Ovid: Starr: Neurosurgery, Volume 43(5).November 1998.989-1013
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Copyright (C) by the Congress of Neurological Surgeons
Volume 43(5)
November 1998
pp 989-1013
Ablative Surgery and Deep Brain Stimulation for Parkinson's Disease
[Topic Review]
Starr, Philip A. MD, PhD; Vitek, Jerrold L. MD, PhD; Bakay, Roy A.E. MD
Departments of Neurosurgery (PAS, RAEB) and Neurology (JLV), Emory University, Atlanta, Georgia
Received, November 21, 1996. Accepted, June 3, 1998.
Reprint requests: Philip A. Starr, M.D., Ph.D., Department of Neurological Surgery, University of California, San Francisco, 779
Moffitt Hospital, 505 Parnassus Avenue, San Francisco, CA 94143-0112.
Outline
Abstract
THEORETICAL BASIS
Mechanisms of lesioning versus DBS
Rationale for the motor thalamus as a target site
Anatomy of the motor thalamus
Tremor cells and the pathophysiology of parkinsonian tremor
Rationale for using the GPi and STN as target sites
The basal ganglia-thalamocortical motor circuit
Alterations of the circuit in PD
Basis for using the GPi as a target
Basis for using the STN as a target
STN: lesioning versus stimulation
TECHNICAL ASPECTS OF SURGERY
Target localization
Image-guided localization
Microelectrode recording and microstimulation
Microelectrode localization of GPi
Microelectrode localization of the motor thalamus
Microelectrode localization of the STN
Macrostimulation
Lesioning techniques
Stimulator hardware
INDICATIONS FOR SURGERY
RESULTS OF SURGERY
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Standardized rating scales
Thalamotomy
Results
Complications
Optimal thalamic target location
Bilateral thalamotomy
Thalamic stimulation
Results
Complications
Optimal thalamic electrode placement
GPi pallidotomy
Changes in standardized rating scale scores
Effects on cardinal motor signs of PD in the off state
Ipsilateral effects
Effects during the on state and on-off fluctuations
Effects on medication dosage
Complications
Predictors of outcome
Radiosurgical pallidotomy
Bilateral pallidotomy for PD
Optimal pallidal lesion location
Pallidal stimulation
Results
Complications
Time course of pallidal stimulation effect
Optimal pallidal stimulator location
STN stimulation
DEFICIENCIES IN THE CURRENT MODEL OF PD
WHAT IS THE BEST OPERATION FOR PD?
Lesioning versus stimulation
Choice of surgical targets
SUMMARY
REFERENCES
Graphics
Table 1
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Table 2
Table 3
Table 4
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Table 5
Abstract
SURGICAL OPTIONS FOR Parkinson's disease (PD) are rapidly expanding and include ablative
procedures, deep brain stimulation, and cell transplantation. The target nuclei for ablative surgery and
deep brain stimulation are the motor thalamus, the globus pallidus, and the subthalamic nucleus.
Multiple factors have led to the resurgence of interest in the surgical treatment of PD: 1) recognition
that long-term medical therapy for PD is often unsatisfactory, with patients eventually suffering from
drug-induced dyskinesias, motor fluctuations, and variable responses to medication; 2) greater
understanding of the pathophysiology of PD, providing a better scientific rationale for some previously
developed procedures and suggesting new targets; and 3) use of improved techniques, such as
computed tomography- and magnetic resonance imaging-guided stereotaxy and single-unit
microelectrode recording, making surgical intervention in the basal ganglia more precise. We review
the present status of ablative surgery and deep brain stimulation for PD, including theoretical aspects,
surgical techniques, and clinical results.
Parkinson's disease (PD) is a progressive degenerative disease of the basal ganglia. Pathologically, it
is characterized by the loss of dopaminergic cells of the substantia nigra, pars compacta (SNc) (79). The
major dopaminergic projection from the SNc innervates the striatum (nigrostriatal tract), although
dopaminergic SNc neurons also innervate other regions of the basal ganglia involved in motor control
(21,79,108,132). The cardinal clinical signs of PD are resting tremor, rigidity, bradykinesia, and postural
instability. The criteria for the diagnosis of idiopathic PD include at least two of these four cardinal
signs, as well as a history of a beneficial response to L-dopa.
Three types of approaches to surgery for PD have been rapidly evolving: ablative surgery, deep
brain stimulation (DBS), and "restorative" therapies. These are summarized in Table 1. Ablative surgery
and DBS procedures attempt to compensate for, rather than correct, the biochemical defect in PD. In
contrast, the restorative therapies, intracerebral cell transplantation and growth factor infusion, attempt
to correct the biochemical defect of PD by replacing lost dopaminergic cells or promoting the survival
of host dopaminergic cells. The restorative therapies, however, are entirely experimental and are
restricted to a few research centers. This article focuses on ablative surgery and DBS. These categories
of procedures share similar targets, technical approaches, and theoretical rationales.
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TABLE 1. Overview of Current Neurosurgical Procedures for Human Parkinsonisma
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There are currently three subcortical targets for ablative surgery and DBS: the globus pallidus (GP),
the subthalamic nucleus (STN), and the motor thalamus. Surgical destruction of portions of the internal
segment of the GP (GPi), called GPi pallidotomy, is an old procedure that was recently repopularized
by Laitinen et al. (103). A remarkable resurgence of pallidotomy has occurred, because it seems to be
effective for most parkinsonian motor signs (10,34,51,53,55,56,60,67,87,90,96,99,101,103106,125,126,149,159,161,162,172,176,182,188,189,199). Destruction of portions of the motor thalamus, called
thalamotomy, continues to be performed for parkinsonian tremor (49,52,59,89,94,131,134,179,193). The STN
has attracted attention as a possible lesioning target (70,72,137). Chronic stimulation of the motor
thalamus has well-documented efficacy for tremor, similar to that of thalamotomy (3,12,23,24,31,80,164).
DBS in the GPi (11,68,85,97,98,121,144,163) and the STN (98,121-123) is an exciting new procedure that
seems to improve most parkinsonian motor signs and may supplement or replace ablative therapies.
The exact target locations and indications for each of these procedures have not been standardized.
The surgical treatment of PD has a long history (62,69). Beginning in the 1940s, surgical ablations of
regions of the GPi and motor thalamus were performed before a solid scientific basis for these
procedures was established. L-dopa therapy for PD became widespread in the 1960s (38) and was
highly successful during the short term. As a result, surgical therapy fell out of favor in the late 1960s
and 1970s. However, long-term (>5 yr) L-dopa therapy declines in effectiveness and leads to
debilitating drug-induced dyskinesias and fluctuations between on-medication and off-medication states
(motor fluctuations) (130). Recognition of this, along with advances in surgical techniques and the
theoretical understanding of the rationale for different surgical interventions (45), has led to renewed
interest in the use of surgical therapy for the treatment of PD.
In considering the current options, historical perspective is of only limited value (62,69). It is difficult
to compare surgical studies from the pre-L-dopa era with contemporary ones. In the pre-L-dopa era,
standard parkinsonian rating scales to assess outcome were not available, rigorous long-term follow-up
examinations were rarely performed, and documentation of lesion location in the brain was possible
only by autopsy. For pallidotomy, the historical target within the GPi (anterodorsal GPi) differed
significantly from the contemporary one (posterolateral GPi). Also, the patient population in the pre-Ldopa era was different in that it included many patients with postencephalitic parkinsonism, which is
now rare, and the patients did not suffer from on-off fluctuations or drug-induced dyskinesias, which
are now major sources of morbidity. Therefore, discussion of the options for surgery for PD must focus
on contemporary reports, even though some of the procedures reviewed in this article (pallidotomy and
thalamotomy) have been performed for many years. In this article, we review the theoretical basis for
the procedures discussed, the surgical techniques, and the reported results.
THEORETICAL BASIS
Mechanisms of lesioning versus DBS
The theoretical mechanism of ablative surgery is relatively easy to understand. Destruction of a
nucleus eliminates excessive or abnormally patterned activity from that nucleus. This releases its
afferent targets from abnormal influences, although it obviously does not restore the normal afferent
activity from the lesioned region. If the lesion is created by thermocoagulation, which is the most
common method now in use, axons that pass through the lesioned area are also interrupted.
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DBS at high frequency often has behavioral effects that are similar to those of lesioning.
Intraoperative stimulation of the motor thalamus has long been performed during ablative surgery for
various movement disorders to provide electro-physiological confirmation of target location before
lesioning. Early investigators (77,139) found empirically that intraoperative stimulation at high frequency
(>100 Hz) in the motor thalamus produces tremor arrest. The effect is similar to that of permanent
lesioning, but it reverses when stimulation is stopped. Subsequently, stimulation-induced tremor arrest
became a standard means of physiological localization during thalamotomy (6,78,178). More recent
reports confirm the effects of chronic thalamic stimulation on tremor, using implanted electrodes for
long-term DBS (3,12,13,23,24,31,80,164). In the GPi, DBS can produce similar clinical effects
(11,68,85,97,98,121,144,163,180,181) and a pattern of cortical activation (34,40,67,153) similar to that of lesioning.
DBS of the STN in humans (98,121-123) and in monkeys (14,15) produces behavioral effects similar to
those of lesioning the STN in monkeys (8,17,71). All of this circumstantial evidence has led to the
working hypothesis that DBS at high frequency (>100 Hz) is approximately equivalent to lesioning on
a behavioral level, except that it is reversible and adjustable.
On a cellular level, however, the mechanism of action of DBS is potentially much more complex
than that of lesioning. Theoretically, a stimulating electrode could activate or inactivate nearby neurons
or axons, depending on their morphology, distance from the stimulating electrode, baseline discharge
rate, and exact stimulation parameters (148,155). Stimulation could directly activate cells or axons by
depolarization but could also inactivate cells or axons by depolarization blockade (148,155). Furthermore,
the effects on fibers of passage may be different from the effects on cell bodies. Fiber activation, if
present, could occur either orthodromically or antidromically. At typical stimulation parameters, tissue
within 2 to 3 mm of the stimulating electrode is likely to be affected (25), but this estimate could vary
greatly with changes in the stimulation parameters and it has not been well documented.
The apparent similarity in the behavioral consequences of lesioning and high-frequency DBS does
not prove that DBS inactivates cells. Activation of cells or fibers could have behavioral effects similar
to those of inactivation by increasing release of inhibitory neurotransmitters, overriding abnormally
patterned activity (such as bursting) with a constant frequency signal, or by numerous other
hypothetical mechanisms. There is very little experimental data on the effects of DBS under
behaviorally relevant conditions. However, some circumstantial evidence from animal and human
studies suggests that fiber activation may be an important mechanism for DBS (25,43). Considering the
complexity of DBS on a cellular level, differences between the behavioral effects of stimulation and
lesioning at the same brain target may become apparent as further clinical data emerges.
