CNS

Central Nervous System3rd year Medicine

Cerebellum & Basal Ganglia

Objectives:The students should be able to:

Outline the afferent and efferent connections of the cerebellum. Describe the neuronal circuits in the cerebellum . Identify and explain the role of the cerebellum as regard control of motor function. List and analyze the manifestations of neocerebellar syndrome. Outline the functional structure of the basal ganglia. Describe the cortical connections (circuits) with the basal ganglia. Identify the balance between different neurotransmitters in the basal ganglia. Explain the role of the basal ganglia as regard the control of motor function. Describe the pathophysiology and characteristics of Parkinson’s disease.

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The cerebellum is vital to the control of rapid muscular activities such a running, typing, playing the piano, and talking. Loss of cerebellar function causes incoordination of these activities.

Functional anatomy:From the functional point of view, the cerebellum is divided into 3 parts, it is organized along its longitudinal axis into 3 parts:

1- The vestibulocerebellum: which consists of the vermis nodulus and the flocculus on each side (flocculonodular lobe). This lobe is phylogenetically the oldest part of the cerebellum, it has vestibular connections, and is concerned with equilibrium. It is thus referred as archicerebellum.

2- Spinocerebellum: (Paleocerebellum): It consists of the intermediate zone of the cerebellar hemisphere., This region receives proprioceptive input from the body and a copy of the motor plan from the motor cortex. It is concerned with coordination of movement.

3- Cerebrocerebellum: (neocerebellum): It is the lateral portion of the cerebellar hemisphere. It is concerned with planning and programming of movements. It is connected mainly to the cerebral cortex.

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Functional parts of the cerebellum and body representation in it

The Functional structure of the cerebellum:

The cerebellum has an external layer of grey matter, which form the cerebellar cortex and an inner white matter. Located deep in the cerebellar mass are three deep nuclei, the dentate which lies most laterally, fastigial which lies most a medially and interpositus (globose and emboliform) between the fastigial and dentate nuclei.

The cerebellar cortex is made up of three layers:

1- An external molecular layer containing mainly interconnecting fibers.

2- An intermediate Purkinje cell layer containing the giant Purkinje cells, their axons are the only fibers that pass out of the cortex to the deep nuclei. They discharge inhibitory signals.

3- An internal granular layer containing the granule cells.N.B. The other 3 types of neurons in cerebellar cortex are inhibitory iterneurones.

Basket and stellate cells are located in the molecular layer, they are excited by the granule cells through parallel fibers. Their axons project to purkinje cells to inhibit them.

Golgi cells are located in the granular layer but their dendrites project to the molecular layer, they are excited by the granule cells through parallel fibers they also receive collaterals from mossy fibers. Their axons project to granule cells to inhibit them.

Granule cells release the excitatory transmitter glutamate while the other 4 cell

types release the inhibitory transmitter GABA.

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Cerebellar cortex, climbing and mossy fibers

Neuronal circuits in the cerebellum

All the afferent fibers enter the cerebellum through two main sources of inputs: a) Climbing fibers: They come from the inferior olive, they give off excitatory collaterals to the deep cerebellar nuclei and terminate on dendrites of Purkinje cells.

b) Mossy fibers: They constitute most of the incoming fibers to the cerebellum from multiple sources, the brain, the brain stem, and the spinal cord beside few fibers from the inferior olive.

These fibers send excitatory collaterals to the deep nuclei and they proceed to terminate on the granule cells, which in turn send signals to the giant Purkinje cells.

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•All the afferent fibers to the cerebellum terminate in the cortex. The cerebellar cortex sends inhibitory signals to deep nuclear cells through the Purkinje cells projection fibers.

• The deep cerebellar nuclei receive excitatory signals from both the mossy and climbing fibers, followed by inhibitory signals from the Purkinje cells. Normally, the balance between these two effects is in favor of excitation, so that the output from deep nuclear cells to the motor cortex and brain stem remains at a moderate level of excitation. - The entire cerebellar circuits seem to be concerned with modulation or timing of the excitatory output of deep cerebellar nuclei during muscle contraction.

- There are initial excitatory signals from deep cerebellar nuclei to help initiation of movement, followed by inhibitory signals to prevent overshooting.

N.B. Cerebellar circuits contain no reverberators, so their effects are transient.

