Figure 33.2 is derived from Figure 33.1A. It is a schematic coronal section including the posterior part of the striatum, depicting component parts of the motor loop. Two pathways are known. The ‘direct’ pathway traverses the corpus striatum and thalamus and involves five consecutive sets of neurons (Figure 33.2A). The ‘indirect’ pathway engages the subthalamic nucleus in addition and involves seven sets of neurons (Figure 33.2B). Separate from these pathways are two thalamic projections from the medial pallidum (ansa lenticularis and lenticular fasciculus) shown in Figure 33.3.

Figure 33.2 Coronal section through the motor loop, based on Figure 33.1A. (A) The sequence of five sets of neurons involved in the ‘direct’ pathway from sensorimotor cortex to thalamus with final return to sensorimotor cortex via SMA. (B) The sequence of seven sets of neurons involved in the ‘indirect’ pathway.

The red/pink neurons are excitatory utilizing glutamate. The black/gray neurons are inhibitory utilizing γ-aminobutyric acid. The brown, nigrostriatal neuron utilizes dopamine which is excitatory via D₁ receptors on target striatal neurons and inhibitory via D₂ receptors on the same and other striatal neurons. CST/CRST, corticospinal, corticoreticular fibers; GPL, GPM, lateral and medial segments of globus pallidus; SMA, supplementary motor area; SNpc, compact part of substantia nigra; STN, subthalamic nucleus; VLN, ventral lateral nucleus of thalamus.

Figure 33.3 Part of the projection from the medial segment of globus pallidus (GPM) to the ventral lateral nucleus (VLN) of the thalamus sweeps around the base of the internal capsule as the ansa lenticularis (AL); the remainder traverses this region as the lenticular fasciculus (LF). The two parts come together as the thalamic fasciculus (TF) before entering the thalamus. CST/CRST, corticospinal and corticoreticular fibers; GPL, lateral segment of globus pallidus; OT, optic tract; P, putamen; TCF, thalamocortical fibers.

All projections from the cerebral cortex arise from pyramidal cells and are excitatory (glutaminergic). So, too, is the projection from thalamus to SMA. Those from striatum and from both segments of pallidum arise from medium-sized spiny neurons and are inhibitory. They are GABAergic, and also contain neuropeptides of uncertain function.

The nigrostrial pathway projects from the compact part of the substantia nigra to the striatum, where it makes two kinds of synapses upon the projection neurons there (Figure 33.4). Those upon ‘direct’ pathway neurons are facilitatory, by way of dopaminergic type 1 (D₁) receptors on the dendritic spines; those upon ‘indirect’ pathway neurons are inhibitory, by way of type 2 (D₂) receptors. Cholinergic internuncial neurons within the striatum are excitatory to projection neurons, and they are inhibited by dopamine.

Figure 33.4 Activities in the striatal motor loops, prior to movement.

The SMA (supplementary motor area) is activated through the ‘direct’ pathway as follows. (1) Corticostriate fibers from the sensorimotor cortex activate those GABAergic spiny neurons in striatum having D₁ receptors tonically facilitated by nigrostriatal inputs. (2) The activated striatal neurons inhibit medial pallidal (GPM) neurons (3) with consequent disinhibition of ventral lateral nucleus (VLN) thalamocortical neurons (4) and activation of SMA (5), which both modifies ongoing corticostriate activity and initiates impulse trains along corticospinal (CST) and corticoreticular (CRST) fibers.

Activity along the ‘indirect’ pathway is relatively slight because of tonic dopaminergic inhibition of the relevant striatal neurons via D₂ receptors. However, the subthalamic nucleus (STN) is tonically activated by corticosubthalamic fibers, curtailing the inhibition of GPM. GPL, lateral segment of globus pallidus; SNpc, compact part of substantia nigra. (Cerebello-thalamocortical projection is not shown.)

A healthy substantia nigra is tonically active, favoring activity in the ‘direct’ pathway. Facilitation of this pathway is necessary for the SMA to become active before and during movement. SMA activity immediately prior to movement can be detected by means of recording electrodes attached to the scalp. This activity is known as the (electrical) readiness potential, and its manner of production is described in the caption to Figure 33.4. Impulses pass from SMA to the motor cortex, where a cerebello-thalamocortical projection selectively enhances pyramidal and corticoreticular neurons within milliseconds prior to discharge.

The putamen and globus pallidus are somatotopically organized, permitting selective facilitation of neurons relevant to (say) arm movements via the direct route, with simultaneous disfacilitation of unwanted (say) leg movements via the indirect route. For suppression of unwanted movements, the subthalamic nucleus (STN), acting upon the body map in the medial pallidal segment, is especially important, since we know that destruction of STN results in uncontrollable flailing movements of one or more body parts on the opposite side (see later).

