from different striatal cells (see Fig. 24.8). Those
ents from the pallidum and substantia nigra pars reticularis influence projecting to the external pallidum come from neurones that co-localize
the cerebral cortex (either the supplementary motor area or prefrontal GABA and encephalin, and give rise to the so-called ‘indirect pathway’.
and cingulate cortices via the thalamus) and the superior colliculus (see This name refers to the fact that these striatal neurones influence the
below). activity of basal ganglia output neurones in the internal pallidum via
The entire neocortex sends glutamatergic axons to the ipsilateral the intermediary of the subthalamic nucleus. Other striatal neurones,
striatum. Previously, these axons were thought to be collaterals of corti- which co-localize GABA and substance P/dynorphin, project directly to
cal efferents to other regions, but it is now known that they arise exclu- the internal pallidum and are, therefore, described as the ‘direct
sively from small pyramidal cells in layers V and VI. It has also been pathway’.
The striatal projection to the pars reticularis of the substantia nigra
also has both direct and indirect components, via the external pallidum


Centromedian nucleus and subthalamic nucleus (Figs 24.9–24.10). The axons of the direct
Corticostriatal fibres striatonigral projection constitute the laterally placed ‘comb’ system,
Caudate nucleus
which is spatially quite distinct from the ascending dopaminergic
nigrostriatal pathway. Striatonigral fibres end in a spatially ordered way
in the pars reticularis.
The ventral striatum is the primary target of fibres from limbic cor-
Putamen
tices, including allocortex, and from limbic associated regions (see Fig.
24.9). Thus, the hippocampus (through the fornix) and orbitofrontal
cortex (through the internal capsule) project to the nucleus accumbens,
and the olfactory, entorhinal, anterior cingulate and temporal visual
cortices project to both the nucleus accumbens and olfactory tubercle.
The olfactory tubercle also receives afferents from the amygdala. The
contiguity of the cortical areas that project to the ventral striatum and
neighbouring dorsal striatum emphasizes the imprecise nature of the
boundaries between these two divisions. All the cortical regions abut
and overlap with neighbouring areas and they project to neighbouring
parts of the dorsal striatum as well as to the ventral striatum. The fundus
striati and ventromedial caudate nucleus abut the olfactory tubercle and
nucleus accumbens (see Fig. 24.6) and receive connections from the
orbitofrontal cortex and, to a lesser extent, from the lateral prefrontal
and anterior cingulate cortices (which also project to the contiguous
head of the caudate nucleus).
Striatopallidal fibres Globus pallidus (lateral This continuity of the ventral and dorsal striata, as revealed by the
‘Indirect pathway’ segment) arrangements of corticostriatal projections, is reinforced by considera-
Striatopallidal fibres Globus pallidus (medial tion of the aminergic inputs to the ventral striatum. They are derived
‘Direct pathway’ segment) from the dorsal raphe (serotoninergic group B7), the locus coeruleus


(noradrenergic group A6) and the ventral tegmental area (dopamine
Substantia nigra Thalamostriatal fibres
group A10), as well as the most medial part of the substantia nigra pars
Striatonigral fibres Nigrostriatal fibres compacta (A9) (see Fig. 21.17). The dopamine projections constitute
Fig. 24.8 Connections of the striatum. The major afferent projections to the so-called mesolimbic dopamine pathway, which also projects to
the striatum are shown on the right and major efferent projections from the septal nuclei, hippocampus and amygdala, and prefrontal and cin-
the striatum on the left. gulate cortices through the medial forebrain bundle. The lateromedial


