Neurology: Motor systems

Organization of the motor systems

The motor systems are those areas of the nervous system that are primarily responsible for controlling movement. The movement can either be:

guided by inputs from the sensory systems (closed-loop or reflex controlled); or
triggered by a sensory cue or some internal desire to move (open-loop or volitional movement).

In practice, most motor acts involve both types of movement. Closed-loop movements predominantly involve the axial or proximal muscles responsible for balance, posture and locomotion, while the open-loop movements are typically associated with the distal musculature concerned with the control of fine skilled movements.

The organization of the motor structures is best viewed in terms of a hierarchy.

A cautionary note

It is important to remember that the division of the central nervous system into motor and sensory functions is a gross simplification as all the motor areas have some sensory input. It is difficult to know the point at which a highly processed sensory input becomes the impulse for the initiation of a movement. It should also be realized that the division of the motor systems into various levels and different motor pools is a convenient but not strictly accurate
device for understanding the control of movement and the pathophysiology of disorders of the motor system.

Did you know?

Cheetahs can run as fast as 120 km/h, and one of the reasons for this is that their spine is so flexible that it provides an additional ‘spring’ to their movement.

Muscle spindle and lower motor neurone

Lower motor neurone

The lower motor neurone (LMN) is defined as the neurone whose cell body lies in either the anterior or ventral horn of the spinal cord or cranial nerve nuclei of the brainstem and which directly innervates the muscle via its axon. The number of muscle fibres innervated by a single axon is termed the motor unit. The smaller the number of fibres per motor neurone (MN) axon, the finer the control (e.g. the extraocular muscles).

The MNs of the anterior horn are divided into two types:

α-MNs (70 μm in diameter) – which innervate the muscle itself (the force generating extrafusal fibres);
γ-MNs (30 μm in diameter) – which innervate the intrafusal fibres of the muscle spindle.

The muscle spindle is an encapsulated sense organ found within the muscle, which is responsible for detecting the extent of muscle contraction by monitoring the length of muscle fibres. It is the muscle spindle and its connections to the spinal cord that mediates the tendon reflexes:

sudden stretching of a muscle by a sharp tap of a tendon hammer transiently activates the Ia afferent nerve endings which, via an excitatory monosynaptic input to the MN, causes that muscle (the homonymous muscle) to contract briefly (e.g. the knee jerk).
In addition, the Ia afferent input from the muscle spindle, while activating other synergistic muscles with a similar action to the homonymous muscle, also inhibits muscles with opposing actions (antagonist muscles) through a Ia inhibitory interneurone (IN) in the spinal cord.
However, it must be stressed that tendon jerks reflect not only the integrity of this circuit but the overall excitability of the MN, which is increased in cases of an upper MN (UMN) lesion.

Muscle spindle

Structure

The muscle spindle lies in parallel to the extrafusal muscle fibres and consists of the following:

nuclear bag and chain fibres – which have different morphological properties: the bag 1 or dynamic fibres are very sensitive to the rate of change in muscle length, while the bag 2 or static bag fibres are like the nuclear chain fibres in being more sensitive to the absolute length of the muscle;
γ-MN – which synapses at the polar ends of the intrafusal muscle fibres and which can be one of two types: dynamic or static, with the latter innervating all but the bag 1 fibres. Both types of γ-MN are usually coactivated with the α-MN so that the intrafusal fibres contract at the same time as do the extrafusal fibres, thus ensuring that the spindle maintains its sensitivity during muscle contraction. Occasionally, the γ-MN can be activated independently of the α-MN, typically when the animal is learning some new complex movement, which increases the sensitivity of the spindle to changes in length;
two types of afferent fibres and nerve endings – a Ia afferent fibre associated with an annulospiral nerve ending winding around the centre of all types of intrafusal fibres (primary ending); and a slower conducting type II fibre which is associated with flower-spray endings on the more polar regions of the intrafusal fibres (with the exception of the bag 1 fibres; the secondary ending). The stretching of the intrafusal fibre activates both types of fibre.
However, the Ia fibre is most sensitive to the rate of change in fibre length, while the type II fibres respond more to the overall length of the fibre rather than the rate of change in fibre length.

Connections

The spindle relays via the dorsal root to a number of sites in the central nervous system (CNS) including:

MNs innervating the homonymous and synergistic muscles (the basis of the stretch reflex);
INs inhibiting the antagonist muscles;
the cerebellum via the dorsal spinocerebellar tract;
the somatosensory cortex;
the primary motor cortex via the dorsal column–medial lemniscal pathways.

