Striatum

The striatum consists of the caudate nucleus, putamen and ventral striatum, which are all highly cellular and well vascularized. The caudate and putamen are traversed by numerous small bundles of thinly myelinated or non-myelinated small-diameter axons, which are mostly striatal afferents and efferents. They radiate through the striatal tissue as though converging on, or radiating from, the globus pallidus. The bundles are occasionally referred to by the archaic term ‘Wilson’s pencils’ and they account for the striated appearance of the corpus striatum.

Neurones of both dorsal and ventral striata are mainly medium-sized multipolar cells. They have round, triangular or fusiform somata, mixed with a smaller number of large multipolar cells. The ratio of medium to large cells is at least 20:1. The large neurones have extensive spherical or ovoid dendritic trees up to 600 µm across. The medium-sized neurones also have spherical dendritic trees, approximately 200 µm across, which receive the synaptic terminals of many striatal afferents. The dendrites of both medium and large striatal cells may be either spiny or non-spiny. The most common neurone (usually 75% of the total) is a medium-sized cell with spiny dendrites. These cells use γ-aminobutyric acid (GABA) as their transmitter and also express the genes coding for either enkephalin or substance P/dynorphin. Enkephalinergic neurones appear to express D2 dopamine receptors. Substance P/dynorphin neurones have D1 receptors. These neurones are the major, and perhaps exclusive, source of striatal efferents to the pallidum and substantia nigra pars reticulata. The remaining medium-sized striatal neurones are non-spiny and are intrinsic cells that contain acetylcholinesterase, choline acetyltransferase and somatostatin. Large neurones with spiny dendrites contain acetylcholinesterase and choline acetyltransferase. Most, perhaps all, are intrinsic neurones, as are non-spiny large neurones.

Intrinsic synapses are probably largely asymmetric (Type II), whereas those derived from external sources are symmetric (Type I). The aminergic afferents from the substantia nigra, raphe and locus coeruleus all end as profusely branching axons with varicosities that contain dense-core vesicles (the presumed store of amine transmitters). Many of these varicosities have no conventional synaptic membrane specializations and may release transmitter in a way analogous to that found in peripheral postsynaptic sympathetic axons.

Neuroactive chemicals, whether intrinsic or derived from afferents, are not distributed uniformly in the striatum. For example, serotonin and glutamic acid decarboxylase concentrations are highest caudally, whereas substance P, acetylcholine and dopamine are highest rostrally. However, there is a finer-grain neurochemical organization that informs the view of the striatum as a mosaic of islands or striosomes (sometimes referred to as patches), each 0.5 to 1.5 mm across, packed into a background matrix. Striosomes contain substance P and enkephalin. During development, the first dopamine terminals from the substantia nigra are found in striosomes. Although this exclusivity does not persist after birth, striosomes in the caudate nucleus still contain a higher concentration of dopamine than the matrix does. The latter contains acetylcholine and somatostatin and is the target of thalamostriate axons. Receptors for at least some neurotransmitters are also differentially distributed. For example, opiate receptors are found almost exclusively within striosomes, and muscarinic receptors predominantly so. Moreover, the distribution of neuroactive substances within the striosomes is not uniform. In humans, the striosome–matrix patchwork is less evident in the putamen, where it appears to consist predominantly of matrix, than it is in the caudate nucleus.

All afferents to the striatum terminate in a mosaic manner. The size of a cluster of terminals is usually 100 to 200 µm across. Some afferent terminal clusters are not arranged in register with the clear striosome–matrix distributions seen in nigrostriatal and thalamostriatal axons. In general, afferents from neocortex end in striatal matrix, and those from allocortex end in striosomes. However, the distinction is not absolute. Thus, although afferents from the neocortex arise in layers V and VI, those from the superficial part of layer V end predominantly in striatal matrix, whereas those from deeper neocortex project to striosomes. Striatal cell bodies, which are the sources of efferents, also form clusters, but again, they are not uniformly related to striosomes. For example, the cell bodies of some striatopallidal and striatonigral axons lie clustered within striosomes; others lie outside them, but still in clusters. The neurones and neuropil of the ventral striatum are essentially similar to those of the dorsal striatum, but the striosome–matrix organization is less well defined and seems to consist predominantly of striosomes.

