be the sole activity of the pretectal nucleus. Some of its efferents project vocellular’ regions). However, there are a few areas where these mingle
to the pulvinar and deep laminae of the superior colliculus, and provide with large multipolar neurones in ‘gigantocellular’ or ‘magnocellular’
another extrageniculate path to the cerebral cortex. nuclei.
In general terms, the reticular formation is a continuous core that
traverses the whole brainstem, and is continuous below with the reticu-
BRAINSTEM RETICULAR FORMATION
lar intermediate spinal grey. It is divisible, on the basis of cytoarchitec-
tonic, chemoarchitectonic and functional criteria, into three bilateral
The brainstem contains extensive fields of intermingled neuronal cell longitudinal columns: median; medial, containing mostly large reticu-
bodies and nerve fibres, which are collectively termed the reticular lar neurones; and lateral, containing mostly small to intermediate neu-
formation (Haines 2013, Nieuwenhuys et al 2008, Olszewski and rones (Fig. 21.18).
Baxter 1954). The reticular regions are often regarded as phylogeneti-
cally ancient, representing a primitive nerve network on which more
anatomically organized, functionally selective connections have devel- MEDIAN COLUMN OF RETICULAR NUCLEI
oped during evolution.
Reticular regions tend to be ill-defined collections of neurones with The median column of reticular nuclei extends throughout the medulla,
diffuse connections. Their conduction paths are difficult to define, often pons and midbrain and contains neurones that are largely aggregated
complex and polysynaptic, and they have ascending and descending in bilateral, vertical sheets, located immediately adjacent to the midline
components that are crossed, uncrossed and sometimes bilateral. Their and occupying the paramedian zones. Collectively they are called the
components subserve somatic and visceral functions. They also include nuclei of the raphe, or raphe nuclei. Many neurones in raphe nuclei are
some distinct and important cell groups, which are distinguished on serotoninergic and are grouped into nine clusters, B1–9 (see Fig. 21.17)
the basis of their connections and neurotransmitter substances. These (Dahlström and Fuxe 1964, Dahlström and Fuxe 1965, Nieuwenhuys


include dopaminergic and noradrenergic neurones (group A), sero- 1985, Hornung 2003). The raphe pallidus nucleus (B1) and associated
toninergic (group B), adrenergic (group C) and cholinergic (group Ch) raphe obscurus nucleus (B2) lie in the upper two-thirds of the medulla
neurones (Dahlström and Fuxe 1964, Dahlström and Fuxe 1965, Nieu- and cross the pontomedullary junction. The raphe magnus nucleus,
wenhuys 1985, Siegel et al 1999). corresponding to many B3 neurones, minimally overlaps with B1 and
Third ventricle Fig. 21.18 The dorsal aspect of the brainstem
showing the approximate location of nuclei of the
reticular formation. Nuclei of the median and
Dorsal thalamus paramedian nuclear column, pink; medial column
Pineal gland nuclei, purple; lateral column nuclei, blue.
Superior colliculus Pedunculopontine tegmental
nucleus (nucleus tegmentalis
Dorsal raphe nucleus pedunculopontinus
pars compacta)
Inferior colliculus
Lateral parabrachial nucleus
Cuneiform and
subcuneiform nuclei Medial parabrachial nucleus
Superior central nucleus Caudal pontine reticular
nucleus
Oral pontine reticular nucleus
Motor nucleus of trigeminal
Pontine raphe nucleus nerve
Central pontine nucleus
Pontine tegmental reticular
nucleus (nucleus reticularis Motor nucleus of facial nerve
tegmenti pontis)
Superior cerebellar peduncle Middle cerebellar peduncle
Nucleus raphe magnus Inferior cerebellar peduncle
Gigantocellular nucleus Nucleus ambiguus
(magnocellularis)
Central nucleus of the
Floor of fourth ventricle medulla oblongata
Lateral funicular nucleus
Nuclei raphe obscurus (nucleus reticularis lateralis
and pallidus of medulla)
Olivary eminence


Brainstem
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A tecto-olivary projection, from deeper collicular laminae to the
upper third of the medial accessory olivary nucleus, exists in primates.
It is crossed and links with the posterior vermis.
In animals, central collicular stimulation produces contralateral
head movement as well as movements involving the eyes, trunk and
limbs, which implicates the superior colliculus in the integration of
vision and body movement.
As an example, a bifurcating axon from a cell in the magnocellular
medullary nucleus may project rostrally into the upper medulla, pons,
midbrain tegmentum, subthalamus, hypothalamus, dorsal thalamus,
septum, limbic system and neocortex, while its descending branch
innervates the reticular core of the lower medulla and may reach the
cervical spinal intermediate grey of laminae V and VI. Many reticular
neurones have unidirectional, shorter axons that synapse with the radi-
ating dendrites of numerous other neurones en route, and give off col-
laterals that synapse with cells in ‘specific’ brainstem nuclei or cortical
formations, such as the cerebellum.


Brainstem reticular formation
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B2, and ascends into the caudal pons. Above it is the pontine raphe at all levels of the medial column of reticular nuclei but also in the
nucleus, which is formed by cell group B5. Also located in the pons is intralaminar nuclei of the thalamus.
the central superior raphe nucleus, which contains parts of cell groups
B6 and B8. The dorsal (rostral) raphe nucleus, approximating to cell
group B7, extends through much of the midbrain. B4 and B9 are small LATERAL COLUMN OF RETICULAR NUCLEI
cell groups located in the medulla and midbrain, respectively.
Axons originating from the serotoninergic raphe neurones ramify The lateral column of reticular nuclei contains six nuclear groups. These
extensively throughout the CNS. are the parvocellular reticular area, superficial ventrolateral reticular
All raphe nuclei provide descending serotoninergic projections, area, lateral pontine tegmental noradrenergic cell groups A1, A2, A4–A7
which terminate in the brainstem and spinal cord. Brainstem connec- (A3 is absent in primates), adrenergic cell groups C1–C3 and choliner-
tions are multiple and complex. For example, the dorsal raphe nucleus, gic cell groups Ch5–Ch6 (Nieuwenhuys 1985, Siegel et al 1999). Cell
in addition to sending a large number of fibres to the locus coeruleus, groups Ch1–Ch4 are located in the basal forebrain. The column
projects to the dorsal tegmental nucleus and most of the rhomben- descends through the lower two-thirds of the lateral pontine tegmen-
cephalic reticular formation, together with the central superior, pontine tum and upper medulla, where it lies between the gigantocellular
raphe and raphe magnus nuclei. nucleus medially, and the sensory nuclei of the trigeminal nerve later-
Raphe-spinal serotoninergic axons originate mainly from neurones ally. It continues caudally and expands to form most of the reticular
in the raphe magnus, pallidus and obscurus nuclei. They project as formation lateral to the raphe nuclei. It abuts the superficial ventrola-


ventral, dorsal and intermediate spinal tracts in the ventral and lateral teral reticular area, nucleus solitarius, nucleus ambiguus and vagal
funiculi, and terminate respectively in the ventral horns and laminae I, nucleus, and there contains the adrenergic cell group C2 and the
II and V of the dorsal horns of all segments, and in the thoracolumbar noradrenergic group A2.
intermediolateral sympathetic and sacral parasympathetic pregangli- The lateral paragigantocellular nucleus lies at the rostral pole of the
onic cell columns. The dorsal raphe spinal projections function as a diffuse superficial ventrolateral reticular area (at the level of the facial
pain control pathway that descends from a mesencephalic pain control nucleus). The zone extends caudally as the nucleus retroambiguus and
centre located in the periaqueductal grey matter, dorsal raphe and descends into the spinal cord. It contains noradrenergic cell groups A1,
cuneiform nuclei. The intermediate raphe-spinal projection is inhibi- A2, A4 and A5, and the adrenergic cell group C1. The ventrolateral
tory and, in part, modulates central sympathetic control of cardiovas- reticular area is involved in cardiovascular, respiratory, vasoreceptor and
cular function. The ventral raphe-spinal system excites ventral horn chemoreceptor reflexes, and in the modulation of nociception. The A2
cells and could function to enhance motor responses to nociceptive or noradrenergic dorsal medullary cell group lies in the nucleus of the
stimuli. tractus solitarius, vagal nucleus and adjoining parvocellular reticular
Principally, the mesencephalic serotoninergic raphe system is recip- area. Adrenergic group C1 lies rostral to the A2 cell group. Noradren-
rocally interconnected rostrally with the limbic system, septum, pre- ergic cell group A4 extends into the lateral pontine tegmentum, along
frontal cortex and hypothalamus. Efferents ascend and form a large the subependymal surface of the superior cerebellar peduncle. Noradren-
ventral and a diminutive dorsal pathway. ergic group A5 forms part of the paragigantocellular nucleus in the


Major afferents to the mesencephalic raphe nuclei include those caudolateral pontine tegmentum. Noradrenergic cell group A5 and
from the interpeduncular nucleus, linking the limbic and serotoniner- adrenergic cell group C1 probably function as centres of vasomotor
gic systems; from the lateral habenular nucleus, linking the septum, control. The entire region is subdivided into functional areas on the
preoptic hypothalamus and prefrontal cortex via the fasciculus retro- basis of experiments in animals, in which vasoconstrictor, cardio-
flexus and the medial forebrain bundle; and from the pontine central accelerator, depressor, inspiratory, expiratory and sudomotor responses
grey matter. have been elicited.
The ascending raphe system probably functions to moderate fore- The lateral pontine tegmental reticular grey matter is related to the
brain activities, particularly limbic, septal and hypothalamic activities. superior cerebellar peduncle and forms the medial and lateral parabra-
A degree of region-specific connectivity suggests that it exerts precise, as chial nuclei and the ventral Kölliker–Fuse nucleus, a pneumotaxic
well as tonal, control. centre. The locus coeruleus (noradrenergic cell group A6), area sub-
coeruleus, noradrenergic cell group A7 and cholinergic group Ch5 in
the pedunculopontine tegmental nucleus (nucleus tegmentalis pedun-
MEDIAL COLUMN OF RETICULAR NUCLEI culopontinus) are all located in the lateral pontine and mesencephalic
tegmental reticular zones. A4 is sometimes considered part of the coeru-
The medial column of reticular nuclei is composed predominantly of leus complex. The mesencephalic group Ch5 is continuous caudally
neurones of medium size, although very large neurones are found in with cell group Ch6 in the pontine central grey matter.
some regions, and most have processes orientated in the transverse Cell group A6 (also parts of A4) contains all the noradrenergic cells
plane. In the lower medulla the column is indistinct, and is perhaps in the central region of the locus coeruleus. Group A6 has ventral


represented by a thin lamina lateral to the raphe nuclei. However, in (nucleus subcoeruleus, A6sc), rostral and caudolateral extensions
the upper medulla it expands into the medullary gigantocellular (mag- (A6cg), the latter merging with the A4 group. The locus coeruleus
nocellular) nucleus, which lies ventrolateral to the hypoglossal nucleus, probably functions as an attention centre, focusing neural functions to
ventral to the vagal nuclei and dorsal to the inferior olivary complex. prevailing needs. The noradrenergic A7 group occupies the rostroven-
Ascending further, the column continues as the pontine gigantocellular tral part of the pontine tegmentum and is continuous with groups
(magnocellular) nucleus, which lies medially in the tegmentum. Its A5 and A1 through the lateral rhombencephalic tegmentum. The
neurones suddenly diminish in size to form, in rostral order, the almost A7, A5, A1 complex is also connected by noradrenergic cell clusters
coextensive caudal and oral pontine tegmental reticular nuclei. It then with group A2, caudally, and group A6, rostrally. The A5 and A7 groups
expands into the cuneiform nucleus and subcuneiform nucleus, before lie mainly within the medial parabrachial and Kölliker–Fuse nuclei.
fading away in the midbrain tegmentum (Haines 2013, Nieuwenhuys Reticular neurones in the lateral pontine tegmental reticular area, like
et al 2008). those of the ventrolateral zone, function to regulate respiratory, cardio-
Axons of medial reticular column neurones form a multisynaptic vascular and gastrointestinal activity. Two micturition centres are
ascending and descending system within the column, and ultimately located in the dorsomedial and ventrolateral parts of the lateral
enter the spinal cord and diencephalon. Descending fibres form pontine pontine tegmentum.
(medial) reticulospinal and medullary (lateral) reticulospinal tracts. The connections of the lateral column reticular nuclei are complex.