Thus, the muscle spindle is responsible for mediating simple stretch or tendon reflexes as well as muscle tone, and it is also involved in the coordination of movement, the perception of joint position (proprioception) and the modulation of long–latency or transcortical reflexes.

Effects of damage to this structure

Damage to the spindle afferent fibres (e.g. in large-fibre neuropathies) produces hypotonia (as the stretch reflex is important in controlling the normal tone of muscles), incoordination, reduced joint position sense and, occasionally, tremor with an inability to learn new motor skills in the face of novel environmental situations.

In addition, large fibre neuropathies disrupt other somatosensory afferent inputs.

Golgi tendon organ

The Golgi tendon organ is found at the junction between muscle and tendon and thus lies in series with the extrafusal muscle fibres. It monitors the degree of muscle contraction in terms of the muscular force generated and relays this to the spinal cord via a Ib afferent fibre. This sensory organ, in addition to providing useful information to the CNS on the degree of tension within muscles, serves to prevent excessive muscular contractions. Thus, when activated it inhibits the agonist muscle.

Motor neurone recruitment and damage

The principle of recruitment corresponds to the order in which different types of muscle fibres are activated. The smallest “-MNs, which are those most easily excited by any input, innervate type 1 (not to be confused with the bag 1 intrafusal fibres found in the spindle) or slow-contracting fibres (which are responsible for increasing and maintaining the tension in a muscle).

The next population of MNs to be activated are those that innervate the type 2A or fast-contracting/resistant to fatigue fibres, which are responsible for virtually all forms of locomotion. Finally, the largest MNs are only activated by maximal inputs, which innervate type 2B or fast-contracting/easily fatigued fibres that are responsible for running or jumping.

The order of recruitment of MNs to a given input follows a simple relationship known as the size principle, which allows
muscles to contract in a logical sequence.

Lower motor neurone lesions

The α-MN itself can be damaged in a number of different conditions but in all cases the clinical features are the same:

wasting of the denervated muscles;
weakness of the same muscles;
reduced or absent reflexes (an LMN lesion).

In some cases one can also see fasciculations (muscle twitchings), as the loss of the motor neuronal input to the muscle leads to a more random redistribution of the acetylcholine receptors away from sites of the old neuromuscular junction.

The features of an LMN lesion are very different from a UMN lesion. Causes of a LMN lesion including infection (poliomyelitis); neurodegenerative disorders (motor neurone disease) as well as entrapment as the nerves exit the spine (radiculopathies) and in the limb itself (e.g. carpel tunnel syndrome).

Did you know?

The human masseter muscle contains 114 spindles.

Spinal cord motor organization and locomotion

Spinal cord motor organization

In addition to containing the α- and γ-motor neurones (MNs), the spinal cord also contains a large number of interneurones (INs).
These INs can form networks that are intrinsically active and whose output governs the activity of MNs, central pattern generators (CPGs). These CPGs, which may underlie locomotion, are modulated by both central and peripheral inputs. Such CPGs are not unique to locomotion as they can be seen in other parts of the central nervous system (CNS) controlling rhythmical motor activities, e.g. respiration and the brainstem respiratory network.

Descending motor pathways

The descending motor pathways – (see Table 37.1); can be classified according to:

their site of origin, namely pyramidal or extrapyramidal tracts (although clinically extrapyramidal disorders refer to diseases of the basal ganglia;
their location within the cord and the muscles they ultimately
innervate.
Thus, the pyramidal (corticospinal) and rubrospinal tracts are associated with a lateral MN pool that innervates the distal musculature, while the vestibulo-, reticulo- and tectospinal tracts are more associated with a ventromedial MN pool that innervates the axial and proximal musculature.
These latter MNs are linked by long propriospinal neurones, while the converse is true for the lateral MN pool. Thus, the lateral motor system is more involved in the control of fine distal movements, while the ventromedial system is more concerned with balance and posture.
The MNs of the anterior horn are further organized such that the most ventral MNs innervate the extensor muscles, while the more dorsally located MNs innervate the flexor musculature.

Locomotion

The control of locomotion is complex, as it requires the coordinated movement of all four limbs in most mammals. Each cycle in locomotion is termed a step and involves a stance and a swing phase – the latter being that part of the cycle when the foot is not in contact with the ground.

