Download The subthalamic nucleus in the context of movement disorders

DOI: 10.1093/brain/awh029
Advanced Access publication November 7, 2003
Brain (2004), 127, 4±20
REVIEW ARTICLE
The subthalamic nucleus in the context of
movement disorders
Clement Hamani,1 Jean A. Saint-Cyr,1 Justin Fraser,2 Michael Kaplitt2 and Andres M. Lozano1
1Division of Neurosurgery, Toronto Western Hospital,
Toronto Western Research Institute, Ontario, Canada and
2Department of Neurological Surgery, Weill Medical
College of Cornell University and Division of
Neurosurgery, Memorial-Sloan Kettering Cancer Center,
New York, NY, USA
Summary
The subthalamic nucleus (STN) has been regarded as
an important modulator of basal ganglia output. It
receives its major afferents from the cerebral cortex,
thalamus, globus pallidus externus and brainstem, and
projects mainly to both segments of the globus pallidus,
substantia nigra, striatum and brainstem. The STN is
essentially composed of projection glutamatergic neurons. Lesions of the STN induce choreiform abnormal
movements and ballism on the contralateral side of the
body. In animal models of Parkinson's disease this
nucleus may be dysfunctional and neurons may ®re in
Correspondence to: Andres M. Lozano Division of
Neurosurgery, Toronto Western Hospital, West Wing
4-447, 399 Bathurst Street, Toronto, Canada ON M5T 2S8
E-mail: [email protected] or c.hamani@
sympatico.ca
oscillatory patterns that can be closely related to tremor. Both STN lesions and high frequency stimulation
ameliorate the major motor symptoms of parkinsonism
in humans and animal models of Parkinson's disease
and reverse certain electrophysiological and metabolic
consequences of dopamine depletion. These new ®ndings
have led to a renewed interest in the STN. The aim of
the present article is to review brie¯y the major anatomical, pharmacological and physiological aspects of
the STN, as well as its involvement in the pathophysiology and treatment of Parkinson's disease.
Keywords: subthalamic nucleus; Parkinson's disease; basal ganglia; deep brain stimulation; movement disorders
Abbreviations: AMPA = 2-aminomethyl-phenylacetic acid; BG = basal ganglia; CM = centromedian; EPSP = excitatory
post-synaptic potential; GPe = globus pallidus externus; GPi = globus pallidus internus; HFS = high frequency stimulation;
IPSP = inhibitory post-synaptic potential; mGluR = multiple glutamate receptors; MPTP = 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine; NMDA = N-methyl-D-aspartate; Pf = parafascicular; PPN = pedunculopontine nucleus; SNc =
substantia nigra compacta; SNr = substantia nigra reticulata; STN = subthalamic nucleus
Introduction
The subthalamic nucleus has been regarded as an important
structure in modulation of activity of output basal ganglia
structures and has been implied in the pathophysiology of
Parkinson's disease. Despite the current interest, little is
known about its normal function in relation to movement. In
the present study we review the anatomical, pharmacological
and physiological attributes of the STN, with particular
attention to its involvement in the pathophysiology of
movement disorders and other neurological conditions.
Anatomy of the subthalamic nucleus
The subthalamic nucleus is a biconvex-shaped structure
surrounded by dense bundles of myelinated ®bres (Fig. 1)
(Yelnik and Percheron, 1979). Its anterior and lateral limits
are enveloped by ®bres of the internal capsule that separate
this nucleus laterally from the globus pallidus.
Rostromedially, the STN abuts on the nucleus of the Fields
of Forel, the Field H of Forel and the posterior lateral
hypothalamic area. Posteromedially it is adjacent to the red
nucleus. Its ventral limits are the cerebral peduncle and the
substantia nigra (ventrolaterally). Dorsally the STN is limited
by a portion of the fasciculus lenticularis and the zona incerta,
which separate this nucleus from the ventral thalamus
(Schaltenbrand and Wahren, 1977; Yelnik and Percheron,
1979; Williams and Warwick, 1980; Chang et al., 1983; Kita
et al., 1983; Parent and Hazrati, 1995).
Brain Vol. 127 No. 1 ã Guarantors of Brain 2003; all rights reserved
Subthalamic nucleus
Fig. 1 Representation of the major anatomical structures and ®bre
tracts associated with the subthalamic nucleus. AL = ansa
lenticularis; CP = cerebral peduncle; FF = Fields of Forel; GPe =
globus pallidus externus; GPi = globus pallidus internus; H1 = H1
Field of Forel (thalamic fasciculus); IC = internal capsule; LF =
lenticular fasciculus (H2); PPN = pedunculopontine nucleus; Put =
putamen; SN = substantia nigra; STN = subthalamic nucleus; Thal
= thalamus; ZI = zona incerta.
Several ®bre tracts course near the borders of the STN. The
subthalamic fasciculus consists of ®bres that interconnect the
STN and globus pallidus. This ®bre bundle arises from the
inferolateral border of the STN and crosses the internal
capsule in its trajectory.
The ansa lenticularis contains ®bres from the globus
pallidus internus (GPi) that project towards the thalamus. It
originates mainly from the lateral portion of the GPi coursing
in a medial, ventral and rostral direction, sweeping anteriorly
around the posterior limb of the internal capsule. Thereafter,
these ®bres course posteriorly to enter the H Field of Forel.
The lenticular fasciculus also contains pallidothalamic
®bres and is designated H2 Field of Forel. This tract arises
from the medial aspect of the GPi, perforates the internal
capsule, and forms a bundle ventral to the zona incerta.
Although some ®bres from the lenticular fasciculus may be
found dorsal to the STN, most of this tract courses rostral to
the nucleus. In the H Field of Forel, the lenticular fasciculus
joins the ansa lenticularis and ®bres that come from the
superior cerebellar peduncle and brainstem, forming the
thalamic fasciculus (H1 Field of Forel) (Parent et al., 2000).
5
The view of the ansa lenticularis and lenticular fasciculus as
distinct anatomic pathways has been challenged by recent
papers (Baron et al., 2001).
Dopaminergic nigrostriatal ®bres leave the dorsal and
medial aspects of the substantia nigra compacta and course
medially and dorsally in relation to the STN (through the
medial forebrain bundle), reaching the H Field of Forel from
where they ascend to terminally arborize in the striatum. This
system gives rise to ®bres that innervate all major structures
of the basal ganglia, including the STN and the globus
pallidus (Parent et al., 2000). Fibre tracts that lie posterior to
the STN include the medial lemniscus, spinothalamic tract,
trigeminothalamic tract and reticulothalamic tract (Butler and
Hodos, 1996).
The average number of neurons in each STN nucleus varies
from species to species and has been estimated to be ~25 000
in rats, 35 000 in marmosets, 155 000 in macaques, 230 000
in baboons and 560 000 in humans (Oorschot, 1996;
Hardman et al., 1997, 2002). The density of STN neurons
(number of neurons per volume of tissue) in rodents, primates
and humans does not vary signi®cantly, as the volume of this
nucleus progressively increases among species. The volume
of the STN is ~0.8 mm3 in rats, 2.7 mm3 in marmosets,
34 mm3 in macaques, 50 mm3 in baboons and 240 mm3 in
humans (Hardman et al., 2002). The relationship between the
volume of the STN and the total volume of the brain in nonhuman primates and humans is proportionally similar
(Carpenter, 1982).