BASAl gAngliA
368
3
nOiTCES
A
Thalamic nuclei:
Cerebral cortex
(including motor, Ventralis lateralis, pars anterioris Supplementary motor cortex
prefrontal and Dorsal striatum Dorsal pallidum
cingulate areas) Centromedian Somato-sensory-motor cortices
Intralaminar thalamus
Nucleus tegmentalis pedunculopontinus Medullary reticular formation
DA: Substantia nigra
pars compacta (A9);
Retrorubral nucleus (A8) Ventralis lateralis, pars medialis Prefrontal and cingulate cortices
5-HT: Raphe (B7) Substantia nigra
NA: Locus coeruleus (A6) pars reticularis Superior colliculus (deep layers) Medullary reticular formation;
spinal cord
B
Thalamic nuclei:
Limbic, prefrontal and
temporal lobe cortices Mediodorsalis Prefrontal and cingulate cortices
Ventral striatum Ventral pallidum
Olfactory cortex Midline Hippocampus
and amygdala
Habenular nuclei ‘Limbic’ midbrain
DA: Paranigral nucleus (A10)
5-HT: Raphe (B7)
NA: Locus coeruleus (A6) Ventralis lateralis, pars medialis Prefrontal and cingulate cortices
Substantia nigra
pars reticularis Superior colliculus (deep layers) Medullary reticular formation;
spinal cord
Fig. 24.9 The principal output connections of the basal ganglia derived from dorsal (A) and ventral (B) divisions of the striatum. In each case, pathways
established through the pallidum are distinguished from those passing through the substantia nigra pars reticularis. Abbreviations: DA, dopamine; NA,
noradrenaline (norepinephrine); 5-HT, 5-hydroxytryptamine (serotonin).
Cerebral cortex
Ventral anterior and ventral lateral nuclei of thalamus
Caudate nucleus
Habenula
Centromedian nucleus of thalamus
Putamen Subthalamic nucleus
Superior colliculus
Globus pallidus (lateral segment)


Globus pallidus (medial segment)
Substantia nigra,
pars compacta
Substantia nigra,
pars reticularis
Glutamatergic neurones
Crus cerebri
GABAergic neurones
Dopaminergic neurones
Pedunculopontine nucleus
Brachium conjunctivum
Fig. 24.10 The principal connections of the basal ganglia with the diencephalon and brainstem.
contin uity of cell groups A9 and 10 is thus reflected in the relative posi- As with the dorsal striatum, efferents from the ventral striatum
tions of their ascending fibres in the subthalamus and hypothalamus project to the pallidum (in this case, the ventral pallidum) and the
(the H fields and medial forebrain bundle, respectively), as well as in substantia nigra pars reticularis (see Figs 24.9–24.10). In the latter
the lateromedial topography of the dorsal and ventral striata (see Fig. case, the connection is both direct and indirect, via the subthalamic
24.6), which in turn have contiguous and overlapping sources of corti- nucleus. The projections from the pars reticularis are as described for
cal afferents. the dorsal system, but axons from the ventral pallidum reach


Substantia nigra
369
42
RETPAHC
the thalamic mediodorsal nucleus (which projects to cingulate and capsule, both pathways unite in the subthalamic region, where they
prefrontal association cortex) and midline nuclei (which project to the follow a horizontal hairpin trajectory, and turn upwards to enter the
hippocampus). Ventral pallidal axons also reach the habenular complex thalamus as the thalamic fasciculus. The trajectory circumnavigates the
of the limbic system. zona incerta and creates the so-called ‘H’ fields of Forel (see Figs 24.5,
The brain areas beyond the basal ganglia, substantia nigra and sub- 24.11). Within the thalamus, pallidothalamic fibres end in the ventral
thalamic nucleus to which both ventral and dorsal systems appear to anterior and ventral lateral nuclei and in the intralaminar centromedian
project are, therefore, the prefrontal association and cingulate cortices nucleus. These in turn project excitatory (presumed glutamatergic)
and the deep superior colliculus. fibres primarily to the frontal cortex, including the primary and sup-
plementary motor areas. The internal pallidum also projects fibres
caudally to the pedunculopontine nucleus, as described below (see
GLOBUS PALLIDUS
Fig. 24.10).
The globus pallidus (pallidum) lies medial to the putamen and lateral
SUBTHALAMIC NUCLEUS
to the internal capsule. It consists of external (lateral) and internal
(medial) segments separated by an internal medullary lamina, which
have substantially different connections. Both segments receive large The subthalamic nucleus is a biconvex, lens-shaped nucleus in the
numbers of fibres from the striatum and subthalamic nucleus. The subthalamus of the diencephalon. It lies medial to the internal capsule,
external segment projects to the subthalamic nucleus as part of the immediately rostral to the level at which the latter becomes continuous
‘indirect pathway’. The internal segment is considered to be a homo- with the crus cerebri of the midbrain (see Figs 24.5, 24.3). Within the