Pontine reticulospinal axons arise from neurones in the caudal and oral The short ascending and descending axons of the parvocellular reticular
parts of the pontine reticular nucleus, descend largely uncrossed in the area constitute medullary reflex pathways, which connect all branchio-
ventral spinal funiculus, and terminate in spinal cord laminae VII, VIII motor nuclei and the hypoglossal nucleus with central afferent cranial
and IX. Medullary reticulospinal axons descend bilaterally with an ipsi- nerve complexes through a propriobulbar system. This area also receives
lateral preponderance to end in laminae VII, VIII, IX and X, and ipsi- descending afferents from the contralateral motor cortex via the corti-
laterally to end in laminae IV, V and VI. The system modulates spinal cotegmental tract, and from the contralateral red nucleus via the rubro-
motor function and segmental nociceptive input. spinal tract. The longitudinal catecholamine bundle passes through the
Afferent components to the medial reticular nuclear column include parvocellular reticular formation.
the spinoreticular projection and collaterals of centrally projecting The superficial ventrolateral reticular area receives its principal input
spinal trigeminal, vestibular and cochlear fibres. Spinoreticular fibres, from the nucleus solitarius, and subserves cardiovascular, baroreceptor,
part of the anterolateral system, arise from neurones in the intermediate chemoreceptor and respiratory reflexes; it also receives some input from
grey matter of the spinal cord. They decussate in the ventral white com- the spinal cord, insular cortex and amygdala. Reticulospinal fibres from
missure, ascend in the ventrolateral funiculus, and terminate not only this region terminate bilaterally on sympathetic preganglionic neurones


Brainstem
327.e1
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Although many of these fibres are diffusely distributed, some have serotoninergic pathway enters the medial forebrain bundle in the lateral
more specific connections. For example, whereas the central superior hypothalamic area and splits to pass medially and laterally. The fibres
raphe nucleus projects divergently to all areas of the cerebral cortex, in the medial tract terminate in the mammillary body, dorsomedial,
different neurones in the dorsal raphe nucleus project specifically not ventromedial, infundibular, anterior and lateral hypothalamic, medial
only to circumscribed regions of the frontal, parietal and occipital cor- and lateral preoptic and suprachiasmatic nuclei. Those in the lateral
tices, but also to functionally related regions of the cerebellar cortex. tract take the ansa peduncularis–ventral amygdalofugal path to the
Similarly, the caudate nucleus and putamen receive a preferential input amygdala, striatum and neocortex. The medial forebrain bundle carries
from the dorsal raphe nucleus, whereas the hippocampus, septum and the remaining ventral ascending serotoninergic axons into the medul-
hypothalamus are innervated mainly by cells in the central superior lary stria, stria terminalis, fornix, diagonal band, external capsule, cin-
mesencephalic raphe nucleus. gulate fasciculus and medial olfactory stria, to terminate in all the
Both originate from neurones in the dorsal and central superior structures that these systems interconnect.
raphe nuclei. The raphe magnus nucleus also contributes to the dorsal Three areas of the medial reticular zone receive particularly high
ascending serotoninergic pathway, which is at first incorporated into densities of terminations. These are the combined caudal and rostral
the dorsal longitudinal fasciculus (of Schütz). A few fibres terminate in ends of the gigantocellular and central nuclei, respectively, and the
the central mesencephalic grey matter and posterior hypothalamus, but caudal pontine reticular nucleus and the pontine tegmentum. Retino-
most continue into the medial forebrain bundle and merge with the tectal and tectoreticular fibres relay visual information and the medial
axons of the ventral pathway, which are distributed to the same targets. forebrain bundle transmits olfactory impulses.


The fibres of the ventral ascending serotoninergic pathway exit the Efferents from the medial column of reticular nuclei project through
ventral aspect of the mesencephalic raphe nuclei, and then course ros- a multisynaptic pathway within the column to the thalamus. Areas of
trally through the ventral tegmentum from where fibres pass to the maximal termination of spinoreticular fibres also project directly to the
ventral tegmental area, substantia nigra and interpeduncular nucleus. A intralaminar thalamic nuclei. The multisynaptic pathway is integrated
large number of fibres then enter the fasciculus retroflexus (habenulo- into the lateral column of reticular nuclei with cholinergic neurones in
interpeduncular tract) and run rostrally to innervate the habenular the lateral pontine tegmentum. The intralaminar thalamic nuclei
nucleus, intralaminar, midline, anterior, ventral and lateral dorsal tha- project directly to the striatum and neocortex.
lamic nuclei, and the lateral geniculate body. The ventral ascending


Brainstem
328
3
nOitCes
in the thoracic spinal cord. Fibres from the pneumotaxic centre project that the pedunculopontine nucleus is bounded laterally by the medial
to an inspiratory centre in the ventrolateral part of the nucleus soli- lemniscus, medially by the superior cerebellar peduncle and its decus-
tarius, and a mixed expiratory–inspiratory centre in the superficial sation, dorsally by the pontine cuneiform and subcuneiform nuclei and
ventrolateral reticular area. Inspiratory neurones in both centres mono- ventrally by the pontine reticular formation. Rostrally, its ventral border
synaptically project to the phrenic and intercostal motor neurones. contacts the dorsomedial aspect of the substantia nigra and it is sepa-
Axons of expiratory neurones terminate on lower motor neurones that rated from the subthalamic nucleus by the retrorubral field. Its most
innervate intercostal and abdominal musculature. caudal pole is adjacent to the locus coeruleus (Pahapill and Lozano
Reticulospinal fibres descend from the lateral pontine tegmentum. 2000).
A mainly ipsilateral subcoeruleospinal pathway is distributed to all The pedunculopontine nucleus has been subdivided into two terri-
spinal segments of the cord through the lateral spinal funiculus. Crossed tories based on their cytoarchitectonic and neurochemical characteris-
pontine reticulospinal fibres descend from the ventrolateral pontine tics: namely, a caudal pars compacta consisting mainly of cholinergic
tegmentum, decussate in the rostral pons and occupy the contralateral neurones, and a rostral pars dissipata consisting of approximately equal
dorsolateral spinal funiculus. They terminate in laminae I, II, V and VI numbers of cholinergic and glutamatergic neurones scattered from the
of all spinal segments of the cord. Fibres from the pneumotaxic centre mid-mesencephalic to mid-pontine levels (Hamani et al 2007). The


innervate the phrenic nucleus and T1–T3 sympathetic preganglionic pedunculopontine nucleus is encircled by the mesencephalic locomo-
neurones bilaterally through this projection system. tor region (MLR), a region that also includes the cuneiform and subcu-
Bilateral projections from the micturition centres travel in the lateral neiform nuclei. Based on experimental studies in animals, where
spinal funiculus. They terminate on preganglionic parasympathetic stimulation of the mesencephalic locomotor region elicits locomotion,
neurones in the sacral cord (which innervate the detrusor muscle in the the pedunculopontine nucleus has been implicated in the initiation
urinary bladder), and on neurones in the nucleus of Onuf (which and modulation of gait and other stereotyped movements. Function-
innervate the musculature of the pelvic floor and the anal and urethral ally, the pedunculopontine nucleus is associated with the reticular acti-
sphincters). vating system via its cholinergic and glutaminergic connections with
Descending fibres of the A6 noradrenergic neurones of the locus intralaminar thalamic nuclei. However, its most important and complex
coeruleus project into the longitudinal dorsal fasciculus (as the caudal connections are reciprocal pathways with the basal ganglia, especially
limb of the dorsal periventricular pathway), and into the caudal limb the internal globus pallidus and the substantia nigra; these pathways
of the dorsal noradrenergic bundle (as part of the longitudinal catecho- are described in detail in Chapter 24.
lamine bundle). In this way they innervate, mainly ipsilaterally, all
other rhombencephalic reticular areas, principal and spinal nuclei of
BRAINSTEM LESIONS
the trigeminal nerve, pontine nuclei, cochlear nuclei, nuclei of the
lateral lemniscus, and bilaterally, all spinal preganglionic autonomic
neurones and the ventral region of the dorsal horn in all segments of GENERAL CONCEPTS
the spinal cord.
Most ascending fibres from the locus coeruleus pass in the dorsal Brainstem lesions (Figs 21.19–21.20) may arise as a result of extrinsic


noradrenergic (or tegmental) bundle; others run either in the rostral compression of the brainstem by space-occupying tumours (e.g. men-
limb of the dorsal periventricular pathway or in the superior cerebellar ingioma, vestibular schwannoma, metastatic carcinoma) or may be
peduncle. The latter fibres terminate on the cerebellar nuclei. The dorsal caused by intrinsic disease (e.g. glioma, demyelination, stroke). The
noradrenergic bundle is large and runs through the ventrolateral peri- clinical syndrome is generally characterized by: ipsilateral cranial nerve
aqueductal grey matter to join the medial forebrain bundle in the deficits, and a contralateral hemiplegia (corticospinal involvement)
hypothalamus, from where fibres continue forwards to innervate all and/or contralateral hemianaesthesia (anterolateral system, dorsal
rostral areas of the brain. The pathway contains efferent and afferent column–medial lemniscus). Brainstem lesions may also result in cere-
axons that reciprocally connect the locus coeruleus with adjacent struc- bellar signs (damage to cerebellar afferents or efferents) or in symptoms
tures along its course, e.g. central mesencephalic grey matter, dorsal reflecting small defects (nystagmus, internuclear ophthalmoplegia)
raphe nucleus, superior and inferior colliculi, interpeduncular nucleus, (Haines 2013, Posner et al 2007).
epithalamus, dorsal thalamus, habenular nuclei, amygdala, septum, In cases of brainstem lesions, the cranial nerve deficit is the best
olfactory bulb and anterior olfactory nucleus, the entire hippocampal localizing sign; it specifies the side of the lesion (cranial nerves receive
formation and neocortex. input from and project to the ipsilateral side) and the level within the
brainstem. Midbrain lesions (cranial nerves III, IV) cause ophthalmo-
Pedunculopontine nucleus
plegia, pupillary dilation and ptosis (oculomotor nerve palsy), and


The pedunculopontine nucleus (nucleus tegmentalis pedunculoponti- impaired upward gaze (e.g. due to a pinealoma). Mid-pontine lesions
nus; PPN) lies in the dorsolateral part of the pontomesencephalic teg- (cranial nerve V) may result in a loss of sensation on the face and in
mentum. Despite some terminological confusion, most authors agree the oral cavity and weakness of the masticatory muscles. Tumours or
Cranial nerves and motor system Reflexes Sensation Coordination
+++
+++
+
+
+
– +
+++
+++ +
Fig. 21.19 Brainstem lesions. (With permission from Crossman AR, Neary D 2010 Neuroanatomy, 4th edn. Edinburgh: Churchill Livingstone.)