The major connections of the striatum are summarized in Figure 14.9. Although the connections of the dorsal and ventral divisions overlap, a generalization can be made: the dorsal striatum is predominantly connected with motor and associative areas of the cerebral cortex, whereas the ventral striatum is connected with the limbic system and orbitofrontal and temporal cortices. For both dorsal and ventral striata, the pallidum and substantia nigra pars reticulata are key efferent structures. The fundamental arrangement is the same for both divisions. The cerebral cortex projects to the striatum, which in turn projects to the pallidum and substantia nigra pars reticulata. From these, efferents leave to influence the cerebral cortex (either the supplementary motor area or the prefrontal and cingulate cortices via the thalamus) and the superior colliculus.

Fig. 14.9 Connections of the striatum. The major afferent projections to the striatum are shown on the left, and the major efferent projections from the striatum are shown on the right. CM, centromedian nucleus; GP, globus pallidus; IC, internal capsule; MD, medial dorsal nucleus; PUT, putamen; RN, red nucleus; SN, substantia nigra; VPL, ventral posterolateral nucleus of the thalamus; VPM, ventral posteromedial nucleus of the thalamus.

The entire neocortex sends glutamatergic axons to the ipsilateral striatum. For a long time, these axons were thought to be collaterals of other cortical efferents, but it is now known that they arise exclusively from small pyramidal cells in layers V and VI. It has also been suggested that some of the cells of origin lie in the supragranular ‘cortical association’ layers II and III. The projection is organized topographically. The greater part of the input from the cerebral cortex to the dorsal striatum is derived from the frontal and parietal lobes, and that from the occipitotemporal cortex is relatively small. Thus, the orbitofrontal association cortex projects to the inferior part of the head of the caudate nucleus, which lies next to the ventral striatum. The dorsolateral frontal association cortex and frontal eye fields project to the rest of the head of the caudate nucleus, and much of the parietal lobe projects to the body of the nucleus. The somatosensory and motor cortices project predominantly to the putamen. Their afferents establish a somatotopic pattern, in which the lower body is represented laterally and the upper body is represented medially. The motor cortex is unique in sending axons through the corpus callosum to the opposite putamen, where they end with the same spatial ordering. The occipital and temporal cortices project to the tail of the caudate nucleus and to the inferior putamen.

The striatum also receives afferents, which are more crudely spatially organized, from the polysensory intralaminar thalamus. The cerebelloreceptive nucleus centralis lateralis projects to the anterior striatum (especially the caudate nucleus), and the cerebello- and pallidoreceptive centromedian nucleus projects to the putamen.

The aminergic inputs to the caudate and putamen are derived from the substantia nigra pars compacta (dopaminergic group A9; Figs 14.10, 14.11), the retrorubral nucleus (dopaminergic group A8; see Fig. 14.5), the dorsal raphe nucleus (serotoninergic group B7; see Fig. 14.10) and the locus coeruleus (noradrenergic group A6). The nigrostriatal input is sometimes referred to as the ‘mesostriatal’ dopamine pathway. It reaches the striatum by traversing the H fields of the subthalamus. These aminergic inputs appear to modulate the responses of the striatum to cortical and thalamic afferent influences.

Fig. 14.10 Transverse section through the midbrain to show the arrangement of dopaminergic cell groups A9 and A10 in the substantia nigra (left) and serotoninergic cell groups B7 and B8 in the raphe.

Fig. 14.11 Scheme of the organization of the substantia nigra in transverse section. Compare with Figure 14.10. Medially, there is no sharp distinction between dopaminergic cells projecting to the dorsal striatum (pars compacta, A9) and those projecting to the ventral striatum and limbic system (paranigral nucleus, A10). Dendrites of dopaminergic neurones intrude into the pars reticulata. Note the distinctive projection systems from the pars reticulata.

(From Paxinos (Ed.), 1990. The Human Nervous System, vol. 1, Webster. pp. 889–944. Modified with permission from Elsevier.)

