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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, Correspondence to: Andres M. Lozano Division of
Toronto Western Research Institute, Ontario, Canada and Neurosurgery, Toronto Western Hospital, West Wing
2Department of Neurological Surgery, Weill Medical 4-447, 399 Bathurst Street, Toronto, Canada ON M5T 2S8
College of Cornell University and Division of E-mail: lozano@uhnres.utoronto.ca or c.hamani@
Neurosurgery, Memorial-Sloan Kettering Cancer Center, sympatico.ca
New York, NY, USA
Summary
The subthalamic nucleus (STN) has been regarded as oscillatory patterns that can be closely related to tre-
an important modulator of basal ganglia output. It mor. Both STN lesions and high frequency stimulation
receives its major afferents from the cerebral cortex, ameliorate the major motor symptoms of parkinsonism
Keywords: subthalamic nucleus; Parkinson's disease; basal ganglia; deep brain stimulation; movement disorders
Introduction
The subthalamic nucleus has been regarded as an important (Yelnik and Percheron, 1979). Its anterior and lateral limits
structure in modulation of activity of output basal ganglia are enveloped by ®bres of the internal capsule that separate
structures and has been implied in the pathophysiology of this nucleus laterally from the globus pallidus.
Parkinson's disease. Despite the current interest, little is Rostromedially, the STN abuts on the nucleus of the Fields
known about its normal function in relation to movement. In of Forel, the Field H of Forel and the posterior lateral
the present study we review the anatomical, pharmacological hypothalamic area. Posteromedially it is adjacent to the red
and physiological attributes of the STN, with particular nucleus. Its ventral limits are the cerebral peduncle and the
attention to its involvement in the pathophysiology of substantia nigra (ventrolaterally). Dorsally the STN is limited
movement disorders and other neurological conditions. by a portion of the fasciculus lenticularis and the zona incerta,
which separate this nucleus from the ventral thalamus
Anatomy of the subthalamic nucleus (Schaltenbrand and Wahren, 1977; Yelnik and Percheron,
The subthalamic nucleus is a biconvex-shaped structure 1979; Williams and Warwick, 1980; Chang et al., 1983; Kita
surrounded by dense bundles of myelinated ®bres (Fig. 1) et al., 1983; Parent and Hazrati, 1995).
Brain Vol. 127 No. 1 ã Guarantors of Brain 2003; all rights reserved
Subthalamic nucleus 5
extensive membrane apposition between the cell bodies, O'Rahilly, 1990). Between 48 and 51 days, the nucleus
dendrites, and initial segments of the axons is observed assumes its characteristic lens-shaped appearance (Lemire
(Chang et al., 1983). et al., 1975). As observed in other cerebral structures, from
STN neurons have two to eight dendritic trunks that give birth to 16 weeks after birth, the number of synapses in the
rise to thinner dendrites, whose ®elds are usually oval with STN of non-human primates declines by ~45% (Fisher et al.,
their long axis parallel to the long axis of the nucleus, 1987).
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
Intrinsic organization of the STN
between 18 and 100 mm from the cell body and may extend up
The basal ganglia have been subdivided into three functional
to 500 mm from the point of branching (Afsharpour, 1985a).
units (Alexander et al., 1990; Parent and Hazrati, 1993;
The dendritic ®eld of a single STN neuron can cover up to
Parent and Hazrati, 1995; Joel and Weiner, 1997). Motor,
one-half of the nucleus in rats (Kita et al., 1983). The majority
associative and limbic cortical regions innervate, respect-
of STN dendrites and some portions of the soma are sparsely ively, motor, associative and limbic regions of the striatum,
covered with spines (Rafols and Fox, 1976; Chang et al.,
pallidum and SNr. The motor circuit comprises: (i) motor
1983; Sato et al., 2000a). In rodents, two major types of
cortical areas (primary motor cortex, supplementary motor
synaptic terminals have been described on STN dendrites: a
cortex, pre-motor cortex, and portions of the somatosensory
small type, which forms asymmetrical synapses and contains
dorsal parietal cortex); (ii) the dorsolateral portion of the post-
round vesicles (possibly glutamatergic) and a larger type,
commissural putamen and a small rim of the head of the
which forms symmetrical synaptic contacts and contains
caudate; and (iii) the lateral two-thirds of the globus pallidus
round and ¯attened vesicles (possibly GABAergic) (Chang
(GPe and GPi) and a small portion of the substantia nigra. The
et al., 1983). associative circuit is composed of (i) associative cortical
Pallido-subthalamic projections
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 rostrocau-
dal 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
Fig. 2 Schematic representation of the intrinsic organization of the (Parent and Hazrati, 1995). In primates, a more complex
subthalamic nucleus (STN) according to the tripartite functional topographic distribution of ®bres has been reported. The
subdivision of the basal ganglia. 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
cortices (respectively PMd and PMv) (Nambu et al., 1996,
GPe (associative dorsomedially and sensorimotor ventrolat-
1997, 2002). These projections innervate predominantly the
erally) projects to the lateral, caudal and, to a lesser extent, the
dorsal aspects of the nucleus and are integral components in
A mediolateral topographic distribution of Pf-STN ®bres (Brown et al., 1979; Lavoie et al., 1989; FrancËois et al.,
has been described in rodents (Feger et al., 1994). In primates, 2000). The major neurotransmitter in this pathway is
however, Pf projects to the medial third of the rostral STN, dopamine, which modulates the activity of glutamatergic
whereas the CM projects to the dorsolateral motor territory of cortical and GABAergic pallidal afferents to the subthalamic
the nucleus (Sadikot et al., 1992). According to the intrinsic nucleus. Dopaminergic terminals contact mainly the neck of
organization of the STN, Pf projections innervate the dendritic spines in the STN (Fig. 3).