Brainstem
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The superficial ventrolateral area is also the seat of the ‘visceral alert- processing. In animals, firing rates of locus coeruleus neurones peak
ing response’. Fibres from the hypothalamus, periaqueductal grey during wakefulness and decrease during sleep – they cease almost com-
matter and midbrain tegmentum mediate increased respiratory activity, pletely during rapid eye movement (REM) sleep. During wakefulness,
raised blood pressure, tachycardia, vasodilation in skeletal muscle and firing rates are augmented when novel stimuli are presented. The locus
renal and gastrointestinal vasoconstriction. Ascending efferents from coeruleus may, therefore, function to control the level of attentiveness.
the superficial ventrolateral area synapse on neurones of the supraoptic Other functions that have been ascribed to the locus coeruleus include
and paraventricular hypothalamic nuclei. Excitation of these neurones control of the wake–sleep cycle, regulation of blood flow, and mainte-
causes release of vasopressin from the neurohypophysis. Medullary nance of synaptic plasticity.
noradrenergic cell groups A1 and A2 also innervate (directly and indi- The A1, A2, A5 and A7 noradrenergic cell groups project rostrally,
rectly) the median eminence, and control the release of growth mainly through the central tegmental tract. Their axons constitute a
hormone, luteinizing hormone and adrenocorticotrophic hormone. major longitudinal catecholamine pathway that continues through the
The lateral pontine tegmentum, particularly the parabrachial region, medial forebrain bundle and ends in the amygdala, lateral septal
is reciprocally connected to the insular cortex. It shares reciprocal pro- nucleus, bed nucleus of the stria terminalis, nucleus of the diagonal
jections with the amygdala through the ventral amygdalofugal pathway, band and the hypothalamus. The ascending dorsal periventricular
medial forebrain bundle and central tegmental tract, and with hypotha- pathway contains a few non-coerulean noradrenergic fibres, which ter-


lamic, median preoptic and paraventricular nuclei, which preferentially minate in the periventricular region of the thalamus.
project to the lateral parabrachial nucleus and the micturition centres. Projections arising in the rhombencephalon receive contributions
It also shares reciprocal bulbar projections, many from the pneumotaxic from the diffusely organized dorsal medullary and lateral tegmental
centre, with the nucleus solitarius and superficial ventrolateral reticular noradrenergic cell groups. These interconnect cranial nerve nuclei and
area. other reticular cell groups, particularly those of the vagus, facial and
Other axons that contribute to the longitudinal catecholamine trigeminal nerves, and the rhombencephalic raphe and parabrachial
bundle originate from cell groups C1, A1, A2, A5 and A7. The main nuclei.
projection is a descending one from cell groups C1 and A5, which are Precerebellar nuclei are those that send axons to the cerebellar cortex
sudomotor neural control centres and innervate preganglionic sympa- and nuclei. The three related to the reticular formation are the lateral
thetic neurones. and paramedian reticular nuclei, and the reticulotegmental nucleus;
Fibres from the locus coeruleus that travel in the rostral limb of the these are involved in the relay of spinal information into primarily the
dorsal periventricular pathway ascend in the ventromedial periaqueduc- vermis and paravermal regions of the ipsilateral cerebellar hemisphere.
tal grey matter adjacent to the longitudinal dorsal fasciculus and termi- They receive inputs from the contralateral primary motor and sensory
nate in the parvocellular part of the paraventricular nucleus in the neocortices, and the ipsilateral cerebellar and vestibular nuclei and
hypothalamus. spinal cord (the latter through the ascending spinoreticular pathway).
The functions of the locus coeruleus and related tegmental noradren- This system augments the dorsal and ventral spinocerebellar, cuneocere-
ergic cell groups are incompletely understood. The diversity of their bellar, accessory cuneocerebellar and trigeminocerebellar tracts.
rostral and caudal projections suggests a widespread role in central


329
12
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Key references
intra cranial pressure, signalled by headache, nausea and papilloedema
in one compartment (tumour, haemorrhage, abscess, metabolic dis-
Falx cerebri order), usually results in an extrusion of CNS structures from a location
of higher pressure to an adjacent location of lower pressure: the brain
herniates. All herniation syndromes, directly or indirectly, will compro-
mise brainstem viability (Posner et al 2007, Haines 2015).
An expanding lesion in parietofrontal areas, a supratentorial posi-
SOL A tion, may result in herniation of structures such as the cingulate gyrus
underneath the edge of the falx cerebri (see Fig. 21.20A). This may
initially be a ‘silent’ event (no signs or symptoms) or may present as
lower-extremity weakness related to compression of the anterior cere-
B bral artery (ipsilateral, contralateral or bilateral) and decreased levels of
consciousness.
SOL C Hemisphere lesions may enlarge, impinge into the opposite side of
the brain, and produce a characteristic series of deficits (see Fig. 21.20B).
These include decrease in consciousness indicating damage to the tha-
D E lamic relays of the reticular activating system, generally increased
muscle tone, a change in respiratory patterns, and altered pupils and
eye movements. These patients may become decorticate: lower extremi-
SOL ties extended, upper extremities flexed.
As a cerebral mass compromises the available supratentorial space
Tentorium
and the clinical picture deteriorates, the herniation traverses the tento-
cerebelli
SOL rial notch as a transtentorial (or central) herniation (see Fig. 21.20C).
These patients have a significant decrease in the level of consciousness
(some may be stuporous or in coma); breathing patterns are irregular
(tachypnoea, Cheyne–Stokes); and eye movements are compromised
F – pupils are dilated and may be fixed. A state of decortication may
convert to decerebrate rigidity, when all extremities are extended.
Lesions located in the temporal lobe may expand medially, forcing
the uncus and possibly the parahippocampal gyrus over the edge of


the tentorium cerebelli with impingement on the midbrain (see Fig.
21.20D). This is uncal herniation and may present in two forms. First,
A Cingulate herniation under falx, potential anterior cerebral artery damage the midbrain injury involves structures on the side of the herniation
B Herniation into opposite hemisphere, potential decorticate posturing with predictable deficits: ipsilateral pupil dilation and ophthalmople-
C Transtentorial or central herniation, potential decerebrate posturing, somnolence gia, contralateral weakness of upper and lower extremities, an altered
D Uncal/parahippocampal gyrus herniation, pupil signs, hemiparesis, somnolence, stupor level of consciousness and hyperactive reflexes. Second, the herniation
E Upward cerebellar herniation, increased intracranial pressure, hydrocephalus, impaired upward gaze may shift the midbrain to the side opposite the herniation (e.g. with
F Tonsillar herniation, potential cardiac and respiratory arrest herniation on the right, the midbrain shifts to the left). In this case the
dilated pupil and third nerve ophthalmoplegia are on the right, and the
Fig. 21.20 Space-occupying lesions (SOL).
crus cerebri damaged on the left results in a right hemiplegia; both
motor deficits are on the right side. The corticospinal deficit, in this
lesions at the level of the pontomedullary junction (cranial nerves VI,
case, is a false localizing sign.
VII, VIII) may produce weakness of the lateral rectus muscle, a loss of
Pressure increase in the posterior fossa, an infratentorial location,
facial sensation, and deafness, vertigo or tinnitus. Medullary lesions
may result in herniation upwards through the tentorial notch or down-
(cranial nerves IX, X, XII and traversing fibres of XI) may cause a ‘bulbar
wards into the foramen magnum. Upward cerebellar herniation (see
palsy’: dysarthria, dysphagia and dysphonia, with wasting of the hemi-
Fig. 21.20E) displaces the brainstem against the tentorium and into the


tongue, and deviation, weakness and wasting of sternocleidomastoid
notch with resultant symptoms of increased intracranial pressure, paral-
and trapezius. All are usually accompanied by signs or symptoms of
ysis of upward gaze, motor deficits and altered consciousness. Extrusion
long tract involvement (motor, sensory or both).
of the cerebellar tonsils (see Fig. 21.20F) downwards into the foramen
magnum may result in damage to medullary cardiac and respiratory
Herniation syndromes
centres, with resultant changes in heart and respiratory rates. Both of
these syndromes may constitute a medical emergency, the former due
Damage to the brainstem resulting in characteristic deficits is a major to rapidly developing hydrocephalus, the latter due to compromise of
element of what are called herniation syndromes. An increase in cardiac and respiratory centres.
KEY REFERENCES
Dahlström A, Fuxe K 1964 Evidence for the existence of monamine- Kozicz, T, Bittencourt JC, May PJ et al 2011 The Edinger–Westphal nucleus:
containing neurones in the central nervous system. Acta Physiol Scand a historical, structural, and functional perspective on a dichotomous
Suppl 232:1–55. terminology. J Comp Neurol 519:1413–34.
A historically significant paper elucidating the organization of monamine- A pivotal reference clearly explaining that the Edinger–Westphal complex
containing cells within the brain; a particularly useful source of (nucleus) is actually comprised of two parts: a centrally projecting nucleus
information. that projects to a variety of central targets that do not communicate with
the ciliary pathways, and a preganglionic nucleus that projects only to the
Haines DE 2013 Fundamental Neuroscience for Basic and Clinical Applica-
ciliary ganglion.
tions, 4th ed. Philadelphia: Elsevier, Saunders.
A comprehensive treatment of the brainstem that includes development, Lachman N, Acland RD, Rosse C 2002 Anatomical evidence for the absence
external and internal anatomy, with a particular emphasis on cranial nerves of a morphologically distinct cranial root of the accessory nerve in man.
and detailed treatment of vasculature territories. This source also contains Clin Anat 15:4–10.


comprehensive coverage of clinical syndromes affecting the brainstem. A citation that offers details of the view that the accessory nerve may receive
little or no contribution from the brainstem. Rather, this cranial nerve is
Haines DE 2015 Neuroanatomy In Clinical Context: An Atlas of Structures,
composed of axons that arise predominately from upper cervical levels.
Sections, Systems, and Syndromes, 9th ed. Baltimore: Wolters Kluwer/
Lippincott Williams & Wilkins. Nathan PW, Smith MC 1982 The rubrospinal and central tegmental tracts
A very useful source of information on brainstem anatomy, vasculature and in man. Brain 105:223–69.
selected clinical syndromes that are seen following injury to the brainstem, A historically important source of information on the arrangement of select
whether these are vascular lesions or otherwise. There is particular emphasis brainstem pathways in the human brainstem.
on nuclei and pathways of the brainstem.


Brainstem
330
3
nOitCes
Nieuwenhuys R 1985 Chemoarchitecture of the Brain. Berlin: Springer. Information on brainstem syndromes, especially those related to increases in
A particularly useful and nicely organized source of information on the intracranial pressure with the probable outcome of herniation of the brain
locations of cell bodies containing particular neurotransmitter substances, from one intracranial compartment to another.
their trajectory and termination sites.
Ryan S, Blyth P, Duggan N et al 2007 Is the cranial accessory nerve really a
Olszewski J, Baxter D 1954 Cytoarchitecture of the Human Brain Stem, portion of the accessory nerve? Anatomy of the cranial nerves in the
2nd ed. Basel: Karger. jugular foramen. Anat Sci International 82:1–7.
A classic, detailed source of information on the organization of the nuclei of A consideration of the issue of whether or not the accessory nerve receives
the human brainstem. contributions from the medulla, concluding that such connections are rare.
Posner JB, Saper CB, Schiff ND et al 2007 Plum and Posner’s Diagosis of
Stupor and Coma, 4th ed. Oxford: Oxford University Press.