Efferents from the striatum pass to both segments of the globus pallidus and to the substantia nigra pars reticulata, where they end in a topically ordered fashion. Fibres ending in either the lateral or medial pallidal segment originate from different striatal cells (Figs 14.9, 14.12). Those to the lateral pallidum come from neurones that co-localize GABA and enkephalin and give rise to the so-called indirect pathway. This name refers to the fact that these striatal neurones influence the activity of basal ganglia output neurones in the medial pallidum via the intermediary of the subthalamic nucleus. Other striatal neurones, which co-localize GABA and substance P/dynorphin, project directly to the medial pallidum and are therefore described as the direct pathway.

Fig. 14.12 Major interconnections of the basal ganglia.

A second outflow is established from the striatum to the pars reticulata of the substantia nigra. This also has both direct and indirect components, via the lateral pallidum and subthalamic nucleus (Fig. 14.13). The axons of the direct striatonigral projection constitute the laterally placed ‘comb’ system, which is spatially quite distinct from the ascending dopaminergic nigrostriatal pathway. Striatonigral fibres end in a spatially ordered way in the pars reticulata.

Fig. 14.13 Schemes of the principal output connections of the basal ganglia derived from dorsal (A and B) and ventral (C and D) divisions of the striatum. In each case, pathways established through the pallidum are distinguished from those passing through the substantia nigra pars reticulata. DA, dopamine; 5HT, 5-hydroxytryptamine; NA, noradrenaline (norepinephrine).

The ventral striatum is the primary target of cortical afferents from limbic cortices, including allocortex, and from limbic-associated regions (see Fig. 14.13). Thus, the hippocampus (through the fornix) and the orbitofrontal cortex (through the internal capsule) project to the nucleus accumbens, and the olfactory, entorhinal, anterior cingulate and temporal visual cortices project to both the nucleus accumbens and the olfactory tubercle in varying degrees. The tubercle also receives afferents from the amygdala. The contiguities of the cortical areas, which project to the ventral striatum and neighbouring dorsal striatum, emphasize the imprecise nature of the boundaries between the two divisions. All the cortical regions overlap and abut one another, and they project to neighbouring parts of the dorsal striatum as well as to the ventral striatum. The fundus striati and ventromedial caudate nucleus abut the olfactory tubercle and nucleus accumbens (see Fig. 14.6) and receive connections from the orbitofrontal cortex and, to a lesser extent, the lateral prefrontal and anterior cingulate cortices (which also project to the contiguous head of the caudate nucleus).

This continuity of the ventral and dorsal striata, as revealed by the arrangements of corticostriate projections, is reinforced by consideration of the aminergic inputs to the ventral striatum. They are derived from the dorsal raphe (serotoninergic group B7), the locus coeruleus (noradrenergic group A6) and the paranigral nucleus (dopamine group A10), as well as from the most medial part of the substantia nigra pars compacta (group A9; see Figs 14.10, 14.11). The dopamine projections constitute the so-called mesolimbic dopamine pathway, which also projects to the septal nuclei, hippocampus, amygdala and prefrontal and cingulate cortices through the medial forebrain bundle. The lateromedial continuity of cell groups A9 and 10 (see Fig. 14.10) is thus reflected in the relative positions of their ascending fibres in the subthalamus and hypothalamus (the H fields and median forebrain bundle, respectively), as well as in the lateromedial topography of the dorsal and ventral striata (see Fig. 14.6), which in turn have contiguous and overlapping sources of cortical afferents.

As for the dorsal striatum, efferents from the ventral striatum project to the pallidum (in this case, the ventral pallidum) and the substantia nigra pars reticulata (Figs 14.13, 14.14). In the latter case, the connection is both direct and indirect via the subthalamic nucleus. The projections from the pars reticulata are as described for the dorsal system, but axons from the ventral pallidum reach the thalamic mediodorsal nucleus (which projects to the cingulate and prefrontal association cortex) and midline nuclei (which project to the hippocampus). Ventral pallidal axons also reach the habenular complex of the limbic system.

Fig. 14.14 Transverse section through the basal ganglia showing the principal connections of the globus pallidus with the thalamus and subthalamic nucleus.

The brain areas beyond the basal nuclei, substantia nigra and subthalamic nucleus, to which both ventral and dorsal systems appear to project, are therefore the prefrontal association and cingulate cortices and the deep superior colliculus.

