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Cerebellar Anatomy,
Biochemistry, and Physiology
Introduction
The objective of this chapter is to provide an overview
of the basic anatomic and functional organization of
the cerebellum and its inflow and outflow pathways
relevant to medical decision making in children. This
information provides a context for understanding the
symptoms of congenital, genetic, and acquired ataxias
and aids in making decisions about a diagnostic assessment, particularly in cases where the initial clinical presentation and neuroimaging findings are nonspecific.
Topics of more limited relevance to children, such as
the circulatory system, are omitted.
A number of challenges make diagnosis of cerebellar
disorders and diseases more difficult in pediatric movement disorders. First, in children these diagnoses are made
in the context of a developing motor system. Thus potentially abnormal findings must be judged in the context of
the broad limits of normal motor development. Second,
movement disorders in children are usually mixed, not
pure. Multiple symptoms, including both involuntary
movements from the basal ganglia and abnormal motor
control or coordination from the cerebellum, may be
involved in the same disease process. Third, in the presence
of epilepsy, cognitive dysfunction, or behavior problems,
medications may be prescribed that precipitate, exacerbate, or cause cerebellar (or basal ganglia) dysfunction.
This chapter provides merely an overview.
Overview of Cerebellar Structure,
Function, and Symptoms
Our present, incomplete understanding of cerebellar
function and disease has evolved over the last 100 years
through painstaking clinical and pathologic observation
and ablational studies in animals.1,2 Neuroimaging of
structure and function has vastly increased our understanding of the cerebellum in motor control, as well as
other functions. Neurophysiologic studies in animals
and humans continue to provide new information.
Genetic discoveries and the back-and-forth ­interplay
2
between human genetics and animal models may
eventually improve our therapeutics for these diseases.
The child’s cerebellar gray and white matter are
both developing, resulting in the child learning to
control eye movements, muscles of speech, axial
truncal muscles, and distal muscles.
At a gross structural level, one can think about the
spectrum of cerebellar signs in terms of the three functional divisions of the cerebellum: (1) the vestibulocerebellum, in the flocculonodular lobe, involved in axial
control and balance and positional reflexes; (2) the spinocerebellum, in the vermis and intermediate part of the
cerebellar hemispheres, involved in ongoing maintenance
of tone, execution, and control of axial and proximal
(vermis) and distal movements; and (3) the cerebrocerebellum, in the lateral part of the hemisphere, involved in
initiation, motor planning, and timing of coordinated
movements. Functional Anatomy of the Cerebellum
and Associated Signs are presented in Table 2-1.
Macroscopic to Microscopic
Cerebellar Structure
The cerebellum contains more than half of all neurons
in the central nervous system.3 Its organization is hierarchic and highly regular. Understanding a simplified
model of cerebellar neurotransmission and anatomy is
helpful for understanding management of diseases and
disorders causing ataxia. Understanding this system in
greater detail may be useful for making more challenging diagnostic and treatment decisions, as well as for
understanding the direction future research and treatments may take.