The vascular supply to the STN is from perforating
branches of the anterior choroidal artery (peduncolosubthalamic arteries), posterior communicating artery
(pedunculosubthalamic arteries and branches of the thalamic
polar artery) and posteromedial choroidal arteries (lateral
mesencephalosubthalamic arteries). The former two arteries
are branches of the internal carotid artery, whereas the latter
vessels are part of the posterior circulation. The contribution
of each of these vessels to the arterial supply of the STN is
variable and their vascular territories intermingle (Percheron,
1982). The antiparkinsonian effects of anterior choroidal
artery ligation, proposed in the past for the treatment of
Parkinson's disease (Cooper, 1953), might have been related,
at least in part, to the infarction of the STN and related
structures.
Histology of the subthalamic nucleus
The subthalamic nucleus is populated mainly by projection
neurons (Rafols and Fox, 1976; Iwahori, 1978; Chang et al.,
1983, 1984; Afsharpour, 1985a). Their somata (10±25 mm in
rodents and 35±40 mm in primates) are abundant with
mitochondria, lysosomes, microtubules, neuro®laments, ribosomes and Golgi apparatus, but not endoplasmatic reticulum
(Rafols and Fox, 1976; Chang et al., 1983). The nucleus and
nucleoplasm are pale, containing dispersed chromatin and an
invaginated nuclear envelope (Rafols and Fox, 1976; Chang
et al., 1983). As the STN is a densely populated nucleus,
6
C. Hamani et al.
extensive membrane apposition between the cell bodies,
dendrites, and initial segments of the axons is observed
(Chang et al., 1983).
STN neurons have two to eight dendritic trunks that give
rise to thinner dendrites, whose ®elds are usually oval with
their long axis parallel to the long axis of the nucleus,
extending up to 750 mm in primates (Rafols and Fox, 1976;
Yelnik and Percheron, 1979; Afsharpour, 1985a; Sato et al.,
2000a). In rodents, secondary dendrites bifurcate at distances
between 18 and 100 mm from the cell body and may extend up
to 500 mm from the point of branching (Afsharpour, 1985a).
The dendritic ®eld of a single STN neuron can cover up to
one-half of the nucleus in rats (Kita et al., 1983). The majority
of STN dendrites and some portions of the soma are sparsely
covered with spines (Rafols and Fox, 1976; Chang et al.,
1983; Sato et al., 2000a). In rodents, two major types of
synaptic terminals have been described on STN dendrites: a
small type, which forms asymmetrical synapses and contains
round vesicles (possibly glutamatergic) and a larger type,
which forms symmetrical synaptic contacts and contains
round and ¯attened vesicles (possibly GABAergic) (Chang
et al., 1983).
In primates, distinct types of axonal branching patterns
have recently been described in STN neurons, projecting,
respectively, to (i) globus pallidus externus (GPe), GPi and
substantia nigra reticulata (SNr) (21.3%), (ii) GPe and SNr
(2.7%), (iii) GPe and GPi (48%), and (iv) GPe only (10.7%).
The remaining projecting ®bres course towards the striatum,
but their terminals have not been fully characterized (17.3%)
(Sato et al., 2000a). Axons that provide collaterals to the
pallidum and substantia nigra bifurcate into rostral and caudal
branches, whereas axons that provide collaterals only to the
pallidum or to the striatum have a single branch that courses
rostrally and dorsally and subsequently bifurcates (Sato et al.,
2000a).
Embryology of the STN
The embryological diencephalic wall is divided into ®ve
zones during development: The epithalamus, the dorsal
thalamus, the ventral thalamus and the hypothalamus sensu
lato, which is further subdivided in hypothalamus sensu
strictu and subthalamus, which will ultimately originate the
subthalamic nucleus (Kuhlenbeck, 1948; Cooper, 1950;
Marchand, 1987; Muller and O'Rahilly, 1988). In rodents, a
germinative zone lying caudally along the dorsal aspect of the
mammillary recess is responsible for the formation of the
neurons of the subthalamic nucleus (Marchand, 1987). In
humans, the subthalamic nucleus is derived from the
proliferative epithelium of the marginal layer of the
subthalamus, and is initially seen as part of the intermediate
layer around 33±35 days of gestational age (Muller and
O'Rahilly, 1988). At ~44±48 days of gestational age, the STN
can be seen as a condensation of cells in the periphery of the
intermediate layer of the subthalamus, close to the mesencephalon and adjacent to the mammillary body (Muller and
O'Rahilly, 1990). Between 48 and 51 days, the nucleus
assumes its characteristic lens-shaped appearance (Lemire
et al., 1975). As observed in other cerebral structures, from
birth to 16 weeks after birth, the number of synapses in the
STN of non-human primates declines by ~45% (Fisher et al.,
1987).
Intrinsic organization of the STN
The basal ganglia have been subdivided into three functional
units (Alexander et al., 1990; Parent and Hazrati, 1993;
Parent and Hazrati, 1995; Joel and Weiner, 1997). Motor,
associative and limbic cortical regions innervate, respectively, motor, associative and limbic regions of the striatum,
pallidum and SNr. The motor circuit comprises: (i) motor
cortical areas (primary motor cortex, supplementary motor
cortex, pre-motor cortex, and portions of the somatosensory
dorsal parietal cortex); (ii) the dorsolateral portion of the postcommissural putamen and a small rim of the head of the
caudate; and (iii) the lateral two-thirds of the globus pallidus
(GPe and GPi) and a small portion of the substantia nigra. The
associative circuit is composed of (i) associative cortical
regions (i.e. the dorsolateral and ventrolateral pre-frontal
cortices, portions of the intraparietal sulcus, the border of the
superior temporal sulcus), (ii) most of the caudate nucleus
and the putamen rostral to the anterior commissure and (iii)
the dorsal aspect of the medial third of the globus pallidus
(GPe and GPi) and most of the substantia nigra. The limbic
circuit is composed of (i) limbic cortical afferents (i.e.
orbitofrontal cortical regions and the anterior cingulate
gyrus), (ii) the nucleus accumbens and the most rostral
portions of the striatum and (iii) the subcommissural ventral
pallidum, small limbic regions in the ventral portion of the
medial third of the globus pallidus (GPe and GPi), the medial
tip of the substantia nigra, and the ventral tegmental area.
This distinct functional subdivision has also been applied
to the STN. The STN is subdivided in two rostral thirds and a
caudal third. Furthermore, the two rostral thirds are subdivided into medial (medial third) and lateral portions (lateral
two-thirds).
The medial portion of the rostral two-thirds is thought to
comprise the limbic and part of the associative territories. The
ventral aspect of the lateral portion of the rostral two-thirds
composes the other portion of the associative territory. The
dorsal aspect of the lateral portion of the rostral two-thirds
and the caudal third of the nucleus are related to motor
circuits (Fig. 2) (Parent and Hazrati, 1995; Shink et al., 1996;
Joel and Weiner, 1997).
Subthalamic nucleus afferents
Cortico-subthalamic projections
In primates, most of the cortical afferents to the STN arise
from the primary motor cortex, supplementary motor area
(SMA), pre-SMA, and the dorsal and ventral pre-motor
Subthalamic nucleus
7
1985). These pathways utilize glutamate as their neurotransmitter and their terminals make contact with small dendrites
in the STN (Fig. 3) (Romansky et al., 1979; Moriizumi et al.,
1987).
