Cerebellum
For assistance with anatomical location terms, see Anatomical terms of location
The cerebellum ("little brain") is a brain region important for the integration of sensory perception with motor output. The numerous loops within and through the cerebellum with the motor cortex and spinocerebellar tracts indicate that the cerebellum is as an integrative region of which the purpose is to modulate function. Lesions of the cerebellum cause not paralysis but feedback deficits, manifesting as disorders in fine movement, equilibrium, posture, and motor learning. The cerebellum is thought to play a role in certain cognitive functions, including attention, the processing of language and music, and other sensory temporal stimuli.
General features
The Cerebellum is located in the inferior posterior portion of the head (the hindbrain), directly dorsal to the brainstem and pons, inferior to the occipital lobe (Figs. 1 and 3). Because of its large number of tiny granule cells, the cerebellum contains nearly 80% of all neurons in the brain. despite constituting only 10% of the total brain volume. The cerebellum receives nearly 200 million input fibers (in contrast, the optic nerve comprises a mere one million fibers).
The cerebellum is divided into two large hemispheres, much like the cerebrum, and contains ten smaller lobules. The cytoarchitecture (cellular organization) of the cerebellum is highly uniform, with connections organized into a rough, three-dimensional array of perpendicular circuit elements. The circuits in the cerebellar cortex look similar across all classes of vertebrates, including fish, reptiles, birds, and mammals (See for example Fig. 2). This has been taken as evidence that the cerebellum performs an evolutionarily primitive function important to all vertebrate [[species.
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Development and evolution
During the early stages of embryonic development, the brain starts to form in three distinct segments: the prosencephalon, mesencephalon, and rhombencephalon. The rhombencephalon is the most caudal segment of the embryonic brain; it is from this segment that the cerebellum develops. Along this embryonic rhombencephalic segment develop eight swellings, called rhombomeres. The cerebellum arises from two rhombomeres located in the alar (dorsal, or upper) plate of the neural tube—a structure that eventually forms the brain. The specific rhombomeres from which the cerebellum forms are rhombomere 1 (Rh.1) caudally (near the tail) and the "isthmus" rostrally (near the front) (Muller & O'Rahilly R, 1990).
The organization of the neural tube is such that the alar plate usually gives rise to structures involved in sensory functions, while the basal (ventral, or lower) plate gives rise to motor functioning structures. Given its alar plate origins, the cerebellum would be expected to be devoted primarily to sensory functions, however, it is primarily associated with motor functions. This is yet another of many of the great ironies of the “little brain”.
Two primary regions are thought to give rise to neurons that make up the cerebellum. The first region is the ventricular zone located in the roof of the fourth ventricle. This area produces Purkinje cells and deep cerebellar nuclear neurons. These cells are the primary output neurons of the cerebellar cortex and cerebellum (respectively). The second germinal zone (cellular birthplace) is known as the external granular layer. This layer of cells—found on the exterior the cerebellum—produces the granule neurons. Once born, the granule neurons migrate from this exterior layer to form the inner layer known as the internal granule layer. Once the cerebellum has reached maturity, the external granular layer ceases to exist, leaving only granule cells in the internal granule layer. The cerebellar white matter may be a third germinal zone in the cerebellum; however its function as a germinal zone is controversial.
The cerebellum is of archipalliar phylogenetic origin, meaning that it is one of the most evolutionarily primitive brain regions. The circuits in the cerebellar cortex look similar across all classes of vertebrates, including fish, reptiles, birds, and mammals. This has been taken as evidence that the cerebellum performs functions important to all vertebrate species.
Anatomy
The cerebellum contains similar grey and white matter divisions as the cortex. Embedded within the white matter—known as the arbor vitae (Tree of Life) in the cerebellum due to its branched, treelike appearance—are four deep cerebellar nuclei. Three gross phylogenetic segments are largely grouped by general function. The three cortical layers contain various cellular types that often create various feedback and feedforward loops. Oxygenated blood is supplied by three arterial branches off the basilar and vertebral arteries.
