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 striatum 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 60 μm across. The medium-sized neurones also have spherical dendritic trees, approximately 20 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 utilize γ-aminobutyric acid (GABA) as their transmitter and also express the genes coding for either enkephalin or substance P/dynorphin. Enkephalinergic neurones express D2 dopamine receptors. Substance P/dynorphin neurones express 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 aspiny, and are intrinsic cells that contain acetylcholinesterase (AChE), choline acetyltransferase (CAT) and somatostatin. Large neurones with spiny dendrites contain AChE and CAT; most, perhaps all, are intrinsic neurones. Aspiny large neurones are all intrinsic neurones.

Intrinsic synapses are probably largely asymmetric (type II), while 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, which 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 (GAD) concentrations are highest caudally, while substance P, acetylcholine (ACh) 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 0.5–1.5 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 adult caudate nucleus still contain a higher concentration of dopamine than the matrix. The latter contains ACh 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 100–200 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: 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 are not uniformly related to striosomes. For example, the cell bodies of some striatopallidal and striatonigral axons lie clustered within striosomes, and 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 striosomal/matrix organization is less well-defined, and seems to consist predominantly of striosomes.

The major connections of the striatum are summarized in Fig. 22.9. Although the connections of the dorsal and ventral divisions overlap, the generalization can be made that the dorsal striatum is predominantly connected with motor and associative areas of the cerebral cortex, whilst the ventral striatum is connected with the limbic system and orbitofrontal and temporal cortices. For both dorsal and ventral striatum, 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, and efferents from the pallidum and substantia nigra pars reticulata influence the cerebral cortex (either the supplementary motor area or prefrontal and cingulate cortices via the thalamus) and the superior colliculus (see below).

Fig. 22.9 Connections of the striatum. The major afferent projections to the striatum are shown on the right and major efferent projections from the striatum on the left.

The entire neocortex sends glutamatergic axons to the ipsilateral striatum. Previously, these axons were thought to be collaterals of cortical efferents to other regions, 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, that from the occipitotemporal cortex being 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 cerebello-receptive 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; Fig. 22.10), the retrorubral nucleus (dopaminergic group A8), the dorsal raphe nucleus (serotoninergic group B7; Fig. 22.10) 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 Forel) in the subthalamus and running in the median forebrain bundle. These aminergic inputs appear to modulate the responses of the striatum to cortical and thalamic afferent influences.

Fig. 22.10 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.

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 (Fig. 22.9). Those to the lateral pallidum come from neurones which 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’.

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 (Figs 22.11, 22.12). 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. 22.11 The principal output connections of the basal ganglia derived from dorsal (A) and ventral (B) 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; NA, noradrenaline (norepinephrine); 5HT, 5-hydroxytryptamine.

Fig. 22.12 The principal connections of the basal ganglia with the diencephalon and brain stem.

The ventral striatum is the primary target of cortical afferents from limbic cortices, including allocortex, and from limbic associated regions (Fig. 22.11). Thus, the hippocampus (through the fornix) and 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 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 (Fig. 22.6), and receive connections from the orbitofrontal cortex and, to a lesser extent, from 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 from the paranigral nucleus (dopamine group A10), as well as the most medial part of the substantia nigra pars compacta (A9) (Fig. 22.10). The dopamine projections constitute the so-called mesolimbic dopamine pathway, which also projects to the septal nuclei, hippocampus and amygdala and prefrontal and cingulate cortices through the medial forebrain bundle. The lateromedial continuity of cell groups A9 and 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 (Fig. 22.6), which in turn have contiguous and overlapping sources of cortical afferents.

As with 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 22.11, 22.12). 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 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.

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.

GLOBUS PALLIDUS

The globus pallidus (pallidum) 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 which 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 of 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, therefore, 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 either to the lateral or the medial pallidal segment. Those projecting to the lateral segment constitute the beginning of the so-called ‘indirect pathway’. They utilize 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 (Fig. 22.13).