Each cycle requires the correct sequential activation of flexors and extensors. The simplest way to achieve this is to have two CPGs (half centres) which activate flexors and extensors, respectively, and which mutually inhibit each other.
This mutual inhibition can perhaps best be modelled using the inhibitory Ia IN and Renshaw cells.
Renshaw cells are INs that, when activated by MNs, inhibit those same MNs. Thus, the activation of a MN pool by a CPG leads to its own inhibition and the removal of an inhibitory input to the antagonistic CPG, thus switching the muscle groups activated.

This half centre model for locomotion can be modulated by a range of descending and peripheral inputs. The Golgi tendon organ can switch the CPGs, while a range of cutaneous inputs can cause the cycle to be modified when an obstacle is encountered. These afferents, termed flexor reflex afferents, cause the limb to be flexed so stepping over or withdrawing from the noxious or obstructive object.
CPGs within the spinal cord communicate with each other through propriospinal neurones.
In contrast, supraspinal communication of information from and about the CPGs is relayed indirectly in the form of muscle spindle Ia afferent activity via the dorsal spinocerebellar tract (DSCT) and dorsal columns and spinal cord interneuronal activity via the ventral spinocerebellar tract (VSCT).

Clinical disorders of spinal cord motor control and locomotion

Although experimental animals can locomote in the absence of any significant supraspinal inputs (fictive locomotion), this is not the case in humans. However, clinical disorders of gait are relatively common and may occur for a number of reasons.

Disorders of spinal cord INs such as in stiff person syndrome are rare and present with increased tone or rigidity in the axial muscles with or without spasms caused by the continuous firing of the MNs as a result of the loss of an inhibitory interneuronal input primarily to the ventromedial MNs. This condition is associated with antibodies
against the synthetic enzyme for -aminobutyric acid (GABA), glutamic acid decarboxylase (GAD).
Damage to the descending pathways can produce a range of deficiencies. The most devastating is that seen with extensive brainstem damage when the patient adopts a characteristic decerebrate posture with arching of the neck and back and rigid extension of all four limbs. In contrast, a more rostrally placed lesion in one of the cerebral hemispheres produces weakness down the contralateral side (hemiplegia or hemiparesis) with increased tone (hypertonia) and increased tendon reflexes (hyperreflexia) which may produce spontaneous or stretch–induced rhythmic involuntary muscular contractions (clonus) (an upper motor neurone lesion). This situation is also seen with interruption of the descending motor pathways in the spinal cord. The pattern of weakness in such lesions characteristically involves the extensors more than the flexors in the upper limb and the converse in the lower limb. This is misleadingly termed a pyramidal distribution of weakness, as damage confined to the pyramidal tract in monkeys leads only to a deficiency in fine finger movements with a degree of hypotonia and hypo- or areflexia.

Did you know?

It is well known that chickens can still walk when they have lost most of their head but the longest reported case for this is 18 months!

Cortical motor areas

A number of cortical areas are involved with the control of movement, including the primary motor cortex, premotor cortex (PMC), supplementary motor area (SMA) and several adjacent areas in the anterior cingulate cortex. In addition, there are other areas that play specific roles in the cortical control of movement, including the frontal eye fields and posterior parietal cortex. This chapter briefly discusses the organization of the motor cortical areas and their relative roles in movement control, while the next chapter concentrates on the primary motor cortex.

Primary motor cortex

The primary motor cortex (MsI) is that part of the cerebral cortex that produces a motor response with the minimum electrical stimulation. It corresponds to Brodmann’s area 4 and lies just in front of the central sulcus and projects to the motor neurones (MNs) of the brainstem via the corticobulbar tracts and to the MNs of the spinal cord directly via the corticospinal tract (CoST) and indirectly via the subcortical extrapyramidal tracts. Indeed, MsI is closely associated with the pyramidal tract (even though 60–70% of it originates in other cortical areas) and so has a role in the control of distal musculature and fine movements.

Other cortical areas

A range of other cortical areas are involved in the control of movement, including the PMC (corresponding to the lateral part of Brodmann’s area 6); the SMA (corresponding to the medial aspect of Brodmann’s area 6); a number of motor areas centred on the anterior cingulate cortex on the medial aspect of the frontal lobe; the frontal eye fields (corresponding to Brodmann’s area 8); and the posterior parietal cortex (especially Brodmann’s area 7).