Divisions
There are three phylogenetic divisions within the cerebellum: the flocculonodular, anterior, and posterior lobes (Fig. 3). These three regions are also called the archicerebellum, paleocerebellum, and neocerebellum, respectively, terms that more clearly reflect the method of dividing the lobes by their evolutionary age. The archicerebellum represents the oldest evolutionary cerebellar structure and the neocerebellum represents the most recently evolved region.
These divisions are divided from the front to the back of the cerebellum; starting with the flocculonodular lobe in the front, and ending with the posterior lobe in the back. The anterior and posterior lobes are separated by the primary fissure. The posterior and flocculonodular lobes are separated by the posterolateral fissure (Fig. 4).
The cerebellum can also be divided by function rather than evolutionary age. This method results in three functional divisions that run perpendicular to the previously mentioned phylogenetic divisions. Rather than running from front to back, like the phylogenetic divisions, the functional regions align from the midline outwards toward the sides of the body.
The midline division is called the medial zone, also known as the cerebellar vermis (“worm”) due to its long, slender shape; the vermis is further subdivided into smaller regions called lobules. The region just lateral (away from the center) of the vermis is called the intermediate zone; the most lateral, outside region is the lateral zone (Fig. 4).
Much of what is understood about the functions of the cerebellum stems from careful documentation of the effects of focal lesions in human patients who have suffered from injury or disease or through animal lesion research. For more specific details of the effect of cerebellar lesions or damage, see "Dysfunctions" below.
The phylogenetic division
Archicerebellum
The archicerebellum is associated with the flocculonodular lobe and is mainly involved in vestibular and eye movement functions. It receives input from the inferior and medial vestibular nuclei and sends fibers back to the vestibular nuclei, creating a feedback loop that allows for the constant maintenance of balance.
Paleocerebellum
The paleocerebellum controls proprioception (sense of body position) related to muscle tone (constant, partial muscle contraction that is important for maintenance of posture). The paleocerebellum receives its inputs from the posterior and anterior spinocerebellar tracts, which carry information about the position and forces acting on the legs. The paleocerebellum then sends axonal projections to the deep cerebellar nuclei.
Neocerebellum
The neocerebellum receives input from the pontocerebellar tract and projects to the deep cerebellar nuclei. The pontocerebellar tract originates at the pontine nuclei, which receive their input from the cerebral motor cortex. Thus, the neocerebellum is associated with motor control, specifically in coordinating fine finger movements (such as in typing).
The functional division
Vermis
The vermis receives its inputs mainly from the spinocerebellar tracts from the trunk of the body. These tracts carry information to the vermis regarding position and balance of the torso. The vermis sends projections to the fastigial nucleus of the cerebellum, which then sends output to the vestibular nuclei. The vestibular nuclei are structures important for the maintenance of balance.
Intermediate zone
The intermediate zone receives input from the corticopontocerebellar fibers originating from the motor cortex. These fibers carry a duplicate of the information that was sent from the motor cortex to the spine in order to effect a movement. The intermediate zone also receives sensory feedback from the muscles. These two streams of information are integrated by this region, allowing for feedback comparisons of what the muscles are supposed to be doing with what they are actually doing.
Lateral zone
The lateral zone receives input from the parietal cortex via pontocerebellar mossy fibers regarding location of the body in the world. The large numbers of feedback circuits allow for integration of this body position information with indications of muscle position, strength, and speed.
Deep nuclei
The four deep cerebellar nuclei are located in the center of the cerebellum, embedded within the white matter. These nuclei receive inhibitory ( GABAergic) inputs from Purkinje cells in the cerebellar cortex and excitatory ( glutamatergic) inputs from mossy fiber pathways; these nuclei constitute the sole output of the cerebellum.
The four nuclei are known as the dentate, emboliform, globose, and fastigial nuclei. An easy mnemonic device to remember these names and positions relative to their position from the midline is the phrase "Don't Eat Greasy Food", where each letter indicates the lateral to medial location within the cerebellar white matter. The nonhuman analogue of the emboliform and globose nuclei is a single, fused nucleus interpositus (interposed nucleus). The vestibular nuclei in the brainstem are analogous structures to the deep nuclei and receive inputs from the flocculonodular lobe of the cerebellum.