associative and limbic territories, whereas the CM nucleus The pedunculopontine nucleus (PPN) and laterodorsal
projects to the sensorimotor territory (Parent and Hazrati, tegmental nuclei send cholinergic inputs to the STN in
1995). rodents, contacting mostly dendrites (Gerfen et al., 1982;
The axonal terminals of the thalamic afferents are Jackson and Crossman, 1983; Scarnati et al., 1987; Lee et al.,
glutamatergic and contact mainly the dendrites of STN cells 1988; Lavoie and Parent, 1994). The non-cholinergic
(Scatton and Lehmann, 1982; Nieoullon et al., 1985; components of the PPN also project to the STN (Rye et al.,
Mouroux and Feger, 1993). 1987; Mesulam et al., 1992).
Another source of afferent innervation to the STN in
rodents is the dorsal raphe nucleus (mainly its rostral section)
Brainstem afferents to the STN (Woolf and Butcher, 1986; Canteras et al., 1990). This
The STN receives direct projections from the substantia nigra serotoninergic pathway may also be involved in the modu-
compacta in rodents, non-human primates and humans lation of STN activity.
Subthalamic nucleus 9
In addition to the above-mentioned projections, several nucleus in non-human primates (Parent and Smith, 1987).
other regions provide minor innervation to the STN in Once in the nigra, STN axons arborize and give rise to several
rodents, such as the reticular nucleus of the thalamus, the local collaterals, which are thinner than the ones that project
zona incerta, the locus coeruleus, the hypothalamus, to the pallidum (Sato et al., 2000a). In rodents and felines,
the amygdala, the bed nucleus of the stria terminalis, the their terminal boutons contain glutamate vesicles and
parabrachial nuclear complex and the dorsolateral tegmental innervate mainly dendritic shafts in nigral cells (Chang
nucleus (Canteras et al., 1990). Little is known about their et al., 1984; Kita and Kitai, 1987; Rinvik and Ottersen, 1993).
organization and role in STN physiology.
Subthalamo-striatal projections
The subthalamic nucleus sends scant projections to the
Subthalamic nucleus efferents
striatum in rodents and non-human primates (Kita and Kitai,
Subthalamo-pallidal projections 1987; Smith et al., 1990b). In non-human primates,
The major efferent projections from the STN are directed to
ventromedial associative and limbic regions of the STN
both segments of the globus pallidus (GPe and GPi/ innervate mostly the caudate, whereas dorsolateral motor
entopeduncular nucleus) in primates and rodents. STN ®bres
portions of this nucleus innervate mostly the putamen (Parent
enter the pallidum through its posterior portion, coursing in a
and Smith, 1987). Contrasting with the efferents to the
caudorostral direction (Smith et al., 1990b; Parent and
pallidum and nigra, STN projections to the striatum are
Hazrati, 1995; Feger et al., 1997). In both segments of the
poorly branched and provide generally en passant excitatory
pallidum, STN projections are uniformly arborized, affecting
in¯uence over striatal cells (Parent and Hazrati, 1995).
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 Additional efferent projections
tropic receptors (mGluR). Recent electrophysiological stud- most prominent effects on the IPSPs account for a ®nal
ies suggest that mGluR5 is the main subtype involved in excitatory dopaminergic activity in the STN (Shen and
mediating post-synaptic depolarization, excitation and po- Johnson, 2000).
tentiation of NMDA-evoked currents, although mGluR1 Studies in which the topical application of dopaminergic
receptors and group III mGluR receptors also seem to play agonists in the STN was performed revealed different results.
a role in the physiology of the STN (Awad et al., 2000; Awad- While some authors advocate that dopaminergic agonists
Granko and Conn, 2001). While the complexity of glutamate exert an excitatory effect, particularly through the activation
signalling and post-synaptic potentiation is not yet fully of D1 receptors (Mintz et al., 1986; Kreiss et al., 1996), others
elucidated, it is clear that a combination of multiple glutamate state that D1, D2 and non-speci®c agonists (particularly
receptor subtypes mediates a complex signalling pathway in apomorphine) decrease STN activity (Campbell et al., 1985;
the STN (Bevan and Wilson, 1999; Awad et al., 2000; Awad- Hassani and Feger, 1999).