Pallido-subthalamic projections
Fig. 2 Schematic representation of the intrinsic organization of the
subthalamic nucleus (STN) according to the tripartite functional
subdivision of the basal ganglia.
cortices (respectively PMd and PMv) (Nambu et al., 1996,
1997, 2002). These projections innervate predominantly the
dorsal aspects of the nucleus and are integral components in
the motor loops of the basal ganglia. The ventromedial
portion of the STN receives afferents from the frontal eye
®eld (area 8) and the supplementary frontal eye ®eld (within
area 9), and is involved in circuits related to eye movements
(Matsumura et al., 1992; Stanton et al., 1988). In rodents,
prelimbic-medial orbital areas of the prefrontal cortex project
to the medial STN as part of the limbic loop (Groenewegen
and Berendse, 1990). Additional projections from the
cingulate cortex, somatosensory cortex, and insular cortex
have been described in rodents and primates but their
functional role is still unknown (Kunzle, 1977, 1978;
Monakow et al., 1978; Carpenter et al., 1981b; Kitai and
Deniau, 1981; Afsharpour, 1985b; Jurgens, 1984; Canteras
et al., 1990; Rinvik and Ottersen, 1993; Takada et al., 2001).
A complex and controversial intrinsic pattern of somatotopy has recently been reported in the STN (Monakow et al.,
1978; Nambu et al., 1996, 1997, 2002). Former studies
(Monakow et al., 1978) have described the somatotopic
representation of the leg, arm and orofacial structures in the
medial, lateral and dorsolateral portions of the STN, whereas
recent reports have described multiple homunculi within the
nucleus (Nambu et al., 1996, 1997). Primary motor cortex
®bres related to the leg, arm and face are represented from
medial to lateral in the lateral portion of the STN, whereas the
medial portion of the nucleus receives ®bres from the SMA,
PMd and PMv in an inverse somatotopic distribution (leg,
arm and face, respectively, represented from medial to
lateral) (Nambu et al., 1996, 1997, 2002).
Cortical afferents from the primary motor cortex to the
STN in rodents and cats originate mainly in layer V and are
composed of collaterals of the pyramidal tract or cortical
®bres that also innervate the striatum, although the former are
more prevalent (Kitai and Deniau, 1981; Giuffrida et al.,
The external pallidal projection to the STN comprises one of
its major afferents. Virtually the entire nucleus receives
pallidal ®bres, which course in a mediolateral and rostrocaudal direction (Parent and Hazrati, 1995). The topographic and
somatotopic distribution of these afferents varies from
species to species. In rodents, the lateral portions of the
pallidum innervates the lateral STN, whereas the medial parts
of the STN are innervated by the medial and ventral pallidum
(Parent and Hazrati, 1995). In primates, a more complex
topographic distribution of ®bres has been reported. The
rostral GPe (associative) innervates the medial two-thirds of
the rostral STN, the central portion of the middle STN, and to
a lesser extent the medial third of the middle STN. The central
GPe (associative dorsomedially and sensorimotor ventrolaterally) projects to the lateral, caudal and, to a lesser extent, the
central part of the rostral two-thirds of the STN. The ventral
portion of the central GPe and the caudal GPe innervate the
lateral and caudal STN (Carpenter et al., 1981a; Shink et al.,
1996; Joel and Weiner, 1997). In summary, although motor
and limbic portions of the GPe innervate their corresponding
counterparts in the STN, it has been suggested that
associative pallidal afferents innervate the associative portion
of the STN as well as the motor territory, providing evidence
for open circuits (that do not innervate their respective
counterparts) in the tripartite model of functioning of the
basal ganglia (Joel and Weiner, 1997; Parent and Cicchetti,
1998).
In primates, distinct GPe projection neurons have been
identi®ed. Of the GPe neurons 13.2% send projections to the
GPi, STN and SNr, 18.4% only to the GPi and STN, and
52.6% only to the STN and SNr (Sato et al., 2000b). Pallidal
terminals contact principally the proximal dendrites and cell
bodies of STN neurons, although distal dendrites are also
innervated (Parent and Hazrati, 1995). GABA is the main
neurotransmitter in this pathway, which comprises the major
inhibitory projection to the STN (Fig. 3) (Fonnum et al.,
1978; Oertel and Mugnaini, 1984; Smith et al., 1987, 1990a;
Smith and Parent, 1988).
Thalamo-subthalamic projections
The main projections from the thalamus to the STN originate
in the parafascicular (Pf) and centromedian nuclei (CM)
(Sugimoto and Hattori, 1983; Sugimoto et al., 1983; Sadikot
et al., 1992; Feger et al., 1994, 1997). In primates, the Pf
nucleus is the predominant thalamic source of input to the
STN, while it receives only a small number of centromedian
®bres (Sadikot et al., 1992). In rodents, the Pf and CM form
an undifferentiated complex.
8
C. Hamani et al.
Fig. 3 Schematic representation of the synaptic contacts of the major afferents to the subthalamic nucleus. Fibres from the tegmentum,
SNc, motor cortex, CM/Pf of the thalamus, and dorsal raphe, contact principally distal dendrites, whereas pallidal inhibitory ®bres
innervate mostly proximal dendrites and the cell body. ACh = acetylcholine; CM/Pf = centromedian/parafascicular complex of the
thalamus; DA = dopamine; GABA = g-aminobutyric acid; GLU+ = glutamate; GPe = globus pallidus externus; 5HT = serotonin;
SNc = substantia nigra compacta.
A mediolateral topographic distribution of Pf-STN ®bres
has been described in rodents (Feger et al., 1994). In primates,
however, Pf projects to the medial third of the rostral STN,
whereas the CM projects to the dorsolateral motor territory of
the nucleus (Sadikot et al., 1992). According to the intrinsic
organization of the STN, Pf projections innervate the
associative and limbic territories, whereas the CM nucleus
projects to the sensorimotor territory (Parent and Hazrati,
1995).
The axonal terminals of the thalamic afferents are
glutamatergic and contact mainly the dendrites of STN cells
(Scatton and Lehmann, 1982; Nieoullon et al., 1985;
Mouroux and Feger, 1993).
Brainstem afferents to the STN
The STN receives direct projections from the substantia nigra
compacta in rodents, non-human primates and humans
(Brown et al., 1979; Lavoie et al., 1989; FrancËois et al.,
2000). The major neurotransmitter in this pathway is
dopamine, which modulates the activity of glutamatergic
cortical and GABAergic pallidal afferents to the subthalamic
nucleus. Dopaminergic terminals contact mainly the neck of
dendritic spines in the STN (Fig. 3).
The pedunculopontine nucleus (PPN) and laterodorsal
tegmental nuclei send cholinergic inputs to the STN in
rodents, contacting mostly dendrites (Gerfen et al., 1982;
Jackson and Crossman, 1983; Scarnati et al., 1987; Lee et al.,
1988; Lavoie and Parent, 1994). The non-cholinergic
components of the PPN also project to the STN (Rye et al.,
1987; Mesulam et al., 1992).
Another source of afferent innervation to the STN in
rodents is the dorsal raphe nucleus (mainly its rostral section)
(Woolf and Butcher, 1986; Canteras et al., 1990). This
serotoninergic pathway may also be involved in the modulation of STN activity.