Brainstem
330.e1
12
retPaHC
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Benninger B, McNeil J 2010 Transitional nerve: a new and original classifica- Liu HF, Won HS, Chung IH et al 2014 Variable composition of the internal
tion of a peripheral nerve supported by the nature of the accessory nerve and external branches of the accessory nerve. Clin Anat 27:97–101.
(CN XI). Neurol Res Int. Article ID 476018:1–15. McGarvey L 2014 Update: The search for the human cough receptor. Lung
Brodal P, Bjaalie JG 1992 Organization of the pontine nuclei. Neurosci Res 192:459–65.
13:83–118. Millar J, Basbaum AI 1975 Topography of the projection of the body sur-
Ciriello J 1983 Brainstem projections of aortic baroreceptor afferent fibres face of the cat to cuneate and gracile nuclei. Exp Neurol 49:281–90.
in the rat. Neurosci Lett 36:37–42. Nathan PW, Smith MC 1982 The rubrospinal and central tegmental tracts
Dahlström A, Fuxe K 1964 Evidence for the existence of monamine- in man. Brain 105:223–69.
containing neurones in the central nervous system. Acta Physiol Scand A historically important source of information on the arrangement of select
Suppl 232:1–55. brainstem pathways in the human brainstem.
A historically significant paper elucidating the organization of monamine-
Nieuwenhuys R 1985 Chemoarchitecture of the Brain. Berlin: Springer.
containing cells within the brain; a particularly useful source of information.
A particularly useful and nicely organized source of information on the
Dahlström A, Fuxe K 1965 Evidence for the existence of monoamine neu- locations of cell bodies containing particular neurotransmitter substances,
rones in the central nervous system. II. Experimentally induced changes their trajectory and termination sites.
in the intraneuronal amine levels of bulbospinal neurone systems. Acta
Nieuwenhuys R, Voogd J, van Huijzen C 2008 The Human Central Nervous
Physiol Scand Suppl 247:1–36.
System. A Synopsis and Atlas, 4th ed. Berlin: Springer.


Haines DE 2013 Fundamental Neuroscience for Basic and Clinical Applica-
Olszewski J 1950 On the anatomical and functional organization of the
tions, 4th ed. Philadelphia: Elsevier, Saunders.
spinal trigeminal nucleus. J Comp Neurol 92:401–9.
A comprehensive treatment of the brainstem that includes development,
external and internal anatomy, with a particular emphasis on cranial nerves Olszewski J, Baxter D 1954 Cytoarchitecture of the Human Brain Stem,
and detailed treatment of vasculature territories. This source also contains 2nd ed. Basel: Karger.
comprehensive coverage of clinical syndromes affecting the brainstem. A classic, detailed source of information on the organization of the nuclei of
the human brainstem.
Haines DE 2015 Neuroanatomy In Clinical Context: An Atlas of Structures,
Sections, Systems, and Syndromes, 9th ed. Baltimore: Wolters Kluwer/ Pahapill PA, Lozano AM 2000 The pedunculopontine nucleus and Parkin-
Lippincott Williams & Wilkins. son’s disease. Brain 123:1767–83.
A very useful source of information on brainstem anatomy, vasculature and Posner JB, Saper CB, Schiff ND et al 2007 Plum and Posner’s Diagosis of
selected clinical syndromes that are seen following injury to the brainstem, Stupor and Coma, 4th ed. Oxford: Oxford University Press.
whether these are vascular lesions or otherwise. There is particular emphasis Information on brainstem syndromes, especially those related to increases in
on nuclei and pathways of the brainstem. intracranial pressure with the probable outcome of herniation of the brain
from one intracranial compartment to another.
Hamani C, Stone S, Laxton A et al 2007 The pedunculopontine nucleus and
movement disorders: anatomy and the role for deep brain stimulation. Ryan S, Blyth P, Duggan N et al 2007 Is the cranial accessory nerve really a
Parkinsonism Relat Disord 13:S276–S280. portion of the accessory nerve? Anatomy of the cranial nerves in the
Hamilton RB, Norgren R 1984 Central projections of gustatory nerves in the jugular foramen. Anat Sci International 82:1–7.


rat. J Comp Neurol 222:560–77. A consideration of the issue of whether or not the accessory nerve receives
contributions from the medulla, concluding that such connections are rare.
Hornung JP 2003 The human raphe nuclei and the serotonergic system.
J Chem Neuroanat 26:331–43. Seijo-Martínez M, Varela-Freijanes A, Grandes J et al 2006 Sneeze related
Kozicz, T, Bittencourt JC, May PJ et al 2011 The Edinger–Westphal nucleus: area in the medulla: localisation of the human sneezing centre? Neurol
a historical, structural, and functional perspective on a dichotomous Neurosurg Psychiatry 77:559–61.
terminology. J Comp Neurol 519:1413–34. Shoja MM, Oyesiku NM, Shokouhi G et al 2014 A comprehensive review
A pivotal reference clearly explaining that the Edinger–Westphal complex with potential significance during skull base and neck operations, Part
(nucleus) is actually comprised of two parts: a centrally projecting nucleus II: Glossopharyngeal, vagus, accessory, and hypoglossal nerves and cer-
that projects to a variety of central targets that do not communicate with vical spinal nerves 1–4. Clin Anat 27:131–44.
the ciliary pathways, and a preganglionic nucleus that projects only to the
Siegel GA, Agranoff BW, Albers AW et al 1999 Basic Neurochemistry: Molecu-
ciliary ganglion.
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Krammer EB, Lischka MF, Egger TP et al 1987 The Motoneuronal Organiza- Raven.
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Embryology and Cell Biology 103. Berlin: Springer. hypoglossal nerve, and the spinomedullary region. J Clin Neurophysiol
Lachman N, Acland RD, Rosse C 2002 Anatomical evidence for the absence 28:587–98.


of a morphologically distinct cranial root of the accessory nerve in man. Tubbs RS, Benninger B, Loukas M et al 2014 Cranial roots of the accessory
Clin Anat 15:4–10. nerve exist in the majority of adult humans. Clin Anat 27:102–7.
A citation that offers details of the view that the accessory nerve may receive
Wiles CC, Wrigley B, Greene JR 2007 Re-examination of the medullary
little or no contribution from the brainstem. Rather, this cranial nerve is
rootlets of the accessory and vagus nerves. Clin Anat 20:19–22.
composed of axons that arise predominately from upper cervical levels.


CHAPTER
22
Cerebellum
The cerebellum occupies the posterior cranial fossa, separated from the
occipital lobes of the cerebral hemispheres by the tentorium cerebelli. 1 10
It is the largest part of the hindbrain; in adults, the weight ratio of
11
cerebellum to cerebrum is approximately 1 : 10, and in infants 1 : 20.
The cerebellum lies dorsal to the pons and medulla, from which it is
separated by the fourth ventricle. It is joined to the brainstem by three
bilaterally paired cerebellar peduncles.
2
The basic internal organization of the cerebellum is of a superficial
12
cortex overlying a core of white matter. The cortex is highly convoluted,
forming lobes and lobules that are further subdivided into folia (leaf
lets), separated by intervening transverse fissures. Aggregations of neu 13
ronal cell bodies embedded within the white matter form the fastigial
3
(medial), globose (posterior interposed), emboliform (anterior inter
posed) and dentate (lateral) nuclei, which are collectively known as the
(deep) cerebellar nuclei.
The cerebellum may be subdivided into a number of modules, each 4 14
consisting of a longitudinal cortical zone, a cerebellar or vestibular
target nucleus, and a supporting olivocerebellar climbing fibre system. 15
Apart from their connections, the longitudinal cortical zones are char 5
acterized by their immunohistochemical properties. The cerebellum
receives input from peripheral receptors and from motor centres in the 6
spinal cord and brainstem and from large parts of the cerebral cortex
through two different afferent systems: mossy and climbing fibres. It is
located as a side path to the main ascending sensory and descending 7
motor systems, and it functions to coordinate movement. During move
8 16
ment, the cerebellum provides corrections that are the basis for preci
sion and accuracy, and it is critically involved in motor learning and 17
9
reflex modification. Cerebellar output is directed to the thalamus and
from there to the cerebral cortex, and also to brainstem centres such as


the red nucleus, vestibular nuclei and reticular nuclei, which themselves
give rise to descending spinal pathways. Fig. 22.1 A horizontal section through the cerebellum and brainstem.
Ideas on the involvement of the cerebellum in motor functions were 1. Ethmoidal air cells. 2. Temporal lobe of brain. 3. Hypophysis. 4. Pons.
derived mainly from movement disorders seen in experimental studies, 5. Cochlea. 6. Sigmoid sinus. 7. Fourth ventricle. 8. Vermis. 9. Diploë of
summarized by Luciani (1891) in his triad of atonia, astasia and asthe occipital bone. 10. Eyeball. 11. Optic nerve. 12. Internal carotid artery.
nia, and in human patients with cerebellar lesions who displayed the 13. Middle cerebellar peduncle. 14. Petrous temporal bone. 15. Superior
wellknown symptoms of gait disturbances, limb ataxia, dysmetria, cerebellar peduncle. 16. Dentate nucleus. 17. Folia of cerebellar cortex.
atonia and eye movement disorders (Glickstein et al 2009). Latterly, the (Courtesy of Dr GJA Maart.)
observation that lesions of the cerebellar hemisphere not only resulted
in minor and transient motor symptoms but also induced a cerebellar
cognitive/affective syndrome (Schmahmann 2004) prompted the sug nineteenth centuries from their shape, their position or their likeness
gestion that the human cerebellum is also concerned with nonmotor to anatomical structures in other body parts (Glickstein et al 2009).
functions. These conceptual developments went hand in hand with the This classical nomenclature (see Fig. 22.4, right panel) was largely
use of more sensitive experimental methods to trace cerebellar con replaced in the early twentieth century by a nomenclature based on
nectivity, mainly in subhuman primates, and the application of modern Bolk’s (1906) comparative anatomical investigations (see Fig. 22.4,
imaging techniques to the human brain. Although it is now recognized left panel).
that the cortex is more heterogeneous than previously supposed, and Bolk distinguished the relatively independent ‘folial chains’ of the


despite our extensive knowledge of the sphere of influence of the cere vermis and the hemispheres. In later studies, this relative independence
bellum and the microcircuitry of its cortex and nuclei, we still do not was found to reflect the continuity or discontinuity of the cortex
fully understand how it contributes to motor and nonmotor systems. between the lobules within a folial chain, or between the folial chains
The observation by Thomas Willis (1681) that ‘the Spirits inhabiting of the vermis and the hemispheres. Bolk used the cerebellum of a small
the Cerebel perform unperceivedly and silently their Work of Nature lemur for his initial description (see Fig. 22.5F–G) and summarized the
without our Knowledge or Care’ remains true today. configuration of the folial chains in a stick diagram (see Fig. 22.5H).
His description proved to be applicable to the cerebella of all the
mammals he studied, including the human cerebellum.
EXTERNAL FEATURES AND RELATIONS
Larsell (Larsell and Jansen 1972) based his subdivision of the cere
bellum on embryological studies of the emergence of the transverse
The cerebellum consists of two large, laterally located hemispheres fissures with time. Contrary to Bolk, who emphasized the continuity
that are united by a midline vermis (Figs 22.1–22.3). Numerous sulci within the folial chains, Larsell attached great importance to the medio
and fissures of varying depth subdivide it into lobes, lobules and folia lateral continuity of the lobules of the vermis and the hemispheres, and
(leaflets) (Figs 22.4–22.5). The primary fissure, the deepest fissure on distinguished 10 lobules in the cerebellum, indicated using Roman
a sagittal section, divides it into anterior and posterior lobes. Paramed numerals I–X for the vermis and the prefix H for the hemisphere. The
ian fissures, shallow in the anterior cerebellum but prominent more correspondence of Larsell’s lobules with the classical nomenclature is
posteriorly, separate the vermis from the cerebellar hemispheres. shown in Figure 22.4.