Granko and Conn, 2001). In normal rodents, it is reported that the systemic
administration of apomorphine increases STN activity,
although the systemic effects of selective agonists are not
GABA so clear-cut. In general, it seems that D1 agonists increase
GABA has a major role in several aspects of the STN STN activity, but only when D2 receptors are co-activated,
physiology, modulating its ®ring rate, pattern of discharges whereas D2 agonists do not exert signi®cant effects (Kreiss
and bursting activity. The topical application of GABAergic et al., 1997; Ni et al., 2001). As most of the structures that
agonists in the STN inhibits neuronal activity, whereas the give rise to STN afferents are also modulated by dopamine, it
reverse is true for GABAergic antagonists (Rouzaire-Dubois is clear that the systemic administration of dopaminergic
et al., 1980). The impact of GABAergic transmission in the agents is linked to a complex cascade of responses and, so far,
STN is related to the initial membrane potential of the cells, the exact role played by each structure and speci®c receptors
It is estimated that in vivo 55±65% of the STN neurons ®re (Beurrier et al., 1999). Units that do not develop plateaus
irregularly, whereas 15±25% ®re regularly and 15±50% generally do not present bursting activity.
present bursting activity in non-human primates (Wichmann In rats, low threshold calcium currents are generated
et al., 1994a). The predominant pattern of activity in a single through the activation of T-type calcium channels, located
STN cell is mainly dictated by its initial membrane potential. mostly in STN dendrites (Song et al., 2000). When the cells
Tonic ®ring is evoked with neuronal potentials around ±35 to reach a more depolarized state, high threshold calcium
±50 mV, whereas bursting activity requires a more hyperpo- channels (N, L, Q, R types) located in both dendrites and
larized condition, with the membrane potential around ±40 to soma are activated (Song et al., 2000). Once high concen-
±60 mV. Below ±60 mV neurons usually become silent and trations of intracellular calcium are achieved, plateau
above ±30 mV, activity increases in frequency and decreases potentials are produced. Thereafter, action potentials and
in amplitude until its complete cessation (Beurrier et al., bursting activity are generated and calcium-dependent potas-
1999; Bevan and Wilson, 1999; Bevan et al., 2000, 2002a). sium channels are subsequently activated, leading the cells
The average ®ring rate of STN neurons is 13±18 Hz in back to a hyperpolarizaded state, which culminates with the
normal rats and 18±25 Hz in non-human primates beginning of a new cycle (Beurrier et al., 1999).
(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; Excitatory potentials and depolarization
Hassani et al., 1996, 1997; Kreiss et al., 1996, 1997; Beurrier In rodents and non-human primates, almost all STN cells
et al., 1999; Urbain et al., 2000). respond to cortical stimulation, usually with triphasic
potentials (positive, negative and positive) that are followed
by long hyperpolarizations (Kitai and Deniau, 1981; Fujimoto
Oscillatory neuronal cycle in the STN and Kita, 1993; Nambu et al., 2000).
Mouroux et al., 1997). Stimulation of the contralateral Pf and Steriade, 1995; Charpier et al., 1999; Wichmann et al.,
nucleus induces the opposite effects said to be due to the 2002).
activation of the thalamic reticular nucleus and the subse-
quent inhibition of the ipsilateral Pf nucleus and STN
(Mouroux et al., 1995; Feger et al., 1997; Mouroux et al., Units related to body and eye movements
1997). 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
Inhibitory potentials and hyperpolarization active movements of single contralateral joints (DeLong et al.,
IPSPs generated by pallidal afferents from the GPe comprise 1985; Bergman et al., 1994; Wichmann et al., 1994a).
the most important inhibitory mechanism controlling STN Although electrophysiological somatotopy has been reported
activity. Almost every cell in the STN responds to pallidal in the STN (arm, leg and orofacial representations, respect-
GABAergic stimulation (Overton et al., 1995). In fact, the ively, in the lateral, medial and dorsolateral regions of the
pattern of STN response depends on the inhibitory activity nucleus), studies in which a large number of cells were
provided by the afferents. Small IPSPs simply promote assessed have described that neurons related to speci®c joints
phase-dependent delays in ®ring between spikes, culminating (i.e. shoulder, elbow, wrist, hip, knee, ankle) are not restricted
with desynchronization (Bevan et al., 2002a, b). In contrast, to a single region of the STN but located in various sites
large IPSPs are strong enough to reset an oscillatory cycle and within the nucleus (DeLong et al., 1985; Bergman et al.,
promote the synchronization of the circuit (Bevan et al., 1994; Wichmann et al., 1994a).