The long-term effects of DBS in the brain are not well known, although an autopsy report of a
patient 8 years after implantation of a ventralis intermedius nucleus (Vim) stimulator showed no ill
effects other than a thin rim of gliosis around the electrode track (32). In cats, chronic stimulation of the
motor thalamus results in synaptic proliferation of the motor cortex, which could affect motor learning
(93). It is unknown whether stimulation-induced synaptic changes occur in humans. The mechanism of
DBS needs further study.
Rationale for the motor thalamus as a target site
Lesioning or stimulation of portions of the thalamus has been practiced for a variety of neurological
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and psychiatric conditions. When performed for movement disorders, the target is within the motor
nuclei of the thalamus. Tremor is the parkinsonian symptom that is best treated by thalamic lesioning or
stimulation. Thalamotomy for PD was first reported 40 years ago by Hassler (77), and for many years,
thalamotomy was the mainstay of surgical treatment of parkinsonism, until it was eclipsed by the
advent of L-dopa therapy. It is still used for the treatment of many forms of tremor, including
parkinsonian, essential, and cerebellar outflow tremors. Chronic thalamic stimulation has been used to
treat parkinsonian and other tremors since the 1980s. Nevertheless, the theoretical basis for the
thalamus as a target site for tremor relief is still debated.
Anatomy of the motor thalamus
Thalamic subdivisions relevant to surgical interventions are illustrated in Figure 1. The motor thalamus
lies relatively ventral, lateral, and anterior within the thalamus as a whole. It can be subdivided into
three distinct regions according to its afferent pathways. From posterior to anterior, there is a cerebellar
receiving area with afferents from the deep cerebellar nuclei, a pallidal receiving area with afferents
from the motor (posterolateral) area of the GPi via the ansa lenticularis and fascicularis lenticularis, and
a nigral receiving area with afferents from the substantia nigra, pars reticulata (SNr) (127). The cerebellar
receiving area projects predominantly to the motor cortex. The pallidal and nigral receiving areas
project predominantly to the supplementary and premotor cortices (127). Posterior to the motor thalamus
is the lemniscal receiving area of the sensory thalamus, which is divided into two parts: a thin
proprioceptive layer (often called the "shell") anteriorly and a larger cutaneous sensory area posteriorly
(127). The spinothalamic tract also contributes fibers to both the cerebellar and lemniscal receiving areas,
and cells responsive to nociceptive input have been identified in these nuclei (115,116).
FIGURE 1. Illustration of thalamic anatomy relevant to surgery for tremor. Each nucleus is shaded according to the origin of its major
afferent input and is labeled according to the nomenclature of Hassler (74) , Jones (91) , Walker (191), and Olszewski (127). VPLc, caudal
ventral posterior lateral; VPLo, oral ventral posterior lateral; VLo, oral ventrolateral; VPL, ventroposterolateral; VL, ventrolateral; VLp,
posterior ventrolateral; VLa, anterior ventrolateral; Rt, reticular; VA, ventral anterior; Lpo, lateropolaris; Schalt, Schaltenbrand Bailey (154).
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The classification of nuclei in the human thalamus has been plagued by the lack of a single,
standardized terminology. Historically, the two major classification systems for the human motor
thalamus have been those presented by Hassler (74) and Walker (191). The accepted terminology for the
monkey thalamus is that presented by Olszewski (127). Hassler's system is the most prevalent in the
movement disorders literature. However, it fails to correlate human anatomy and physiology with that
of the nonhuman primate, in which the majority of anatomic and physiological studies have been
performed. Recently, Jones (91) and Macchi and Jones (127) proposed a unified system, describing both
humans and non-human primates, in which nuclei of the motor thalamus are subdivided in a
conceptually useful way according to the different receiving areas. Each human subdivision has a
primate homolog of the same name. The Hassler system and its relation to the Jones, Walker, and
Olszewski terminologies are illustrated in Figure 1. In this review, we use the standard Hassler
terminology. The cerebellar receiving area is the Vim. The pallidal receiving area consists of the
ventralis oralis posterior (Vop) and ventralis oralis anterior (Voa) nuclei. The nigral receiving area is the
lateropolaris, magnocellularis. The lemniscal receiving area of the sensory thalamus, immediately
posterior to the Vim, is the ventrocaudal nucleus (Vc). This is divided into anterior and posterior
subdivisions, corresponding to the proprioceptive and cutaneous sensory areas, respectively.
Tremor cells and the pathophysiology of parkinsonian tremor
Microelectrode recordings obtained during thalamotomy for tremor have suggested a rationale for
using the motor thalamus as a target site for tremor. Early investigations of the motor thalamus during
surgery for parkinsonian tremor revealed that many cells have a bursting discharge pattern with the
burst frequency equal to the patient's tremor frequency (1,19). These "tremor cells" have been studied by
Lenz et al. (112,117). Tremor cells were defined as those cells the power spectrum of which (by Fourrier
analysis of the microelectrode signal) showed a peak of activity at tremor frequency that correlated to a
high degree with the electromyographic signal. Tremor cells are found at sites that are presumed (based
on location relative to tactile cells) to be the Vim and Vop, that is, in both cerebellar and pallidal
receiving areas. Some tremor cells are simply somatosensory cells responding to joint movements, as
revealed by the cell discharge's lagging the corresponding electromyographic signal. However, the
majority of tremor cells have peak discharges that lead the electromyographic signal, indicating that
they are not merely responding passively to sensory feedback. Surgical lesioning and intraoperative
stimulation in the region where tremor cells are recorded correlates with long-term tremor relief (78,114).
This empirical observation has led to speculation that tremor cells may represent central oscillators that
are "tremorogenic" (112). DBS could then arrest tremor either by blockade of abnormal oscillatory
signals or by overriding oscillatory signals with a constant frequency.
The pathophysiology of tremor and the role played by tremor cells, however, remain incompletely
understood. In the parkinsonian state, cells firing at tremor frequency are also found in the human GPi
(84,176) and in the monkey STN (18), and lesions in the human GPi (10,176) or the monkey STN (71,196)
are effective for parkinsonian tremor. Thus, it seems unlikely that in the parkinsonian state, the central
oscillator is localized in a focal brain region. Tremor in PD may arise from an abnormal pattern of
activity at many interconnected locations in motor circuitry, susceptible to interruption by lesioning or
high-frequency stimulation at a variety of sites (196).
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Rationale for using the GPi and STN as target sites
The rationale for choosing the GPi or STN as surgical targets in cases of PD is based on the
abnormal physiology of these structures in the parkinsonian state. These abnormalities can best be
understood by considering the current model of PD, in which parkinsonian pathophysiology is
modeled by a set of alterations in a loop circuit that connects the basal ganglia, thalamus, and cortex
known as the basal ganglia-thalamocortical motor circuit. Many theoretical aspects of surgery for PD
are based on studies performed in the primate model of PD. The primate model was developed in the
1980s after the discovery that the intravenous injection of the toxin 1-methyl-4-phenyl-1,2,3,6tetrahydropyridine (MPTP), a by-product of illicit drug synthesis, causes parkinsonism in humans (41).
When administered systemically to primates, MPTP produces a syndrome of rigidity and bradykinesia,
with tremor as well in many species (29). The syndrome is responsive to L-dopa and closely resembles
PD, except that it is nonprogressive. Physiological and behavioral studies of the MPTP-treated primate
have a scientific rationale for surgical interventions in the GPi and STN.
The basal ganglia-thalamocortical motor circuit
The cortex, basal ganglia, and thalamus participate in multiple circuits controlling motor, limbic, and
associative functions (4). The basal ganglia-thalamocortical motor circuit plays a key role in regulating
motor behavior. A current model of the basal ganglia-thalamocortical motor circuit is illustrated
schematically in Figure 2A (4). The cortical regions participating in the motor circuit are the motor,
premotor, and somatosensory cortices. The basal ganglia structures that participate in this circuit include
parts of the putamen, the GPi and the external segment of the GP (GPe), the STN, the SNr, and the
SNc. The portions of these nuclei that participate in the motor circuit are called the sensorimotor
portions and contain neurons the discharge rates of which are modulated by passive or active
movements. Sensorimotor regions are anatomically separate from the regions that regulate nonmotor
functions. Because of this, it is possible to design surgical interventions that alter function in the motor
circuit while limiting involvement of nonmotor circuits.
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FIGURE 2. Schematic diagram of the basal ganglia-thalamocortical motor circuit in the normal state, in PD, and in PD after interruption of
the GPi or STN. PPN, pedunculopontine nucleus. Open arrows , excitatory connections; filled arrows, inhibitory connections. Changes in
the widths of the arrows among Panels A, B, C, and D indicate changes in the relative activity of the pathway represented. Wider lines
indicate increased activity; narrower lines indicate decreased activity. A, normal. B, PD. C, PD, showing the effect of pallidotomy on basal
ganglia output and thalamocortical activity in comparison with findings shown in Panel B. D, PD, showing the effect of STN lesioning on
basal ganglia output in comparison with the findings shown in Panel B.
As shown in Figure 2A, cortical efferent projections to the motor circuit enter the basal ganglia via the
putamen. The major basal ganglia output nuclei are the GPi and SNr nuclei, which project to the motor
thalamus (Vop/Voa and lateropolaris). Collaterals from the pallidothalamic and nigrothalamic pathways
also innervate the noncholinergic part of the pedunculopontine nucleus, a motor area that may be
involved in locomotion and posture (152). Within the basal ganglia, motor function is thought to be
regulated by two major pathways, the "direct" and the "indirect" pathways, both of which are
modulated by striatal dopamine (45). The direct pathway is a monosynaptic projection from the putamen
to the GPi/SNr. In the indirect pathway, the putamen projects to the GPi/SNr via intermediate nuclei,
the GPe, and the STN. Dopaminergic innervation of the putamen by the SNc is inhibitory to
striatopallidal neurons via D2 receptors in the indirect pathway but excitatory to striatopallidal neurons
via D1 receptors in the direct pathway. The nondopaminergic projections between the basal ganglia
nuclei are [gamma]-aminobutyric acidic (inhibitory), except for the projection from the STN to the
GPi/SNr, which is glutamatergic (excitatory).