Subthalamic nucleus
In addition to the above-mentioned projections, several
other regions provide minor innervation to the STN in
rodents, such as the reticular nucleus of the thalamus, the
zona incerta, the locus coeruleus, the hypothalamus,
the amygdala, the bed nucleus of the stria terminalis, the
parabrachial nuclear complex and the dorsolateral tegmental
nucleus (Canteras et al., 1990). Little is known about their
organization and role in STN physiology.
9
nucleus in non-human primates (Parent and Smith, 1987).
Once in the nigra, STN axons arborize and give rise to several
local collaterals, which are thinner than the ones that project
to the pallidum (Sato et al., 2000a). In rodents and felines,
their terminal boutons contain glutamate vesicles and
innervate mainly dendritic shafts in nigral cells (Chang
et al., 1984; Kita and Kitai, 1987; Rinvik and Ottersen, 1993).
Subthalamo-striatal projections
Subthalamic nucleus efferents
Subthalamo-pallidal projections
The major efferent projections from the STN are directed to
both segments of the globus pallidus (GPe and GPi/
entopeduncular nucleus) in primates and rodents. STN ®bres
enter the pallidum through its posterior portion, coursing in a
caudorostral direction (Smith et al., 1990b; Parent and
Hazrati, 1995; Feger et al., 1997). In both segments of the
pallidum, STN projections are uniformly arborized, affecting
an extensive number of cells (Hazrati and Parent, 1992;
Fujimoto and Kita, 1993). In non-human primates, STN ®bres
are distributed in elongated caudorostral pallidal bands that
are parallel to the medullary laminae, obeying the dendritic
®elds of pallidal cells (Carpenter et al., 1981a, b; Smith et al.,
1990b). Terminals within this pathway are glutamatergic and
innervate mostly the dendritic shafts of pallidal neurons. STN
projections to both segments of the globus pallidus obey a
point-to-point distribution. The medial part of the rostral twothirds of the STN projects primarily to the rostral GPe, ventral
pallidum, and rostroventromedial portions of the GPi
(associative and limbic territories). The ventral part of the
lateral two-thirds of the rostral two-thirds of the STN project
primarily to the dorsomedial third of GPe and GPi
(associative territory). The dorsal two-thirds of this same
STN region project to the ventrolateral GPe and GPi (motor
territory). The caudal STN projects predominantly to the
motor territory of the GPe and GPi, except for a small portion
of the ventromedial aspect of this STN region, which projects
to the associative pallidum (Parent and Hazrati, 1995; Shink
et al., 1996; Joel and Weiner, 1997).
Subthalamo-nigral projections
The subthalamic nucleus innervates both components of the
substantia nigra in rodents and non-human primates: the pars
reticulata (SNr) and the pars compacta (SNc). Fibres from the
STN enter the nigra mostly through its ventromedial region,
spreading laterally in a rostrocaudal direction (Smith et al.,
1990b; Parent and Hazrati, 1995). Although most of these
®bres innervate the pars reticulata, some axons ascend and
reach the pars compacta, comprising one of the mechanisms
responsible for the regulation of dopamine release
(Groenewegen and Berendse, 1990; Smith et al., 1990b;
Parent and Hazrati, 1995). STN-nigral projections have their
origin mostly in the ventromedial portion of the subthalamic
The subthalamic nucleus sends scant projections to the
striatum in rodents and non-human primates (Kita and Kitai,
1987; Smith et al., 1990b). In non-human primates,
ventromedial associative and limbic regions of the STN
innervate mostly the caudate, whereas dorsolateral motor
portions of this nucleus innervate mostly the putamen (Parent
and Smith, 1987). Contrasting with the efferents to the
pallidum and nigra, STN projections to the striatum are
poorly branched and provide generally en passant excitatory
in¯uence over striatal cells (Parent and Hazrati, 1995).
Additional efferent projections
Aside from the main efferent projections described above, the
STN also send projections to the PPN and ventral tegmental
area in rodents and non-human primates, through which it
modulates their activity (Jackson and Crossman, 1981;
Granata and Kitai, 1989; Smith et al., 1990b; Parent and
Hazrati, 1995). The activation of the PPN increases activity in
the nucleus reticularis gigantocellularis, which modulates
part of the motor activity over the spinal cord (mostly spinal
interneurons) through the reticulopinal tract (Pahapill and
Lozano, 2000).
Pharmacology of the subthalamic nucleus
Glutamate
Excitatory amino acids provide the main excitatory drive to
the STN. Although N-methyl-D-aspartate (NMDA), 2-aminomethyl-phenylacetic acid (AMPA) and metabotropic
receptors have been described in STN neurons, the role
played by each particular subtype is disputed. In slices, the
application of both NMDA and non-NMDA glutamatergic
antagonists reduces STN excitatory activity, though the latter
agents evoke more pronounced responses (Shen and Johnson,
2000). Indeed, AMPA receptors are enriched in the STN
compared with NMDA receptors (Klockgether et al., 1991).
Nevertheless, internal capsule stimulation-evoked excitatory
post-synaptic potentials (EPSPs) are signi®cantly blocked by
NMDA antagonists and the topical application of these agents
in the STN signi®cantly decreases its metabolic activity
(Nakanishi et al., 1988; Blandini et al., 2001). As in other
cerebral structures, however, the activation of gated NMDA
receptors is favoured in a more depolarized state, which in the
STN is in part achieved through the activation of metabo-
10
C. Hamani et al.
tropic receptors (mGluR). Recent electrophysiological studies suggest that mGluR5 is the main subtype involved in
mediating post-synaptic depolarization, excitation and potentiation of NMDA-evoked currents, although mGluR1
receptors and group III mGluR receptors also seem to play
a role in the physiology of the STN (Awad et al., 2000; AwadGranko and Conn, 2001). While the complexity of glutamate
signalling and post-synaptic potentiation is not yet fully
elucidated, it is clear that a combination of multiple glutamate
receptor subtypes mediates a complex signalling pathway in
the STN (Bevan and Wilson, 1999; Awad et al., 2000; AwadGranko and Conn, 2001).
GABA
GABA has a major role in several aspects of the STN
physiology, modulating its ®ring rate, pattern of discharges
and bursting activity. The topical application of GABAergic
agonists in the STN inhibits neuronal activity, whereas the
reverse is true for GABAergic antagonists (Rouzaire-Dubois
et al., 1980). The impact of GABAergic transmission in the
STN is related to the initial membrane potential of the cells,
which is strongly dictated by pallidal afferents (Bevan and
Wilson, 1999; Bevan et al., 2000, 2002a, b).
GABAergic activity within the STN occurs mainly through
the activation of post-synaptic GABAA receptors, although
recent evidence has shown that GABAB also plays a role in its
physiology (Bevan et al., 2000; Shen and Johnson, 2001;
Urbain et al., 2002). GABAB agonists reduce both glutamate
EPSPs and GABAA IPSPs, ultimately decreasing the ®ring
rate in STN neurons (Shen and Johnson, 2001; Urbain et al.,
2002). Although minor post-synaptic activity has been
described, most GABAB effects are pre-synaptic (Shen and
Johnson, 2001).
Dopamine
Several studies have addressed the effects of both systemic
and topical administration of dopaminergic agonists on STN
activity, presenting sometimes contradictory results
(Campbell et al., 1985; Mintz et al., 1986; Kreiss et al.,
1996; Hassani et al., 1997; Kreiss et al., 1997; Hassani and
Feger, 1999; Shen and Johnson, 2000; Ni et al., 2001).