CASE 1 Huntington’s Disease

A 40-year-old woman has been clinically depressed for over 5 years. She has now developed mild memory impairment and progressive cognitive decline. Her family notes that she has become ‘jittery,’ with frequent random, small-amplitude jerking movements of her limbs, along with facial grimacing. The patient’s mother was hospitalized with a diagnosis of schizophrenia, and a sibling committed suicide at age 36 years.

Examination demonstrates a moderately demented woman who exhibits facial grimacing and random choreic movements of her limbs and trunk. Her gait is abnormal, at times alarmingly so, but she does not fall. She exhibits motor impersistence, exemplified, for example, by a so-called serpentine tongue. Ocular saccades are defective.

Discussion: This woman has moderately advanced Huntington’s disease (also called Huntington’s chorea), characterized anatomically by progressive atrophy of the caudate nucleus and putamen, with neuronal loss involving especially the medium spiny neurones. The major symptoms of Huntington’s disease are chorea—an irregular, non-repetitive contraction of muscles, often described as ‘dance-like’ movements—and neurocognitive changes, initially psychiatric symptoms and eventually progressing to dementia. Cortical atrophy may be advanced, and ventriculomegaly is at times striking, reflecting both cortical and caudate atrophy (Fig. 14.15). Late in the course of the disease, as the striatum is severely affected, the chorea becomes less obvious and the patient may develop a relatively akinetic state. The disease is well recognized as genetically determined, with autosomal dominant inheritance evident in a great majority of cases, characterized by expanded trinucleotide repeats (CAG) on DNA analysis.

Fig. 14.15 Huntington’s disease. Section through the cerebral hemisphere demonstrating marked atrophy of the caudate nuclei (arrows), with compensatory enlargement of the lateral ventricles.

Other causes of chorea include post-streptococcal infection (Sydenham’s chorea, St. Vitus’ dance), pregnancy (chorea gravidarum), polycythemia vera, drug induced (e.g. levodopa), neuroacanthocytosis and a variety of inherited metabolic disorders.

Globus Pallidus

The globus pallidus lies medial to the putamen and lateral to the internal capsule. It consists of two segments, lateral (external) and medial (internal), which are separated by an internal medullary lamina and have substantially different connections. Both segments receive large numbers of fibres from the striatum and subthalamic nucleus. The lateral segment projects reciprocally to the subthalamic nucleus as part of the indirect pathway. The medial segment is considered to be a homologue of the pars reticulata of the substantia nigra, with which it shares similar cellular and connectional properties. Together, these segments constitute the main output of the basal ganglia to other levels of the neuraxis, principally to the thalamus and superior colliculus.

The cell density of the globus pallidus is less than one-twentieth that of the striatum. The morphology of the majority of cells is identical in the two segments. They are large multipolar GABAergic neurones that closely resemble those of the substantia nigra pars reticulata. The dendritic fields are discoid, with planes at right angles to incoming striatopallidal axons, each of which potentially contacts many pallidal dendrites en passant. This arrangement, coupled with the diameters of the dendritic fields (>500 µm), suggests that a precise topographical organization is unlikely within the pallidum.

Striatopallidal fibres are of two main types. They project to either the lateral or medial pallidal segment. Those projecting to the lateral segment constitute the beginning of the so-called indirect pathway. They use GABA as their primary transmitter and also contain enkephalin. Efferent axons from neurones in the lateral segment pass through the internal capsule in the subthalamic fasciculus and travel to the subthalamic nucleus (see Fig. 15.18).

Striatopallidal axons destined for the medial pallidum constitute the so-called direct pathway. Like the indirect projection, these also use GABA as their primary transmitter, but they also contain substance P/dynorphin, rather than enkephalin. Efferent axons from the medial pallidal segment project through the ansa lenticularis and fasciculus lenticularis (see Figs 14.12, 15.18). The former runs around the anterior border of the internal capsule, and the latter penetrates the capsule directly. Having traversed the internal capsule, both pathways unite in the subthalamic region, where they follow a horizontal hairpin trajectory and turn upward to enter the thalamus as the thalamic fasciculus. The trajectory circumnavigates the zona incerta and creates the so-called H fields of Forel (see Figs 14.5, 14.14, 15.18). Within the thalamus, pallidothalamic fibres end in the ventral anterior and ventral lateral nuclei and in the intralaminar centromedian nucleus. These, in turn, project excitatory (presumed glutamatergic) fibres primarily to the frontal cortex, including the primary and supplementary motor areas. The medial pallidum also projects fibres caudally to the pedunculopontine nucleus (see Fig. 14.14). This lies at the junction of the midbrain and the pons, close to the superior cerebellar peduncle, and corresponds approximately to the physiologically identified mesencephalic locomotor region.