In this model, the indirect pathway provides negative feedback to cortical regions, whereas the direct
pathway provides positive feedback. Balance between the direct and indirect pathways is critical for
maintaining the appropriate modulation of neuronal activity within cortical regions concerned with
motor control.
Alterations of the circuit in PD
Abnormalities in the basal ganglia-thalamocortical circuit may account for disorders characterized by
a paucity of movement (hypokinetic states) as well as those characterized by excessive movement
(hyperkinetic states). The loss of dopaminergic cells in the SNc, which is the fundamental defect in PD,
results in alterations in the basal ganglia-thalamocortical motor circuit, as shown in Figure 2B (45).
Depletion of striatal dopamine leads to increased activity in the basal ganglia output nuclei, GPi and
SNr nuclei, which in turn leads to excessive inhibition of the thalamocortical pathway (45). The
reduction in cortical excitation is thought to be manifested by the hypokinetic motor signs of
parkinsonism. Much of the abnormality in basal ganglia output is thought to be caused by the indirect
pathway, in which hyperactivity in the excitatory projections from the STN "drives" the output nuclei
excessively. This model of PD is supported by metabolic and electrophysiological studies of the basal
ganglia of the parkinsonian (MPTP-treated) monkey. In this animal model, metabolic activity and
neuronal discharge frequencies in the GPi and STN are increased compared with normal readings
(17,18,57,71,133,157).
Basis for using the GPi as a target
The theoretical basis for the selection of the GPi as a surgical target is illustrated in Figure 2C. The
interruption of activity in the motor region of the GPi should decrease the inhibitory influence of basal
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ganglia output nuclei on the motor thalamus and restore thalamocortical activity. Normalization of
thalamocortical activity should in turn lead to amelioration of the motor signs associated with
parkinsonism. In support of this theory, pallidotomy in patients with PD is associated with increased
activation of cortical motor areas, as determined by positron emission tomography (34,67,153) and by
transcranial magnetic stimulation (198). Pallidal stimulation in patients with PD also increases the
activation of cortical motor areas (40). Thus, the net physiological effect of pallidal DBS may be similar
to that of pallidotomy, even if the cellular mechanism is likely to be more complex.
Basis for using the STN as a target
STN overactivity is a central abnormality in the basal ganglia-thalamocortical circuit in the
parkinsonian state (Fig. 2B). Because the projection from the STN to the GPi is excitatory, one effect of
interruption of STN activity should be to correct over-activity in the GPi, producing effects similar to
those of pallidotomy. Theoretically, however, the STN may be an even more attractive target than the
GPi for the alleviation of parkinsonian signs. Because the STN affects the function of both basal
ganglia output nuclei (SNr and GPi nuclei), interruption of STN activity might potentially alleviate
more motor abnormalities than interruption of GPi activity alone. In the monkey model of PD, it has
been confirmed that STN lesions decrease spontaneous and movement-evoked neuronal discharges in
the GPi (17,196) and alleviate parkinsonian motor signs (8,17,71,196). Not only are tremor, rigidity, and
akinesia effectively alleviated but, in some cases, axial symptomatology, such as freezing and stopped
posture, are also improved (8,71). In addition, there is evidence in a rat model of PD that interruption of
activity in the STN may protect the SNc from further degeneration, presumably by a decrease in the
release of excitatory amino acids in the SNr, which is a prime target of the glutamatergic projection
from the STN (146).
STN: lesioning versus stimulation
Based on the above theoretical considerations and experimental data, there is current interest in STN
lesioning for PD (72). In five reported cases of unilateral STN lesioning for PD, symptom alleviation
was evident in most cases (70,137). The potential risks associated with this procedure, however, must be
considered. In nonparkinsonian humans, it is well known that spontaneous lesions of the STN and
surrounding areas (usually produced by infarction or hemorrhage) can produce hemiballismus (47,183).
This is also true of experimental STN lesions in otherwise normal (nonparkinsonian) monkeys (33,39),
although lesions restricted to the motor territory of the STN seem less likely to produce persistent
hemichorea (73).
There are a few case reports of spontaneous STN lesions occurring in patients with PD and
producing significant alleviation of parkinsonian motor signs (28,88,158,160,183). Some of these have
produced only mild or transient hemichorea (160,183), although others have produced persistent
hemichorea (28,88,158,183). Historically, surgical lesions in the motor thalamus performed for PD
occasionally extended inferiorly (7,54,136) and sometimes included parts of the STN (26,50).
Hemiballismus has occasionally been reported to occur after such interventions (26,50). In none of these
spontaneous or iatrogenic cases was the lesion clearly restricted to the STN. In five reported cases of
deliberate STN lesioning in humans with PD, hemichorea was observed but was not severe or
debilitating (70,137).
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In the parkinsonian brain, the risk of severe, permanent dyskinesias from STN lesioning is probably
less than in the nonparkinsonian brain. In parkinsonian monkeys, STN lesions can produce
hemiballism or hemichorea, but it is significantly milder than is the case for STN lesions in normal
monkeys (71). A possible explanation is that the electrophysiological abnormalities in parkinsonism
(decrease in the inhibitory direct striatopallidal and straitonigral pathways) act to balance the effect of
STN lesioning, which is to reduce the excitatory drive to basal ganglia output nuclei. That is, for the
same reason that STN lesions alleviate the bradykinesia of parkinsonism, the parkinsonian state helps to
alleviate the ballism/chorea produced by STN lesions. Nevertheless, the potential risks associated with
permanent STN lesioning in patients with PD has dampened enthusiasm for lesioning this structure. It
is still unclear whether an STN lesion can be consistently produced so as to alleviate parkinsonism
without causing severe persistent hemichorea.
Stimulation techniques seem to achieve behavioral effects that are similar to those of lesioning the
STN but with the added safety factor of adjustability. In the rat, high-frequency stimulation of the STN
decreases the activity of the basal ganglia output nuclei (16,27), as is true for STN lesioning in the
monkey (17,18). In the MPTP-treated primate model, STN stimulation has been shown to be effective
for the alleviation of contralateral rigidity and bradykinesia (14,15). In humans, with the exception of one
case series described above (70,137), DBS rather than ablation has thus far been the technique of choice
for intervention in the STN (98,121-123).
The exact mechanisms underlying the effects of STN stimulation are not known (14-16). Direct
inhibition of STN neurons is one possibility. However, antidromic activation of the projection of the
GPe to the STN could also account for the observed effects, because this projection sends inhibitory
collaterals to the basal ganglia output nuclei. Furthermore, stimulation in the region of the STN could
have a direct effect on pallidothalamic or nigrothalamic pathways, because these fiber bundles pass
close to the STN.
Metabolic studies of brain function support the view that STN stimulation alters cortical function in a
manner that is different from that of pallidotomy or pallidal stimulation. In a positron emission
tomographic study of six patients, clinically effective STN stimulation produced movement-related
increases in regional cerebral blood flow in several cortical motor areas. The most significantly affected
was the dorsolateral prefrontal cortex, a cortical motor area that receives input from the SNr (via the
thalamus) but not from the GPi. (121). Dorsolateral prefrontal cortex is not affected by pallidotomy
(34,67,153) or by pallidal stimulation (40,121). Thus, functional imaging data support the hypothesis that
surgical interruption of the STN can affect cortical function by pathways that do not involve the GP
and that one potential avenue for the effect of STN stimulation involves nigrothalamocortical pathways.
TECHNICAL ASPECTS OF SURGERY
Target localization
The methods for localization of the GPi, STN, and Vim are rapidly evolving and vary significantly
among centers. Three types of methods may be used to determine target location before lesioning or
stimulator placement: image-guided stereotactic localization, microelectrode mapping, and
macrostimulation. The first of these is based on anatomy, whereas the latter two are based on
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physiology. All centers perform some form of image-guided localization. Most, with the exception of
those performing radiosurgical ablations, use physiological confirmation of the target by
macrostimulation. Several centers use microelectrode recording and microstimulation to guide
placement of the DBS electrode before final confirmation of the lead placement by macrostimulation.
We have found the microelectrode technique to be extremely useful, although the necessity of using
microelectrode recording during surgery for movement disorders has not been established.
Image-guided localization
Classically, image-guided localization has been based on identification of internal landmarks, usually
the anterior commissure (AC) and the posterior commissure (PC), in reference to a stereotactic frame
system rigidly fixed to the patient's head. The AC and PC may be visualized using ventriculography,
computed tomography (CT), or magnetic resonance imaging (MRI). The motor thalamus, GPi, and
STN may all be localized indirectly by measuring fixed distances from these landmarks. However,
there is significant individual variability in the spatial coordinates of these targets in AC-PC-based
coordinates (95).
MRI-based stereotactic localization provides the advantage of allowing the visualization of at least
some borders of these nuclei, which allows direct targeting that can account for individual variation.
MRI has the disadvantage, compared with the other techniques, of spatial distortion. Distortion effects
can vary widely among scanners, sequence protocols, and frame systems. The degree of distortion may
be estimated by phantom studies (192) and partially corrected using computational algorithms (171) or
CT-MRI fusion techniques (5,159).
The accuracy of any stereotactic system, regardless of imaging modality, is limited by mechanical
properties of the frame and, in CT- or MRI-based stereotaxy, by slice thickness. The theoretical
maximum accuracy of standard stereotactic systems, with 1-mm-thick slice CT-based imaging, is
approximately 1.5 mm at the 95% confidence limit (128). Thus, image-guided stereotaxy alone is
adequate for placing a stimulator or lesion probe within several millimeters of the target, but
physiological studies are important to adjust or confirm final placement. Also, because physiological
studies are performed intraoperatively, they can be used to adjust for brain shifts that may occur during
head positioning or after dural opening.
Microelectrode recording and microstimulation
Since its introduction by Albe-Fessard et al. (2) in the early 1960s, microelectrode recording has been
performed in the human thalamus during surgery for parkinsonism and other movement disorders
(19,61,64,109-112,114,117,138,140). There is now a growing availability of literature on microelectrode
recording in the GPi in humans (82-84,125,170,175,176,189) and monkeys (44,46,57,58,133) and in the STN in
monkeys (17,18,195). The most common technique is the recording of single-unit, extracellular action
potentials using tungsten or platinum-iridium microelectrodes (109,125,189).