Some of these areas have specialist functions such as the frontal eye fields with eye movement control and the posterior parietal cortex with the visual control of movement. The remaining areas in the frontal lobe are involved with more complex aspects of movement. Most of these other cortical areas therefore occupy a higher level in the motor hierarchy than MsI, and their connections and functions are summarized in the figure and Table 38.1.

The PMC refers to a specific area of Brodmann’s area 6, and like the primary motor cortex has an input directly to the spinal MNs via the corticospinal or pyramidal tract. This area therefore occupies two levels of the motor hierarchy as it also has a role in the planning of movement. In contrast, the SMA lies medial to the PMC, and has a much more clearly defined role in the planning of movements especially in response to sensory cues. Furthermore, it is now clear that the SMA is part of a much larger number of higher order motor cortical areas that lie along the medial side of the frontal cortex and which are involved in the planning of movements more than their execution. It is these cortical areas that receive the predominant outflow of the basal ganglia, which helps explain the abnormal movements that are seen with diseases of this area of the brain. For example, in Parkinson’s disease there is a slowness and poverty of movement that is associated with underactivation of these cortical areas, a situation that is rectified by the administration of antiparkinsonian medication or successful neurosurgical interventions.

Did you know?

Transcranial magnetic stimulation (TMS) is a technique for stimulating cortical areas by placing a magnet on the outside of the skull, which modifies ongoing activity in the brain. TMS is emerging as a possible therapy for patients with neurological disorders.

Primary motor cortex

The primary motor cortex (MsI) receives afferent information from the cerebellum (via the thalamus) and more anteriorly placed motor cortical areas such as the supplementary motor area (SMA) and a sensory input from the muscle spindle as well as cortical sensory areas. This latter sensory input emphasizes the artificial way in which the central nervous system (CNS) is divided up into motor and sensory systems. In order to acknowledge this, the
primary motor cortex is termed the MsI while the primary somatosensory cortex is termed the SmI.

Investigation of the organization of MsI has shown that the motor innervation of the body is represented in a highly topographical fashion, with the cortical representation of each body part being proportional to the degree of motor innervation – so, for example, the hand and orobuccal musculature have a large cortical representation. The resultant distorted image of the body in MsI is known as the motor homunculus, with the head represented laterally and the feet medially. This organization may manifest clinically in patients with epilepsy that originates in the motor cortex. In such cases, the epileptic fit may begin at one site, typically the hand, and then spread so that the jerking marches out
from the site of origin (Jacksonian march, named after the neurologist, Hughlings Jackson). This is in contrast to the clinical picture seen with seizures arising from the SMA, in which the patient raises both arms and vocalizes with complex repetitive movements suggesting that this area has a higher role in motor control.

These studies on the motor homunculus by Penfield and colleagues in the 1950s revealed the macroscopic organization of MsI, but subsequent microelectrode studies in animals showed that MsI is composed of cortical columns. The inputs to a column consist of afferent fibres from the joint, muscle spindle and skin which are maximally activated by contraction of those muscles innervated by that same area of cortex. So, for example, a group
of cortical columns in MsI will receive sensory inputs from a finger when it is flexed – that input being provided by the skin receptors on the front of the finger, the muscle spindles in the finger flexors and the joint receptors of the finger joints. That same column will also send a projection to the motor neurones (MNs) in the spinal cord that innervate the finger flexors. Activation of the corticospinal neurone from that column will ultimately activate the receptors that project to that same column, and vice versa.

Thus, each column is said to have input–output coupling and this may be important in the more complex reflex control of movement as, for example, with the long–latency or transcortical reflexes. These reflexes refer to the delayed and smaller electromyographical (EMG) changes that are seen following the sudden stretch of a muscle – the first EMG change being the M1 response of the monosynaptic stretch. The afferent limb of the transcortical reflex is from the muscle spindle input via the Ia fibre (relayed via the dorsal column–medial lemniscal pathway) and the efferent pathway involves the corticospinal tract (CoST). The exact role of this reflex is not known but it may be important in controlling movements precisely, especially when unexpected obstacles are encountered which activate the muscle spindle.