Connections:

• All afferent fibers that reach the cerebellum go to deep nuclei and then to the cerebellar cortex.• All the efferent, which leave the cerebellum, originate from the deep nuclei.

Input pathways to the cerebellum:

1- Corticoponto cerebellar pathway: It originates mainly in the motor and premotor cortices and then passes to the pontile nuclei and then to the contralateral hemisphere of the cerebellum.

2- Olivocerebellar tract: Fibers originate from the inferior olive then to all parts of cerebellum. Inferior olive receives signals from the motor cortex, basal ganglia, reticular formation, and the spinal cord.

3-Vestibule cerebellar fibers: Fibers originate from the vestibular apparatus and the vestibular nuclei and terminate in the focculonodular lobe and fastigial nucleus. They transmit signals about body posture and equilibrium.

4- Reticulocerebellar fibers: They originate in reticular formation and terminate in the vermis.

5- Tecto cerebellar fibers: Transmit visual and auditory signals to the cerebellum.

6- Fibers from Cuneate and Gracil nuclei which transmit proprioceptive signals.

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7-Afferent pathway from the periphery; Signals from the periphery reach the cerebellum mainly through:

a) Direct pathway the dorsal and ventral spinocerebellar tracts.

They transmit signals from the muscle spindles, Golgi tendon organs, joint receptors, and tactile receptors to inform the cerebellum about momentary state of the position of limbs, muscle tension, rate of movements and forces acing on surface of the body.The spinocerebellar pathways transmit impulses at velocities of up 120 m/sec. The rapid conduction is important for appraisal of the cerebellum of the changes that take place in the periphery.

b) Cerebellum receives signals from the periphery indirectly through: - Spinoreticular pathway. - Spinoolivary pathway.

Afferent pathways into the cerebellum

Output Pathways from the Cerebellum:

- Efferent fibers from the cerebellum are axons of the deep nuclei:

1-From the vestibulocerebllum:Fibers originate in the vermis and pass from the fastigial nuclei to reticular formation and to the vestibular nuclei which then give origin to reticulospinal and vestibulospinal tracts. Thus this part is concerned with the control of equilibrium as it helps the control of movements in axial, neck, shoulders and hips muscles.

2- From the spinocerebellum:Fibers pass from the nucleus interpositus located in the medial part of the cerebellar hemisphere to

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a) The ventrolateral and ventoanterior nuclei of the thalamus and then to themotor areas of the cerebral cortex.b) The medial thalamic nuclei and then to the basal ganglia. c) The red nucleus and reticular formation:This circuit is important in the coordination of movements in muscles of the peripheral parts of limbs.

3-From the cerebrocerebellum:A pathway from the lateral zone of cerebellar hemisphere, passes to the dentate nucleus, to the ventrolateral and ventroanterior nuclei of the thalamus and finally to the cerebral cortex. This parts pathway is important in coordinating and planning sequential movements.

Cortico-ponto-cerebello-dentato-thalamo-cortical fibers

Overall function of the Cerebellum in Controlling Movements:

1) Control of posture and equilibrium:It is the function of the flocculondular lobe and part of the vermis. The cerebellum receives signals from the vestibular apparatus during rapid motions and sends output signals to the brain stem which in turn sends impulses through the retiuculospinal and vestibulospinal tracts for maintain equilibrium through changes in tone of axial and gridle muscles.

2) Effects on stretch reflexes: The neocerebellum is facilitatory to the stretch reflex, while the paleocerebellum is inhibitory to stretch reflex.

3) Control of voluntary movements: The cerebellum controls voluntary movements through the following functions:

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A) Servo Comparator function: The intermediate zone of cerebellum (spinocerebellum) receives input signals when movement is performed from:a- The motor cortex and red nucleus about the sequential intended plan of movement for the next few fractions of a second..

b- From the periphery through the spinocerebellar tracts, telling the cerebellum about the performance of movement.

c- The spinocerebellum then compares the intention of motor cortex with the actual movement performance.

d- The nucleus interpositus sends corrective signals to the:

1- Motor cortex which give rise to the corticospinal tract.2- To the red nucleus which give rise to the rubrospinal tract.• Both the corticospinal and rubrospinal terminate on the lateral motor neurons in the anterior horn of the spinal cord to control distal parts of the limbs.

e- The cerebellum provides turn-on of agonist muscle at the onset of the movement and inhibiting the antagonistic muscle. At the end of movement it provides turn-off the agonist and turn on of the antagonist muscles which is important during rapid movements as typing.