CASE 2 Wilson’s Disease

A 22-year-old man develops an increasingly severe tremor of the limbs, sometimes with a distinct wing-beating character, along with dysarthria, an ataxic gait and occasional dystonic features involving the face or limbs. Variable muscular rigidity sometimes interferes with swallowing. Family members describe psychiatric symptoms such as depression and emotional lability preceding the onset of neurological symptoms; he has also exhibited frankly psychotic behaviour.

In addition to the neurological abnormalities predicted by these symptoms, ophthalmic examination demonstrates a yellowish brown Kayser–Fleischer ring involving the corneal limbus, representing a deposition of copper in Descemet’s membrane (Fig. 14.16). Imaging demonstrates symmetric ventricular enlargement with widespread atrophic changes, most pronounced in the basal ganglia and thalamus; the putamen is especially involved, with striking vacuolization.

Fig. 14.16 Wilson’s disease (hepatolenticular degeneration). Typical Kayser–Fleischer ring reflecting deposition of copper in Descemet’s membrane.

Discussion: This man has Wilson’s disease (hepatolenticular degeneration), a progressive familial metabolic disorder reflecting abnormal copper metabolism, with a significant reduction or absence of the protein ceruloplasmin and widespread copper deposition. The liver is typically involved, often with changes suggesting cirrhosis (so-called hobnail liver). Hepatic changes may precede the development of neurological abnormalities. The Kayser–Fleischer ring is often considered the only truly pathognomonic sign in clinical neurology.

Substantia Nigra

The substantia nigra is a nuclear complex deep to the crus cerebri in each cerebral peduncle of the midbrain. It consists of a pars compacta and a pars reticulata (see Figs 14.10, 14.11). The pars compacta, together with the smaller pars lateralis, corresponds to dopaminergic cell group A9. With the retrorubral nucleus (group A8), it makes up most of the dopaminergic neurone population of the midbrain and is the source of the mesostriatal dopamine system that projects to the striatum. The pars compacta of each side is continuous with its opposite counterpart through the ventral tegmental dopamine group A10, which is sometimes known as the paranigral nucleus. This is the source of the mesolimbic dopamine system, which supplies the ventral striatum and neighbouring parts of the dorsal striatum, as well as the prefrontal and anterior cingulate cortices. The dopaminergic neurones of the pars compacta (group A9) and paranigral nucleus (ventral tegmental group A10) also contain cholecystokinin or somatostatin.

The pars reticulata contains large multipolar cells that are very similar to those of the pallidum. Together they constitute the output neurones of the basal ganglia system. Their disc-like dendritic trees, like those of the pallidum, are oriented at right angles to afferents from the striatum, probably making en passant contacts. Like the striatopallidal axons, of which they may be collaterals, striatonigral axons use GABA and substance P or enkephalin. They distribute differentially in the pars reticulata, such that the enkephalinergic axons terminate in the medial part, whereas substance P axons terminate throughout.

The efferent neurones of the pars reticulata are GABAergic. They project to the deep (polysensory) layers of the superior colliculus and to the brain stem reticular formation, including the pedunculopontine nucleus. The pathway from the striatum to the superior colliculus, via the substantia nigra pars reticulata, is thought to function in the control of gaze in a manner analogous to the pathway that initiates general body movement via the pallidum, thalamus and supplementary motor cortex. The uncontrolled or fixed gaze disturbances of advanced Parkinson’s disease, progressive supranuclear palsy and Huntington’s disease tend to support this.