The usefulness of microelectrode recording for target localization is based on several principles
(109,125,189). Transitions between gray and white matter may be identified, because extracellularly
recorded action potentials in gray and white matter have distinguishable waveforms. Different basal
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ganglia nuclei have characteristic patterns of spontaneous discharge, which are relatively easy to
identify. Motor subterritories of a region can be distinguished from nonmotor regions by finding
neurons the discharge frequency of which is modulated by movement. Localization within a motor
region can be accomplished by mapping the receptive field of a movement-sensitive cell during motor
examination of the patient and then comparing the cell's receptive field with the known somatotopic
organization of the nucleus (125,189). Microstimulation, or passing a current through the microelectrode,
can evoke motor and sensory phenomena and thus localize motor and sensory pathways. Finally, the
spatial resolution of microelectrode techniques is high; structural boundaries may be identified with
submillimetric precision (109,125,189).
Microelectrode localization of GPi
As the microelectrode is lowered from a frontal approach toward the posterior portion of the GPi, it
may encounter striatum and always encounters the GPe before entering the GPi. Neuronal discharge
patterns in these structures are characteristic (83,84,125,170,175,176,189). The majority of striatal neurons
have very low (0-10 Hz) spontaneous discharge rates. GPe neurons have higher spontaneous rates and
typically discharge in burst or "pausing" patterns. GPi neurons have still higher and more regular mean
spontaneous discharge rates than do GPe neurons. Cells with slower, very regular discharge rates,
"border" cells, are typically found in the white matter laminae surrounding the GPe and GPi (44). The
optic tract (OT), can be identified by light-evoked fiber activity, below the inferior margin of the GPi
(125,189).
Cells in the GPi that are responsive to joint movements usually respond to the movement of one or of
a small number of joints in a restricted region on the contralateral side of the body (125,170,189). Because
the sensorimotor territory of the GPi is somatotopically organized, with leg representations tending to
be more dorsal and more medial than arm representations (189), the recorded distribution of neuronal
receptive fields helps to determine the mediolateral coordinate of an electrode track. Microstimulation
can be used to localize both the corticospinal tract (CST) and the OT (125,189). The CST in the internal
capsule is identified by the current threshold for producing muscle contractions (usually of the tongue,
face, or hand). The OT is identified by the current threshold required to evoke visual phenomena
(phosphenes).
The use of microelectrode recording for localization of the sensorimotor territory of the GPi has been
previously described (125,169,189) and is illustrated in Figure 3. Beginning with the entry of the
microelectrode into subcortical gray matter, the depths of neuronal cell bodies encountered are recorded
as tick marks along a scaled reconstruction of the electrode track (Fig. 3A). Each neuron is assigned to a
nuclear region by its pattern of discharge. Segments of the track reconstruction are shaded to indicate
the identity of the nucleus traversed. Neuronal receptive fields and microstimulation thresholds are
labeled on the track reconstructions. Accuracy of localization may be increased by studying several
microelectrode tracks along parallel trajectories separated by 2 to 4 mm, as shown in Figure 3B. As data
are gathered during the operation, the scaled, shaded microelectrode track reconstructions are
superimposed on drawings of parasagittal sections adapted from a standard human brain atlas, using the
surgical team's judgment of "best fit" of the microelectrode tracks to the atlas (Fig. 3B). Because the
stereotactic coordinates of the microelectrode tracks are known, this technique registers the
physiologically determined boundaries of the GPi and surrounding structures in reference to the
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stereotactic coordinate system. The microelectrode-derived atlas registration is then used to plan the
placement of the lesions (Fig. 4) or the DBS lead in the motor territory of the GPi (125,189).
FIGURE 3. Method of localization of the GPi by superposition of microelectrode tracks on scaled parasagittal brain maps (modified from
the Schaltenbrand and Bailey [154] human brain atlas parasagittal 20 and 23 cuts). Segments of the track reconstructions are shaded to
indicate striatal cells (gray-shaded segment), GPe cells (stippled segment), or GPi cells (black segment). Locations of movement-related
cells are indicated by triangles (leg), circles (arm), or squares (jaw). T, stereotactic target; lat., lateral. Microstimulation thresholds (stim)
are indicated where measured (bipolar stimulation, frequency = 300 Hz, pulse width = 200 [micro]s). A, detail of the first microelectrode
track. The depths of neuronal cell bodies encountered are recorded as tick marks. B, use of multiple microelectrode tracks for threedimensional localization. Data were obtained from an actual case (modified from, Starr PA, Vitek JL, Bakay RAE: Surgery for movement
disorders, in Kaye AH, Black PMcL (eds): Operative Neurosurgery. London, Churchill Livingstone, in press [169]).
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FIGURE 4. Lesioning strategy and macrostimulation thresholds at the inferior extent of each lesion track during pallidotomy. In this case,
three lesion tracks were made; these are shown superimposed on the nearest parasagittal planes from the Schalten-brand and Bailey human
brain atlas (154). Ellipses represent multiple overlapping lesions, made by heating a 1.1 x 3-mm probe tip for 60 seconds, at multiple points
along three parallel tracks. Ellipses of three different diameters represent lesions at three different temperatures: 70[degrees]C lesions
(2.6-mm diameter), 75[degrees]C lesions (3.3-mm diameter), and 80[degrees]C lesions (4-mm diameter). Stimulation parameters were
monopolar (frequency = 300 Hz, pulse width = 200 [micro]s). lat., lateral (modified from, Starr PA, Vitek JL, Bakay RAE: Surgery for
movement disorders, in Kaye AH, Black PMcL (eds): Operative Neurosurgery. London, Churchill Livingstone, in press [169]).
The role of microelectrode recording during pallidotomy is actively debated. Many reports that have
documented clear benefit, measured by standard rating scales, come from centers that use
microelectrode recording (10,51,56,99,105,126,161,182,185). However, in three recent series, pallidotomy
without microelectrode recording yielded short-term (<=1 yr) results that were similar to those achieved
at centers that perform pallidotomy with microelectrode recording (66,96,159). Resolution of this issue
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will require a large randomization of a patient population to be operated on identically except for the
use of microelectrode guidance and to be evaluated by independent movement disorder specialists
using standardized outcome measures.
Microelectrode localization of the motor thalamus
As is true for the motor territory of the GPi, many of the cells encountered in the motor thalamus
with an extracellular microelectrode are movement-related cells. Lenz et al. (111) detected 107
movement-related cells among 1012 cells recorded along electrode trajectories that included both the
motor and sensory territories of the thalamus. These cells usually respond to movements of one or a
small number of contralateral joints (111,147). They are further classified as passive or active cells
according to whether their discharge frequencies are modulated by passive or active movements (111).
In the monkey, active cells are more likely to be found in the pallidal receiving area, whereas passive
cells are more likely to be found in the cerebellar receiving area (186). This may be true in humans with
PD, but it has not been confirmed (111). In the Vim and Vop, cells firing at tremor frequency are
frequently encountered and are easily recognized on the audio monitor of the microelectrode signal.
As the microelectrode descends toward the thalamic target, the caudate nucleus may be encountered
first. The caudate has a very slow rate of spontaneous discharge (0-10 Hz) (189). The next structure
encountered, the dorsal thalamus, is relatively quiet in the awake patient but shows occasional slow
bursting activity. Microelectrode entry into the motor thalamus can be indicated by the identification of
movement-responsive cells and/or cells discharging at tremor frequency (112,113). The posterior border
of motor thalamus, formed by the lemniscal receiving area of the sensory thalamus, contains neurons
the sensory receptive fields of which are extremely well localized (110). The thin anterior rim of the Vc
contains cells responding to deep muscle pressure. The remainder of the Vc, the posterior subdivision,
responds to extremely light cutaneous stimuli (110). Recording cutaneous sensory cells provides a
precise, reproducible demarcation of the posterior edge of the motor thalamus (9). The mediolateral
position of a microelectrode track can be estimated by the somatotopic organization of motor and
sensory cells, because face/jaw, arm, and leg representations are organized along a medial to lateral
axis. This is true of both the cerebellar (Vim) and pallidal (Voa/Vop) receiving areas (111) and the
sensory Vc (110).
Microstimulation can identify the posterior and lateral borders of the Vim. Laterally, low stimulation
thresholds for evoked muscle contractions indicate that the electrode is at or has traversed the border
between the Vim and the internal capsule (9). Posteriorly, low thresholds for evoked paresthesias
indicate that the electrode has traversed the border between the Vim and the Vc (9,109).
Microelectrode localization of the STN
Electrophysiological investigation of the human STN is just beginning. However, the characteristics
of the STN and surrounding structures in patients with PD (168) appear very similar to those already
observed in the parkinsonian monkey (18), in which the STN has a characteristic electrophysiology that
allows it to be distinguished from surrounding structures. Because cell density is extremely high,
background noise is high and individual cells are difficult to isolate (18). Single neurons discharge at 20
to 30 Hz (18), but typical recordings are of multiple cells and, therefore, the apparent discharge
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frequency is higher. As the microelectrode passes through the inferior border of the STN into the SNr,
the discharge pattern changes abruptly (168). Background noise diminishes greatly, single neurons again
become easy to isolate, and the discharge rate is high (50-70 Hz) (T Wichmann, unpublished
observations). In the human, the medial and lateral borders of the STN, formed by lemniscal and
corticospinal fibers, respectively, may be identified by microstimulation-evoked sensory and motor
responses (168). The mapping procedure, in which track reconstructions are superimposed on
parasagittal cuts from a human brain atlas, is similar to that described above for localization of the GPi
(168).
Macrostimulation
Macrostimulation refers to passing a current through the lesioning probe or deep brain stimulator.
Macrostimulation provides the final check on target localization just before lesioning or permanent
stimulator placement and has been used during surgery for PD for many years (77,139). As with
microstimulation, macrostimulation can evoke visual, motor, and cutaneous sensory responses by
activation of the OT, CST, and somesthetic pathways, respectively. Almost all groups performing
surgery for PD use this technique, but for those who do not perform microelectrode mapping, macrostimulation provides the only physiological guidance for target identification. In the GPi, proximity of
the probe to the inferior and posteromedial borders is indicated by the current thresholds for activating
the OT and CST, respectively (189). This is illustrated in Figure 4, which shows the relationship of
macrostimulation thresholds to the borders of the GPi and to the subsequent lesion tracks. In the motor
thalamus, proximity to the posterior and lateral borders is indicated by activation of the sensory
thalamus and CST, respectively (9,177). In STN, proximity to the medial and lateral borders is indicated
by activation of the lemniscal fibers and CST, respectively (168).
In the Vim and STN, response of parkinsonian symptoms to macrostimulation provides another
indication of the adequacy of the probe placement. Intraoperative suppression of tremor in the Vim
predicts a good response to subsequent lesioning or chronic stimulation (12,77,78,178). Intraoperative
suppression of rigidity and bradykinesia is important as a guide to the placement of chronic STN
stimulators (122).