Cortical layers
The cerebellar cortex has three layers. From outer to inner layer they are the: molecular; Purkinje, and granular layers. In essence, the function of the cerebellar cortex is to modulate information flowing through the deep nuclei. The microcircuitry of the cerebellum is schematized in Figure 5. Mossy fibers and climbing fibers carry sensorimotor information into the deep nuclei, which in turn pass it on to various pre-motor areas regulating the gain and timing of motor actions. Mossy and climbing fibers also feed this information into the cerebellar cortex, which performs various computations, the end result of which is to regulate firing of the purkinje cell. Purkinje neurons feedback into the deep nuclei via a potent inhibitory synapse. This synapse will regulate how well mossy and climbing fibers activate the deep nuclei, and therefore controls the effect the cerebellum ultimately has on motor function. The synaptic strength of almost every synapse in the cerebellar cortex has been shown to undergo synaptic plasticity. This allows the circuitry of the cerebellar cortex to continuously adjust and fine-tune the output of the cerebellum, forming the basis of some types of motor learning and coordination. Each layer in the cerebellar cortex contains different cell types which make up this circuitry.
Granular layer
The innermost layer contains the cell bodies of two types of cells: the numerous and tiny granule cells as well as the larger Golgi cells.
Mossy fibers enter the granular layer from their main point of origin, the pontine nuclei. These fibers make excitatory synapses with the granule cells as well as the cells of the deep cerebellar nuclei. The granule cells send their axons — known as parallel fibers — up into the superficial molecular layer where they form hundreds of thousands of synapses with Purkinje cell dendrites.
Humans are estimated to have on the order of 1010 granule cells.
Golgi cells provide inhibitory feedback to granule cells, forming a synapse with the granule cell and sending an axon into the molecular layer.
Purkinje layer
The middle layer contains only one type of cell body — that of the large Purkinje cell. Purkinje cell dendrites are large arbors with hundreds of spiny branches reaching up into the molecular layer (Fig. 6). These dendritic arbors are flat — nearly all in plane — with neighboring Purkinje arbors in parallel planes. The parallel fibers from the granule cells run orthogonally through these arbors like a wire passing through many layers. Purkinje neurons are GABAergic and make inhibitory synapses onto the neurons of the deep cerebellar nuclei and vestibular nuclei in the brainstem.
Each Purkinje cell receives excitatory input from 100,000 to 200,000 parallel fibers. Parallel fibers are said to be responsible for simple spiking of the Purkinje cell.
Purkinje cells also receive input from the inferior olivary nucleus via climbing fibers. A good mnemonic to remember this interaction is the phrase “climb the olive tree”, given that climbing fibers originate from the inferior olive. Each Purkinje cell receives input from a single climbing fiber, in the form of a powerful excitatory signal. Climbing fiber inputs generate a complex excitatory postsynaptic response in the Purkinje neuron. These responses are known as complex spikes.
Molecular layer
This outermost layer of the cerebellar cortex is made up of two types of inhibitory interneurons: the stellate cells and the basket cells. It also contains the dendritic arbors of Purkinje neurons and parallel fiber tracts from the granule cells. Both stellate and basket cells form GABAergic — or inhibitory — synapses onto Purkinje dendrites.
Peduncles
Again the cerebellum follows the trend of “threes”, with three major input and output peduncles (fiber bundles). These are the superior (brachium conjunctivum), middle (brachium pontis), and inferior (restiform body) cerebellar peduncles.
There are three sources of input to the cerebellum in two categories consisting of mossy and climbing fibers. Mossy fibers originate either from pontine nuclei originating within the pons and carrying information from the contralateral cerebral cortex or from the spinocerebellar tract originating from the ipsilateral spinal cord.
The majority of the output from the cerebellum first synapses onto the deep cerebellar nuclei before exiting via the three peduncles. The most notable exception would be direct inhibition of the vestibular nuclei by Purkinje cells.