Both the anterior and posterior vermis and hemisphere are subdi Lobules (H)I–V constitute the anterior lobe. Lobule I, the lingula, is
vided into lobules that received their names in the eighteenth and conjoined with the superior medullary velum. Lobules VI (declive) and 331


Cerebellum
332
3
NOITCeS
A Pons Corpus callosum Thalamus Occipital lobe Superior cerebellar peduncle Arbor vitae
Medulla oblongata Foramen magnum Tonsil of cerebellum
Medulla Fourth
Internal jugular vein Tonsil Sigmoid sinus
oblongata ventricle
B
Falx cerebelli Confluence of sinuses Vermis
C
Transverse sinus
Vermis
Tonsil
Vallecula
Fig. 22.2 Magnetic resonance images of the cerebellum of a 16-year-old female. A, Sagittal view. B, Axial view. C, Coronal view. (Courtesy of Drs JP
Finn and T Parrish, Northwestern University School of Medicine, Chicago.)


333
22
reTPAHC
external features and relations
A B
pcen
2a
precul
1 prim
3a
2
2 psup
3
4a
3
4
5 hzl
6
5a
4
7
5
8
apm
9
preb
plat intb
D
C sec 2 1a
1 2a
2 3
9 10a
1 4
9 5 8 9a
8 6
7
8a
7
6 7a
6a
Fig. 22.3 The terminology of the cerebellar lobes and fissures, using a schematic ‘unrolled’ diagram as a frame of reference. A, Unrolled cerebellar
cortex. The lobules are labelled by numbers and the fissures between the lobules are listed. B, The cerebellum viewed from above. C, A median sagittal
section of cerebellum. The lobules are numbered and listed. D, The cerebellum viewed from below. Key and abbreviations: Anterior lobe: 1, lingula; 2,
central; 3, culmen, vermis. Posterior lobe: 4, declive; 5, folium; 6, tuber; 7, pyramis; 8, uvula; 9, nodule. Fissures: apm, ansoparamedian; hzl, horizontal;
intb, intrabiventral; pcen, precentral; plat, posterolateral; preb, prebiventral; precul, preculminate; prim, primary; psup, posterior superior; sec, secondary.
Hemisphere: 1a, wing of lingula; 2a, wing of central lobule; 3a, anterior quadrangular lobule; 4a, posterior quadrangular lobule; 5a, superior semilunar
lobule; 6a, inferior semilunar lobule; 7a, gracile lobule; 8a, biventral lobule; 9a, tonsil of cerebellum, 10a, flocculus.
Hemisphere Vermis Hemisphere
Vincingulum lingulae
Ala lobuli centralis
I Lingula Anterior quadrangular lobule


Anterior lobe II Central Posterior quadrangular lobule
lobe
III
Simplex lobule IV
Culmen
1 V Superior semilunar lobule
1. Primary fissure
2. Posterior superior fissure Crus I 2 VI Declive
3. Intercrural fissure Horizontal fissure
Ansiform lobule 3 VIIA Folium
4. Ansoparamedian fissure
5. Prepyramidal fissure Crus II 4 VIIB Tuber
6. Secondary fissure 5 Inferior semilunar lobule
Paramedian lobe
7. Posterolateral fissure VIII Pyramis
6
Dorsal paraflocculus
Gracile lobule
IX Uvula
Ventral paraflocculus X Nodulus Biventral lobule
7 Accessory paraflocculus
Flocculus
Posterior medullary velum
Tonsil Flocculus
Fig. 22.4 Cerebellar nomenclature. The left-hand panel illustrates the comparative anatomical nomenclature for the hemisphere and Larsell’s numbering
system for the lobules of the vermis (Larsell and Jansen 1972). The right-hand panel shows the classical nomenclature. The homology of these lobules is
indicated using the same colour. Asterisks denote areas devoid of cortex in the centre of the folial rosettes of the ansiform lobule and the paraflocculus.


Cerebellum
334
3
NOITCeS
Horizontal fissure
F/T
Superior semilunar lobule Posterior superior fissure Semilunar lobules
Posterior quadrangular lobule SI
De
Primary fissure Ansoparamedian
Posterior fissure
superior fissure
Gracile lobule
Cu
Biventral lobule
Ce Prepyramidal
fissure
Anterior lobe Vma Li FANod Vmp
Posterolateral Uv Py Tonsil A E
fissure
Primary fissure
Anterior lobe Anterior lobe
Primary fissure Simplex lobule
Posterior quadrangular lobule
Ansiform lobule
Posterior superior fissure
1 PFLD 1
Superior semilunar
lobule
Horizontal fissure Caudal vermis
B F Dorsal Paramedian lobe
F/T Py Inferior semilunar lobule
Anterior lobe
Superior semilunar lobule
1 Horizontal fissure
Inferior semilunar
lobules
Gracile lobule 2
2 Ansoparamedian
fissure PFLV
Caudal vermis
PFLD
Prepyramidal fissure Paramedian lobe
C Biventral lobule G Ventral
Tonsil
Anterior lobe Anterior lobe
Scp
Icp
Mcp
Simplex lobule
PFLV
2
1 Flocculus
Ansiform lobule
2
PFLD
Flocculus
Nod Tonsil Paramedian lobule
D Uv H Caudal vermis
Fig. 22.5 A–D, Anterior, dorsal, posterior and ventral views of the human cerebellum. E, A sagittal section of the human cerebellum. F–G, Dorsal and
ventral views of the cerebellum of Lemur albifrons, Bolk’s (1906) prototype for his ground plan of the mammalian cerebellum. Two loops are present in
the folial chain of the hemisphere: (1) as the ansiform lobule, (2) as the paraflocculus. The course of the folial chains of the vermis and hemisphere in


A–D and F–G is indicated with red lines. H, Bolk’s stick diagram of the folial chains of the vermis and hemisphere. Key and abbreviations: 1, 2, Ansiform
and parafloccular loops of the folial chain of the hemisphere; Ce, central lobule; Cu, culmen; De, declive; FA, fastigium; F/T, folium and tuber; Icp, inferior
cerebellar peduncle; Li, lingula; Mcp, middle cerebellar peduncle; Nod, nodulus; PFLD, dorsal paraflocculus; PFLV, ventral paraflocculus; Py, pyramis;
Scp, superior cerebellar peduncle; SI, simplex (posterior quadrangular) lobule; Uv, uvula; Vma, anterior (superior) medullary velum; Vmp, posterior
medullary velum.
HVI (posterior quadrangular lobule) are also known as Bolk’s simplex formed by the biventral lobule (HVIII), the hemisphere from the
lobule. Behind the primary fissure, the folium (lobule VIIA) and tuber pyramis (VIII). Lobule VIII (the pyramis) is continuous with the biven
vermis (VIIB) are separated by the deep paramedian fissure from the tral lobule (HVIII) laterally. The gracile lobule corresponds to the rostral
superior semilunar lobule (HVIIA), the inferior semilunar lobule and part of Bolk’s paramedian lobule; the biventral lobule corresponds to
the gracile lobule (together corresponding to HVIIA). Superior and its caudal portion. The tonsil (HIX) corresponds to the dorsal parafloc
inferior semilunar lobules correspond to the crus I and II of Bolk’s culus in the monkey. In the human, the folial loop of the tonsil is
ansiform lobule. Their folia fan out from the deep horizontal fissure directed medially, contrary to the situation in most mammals, where
that represents the intercrural fissure. The gracile lobule corresponds to the paraflocculus arches laterally. The flocculus appears as a double


the rostral part of Bolk’s paramedian lobule. Its caudal portion is folial rosette; its dorsal leaf is known as the accessory paraflocculus of


Internal organization
335
22
reTPAHC
Cerebral peduncle Superior cerebellar peduncle characteristic branching pattern of nerve fibres (arbor vitae) extends
towards the cortical surface (see Fig. 22.2). The white matter consists
Trigeminal Inferior cerebellar of afferent and efferent fibres travelling to and from the cerebellar
nerve peduncle cortex. Fibres cross the midline in the white core of the cerebellum
Middle cerebellar and the superior medullary velum, effectively constituting a cerebellar
peduncle ‘commissure’.
CEREBELLAR CORTEX
Although the human cerebellum makes up approximately onetenth of
Pyramid the entire brain by weight, the surface area of the cerebellar cortex, if
unfolded, would be about half that of the cerebral cortex. The great
Olive majority of cerebellar neurones are small granule cells, so densely
packed that the cerebellar cortex contains many more neurones than
the cerebral cortex. Unlike the cerebral cortex, where a large number of
diverse cell types are arranged differently in different regions, the cere
bellar cortex contains a relatively small number of different cell types,
which are interconnected in a highly stereotyped way.
The elements of the cerebellar cortex possess a precise geometric
order, arrayed relative to the tangential, longitudinal and transverse
Vestibulocochlear nerve Inferior cerebellar peduncle
planes in individual folia. Three layers are distinguished in the cerebel
Fig. 22.6 Dissection of the left cerebellar hemisphere and its peduncles.
lar cortex (Figs 22.7–22.8). A monolayer of large neurones with apical
dendrites, first identified by Purkinje (Glickstein et al 2009), separates
Henle, while its ventral leaf represents the true flocculus. The accessory a layer of small granule cells from the superficial, cellpoor molecular
paraflocculus corresponds to the ventral paraflocculus in the monkey. layer. The Purkinje cell layer contains the large, pearshaped somata of
Both these lobules belong to the vestibulocerebellum. The cortex the Purkinje cells and the smaller somata of Bergmann glia. Clumps of


between the tonsil and the accessory paraflocculus is interrupted. granule cells and occasional Golgi cells penetrate between the Purkinje
Between lobule X (the nodulus) and the flocculus (HX) with the acces cell somata. The granular layer consists of the somata of granule cells
sory paraflocculus, the cortex is absent and the tissue is stretched out and the initial segments of their axons; dendrites of granule cells;
as the inferior medullary velum. branching terminal axons of afferent mossy fibres; climbing fibres
Two magnetic resonance imaging (MRI) atlases of the cerebellum passing through the granular layer en route to the molecular layer; and
have been published to aid localization in functional MRI (fMRI) the somata, basal dendrites and complex axonal ramifications of Golgi
(Schmahmann et al 1999, Diedrichsen 2006). The authors use Larsell’s neurones.
numerals and retain Bolk’s terms crus I and II, but discard Larsell’s use The molecular layer contains a sparse population of neurones, den
of the prefix H for the lobules of the hemisphere. As a consequence, it dritic arborizations, unmyelinated axons and radial fibres of neuroglial
is difficult to determine whether descriptions of lobules using these cells.
criteria refer to the vermis or to the hemisphere.
Purkinje cells
CEREBELLAR PEDUNCLES
Purkinje cells are the only output neurones of the cortex. They are
arranged in a single layer between the molecular and granular layers,
Three pairs of peduncles connect the cerebellum with the brainstem
and have a specific geometry that is conserved in all vertebrate classes
(Fig. 22.6; see also Fig. 21.19).
(Fig. 22.9).
The middle cerebellar peduncle is the most lateral and by far the
Their dendritic trees are flattened and orientated perpendicular to
largest of the three. It passes obliquely from the basal pons to the cere
the parallel fibres in a plane transverse to the long axes of the folia (see
bellum and contains the massive pontocerebellar mossy fibre pathway,
Figs 22.7–22.8; see also Figs 3.3, 3.6). Large primary dendrites arise