Subthalamic Nucleus

The subthalamic nucleus is a biconvex, lens-shaped nucleus in the subthalamus of the diencephalon. It lies medial to the internal capsule, immediately rostral to the level at which the latter becomes continuous with the crus cerebri of the midbrain (see Figs 14.2, 14.5, 14.8). Within its substance, small interneurones intermingle with large multipolar cells with dendrites, which extend for about one-tenth the diameter of the nucleus. It is encapsulated dorsally by axons, many of which are derived from the subthalamic fasciculus and carry a major GABAergic projection from the lateral segment of the globus pallidus as part of the indirect pathway. It also receives afferents from the cerebral cortex. The subthalamic nucleus is unique in the intrinsic circuitry of the basal ganglia, in that its cells are glutamatergic. They project excitatory axons to both the globus pallidus and the substantia nigra pars reticulata. Within the pallidum, subthalamic efferent fibres end predominantly in the medial segment, but many also end in the lateral segment.

The subthalamic nucleus plays a central role in the normal function of the basal ganglia and in the pathophysiology of basal ganglia–related disorders. Destruction of the nucleus, which occurs rarely as a result of stroke, results in the appearance of violent, uncontrolled involuntary movements, known as ballism (ballismus). The subthalamic nucleus is also crucially involved in the pathophysiology of Parkinson’s disease and is the target of functional neurosurgical therapy for the condition.

Pathophysiology of Basal Ganglia Disorders

The normal functions of the basal ganglia are difficult to summarize succinctly. As far as their role in movement control is concerned, however, a reasonable definition is that they function to promote and support patterns of behaviour and movement that are appropriate in the prevailing circumstances and to inhibit unwanted or inappropriate behaviour and movements. This is exemplified by disorders of the basal ganglia, which are characterized, depending on the underlying pathology, by an inability to initiate and execute wanted movements (as in Parkinson’s disease) or an inability to prevent unwanted movements (as in Huntington’s disease).

CASE 5 Parkinson’s Disease

A middle-aged man finds that he can no longer play tennis with his usual facility. His gait has become somewhat slow and shuffling, and he sometimes experiences defective equilibrium. His wife notes that his posture has become stooped and his speech is often muffled and difficult to understand, tending to fade away during a conversation. His handwriting has become small, at times virtually illegible. The patient admits to having difficulty rising from a chair or turning over in bed. Rapid tremor of the hands has appeared, initially involving only one hand and associated with impaired dexterity in that limb.

Examination demonstrates a stooped posture; widespread but asymmetric cogwheel rigidity; impaired hand dexterity; a distal tremor at repose, lessening with intention; impaired ocular convergence; a masked facies; and a loss of spontaneous movements, with striking difficulty initiating movements. Once instituted, all movements are carried out slowly (bradykinesia). Postural reflexes are defective. His gait is shuffling, with a decidedly propulsive and festinating quality (marche a petit pas).

Discussion: This patient exhibits the typical features of Parkinson’s disease (true paralysis agitans), with a characteristic combination of hypokinetic (lack of spontaneous movements, bradykinesia, muscle rigidity, impaired dexterity) and hyperkinetic (tremor) signs. Many patients also exhibit bradyphrenia (i.e. slowing of mental processes), and a substantial number become frankly demented.

Parkinsonian symptoms (‘Parkinsonism’) may appear in a variety of other degenerative disorders, including corticobasal ganglionic degeneration, progressive supranuclear palsy, olivopontocerebellar atrophy, Alzheimer’s disease and other dementing illnesses, multiple system atrophy and a host of metabolic derangements secondary to toxic exposure to manganese, carbon monoxide, MPTP (methyl-phenyl-tetrahydropyridine) and drugs such as phenothiazines.

Pathological changes in Parkinson’s disease predominate in the zona compacta of the substantia nigra (Fig. 14.17), with loss of melanin-containing neurons and the appearance of intracytoplasmic Lewy bodies, representing an accumulation of the protein synuclein and a resultant degeneration of the nigrostriatal pathway and reduction in striatal dopamine. Anatomical changes may in fact be much more widespread, involving a variety of brain stem nuclei as well as the cerebral cortex.

Fig. 14.17 Parkinson’s disease. Section through the midbrain demonstrating depigmentation in the substantia nigra due to loss of melanin (arrow).