There has been great controversy as to whether MsI controls individual muscles, simple movements or some other aspect of movements. Neurones within MsI fire before any EMG changes and appear to code for the direction and force of a movement, although this activity is dependent on the nature of the task being performed. Therefore, as a whole, the motor cortex controls movement by its innervation of populations of MNs, as individual corticospinal axons innervate many different MNs.

MsI is capable of being remodelled after lesions or changes in sensory feedback, implying that it maintains a flexible relationship with the muscles throughout life. Thus, cells in a region of MsI can shift from the control of one set of muscles to a new set. Within given areas of cortex there is some evidence that synaptic strengths can be altered with long–term potentiation, which suggests that the MsI may be capable of learning new movements,
a function traditionally ascribed to the cerebellum.

Damage to MsI in isolation is rare and experimentally tends to produce deficiencies similar to those seen with selective pyramidal tract lesions. However, damage to both MsI and adjacent premotor areas, as occurs in most cerebrovascular accidents (CVAs) involving the middle cerebral artery, produces a much more significant deficiency, with marked hemiparesis.

Did you know?

Scientists have now developed brain–computer interfaces so that patients can move paralysed parts of their body simply by thinking about it.

Cerebellum

Organization of the cerebellum

The cerebellum (CBM) is a complex structure found below the tentorial membrane in the posterior fossa and connected to the brainstem by three pairs of (cerebellar) peduncles . It is primarily involved in the coordination and learning of movements, and is best thought of in terms of three functional and anatomical systems:

spinoCBM – involved with the control of axial musculature and posture + ;
pontoCBM – involved with the coordination and planning of limb movements ;
vestibuloCBM – involved with posture and the control of eye movements .
These three systems have their own unique pattern of connections
(see Table 40.1).
The spinoCBM can be divided into a vermal and paravermal (intermediate) region with the former having a close association with the axial musculature. It is therefore associated with the ventromedial descending motor pathways and motor neurones (MNs) while the paravermal part of the spinoCBM is more concerned with the coordination of the limbs.
The pontoCBM has a role in this coordination but is associated with the visual control of movement and relays information from the posterior parietal cortex to the motor cortical areas.
The vestibuloCBM has no associated deep cerebellar nucleus and is phylogenetically one of the oldest parts of the cerebellum. Like the vermal part of the spinoCBM, it is involved with balance through its connections with the ventromedial motor pathways but also has a role in the control of eye movements.

Long-term depression (LTD) and motor learning

In general, the CBM compares the intended movement originating from the motor cortical areas with the actual movement as relayed by the muscle afferents and spinal cord interneurones, while receiving an important input from the vestibular and visual system. The comparison having been made, an error signal is relayed via descending motor pathways, and the correction factor stored as part of a motor memory in the synaptic inputs to the Purkinje cell(PuC). This modifiable synapse at the level of the PuC is an example of long-term depression (LTD). It describes the reduced synaptic input of the parallel fibre (pf) to PuC when it is activated in phase and at low frequency with the
climbing fibre input to that same PuC and persists at least for several hours. In other words, at times of new movements the climbing fibre input to the PuC increases which has a modifying effect on the pf input to that same PuC. As the movement becomes more routine, the climbing fibre (cf) lessens but the modified (reduced) pf input persists: it is this modification that is thought to underlie the learning and memory of movements.

This modifiable synapse was first proposed by Marr in 1969 and subsequently has been verified, especially with respect to the vestibulo-ocular reflex . The biochemical basis of LTD in the CBM is unknown but appears to rely on the activation
of different glutamate receptors in the PuC and the subsequent influx of calcium and the activation of a protein kinase. The presence of a modifiable synapse implies that the CBM is capable of learning and storing information in a motor memory (seeTable 40.1).

The microscopic organization of the cerebellum

The microscopic organization of the cerebellum, which allows for the generation of LTD, is well characterized even if the biochemical basis for it remains obscure. The excitatory input to the cerebellum is provided by a mossy and climbing fibre input. The mossy fibre indirectly activates PuC through parallel fibres that originate from granule cells (GrC). In contrast, the climbing fibre directly synapses on the PuC and, as with the mossy fibre input, there is an input to the deep cerebellar nuclei neurones (DCNNs). These neurones are therefore tonically excited by the input fibres to the cerebellum, and are inhibited by the output from the cerebellar cortex (the PuC). The PuC in turn are inhibited by a number of local interneurones, while Golgi cells (GoC) in the outer granule cell layer provide an inhibitory input to the GrC. All of these interneurones have the effect of inhibiting submaximally activated PuC and GrC, and by so doing highlight the signal to be analysed.