In the GPi, however, it is not as clear that acute suppression of parkinsonian symptoms by
intraoperative macrostimulation is predictive of the long-term effects of chronic stimulation. During
pallidotomy, we often do not observe macrostimulation-induced symptom relief when stimulating in the
posterolateral (motor) area of the GPi (189), which is the target for most groups performing pallidal
lesioning or chronic stimulation. After implantation of a pallidal stimulator, symptomatic benefit may
require time (up to several weeks) to appear (68). Further target refinement and experience with DBS in
the GPi are necessary before the predictive value of acute stimulation can be determined.
Lesioning techniques
The most common technique for lesion generation is that of radiofrequency (RF) thermocoagulation,
which was developed during the 1940s and 1950s (37,174). Alternating current at a RF of approximately
500,000 Hz is passed through a monopolar electrode at the lesioning site to a large surface area
dispersive electrode taped to the patient's skin. In the immediate region of the active electrode, the
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rapidly oscillating electrical field produces movement of electrolytes that is sufficient to cause
significant frictional heating (37). The temperature at the lesion center is monitored with a thermistor on
the active electrode tip. In the brain, temperatures greater than 45[degrees]C produce permanent tissue
destruction. Acutely, RF lesioning produces a central zone of coagulation necrosis surrounded by
edema (48). With commercially available active electrodes of 1.1 x 3 mm (Radionics, Burlington, MA),
the diameter of the coagulum, in laboratory tests, varies nearly linearly from 1 to 4 mm for temperatures
from 60 to 80[degrees]C applied for 60 seconds (37,189). Thus, once the target site is selected based on
anatomic targeting and physiological confirmation, the size of the lesion can be planned according to
the predicted spread of the zone of coagulation at different times and temperatures. The lesion may also
be "shaped" to the target structure by making multiple lesions, either along a single lesioning track or
multiple adjacent tracks (125,189). One example of an RF lesioning strategy, from a case of GPi
pallidotomy, is illustrated in Figure 4. Postoperative magnetic resonance (MR) images of thalamic and
pallidal RF lesions are shown in Figures 5 and 6.
FIGURE 5. Axial MR image of the brain, obtained 6 hours after Vim thalamotomy. Fast spin echo inversion recovery sequence; TI, 200
ms; TR, 2000 ms; TE, 24 ms; slice thickness, 2.0 mm. There is a ring of edema (black) around the actual lesion.
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FIGURE 6. Axial MR images of the brain, obtained 4 hours after pallidotomy. Fast spin echo inversion recovery sequence; TI, 200 ms;
TR, 3000 ms; TE, 40 ms; slice thickness, 2 mm; interslice spacing, 0. A, at the level of the AC-PC line. B, 2 mm below the AC-PC line.
The arrows indicate the lesion-edema complex.
Other techniques for lesion generation are being explored. Lesioning of the thalamus and GPi by
stereotactic radiosurgery has been reported (52,60,149,199). With this technique, the lesion is generated by
radiation necrosis. There is a latent period between treatment and clinical effect. Only image-based
anatomic targeting is used to guide lesion location, without physiological verification. Chemical
lesioning of the GPi, by infusion of excitotoxins, has been successful in a primate model of
parkinsonism (119). This technique has the theoretical advantage of being axon-sparing, thus potentially
avoiding damage to white matter structures surrounding the target. Historically, however, the size of the
lesion using chemical infusion techniques has been difficult to control (65,194).
Stimulator hardware
The most commonly used device for DBS is the Medtronic Model 3387 quadripolar lead
(Medtronic, Inc., Minneapolis, MN), which recently received approval from the United States Food
and Drug Administration for unilateral thalamic stimulation in parkinsonian and essential tremors. The
intracranial end of this device has four platinum-iridium contacts, 1.5 mm in length, separated by 3 mm
(center to center). This is connected to a battery-operated, programmable pulse generator (ITREL 2;
Medtronic, Inc.), which is implanted subcutaneously in the infraclavicular area. Any one of the four
contacts may be used for monopolar stimulation (with the pulse generator as the anode), and any two
contacts or groups of contacts may be used together for bipolar stimulation. The pulse width,
stimulation amplitude, and stimulation frequency (>= 185 Hz), as well as the choice of active contacts
and stimulation mode (bipolar or monopolar) are all adjustable by the physician, using an external
programming unit. The patient may turn the stimulator on or off at home using an external magnet.
Stimulation parameters may vary but typically range as follows: pulse width = 60-120 [micro]s,
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amplitude = 1-3 V, and frequency = 135-185 Hz. A lateral cranial film of a lead implanted at the
thalamic site is shown in Figure 7, and an MR image of a lead implanted in the thalamus is shown in
Figure 8.
FIGURE 7. Lateral cranial x-ray obtained after the placement of a Medtronic quadripolar DBS electrode into the motor thalamus
(reproduced from, Starr PA, Vitek JL, Bakay RAE: Deep brain stimulation for movement disorders. Neurosurg Clin N Am 9:381-402,
1998 [168]).
FIGURE 8. MR image obtained 1 day after the placement of a Medtronic quadripolar DBS electrode into the motor thalamus for
parkinsonian tremor. Fast spin echo inversion recovery sequence; TI, 200 ms; TR, 2000 ms; TE, 24 ms; slice thickness, 2.0 mm. A, axial
scan at the level of the PC. B, coronal scan 20 mm posterior to the AC. C, sagittal scan 14 mm from the midline. White arrows indicate the
artifact from the most distal contact. This contact is 5 mm anterior to the PC and 14 mm lateral to the midline.
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INDICATIONS FOR SURGERY
Candidates for thalamotomy or thalamic stimulation should have disabling tremor (such as tremor
that interferes with writing and eating) as their predominant symptom. For patients with PD with
predominant bradykinesia, the GPi and STN are considered to be better target sites, because thalamic
lesioning and stimulation have little effect on bradykinesia. Indications for GPi pallidotomy have been
discussed in several recent articles (10,51,56,87,90,92,96,99,101,103,105,126,159,161,162,172,182). Candidates for
pallidotomy should have histories consistent with idiopathic PD rather than "Parkinson's plus"
syndromes. (Evidence of Parkinson's plus syndromes includes evidence revealed by history or MRI of
parkinsonism that is secondary to trauma, encephalitis, or multiple infarctions or evidence revealed by
physical examination of coexisting cerebellar, corticospinal, or autonomic signs.) Patients should have
histories of beneficial response to L-dopa and motor signs (bradykinesia, rigidity, or tremor) that are no
longer adequately controlled by medication. Most candidates are significantly disabled, because mild
symptoms are often well controlled medically. Because STN and pallidal stimulation share similar
theoretical rationales as those of GPi pallidotomy, these procedures will likely be applicable to the same
population that benefits from GPi pallidotomy. Because these procedures are new, however, clinical
outcome data are insufficient to define their indications in detail.
Contraindications to either ablative surgery or DBS include dementia and extensive brain atrophy or
any systemic medical problem (coagulopathy or untreated chronic hypertension) that greatly increases
surgical risks. For DBS procedures, there are additional considerations. A stimulator should not be
placed in a patient who is unwilling or unable to comply with regular follow-up, because stimulation
parameters may require adjustment over time, particularly during the initial months after surgery. As an
indwelling device, a stimulator should not be placed in any patient with a concurrent infection.
RESULTS OF SURGERY
Standardized rating scales
To objectively quantify the clinical results of surgery for PD, patients must be assessed before and
after the procedure using standardized rating scales of motor function and disability. The most
commonly used set of rating scales for evaluating treatments for PD is the core assessment program for
intracerebral transplantation (CAPIT) (107). The major rating scale in the CAPIT protocol is the Unified
PD Rating Scale (UPDRS). This scale has four subscales: I, mentation, behavior, and mood; II,
activities of daily living (ADL); III, motor examination; and IV, complications of therapy. The ADL
and motor examination subscores are often reported separately from the total score. The total UPDRS
score may vary from 0 (no signs or symptoms) to 199 (most disabled). Because motor signs in patients
with PD typically fluctuate widely between the on and off states, ratings must be performed in both
states at multiple time points.
Other standard rating scales for PD that are included in the CAPIT battery are the Hohn and Yahr
staging scale (measures overall disability from PD on a scale of 1 to 5, with 5 being the worst), the
dyskinesia rating scale (measures both the intensity and duration of dyskinesias on a scale of 0 to 5,
with 5 corresponding to violent dyskinesias 100% of the day), and the CAPIT timed motor tests
(pronation-supination, hand/arm movement between two points, finger dexterity, and the stand-walk-sit
test) (107). An additional scale commonly used to measure overall disability in PD is the Schwab and
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England ADL score, which measures functional independence on a scale from 0% (totally dependent)
to 100% (totally independent) (156).
Thalamotomy
Results
Several publications from the L-dopa era have examined the efficacy of thalamotomy for long-term
control of parkinsonian tremor (49,59,89,94,134,179). These are summarized in Table 2. In most of these
studies, lesions were targeted to the Vim, although one study included lesions that extended inferior to
the motor thalamus (49). Lesions targeted to the Vim region seem to be 60 to 90% effective for relief of
parkinsonian tremor at 2 to 10 years of follow-up. Improvement in rigidity was often noted but rarely
studied quantitatively, and bradykinesia/akinesia was not reported to improve. Several more recent
series document the long-term efficacy of unilateral thalamotomy in terms of quality-of-life outcome
ratings but did not examine the effect of the procedure on specific symptoms (131,193).
TABLE 2. Long-term Results of Radiofrequency Thalamotomy of the Ventralis Intermedius Nucleus for Parkinsonian Tremor
Complications
Common short-term complications associated with unilateral thalamotomy, from the series presented
in Table 2, are lip or hand numbness, dysarthria, hypotonia, confusion, and contralateral weakness.
Persistent complications are noted in Table 2. The most consistently noted is a worsening of preoperative
dysarthria or hypophonia (1-10%). Cerebellar signs (dysmetria and hypotonia) are occasionally
reported after unilateral thalamotomy but are much more prevalent if the lesion is targeted to extend
beyond the inferior border of the thalamus (197). Patients with cognitive dysfunction pre-operatively are
at increased risk for further decline postoperatively (151).