Servocomparator function of the cerebellum

B) Function of the cerebellum to prevent overshoot and damp movements:All movements of the body are pendular. When an arm is moved momentum develops and because of the momentum all movements have a tendency to over-shoot.The cerebellum sends signals to stop the movement at the intended point, thereby preventing the overshoot.

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C) Function of the cerebellum in sequencing and timing of movements:• The planning of sequential movements:The lateral part of the cerebellar hemispheres provides the plan of the rapid sequential movements, it is necessary to provide transition from movement to the next. It is important for the ability to progress smoothly from one movement to the next in an order of succession.

• The timing function:The lateral cerebellar hemispheres provide the timing for the start and termination for each movement. Without this timing capability one becomes unable to determine when the next movement should begin, and the succeeding movement may begin too early or too late. Therefore, cerebellar lesions cause complex movements as writing, running or talking to become incoordinate.

Clinical abnormalities of the cerebellum:Dysfunction of the cerebellum occurs by lesion of cerebellum that involves the deep cerebellar nuclei. Destruction of large parts of the cerebellar cortex only rarely causes abnormalities in motor function. For this reason care should be taken to avoid damaging the nuclei when surgical removal of the parts of the cerebellum is necessary.The effects of cerebellar dysfunction (syndrome) appear on the same side of the lesion. They are:

1) Hypotonia:There is marked decrease in muscle tone on the side of the lesion and tendon jerks are pendular e.g. when the knee jerk is elicited the legs oscillate up and down several times before it stops.

2) Asthenia:The patient feels muscle weakness because there is difficulty in maintain muscle contraction.

3) Ataxia:Ataxia is defined as incoordination of movement due to error in the rate, range, force and direction of movement.

Types of Ataxia: 1)- Sensory ataxia: discussed in sensory division of CNS.

2) Motor ataxia: • Cerebellar ataxia. • Lesion in motor cortex or vestibular system.

Cerebellar ataxia is manifested by:

a) Dysmetria:It is the inability to adjust the movements to a certain distance when attempting to touch an object with a finger, overshooting the intended point (hypermetria) or stoppage before the intended point (hypometria) result. Dysmetria is due o failure of damping and timing functions of the cerebellum. It is tested by the "finger nose test".

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b) Intention tremor (kinetic tremor):When a person performs a voluntary act, the movements oscillate back and forth at the intended point, because overshooting of the movement at the intended point cause the motor cortex to correct the overshooting by an opposite movement, which again overshoot to the other side. This continues until the movement finally settles to the intend mark. The intention tremor is absent at rest and it appears when the patient performs voluntary action.

c) Rebound phenomenon:It is an overshooting of a limb when a resistance to its movement is removed. Normally flexion of the forearm against resistance is checked when the resistance is broken off. The patient with cerebellar disease cannot stop movement of the limb and the forearm flies backward. It is due to inability to stop the movement.

d) Adiadokokinesia:It is the inability to perform rapid alternate opposite movements such as repeated pronation and supination of the hands. This is due to the failure of predictive and smooth progression function of the cerebellum.

Rebound phenomenon and adiadokinesia

e) Decomposition of movement:The patient has difficulty in performing simultaneous movements at more than one joint. They dissect the movements and carry them one joint at a time.

f) Dysarthena:There is difficulty in producing clear speech, due to failure of smooth progression and prediction of movements in muscles of larynx, mouth, and respiratory muscles. The

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volume of sound is not controlled, it is either loud or weak speech may be scanning or staccato speech.

h) Nystagmus:There is a tremor of the eyeballs, which occurs when one tries to fix an object to one side of the head.

i) Staggering gait:The patient walks on a wide base in an unsteady drunken, swaying manner and tends to fall on the diseased side. This is a manifestation of archicerebellum lesion.

The cerebellum and learning:The cerebellum is concerned with learned adjustments that make coordination easier when task is performed. Each Purkinje cell has only a single climbing fiber from the inferior olive, and this fibers makes 2000-3000 synapses on the Purkinje cell. Climbing fiber activity is increased when a new movement is being learned and selective lesions of the olivary complex abolish the ability to produce long term adjustment in certain motor responses.