Superior cerebellar peduncle
The superior cerebellar peduncle contains both input and output pathways. The afferent fibers are mainly composed of fibers of the anterior spinocerebellar tract and are conveyed to the anterior cerebellar lobe. The majority of the efferent pathway sends fibers from the dentate nucleus to various midbrain structures including the red nucleus, ventrolateral nucleus of the thalamus, and the medulla.
Middle cerebellar peduncle
The middle cerebellar peduncle only carries afferent fibers originating at the pontine nuclei into the cerebellum. These fibers descend from the sensory and motor areas of the cerebral neocortex and make the middle cerebellar peduncle the largest of the three cerebellar peduncles.
Inferior cerebellar peduncle
The inferior cerebellar peduncle carries many different types of input and output fibers mainly concerned with integrating proprioceptive sensory input with motor vestibular functions such as balance and posture maintenance. Proprioceptive information from the body is carried to the cerebellum via the posterior spinocerebellar tract. This tract passes through the inferior cerebellar peduncle and synapses within the paleocerebellum. Vestibular information projects onto the archicerebellum. This peduncle also carries information directly from the Purkinje cells to the vestibular nuclei located in the dorsal brainstem, spanning between the pons and medulla.
Blood supply
Three arteries supply blood to the cerebellum (Fig. 7): the superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA), and posterior inferior cerebellar artery (PICA).
Superior cerebellar artery
The SCA branches off the lateral portion of the basilar artery just inferior to its bifurcation into the posterior cerebral artery. Here it wraps posteriorly around the pons (to which it also supplies blood) before reaching the cerebellum. The SCA supplies blood to most of the cerebellar cortex, the cerebellar nuclei, and the middle and superior cerebellar peduncles.
Anterior inferior cerebellar artery
The AICA branches off the lateral portion of the basilar artery just superior to junction of the vertebral arteries. From its origin it branches along the most inferior portion of the pons at the cerebellopontine angle before reaching the cerebellum. This artery supplies blood to the anterior portion of the inferior cerebellum as well as the facial (CN VII) and vestibulocochlear nerves (CN VIII).
Posterior inferior cerebellar artery
The PICA branches off the lateral portion of the vertebral arteries just inferior to their junction with the basilar artery. Before reaching the inferior surface of the cerebellum, PICA sends branches into the medulla supplying blood to several cranial nerve nuclei. In the cerebellum it supplies blood to the posterior inferior portion of the cerebellum, the inferior cerebellar peduncle, nucleus ambiguus, vagus motor nucleus, spinal trigeminal nucleus, solitary nucleus, and vestibulocochlear nuclei.
Obstruction of AICA can cause facial paresis, paralysis, and loss of sensation as well as hearing impairment.
Dysfunctions
Patients with cerebellar dysfunction have problems with walking, balance, and accurate hand and arm movements. Recent brain imaging studies (using fMRI) show that the cerebellum is important for language processing and selective attention. The cerebellum is thought to be deficient in neuropsychiatric disorders such as dyslexia and autism. It is also important in development of certain ataxias, including a form of cerebral palsy. Spinocerebellar ataxia patients suffer a degeneration of the cerebellum.
Lesions of the cerebellum
Patients with cerebellar lesions generally exhibit deficits during movement execution. For example, they show “intention tremors” — a tremor occurring only during movement rather than at rest (as seen in Parkinson’s Disease). Patients may also show dysmetria, which is an overestimation or underestimation of force. This results in overshoot or undershoot when reaching for a target. Another common sign of cerebellar damage is an inability to perform rapid alternating movements.
Alcohol abuse leads to degeneration of the anterior cerebellum which leads to a wide staggering gait but does not affect arm movements or speech. The anterior and medial aspects of the cerebellum represent information ipsilaterally, so damage to this region on one side affects the movement on the same side of the body. The posterior and lateral aspects of the cerebellum represent information bilaterally and damage to this region has been shown to impair sensory-motor adaptation, while leaving motor control unaffected.