Optimal thalamic target location
For thalamotomy, detailed studies of long-term symptom control versus lesion location revealed by
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postoperative MRI are lacking. However, several groups have correlated tremor control with
intraoperative physiology. Lenz et al. (114) retrospectively studied the effect of small (60 mm3 ) lesions
as a function of their proximity to the center of a cluster of tremor cells, the activity of which at tremor
frequency correlated strongly with with electromyographic activity. Lesions centered within 2 mm of
the center of the tremor cluster produced long-term benefit, whereas lesions greater than 2 mm away
produced only transient tremor relief. Nagaseki et al. (134) and Ohye and Narabayashi (138) emphasized
that small (40 mm3 ) lesions in the area containing movement-related cells are effective for tremor. In
both cases, lesions are made so that they are within 1 to 2 mm of, but do not include, the region of the
thalamus responding to cutaneous sensory stimuli, the Vc. Thus, such lesions probably include the
cerebellar receiving area of the Vim but may also include portions of the Vop. Autopsy reports confirm
that lesions that include the Vim are effective for tremor (36,75,143). Figure 5 shows a postoperative MR
image of a thalamic lesion.
Target choice is also influenced by the location of the patient's worst symptoms, taking into account
the somatotopic organization of the Vim (111). Isolated distal arm tremor warrants a fairly small lesion in
the arm territory of the Vim (78). Leg involvement suggests that the lesion should be extended laterally
within the Vim. Proximal involvement indicates that a larger lesion is necessary (78). This is probably
because the somatotopic representation of proximal musculature within the subhuman primate
homologue of the Vim is anatomically more dispersed than that of distal musculature (186). Thus, the
exact boundaries of the lesion are determined mainly by identifying the region of the Vim where
neuronal discharges are modulated by passive movements in the body distribution affected by the
tremor.
Can thalamic lesions affect PD symptoms other than tremor? If the lesion extends anterior to the
cerebellar receiving area (Vim), into the pallidal receiving area (Vop/Voa), it could alter the function of
the basal ganglia-thalamocortical circuit and affect motor behavior governed by this circuit. Some have
found that extending the thalamic lesion anteriorly into the presumed Vop/Voa provides better control
of rigidity (59,75,76,135) and of L-dopa-induced dyskinesias (59,135). Few investigators think that lesioning
any area of the motor thalamus affects bradykinesia. Although the effect of anterior (Vop/Voa) lesions
on bradykinesia has important theoretical implications for models of basal ganglia function, it is poorly
documented in the literature (129). Hassler et al. (76) reported four autopsy-documented cases in which
lesions that extended very anteriorly (into the Voa) did improve bradykinesia. Contemporary thalamic
ablation studies, however, have not reported changes in bradykinesia (49,59,89,94,134,179).
Bilateral thalamotomy
Bilateral thalamotomy is effective for bilateral tremor but has a high incidence of severe permanent
dysarthria (77,89,94,131,193). After the second of staged bilateral thalamotomies, Kelly and Gillingham
(94) found worsened dysarthria in 9 of 24 patients (37%), although Matsumoto et al. (131) reported
speech deficits in only 4 of 22 (18%). Early investigators frequently noted persistent cognitive devicits
after bilateral thalamotomy (77,100), which may relate to medial extension of the lesion.
Thalamic stimulation
Results
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Chronic stimulation of the motor thalamus is effective for medically intractable parkinsonian tremor.
Published studies on DBS for tremor relief are summarized in Table 3. In a series of 80 patients with PD
who received 118 stimulators for parkinsonian tremor, Benabid et al. (12) found that 88% had complete
or nearly complete tremor resolution at the time of the longest follow-up (range, 6 mo-8 yr). Similar
efficacy has been noted in smaller series from Lille, France (24,31), Zurich (23,164), Vienna (3), and the
University of Kansas (80). These results are similar to the fairly high rate of long-term relief of
parkinsonian tremor reported for Vim thalamotomy (49,59,89,94,134,179). One group has emphasized that
thalamic stimulation is highly effective for L-dopa-induced dyskinesias (31). Relief of rigidity, however,
is minimal in most series reporting such relief, and akinesia is reportedly unaffected (12).
TABLE 3. Results of Stimulation of the Ventralis Intermedius Nucleus for Tremora
Complications
As with thalamotomy, the most common complication of thalamic DBS is a worsening of dysarthria
(Table 3). However, the degree of dysarthria is reportedly mild and is completely reversible when the
stimulation is reduced or eliminated (12). Stimulation-induced dysarthria is common (27-30%) in
patients who have undergone contralateral thalamotomies (12,164). Similarly, bilateral thalamic
stimulation has a high incidence of dysarthria, but stimulation parameters may be adjusted so that side
effects are acceptable. This is in contrast to bilateral thalamotomy, which carries a relatively high risk of
irreversible speech and cognitive deficits (77,89,94,100,131,193).
Optimal thalamic electrode placement
As is the case with thalamotomy and acute thalamic stimulation, the optimal target for tremor arrest
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with chronic thalamic stimulation has been shown to be in the cerebellar receiving area, the Vim, close
to the border with the sensory thalamus, the Vc (114,134,138). In the large series presented by Benabid et
al. (12), in which the final electrode position was confirmed with intraoperative ventriculography, the
optimal tremor arrest site was usually located 4 to 8 mm anterior to the PC, 12 to 15 mm lateral to the
midline, and 0 to 2 mm superior to the AC-PC line. As judged from standard human brain atlases (154),
these coordinates probably correspond to the Vim, although the Vop is probably also affected by
spread of the stimulation current. Other groups performing intraoperative ventriculography have
documented similar coordinates for tremor relief (24,31). Figure 8 shows a postoperative MR images of a
DBS electrode in the motor thalamus. Anecdotal cases suggest that slightly more anterior electrode
placement, 8 mm anterior to the PC, results in excellent relief of L-dopa-induced dyskinesias (24). This
would likely place the electrode in or very near the Voa/Vop, corresponding well with the observed
site for dyskinesia relief from thalamotomy (135).
GPi pallidotomy
Changes in standardized rating scale scores
Several groups have published the effects of unilateral pallidotomy on off-state symptomatology
using standardized rating scales (10,51,56,66,96,99,105,126,142,159,161,172,182,190). These studies are
summarized in Table 4. In all of these studies, lesions were made by RF thermocoagulation, and all
except four (66,96,159,172) used microelectrode recording to guide lesion placement. UPDRS total and
motor scores improved in all except one study. Improvement in total UPDRS scores in the off-state
ranged from 16 to 25%. Improvements in the UPDRS motor subscale ranged from 17 to 75%. In the
initial Toronto study, UPDRS rating was performed by blinded investigators based on videotaped
examinations, and this study showed a 30% improvement (mean score of 33 to mean score of 23) in
UPDRS motor scores at 6 months (126). The New York University (NYU) group reports the longest
follow-up and documents that the substantial motor subscore improvements observed at 1 year
persisted at 3 and 4 years (56). Scales that measure overall functional disability, such as the Schwab and
England scale and the ADL subscale of the UPDRS, also showed significant improvement in most
reports, varying from 28 to 66% (Table 2) (10,51,56,96,99,105,126).
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TABLE 4. Effect of Unilateral Pallidotomy on Patients with Parkinson's Disease as Measured by Standard Rating Scalesa
Only one group (172) reported no improvement in standardized rating scale scores after pallidotomy.
In five patients with advanced PD who were followed for 2 months, none showed a significant
reduction in the total or the subscores of the UPDRS. Factors contributing to the lack of significant
improvement may have been the relatively high mean age of the patients, choice of surgical technique,
or small sample size.
Effects on cardinal motor signs of PD in the off state
Pallidotomy consistently improves contralateral tremor, rigidity, and bradykinesia in the off state. In
the Emory series, tremor was nearly eliminated in seven of eight patients (88%) who had significant
tremor preoperatively (10). Similar effects on tremor have been reported by others (51,96,101,126,142).
Blinded evaluations of bradykinesia have shown contralateral improvements of 37% (CAPIT timed
motor tasks) in the NYU study (51) and 26% (UPDRS akinesia score) in the Toronto study (126).
Improvements in axial symptoms (gait, posture, falling, and freezing) have been observed by many
(51,87,96,103,150,182). Two studies, however, have shown that improvements in axial symptomatology that
were initially significant were lost at the 1-year (10) or 2-year (105) evaluations. Thus, patients should be
counseled that significant improvement in axial symptomatology in the off state is less predictable than
that for tremor, rigidity, and bradykinesia.
Ipsilateral effects
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Multiple reports agree that there is a modest ipsilateral benefit of pallidotomy for off-state
bradykinesia (10,51,103,126). The NYU group reported a 24% improvement in ipsilateral bradykinesia by
standard CAPIT timed movement tasks (pronation/supination, finger dexterity, and hand/arm
movement between two points), as compared with 38% contralateral improvement for the same set of
tasks. Ipsilateral improvements in motor signs in the off state, other than bradykinesia, have not been
consistently observed.
Effects during the on state and on-off fluctuations
Pallidotomy is reported to increase the amount of time spent in the on state (10,87,182) and to decrease
motor fluctuations (10). Virtually all groups report dramatic and sustained amelioration of peak dose Ldopa-induced dyskinesias on the contralateral side, with ipsilateral improvements in some patients
(10,51,66,87,90,96,99,103,126,142,159,172,182). This is the only consistently reported benefit in the on state. The
ipsilateral, but not contralateral, improvements in dyskinesias tend to fade by the time of the 2-year
evaluations (105). Although some have reported dramatic (87) or significant (51,159,182) improvements in
UPDRS motor subtest scores in the on state, most report only modest improvements that may not reach
statistical significance (10,90,96,126).
Effects on medication dosage
In most studies in which this was examined, intake of L-dopa did not change significantly
(10,51,105,126,182). Some patients may increase L-dopa usage, because of amelioration of the rate-limiting
side effect of dyskinesias, but others may reduce intake because of improved off periods (51).
Complications
Because of the proximity of the OT to the inferior border of the GPi, OT injury is a potential
complication of pallidotomy. In the first 38 patients presented by Laitinen et al. (103), there was a 14%
incidence of visual field deficits, presumably caused by injury to the OT. However, Laitinen (101) later
reported only three additional field cuts in more than 200 additional patients. In studies using
microelectrode recording, few field cuts have been reported (10,20,51,126,182,189). Most series report
isolated cases of hypophonia or worsened speech articulation. Other major complications include
capsular infarction, which may occur weeks or months after pallidotomy (120), and intracranial
hemorrhage. The use of microelectrode recording may theoretically increase the risk of hemorrhage
because it increases the number of instrument passes in the brain, but the published literature neither
supports nor refutes this possibility.
The risk of neuropsychological changes after unilateral pallidotomy is not yet clear (10,106,159,166,182).