which is composed almost entirely of fibres that arise from the contra
from the outer pole of a Purkinje cell. The proximal dendritic branches
lateral basal pontine nuclei, with a small addition from nuclei in the
are smooth and are contacted by climbing fibres. The distal branches
pontine tegmentum.
carry a dense array of dendritic spines (spiny branchlets) that receive
The inferior cerebellar peduncle is located medial to the middle
synapses from the terminals of parallel fibres. Inhibitory synapses are
peduncle. It consists of an outer, compact fibre tract – the restiform
also received from basket and stellate cells, and from the recurrent col
body – and a medial, juxtarestiform body. The restiform body is
laterals of Purkinje cell axons that contact the shafts of the proximal
a purely afferent system; it receives spinocerebellar fibres and the
dendrites. The total number of dendritic spines per Purkinje neurone
trigeminocerebellar, cuneocerebellar, reticulocerebellar and olivocere
is in the order of 180,000. The axon of a Purkinje cell leaves the inner
bellar tracts from the medulla oblongata (see Fig. 21.19). The juxtares
pole of the soma and crosses the granular layer to enter the subjacent
tiform body is mainly an efferent system, made up almost entirely of
white matter. The initial axon segment receives axoaxonal synaptic
efferent Purkinje cell axons destined for the vestibular nuclei and
contacts from distal branches of basket cell axons. Beyond the initial
uncrossed fibres from the fastigial nucleus. It also contains primary
segment, the axon enlarges, becomes myelinated and gives off collateral
afferent mossy fibres from the vestibular nerve and secondary afferent
branches. The main axon ultimately terminates in one of the cerebellar
fibres from the vestibular nuclei. The crossed fibres from the fastigial
or vestibular nuclei; recurrent axonal collaterals form a sagittally orien
nucleus pass dorsal to the superior cerebellar peduncle as the uncinate
tated plexus with terminations on neighbouring Purkinje cells and


tract, and enter the brainstem at the border of the juxtarestiform and
Golgi cells. Purkinje cells are inhibitory and use γaminobutyric acid
restiform bodies.
(GABA) as their neurotransmitter.
The superior cerebellar peduncle contains all of the efferent fibres
from the dentate, emboliform and globose nuclei, and a small fascicle
from the fastigial nucleus. Its fibres decussate in the caudal mesen Cortical interneurones
cephalon, and are destined to synapse in the contralateral red nucleus
and thalamus. The ventral spinocerebellar tract reaches the upper part The cerebellar cortical interneurones were described by Ramón y Cajal
of the pontine tegmentum, looping around the entrance of the trigemi (1906) (see Fig. 22.8). They can be divided into the interneurones of
nal nerve to join this peduncle and unite with the spinocerebellar fibres the molecular layer, the stellate and basket cells, and the Golgi cells of
entering through the restiform body. the granular layer. All interneurones are inhibitory. Those of the mole
cular layer use GABA as their neurotransmitter. Most Golgi cells are
glycinergic. Stellate cells are located in the upper molecular layer, their
INTERNAL ORGANIZATION
axons terminating on Purkinje cell dendrites. Basket cells occupy the
deep molecular layer, their axons terminating on a series of Purkinje
The vast majority of cerebellar neuronal cell bodies are located within cells with baskets surrounding their somata, ending in a plume around
the outer, highly convoluted cortical layer. Beneath the cortex, the cere their initial axon. The dendrites of these interneurones and their axons
bellar white matter forms an extensive central core, from which a are oriented in the sagittal plane. Golgi cell dendrites are located in the


Cerebellum
336
3
NOITCeS
Climbing fibre Purkinje cell with collateral plexus Fig. 22.7 The circuitry of the cerebellar cortex.
Mossy fibre
Glutamatergic neurones are shown in dark grey,
GABAergic neurones in red and glycinergic
elements in blue. A, A transparent dorsal view of
the cortex showing the orientation of its major
elements. Dendrites of Purkinje, stellate and basket
Parallel fibre
cells, the collateral plexus of Purkinje cells, the cell
Granule cell bodies of the Lugaro cells, and the climbing fibres
P
Meningeal surface P and the axonal plexus of the Golgi cells are
molecular layer orientated in the sagittal plane. B, A transverse
P P
P section. Parallel fibres and the axons of the Lugaro
Golgi cell with cells are the only elements with a transverse
P
P axonal plexus orientation.
Sagittal plane
A
Lugaro cell
Basket cell Stellate cell
Parallel fibre
Molecular layer
Lugaro cell
Golgi cell
Purkinje cell layer
Unipolar brush cell
Granular layer
B
Climbing fibre Purkinje cell collateral Mossy fibre
Cerebellar nuclear Granule cell
neurones
GABAergic nucleo-olivary pathway
Inferior olive neurone
Cerebellar output system
granular and molecular layers. Their axonal plexus occupies the granu
lar layer, where it terminates on the granule cell dendrites, and also has
its greatest dimension in the sagittal plane (see Fig. 22.7). Golgi cells
are innervated by collaterals of mossy fibres and Purkinje cell axons.
The dendrites of interneurones in the molecular layer are contacted by
e the parallel fibres. Synaptic contacts between climbing fibres and the
dendrites or cell bodies of cerebellar interneurones in the molecular or
a
granular layers have not been observed. However, interneurones of the
n o d b molecular layer can be activated by ‘spillover’ of glutamate from the
climbing fibres (Galliano et al 2013, Szapiro and Barbour 2007). Golgi


n cells, therefore, provide feedback inhibition to the granule cells.
b
Interneurones of the molecular layer provide feedforward inhibition
g
to the Purkinje cells. Stellate cells (MannMetzer and Yarom 2000) and
f Golgi cells (Dugué et al 2009) are electrotonically coupled. The extent
of this coupling is not known; it may be restricted to the sagittal com
partments that are one of the main features of the connectivity of the
h cerebellum, discussed below.
Two other types of interneurone exist. Lugaro cells are cigarshaped
neurones located at the level of the Purkinje cells (Lainé and Axelrad
1996) (see Fig. 22.7). These glycinergic neurones innervate the stellate
p and basket cells, and provide a long, transversely orientated axon that
h terminates on Purkinje cells. They receive a strong input from an extra
j cerebellar serotoninergic system. Monopolar brush cells are excitatory
m C B j A neurones, mainly found in vestibulardominated regions of the cerebel
lum (Mugnaini et al 1997), where they are considered to be a ‘booster’
Fig. 22.8 A sagittal section through a cerebellar folium showing the
system for vestibular mossy fibre input. Mossy fibres terminate with
different cell types of the cerebellar cortex. Abbreviations: A, molecular
layer; a, Purkinje cell; B, granular layer; b, basket cells; C, white matter; extremely large synapses on the base (the ‘brush’) of these cells. Their
d, baskets of basket cell; e, stellate cell; f, Golgi cell; g, granule cell with axons terminate as mossy fibres on the granule cells.
ascending axon; h, mossy fibre; m, astrocyte; n, climbing fibre; o, Purkinje
cell axon with collaterals; j, p, Bergmann glial cells. (Redrawn from Cajal
CEREBELLAR NUCLEI
SR y. 1906 Histologie du système nerveux de l’homme et des vertebrés.
Maloine, Paris.)


The four cerebellar nuclei were first described by Stilling (1864) as
comprising (from medial to lateral) the fastigial nucleus, the emboli
form and globose nuclei, and the dentate nucleus (Fig. 22.10). The


Cerebellar circuitry
337
22
reTPAHC
Dendritic tree of one Golgi cell Fig. 22.9 The general organization of the
cerebellar cortex. A single folium has been
Granule cells
sectioned vertically, both in its longitudinal axis
Parallel fibres (right side of diagram) and transversely.
Molecular layer
Basket cell
Granule cell
Synaptic
glomerulus
Ramification of
Dendritic Golgi cell axon
tree of one in granular layer
Purkinje cell Climbing fibres
*
Axon of Mossy fibres
basket cell *
Climbing fibre
Axons of Purkinje cells
*
Recurrent collateral branches of Purkinje cell axons
Emboliform nucleus Fig. 22.10 The human cerebellar nuclei.
A–E, Transverse sections through the cerebellar
Dentate nucleus microgyric
Fastigial nucleus nuclei, A being the most rostral level. The dentate
nucleus can be subdivided into dorsomedial
microgyric and ventrocaudal macrogyric parts.
Globose nucleus
F, A Weigert-stained section through the dentate
A nucleus, showing its subdivision into micro- and
macrogyric parts. (A–E Redrawn from Larsell O,
Jansen J 1972 The comparative anatomy and
histology of the cerebellum. III. The human
cerebellum, cerebellar connections, and cerebellar
cortex. Minneapolis, University of Minnesota
Press. F, Reproduced with permission from
D
B Winkler C 1926 De bouw van het zenuwstelsel.
Dentate nucleus Haarlem, de erven Bohn.)
Dentate nucleus microgyric macrogyric
Globose nucleus
Emboliform nucleus
F
C E
Dentate nucleus macrogyric
emboliform and globose nuclei are also known as the anterior and 2011); as far as we know, all cell types receive an inhibitory input from
posterior interposed nuclei. The nuclei form two interconnected groups: Purkinje cells and an excitatory input from mossy and climbing fibre
a rostrolateral group consisting of the emboliform and dentate nuclei, collaterals.
and a caudomedial group including the fastigial and globose nuclei.


A collection of small, cholinergic neurones extends from the flocc
CEREBELLAR CIRCUITRY
ulus to the nodulus in the roof of the fourth ventricle, invading the
spaces between the nuclei. These cells are known as the basal interstitial
nucleus (Langer 1985); their connections are not known. The main circuitry of the cerebellum was described by Ramón y Cajal
The dentate nucleus is located most laterally and is by far the largest in the late nineteenth century and published in his Histologie du système
of the group. It has the shape of a crumpled purse; the main efferent nerveux (1906). It involves two extracerebellar afferent systems (climb
pathway of the cerebellum, the brachium conjunctivum, emerges from ing fibres and mossy fibres), intrinsic cortical neurones, including
its hilus. The convolutions of the dentate nucleus are narrow rostro Purkinje, granule, stellate and basket cells, and neurones in the cerebel
medially and much wider ventrocaudally. Interestingly, these micro lar nuclei (see Figs 22.7–22.9). The widely diverging mossy fibreparallel
and macrogyral characteristics of the human dentate were observed by fibre system terminates on Purkinje cells (the only output neurones of
Vicqd’Azir, who coined its name in the eighteenth century (Glickstein the cortex projecting to the cerebellar and vestibular nuclei); a climbing
et al 2009). Recently, rostromedial motor and ventrocaudal nonmotor fibre terminates on the proximal, smooth Purkinje cell dendrites; Golgi
divisions have been distinguished in the human dentate nucleus using cells provide backward inhibition to granule cells; and stellate and
fMRI (Küper et al 2012). Their significance and the possible correspond basket cells provide forward inhibition to Purkinje cells.
ence with the anatomical subdivisions of the dentate are considered Climbing fibres and most mossy fibres are excitatory and use gluta
below. mate as their neurotransmitter. All climbing fibres take their origin from
The cerebellar nuclei contain cells of all sizes. Glutamatergic relay the contralateral inferior olivary nucleus in the medulla oblongata. In


neurones provide the main output of the nuclei. Small GABAergic neu the cerebellum, they split into several branches, each branch providing
rones innervate the contralateral inferior olive. Both GABAergic and a climbing fibre to a single Purkinje cell. The branches of a single
glycinergic interneurones have been identified (Uusisaari and Knöpfel olivocerebellar fibre innervate one or more sagittally orientated strips