N.B. The following table shows the differences between the 2 types of ataxia

Sensory ataxia Motor ataxiaMost common cause Tabes dorsalis Cerebellar disease

Gait High steppage (stamping) Staggering (drunken)

Romberg’s sign Positive Negative

Effect of vision Corrected by vision Not affected by vision

Deep sensations Impaired or lost Normal

Tremors Absent Kinetic tremors present

Nystagmus Absent Present

Speech Normal Scanning or staccato

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Basal ganglia

The basal ganglia are subcortical masses of gray matter that include the following nuclei:

1. The caudate nucleus.

2. The putamen.

3. The globus pallidus

The putamen and globus pallidus are called lentiform or lenticular nucleus.

The caudate and putamen are called corpus striatum.

Besides to 2 functionally related nuclei:

4. The subthalamic nucleus.

5. The substantia nigra in the midbrain.

Structure of the basal ganglia

Neuronal connections of the basal ganglia:

The main connections are:

(I) Cortical connections: These include 2 circuits:

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a)- Caudate circuit:

Fibers arise from the cortical association areas, motor, sensory, visual and auditory

association areas which integrate different information into thoughts, go to the caudate

nucleus, then to the internal globus pallidus. These fibers then relay at the thalamus and

finally end at the premotor and motor association area.

Caudate circuit

b)- Putamen circuit:

Fibers start from the premotor and motor association area, go to the putamen, to the

internal globus pallidus, to the thalamus, and finally end at the cortical motor area 4.

Putamen circuit through the basal ganglia.

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(II) Interconnections within the basal ganglia and main neurotransmitters:

Fibers from the striatum pass to subestantia nigra, they secret GABA.

Fibers from the striatum to globus pallidus, they secret GABA.

Fibers from substantia nigra to striatum, they secret dopamine.

Fibers from the cortex to the striatum, they secret acetyl choline.

NB.

There are also neurons that release glutamate, which together with acetylcholine

and norepinephrine are excitatory transmitters.

All the remaining transmitters are inhibitory.

The normal functions of the basal ganglia depend on the balance between excitatory

and inhibitory influences of various transmitters.

* The predominance of inhibitory neurons in the basal ganglia, specially the

GABA-neurons, makes the above circuits specially the putamen circuit , negative

feedback loops that inhibit excessive activity of the motor cortex thus stabilizing the

motor control system, and preventing excessive and undesirable movemens.

Neuronal connections within the basal ganglia

(III) Efferent pathways from the basal ganglia (brain stem connections):

The globus pallidus is the chief efferent pathway of the basal ganglia. Fibers from the

globus pallidus project to;

(a) Reticular formation.

(b) Red nucleus.

(c) Vestibular nucleus.

These signals are transmitted through reticulospinal, rubrospinal and vestibulospinal

tracts to the spinal motor neurons.

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Metabolic considerations:* The metabolic rate and oxygen consumption of the basal ganglia are normally high.

* In Wilson’s disease, there is lack of ceruloplasmin, a copper-binding protein

synthesized by the liver, so the free plasma copper level markedly increases. This leads

to excessive deposition of copper in the liver and lenticular nucleus resulting in its

damage.

* In infants, when the blood level of the bile pigments markedly increases, it cross the

blood brain barrier and deposit in the basal ganglia leading to neurological symptoms

(a condition called kernicterus).

Functions of the basal ganglia:

The basal ganglia play a very important role in control of motor functions:

1)- Control of motor activity:

-The caudate circuit is concerned with the cognitive control of motor activity, converting

thoughts into motor action as it helps in planning sequences of patterns of movements. It

is also responsible for timing of these patterns, i.e. they can occur rapidly or slowly and

responsible for scaling, i.e. one can write very small or very large letter.

-The putamen circuit helps in execution of the subconscious learned patterns of motor

activity as cutting with scissors or writing the alphabet.

- The basal ganglia are responsible for initiation of subconscious automatic movements

like swinging of the arms during walking.

- The basal ganglia produce postural adjustments to facilitate fine movements.

2)- Control of the muscle tone:

The lentiform nucleus decreases the muscle tone by stimulating the inhibitory reticular

formation.

On the other hand, the caudate nucleus increases the muscle tone by stimulating the

facilitatory reticular formation.

There is predominance of the inhibitory effect of the lentiform nucleus.