Progressive failure of dopamine production by the compact part of substantia nigra is the precipitating cause of Parkinson’s disease (PD) (Clinical Panel 33.1).

Clinical Panel 33.1 Hypokinesia

Parkinson’s disease

Parkinson’s disease (PD) affects about 1% of people over 65 years of age in all countries. The primary underlying pathology is degeneration of nigrostriatal neurons, resulting in diminished dopamine content within the striatum. [¹⁸F]fluorodopa is a mildly radioactive compound which, when injected intravenously, binds with dopamine receptors in the striatum. In symptomatic PD, a significant reduction of [¹⁸F]fluorodopa binding (and therefore of receptors) is revealed by means of PET scanning (Figure CP 33.1.1). One consequence is increased striatal activity, with a shift from the direct to the indirect motor pathway (Figure CP 33.1.2).

Nigrostriatal degeneration seems to take the form of a dying back neuropathy, because dopamine is lost from the striatum earlier than in the midbrain. The spiny striatal neurons also deteriorate, with reduction in the length of dendrites and the numbers of spines. It may be that the spiny neurons depend upon dopaminergic inputs for protection against potentially toxic effects of ongoing glutamate activity.

Some 60% of nigral neurons have been lost before the first symptoms appear. This delay is accounted for by (a) increased dopamine production by surviving neurons, and (b) increased production (‘upregulation’) of dopamine receptors in the target striatal neurons.

The following symptoms/signs are characteristic: tremor, bradykinesia, rigidity, and impairment of postural reflexes. Not all are expressed in every patient.

Tremor

Tremor, at 3–6 Hz (hertz, times per second) in one limb is the initial feature in two-thirds of patients with PD. The commonest sequence of limb involvement is from one upper limb to the ipsilateral lower limb within 1 year, followed by contralateral limb involvement within 3 years. Rhythmic tremor of lips and tongue, pronation–supination of the forearm, and flexion–extension of the fingers may be obvious. A ‘pill-rolling’ movement of the index and middle fingers against the thumb pad is characteristic. Typically, the tremor only involves muscle groups that are ‘at rest’ and vanishes during voluntary movement. A patient with an exclusively resting tremor has no difficulty in raising and draining a tumblerful of water. The term resting tremors is used to distinguish it from the intention tremor of cerebellar disease. Intention tremor is absent at rest (unless cerebellar dysfunction is severe) and is brought on by voluntary movement.

Tremor is associated with rhythmic bursting activity within all five cell groups of the direct motor loop (Figure 28.2A) and in anterior horn cells of the spinal cord. The contribution of disordered autogenic inhibition to both resting tremor and rigidity is described below.

A fine action tremor is often detectable in patients having pronounced resting tremor, and it is more pronounced on the side more affected by resting tremor. The action tremor is best seen in the fingers when the arms are fully outstretched, and it may be manifested by tremulous handwriting. Note particularly that in the absence of a resting tremor, a fine action tremor is indicative of benign essential tremor (see later).

Rigidity

Rigidity affects all of the somatic musculature simultaneously, but a predilection for flexors imposes a stooped posture. Passive flexion and extension of the major joints evince resistance through the full range of movement. The term ‘lead pipe rigidity’ is used to distinguish this type of resistance from the ‘clasp knife rigidity’ of the spastic state that accompanies upper motor neuron lesions. The clinician may detect a subtle underlying tremor in the form of ratchety, ‘cogwheel’ sensation (tremor superimposed on rigidity).

Historically, rigidity has been abolished by section of dorsal nerve roots, thus proving its peripheral sensory origin. It can also be alleviated by a surgical lesion of the pallidum or of the VL nucleus of the thalamus. Because muscle spindle stretch reflexes are not exaggerated in PD, attention has focused on the Golgi tendon organ afferents responsible for autogenetic inhibition. As illustrated in Chapter 10, these afferents synapse upon inhibitory, 1b internuncials which, when activated by muscle contraction, dampen activity of motor neurons supplying the same muscle and any homonymous contributors to the same movement (e.g. impulses generated in biceps brachii tendon organs will depress both brachialis and biceps motor neurons). In PD patients, autogenetic inhibition is reduced, and it is also delayed to the extent that it becomes entrained with the pulses descending from the brain, with the effect of contributing to the tremor. It may also contribute to the rigidity, because in PD there is some degree of co-contraction of prime movers and antagonists.

Given that muscular contraction is required to activate tendon organs, why do patients display ‘resting tremor’, with supposedly inactive muscles? It transpires that, when the forearms (say) are resting on the lap or on the arms of a chair, the forearm/hand muscles are not fully at rest. If the limb is properly supported at elbow and wrist, the tremor disappears. The tremor also disappears during sleep.