Cerebellar Structural “Threes”
Heuristically, three is a helpful mnemonic for remembering cerebellar anatomy. The cerebellum has three major
anatomic components that may be affected by focal
pathologic processes; three major functional regions
that correspond moderately to these ­components and
9
10
Section 1 OVERVIEW
Table 2-1 Functional Anatomy of the Cerebellum
Eye Movements
Anatomy
Vestibulocerebellum
Vestibular system afferents to the cerebellar flocculus, paraflocculus, dorsal vermis
Function
Integration of both position and velocity information so that the eyes remain on target
Signs
Nystagmus—oscillatory, rhythmic movements of the eyes
Impairment with maintaining gaze
Difficulties with smooth visual pursuit
Undershooting (hypometria) or overshooting (hypermetria) of saccades
Speech
Anatomy
Spinocerebellum—vermis
Cerebrocerebellum
Sensory afferents from face
Corticocerebellar pathway afferents, via pons
Function
Ongoing monitoring, control of facial muscles
Signs
Dysarthria, imprecise production of consonant sounds (“ataxic dysarthria”)
Dysrhythmia of speech production
Poor regulation of prosody; slow, irregularly emphasized (i.e., scanning) speech
Trunk Movements
Anatomy
Vestibulocerebellum
Spinocerebellum
Sensory, vestibular, and proprioceptive afferents
Function
Integration of head and body position information to stabilize trunk and head
Signs
Unsteadiness while standing or sitting, compensatory actions such as use of visual input or
stabilization with hands
Titubation—characteristic bobbing of the head and trunk
Limb Movements
Anatomy
Spinocerebellum
Cerebrocerebellum
Sensory and proprioceptive afferents to the spinocerebellum
Corticocerebellar pathway afferents via pons
Function
Integration of input from above—cortical motor areas—about intended commands allows for
control of muscle tone in the execution of ongoing movement
The spinocerebellum monitors and regulates ongoing muscle activity to compensate for small
changes in load during activity and to dampen physiologic oscillation
The cerebrocerebellar pathway input contains information about intended movement
Signs
Hypotonia—diminished resistance to passive limb displacement
Rebound—delay in response to rapid imposed movements and overshoot
Pendular reflexes
Imprecise targeting of rapid distal limb movements
Delays in initiating movement
Intention tremor—tremor at the end of movement seen on finger-to-nose and
heel-to-shin testing
Dyssynergia/asynergia—decomposition of normal, coordinated execution of movement—errors
in the relative timing of components of complex multijoint movements
Difficulties with spatial coordination of hand and fine fractionated finger movements
Dysdiadochokinesia—errors in rate and regularity of movements, including alternating
movements; the terms asynergia or dyssynergia refer to the inability to coordinate voluntary
movements
Chapter 2 Cerebellar Anatomy, Biochemistry, and Physiology
11
Table 2-1 Functional Anatomy of the Cerebellum—Cont’d
Gait
Anatomy
Vestibulocerebellum
Spinocerebellum
Cerebrocerebellum
Function
Maintenance of balance, posture, tone, ongoing monitoring of gait execution
Signs
Broad-based, staggering gait
subserve somewhat distinct functions; three sets of
paired peduncles that carry information into and out
of the cerebellum via the pons; three cortical cell layers
that interconnect via predominantly ­glutamatergic and
GABAergic signals; and three deep cerebellar output
nuclei that transmit cerebellar signal out to ascending
and descending tracts.
The Three Anatomic Regions—
Structures and Afferent Connections
The cerebellum has surface gray matter, medullary
white matter, and deep gray matter nuclei. Analogous
to cerebral gyri and sulci, folia make up the surface
of the cerebellum. Beneath the folia, the white matter myelinates during childhood and is susceptible
to a wide variety of diseases affecting white matter.
Innermost are the deep cerebellar nuclei.
The clefts between folia run transversely, demarcating
the three main anatomic regions, the flocculonodular,
anterior, and posterior lobes, as shown in Figure 2-1
and described in Table 2-2.
The Three Cerebellar Functional Regions
Connect to Three Deep Cerebellar Nuclei
Decades of clinical observations, laboratory animal
ablation studies, and more recent imaging studies have
informed current views of the three functional regions
of the cerebellum. These regions subserve basic functions of execution and integration of information about
balance, body position and movement, and motor planning and timing. Output from these regions goes to the
deep nuclei. The deep cerebellar nuclei, arranged medially to laterally, are the fastigial, interposed, and dentate
nuclei, with the interposed consisting of two nuclei, the
globose and emboliform. Anatomy, output nuclei, and
function of these regions are described in Table 2-3.
The Three Cerebellar Peduncles
Three paired sets of peduncles carry fibers to and
from the cerebellum. Unlike the basal ganglia, the
cere­bellum has a direct connection to the spinal
cord. Cerebellar connections with the spinal cord
Hemisphere Vermis
Primary fissure
Anterior
lobe
Horizontal
fissure
Posterior
lobe
Posterior fissure
Flocculonodular
lobe
Flocculus
Nodulus
Figure 2-1. Schematic of the three lobes of the cerebellum
(anterior, posterior, flocculonodular) and three anatomic
regions (hemispheres, vermis, nodulus). (From Kandel:
Principles of neuroscience, ed 4. McGraw Hill Medical, 2000.)