It has generally been accepted that STN neurons express
mRNA encoding dopamine D5 receptors, but not D1 and D2,
which are present in pre-synaptic terminal afferents
(Bouthenet et al., 1991; Mansour et al., 1991, 1992;
Svenningsson and Le Moine, 2002). Cells in the pre-frontal
cortex express both D1 and D2 mRNA, whereas globus
pallidus neurons contain only D2 mRNA in rodents (Mansour
et al., 1991, 1992; Hassani and Feger, 1999). In slices, the
application of dopamine reduces both glutamatergic EPSPs
and GABAergic inhibitory post-synaptic potentials (IPSPs) in
the STN, in agreement with studies that show that dopamine
has a depressive effect on neuronal excitability (Hassani and
Feger, 1999; Shen and Johnson, 2000). Nevertheless, the
most prominent effects on the IPSPs account for a ®nal
excitatory dopaminergic activity in the STN (Shen and
Johnson, 2000).
Studies in which the topical application of dopaminergic
agonists in the STN was performed revealed different results.
While some authors advocate that dopaminergic agonists
exert an excitatory effect, particularly through the activation
of D1 receptors (Mintz et al., 1986; Kreiss et al., 1996), others
state that D1, D2 and non-speci®c agonists (particularly
apomorphine) decrease STN activity (Campbell et al., 1985;
Hassani and Feger, 1999).
In normal rodents, it is reported that the systemic
administration of apomorphine increases STN activity,
although the systemic effects of selective agonists are not
so clear-cut. In general, it seems that D1 agonists increase
STN activity, but only when D2 receptors are co-activated,
whereas D2 agonists do not exert signi®cant effects (Kreiss
et al., 1997; Ni et al., 2001). As most of the structures that
give rise to STN afferents are also modulated by dopamine, it
is clear that the systemic administration of dopaminergic
agents is linked to a complex cascade of responses and, so far,
the exact role played by each structure and speci®c receptors
is uncertain.
Serotonin/acetylcholine and miscellaneous
In slice preparations, serotonin increases the spontaneous
activity in STN neurons (Flores et al., 1995; Martinez-Price
and Geyer, 2002). The topical administration of serotoninergic agonists in rodents increases locomotor activity, possibly
through 5-hydroxytryptamine (serotonin) (5HT1B) receptors
(Martinez-Price and Geyer, 2002).
In rodents, cholinergic agonists applied topically excite
STN neurons (Feger et al., 1979). Application of muscarinic
agonists in slices induces reduction in the amplitude of both
EPSPs and IPSPs in the STN, particularly through M3
receptors (Flores et al., 1996; Shen and Johnson, 2000). As
the effects in the latter potentials are higher, the end result is a
®nal excitation that provides a subsequent release of
glutamate from STN neurons (Rosales et al., 1994; Shen
and Johnson, 2000). This effect has been suggested as one of
the possible mechanisms for the antiparkinsonian effects of
anticholinergic agents (Feger et al., 1979; Flores et al., 1996;
Shen and Johnson, 2000).
In the STN, opioids inhibit both glutamate and GABA
activity through m and d pre-synaptic receptors (Shen and
Johnson, 2002).
Physiology of the STN
Physiological properties of STN cells
Findings from recordings of neuronal activity in the STN vary
according to the technique employed, the general conditions
of the experiments, and type of anaesthesia utilized.
Subthalamic nucleus
It is estimated that in vivo 55±65% of the STN neurons ®re
irregularly, whereas 15±25% ®re regularly and 15±50%
present bursting activity in non-human primates (Wichmann
et al., 1994a). The predominant pattern of activity in a single
STN cell is mainly dictated by its initial membrane potential.
Tonic ®ring is evoked with neuronal potentials around ±35 to
±50 mV, whereas bursting activity requires a more hyperpolarized condition, with the membrane potential around ±40 to
±60 mV. Below ±60 mV neurons usually become silent and
above ±30 mV, activity increases in frequency and decreases
in amplitude until its complete cessation (Beurrier et al.,
1999; Bevan and Wilson, 1999; Bevan et al., 2000, 2002a).
The average ®ring rate of STN neurons is 13±18 Hz in
normal rats and 18±25 Hz in non-human primates
(Georgopoulos et al., 1983; DeLong et al, 1985;
Matsumura et al., 1992; Fujimoto and Kita, 1993; Bergman
et al., 1994; Wichmann et al., 1994a; Overton et al., 1995;
Hassani et al., 1996, 1997; Kreiss et al., 1996, 1997; Beurrier
et al., 1999; Urbain et al., 2000).
Oscillatory neuronal cycle in the STN
Neuronal oscillatory cycles usually consist of a slow
depolarization, an action potential and a subsequent afterhyperpolarization (AHP) (Bevan and Wilson, 1999; Beurrier
et al., 2000). In the STN, slow depolarization is evoked
through tetrodotoxin (TTX)-sensitive sodium currents (voltage dependent), cationic currents, or low threshold calcium
currents (mostly in the case of bursting activity), which are
activated when the membrane potential of the cells is slightly
more negative than the usual resting state. These events result
in the entry of sodium and calcium into the cells, culminating
with the generation of action potentials. Thereafter, in
addition to usual hyperpolarization mechanisms, oscillatory
cells are characterized by the presence of calcium-dependent
potassium channels that, once activated, lead to a more
hyperpolarized state, evoking the so-called after-hyperpolarized potentials (AFH). This negative potential promotes the
activation of new slow depolarization currents and a subsequent new cycle (Bevan and Wilson, 1999; Beurrier et al.,
2000).
Calcium and bursting activity
Aside from the regular oscillatory activity, STN neurons can
also generate broad plateau potentials and bursting activity.
These events are dependent on the activation of multiple
calcium channels, as well as calcium-dependent potassium
channels. As for regular oscillations, in order for a neuron to
burst, the membrane potential has also to be more negative
than in the resting state. In fact, thresholds for rebound
oscillations and burst ®ring are similar to the equilibrium
potential of GABA (Bevan and Wilson, 1999; Bevan et al.,
2000). When the membrane potential is approximately ±50 to
±75 mV, STN cells submitted to depolarizing currents
develop plateau potentials dependent on calcium channels
11
(Beurrier et al., 1999). Units that do not develop plateaus
generally do not present bursting activity.
In rats, low threshold calcium currents are generated
through the activation of T-type calcium channels, located
mostly in STN dendrites (Song et al., 2000). When the cells
reach a more depolarized state, high threshold calcium
channels (N, L, Q, R types) located in both dendrites and
soma are activated (Song et al., 2000). Once high concentrations of intracellular calcium are achieved, plateau
potentials are produced. Thereafter, action potentials and
bursting activity are generated and calcium-dependent potassium channels are subsequently activated, leading the cells
back to a hyperpolarizaded state, which culminates with the
beginning of a new cycle (Beurrier et al., 1999).
Excitatory potentials and depolarization
In rodents and non-human primates, almost all STN cells
respond to cortical stimulation, usually with triphasic
potentials (positive, negative and positive) that are followed
by long hyperpolarizations (Kitai and Deniau, 1981; Fujimoto
and Kita, 1993; Nambu et al., 2000).