In 12 patients tested in the Emory pilot study, there were no significant changes in 21 of 25
neuropsychological variables (10). Four variables related to frontal lobe function did change between
the preoperative and the 1-year assessments, but there was no significant change revealed by the initial
postoperative assessment, indicating that the declines may have been unrelated to surgery. Two groups
have found slight decrease in verbal fluency without other major cognitive changes (159,182). The
Toronto group, however, studying 40 patients, found persistent mild cognitive impairment (revealed by
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detailed neuropsychological testing) in some patients (106). Some patients in this group experienced
excessive weight gain.
Predictors of outcome
In the Emory pilot study, patients with dementia (2 of 15 patients) had markedly less overall benefit
(10). Age correlated inversely with outcome, including or excluding the two demented patients. Total
UPDRS scores decreased by an average of 52.2% in six patients who were between the ages of 38 and
52 years and 13.8% in seven patients who were between the ages of 58 and 69 years (10). Others have
shown a trend toward less benefit in older patients, although the trend was not statistically significant
(51). However, the Vancouver study, in which the age range was similar to that in the Emory study,
showed a positive correlation of age with outcome (96) and other studies have found no effect of age on
outcome (182). The NYU group reported that preoperative positron emission tomography (with 18 Ffluorodeoxyglucose) can be used to predict outcome, showing that ipsilateral lentiform nucleus
hypermetabolism correlates with clinical benefit from unilateral pallidotomy (92). The extent of clinical
benefit from L-dopa administration also correlated with outcome (92).
Radiosurgical pallidotomy
In the majority of published cases in the modern era, the lesion is created by RF thermocoagulation.
Other techniques, however, are being explored. Radiosurgical pallidotomy for PD, using the Leksell
gamma knife, has been reported (60,149,199). In two small series, symptomatic improvement was
observed in only four of eight patients (149) and one of four patients (60). Young et al. (199), in a series of
15 patients with PD, reported that gamma knife pallidotomy was effective for drug-induced dyskinesias
in all of the patients and was effective for bradykinesia and rigidity in 77% of the patients. No
complications were reported in this series. However, the patients were not assessed by standardized PD
rating scales, so it is impossible to compare these results with those of RF pallidotomy.
Bilateral pallidotomy for PD
Because the major benefit of pallidotomy is contralateral and because most patients with PD have
bilateral disease, some groups have performed bilateral pallidotomy for PD (87,101,159,162). Iacono et al.
(87) reported 68 cases of bilateral pallidotomy, with many "good" or "excellent" results. However, the
effects in the off state are not quantified by standard rating scales, and their series lumps together the
results of unilateral and bilateral pallidotomy. Shima et al. (162) reported 28 cases of bilateral
pallidotomy but without quantification of the results. Only Scott et al. (159), in a study of 8 simultaneous
bilateral and 12 unilateral pallidotomies, compared the outcomes of these two procedures in detail.
Three months after surgery, improvements in UPDRS rating scores were significantly higher for
bilateral pallidotomy than for unilateral procedures.
The complications associated with bilateral pallidotomy have not been reported in detail but are
probably greater than with unilateral lesions. Scott et al. (159) reported significantly worse speech
articulation and verbal fluency in patients after bilateral pallidotomy and major cognitive deficits in one
of eight patients. Our limited experience with seven staged bilateral pallidotomies and anecdotal cases
of others (66) confirm that hypophonia is a common complication. The Toronto group has reported that
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bilateral pallidotomy produced major cognitive deficits in two of two patients treated (104). The safety of
bilateral pallidotomy needs closer scrutiny before it can be recommended.
Optimal pallidal lesion location
The appropriate target location for pallidotomy was originally suggested by trial and error. The
earliest stereotactic pallidotomies targeted the anterodorsal region of the GPi (167). Svennilson et al.
(173), in the 1950s, deliberately varied the target in the GPi from the anterodorsal region to the
posterolateral region and achieved improved symptom control in the latter target location. This
posterolateral target was recently repopularized by Laitinen et al. (103). Electrophysiological studies
have justified the choice of the posterolateral part of the GPi as the appropriate target, because in both
humans (83,125,170,189) and nonhuman primates (46), the posterolateral part of the GPi is the region
containing neurons, the discharge of which is modulated by joint movements. This indicates that the
posterolateral part of the GPi is the sensorimotor region and is therefore the subdivision of the nucleus
participating in the basal ganglia-thalamocortical motor circuit. Lesions in other, nonmotor parts of the
GPi should primarily affect nonmotor functions. Lesions outside the motor territory of the GPi may
temporarily relieve parkinsonian motor signs, presumably by extension of edema into, or partial
lesioning of, the motor territory, but the benefit of such lesions seems to be transient (188,189).
Most groups now target the posterior part of the GPi for lesioning, as is shown in Figure 6, but there is
not universal agreement regarding target choice. In his more recent publications, Laitinen (101,102) has
advocated the GPe as the best target. In two studies that examined the effect of lesion location on
outcome, lesions that encroached on the GPe produced either worse (188) or equivalent (99) outcomes to
lesions entirely restricted to the posterior part of the GPi. In two reported cases from different studies,
pallidotomy restricted to the GPe had no benefit (99,142). Further, postoperative MR images of the
patients presented by Laitinen (101), Laitinen and Hariz (102), and Laitinen et al. (103) clearly show the
lesion involving the posterolateral part of the GPi as well as the GPe. In the MPTP-treated primate
model of PD, pure GPe lesions do not relieve L-dopa induced dyskinesias (22), whereas dyskinesias in
the patients presented by Laitinen (101), Laitinen and Hariz (102), and Laitinen et al. (103) was clearly
relieved, supporting the idea that this therapeutic benefit derives from the GPi component of the lesion.
Others have emphasized ansa lenticularis as the best target choice (87). The ansa lenticularis, however,
is very broad-based (making it anatomically difficult to fully lesion), and it is not clear from animal
studies whether it contains fibers related to motor function. Because so few studies have correlated
precise lesion location with outcome (30,99,188), there is insufficient long-term outcome data to adopt any
position dogmatically.
Target choice may affect the complication rate, particularly of bilateral pallidotomy. The bulbar
complications associated with bilateral GPi pallidotomy may be caused by bilateral damage to
corticobulbar fibers in the internal capsule adjacent to the GPi. If so, then selection of a more lateral
lesioning (GPe) target, as advocated by Laitinen (101), could potentially reduce the bulbar complications
associated with bilateral pallidotomy because the lesion would be further removed from the internal
capsule. There is no evidence, however, that more laterally placed lesions are as effective as posterior
GPi lesions for alleviation of parkinsonian motor signs.
Ideal lesion size is also not standardized. By early postoperative MRI, mean lesion sizes have been
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revealed to be 44 mm3 (99), 75 mm3 (51), 127 mm3 (10), or 6 to 8 mm in diameter (126). Six months after
surgery, lesions may not be visible on MR images, even for patients with persistent benefit (99). The
mean lesion volume reported by Laitinen et al. (103) was 95 mm3 , as revealed by CT performed 3 to 12
months postoperatively. Variations in apparent lesion size on postoperative imaging studies may
correspond to variable techniques. Some groups make multiple lesions along multiple tracks (10,189),
whereas others generally use one lesion track (103). Radiographic measurements of lesion size are
inherently approximate because the precise boundaries of the lesion are subject to interpretation.
Anecdotal cases indicate that enlarging a lesion, when the patient has had initial benefit and then
relapse, may improve long-term results (172). However, the reason for improvement with a second
surgery could be either suboptimal size or suboptimal location of the original lesion.
Pallidal stimulation
Results
Several recent reports have described the effects of chronic pallidal stimulation, both unilateral and
bilateral, for PD (11,68,85,97,98,121,144,163,180,181). These are summarized in Table 5. Four series (reporting a
total of 23 patients) have presented results in terms of standard UPDRS rating scales (68,98,121,144,180).
Improvement in UPDRS motor scores during stimulation were highly variable, ranging from
statistically insignificant in one study (180) to significant changes of 11 to 70% in the three other studies
(68,98,144).
TABLE 5. Results of Chronic Pallidal and Subthalamic Nucleus Stimulation for Parkinson's Diseasea
Similar to pallidotomy, pallidal stimulation (in most reports) improves contralateral tremor, rigidity,
bradykinesia, and L-dopa-induced dyskinesias (11,68,85,98,121,144,163). The percentage of the day spent
"on" increases significantly (144). Although improvements in axial symptoms (gait and instability) are
reported (11), there are too few patients to determine whether this is a consistent benefit. Effects of
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pallidal stimulation and of medical therapy with L-dopa were additive in one study (68), but pallidal
stimulation worsened some aspects of on-medication function in another study (98). Most patients have
not significantly decreased L-dopa intake (11,68,85,98,121,144,163,180,181).
Complications
The reported complications associated with pallidal stimulation have been minimal. Visual
phenomena may be evoked with certain stimulation parameters (68,144). In a series of nine patients
subjected to detailed neuropsychological testing, unilateral stimulation did not cause major changes
(181). There was a trend, however, toward decreased verbal fluency, as has been described for unilateral
pallidotomy (182). In contrast to bilateral pallidotomy (104), adverse effects on speech and cognition were
not observed in patients during bilateral pallidal stimulation, although only a few such patients have
been reported (144,163). It is possible that pallidal stimulation contralateral to a previous pallidotomy
would benefit patients with bilateral disease while avoiding the potential complications associated with
bilateral pallidotomy, but this remains to be confirmed in clinical trials.
Time course of pallidal stimulation effect
Several groups have observed a time lag between the onset and termination of the effects of pallidal
stimulation. In several cases reported by Gross et al. (68), the benefits of stimulation (with stimulation
on) were not apparent immediately after the surgery but became apparent 1 to 2 months later. Pahwa et
al. (144) found that after 3 months of chronic stimulation, the UPDRS motor scores with the stimulators
off were significantly better than the baseline scores and those obtained during the early postoperative
period, indicating that the effects of chronic pallidal stimulation can partially persist after the stimulator
is turned off. The mechanism for such delays in the onset and termination of the stimulator effect is not
clear. This pattern is in contrast to that observed during thalamic stimulation, in which the effects of
stimulation become apparent immediately and disappear immediately when the stimulator is turned off.