Table 2-2 Lobes and Pathways in the
Cerebellum
Anatomic
Region
Structures
Input
Flocculonodular Flocculus—two
Vestibular
lobe
small appendages
inferiorly located
Nodulus—inferior
vermis
Anterior lobe
A smaller region
of the cerebellar
hemispheres and
vermis anterior
to the primary
cerebellar fissure
Spinal cord—
spinocerebellar
pathways
Posterior lobe
Largest, most
lateral, and
phylogenetically
latest region
of cerebellar
hemispheres
Cerebrocortical, via
pons
and body ­(spino­cerebellar) are ipsilateral. Cerebellar
connections with the cerebrum (cerebrocerebellar,
via dentate-rubral-­thalamic tract) are contralateral.
12
Section 1 OVERVIEW
Table 2-3 Summary of Cerebellar Structure and Function
Functional
Anatomic
Output Nuclei
Function
Vestibulocerebellum
Flocculonodular
Vestibular nuclei (medulla,
not cerebellum)
Balance, vestibular reflex,
axial control
Spinocerebellum
Vermis
Fastigial nuclei
Motor control and execution,
axial and proximal muscles
Cerebrocerebellum
Medial aspect of cerebellar Interposed (globose plus
hemispheres
emboliform) nuclei
Motor control and execution,
distal muscles
Lateral cerebellar
hemispheres
Planning, timing coordinated
movements
Dentate nuclei
That is, motor ­control of the right side of the body is controlled by the left cerebrum with the right cerebellum.
Connections from the cerebrum to the cerebellum, via
pons, ­therefore cross on entry and exit. Ascending connections from the spinal cord largely do not. Figure 2-2
shows a schema of the key pathways through the peduncles, and additional detail is provided in Table 2-4.
Types of Afferent Fibers
There are two distinct types of afferent fibers that carry
excitatory signals, predominantly via the inferior and
middle peduncles, into the cerebellum. These are the
mossy and climbing fibers, as shown in Table 2-5. Both
of these fiber types send a few collateral axons to the
deep cerebellar nuclei.
Corticopontine
fibers
Neurotransmitters in the Cerebellum
Understanding the neurotransmitter systems in basal ganglia
allows for more rational decisions about ­pharmacotherapy.
Superior cerebellar
peduncle
Cerebellum
Pons
Pontine
mossy
fibers
Middle
cerebellar
peduncle
To vestib.
nuclei
Dentate
Interposed
Fastigial
Inferior cerebellar
peduncle
The Three Layers of Cerebellar Cortex
Three layers make up the cerebellar cortex.4 A schema
of the predominant cells and their interactions is
shown in Figure 2-3, and additional detail about these
layers and their predominant cell types and functional
connections are shown in Table 2-6.
To thalamus and red nucleus
Climbing fibers
from inferior olive
Proprioceptive
information from
spinocerebellar tract
(mossy fibers)
Figure 2-2. Schematic of the three primary afferent (inferior
peduncles and, middle peduncles) and efferent (superior
peduncles) pathways of the cerebellum. (From Washington
University School of Medicine: Neuroscience tutorial. Basal
ganglia and cerebellum. Retrieved from http://thalamus.wustl.
edu/course/cerebell.html, 21 September 2009.) See Table 2-4.
Table 2-4 Cerebellar Peduncles, Fiber Bundles, and Deep Cerebellar Nuclei Targets
Peduncles
Afferent and Efferent Fibers
Inferior
Afferent fibers (to cerebellum) from multiple sources: the vestibular nerve, the inferior olivary nuclei,
the spinal cord (dorsal and rostral spinocerebellar, cuneocerebellar, and reticulocerebellar tracts)
Efferent fibers (from cerebellum): fastigiobulbar tract projecting to vestibular nuclei, completing a
vestibular circuit
Middle
Afferent fibers: from pons (crossed fibers from cerebral cortex to pontine gray matter nuclei to
middle peduncle)
Superior
Afferent fibers: few fibers from ventral spinocerebellar, rostral spinocerebellar, and
trigeminocerebellar projections
Efferent fibers: rubral, thalamic, reticular projections from deep cerebellar nuclei—dentate,
interposed nuclei
Chapter 2 Cerebellar Anatomy, Biochemistry, and Physiology
At present, this is much less true in the cerebellum because
the main neurotransmitters in the cerebellum are glutamate and gamma-aminobutyric acid (GABA).5 There are
limited therapeutic options involving glutamatergic and
GABAergic systems for improving ataxia.