As latency for the ®rst peak in triphasic potentials is ~2 ms,
it has been suggested that this element is directly related to
the activation of cortico-subthalamic pathways in rats and
non-human primates (Fujimoto and Kita, 1993; Nambu et al.,
2000). Thereafter, the subsequent orthodromic and/or antidromic activation of GPe neurons generates the inhibitory
component that follows. Concomitant with the cortico-STN
excitation, cortico-striatal and striatal-GPe pathways are also
activated, culminating with disinhibition of the STN
(Fujimoto and Kita, 1993; Feger et al., 1997; Nambu et al.,
2000). This phenomenon seems to be responsible for the
second excitatory peak, which takes place 15 ms after cortical
stimulation (Fujimoto and Kita, 1993; Nambu et al., 2000).
Corroborating these observations, lesions of the globus
pallidus (i) do not interfere with the ®rst peak of STN
excitatory responses, (ii) substantially decrease the inhibitory
component of the responses and (iii) increase the second
excitatory peak (Ryan and Clark, 1992; Ryan et al., 1992;
Ryan and Sanders, 1993). Striatal lesions induce the opposite
effects, although of lesser magnitude (Ryan and Clark, 1992;
Ryan et al., 1992; Ryan and Sanders, 1993).
Cortico-STN-pallidal connections bypass the striatum,
conveying excitatory input directly to the STN and pallidum.
The term `hyperdirect pathway' has been proposed for this
pathway (Nambu et al., 1996; Nambu et al., 2002).
A second major source of excitatory input to the STN is the
Pf thalamic nucleus. Stimulation of the parafascicular-STN
projection also evokes a triphasic response. The mechanisms
for the development of each component of the response are
similar to those described for the cortico-STN pathway
(Mouroux et al., 1995; Feger et al., 1997; Mouroux et al.,
1997). Lesions of the Pf nucleus, as well as its pharmacological inhibition, lead to a reduced excitatory response in the
ipsilateral STN (Mouroux et al., 1995; Feger et al., 1997;
12
C. Hamani et al.
Mouroux et al., 1997). Stimulation of the contralateral Pf
nucleus induces the opposite effects said to be due to the
activation of the thalamic reticular nucleus and the subsequent inhibition of the ipsilateral Pf nucleus and STN
(Mouroux et al., 1995; Feger et al., 1997; Mouroux et al.,
1997).
Inhibitory potentials and hyperpolarization
IPSPs generated by pallidal afferents from the GPe comprise
the most important inhibitory mechanism controlling STN
activity. Almost every cell in the STN responds to pallidal
GABAergic stimulation (Overton et al., 1995). In fact, the
pattern of STN response depends on the inhibitory activity
provided by the afferents. Small IPSPs simply promote
phase-dependent delays in ®ring between spikes, culminating
with desynchronization (Bevan et al., 2002a, b). In contrast,
large IPSPs are strong enough to reset an oscillatory cycle and
promote the synchronization of the circuit (Bevan et al.,
2002a, b). Multiple IPSPs not only reset the cycle but can also
bring the potential of the membrane closer to the equilibrium
potential of GABA, restoring rhythmic ®ring and promoting
rebound spiking and bursting activity (Bevan et al., 2002b).
Nevertheless, this amount of hyperpolarization can only be
achieved if a synchronous summation of GABAergic synaptic potentials occurs.
During normal movement, GABAergic activation is asynchronous and provides a small contribution to burst ®ring or
oscillatory activity. In fact, asynchronous feedback inhibition
from GPe to STN acts to limit excitatory drive (Bevan et al.,
2000). Normally, local GPe neurons possess strong collateral
activity, inhibiting synchronization and providing the basis
for parallel activity. If striatal afferents provide an inhibition
stronger than the collateral activity, however, a more regular
and synchronized pattern ensues, enhancing the number of
bursting episodes in the GPe and STN (Bevan et al., 2002b).
Circuit oscillations
Co-culture studies indicate that the STN-GPe circuit possesses intrinsic oscillatory properties (Plenz and Kital, 1999).
Under these circumstances, however, the rhythm of the
oscillations is low, usually around 0.4±1.2 Hz, due to the
absence of the in¯uence of afferent innervation (Plenz and
Kital, 1999). In vivo, STN neurons ®re in low-frequency
bursts during slow wave sleep, when the cortical activity is
synchronized in the delta range (Magill et al., 2000, 2001;
Urbain et al., 2000; Wichmann et al., 2002). Cortical ablative
procedures (but not the topical application of GABAergic
agents in the STN) interrupt these events, emphasizing the
importance of cortico-subthalamic circuits in the genesis of
these patterns (Urbain et al., 2000, 2002). In intact, untreated
animals, only a few units oscillate above 4 Hz (~4%)
(Bergman et al., 1994; Wichmann et al., 1994a). Lowfrequency rhythms are relevant for the sleep-arousal cycle
and for the reinforcement of synaptic connectivity (Amzica
and Steriade, 1995; Charpier et al., 1999; Wichmann et al.,
2002).
Units related to body and eye movements
It is estimated that between 30 and 50% of STN neurons are
related to movement. Most of these units are localized in the
dorsal half of the nucleus and are activated by passive and/or
active movements of single contralateral joints (DeLong et al.,
1985; Bergman et al., 1994; Wichmann et al., 1994a).
Although electrophysiological somatotopy has been reported
in the STN (arm, leg and orofacial representations, respectively, in the lateral, medial and dorsolateral regions of the
nucleus), studies in which a large number of cells were
assessed have described that neurons related to speci®c joints
(i.e. shoulder, elbow, wrist, hip, knee, ankle) are not restricted
to a single region of the STN but located in various sites
within the nucleus (DeLong et al., 1985; Bergman et al.,
1994; Wichmann et al., 1994a).
Nearly 20% of the neurons recorded in the STN are
responsive to eye ®xation, saccadic movements or visual
stimuli (Matsumura et al., 1992). Most of these units are
primarily found in the ventral part of the STN and participate
in circuits that involve the frontal eye ®elds, the caudate
nucleus, the GPe and the SNr. Activation of the STN drives
SNr activity, which subsequently inhibits the superior
colliculus, allowing the maintainance of eye position on an
object of interest or the recovery of eye ®xation once a
saccade is executed (Matsumura et al., 1992).
Stimulation and inhibition of STN activity
STN stimulation
The application of GABAergic antagonists in the STN
reduces the in¯uence of pallidal inhibitory inputs. Under
these circumstances, as well as with low frequency stimulation, an increase in metabolic and electrophysiological
activity is generally observed not only in the STN, but also
in SNr, GPi and GPe (Hammond et al., 1978; Robledo and
Feger, 1990; Blandini et al., 1997).
Low frequency stimulation of the STN evokes a mixed
response inducing EPSPs and IPSPs in the SNc, respectively,
through direct STN-SNc and poly-synaptic pathways (Iribe
et al., 1999). As a net effect, however, excitatory responses
predominate, leading to an increase in the activity of SNc
cells and the subsequent release of dopamine (Rosales et al.,
1994). Indeed, bursting activity in the STN induces a bursting
pattern in the SNc, increasing the release of dopamine from
terminals, thereby in¯uencing the activity of the basal ganglia
and cortex (Smith and Grace, 1992; Chergui et al., 1994).