Fig. 22.13 Coronal section of the brain showing the major connections of the basal ganglia with the diencephalon.

Striatopallidal axons destined for the medial pallidum constitute the so-called ‘direct pathway’. Like the indirect projection, these also utilize GABA as their primary transmitter but they also contain substance P and dynorphin, rather than enkephalin. Efferent axons from the medial pallidal segment project through the ansa lenticularis and fasciculus lenticularis (Fig. 22.13). The former runs round 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 upwards to enter the thalamus as the thalamic fasciculus. The trajectory circumnavigates the zona incerta and creates the so-called ‘H’ fields of Forel (Figs 22.5, 22.13). 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 (Fig. 22.12). 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’.

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, pars reticulata and a smaller pars lateralis (Fig. 22.10). The pars compacta and pars lateralis correspond to the dopaminergic cell group A9. Together with the retrorubral nucleus (A8) they comprise most of the dopaminergic neurone population of the midbrain and are the source of the mesostriatal dopamine system that projects to the striatum. The pars compacta of each side is continuous with its contralateral 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, and the prefrontal and anterior cingulate cortices. The dopaminergic neurones of the pars compacta (A9) and paranigral nucleus (ventral tegmental group A10) also contain cholecystokinin (CCK) or somatostatin.

The neurones of the pars reticulata and pallidum collectively constitute the output neurones of the basal ganglia system. The pars reticulata contains large multipolar cells, very similar to those of the pallidum: their disc-like dendritic trees, like those of the pallidum, are orientated 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 utilize 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 (PSP) 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 (Figs 22.2, 22.5, 22.8). Within the nucleus, small interneurones intermingle with large multipolar cells with dendrites which extend for about one-tenth the diameter of the nucleus. The nucleus is encapsulated dorsally by axons, many of which are derived from the subthalamic fasciculus: they 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 and project excitatory axons to both the globus pallidus and 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 a target for functional neurosurgical therapy of 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, 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).

Parkinson’s disease is the most common pathological condition affecting the basal ganglia. It is characterized by akinesia, muscular rigidity and tremor due to degeneration of the dopaminergic neurones of the substantia nigra pars compacta (which project to the striatum in the nigrostriatal pathway). As a consequence, dopamine terminals are lost in the striatum and dopamine levels are severely depleted. Dopamine receptors, which are located upon medium spiny neurones, and are the target of the nigrostriatal pathway, are spared.

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. 22.14). 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. While 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 upon lesioning and deep brain stimulation of the medial globus pallidus and subthalamic nucleus (see below).

Fig. 22.14 Pathophysiology of Parkinson’s disease (A) and dyskinesias (B).

(Adapted from Crossman AR, Neary D 2000 Neuroanatomy, 2nd edition. Edinburgh: Churchill Livingstone.)

The current medical treatment for Parkinson’s disease relies upon levodopa (L-DOPA; L-dihydroxyphenylalanine), the immediate metabolic precursor of dopamine, or upon dopamine agonists. Whilst these usually provide good symptomatic relief for many years, eventually they lead to the development of side-effects, 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. 22.14). Thus, the indirect pathway becomes underactive, e.g. 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. Whilst 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.

Another manifestation of basal ganglia dysfunction is dystonia, which is characterized by increased muscle tone and abnormal postures. Dystonia may occur as a consequence of levodopa treatment in Parkinson’s disease or inherited disease (e.g. early-onset torsion, or Oppenheim’s dystonia, an autosomal dominant disorder most commonly associated with a mutation in the DYT1 gene that encodes torsinA). The pathophysiological basis of dystonia is unclear. Like dyskinesias it is probably caused by underactivity of basal ganglia output, and 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). This and other evidence has led to the notion that the corpus striatum enables the individual to make motor choices and to avoid ‘stimulus-bound’ behaviour. PET scanning studies in man have shown that sufferers from obsessive-compulsive disorder (OCD), which is characterized by repeated ritualistic motor behaviour and intrusive thoughts, exhibit abnormal activity in the prefrontal cortex and caudate nuclei. There are similar suggestive 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 (Fig. 22.11).