Cerebellum
338
3
NOITCeS
Molecular layer Fig. 22.11 The orientation and branching pattern
Simplex lobule of mossy and climbing fibres. Left-hand panels:
Simplex lobule mossy fibres are orientated transversely. They
Granular layer distribute bilaterally and emit collaterals at
Ansiform lobule specific, symmetrical locations. These collaterals
terminate as sagittally orientated aggregates
of mossy fibre terminals. Right-hand panels:
VII olivocerebellar fibres branch in the sagittal plane.
Each branch provides a Purkinje cell with a single
Pyramis climbing fibre. These climbing fibres form narrow,
longitudinally orientated strips that may
correspond to the microzones; strips of Purkinje
cells that share the same climbing fibre receptive
Uvula fields. Abbreviations: Py, pyramis; Uv, uvula.
(Reproduced with permission from Nieuwenhuys,
Anterior lobe R, Voogd J, van Huijzen 2008 The Human Nervous
Nodulus Nodulus System. 4th Ed Springer Verlag.)
Sagittal plane
Transverse plane
Anterior lobe
Simplex lobule
Ansiform
VII lobules
Py
Uv
Paramedian lobe
Mossy fibre Climbing fibre
of Purkinje cells (Fig. 22.11). These strips probably correspond to a subdivision of the contralateral inferior olive terminate on the
‘microzones’ consisting of a narrow strip of Purkinje cells innervated by Purkinje cells of a particular zone and also send a collateral innervation
climbing fibres sharing the same receptive field. Microzones, with their to the corresponding deep cerebellar nucleus. This collateral innerva
Purkinje cells, are considered to be the basic structural and functional tion is reciprocated by the, mainly crossed, nucleoolivary pathway that
unit of the cerebellar cortex (Andersson and Oscarsson 1978). originates from the small GABAergic neurones of the cerebellar nuclei.
Mossy fibres take their origin from multiple sources in the spinal Modules can be visualized because their Purkinje cell axons and their
cord and brainstem. Their myelinated axons terminate on the clawlike climbing fibre afferents collect in compartments in the cerebellar white


dendrites of the granule cells and on Golgi cells. The granule cells give matter. The borders between these compartments, i.e. between the
rise to an ascending axon that splits in the molecular layer into two modules, become visible when stained for acetylcholine esterase
parallel fibres that run for some distance in the direction of the long (AChE) (Fig. 22.12B). The modular organization of the cerebellum has
axis of the folia. Parallel fibres terminate on the spines of the spiny been studied in most detail in rodents and carnivores, and has been
branches of the Purkinje cell dendritic tree and the dendrites of confirmed in nonhuman primates. For the human cerebellum,
interneurones that they meet along their course (see Figs 22.7, 22.9). evidence for its presence is mainly embryological.
The length of the parallel fibres in the human cerebellar cortex is not The modular organization of the cerebellum appears very early
known but the two branches probably do not exceed 10 mm. Like the during its development, long before the emergence of any of its trans
climbing fibres, mossy fibres branch profusely in the cerebellar white verse fissures. Purkinje cells, born in the ventricular matrix of the cere
matter (see Fig. 22.11). The parent fibres enter the cerebellum laterally bellar anlage, migrate to the meningeal surface, where they form a series
and run a transverse course to decussate in the cerebellar commissure. of mediolaterally arranged clusters (Korneliussen 1968, Kappel 1981).
During their course, they emit thin collaterals that enter the white During the later increase of the cerebellar surface in the rostrocaudal
matter of the lobules and terminate in multiple, longitudinally orien dimension, reflecting the proliferation of millions of granule cells in
tated and symmetrically distributed aggregates of mossy fibre terminals the transient external matrix (the external granular layer) (see Fig.
in the granular layer (Wu et al 1999). 22.15), the Purkinje cell clusters increase in length and thus are trans
The climbing fibre microzones and the subjacent mossy fibre aggre formed into Purkinje cell zones. The Purkinje cells become located in


gates have been found to share the same peripheral receptive fields in a monolayer and the original borders between the clusters are no longer
regions of the cerebellum receiving somatosensory information from visible. This mode of development has been studied in different species
the periphery (Ekerot and Larson 1980, Ekerot and Jörntell 2003). A and can also be recognized in the human fetal cerebellum. Purkinje cell
similar topographical relationship between microzones and mossy fibre clustering in the human does not differ from that in other species, with
terminal aggregates exists in other parts of the cerebellar cortex; their the exception of the immense size of the most lateral cluster, which is
common denominator remains unknown (Pijpers et al 2006). The sig clearly related to the anlage of the dentate nucleus (Fig. 22.13). This
nificance of such a topographical relationship is difficult to understand cluster develops into the D2 zone, the most lateral Purkinje cell zone,
because the parallel fibres would disperse a localized mossy fibre input responsible for the large size of the human cerebellar hemisphere.
over a wide, mediolateral region of the molecular layer. Different Eight or nine of the modules can be recognized in the cerebellum
hypotheses to explain this topographical relationship have been pro of subhuman primates and lower mammals (see Fig. 22.14A). Purkinje
posed, some of the more recent ones involving the interneurones of the cell zones differ in their climbing fibre afferents and their cerebellar or
cerebellar cortex, but the matter remains undecided (Ekerot and Jörntell vestibular target nucleus. Moreover, Purkinje cells of the different zones
2003, Barmack and Yakhnitsa 2011). differ in their immunohistochemical properties (Voogd and Ruigrok
2012). A Purkinje cellspecific antibody, known as ‘zebrin 2’, is distrib
uted in a pattern of zebrinpositive and zebrinnegative Purkinje cell
THE MODULAR ORGANIZATION OF THE
zones (Fig. 22.14D–E). This pattern has been shown to be congruent
CEREBELLUM AND THE CORTICONUCLEAR AND


with the olivocerebellar and corticonuclear projection zones (Voogd
OLIVOCEREBELLAR PROJECTIONS et al 2003, Sugihara and Shinoda 2004). Many substances, such as
the enzymes aldolase C, 5′ nucleotidase, protein kinase C and the
The output of the cerebellum is organized as a series of parallel, sagittal metabotropic glutamate transporter 1A, colocalize with zebrin 2. Neu
modules (Voogd and Bigaré 1980, Voogd and Ruigrok 2012). Each rotransmission in different Purkinje cell zones may therefore differ:
module consists of one or more longitudinal Purkinje cell zones that zebrinpositive Purkinje cells fire at a slower rate than the zebrin
project to one of the cerebellar or vestibular nuclei (Fig. 22.12A). Some negative cells (Zhou et al 2014).
of these Purkinje cell zones are restricted to certain lobules; others span In the following, the olivocerebellar climbing fibre and the efferent
the entire rostrocaudal length of the cerebellum. Climbing fibres from corticonuclear projections of the Purkinje cell zones will be described.


Cerebellar circuitry
339
22
reTPAHC
e
c
ell zone
nj
ki
ur
P
Inferior olive with
climbing fibres
C3 C2 C1 B A
D
Posterior lobule
Purkinje cell
EGL Primary fissure
Cerebellar nucleus
A Reciprocal
nucleo-olivary Anterior lobule
pathways
1mm
Fig. 22.13 A transverse section through the cerebellum of a 65 mm
human fetus, showing the Purkinje cell clusters that will develop into the
m A, B, C1–C3 and D Purkinje cell zones. Note the large size of the D
cluster. Abbreviations: EGL, external granular layer. (From the Schenk
C1 B X A collection of the Dept. of Pathology of the Erasmus Medical Center
C2 Rotterdam.)
C3
anterior and posterior cerebellum (see Fig. 22.14E). The C1, C3 and Y
zones project to the anterior interposed nucleus and receive their climb
ing fibre input from the rostral dorsal accessory olive (DAOr) (Fig.
22.16). This subnucleus receives an input from peripheral receptors
through dorsal column and trigeminal pathways. The climbing fibre
projections of the rostral dorsal accessory olive to the C1, C3 and Y
B zones and the anterior interposed nucleus are somatotopically organ
ized. In each of the zones, the hindlimb is represented rostrally in the
Fig. 22.12 A, A cerebellar module. Purkinje cell axons and climbing fibres
anterior cerebellum and caudally in the posterior lobe; the forelimb
are located in a white matter compartment, shown as a transparent
and face occupy more central areas (Ekerot and Larson 1979) (see Fig.
structure in this diagram. B, An acetylcholinesterase-stained section
22.16). This rostrocaudal distribution clearly differs from the medi
through the anterior lobe: macaque monkey. The borders of the white
olateral somatotopy in the vermal B zone. The somatotopical localiza
matter compartments of the modules A–C are heavily stained.


Abbreviations: m, midline. tion is an extremely detailed one, repeated in each of the zones. The
C1, C3 and Y zones connect with motor centres in the brainstem and
the cerebral cortex. The hemisphere of the anterior lobe and the simplex
lobule, and the paramedian lobule (HVIIB – the gracile lobule, and
Data are from experimental studies in the cat, the rat and subhuman HVIII – the biventral lobule) are considered as the motor regions of the
primates (reviewed in Voogd and Ruigrok (2012)). The subdivision of cerebellum.
the inferior olive, the sole source of the climbing fibres, is summarized The C2, D1 and D2 zones extend beyond the anterior and posterior
in Figure 22.15. motor regions, where they interdigitate with the C1, C3 and Y zones,
The A zone is located next to the midline and extends over the entire over most of the rostrocaudal length of the cerebellum. In rodents, these
vermis (see Fig. 22.14A). It is composed of several zebrinpositive and zones are zebrinpositive. The C2 zone projects to the posterior inter
zebrinnegative subzones that may be present over limited segments of posed nucleus and receives its climbing fibre input from the rostral
its extent. It projects to the fastigial and vestibular nuclei, and receives medial accessory olive (see Fig. 22.18). A somatotopical organization
its climbing fibres from the caudal medial accessory olive. Whereas the is lacking in the C2 zone. The D1 and D2 zones project to the caudal
A zone extends over the entire vermis, the X and B zones are restricted and rostral dentate and receive their climbing fibres from the ventral
to the vermis of the anterior lobe, the simplex lobule (VI) and lobule and dorsal laminae of the principal olive, respectively. The main con
VIII (the pyramis). The narrow X zone separates the A zone from the B nections of the C2 and the D zones are with the cerebral cortex. The
zone, which occupies the lateral vermis of these lobules. The X zone sections of the C2 and D2 zones located in the anterior and posterior


projects to the interstitial cell groups, located between the fastigial and motor regions of the cerebellar hemisphere are connected with motor,
posterior interposed nuclei and receives climbing fibres from the inter premotor and parietal cortical areas; these sections of the D2 zone are
mediate region of the medial accessory olive. The B zone projects to somatotopically organized. Sections of the C2 and the D zones located
Deiters’ lateral vestibular nucleus and is innervated by climbing fibres in the ansiform lobule (HVII) and the paraflocculus (the tonsil, HIX)
from the caudal part of the dorsal accessory olive. The dorsal accessory subserve visuomotor and nonmotor functions.
olive, the B zone and the lateral vestibular nucleus are somatotopically The modular organization of the vestibulocerebellum is fairly
organized. In the B zone, the hindlimb is represented laterally and the complex; multiple Purkinje cell zones, innervated by climbing fibres
forelimb is represented medially (Andersson and Oscarsson 1978). In from subnuclei in the inferior olive, transmit optokinetic and vestibular
rodents, Purkinje cells of the X and B zones are zebrinnegative. information.
The hemisphere is composed of the C1–C3 and the D1, Y and D2 Each lobule of the cerebellum contains a particular set of Purkinje
zones. Like the X and B zones, C1, C3 and the Y are restricted to the cell zones. Apart from the parallel fibres, which may cross several
anterior lobe, the simplex lobule (HVI) and the paramedian lobule Purkinje cell zones or microzones in their course through the molecular
(HVIIB – the gracile lobule, and HVIII – the biventral lobule). Moreover, layer, there is no crosstalk between the modules. Parallel fibres are,
the Purkinje cells of these zones are zebrinnegative and thus appear as therefore, a key element in the integrative function of the cerebellum.
blank spaces in suitably immunostained histological sections of the The relative independence of the cerebellar modules is an important