STN inhibition
Subthalamic lesions or the topical administration of
GABAergic agonists regularize the ®ring patterns in the
Subthalamic nucleus
globus pallidus and SNr, decreasing the overall electrophysiological and metabolic activity within these structures as
well as in the PPN (Robledo and Feger, 1990; Ryan and
Sanders, 1993; Blandini and Greenamyre, 1995; Guridi et al.,
1996; Breit et al., 2001). In non-human primates, excitotoxic
lesions of the subthalamic nucleus reduced the mean
discharge rate of GPi (from an average of 69.8±47.4 Hz)
and GPe (from an average of 63.6±41 Hz) neurons (Hamada
and DeLong, 1992b).
Due to its relevance in neurosurgery, stimulation of the
STN at high frequencies (HFS) has been investigated as an
additional strategy to reduce STN activity. In a study that
applied STN-HFS for 5 s, ®ring rates, after the stimulation
was discontinued, were decreased in the STN, GPe, GPi and
SNr, and increased in the ventrolateral nucleus of the
thalamus (Benazzouz et al., 2000b). This study, however,
did not address what occurs during STN stimulation.
STN-HFS induces alterations in the levels of neurotransmitters in basal ganglia structures. Glutamate increases in the
GPi and SNr and dopamine increases in the striatum, whereas
the levels of GABA increase in the SNr (Windels et al., 2000;
Bruet et al., 2001).
Behavioural effects of STN stimulation and
lesions
STN stimulation
In rodents, STN excitation through the topical infusion of
GABAergic antagonists induces postural asymmetry and
abnormal movements (i.e. jumping, axial torsion, and head
and limb movements), but no signi®cant locomotion activity
(Dybdal and Gale, 2000; Perier et al., 2000). However, if high
current is delivered to the nucleus or high concentrations of
GABAergic antagonists are applied, abnormal movements
such as dyskinesias can be elicited (Perier et al., 2002; Salin
et al., 2002). In primates, dyskinesias and abnormal movements have recently been described with high frequency
stimulation of the STN, whereas low frequency stimulation
did not induce any behavioural effects (Beurrier et al., 1997).
Ballism and lesion of the STN
In the clinical scenario, ballisms are characterized by
irregular, coarse, violent movements of the limbs (mainly
proximal muscles) (Dewey and Jankovic, 1989). Although
the classical description is related to cerebrovascular accidents in the subthalamic nucleus, diverse aetiologies in
various regions of the brain can result in these abnormal
movements (Dewey and Jankovic, 1989; Lee and Marsden,
1994; Ristic et al., 2002). The renaissance of functional
neurosurgery for movement disorders and the suitability of
the STN as a target have raised an important concern
regarding subthalamotomies and the possible emergence of
these involuntary movements.
13
In animals, ballism, as well as choreic and athetoid
movements of the contralateral hemibody, are elicited after
lesions or the topical application of GABAergic agonists in
the STN (Hammond et al., 1979; Crossman et al., 1980;
Beurrier et al., 1997). Although old studies have stated that
>20% of the STN had to be compromised for the occurrence
of abnormal movements (Whittier and Mettler, 1949), more
recent studies have suggested that focal transitory dyskinesias
can be evoked with lesions that involve only 4% of the
nucleus (Crossman, 1987; Hamada and DeLong, 1992a;
Guridi and Obeso, 2001).
Aside from the size of the lesions, their precise location
seems to be important for the development of abnormal
movements. Small lesions in STN efferents induce ballism,
whereas lesions that spill over the STN to compromise the
inner part of the pallidum and its respective ®bre systems, i.e.
in the Fields of Forel, do not induce involuntary movements
(Whittier and Mettler, 1949; Crossman, 1987; Hamada and
DeLong, 1992a; Barlas et al., 2001; Lozano, 2001; Doshi and
Bhatt, 2002). This is likely to be related to the observation
that pallidal or pallidal out¯ow pathway lesions are highly
effective in suppressing dyskinesias (Lozano, 2001).
STN and Parkinson's disease
STN activity in parkinsonian animals and patients with
Parkinson's disease is characterized by an augmented
synchrony, a tendency towards loss of speci®city in receptive
®elds, and a mildly increased ®ring rate with bursting activity
(Hutchison et al., 1998; Magarinos-Ascone et al., 2000;
Magnin et al., 2000; Levy et al., 2002b). In non-human
primates treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrine (MPTP), the ®ring rate of subthalamic neurons
increases to an average of 26 Hz (Bergman et al., 1994). In
addition, the number of STN neurons that demonstrate
oscillatory activity increases from only a few units to ~20%
(Bergman et al., 1994).
In Parkinson's disease patients, the average frequency of
discharge of STN neurons in most studies ranges from 35 to
50 Hz (Hutchison et al., 1998; Bejjani et al., 2000;
Magarinos-Ascone et al., 2000; Magnin et al., 2000; Levy
et al., 2002b; Pralong et al., 2002; Sterio et al., 2002). Most
neurons in the STN in Parkinson's disease patients ®re
irregularly, although regularly ®ring neurons and oscillatory
cells are not uncommon. Oscillatory neurons usually present
a rhythmic activity and may or may not be time-locked with
tremor. Recorded units that are synchronous to the clinical
tremor exhibited by the patients are called tremor cells
(frequency of oscillation around 4±8 Hz in patients with
Parkinson's disease). Movements elicited by the patients as
well as high frequency stimulation of the STN, decrease not
only the patients' tremor but also the related tremor cell
activity.
Another important characteristic of STN neurons in
Parkinson's disease is their relationship to motor activity.
Fifty-®ve per cent of STN cells in Parkinson's disease
14
C. Hamani et al.
patients react to active or passive movements, mostly of
single contralateral joints. In addition, however, 24% of the
units also respond to ipsilateral or multiple joint movements,
re¯ecting the increase in receptive ®eld size and loss in
speci®city previously mentioned (Abosch et al., 2002). Most
movement-related cells (65%) are located in the anterodorsal
portion of the STN, which appears to be the most effective
target for high frequency stimulation in terms of clinical
bene®ts (Abosch et al., 2002; Lanotte et al., 2002; Saint-Cyr
et al., 2002; Starr et al., 2002).
Oscillatory patterns
After dopamine depletion, the STN-GP circuit becomes more
reactive to the in¯uence of the activity of cortical inputs
(Magill et al., 2000, 2001). Even after cortical deafferentation
however, almost 20% of STN units continue to display
oscillatory patterns, suggesting that dopamine depletion
provokes a surge of independent rhythms in the STN-GPe
network (Magill et al., 2001).
Three main patterns of circuit oscillations have been
reported in Parkinson's disease: below 10 Hz (4±8 Hz),
between 15 and 30 Hz and between 70 and 85 Hz (Brown
et al., 2001; Cassidy et al., 2002; Levy et al., 2002a). As
previously mentioned, STN cells with oscillatory frequencies
below 10 Hz (4±8 Hz) are highly related to the characteristic
parkinsonian tremor, which also oscillates between 4 and 8
Hz. In Parkinson's disease patients, oscillations between 15
and 30 Hz (which are also found in the STN) synchronize
motor circuits and are related to the mechanisms of the
bradykinesia and akinesia (Brown et al., 2001; Levy et al.,
2002a). Voluntary movements and the administration of
dopaminergic agonists attenuate this pattern of oscillations.