Before the advent of levodopa therapy, 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 upon akinesia. With the arrival of levodopa therapy, which has a profound effect upon akinesia, the surgical treatment of Parkinson’s disease underwent progressive decline. 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 recent advances in understanding the pathophysiology of movement disorders, and in particular Parkinson’s disease, have stimulated a renaissance in the use of neurosurgery to treat movement disorders.

Lesioning the subthalamic nucleus in experimental primates that had been made parkinsonian with the neurotoxin MPTP dramatically alleviated the parkinsonian symptoms, suggesting that the subthalamic nucleus might be an appropriate clinical target. While therapeutic surgical lesions of the subthalamic nucleus can alleviate tremor, rigidity and bradykinesia in patients with Parkinson’s disease, the risk 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. Perhaps not surprisingly, relatively few centres perform this procedure.

In 1992, Laitinen et al reintroduced pallidotomy for the treatment of end-stage Parkinson’s disease, but confined the lesions to the posteroventral part of the medial 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.

Implantation of deep-brain electrodes through which high-frequency pulses generated by a pacemaker could inhibit cells in the vicinity has been a concept since the early 1970s, but did not become a widespread reality until the late 1980s, as a result of technological advances. The introduction of the technique of deep brain stimulation (DBS), 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 22.15, 22.16). Subthalamic nucleus stimulation is favoured by most groups because, unlike pallidal stimulation, it allows patients to reduce their anti-parkinsonian medication.

Fig. 22.15 MRI image showing placement of deep brain stimulating electrodes bilaterally in the globus pallidus of a patient with Parkinson’s disease.

(By courtesy of Professor TZ Aziz, Radcliffe Infirmary, Oxford and Charing Cross Hospital, London, UK.)

Fig. 22.16 MRI image showing placement of deep brain stimulating electrodes bilaterally in the subthalamic nucleus of a patient with Parkinson’s disease.

(By courtesy of Professor AM Lozano, Toronto Western Hospital, Toronto, Canada.)

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 very promising results. Since it is held that in dystonia the pallidal neurones fire at rates below normal, this presents quite a puzzle as it is open to question how stimulation works. It also would appear that the neural mechanism that underlies this therapeutic effect on dystonia may differ 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.

An even more recent neurosurgical development in the therapy of Parkinson’s disease has involved targeting the pedunculopontine nucleus (nucleus tegmenti pedunculopontinus; PPN). The PPN corresponds approximately to the so-called ‘mesencephalic locomotor region’: stimulation of this region in animals elicits locomotion. The PPN is maximal at the boundary between midbrain and pons, and is bounded laterally by the medial leminiscus and medially by the superior cerebellar peduncle and its decussation. Dorsally it is bounded by the pontine cuneiform and subcuneiform nuclei and ventrally by the pontine reticular formation. Its most caudal pole is adjacent to the locus coeruleus.

The PPN has a caudal pars compacta that consists largely of cholinergic neurones and a rostral pars dissipata that consists largely of glutamatergic neurones. It is known to receive GABAergic efferent fibres from the globus pallidus and substantia nigra. In animal models of Parkinson’s disease these projections are overactive and the PPN is inhibited. Taken in conjunction with other experimental evidence, this suggests the possibility that the PPN is involved in the pathophysiology of disturbances of locomotion, gait and posture in Parkinson’s disease. Recently, DBS of PPN through implanted electrodes has been applied in drug-resistant akinetic parkinsonian patients (Fig. 22.17). Low frequency stimulation alleviates postural instability and on-medication gait freezing, symptoms which conventional medication and surgery fail to improve.

Fig. 22.17 MRI images showing placement of deep brain stimulating electrodes in the pedunculopontine nucleus of a patient with Parkinson’s disease. (A) Coronal view; (B) Axial view.

(By courtesy of Professor AM Lozano, Toronto Western Hospital, Toronto, Canada.)