logue of the pars reticularis of the substantia nigra, with which it nucleus, small interneurones intermingle with large multipolar cells
shares similar cellular and connectional properties. Together, therefore, with dendrites that extend for about one-tenth the diameter of the
these structures constitute the main output of the basal ganglia to nucleus. Dorsally, the nucleus is encapsulated by axons, many of which
other levels of the neuraxis, principally to the thalamus and superior are derived from the subthalamic fasciculus; these carry a major
colliculus. GABAergic projection from the external segment of the globus pallidus
The cell density of the globus pallidus is less than one-twentieth that as part of the indirect pathway. The nucleus also receives afferents from
of the striatum. The morphology of the majority of cells is identical in the cerebral cortex. It is unique in the intrinsic circuitry of the basal
the two segments. They are large multipolar GABAergic neurones that ganglia in that its cells are glutamatergic and project excitatory axons
closely resemble those of the substantia nigra pars reticularis. The den- to both the globus pallidus and substantia nigra pars reticularis. Within
dritic fields are discoid, with planes at right angles to incoming striato- the pallidum, subthalamic efferent fibres end predominantly in the
pallidal axons, each of which, therefore, potentially contacts many internal segment but many also end in the external segment.
pallidal dendrites en passant. This arrangement, coupled with the diam- The subthalamic nucleus plays a central role in the normal function
eters of the dendritic fields (500 µm), suggests that a precise topo- of the basal ganglia and in the pathophysiology of basal ganglia-related
graphical organization is unlikely within the pallidum. disorders. Destruction of the nucleus, which occurs rarely as a result of
Striatopallidal fibres are of two main types. They project to either stroke, results in the appearance of violent, uncontrolled involuntary
the external or the internal pallidum. Those projecting to the external movements of the contralateral side of the body, known as ballism


segment constitute the beginning of the so-called ‘indirect pathway’. (hemiballismus). The subthalamic nucleus is crucially involved in the
They utilize GABA as their primary transmitter and also contain pathophysiology of Parkinson’s disease and is a target for functional
enkephalin. Efferent axons from neurones in the external segment pass neurosurgical therapy of the condition. (For a detailed description of
through the internal capsule in the subthalamic fasciculus and travel to the anatomical structure and variability of the subthalamic nucleus seen
the subthalamic nucleus (Fig. 24.11). using high-field magnetic resonance imaging (MRI) with histological
Striatopallidal axons destined for the internal pallidum constitute validation, see Massey et al (2012) and Massey and Yousry (2010).)
the so-called ‘direct pathway’. Like the indirect projection, these utilize
GABA as their primary transmitter but they also contain substance P
SUBSTANTIA NIGRA
and dynorphin. Efferent axons from the internal pallidum project
through the ansa lenticularis and fasciculus lenticularis (see Fig. 24.11).
The former runs round the anterior border of the internal capsule and The substantia nigra is a nuclear complex deep to the crus cerebri
the latter penetrates the capsule directly. Having traversed the internal in each cerebral peduncle of the midbrain (see Fig. 21.16); its
Fibres of internal capsule
Anterior nuclear group
of thalamus GABAergic neurones
Lateral nuclear group Glutamatergic neurones
of thalamus
Thalamic fasciculus
(field H of Forel)
1 Field H of Forel
2
(continuation of
fasciculus lenticularis)
Third ventricle
External capsule
Internal capsule
Dentatothalamic
and rubrothalamic fibres Claustrum
Lenticular fasciculus
(fasciculus lenticularis)
Zona incerta
Putamen
Prerubral field
(field H of Forel) Subthalamic
fasciculus
Prerubral nucleus
Globus pallidus,
of tegmental field
lateral segment
Subthalamic nucleus Globus pallidus,
medial segment
Column of fornix


Endopeduncular nucleus
(nucleus of ansa lenticularis) Ansa lenticularis
Fig. 24.11 A coronal section of the brain showing the major connections of the basal ganglia with the diencephalon.