Glutamate
Glutamate, the main excitatory neurotransmitter in
the brain, acts at both ionotropic and metabotropic
Table 2-5 Functional Anatomy of Mossy
and Climbing Fibers
Mossy fibers— Excitatory, originating from
the primary
multiple brainstem nuclei and
afferents
spinocerebellar tracts, synapse
at the granule cells, carry tactile
and proprioceptive information
Climbing
fibers—
afferent
Excitatory, originating from the
inferior olivary nucleus in the
cerebellum, climb up to the outer,
molecular layer and synapse on the
soma and dendrites of the Purkinje
cells; carry information critical for
error correction
Purkinje cell
Parallel fiber
receptors. The ionotropic glutamate receptors are a diverse
group classified into three types—AMPA (alpha-amino3-hydroxy-5-methyl-4-isoxazolepropionic acid), NMDA
(N-methyl-d-aspartic acid), and kainate. These are
ligand-gated ion channels, meaning that when glutamate
binds, charged ions pass through a channel in the receptor center. Both basket and stellate cells in the molecular
layer express presynaptic AMPA receptors, to which overflow glutamate from climbing fibers can bind.6
The metabotropic glutamate receptors, which are
G-protein–coupled receptors acting via second messengers, are expressed in a developmentally dependent
fashion in the cerebellum,7 with mGluR1 receptors
playing a significant role in postsynaptic, Purkinje cell
signaling. Clinically, this is relevant in paraneoplastic
and autoimmune cerebellar diseases.8 For example,
mGluR1 antibodies, which can occur in Hodgkin’s
­disease, cause a combination of acute, chronic/plastic,
and degenerative effects in Purkinje cells.9
Glutamate Transporters
Glutamate transporters are important for glutamatergic
neurotransmission, as well as excitatory neuro­pathology.
Excitatory amino acid transporters (EAAT) 1, 2, and 3
Parallel
fiber
Purkinje cell
+
Molecular
layer
Purkinje
cell layer
Granular
layer
+
Molecular
layer
+
+
+
Purkinje
cell layer
Purkinje
cell
+
Granule
cell
Climbing
fiber
Mossy
fiber
Granule
cell
Stellate
cell Basket Climbing
cell
fiber
Purkinje
cell axon
Mossy
fiber
Golgi cell
13
Cerebellar −
nuclear
cell
Granular
layer
+
+
To thalamus
and descending
motor tracts
From
inferior
olive
From brainstem
nuclei and spinal cord
Figure 2-3. Schematic of the three primary cell layers (granular, molecular, and Purkinje) of the cerebellum. (From Apps R,
Garwicz M: Anatomical and physiological foundations of cerebellar information processing, Nature Rev Neurosci
6:297–311, 2005.)
14
Section 1 OVERVIEW
Table 2-6 Cerebellar Layers, Cell Types, and Function
Layer
Cells
Innermost—granular cell Granule cells
layer
Outermost—molecular
layer
Middle—Purkinje
cell layer
Input/Output and Function
Densely packed granule cells receive excitatory input from
ascending mossy fibers. Granule cells are the only excitatory
cells within the cerebellum. Axons ascend toward outer,
molecular layer where they synapse and form parallel fibers.
Golgi cells
Receive excitatory, glutamatergic26 input from granule cells and
provide negative GABAergic feedback to granule cells. Receive
glycinergic and GABAergic input from the Lugaro cells.27
Lugaro cells
Low prevalence interneurons, receive serotonergic input.19
Inhibit golgi cells.
Parallel fibers
These are the bifurcated axons from granule cell layers. They
have excitatory synapses directly on Purkinje cell dendrites
and on stellate and basket interneurons.