Parkinson’s disease is the most common pathological condition affecting the basal ganglia. As noted, it is characterized by akinesia, muscular rigidity and tremor and, due to degeneration of the dopaminergic neurones of the substantia nigra pars compacta, depletion of dopamine levels in the striatum. This has been amply confirmed by postmortem studies. Furthermore, in Parkinsonian patients, positron emission tomography (PET) reveals a deficit of dopamine storage and reuptake, due to a loss of nigrostriatal terminals, but intact dopamine receptors, which are located on the medium spiny neurones, the target of the nigrostriatal pathway.

Dopamine appears to have a dual action on medium spiny striatal neurones. It inhibits those of the indirect pathway and excites those of the direct pathway. Consequently, when dopamine is lost from the striatum, the indirect pathway becomes overactive, and the direct pathway becomes underactive (Fig. 14.18). Overactivity of the striatal projection to the lateral pallidum results in inhibition of pallidosubthalamic neurones and, consequently, overactivity of the subthalamic nucleus. Subthalamic efferents mediate excessive excitatory drive to the medial globus pallidus and substantia nigra pars reticulata. This is exacerbated by underactivity of the GABAergic, inhibitory direct pathway. Overactivity of basal ganglia output then inhibits the motor thalamus and its excitatory thalamocortical connections. Although this description is little more than a first approximation of the underlying pathophysiology, this model of the basis of Parkinsonian symptoms has led to the introduction of new neurosurgical approaches to the treatment of Parkinson’s disease, based on lesioning and deep brain stimulation of the medial globus pallidus and subthalamic nucleus (see later).

Fig. 14.18 Pathophysiology of Parkinson’s disease. Dotted lines indicate dysfunctional pathways.

(By permission from Crossman, A.R., Neary, D., 2000. Neuroanatomy, 2nd ed. Churchill Livingstone, Edinburgh.)

The current medical treatment for Parkinson’s disease relies on levodopa (L-dopa, L-dihydroxyphenylalanine), the immediate metabolic precursor of dopamine; dopamine agonists; or monoamine oxidase inhibitors. Although these drugs usually provide good symptomatic relief for many years, levodopa and, to a lesser extent, dopamine agonists eventually lead to the development of motor complications, including dyskinesias. The involuntary movements that occur as a consequence of long-term treatment of Parkinson’s disease resemble those seen in Huntington’s disease, tardive dyskinesia and ballism. Experimental evidence suggests that these may share a common neural mechanism (Fig. 14.19). Thus, the indirect pathway becomes underactive, due to the effects of dopaminergic drugs in Parkinson’s disease or the degeneration of the striatopallidal projection to the lateral pallidum in Huntington’s disease. This leads to physiological inhibition of the subthalamic nucleus by overactive pallidosubthalamic neurones. The involvement of the subthalamic nucleus explains why the dyskinetic movements of levodopa-induced dyskinesia and Huntington’s disease resemble those of ballism produced by lesion of the subthalamic nucleus. Underactivity of the subthalamic nucleus removes the excitatory drive from medial pallidal neurones, which are known to be underactive in dyskinesias. Once again, this is an oversimplification. Although it is true that underactivity of the medial globus pallidus is associated with dyskinesias, it is also known that lesions of the globus pallidus alleviate them. This suggests that the dynamic aspects of pallidal and nigral efferent activity are important factors in the generation of dyskinesia.

Fig. 14.19 Pathophysiology of dyskinesias. Dotted lines indicate dysfunctional pathways.

(By permission from Crossman, A.R., Neary, D., 2000. Neuroanatomy, 2nd ed. Churchill Livingstone, Edinburgh.)

Another manifestation of basal ganglia dysfunction is dystonia, which is characterized by increased muscle tone and abnormal postures. This may occur as a consequence of levodopa treatment in Parkinson’s disease or in inherited disease (e.g. idiopathic torsion or Oppenheim’s dystonia). Focal dystonic syndromes are widely recognized, including blepharospasm (Meige syndrome), torticollis, spastic dysphonia and writer’s cramp. The pathophysiological basis of dystonia is unclear. Like dyskinesia, it is probably caused by underactivity of basal ganglia output, so deep brain stimulation of the globus pallidus may be beneficial.