Normally, both corticospinal and reticulospinal fibers are tonically facilitatory to 1b inhibitory internuncials. In PD, activation of the primary motor cortex by SMA is known to be both reduced and oscillatory, thus accounting for the pronounced effects in the forearm and hand. Impaired reticulospinal activity is more likely to be significant with respect to the lower limbs.

In addition to its massive projections into the pallidum, the putamen projects to another group of GABAergic neurons, namely the reticular part of the substantia nigra. The compact part of the substantia nigra also projects to the reticular part. The reticular part projects in turn to the brainstem locomotor center (Ch. 24). In PD, the overactive putamen would be expected to have the knock-on effect of inhibiting impulse traffic in the projections from the locomotor area to the pontine and medullary reticular reticulospinal tracts.

Difficulty in writing is a common early feature of PD. The individual written letters become small and irregular. Loss of writing skill is attributable to co-contraction of wrist flexors and extensors, owing to a marked reduction of supraspinal activation of 1a internuncials synapsing on antagonist motor neurons.

Bradykinesia

Bradykinesia means slowness of movement. Patients report that routine activities, such as opening a door, require deliberate planning and consciously guided execution. Electromyographic studies of the limb musculature show a reduction of the ‘initial agonist burst’ of electrical charge accompanying the first contraction of relevant prime movers. Normally, the basal ganglionic contribution to movement comes on stream some milliseconds after the premotor cortex and cerebellum have raised the firing rate of motor-cortex neurons to threshold at a spinal lower motor neuron level. In PD, the boost to lower motor neuron activation is weak because of the weakened contribution from SMA.

Impairment of postural reflexes

Patients go off balance easily, and tend to fall stiffly (‘like a telegraph pole’) in response to a mild accidental push. The underlying fault is an impairment of anticipatory postural adjustments: normally, a push to the upper part of the body elicits immediate contraction of lower limb muscles appropriate for the maintenance of equilibrium.

Two other symptoms, oculomotor hypokinesia and dementia, are mentioned in the main text.

Misdiagnosis

PD has two principal kinds of presentation. In one, tremor is the predominant feature. In the other, akinesia and rigidity predominate. It is now known that more than one in five people initially diagnosed and treated as suffering from PD either do not have PD at all, or have a ‘Parkinson plus’ syndrome.

Benign essential tremor is more than twice as prevalent as PD and is often mistaken for it. It is characterized initially by a faint trembling, most noticeable when the arms are fully outstretched. Later, head-bobbing – not a feature of PD – and orthostatic (when upright) trunk tremor may appear, and a tremulous diaphragm may impart a vocal tremor. Benign essential tremor is sometimes called familial tremor because of autosomal dominant inheritance; it commonly becomes manifest during the fifth decade. When observed in the elderly, it may be called senile tremor.

The cause is unknown. Levodopa (L-dopa) (see below) is ineffective, whereas it relieves both kinds of tremor in Parkinson’s disease.

Multisystem atrophy is a ‘Parkinson plus’ degenerative disorder of brainstem, basal ganglia, and central autonomic neurons. Patients present with one or more of the following:

• akinesia/rigidity with little or no tremor

• one or more signs of autonomic failure: postural hypotension, bladder/bowel dysfunction, impotence, dry eyes and mouth, pupillary abnormalities, impaired sweating

• bilateral pyramidal tract degeneration leading to pseudobulbar palsy (Ch. 18) and ‘upper motor neuron signs’ (Ch. 16) in the limbs

• poor ocular convergence.

L-dopa is of little value.

Clinical neurology texts describe other relevant disorders, e.g. progressive supranuclear palsy and corticobasal degeneration.

Treatment of Parkinson’s disease

Drugs

The first line of treatment of PD is administration of L-dopa which can cross the blood–brain barrier and is metabolized to dopamine by surviving nigral neurons. Some 75% of patients benefit, with a reduction of symptoms by 50% or more. After several years of L-dopa therapy, many patients develop spontaneous choreiform movements (described in Clinical Panel 33.2) owing to excessive striatal response. After a year or more, the effectiveness of L-dopa declines with the progressive loss of nigral neurons, and dopamine agonist drugs are often used instead to stimulate striatal postsynaptic dopamine receptors.

Anticholinergic drugs reduce activity of the cholinergic internuncials in the striatum. They ameliorate tremor (of both kinds) in particular, but the required dosage is liable to produce one or more of the autonomic side effects listed in Clinical Panel 12.3.