Stellate and basket
cells
Excited by glutamatergic input from parallel fibers from granule
cells. Output inhibitory on Purkinje cells.
Purkinje cells
These cells have extensive dendrites in the molecular layer.
Cell bodies are in a single layer. Output is inhibitory to deep
cerebellar nuclei.
are expressed in the motor cortex, but EAAT1 predominates in the cerebellum,10 where it is expressed in
Bergmann glial cell processes and is also known as the
glutamate aspartate transporter (GLAST). This plays
an important role in glutamate reuptake shortly after
synaptic release. Excitatory amino acid transporter 4
(EAAT4) is found on extrasynaptic regions of Purkinje
cell dendrites and reduces spillover of glutamate to
adjacent synapses.11 Colocalization of these transporters with perisynaptic mGluR1 receptors results in competition for glutamate, and this interaction modulates
neuroplasticity in the cerebellum.12,13
Gamma-Aminobutyric Acid (GABA)
GABA is the major inhibitory neurotransmitter in the
cerebellum, as well as the cerebrum. Its synthesis from
glutamate is catalyzed by the enzyme glutamic acid
decarboxylase (GAD). Anti-GAD antibodies have been
reported in adults with ataxia.14 GABA acts via chloride channels to hyperpolarize neurons. GABA receptors include GABA-A and GABA-C receptors, which
are ionotropic, and GABA-B receptors, which are
metabotropic, G-protein–coupled receptors. GABA-A
receptors also have allosteric binding sites for other compounds including barbiturates, ethanol, neurosteroids,
and picrotoxin. Baclofen is a GABA-B agonist.
GABA-A receptors are predominantly in the granule cell layer,15 where they receive GABA input from
the Golgi cells, and to a lesser extent they are present
on the molecular layer interneurons, the basket and
stellate cells.16 GABA-B receptors are predominantly
in the molecular layer.17 Ethanol affects cerebellar
­function via GABA-a receptor binding, but may also
suppress responses in Purkinje cells to mGluR1 excitation from climbing fibers.18
Acetylcholine, Dopamine,
Norepinephrine, and Serotonin
Acetylcholine, dopamine, norepinephrine, and serotonin19 and their receptors occur in the cerebellum.
However, the clinical effects of these neurotransmitter
systems in the cerebellum are poorly understood and at
this time seem not to be very helpful for ataxia. In general, the medications physicians use to suppress or modify
movement disorders, or to improve mood or cognition,
do not improve or worsen ataxia. Recognition, in mixed
movement disorders, of the cerebellar ataxia component can help with realistic assessment of the probable
­benefits of pharmacologic interventions. For example,
in mixed dystonia and ataxia, the dystonia may respond
to anticholinergics but cerebellar symptoms will not.
Endocannabinoids
Another important neurotransmitter system in the cerebellum is the endocannabinoid (endogenous cannabinoid) system.20,21 This system is involved in so-called
retrograde signaling in the hippocampus, basal ganglia,
and cerebellum, whereby postsynaptic neurons release
endocannabinoids from their dendrites. These endocannabinoids bind to cannabinoid receptor 1 (CB1)
on the presynaptic terminal, resulting in a transient
suppression of presynaptic neurotransmitter release.
Chapter 2 Cerebellar Anatomy, Biochemistry, and Physiology
Activation, on Purkinje cells, of metabotropic glutamate
receptors subtype 1 (mGluR1) reduces neurotransmitter
release from excitatory climbing fibers via this system.
In addition, it has recently been shown that GABAergic
basket and stellate cells, in the molecular layer, regulate
presynaptic neurotransmission from excitatory parallel
fibers, from the granule cells. This system is also
involved in cerebellar neuroplasticity22,23 and may
thereby affect cerebellar contribution to learning. The
significance of pathology within this system in children
is currently unknown, although both active marijuana
use and the exposure to cannabis prenatally may have
adverse cognitive effects involving the cerebellum.24,25
Conclusion
This overview of cerebellar function provides a framework for understanding cerebellar disorders and
diseases, including mixed movement disorders that
involve cerebellar function.
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