BASAl gAngliA
370
3
nOiTCES
cytoarchitecture and connections are described in Chapter 21. Briefly, it A B
consists of a pars compacta, a pars reticularis and a smaller pars lateralis. Thalamus
The pars compacta and pars lateralis correspond to the dopaminergic Caudate nucleus
cell group A9. The pars compacta projects heavily to the caudate nucleus
and putamen; lesser projections end in the globus pallidus and the
subthalamic nucleus. The neurones of the pars reticularis and the inter-
nal pallidum collectively constitute the output neurones of the basal
ganglia system. In Parkinson’s disease, the levels of dopamine in the
Putamen
substantia nigra and striatum decrease dramatically as a result of
the degeneration of pars compacta neurones and their terminals in Globus pallidus
the neostriatum. (lateral segment)
Globus pallidus
(medial segment)
PEDUNCULOPONTINE NUCLEUS
Subthalamic
The pedunculopontine nucleus (nucleus tegmentalis pedunculoponti-
nucleus
nus) lies in the dorsolateral part of the pontomesencephalic tegmen-
Substantia
tum. Anterograde tract-tracing studies in non-human primates and
nigra
rodents have revealed multiple afferent and efferent connections
between the pedunculopontine nucleus and the basal ganglia, cerebel- Pedunculopontine
lum, substantia nigra, thalamus, cerebral cortex and spinal cord. nucleus
The pedunculopontine nucleus receives GABAergic efferent fibres
from the globus pallidus and substantia nigra. In animal models of Glutamatergic neurones
Parkinson’s disease, these projections are overactive and the peduncu-
lopontine nucleus is inhibited. Taken in conjunction with other experi-
GABAergic neurones
mental evidence, this suggests that the pedunculopontine nucleus is
involved in the pathophysiology of disturbances of locomotion, gait
and posture in Parkinson’s disease (Mena-Segovia et al 2004). That Dopaminergic neurones
said, the variation in nuclear connectivity between quadripedal and


Bold lines indicate overactivity
bipedal animals must be considered when evaluating evidence from
Interrupted lines indicate underactivity
any non-primate animal model (Alam et al 2011, Stein and Aziz
2012).) Fig. 24.12 The pathophysiology of Parkinson’s disease (A) and
dyskinesias (B). (Adapted with permission from Crossman AR, Neary D
2010 Neuroanatomy, 4th edition. Edinburgh: Churchill Livingstone.)
PATHOPHYSIOLOGY OF BASAL
GANGLIA DISORDERS
treatment of Parkinson’s disease resemble those seen in Huntington’s
The basal ganglia might be said to guide intention into action. As far disease, tardive dyskinesia and ballism. Experimental evidence suggests
as their role in movement control is concerned, they appear to promote that these may share a common neural mechanism (see Fig. 24.12).
and support patterns of behaviour that are appropriate in the prevail- Thus, the indirect pathway becomes underactive, e.g. due to the effects
ing circumstances and to inhibit unwanted or inappropriate move- of dopaminergic drugs in Parkinson’s disease, or the degeneration of
ments. This is exemplified by disorders of the basal ganglia, which are the striatopallidal projection to the external pallidum in Huntington’s
characterized, depending on the underlying pathology, by an inability disease. This leads to physiological inhibition of the subthalamic
to initiate and execute wanted movements (as in Parkinson’s disease) nucleus by overactive pallidosubthalamic neurones. The involvement
or an inability to prevent unwanted movements (as in Huntington’s of the subthalamic nucleus explains why the dyskinetic movements of
disease). levodopa-induced dyskinesia and Huntington’s disease resemble those
Parkinson’s disease is the most common pathological condition of ballism produced by lesion of the subthalamic nucleus. Underactiv-
affecting the basal ganglia. It is characterized by akinesia, muscular ity of the subthalamic nucleus removes the excitatory drive from inter-
rigidity and tremor due to degeneration of the dopaminergic neurones nal pallidal neurones, which are known to be underactive in dyskinesias