The final output of the cerebellum from the deep cerebellar nuclei to various brainstem structures is also inhibitory.

Functional and anatomical systems of the cerebellum

Clinical features of cerebellar damage

Much that can be deduced about the function of the CBM is derived from the clinical features of patients with cerebellar
damage. Dysfunction of the CBM is found in a large number of conditions, and the clinical features of cerebellar damage are as follows:

Hypotonia or reduced muscle tone. This is caused by a reduced input from the DCNN via the descending motor pathways to the muscle spindle.
Incoordination/ataxia. There are a number of manifestations of this including: asynergy (an inability to coordinate the contraction of agonist and antagonist muscles); dysmetria (an inability to terminate movements accurately which can result in an intention tremor and past pointing); and dysdiadochokinesis (an inability to perform rapidly alternating movements). Ataxia is often used to describe incoordinated movements. In cases where the vermis is
predominantly involved, as occurs in alcoholic cerebellar degeneration, this results in a staggering, wide-based, ‘drunk-like’ character to the gait. When there is involvement of the more lateral parts of the cerebellar hemisphere the incoordination involves the limbs.
Dysarthria. This is an inability to articulate words properly caused by incoordination of the oropharyngeal musculature. The words are slurred and spoken slowly (scanning dysarthria)Nystagmus. This describes rapid jerky eye movements caused by a breakdown in the outflow from the vestibular nucleus and its connections with the oculomotor nuclei.
Palatal tremor or myoclonus. This is a rare condition in which there is hypertrophy of the inferior olive, with damage in a triangle bounded by this structure, the dentate nucleus of the CBM and the red nucleus in the midbrain (Mollaret triangle). The patient characteristically has a low-frequency tremor of the palate, which
oscillates up and down.

Finally, there is a recent suggestion that the cerebellum may also subserve some cognitive function, as subtle deficits can be seen in this domain in some patients with cerebellar disease.

Function of the cerebellum

The role of the CBM can be defined by area and correlates well with the localizing signs of cerebellar disease. Exactly how the CBM achieves these functions is unknown, but the repetition of the same elementary circuitry in all parts of the cerebellar cortex implies a common mode of function. Three possibilities exist which are not mutually exclusive.

By acting as a comparator. The CBM compares the descending
supraspinal motor signals (efference copy, intended movement)
with the ascending afferent feedback information (actual movement), and any discrepancy is corrected by the output of the CBM through descending motor pathways. This allows the CBM to coordinate movements so that they are achieved smoothly and accurately.
By acting as a timing device. The CBM (especially the pontoCBM) converts descending motor signals into a sequence of motor activation so that movement is performed in a smooth and coordinated fashion, with balance and posture maintained by the vestibulo- and spinoCBM.
By initiating and storing movements. The existence of a modifiable synapse at the level of the PuC means that the CBM is capable of storing motor information and updating it. Therefore, under the appropriate circumstances, the right sequence for a movement can be accessed and fed through the supraspinal motor pathways, and by so doing an accurate learnt movement is initiated.

Did you know?

The adult human cerebellum weighs 150 g and contains in excess of 20 million Purkinje cells.

Basal ganglia: anatomy and physiology

The basal ganglia consist of the caudate and putamen (dorsal or neostriatum; NS), the internal and external segments of the globus pallidus (GPi and GPe, respectively), the pars reticulata and pars compacta of the substantia nigra (SNr and SNc, respectively) and the subthalamic nucleus (STN).