Optimal pallidal stimulator location
In most preliminary reports of pallidal stimulation, the distal contact of the stimulator is placed in the
posterolateral part of the GPi, in the same area typically targeted for lesioning (11,68,98,144,164). The
optimal location for stimulator placement has yet to be determined. Some have advocated a target for
stimulation that is more anterior to the usual pallidal lesioning site (85,86). Recently, Bejjani et al. (11)
showed, in five patients, that the effects of stimulation varied with lead location within the pallidal
complex. Stimulation in the ventral part of the GPi relieved L-dopa-induced dyskinesias and rigidity
but worsened gait and bradykinesia, whereas stimulation in the dorsal part of the GPi (at the border
with the GPe) improved gait, rigidity, and bradykinesia without an effect on L-dopa induced
dyskinesias. Considering the variety of mechanisms by which DBS may act, it would not be surprising
if the best target for pallidal stimulation differed from the best target for lesioning.
STN stimulation
Benabid and colleagues have implanted bilateral stimulators in the STN in patients with PD with
severe rigidity and bradykinesia (98,121-123). In the first three patients for whom detailed evaluations are
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reported, UPDRS motor scores were improved by 42 to 82% 3 months after surgery (122). An
additional six patients showed similar benefits (121). These changes (for bilateral surgery) are
comparable with or better than the best reported results for unilateral GPi pallidotomy
(10,51,56,87,90,96,99,103,105,126,162,172,190). Akinesia and rigidity were the motor signs that improved the
most. Unlike pallidotomy and pallidal stimulation, STN stimulation did not relieve peak L-dopainduced dyskinesias, although it did not exacerbate them either (123). However, patients were able to
significantly reduce their L-dopa intake (98,122), which has not usually been the case after unilateral
pallidotomy (10,51,56,87,90,96,99,103,105,126,162,172,190).
In three of the first five patients in the series presented by Benabid and colleagues, hemiballism and
axial dystonic movements could be induced by high-voltage stimulation (122,123). In two of these
patients, therapeutic benefit was partially limited by the occurrence of stimulation-induced involuntary
movements at the same voltage threshold required for the optimal antiparkinsonian effect (122).
Stimulation-induced involuntary movements were always reversible by decreasing or stopping
stimulation.
Based on early clinical results, promising data in animal models, and theoretical considerations
previously outlined, the STN seems to be a highly promising target for most if not all parkinsonian
signs. Early studies clearly justify further investigation.
DEFICIENCIES IN THE CURRENT MODEL OF PD
The model shown in Figure 2 illustrates how inactivation of certain parts of the basal gangliathalamocortical motor circuit can compensate for the effects of dopamine loss on cortical activity, even
though such interventions clearly do not restore dopaminergic function. However, many clinical
observations are not accounted for by this model (129), and modifications are being proposed
(35,118,165,184). For example, L-dopa-induced dyskinesias improved greatly after pallidotomy, which is
not predicted by the model, because hyperkinetic states should be associated with pallidal hypoactivity
and should therefore not improve with pallidal lesioning. Furthermore, the model proposes that
bradykinesia results from decreased activity in the thalamocortical projection and thus predicts that
lesioning this pathway should worsen bradykinesia. However, ablation of thalamocortical projection
neurons in the Voa/Vop, as may occur during thalamotomy, has not been reported to significantly
worsen bradykinesia (129).
There are several possible explanations for these paradoxes. In the MPTP-treated primate model,
alterations in the patterns, in addition to the mean rates, of action potential firing have been observed in
the thalamus (187), GP (57), and STN (18). These alterations include a greater tendency to discharge in
bursts, a higher degree of synchronization of discharge between neighboring neurons, and a greater
proportion of neurons the activity of which is affected by joint movements. Although the model shown
in Figure 2 attempts to relate movement disorders only to altered mean discharge rates, motor function is
likely to be affected by these altered patterns of neuronal activity in addition to altered rates.
Interruption of pallidal activity could then benefit both hyper- and hypokinetic states by eliminating
abnormal firing patterns. In addition, there may be anatomically distinct subcircuits within individual
nuclei, as yet ill defined, that mediate different aspects of parkinsonian symptomatology. Early clinical
data from trials of pallidal stimulation support this hypothesis (11,97).
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Finally, motor circuits outside of the basal ganglia-thalamocortical loop may be important in
movement disorders. In particular, collaterals from the pallidothalamic pathway innervate the
pedunculopontine nucleus (165). These collaterals are interrupted by pallidotomy (152). The
pedunculopontine nucleus is a motor structure that is known to be metabolically abnormal in the
parkinsonian state (145). It is possible that some parkinsonian symptoms, such as bradykinesia, may be
mediated via this descending connection to brain stem motor areas rather than by thalamocortical
pathways. This could account for the observation that interruption of pallidal or STN activity improves
bradykinesia, whereas thalamotomy seems to have little effect on bradykinesia.
WHAT IS THE BEST OPERATION FOR PD?
Lesioning versus stimulation
In the three different surgical targets discussed in this article, lesioning and stimulation techniques
seem to produce similar behavioral effects. The advantage of DBS over lesioning is that it is reversible
and adjustable. Thus, DBS is potentially safer in brain regions where lesions might have unacceptable
or unknown risks, such as in the STN or contralateral to preexisting lesions in the Vim or GPi. The
effects of DBS are easy to document objectively, because by varying the status of the stimulator (on or
off), its effects can be readily studied in a double-blinded fashion. Finally, as an essentially reversible
intervention, DBS preserves options for the patient in the event that in the future, practical and effective
therapies emerge from current trials of restorative techniques, such as fetal cell transplantation (141) or
growth factor administration (63,124).
However, the drawbacks of caring for a chronically implanted device are familiar to neurosurgeons
and are significant. As with any implanted foreign body there is a risk of infection and migration.
Batteries must be replaced at regular intervals or an external power source must be worn against the
skin. The device is expensive. A single stimulator may be limited in the volume of tissue it can affect,
thus rendering it potentially less practical in regions in which the physiological target is large (such as
the sensorimotor territory of the GPi). Periodic reprogramming of the stimulator to find the optimal
stimulation parameters may require a large investment of time and personnel.
Choice of surgical targets
The indications for each procedure discussed in this article are still evolving, and several procedures,
particularly GPi and STN stimulation, require more outcome data before long-term results and
complications are defined. Based on preliminary data, it seems that the selection of the target for
surgery should depend on the individual patient's symptomatology. Vim thalamotomy
(49,59,89,94,131,134,179,193) and thalamic stimulation (3,12,23,24,31,80,164) have proven efficacy for relief of
parkinsonian tremor. Thus, these are reasonable procedures for the minority of patients with PD for
whom tremor is the most disabling sign. Thalamic lesions, if extended into the pallidal receiving area of
the Vop/Voa, can be effective for L-dopa-induced dyskinesias and rigidity but are not reported to be
effective for bradykinesia. Because of the well known complications associated with bilateral
thalamotomy, thalamic stimulation seems preferable in cases in which bilateral treatment is indicated or
contralateral to a previous thalamotomy. Whether thalamic stimulation should completely replace
thalamotomy remains to be determined.
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In many patients with moderate to advanced PD, however, the most disabling motor signs are
bradykinesia and axial symptomatology, such as postural instability and freezing. In this situation, the
GPi or STN seems to be the preferred target. Unilateral posterior GPi pallidotomy is currently the best
studied procedure for patients with these symptoms RF
(10,34,51,53,55,56,60,66,67,87,90,92,96,99,101,103106,125,126,142,149,159,161,162,166,172,176,182,188,189,199)*. Posterior GPi pallidotomy is
clearly effective for contralateral off-period bradykinesia, tremor, rigidity, and dystonias, as well as Ldopa-induced dyskinesias. Performed with modern localization techniques, unilateral pallidotomy is
relatively safe, and its effectiveness has been documented for up to 4 years (10,51,56,96,99,105,126,172,190).
The maximum possible effectiveness of this procedure, however, will not be clear until the optimal
lesion size and location, as well as optimal surgical technique, are better defined.
There are important limitations to pallidotomy. Its effects are mainly contralateral, and it is still not
clear that bilateral pallidotomy can be performed in a way that produces maximum symptomatic benefit
with acceptable side effects. After pallidotomy, most patients remain on a complex medication schedule
with numerous potential side effects. Finally, the effectiveness of unilateral pallidotomy for axial
symptomatology (gait, posture, and freezing) has yet to be consistently demonstrated, and in some
patients, these symptoms are extremely disabling. It is possible that pallidal stimulation will prove to be
equally effective as or more effective than pallidotomy and also safe for bilateral use. At present, the
number of cases reported is too small to establish this, however, and the results have been highly
variable (11,68,85,121,144,163,180,181).
The STN is potentially an excellent target. Because of concerns regarding the production of
permanent involuntary movements with lesioning this nucleus, DBS has been the technique of choice
for the first human trials of STN surgery (98,121-123). In preliminary human data, STN stimulation seems
to be highly effective for bradykinesia, as well as for rigidity and tremor, and seems to be safe for
bilateral use. Primate data suggest that interruption of STN activity may ameliorate postural instability
and freezing (8,71), and this possibility merits careful study in humans. STN stimulation does not
ameliorate L-dopa-induced dyskinesias, but this may not be problematic if the procedure allows
significant reductions in L-dopa intake (98). In some patients, STN stimulation may induce involuntary
movements at stimulation levels necessary for maximal relief of parkinsonism (123).
SUMMARY
Although the fundamental defect in the parkinsonian brain is the loss of dopaminergic cells of the
SNc, this results in electrophysiological abnormalities throughout the motor subdivisions of the
thalamus and basal ganglia. Alteration of neuronal activity by ablative surgery or DBS, at a variety of
target sites, can ameliorate parkinsonian symptomatology even though these procedures do not restore
lost dopaminergic cells. The surgical targets, theoretical rationales, and localization techniques for
ablative procedures and DBS are similar. Three target sites are currently under study: the thalamus,
GPi, and STN. Although high-frequency DBS at these targets has behavioral effects that are similar to
those of lesioning, the cellular mechanism of DBS is not well understood and may be extremely
complex.
Vim thalamotomy and Vim thalamic stimulation are now established procedures for parkinsonian
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tremor. Unilateral posterior GPi pallidotomy has been shown to be effective for contralateral tremor,
rigidity, bradykinesia, and L-dopa-induced dyskinesias. Pallidal and STN stimulation are under active
investigation as treatments for all cardinal signs of PD. DBS procedures offer a potential advantage
over ablative therapy in that they are reversible and adjustable and may be safer for bilateral use. At
present, there are too few studies to determine whether these procedures offer a superior clinical result
in comparison with ablative surgery. This will require larger numbers of patients in well-controlled
studies using standardized measures of motor function, patient disability, and quality of life.
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Key words: Basal ganglia; Electrical stimulation therapy; Globus pallidus; Parkinson's disease;
Stereotactic techniques; Thalamus
Accession Number: 00006123-199811000-00001
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