of the substantia nigra pars compacta (which project to the striatum in (Crossman 1990). Once again, this anatomical model of basal ganglia
the nigrostriatal pathway). As a consequence, dopamine terminals are function is an oversimplification. Whilst it is true that underactivity of
lost in the striatum and dopamine levels are severely depleted. the internal globus pallidus is associated with dyskinesias, it is also
Dopamine receptors, which are located on medium spiny neurones and known that lesions of the globus pallidus alleviate them. This so-called
are the target of the nigrostriatal pathway, are spared. ‘pallidotomy paradox’ suggests that the dynamic aspects of pallidal and
Dopamine appears to have a dual action on medium spiny striatal nigral efferent activity are important factors in the generation of dyski-
neurones. It inhibits those of the indirect pathway and excites those of nesia (Marsden and Obeso 1994). A more recent ‘rate model’ of basal
the direct pathway. Consequently, when dopamine is lost from the ganglia function hypothesizes that specific components oscillate in neu-
striatum, the indirect pathway becomes overactive and the direct ronal synchrony at different frequencies to select specific voluntary
pathway becomes underactive (Fig. 24.12). Overactivity of the striatal motor patterns (Little and Brown 2014). Both rodent electrophysiology
projection to the external pallidum results in inhibition of pallidosub- and recording from deep-brain electrodes implanted in patients with
thalamic neurones and, consequently, overactivity of the subthalamic Parkinson’s disease suggest that neuronal activity suppression in the
nucleus. Subthalamic efferents mediate excessive excitatory drive to the 8–30 Hz beta frequency band correlates with relief of parkinsonian
internal globus pallidus and substantia nigra pars reticularis. This is akinesia and rigidity by both dopamine and subthalamic nucleus deep-
exacerbated by underactivity of the GABAergic, inhibitory direct brain stimulation.
pathway. Overactivity of basal ganglia output then inhibits the motor There is evidence that dysfunction of the basal ganglia is also
thalamus and its excitatory thalamocortical connections. While this involved in other complex, less well understood, behavioural disorders.


description is little more than a first approximation of the underlying In animal experiments, lesions of the basal ganglia, especially of the
pathophysiology, this model of the basis of parkinsonian symptoms caudate nucleus, induce uncontrollable hyperactivity (e.g. obstinate
has led to the introduction of new neurosurgical approaches to the progression, incessant pacing and other constantly repeated behav-
treatment of Parkinson’s disease, based upon lesioning and deep-brain iours). This and other evidence has led to the notion that the corpus
stimulation of the internal globus pallidus and subthalamic nucleus striatum enables the individual to make motor choices and to avoid
(see below). ‘stimulus-bound’ behaviour. Positron emission tomography (PET)
The current medical treatment for Parkinson’s disease largely relies studies in humans have shown that sufferers from obsessive–compulsive
on levodopa (L-DOPA; L-dihydroxyphenylalanine), the immediate disorder (OCD), which is characterized by repeated ritualistic motor
metabolic precursor of dopamine, or on dopamine agonists. Whilst behaviour and intrusive thoughts, exhibit abnormal activity in the pre-
these usually provide good symptomatic relief for many years, eventu- frontal cortex and caudate nuclei. There are similar suggestive observa-
ally they lead to the development of side-effects, including dyskinesias. tions in childhood attention deficit hyperactivity disorder (ADHD) and
The involuntary movements that occur as a consequence of long-term Gilles de la Tourette’s syndrome. In this respect, it may be significant


Pathophysiology of basal ganglia disorders
371
42
RETPAHC
that the basal ganglia, besides receiving connections from the frontal
lobe and limbic cortices, also have an ascending influence on the pre-
frontal and cingulate cortices through the substantia nigra pars reticu-
laris and dorsomedial and ventromedial thalamus in parallel,
functionally segregated, corticostriatothalamic circuits subserving loco-
motor, oculomotor, cognitive and affective behaviour (Alexander et al
1986; see Fig. 24.9).
Before the advent of levodopa therapy, neurosurgery for Parkinson’s
disease was commonplace. The globus pallidus and thalamus were
favoured targets for chemical or thermal lesions. Pallidotomy and tha-
lamotomy often improved rigidity and tremor, but they produced little
consistent beneficial effect on akinesia. With the arrival of levodopa
therapy, which very effectively alleviates akinesia, the surgical treatment
of Parkinson’s disease underwent a progressive decline. It soon became
clear, however, that long-term use of levodopa was associated with a
number of side-effects such as dyskinesias, ‘wearing-off’ and the ‘on–off’
phenomenon. More recent advances in understanding the pathophysio-
logy of movement disorders, and of Parkinson’s disease in particular,
have stimulated a renaissance in the use of neurosurgery to treat move-
ment disorders.
Lesioning the subthalamic nucleus in experimental primates that
had been made parkinsonian with the neurotoxin MPTP dramatically
alleviated the parkinsonian symptoms, suggesting that that the subtha-
lamic nucleus might be an appropriate clinical target (Pereira and Aziz
2006). While therapeutic surgical lesions of the subthalamic nucleus
can alleviate tremor, rigidity and bradykinesia in patients with Parkin-
son’s disease, the risk of side-effects is not trivial: the subthalamic
nucleus is a small structure wrapped by fibres of passage and close to
the hypothalamus and internal capsule.
In 1992, Laitinen et al reintroduced pallidotomy for the treatment
of end-stage Parkinson’s disease, but confined the lesions to the postero-
ventral part of the internal pallidum. These lesions were found to be