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Disease of the basal ganglia in human:

They roduce manifestations on the contralateral side of the body, and include the

following:

[1] Chorea:

Lesion in: striatum.

It occurs as a complication of a hereditary disease called Huntington’s chorea, or

rheumatic fever.

Mechanism: Chorea is due to damage of the corpus striatum, specially the caudate

nucleus, with degeneration of the GABA-ergic neurons, leading to loss of inhibition of

the substantia nigra, with interruption of the negative feed back loops from the basal

ganglia to the cortex.

Characters: * Involuntary dancing movements that occur suddenly during rest and may

superimpose voluntary movements.

*Hypotonia and pendular knee jerk, due to loss of the facilitatory effect of the

caudate nucleus on the stretch reflex.

[4] Parkinsonism: (Parkinson’s disease):

Lesion in: subbstantia nigra.

Mechanism: degeneration of the dopaminergic nigro-striatal fibers resulting in marked

reduction of the dopamine content in the basal ganglia and imbalance between excitation

and inhibition in it. The commonest cause is cerebral atherosclerosis occurring at old age.

Characters: there are hyperkinetic features, which are rigidity and tremors, and

hypokinetic feature which is akinesia:

(a) Muscle rigidity:

-Affected muscles: all muscles, particularly the flexor muscles so patients often acquire a

flexion attitude.

-Type: It is either a lead-pipe or cogwheel rigidity, and is usually associated with normal

tendon jerks.

-Mechanism: It is primarily an alpha rigidity due to decrease of dopamine which reduces

the inhibitory effect of the striatum on the cortical motor areas and the vestibular nucleus

(a release phenomenon), so excess excitatory signals to the alpha motor neurons are

discharged via the corticospinal and vestibulospinal tracts resulting in rigidity.

(b) Static tremors:

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-Tremors appear only during rest in the waking hours of the day, and disappear during

sleep and on doing voluntary movements.

They consist of fine involuntary rhythmic alternating contractions of antagonistic

muscles, most marked in the upper limbs and in the hands, they are often discribed as

pill-rolling movements.

(c) Akinesia: the basal ganglia become unable to planning and programming of

movements, which results in a great difficulty in initiating voluntary and spontaneous

movements, it manifests by:

*Difficulty in initiating voluntary movements, so the patient seems as if he is

paralyzed.

* Mask face due to lack of facial expression.

* Slow, monotonous low-volume speech.

* Shuffling gait i.e. walking in short steps without lifting the legs from the ground.

* Absence of the associated movements, swinging of the arms during walking, and any

automatic movements.

Treatment of parkinosim:

1- Anticholinergic drugs e.g. atropine to decrease the cholinergic influence.

2- Increasing the dopamine content by:

*L-Dopa: This is a precursor of dopamine that, unlike it, can cross the blood-brain barrier

and is converted to dopamine in the brain.

*L-Deprenyl: This is a drug that inhibits the monoamine oxidase enzyme which destroys

dopamine after it has been secreted.

3- Surgical interference by destruction of the interconnecting thalamic nuclei or the

globus pallidus to help to restore the output balance toward the normal.

4- Implantation of dopamine-secreting tissue in near to the basal ganglia

N.B.: Gamma rigidity and alpha rigidity

Gamma rigidity clinically called spasticity refers to muscle stiffness that occurs as a result of increased spinal motor activity with relative overexcitation of the gamma motor neurons as in UMNL. It is characterized by hypertonia mainly in the antigravity muscles, it is of the clasp-knife type, and is accompanied by exaggerated tendon jerks and may be clonus as well.

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Alpha rigidity clinically called rigidity, refers to muscle stiffness that occurs as a result of enhanced activity of the alpha motor neurons in absence of gamma motor activity as in Parkinsonism. It is characterized by hypertonia in all muscles at a joint, it is felt throughout the whole length of the movement, lead-pipe rigidity or it may be discontinuous, cogwheel rigidity. It is not necessarily accompanied by hyper-reflexia.

Gamma rigidity (spasticity) Alpha rigidity

Cause Increased gamma discharge Increased alpha discharge

Muscles affected Antigravity muscles All muscles

Type of rigidity Clasp-knife Lead pipe or cog-wheel

Tendon jerks Exaggerated and there may be clonus

Not necessarily exaggerated

Common diseases Upper motor neuron lesion Parkinsonism

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