2002a, b). Multiple IPSPs not only reset the cycle but can also Nearly 20% of the neurons recorded in the STN are
bring the potential of the membrane closer to the equilibrium responsive to eye ®xation, saccadic movements or visual
potential of GABA, restoring rhythmic ®ring and promoting stimuli (Matsumura et al., 1992). Most of these units are
globus pallidus and SNr, decreasing the overall electrophy- In animals, ballism, as well as choreic and athetoid
siological and metabolic activity within these structures as movements of the contralateral hemibody, are elicited after
well as in the PPN (Robledo and Feger, 1990; Ryan and lesions or the topical application of GABAergic agonists in
Sanders, 1993; Blandini and Greenamyre, 1995; Guridi et al., the STN (Hammond et al., 1979; Crossman et al., 1980;
1996; Breit et al., 2001). In non-human primates, excitotoxic Beurrier et al., 1997). Although old studies have stated that
lesions of the subthalamic nucleus reduced the mean >20% of the STN had to be compromised for the occurrence
discharge rate of GPi (from an average of 69.8±47.4 Hz) of abnormal movements (Whittier and Mettler, 1949), more
and GPe (from an average of 63.6±41 Hz) neurons (Hamada recent studies have suggested that focal transitory dyskinesias
and DeLong, 1992b). can be evoked with lesions that involve only 4% of the
Due to its relevance in neurosurgery, stimulation of the nucleus (Crossman, 1987; Hamada and DeLong, 1992a;
STN at high frequencies (HFS) has been investigated as an Guridi and Obeso, 2001).
additional strategy to reduce STN activity. In a study that Aside from the size of the lesions, their precise location
applied STN-HFS for 5 s, ®ring rates, after the stimulation seems to be important for the development of abnormal
was discontinued, were decreased in the STN, GPe, GPi and movements. Small lesions in STN efferents induce ballism,
SNr, and increased in the ventrolateral nucleus of the whereas lesions that spill over the STN to compromise the
thalamus (Benazzouz et al., 2000b). This study, however, inner part of the pallidum and its respective ®bre systems, i.e.
did not address what occurs during STN stimulation. in the Fields of Forel, do not induce involuntary movements
STN-HFS induces alterations in the levels of neurotrans- (Whittier and Mettler, 1949; Crossman, 1987; Hamada and
mitters in basal ganglia structures. Glutamate increases in the DeLong, 1992a; Barlas et al., 2001; Lozano, 2001; Doshi and
GPi and SNr and dopamine increases in the striatum, whereas Bhatt, 2002). This is likely to be related to the observation
the levels of GABA increase in the SNr (Windels et al., 2000; that pallidal or pallidal out¯ow pathway lesions are highly
Bruet et al., 2001). effective in suppressing dyskinesias (Lozano, 2001).
patients react to active or passive movements, mostly of ganglia (Hammond et al., 1978; Robledo and Feger, 1990;
single contralateral joints. In addition, however, 24% of the Blandini et al., 1997; Breit et al., 2001). In the SNc, STN
units also respond to ipsilateral or multiple joint movements, overdrive is predicted to enhance bursting activity and
re¯ecting the increase in receptive ®eld size and loss in increases the release of dopamine. Although this has been
speci®city previously mentioned (Abosch et al., 2002). Most considered an initial compensatory mechanism after dopa-
movement-related cells (65%) are located in the anterodorsal mine depletion, the excessive release of glutamate that
portion of the STN, which appears to be the most effective follows STN hyperactivity may also lead to excitotoxic
target for high frequency stimulation in terms of clinical damage, which is potentially devastating, since it could
bene®ts (Abosch et al., 2002; Lanotte et al., 2002; Saint-Cyr promote a further loss of dopaminergic neurons, accelerating
et al., 2002; Starr et al., 2002). 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
Oscillatory patterns re-establish the normal patterns of activity within the BG and
After dopamine depletion, the STN-GP circuit becomes more suppress STN pathological activity. These include the
reactive to the in¯uence of the activity of cortical inputs administration of dopaminergic agonists and glutamate
(Magill et al., 2000, 2001). Even after cortical deafferentation blockers, focal delivery of neurothrophic factors, change in
however, almost 20% of STN units continue to display the phenotype of STN neurons, lesions and high frequency
oscillatory patterns, suggesting that dopamine depletion stimulation of the STN (Bergman et al., 1990; Aziz et al.,
provokes a surge of independent rhythms in the STN-GPe 1991; Klockgether et al., 1991; Wichmann et al., 1994b;
network (Magill et al., 2001). Limousin et al., 1995; Hutchison et al., 1998; Vila et al.,
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