extremely reliable in abolishing contralateral rigidity and drug-induced
dyskinesias, with slightly less efficacy on tremor and bradykinesia Fig. 24.13 A magnetic resonance image showing the placement of
(Laitinen et al 1992). deep-brain stimulating electrodes (arrows) bilaterally in the globus pallidus
Implantation of deep-brain electrodes, through which high- of a patient with Parkinson’s disease. (Courtesy of Mr L Zrinzo and
frequency pulses generated by a pacemaker could inhibit cells in the Professor M Hariz, National Hospital of Neurology and Neurosurgery,
vicinity, has been a concept since the early 1970s but did not become London, UK.)
a widespread reality until the late 1980s, as a result of technological
advances. The introduction of the technique of deep-brain stimulation
(DBS), which avoids making permanent lesions, made bilateral surgery
safer. There have been numerous reports of the effectiveness of both
bilateral pallidal and subthalamic nucleus stimulation in Parkinson’s
disease (Rodriguez-Oroz et al 2012; Figs 24.13–24.14). Subthalamic
nucleus stimulation is favoured by most for relieving akinesia and rigid-
ity, with pallidal stimulation considered to ameliorate dyskinesias. Sub-
thalamic stimulation is more effective than pallidal stimulation in
allowing patients to reduce their anti-parkinsonian medication. Tremor
is best relieved by stimulation of either the contralateral ventral inter-
mediate thalamic nucleus or the zona incerta.
Another manifestation of basal ganglia dysfunction is dystonia,
which is characterized by increased muscle tone and abnormal pos-
tures. Dystonia may occur as a consequence of levodopa treatment in
Parkinson’s disease or inherited disease (e.g. early-onset torsion, or
Oppenheim’s dystonia, an autosomal dominant disorder most com-
monly associated with a mutation in the DYT1 gene that encodes torsin
A). Although the pathophysiological basis of dystonia is unclear (Hallett
2006), it is probably caused by underactivity of basal ganglia output.
The observation that painful dystonic posturing of the limbs in parkin-
sonian patients responds dramatically to bilateral pallidal stimulation
led to the development of bilateral pallidal stimulation for dystonia.


Intriguingly, in dystonia the pallidal neurones are held to fire at rates
below normal, and so it is open to question how this stimulation works.
Moreover, while the effect of stimulation is immediate in the case of
Parkinson’s disease, in dystonia the improvement may take weeks to
emerge, suggesting that the neural mechanism(s) underlying the thera-
peutic effect of stimulation for these conditions is/are different and
implicating a role for neuroplasticity in dystonia.
An even more recent neurosurgical development in the therapy of
Parkinson’s disease has involved targeting the pedunculopontine
nucleus, which both receives fibres from and sends fibres to basal
ganglia and related nuclei. Recently, DBS of the pedunculopontine
nucleus through implanted electrodes has been applied in drug-resistant Fig. 24.14 A magnetic resonance image showing the placement of
akinetic parkinsonian patients (Fig. 24.15). Low-frequency stimulation deep-brain stimulating electrodes (arrows) bilaterally in the subthalamic
alleviates postural instability and on-medication gait freezing and nucleus of a patient with Parkinson’s disease. (Courtesy of Mr L Zrinzo
falling, symptoms that conventional medication and surgery fail to and Professor M Hariz, National Hospital of Neurology and Neurosurgery,
improve. London, UK.)