The NS is the main receiving area of the basal ganglia and receives information from the whole cortex in a somatotopic fashion as well as the intralaminar nuclei of the thalamus (IL). The major outflow from the basal ganglia is via the GPi and SNr to the ventroanterior–ventrolateral nuclei of the thalamus (VA–VL) which in turn project to the premotor cortex (PMC), supplementary motor area (SMA) and prefrontal cortex. In addition, there
is a projection to the brainstem, especially to the pedunculopontine nucleus (PPN), which is involved in locomotion,
and to the superior colliculus, which is involved with eye movements.
The basal ganglia also have a number of loops within them that are important. There is a striato–nigral–striatal loop with the latter projection being dopaminergic (DA) in nature. There is also a loop from the GPe to the STN which then projects back to the GPi and SNr. This pathway is excitatory in nature and is important in controlling the level of activation of the inhibitory output nuclei of the basal ganglia to the thalamus. However, although a marked degree of convergence and divergence can be seen throughout the basal ganglia, the projections do form parallel
pathways, which at the most simplistic level divide into a motor pathway through the putamen and a non-motor pathway through the caudate nucleus.
The NS consists of patches or striosomes that are deficient in the enzyme acetylcholinesterase (AChE). These are embedded in an otherwise AChE-rich striatum, which forms the large extrastrio-somal matrix. In general, the striosomes are closely related to the dopaminergic nigrostriatal pathway and prefrontal cortex and amygdala, while the matrix is more involved with sensorimotor areas. However, the relationship of these two components of the neostriatum to any parallel pathways is not clear.
This non-motor role of the basal ganglia is perhaps more clearly seen with the ventral extension of the basal ganglia which consists of the ventral striatum (nucleus accumbens), ventral pallidum and substantia innominata (not shown in the figure). It receives a dopaminergic input from the ventral tegmental area that lies adjacent
to the SNc in the midbrain, and projects via the thalamus to the prefrontal cortex and frontal eye fields. These structures are intimately associated with motivation and drug addiction.
The neurophysiology of the basal ganglia shows that many of the cells within it have complex properties that are not clearly sensory or motor in terms of their response characteristics. For example, some units in the NS respond to sensory stimuli but only when that sensory stimulus is a trigger for a movement. In contrast, many units in the pallidum respond maximally to movement about a given joint before any electromyographic (EMG) changes. Thus,
from a neurophysiological point of view, the basal ganglia take highly processed sensory information and convert it into some form of motor programme. This is supported by the clinical disorders that affect the basal ganglia.

Did you know?

Marijuana has actions at many sites in the central nervous system (CNS), and this includes the basal ganglia as they have high levels of the receptors for the active ingredient -9-tetrahydrocannabinol (THC). Chronic use of this drug may cause long-term changes to the brain including the basal ganglia.

Basal ganglia diseases and their treatment

Parkinson’s disease

Parkinson’s disease is a degenerative disorder that typically affects people in the sixth and seventh decades of life. The primary pathological event is the loss of the dopaminergic nigrostriatal tract, with the formation of characteristic histological inclusion bodies, known as Lewy bodies. In the vast majority of cases the disease develops for reasons that are not clear (idiopathic Parkinson’s disease). However, in some cases clear aetiological agents are identified, such as vascular lesions in the region of the nigrostriatal pathway, administration of the antidopaminergic drugs in schizophrenia or genetic abnormalities in young patients and some rare families.

Over 50–60% of the dopaminergic nigrostriatal neurones need to be lost before the classical clinical features of idiopathic Parkinson’s disease are clearly manifest: slowness to move (bradykinesia); increased tone in the muscles (cogwheel rigidity); and rest tremor. However, most patients also display a range of cognitive, affective and autonomic abnormalities, which relates to pathological changes at other sites.

Neurophysiologically, these patients have increased activity of the neurones in the GPi with a disturbed pattern of discharge, which results from increased activity in the STN secondary to the loss of the predominantly inhibitory dopaminergic input to the neostriatum (NS). The increased inhibitory output from the GPi and SNr to the ventroanterior–ventrolateral nuclei of the thalamus (VA–VL) results in reduced activation of the supplementary motor area (SMA) and other adjacent cortical areas. Thus, patients with Parkinson’s disease are unable to initiate movement because of their failure to activate the SMA.

Antiparkinsonian drugs

Currently, no drugs have been shown to slow the progression of Parkinson’s disease. For most patients, dopamine replacement therapy with levodopa (L-dopa) or dopamine agonists is the treatment of choice (dopamine itself does not pass the blood–brain barrier).