Surgery

The optimal approach at present is to paralyze STN neurons by high-frequency (133 Hz) stimulation through implanted electrodes. The paralysis is caused by specific inactivation of Ca²⁺ and Na⁺ voltage-dependent channels. This approach is being used in the STN to dramatic effect in patients with full-blown tremor, bradykinesia, and rigidity. All three are greatly ameliorated in most cases. Unilateral stimulation may be sufficient for bilateral relief, of rigidity in particular. The bilateral effect of deep brain stimulation has been accounted for (in monkey experiments) by paralysis of an excitatory projection from STN to the GABAergic reticular part of the substantia nigra which, as already mentioned, gives an inhibitory supply to the cross-connected right and left locomotor center. According to this interpretation, STN blockage disinhibits the locomotor center. It is also possible that deep brain stimulation generates a new type of discharge endowed with beneficial effects.

Other approaches are under intense investigation, including grafts of fetal substantia nigra, striatal infusion of growth factors, and gene therapy.

The assistance of Dr. Tim Counihan, Department of Medicine, University College Hospital, Galway is gratefully acknowledged.

References

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Benarroch EE. Subthalamic nucleus and its connections. Neurology. 2008;70:1991-1995.

Braak H, Tredici KT. Nervous system pathology in sporadic Parkinson disease. Neurology. 2008;70:1916-1927.

Defazio G, et al. Pain as a nonmotor symptom of Parkinson disease. Arch Neurol. 2008;65:1191-1194.

Manto M. Tremorgenesis: a new conceptual scheme using reciprocally innervated circuits of neurons. J Transl Med. 2008;6:71-76.

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Figure CP 33.1.1 Diagram showing typical results of brain scans following intravenous injection of [¹⁸F]fluorodopa. Intensity of uptake is indicated as red (greatest), yellow, green, blue (least). (A) Control; (B) Parkinson’s disease.

Figure CP 33.1.2 Consequences of degeneration of the pathway from the compact part of the substantia nigra (SNpc) to the striatum (S) in Parkinson’s disease. The effects arise from loss of tonic facilitation of spiny striatal neurons bearing D₁ receptors, together with loss of tonic inhibition of those bearing D₂ receptors. The ‘direct’ pathway is disengaged, and the ‘indirect’ pathway is activated by default. (1) Corticostriate neurons from the sensorimotor cortex now strongly activate those GABAergic neurons (2) in the striatum that synapse upon others (3) in the lateral pallidal segment (GPL). The double effect is disinhibition of the subthalamic nucleus (STN). STN discharges strongly (4) onto the GABAergic neurons of the medial pallidal segment (GPM); these in turn discharge strongly (5) into the ventral lateral nucleus (VLN) of thalamus, resulting in reduced output along thalamocortical fibers (6) traveling to the supplementary motor area (SMA). Inputs (7) from SMA to corticospinal and corticoreticular fibers (CST/CRST) become progressively weaker, with pathetic consequences for initiation and execution of movements.

What are the normal functions of the motor loop?

Although movements can be produced on the opposite side of the body by direct electrical stimulation of the healthy putamen, the basal ganglia do not normally initiate movements. Nevertheless, they are active during movements of all kinds, whether fast or slow. They seem to be involved in scaling the strength of muscle contractions and, in collaboration with SMA, in organizing the requisite sequences of excitation of cell columns in the motor cortex. They come into action after the corticospinal tract has already been activated by ‘premotor’ areas including the cerebellum. Because patients with PD have so much difficulty in performing internally generated movement sequences, it is believed that the putamen provides a reservoir of learned motor programs which it is able to assemble in appropriate sequence for the movements decided upon, and to transmit the coded information to SMA.

Cognitive loop

The head of the caudate nucleus receives a large projection from the prefrontal cortex, and it participates in motor learning. PET scan studies have demonstrated increased contralateral blood flow through the head of the caudate when novel motor actions are performed with one hand. There is also increased activity in the anterior part of the contralateral putamen, globus pallidus and ventral anterior (VA) nucleus of the thalamus. The VA nucleus completes an ‘open’ cognitive loop through its projection to the premotor cortex, and a ‘closed’ loop through a return projection to the prefrontal cortex. The cortical connections of the caudate suggest that it participates in planning ahead, particularly with respect to complex motor intentions. When the novel motor task has been practiced to the level of automatic execution, the motor loop becomes active instead.

Limbic loop

Figure 33.5 depicts the limbic basal ganglia loop. This loop passes from inferior prefrontal cortex through nucleus accumbens (anterior end of the striatum, Figure 33.1D) and ventral pallidum, with return via the mediodorsal nucleus of thalamus to the inferior prefrontal cortex. (The nucleus accumbens, along with the nearby olfactory tubercle (not shown) are known as the ventral striatum.)