Cerebellum
340
3
NOITCeS
A X
B
C1
C2
C3
D1
Anterior lobe
Y
I-V
D2 12 3 4 5 6
Simplex lobule
VI
Crus I
Crus II VII
Paramedian lobe
1 23 4 5 6 7
VIII
Dorsal
paraflocculus
IX
Ventral
paraflocculus
X
Flocculus
A D
Rostral dentate Emboliform nucleus
Fast
ICG
Globose nucleus
Caudal dentate
Cerebellar target M
Lateral vestibular nucleus nuclei
VII ANS
B
Vestibular nucleus
DAOr
Dmcc PY
POvL
MAOr
UV
MAOint VLO DAOc
POdL
Beta Dc 1mm PMD
MAOc
C Flattened right inferior olive E
Fig. 22.14 The connections of the Purkinje cell zones of the mammalian cerebellum. A, The flattened cerebellar cortex. B, Target nuclei of Purkinje cells.
C, Sources of climbing fibres associated with Purkinje cells, shown in the flattened contralateral inferior olive (see Fig. 22.15) and indicated in the same
colour. D, Zebrin-positive and zebrin-negative Purkinje cell bands. The zebrin-positive bands are numbered from 1 to 7. A comparison with panel A
shows that the A zone is a composite of zebrin-positive and zebrin-negative subzones; the X, B, C1, C3 and Y zones consist of zebrin-negative Purkinje
cells. E, The zebrin-positive and zebrin-negative bands of the cerebellum of a rat. Abbreviations: A–D2, Purkinje cell zones A–D2; ANS, ansiform lobule;
Beta, group beta; DAOc/r, caudal/rostral dorsal accessory olive; Dc, dorsal cap; Dmcc, dorsomedial cell column; Fast, fastigial nucleus; ICG, interstitial
cell groups; M, midline, MAOc/int/r, caudal/intermediate/rostral medial accessory olive; PMD, paramedian lobule; POdL, dorsal lamina of the principal


olive; POvL, ventral lamina of the inferior olive; PY, pyramis (lobule VIII); UV, uvula (lobule IX); VII, vermal lobule VII; VLO, ventrolateral outgrowth.
difference between the cerebellum and the cerebral cortex, where dif fastigial nucleus, the interstitial cell groups and the lateral vestibular
ferent functional areas are intimately interconnected. nucleus, respectively (see Fig. 22.14). In all mammals, the fastigial
nucleus gives rise to the uncinate tract, which decussates in the cerebel
lar commissure, hooks around the brachium conjunctivum, and is
CONNECTIONS OF THE CEREBELLAR NUCLEI:
distributed to the vestibular nuclei and the medullary and pontine
RECIPROCAL ORGANIZATION OF THE
reticular formation. A branch of the uncinate tract ascends to the ipsi
CORTICO-OLIVARY SYSTEM lateral midbrain and thalamus. Projections to the cerebral cortex are
bilateral because the crossed ascending fibres of the uncinate fasciculus
The connections of the cerebellar nuclei with the brainstem, the thala subsequently recross in the thalamus. Their projection to the cerebral
mus and the spinal cord determine the sphere of influence of the cere cortex is incompletely known. The uncrossed, direct fastigiobulbar tract
bellar modules. The A, X and B zones of the vermis project to the passes along the lateral margin of the fourth ventricle. It is distributed


Cerebellar circuitry
341
22
reTPAHC
DAOc Motor cortex
POdL
MAOc
Dc
VLO
Beta
Beta C1 C3
Y
MAOr
1
2
POdL DAOr
POdL Thalamus
Dmcc DAOr
Dmcc
POvL
Emboliform nucleus
4 Magnocellular
3 red nucleus
Rostral
C1, C3 and
4 Y zones
POvL
Dmcc DAOr
POdL
3
Rostral DAO
MAOr
2 VLO
Beta DAOc
Rubrospinal tract
MAOc Dc
1
Pyramidal tract
Fig. 22.15 Transverse sections through the human inferior olive, section 1
being the most rostral. Lower panel: the flattened inferior olive showing
the levels of sections 1–4 in the upper panel. Note the large size of the
convoluted dorsal lamina of the principal olive (POdL), and the small Dorsal column
ventral lamina (POvL). Other abbreviations: Beta, group beta; DAOc/r, nuclei
caudal/rostral dorsal accessory olive; Dc, dorsal cap; Dmcc, dorsomedial Motor neurones
cell column; MAOc/r, caudal/rostral medial accessory olive; VLO,
ventrolateral outgrowth.
Fig. 22.16 The connections of the emboliform (anterior interposed)
to the vestibular nuclei and the reticular formation in a symmetrical nucleus. The entire system is somatotopically organized: this organization
manner that mirrors that of the uncinate tract (Batton et al 1977). is more detailed than indicated in the diagram. Abbreviations: rostral
The direct fastigiobulbar tract is an inhibitory, glycinergic system DAO, rostral dorsal accessory olive.
(Bagnall et al 2009). Small GABAergic neurones give rise to a nucleo
olivary pathway terminating in the contralateral caudal medial acces
sory olive.
The caudal pole of the fastigial nucleus receives its Purkinje cell proximal musculature, and in the oculomotor centres in the brainstem.


afferents from lobule VII (folium and tuber vermis). This lobule is also The skeletomotor and oculomotor functions are located in specific seg
known as the visual vermis because it is involved in the longterm ments of the vermis: skeletomotor functions in the anterior vermis and
adaptation of saccades and, possibly, in other eye movements. The posterior lobule VIII (pyramis) (the X and B zones are restricted to these
projections of the oculomotor region of the fastigial nucleus (Fig. lobules), and oculomotor functions in lobule VII. Caudalmost, lobule
22.17) are completely crossed. They terminate in the pontine para X (nodulus) belongs to the vestibulocerebellum and is considered
median reticular formation (the horizontal gaze centre), the superior below. Other functions, such as vegetative regulation, are subserved by
colliculus, the rostral interstitial nucleus of the medial longitudinal the vermis but have not been studied in detail.
fasciculus (the vertical gaze centre) and in the thalamic nuclei that may The anterior interposed (emboliform) nucleus is the target of the
include the frontal and parietal eye fields as their targets (Noda et al C1, C3 and Y zones. The detailed somatotopical organization of these
1990). The fastigial nucleus influences visceromotor systems via pro Purkinje cell zones is maintained in the anterior interposed nucleus,
jections of the vestibular nuclei and connections with the catechol where Purkinje cells of different zones, but with the same climbing fibre
aminergic nuclei of the brainstem and the hypothalamus (Zhu et al input from a particular region of the body, project to a common set of
2006). neurones (see Fig. 22.16). Ascending axons from the anterior inter
The projections of the interstitial cell groups located between the posed nucleus enter the brachium conjunctivum. This tract decussates
fastigial and posterior interposed nuclei, the target nucleus of the X at the border of the pons and the mesencephalon. The ascending
module, have not been studied in primates. In lower mammals, these branch enters and surrounds the magnocellular red nucleus and pro


neurones provide collaterals to the superior colliculus, thalamus and ceeds to the thalamus, from where the anterior interposed nucleus is
spinal cord (Bentivoglio and Kuypers 1982). connected with the contralateral primary motor cortex. The descending
The lateral vestibular nucleus (Deiters’ nucleus) is the target nucleus branch of the brachium conjunctivum terminates in the nucleus reticu
of the lateral vermal B zone. This nucleus might better be considered laris tegmenti pontis (reticular tegmental nucleus of the pons). The
as one of the cerebellar nuclei. It does not receive a primary input from entire system, including the magnocellular red nucleus and the primary
the labyrinth and, contrary to the other vestibular nuclei, receives a motor cortex and their efferent tracts, is somatotopically organized. A
collateral innervation from the climbing fibres innervating the B zone. nucleoolivary pathway from the anterior interposed nucleus terminates
It gives rise to the lateral vestibulospinal tract. Its nucleoolivary pathway in the rostral dorsal accessory olive.
targets the caudal dorsal accessory olive. The motor cortex and the magnocellular red nucleus give rise to the
The zones of the cerebellar vermis are in a position to affect neuro two main descending motor systems: the corticospinal (pyramidal)
transmission in the vestibulospinal and reticulospinal systems, bilat tract and the rubrospinal tract. Both of these tracts cross the midline,
erally controlling postural and vestibular reflexes of the axial and the former at the bulbospinal junction and the latter at its level of origin


Cerebellum
342
3
NOITCeS
(Fig. 22.18A). The nuclei at the mesodiencephalic junction give rise to
Thalamus
the ipsilaterally descending tegmental tracts that terminate in the infe
rior olive, forming reciprocally organized loops; the function of these
prominent recurrent loops has never been studied.
Vertical gaze
centre riMLF The posterior interposed (globose) nucleus projects to the nucleus
of Darkschewitsch and, via the thalamus, to most, if not all, cortical
Superior colliculus areas (Fig. 22.18B). Reciprocal connections of the cerebral cortex to the
nucleus of Darkschewitsch have been reported for most cortical areas.
Caudal The nucleus of Darkschewitsch gives rise to a recurrent climbing fibre
Horizontal gaze Lobule VII: visual vermis
loop to the C2 zone that consists of the medial tegmental tract and the
centre PPRF
rostral medial accessory olive. Motor and visual divisions can be distin
Ascending branch guished in this system. The segments of the C2 zone located in the
of uncinate tract anterior and posterior motor regions of the cerebellum and the rostro
medial posterior interposed nucleus receive input from the motor
cortex. Visual and prefrontal input dominates in segments located in
the ansiform lobule (HVII), the paraflocculus (HIX) and the flocculus
(HX). The nucleoolivary pathway from the posterior interposed nucleus
innervates the contralateral rostral medial accessory olive.
The rostral and caudal dentate nucleus give rise to different path
ways. Neurones of the caudal pole of the dentate nucleus are known to
be activated by eye movements (van Kan et al 1993). The caudal dentate
Fastigial
projects to a dorsomedial subnucleus of the parvocellular red nucleus,
nucleus
located medial to the fasciculus retroflexus (Fig. 22.18C). Its thalamo
Dentate cortical projections include the frontal and parietal eye fields, which are
nucleus reciprocally connected with the dorsomedial subnucleus. The latter
projects to the ventral lamina of the principal olive, which innervates


the D1 zone. Although fairly prominent in lower mammals, the ventral
Bc
lamina of the principal olive is represented by the narrow medial
Uncinate lamina of the human olive (see Fig. 22.15). This module, presumably,
tract is much reduced in the human cerebellum. Crossed nucleoolivary
pathways from the rostral and caudal dentate terminate in the dorsal
and ventral laminae of the principal olivary nucleus, respectively.
The rostral dentate includes the major part of the dentate nucleus.
In monkeys, it has been divided into rostromedial motor and ventro
caudal nonmotor portions (Strick et al 2009) (Fig. 22.18E). The motor
division is somatotopically organized, with the hindlimb represented
rostrally and the face more caudally; it receives projections from motor
Vestibular
nucleus Direct regions of the cerebellum. The caudal nonmotor portion receives its
Vestibulo- and fastigiobulbar corticonuclear projections from the ansiform lobule (HVII) and the
reticulospinal tracts Reticular formation tract paraflocculus (the tonsil, HIX). A similar subdivision of the dentate has
been proposed in humans (Küper et al 2012); it seems likely that these
divisions correspond with the rostromedial microgyric and ventrocau
Fig. 22.17 A transverse section through the cerebellum and medulla dal macrogyric regions of the human dentate (see Fig. 22.10).
oblongata, showing the symmetrical distribution of the crossed and The rostral dentate projects to the major, ventrolateral, portion of
uncrossed connections of the fastigial nucleus. The inset depicts a the parvocellular red nucleus. Its thalamocortical projections target the
sagittal section, showing the connections of the visual vermis (lobule VII) motor, premotor and posterior parietal cortices (Fig. 22.18D–E). Pro
with the caudal pole of the fastigial nucleus and its efferent pathways in
jections from the caudal dentate include the dorsal prefrontal cortex.