L-dopa is the immediate precursor of dopamine and is converted in the brain by decarboxylation to dopamine. Orally administered L-dopa is largely metabolized outside the brain and so it is given with an extracerebral decarboxylase inhibitor (carbidopa or benser-azide), which greatly reduces the effective dose and peripheral
adverse effects (e.g. hypotension, nausea). L-dopa frequently produces adverse effects that are mainly caused by widespread stimulation of dopamine receptors. After five years’ treatment about half of the patients will experience some of these complications. In some the akinesia gradually recurs producing so-called wearing off effects, while in others various dyskinesias may appear in response to L-dopa (so-called L-dopa-induced dyskinesias). These latter
problems may lead to rapid changes in the motor state of the individual (‘on–off’ problems) and are found in all cases of advanced PD.
Selegiline and rasagiline are selective monoamine oxidase type B (MAOB) inhibitors that reduce the metabolism of dopamine in the brain and potentiate the action of L-dopa. They may be used in conjunction with L-dopa to reduce ‘end of dose’ deterioration.
Catecholamine-O-methyltransferase (COMT) inhibitors such as entacapone reduce the peripheral (and also central in the case of tolcapone) metabolism of L-dopa and by so doing increase the amount that can enter the brain.
Dopamine agonists (e.g. ropinirole, pramipexole) are also used often as first-line treatment in young patients or in combination with L-dopa in the later stages of Parkinson’s disease. Dopamine agonists directly bind to the dopamine receptors in the striatum (and substantia nigra) and by so doing activate the postsynaptic output neurones of the striatum.
Other drugs that can be used in Parkinson’s disease include antimuscarinic drugs (e.g. trihexyphenidyl [benzhexol], procyclidine) in the early stages where tremor predominates and in some young patients with PD. These drugs are believed to correct a relative overactivity of central cholinergic activation that results from the progressive decrease of (inhibitory) dopaminergic activity. Adverse effects are common.

Surgical therapies

Although most patients with Parkinson’s disease are best treated with drugs, surgical approaches have been undertaken in advanced disease. Initially this took the form of lesions of the GPi (pallidotomy) but more recently the insertion of electrodes for deep-brain stimulation especially into the STN. This latter approach may work by generating a temporary lesion, possibly by inducing a conduction blocks, although this is not proven.

An alternative surgical approach is the implantation of dopamine-rich tissue into the striatum to replace and possibly
restore the damaged nigrostriatal pathway. The efficacy of this approach is still debatable, as is the use of growth factors such as glial cell line derived neurotrophic factor (GDNF).

Huntington’s disease

Huntington’s disease is an inherited autosomal dominant disorder associated with a trinucleotide expansion in the gene coding for the protein huntingtin on chromosome 4, and as such affected individuals can be diagnosed with certainty using a simple genetic test on the blood.

The disease presents typically in mid-life with a progressive dementia and abnormal movements which usually take the form of chorea – rapid dance-like movements. This type of movement is described as being hyperkinetic in nature, unlike the hypokinetic deficits seen in Parkinson’s disease, and reflects the fact that the primary pathology is the loss of the output neurones of the striatum. This results in relative inhibition of the STN and thus reduced inhibitory outflow from the GPi and SNr, which leads to the cortical motor areas being overactivated, generating an excess of movements.

Treatment of the movement disorder in Huntington’s disease is designed to reduce the level of dopaminergic stimulation within the basal ganglia. However, there are no treatments for the cognitive deficits in Huntington’s disease, although mood disturbances in this condition often do respond to drugs such as antidepressants
.

Other disorders of the basal ganglia

Another example of a hyperkinetic movement disorder is hemiballismus, which is the rapid flailing movements of the limbs contralateral to damage to the STN.
A number of other conditions can affect the basal ganglia including Wilson’s disease (an autosomal recessive condition associated with copper deposition); Sydenham’s chorea (a sequela of rheumatic fever); defects in mitochondrial function (mitochondrial cytopathies); a number of toxins (e.g. carbon monoxide and manganese); and choreoathetoid cerebral palsy (athetosis is defined as an abnormal involuntary slow writhing
movement).
The spectrum of movement disorders seen with these diseases is variable because the damage is rarely confined to one structure so patients may exhibit either parkinsonism, chorea and ballismus, or dystonia, where a limb is held in an abnormal fixed posture.
Many of these conditions, including Parkinson’s disease and Huntington’s disease, have a cognitive impairment – if not frank dementia – and while this relates to additional damage in the cerebral cortex, there is increasing evidence that it may in part be as a direct result of basal ganglia damage. In this respect the ventral extension of the basal ganglia may be important.
The basal ganglia have a major role in the control of eye movements and so many patients with diseases of the basal ganglia have abnormal eye movements, which may be helpful in establishing their clinical diagnosis.

Did you know?

Patients with severe Parkinson’s disease can suddenly move normally when faced by life-threatening situations by using a different motor strategy that bypasses the basal ganglia.