There is evidence that dysfunction of the basal ganglia is involved in other complex, less well-understood behavioural disorders. In animal experiments, lesions of the basal ganglia, especially of the caudate nucleus, induce uncontrollable hyperactivity (e.g. obstinate progression, incessant pacing and other constantly repeated behaviours). Such evidence has led to the notion that the corpus striatum enables the individual to make motor choices and avoid ‘stimulus-bound’ behaviour. PET studies in humans have shown that sufferers from obsessive-compulsive disorder, which is characterized by repeated ritualistic motor behaviour and intrusive thoughts, exhibit abnormal activity in the prefrontal cortex and caudate nuclei. There have been similar observations in the hyperactive child syndrome. In this respect, it may be significant that the basal ganglia, besides receiving connections from the frontal lobe and limbic cortices, also have an ascending influence on the prefrontal and cingulate cortices through the substantia nigra pars reticulata and dorsomedial and ventromedial thalamus (see Fig. 14.13B–D).

Before the advent of levodopa, neurosurgery for Parkinson’s disease was commonplace. The globus pallidus and thalamus were favoured targets for chemical or thermal lesions. Pallidotomy and thalamotomy often improved rigidity and tremor, but they produced little consistent beneficial effect on akinesia. With the introduction of levodopa therapy, which had a profound effect on akinesia, the use of surgical treatment for Parkinson’s disease declined. However, it soon became clear that long-term use of levodopa was associated with a number of side effects, such as dyskinesias, ‘wearing off’ and the ‘on–off’ phenomenon. More recently, better understanding of the pathophysiology of movement disorders, particularly Parkinson’s disease, has stimulated renewed use of neurosurgery to treat movement disorders.

In primates that were made Parkinsonian with the neurotoxin MPTP, lesioning the subthalamic nucleus alleviated tremor, rigidity and bradykinesia. This finding raised the possibility that the subthalamic nucleus could be used as a clinical target. Indeed, lesions of the subthalamic nucleus in humans exert a powerful effect in alleviating tremor, rigidity and bradykinesia; however, the likelihood of side effects is not trivial (the subthalamic nucleus is a small structure wrapped by fibres of passage and close to the hypothalamus and internal capsule).

In 1992, Laitinen and colleagues reintroduced pallidotomy for the treatment of end-stage Parkinson’s disease but confined the lesions to the posteroventral part of the internal pallidal segment. These lesions were found to be extremely reliable in abolishing contralateral rigidity and drug-induced dyskinesias, with slightly less efficacy on tremor and bradykinesia.

The implantation of deep brain electrodes to inhibit cells in the vicinity through high-frequency pulses generated by a pacemaker has been a concept since the early 1970s, but it did not become a widespread reality until the late 1980s, as a result of technological advances. The introduction of this technique, which avoids making permanent lesions, made bilateral surgery safer. There have been numerous reports of the effectiveness of both bilateral pallidal and subthalamic nucleus stimulation (Figs 14.20, 14.21). Subthalamic nucleus stimulation is favoured by most groups because, unlike pallidal stimulation, it allows patients to reduce their anti-Parkinsonian medication.

Fig. 14.20 Magnetic resonance image showing placement of deep brain stimulating electrodes bilaterally in the globus pallidus of a patient with Parkinson’s disease.

(Courtesy of Professor T. Z. Aziz, Radcliffe Infirmary, Oxford and Charing Cross Hospital, London.)

Fig. 14.21 Magnetic resonance image showing placement of deep brain stimulating electrodes bilaterally in the subthalamic nucleus of a patient with Parkinson’s disease.

(Courtesy of Professor A. M. Lozano, Toronto Western Hospital.)

Serendipity also has a role in such surgery. Clinically, Parkinsonian patients can develop painful dystonic posturing of their limbs, which responds dramatically to bilateral pallidal stimulation. This has led to preliminary studies of bilateral pallidal stimulation for dystonia, with promising results. Because it is believed that pallidal neurones fire at rates below normal in dystonia, this presents a conceptual puzzle, and it is unknown how stimulation works. It appears that the neural mechanism underlying this therapeutic effect on dystonia differs from that in Parkinson’s disease and tremor, because in dystonia, the improvement may take weeks to emerge, whereas it is immediate in the case of Parkinson’s disease.