Oscillations in the 70±85 Hz range, in contrast, occur during
movement and after treatment with dopaminergic agonists,
and are apparently important for an accurate execution of
motor programs (Magill et al., 2001; Cassidy et al., 2002;
Levy et al., 2002a).
STN hyperactivity
In the current model of Parkinson's disease, the preponderance of STN hyperactivity has been attributed to the
underactivation of the GPe due to abnormalities in the
indirect pathway. Recent studies, however, have provided
evidence that does not fully support this hypothesis, suggesting that other brain regions, such as the cerebral cortex and
the Pf nucleus of the thalamus, may also be responsible for
the increased STN activity observed after dopamine depletion
(Hassani et al., 1996; Feger et al., 1997; Levy et al., 1997;
Orieux et al., 2000; Orieux et al., 2002). Independent of the
mechanism, the pathological STN drive in parkinsonian
states, which includes variations in ®ring pattern, enhanced
oscillatory and synchronized activity, modi®es the overall
electrophysiological and metabolic activity in the SNr, GPi,
GPe and PPN, disrupting the normal physiology of the basal
ganglia (Hammond et al., 1978; Robledo and Feger, 1990;
Blandini et al., 1997; Breit et al., 2001). In the SNc, STN
overdrive is predicted to enhance bursting activity and
increases the release of dopamine. Although this has been
considered an initial compensatory mechanism after dopamine depletion, the excessive release of glutamate that
follows STN hyperactivity may also lead to excitotoxic
damage, which is potentially devastating, since it could
promote a further loss of dopaminergic neurons, accelerating
the progression of the disease (Piallat et al., 1996; Bezard
et al., 1999; Piallat et al., 1999).
A number of therapeutic strategies have been proposed to
re-establish the normal patterns of activity within the BG and
suppress STN pathological activity. These include the
administration of dopaminergic agonists and glutamate
blockers, focal delivery of neurothrophic factors, change in
the phenotype of STN neurons, lesions and high frequency
stimulation of the STN (Bergman et al., 1990; Aziz et al.,
1991; Klockgether et al., 1991; Wichmann et al., 1994b;
Limousin et al., 1995; Hutchison et al., 1998; Vila et al.,
1999; Benabid et al., 2000a,b; Blandini et al., 2001; Levy
et al., 2001; Luo et al., 2002; Gill et al., 2003; Nutt et al.,
2003).
Dopamine and the parkinsonian STN
The speci®c role of dopamine in the STN in parkinsonian
states is complex and depends on different receptor subtypes
and various anatomical pathways. In rodents, the topical
application of apomorphine and D2 agonists increases STN
activity, whereas D1 agonists exert the opposite effect
(Hassani and Feger, 1999). Contrariwise, the systemic
administration of apomorphine and D2 agonists reduces,
whereas D1 agonists increase the ®ring rate of STN neurons
(Kreiss et al., 1997; Ni et al., 2001). In Parkinson's disease
patients the administration of apomorphine does not change
the mean frequency of discharge in non-oscillatory cells, but
signi®cantly reduces the number of units displaying oscillatory behaviour (Levy et al., 2001).
In animal models of parkinsonism and patients with
Parkinson's disease, the administration of dopaminergic
agonists partially reverses some of the abnormalities
observed in the subthalamic nucleus, improving the major
motor symptomatology related to these conditions (Vila et al.,
1996; Kreiss et al., 1997; Hutchison et al., 1998; Hassani and
Feger, 1999; Levy et al., 2001).
Lesions and high frequency stimulation
Both STN lesions and high frequency stimulation ameliorate
the major motor symptoms of parkinsonism in humans and
animal models of Parkinson's disease and reverse certain
electrophysiological and metabolic consequences of dopamine depletion (Bergman et al., 1990; Aziz et al., 1992;
Benazzouz et al., 1993; Benazzouz et al., 1996; Vila et al.,
1996; Kreiss et al., 1997; Hutchison et al., 1998; Hassani and
Subthalamic nucleus
Feger, 1999; Benazzouz et al., 2000a, b; Barlas et al., 2001;
Levy et al., 2001; Lopiano et al., 2001). Based on these
®ndings, it has been suggested that high frequency stimulation inhibits STN output. Recent studies, however, have
challenged this view. In non-human MPTP primates, high
frequency stimulation of the STN at therapeutic levels drove
GPi (from an average of 63.2 to 81.7 Hz) and GPe (from an
average of 50.4 to 65.4 Hz) activity (Hashimoto et al., 2003).
These data suggest to the contrary that STN stimulation
drives STN output.
In patients with Parkinson's disease tremor and rigidity
improve to a larger extent, whereas akinesia, gait disturbances and postural abnormalities are less responsive.
Involuntary movements induced by L-dopa respond dramatically to surgery. The mechanism through which high
frequency stimulation of the STN ameliorates these symptoms is still unclear and controversial (reviewed in
Dostrovsky and Lozano, 2002; Lozano et al., 2002).
The main disadvantage reported for lesions to the STN, is
the potential risk for the development of choreiform abnormal
movements. As for normal primates, however, it appears that
only STN lesions con®ned within borders of the nucleus
induce abnormal movements, whereas lesions that extend to
the pallidal-related ®bre systems do not (Crossman, 1987;
Hamada and DeLong, 1992a; Barlas et al., 2001; Lozano,
2001; Doshi and Bhatt, 2002; Vilela Filho and Silva, 2002).
Supporting this statement, in surgical procedures, dyskinesias
are sometimes observed during the insertion of stimulation
probes, which may induce a small lesion effect in the STN.
Moreover, dyskinesias and choreiform movements can be
elicited with high frequency stimulation in the subthalamic
nucleus during the adjustment of the electrical settings in
patients treated with STN deep brain stimulation (Benabid
et al., 2000a).
STN and degenerative disorders
Pathological abnormalities in the subthalamic nucleus have
been described in several neurodegenerative disorders.
Nevertheless, most studies consist of small case series and
case reports and the exact role of the STN in these conditions
is still disputed. Patients with progressive supranuclear palsy
(PSP) present an important volumetric reduction of the STN
as well as signi®cant neuronal loss (45±85%), gliosis,
neuro®brillary tangles, and the accumulation of Tau protein
in astrocytes (Hardman et al., 1997; Togo and Dickson,
2002). Patients with corticobasal degeneration present similar
®ndings, although to a lesser extent (Dickson, 1999). Patients
with pallidonigroluysian atrophy also present neuronal loss
and gliosis in the STN (Mori et al., 2001). STN neuro®brillary tangles have been reported in argyrophilic grain
disease and advanced Alzheimer's disease (Mattila et al.,
2002). In Parkinson's disease, the volume and the number of
neurons in the STN is said to be unaffected (Hardman et al.,
1997).
15
Summary
The STN is a major glutamatergic structure within the basal
ganglia, strongly in¯uencing the activity of its major output
channels. It has been involved in the physiopathology of
parkinsonian states and the disruption of its pathological
activity, either through lesions, the topical administration of
GABAergic agonists, or high frequency stimulation, partially
reverses some of the clinical, electrophysiological and
metabolic abnormalities related to Parkinson's disease.
Acknowledgements
We wish to thank Valerie Oxorn for assistance and the
Parkinson's Society of Canada. Clement Hamani is receiving
a CAPES post-doctoral sponsorship.
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Received June 18, 2003. Revised September 3, 2003.
Accepted September 8, 2003