Physical Address
304 North Cardinal St.
Dorchester Center, MA 02124
Cerebellar Anatomy, Biochemistry, Physiology, and Plasticity
Introduction and Overview
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 as they relate to motor function and diseases affecting motor control. Understanding structures, pathways, circuits, and receptor systems will gain increasing importance to pediatric neurologists as insights are gained into disease pathophysiology and options for treatments emerge. The information in this chapter provides a context for understanding the development of motor control in healthy children as well as the failure to develop, or loos of, normal cerebellar function in conditions such as the ataxias, cerebellar structural malformation syndromes, and acquired cerebellar injuries (see Chapter 14 ). Involvement of cerebellar circuits in cognition and mood is not emphasized herein. Topics of anatomy of limited relevance to children, such as the circulatory system, are not discussed.
Pediatric neurologists encounter many challenges in the diagnosis and management of cerebellar disorders. First, in children, symptoms of cerebellar dysfunction emerge in the context of a developing motor system. The child is developing motor control of eye movements, muscles of speech, axial truncal muscles, and distal muscles. Clinical experience with the range of trajectories of typical development in healthy children is often vital for discerning pathology. Second, movement disorders in children are usually mixed. For example, diseases named for their ataxia may have prominent dystonia, and complicated spastic paraplegias may involve cerebellum and basal ganglia. This chapter will review some emerging information about why this occurs. Third, in the presence of epilepsy, cognitive dysfunction, or behavior problems, medications may be prescribed that precipitate, exacerbate, or cause cerebellar dysfunction. These issues are addressed more specifically in the chapters on the relevant disease phenomenologies.
The goal of this chapter is to provide a clinically relevant overview. For more comprehensive descriptions of emerging neuroscience and techniques that are producing insights, readers are referred to a number of excellent reviews and technical papers.
Overview of Cerebellar Structure, Function, and Symptom Localization
This section addresses cerebellar structure, emphasizing systems important for motor control. Our present understanding of cerebellar structure and motor function has evolved over the last 100 years through painstaking clinical and pathologic observation and gross ablation and neurophysiologic studies in animals. More recently, insights from imaging studies have been augmented through experiments utilizing trans-neuronal virus tracers to identify cerebellar projections and loops to motor and nonmotor cerebral and basal ganglia nodes. Understanding the roles of specific cell types, synapses, and calcium flux in motor control and neuroplasticity has expanded due to electrophysiological recording and targeted mutations in rodent and primate models. , Combining ablation and optogenetic stimulation in animal models has allowed for a greater understanding of loss of motor control in cerebellar disease through characterizing the roles of specific cell types in deep cerebellar nuclei. ,
Increasingly, it has become possible to test and validate some of these relationships noninvasively in healthy (primarily adult) humans via cerebellar stimulation using transcranial magnetic stimulation (TMS; single pulse, paired pulse, or repetitive) and transcranial direct current stimulation (tDCS; anodal or cathodal). , Although many scientific questions remain, methods for more precise invasive stimulation of cerebellar cortex and deep cerebellar nuclei may be on the horizon as treatments for a variety of diseases affecting motor control. Collectively, these techniques will continue to advance our understanding of motor and nonmotor functions of the cerebellum and improve our therapeutics for diseases of the cerebellum.
The canonical view is that the cerebellum is an integral component of the motor system, integrating sensory input, supporting motor learning, and coordinating movements through utilization of models predicting the outcome of motor commands. Of particular recent interest is the testing of models to understand basic operations by which the cerebellum integrates sensory information to produce adaptive, controlled movements. , , Proprioceptive, visual, and tactile information are transmitted to cerebellum via afferent pathways, providing online feedback about movements. While critical for precise motor control and learning, the inherent delay of this feedback is problematic. Therefore, for certain types of tasks, precise motor control also relies on cerebellar “internal copies of motor commands,” implemented as “forward models” for more rapid online correction based on predicted movement outcomes. These models account for the necessary time interval between motor activities and the sensory feedback from these motor activities and function as an “estimate” of future motor positions in order to perform fast and accurate movements. Differences between predicted movement outcomes and actual movement outcomes, that is, error signals, generate calcium spikes in Purkinje cell dendrites. These signals, so-called complex spikes, over time induce plastic changes on upstream inputs from mossy fibers. The integration of sensory information and detected errors into updated internal models is “cerebellar dependent supervised motor learning.” A general model of motor commands, sensory input, model implementation and adaptation is shown in Fig. 2.1 .
Macroscopic to Microscopic Cerebellar Structure
The cerebellum contains more than half of all neurons in the central nervous system, with cerebellar granule cells outnumbering any other single type of neuron. Its organization is hierarchic and has been considered to be highly regular. Some recent evidence has emerged that the mammalian cerebellar cortex's cytoarchitecture contains microcircuits with differing properties, underlying functional variations in information processing. This section presents a simplified, hierarchical model of cerebellar anatomy, circuits, and neurotransmission as a basis for understanding the cerebellum's role in development of motor (and behavioral) control as well as how perturbations produce symptoms cerebellar diseases.
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 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 the cerebrum.
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 myelin develops 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 Fig. 2.2 and described in Table 2.1 .
Table 2.1
Lobes and Pathways in the Cerebellum
| Anatomic region | Structures | Input |
|---|---|---|
| Flocculonodular lobe | Flocculus—two small appendages inferiorly located Nodulus—inferior vermis |
Vestibular |
| Anterior lobes | A smaller region of the cerebellar hemispheres and vermis anterior to the primary cerebellar fissure | Spinal cord—spinocerebellar pathways |
| Posterior lobes | Largest, most lateral, and phylogenetically latest region of cerebellar hemispheres | Cerebrocortical, via pons |
The Three Cerebellar Functional Regions Connect to Three Deep Cerebellar Nuclei
At a gross structural level, it can be helpful to think about the motor control and signs of cerebellar disease 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 medial portion 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, localizing signs of cerebellar diseases is presented in Table 2.2 and Fig. 2.2 .
Table 2.2
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, rhythmical 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 Dysrhythmia of speech production Poor regulation of prosody. Slow, irregularly emphasized, that is, 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 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 physiological 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 Dysynergia/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 |
| Gait | |
| Anatomy | Vestibulocerebellum Spinocerebellum Cerebrocerebellum |
| Function | Maintenance of balance, posture, tone, ongoing monitoring of gait execution |
| Symptoms | Broad based, staggering gait |
The vestibulocerebellum, spinocerebellum, and cerebrocerebellum 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 cerebellar nuclei.
The deep cerebellar nuclei, arranged medially to laterally, are the fastigial, interposed, and dentate nuclei. The interposed nucleus consists of the globose (medial) and emboliform (lateral) nuclei. Anatomy, output nuclei, and function of these regions are described in Table 2.3 .
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 |
| Medial aspect of cerebellar hemispheres | Interposed (globose plus emboliform) nuclei | Motor control and execution, distal muscles | |
| Cerebrocerebellum | Lateral cerebellar hemispheres | Dentate nuclei | Planning, timing coordinated movements |
You're Reading a Preview
Become a Clinical Tree membership for Full access and enjoy Unlimited articles
If you are a member. Log in here