In certain instances a patient will undergo a very focal lesion. Such localized lesions cause a wide variety of symptoms dependant upon their location within the cerebellum. One of the more striking is a lesion to the archicerebellum. Archicerebellar lesions cause motor symptoms not unlike those seen during intoxication: uncoordinated movements, swaying, unstable walking, and a wide gait. In the United States, patients suffering archicerebellar lesions carry identification cards written by their physicians that indicate the nature of their medical condition so as to avoid suspicion of public drunkenness by the police.
Lesions to the paleocerebellum will cause a severe disturbance in muscle tone and bodily posture resulting in weakness to the side of the body opposite the lesion. A neocerebllar lesion is associated with deficits in skilled voluntary movement, such as playing the piano as mentioned above.
A lesion to the intermediate zone causes problem with fine-tuning and correcting movements. A patient such a lesion who was holding their fingers in front of them would have a very difficult time touching those fingers together. A lesion to the lateral zone would have difficulties in controlling fine muscle movements and would exhibit symptoms much like a patient with an intermediate zone lesion.
Ischemia and thrombosis
An obstruction of the posterior inferior cerebellar artery (PICA syndrome) can cause a wide range of characteristic effects. There can be loss of sensation to the contralateral limbs due to inferior cerebellar peduncle as well as dizziness and nausea due to loss of blood to the nucleus ambiguus and vestibulocochlear nuclei.
Theories about cerebellar function
Two main theories address the function of the cerebellum. One claims that the cerebellum functions as a regulator of the “timing of movements”. This has emerged from studies of patients whose timed movements are disrupted (Ivry et al., 1988).
The other claims that the cerebellum operates as a learning machine, encoding information like a computer. This was first proposed by Marr and Albus in the early 1970s (Marr, 1969).
Like many controversies in biology, there is evidence supporting parts of both hypotheses. Studies of motor learning in the vestibulo-ocular reflex and eyeblink conditioning demonstrate that timing and amplitude of learned movements are encoded by the cerebellum (Boyden et al., 2004). Many synaptic plasticity mechanisms have been found throughout the cerebellum. The Marr-Albus model mostly attributes motor learning to a single plasticity mechanism, long-term depression of parallel fiber synapses.
With the advent of more sophisticated neuroimaging techniques such as positron emission tomography in the 1970s and fMRI in the 1990s, as well as more elegant behavioral and psychophysics designs, greatly divergent functions are now being at least in part attributed to the cerebellum. What was once thought to be primarily a motor/sensory integration region is now proving to be involved in many diverse cognitive functions. Paradoxically, despite the importance of this region and the heterogeneous role it plays in function, a person who has lost their entire cerebellum through disease, injury, or surgery can live a fairly normal, healthy life. In fact, many of the lesion symptoms described above disappear if the lesion occurs in both sides of the cerebellum, or if the cerebellum is removed entirely!
See also
External links
- A list of laboratories that do research on the cerebellum, around the world.
References
- Muller F, O'Rahilly R (1990) The human brain at stages 21-23, with particular reference to the cerebral cortical plate and to the development of the cerebellum. Anat Embryol (Berl) 182(4): 375-400
- Ivry RB, Keele SW, Diener HC (1988) Dissociation of the lateral and medial cerebellum in movement timing and movement execution. Exp Brain Res 73(1): 167-80
- Marr D (1969) A theory of cerebellar cortex. J Physiol 202(2): 437-70
- Boyden ES, Katoh A, Raymond JL (2004) Cerebellum-dependent learning: The role of multiple plasticity mechanisms. Annu Rev Neurosci 27: 581-609.
- Ito, M. Cerebellum and Neural Control.1984. Raven Press. ISBN 0890041067
- Eric Kandel, James Schwartz, and Thomas Jessel. 2000. Principles of Neural Science. 4th ed. McGraw-Hill, New York. ISBN 0838577016
- Parent, A., Carpenter, M.B. 1995. Carpenter's Human Neuroanatomy. 9th ed. Williams and Wilkins. ISBN 0683067524