Continuation of posting of Robert A. Fink, M.D.

 Mechanisms of Action
Pallidal Stimulation
The specific mechanism of pallidal DBS in reducing dyskinesias is unknown.
The current view of basal ganglia circuitry indicates that reduction of
activity in the ventral GPi (for example, with pallidotomy), which reduces
akinesia, should worsen dyskinesias. In fact, lesioning of the ventral
pallidum provides good relief of dyskinesias.[1,16] This observation has
led some authors to suggest that dyskinesias arise from abnormal patterns
of neuronal activity within the GP and that relief of dyskinesias by
surgical intervention is a result of modification of these patterns of
activity.[1,16,36] Surgical modification of this patterned activity might
be accomplished through direct neuronal inhibition (for example, with
surgical lesioning or focal electrical stimulation) or, in the case of
DBS, by activation of axons close to the stimulation electrode, which in
turn produces downstream inhibition that interferes with patterned output
from the GPi.[36] Dyskinesias might also arise from an abnormal balance of
activity within different functional zones of the GP.[1] Ventral pallidal
stimulation, which is typically antidyskinetic, might relieve dyskinesias
by suppressing an abnormal mixture of activity, perhaps by attenuating
disequilibrium between striatopallidal and subthalamopallidal in puts.[16]

The anatomical and physiological basis of discrete functional zones within
the GP in which DBS may have opposite effects, as described earlier, has
not been fully characterized. Stimulation through dorsal and ventral
pallidal contacts might selectively activate different fiber tracts with
differing downstream effects. For example, stimulation through ventral DBS
contacts might activate fibers in the ansa lenticularis, whereas
stimulation through dorsal contacts might activate the lenticular
fasciculus.[16] Alternatively, differential DBS effects might be mediated
through effects on the subthalamopallidal tract, which projects to the
dorsal GP externus and GPi. Dorsal GPi stimulation might inhibit this
projection and would be expected to improve PD symptoms and induce
dyskinesias.

Stimulation of the STN
Compared with DBS of the GPi, in the STN this procedure seems to have a
more straight forward effect in relieving dyskinesias. Deep brain
stimulation of the STN mimics the effects of levodopa on parkinsonian
motor symptoms and allows reduction of dopaminergic medication,
secondarily relieving dyskinesias as medications are reduced or withdrawn
postoperatively. According to my observations, attenuation of dyskinesias
is sometimes seen in the early postoperative period after implantation of
DBS electrodes in the STN in the absence of reduction of medications. This
indicates a direct antidyskinetic effect of manipulation of the STN (or
directly superior tissues), but long-term relief of dyskinesias generally
requires reduction of medications.

The specific site of action in stimulation of the STN is unknown. Some
data indicate that the best effect at the lowest intensity is achieved not
by stimulation of neurons within the STN but by stimulation of tissue
dorsal to it, which might affect the pallidothalamic bundle, the
pallidosubthalamic tract, and/or the zona incerta.[34] Other data indicate
that the most effective contact location appears to be within the
anterodorsal portion of the STN, although current could spread from this
location into the directly superior fields of Forel and zona incerta.[26]
The observation that an active DBS contact dorsal to the STN may provide
better control of dyskinesias (indicative of a direct antidyskinetic
effect) supports the notion that activation of structures dorsal to the
STN is important in providing relief of parkinsonian symptoms by DBS of
the STN (W Marks and S Heath, unpublished data).




Outcomes of DBS of the STN and GPi for Dyskinesias
Consistent with their different mechanisms of action, DBS of the GPi tends
to decrease and DBS of the STN tends to increase peak dose dyskinesias
immediately after the treatment.[24] Long-term follow up conducted after
postoperative medication adjustment reveals that DBS, whether in the STN
or GPi, provides good relief of dyskinesias associated with PD. Published
reports indicate that DBS of the STN reduces dyskinesias from 41 to 83%;
the mean reduction of dyskinesias is 56% (derived from eight published
reports of outcomes of this treatment).[3,6,13, 14,17,18,20,27] In
comparison, DBS of the GPi reduces dyskinesias from 47 to 88%; a mean
reduction of 73% (derived from seven published
reports).[3,6,9,18,20,21,32] Outcomes of DBS of the STN and GPi cannot be
compared directly because the data are derived from nonrandomized,
noncontrolled case series, with one exception. Burchiel, et al.,[3]
reported a small randomized series comparing DBS of the STN and GPi. In
this series, dyskinesias decreased 67% in the STN group and 47% in the GPi
group. This difference was not statistically significant. Complications,
morbidity, and deaths associated with DBS for the treatment of dyskinesias
are associated with DBS in general[25,31] and are not unique to the
treatment of dyskinesias.




Thalamic DBS for Parkinsonian and Nonparkinsonian Dyskinesias
The GP and STN are the most common targets for DBS used to treat
dyskinesias. This is true for the following reasons. 1) Dyskinesias are
common in patients with PD. 2) Parkinson disease is a relatively common
movement disorder. 3) Deep brain stimulation of both the GPi and the STN
is approved by regulatory agencies for the treatment of symptoms of PD.
Deep brain stimulation of the thalamic ventral intermediate nucleus is
approved for the treatment of parkinsonian and essential tremor and has
also been used as a primary treatment for dyskinesias associated with
PD.[4,10,30] In general, thalamic DBS is less effective than interventions
in the pallidum and STN for the relief of parkinsonian dyskinesias,[30]
and it is not widely used for this purpose. Thalamic stimulation seems
most effective if the electrode is positioned slightly more medially,
posteriorly, and deeply than it is typically placed for treatment of
tremor. The region stimulated by an electrode in this location may include
the centre median and parafascicular complex.[4] Thalamic DBS has been
reported on a limited basis for the "off-label" treatment of
nonparkinsonian dyskinesias[22] (these forms of dyskinesias may be
categorized more accurately as dystonias).[12]




Conclusions
Deep brain stimulation can relieve dyskinesias effectively and safely.
Dyskinesias treated most commonly with DBS are those associated with PD,
and the STN and GPi are the typical surgical targets. Although the STN has
become the surgical target of choice for DBS in many movement disorders
programs, comparisons of the outcomes of DBS of the STN and of the GPi
have not been made in randomized controlled trials, and therefore the
superiority of DBS of the STN remains unproven.[29,33] Deep brain
stimulation of the GPi and of the STN has different mechanisms of action
but appears comparable in its ability to reduce dyskinesias associated
with PD. In the absence of data demonstrating superiority of one site over
another, selection of the stimulation target should be individualized to
meet the needs of each patient. The choice of target should be based on
the patient's most disabling symptoms, response to medications (including
side effects), goals of therapy, and taking into account the different
antidyskinetic effects of DBS of the STN and GPi.


References
Bejjani B, Damier P, Arnulf I, et al: Pallidal stimulation for Parkinson's
Disease. Two targets? Neurology 49:1564­1569, 1997 Benabid AL,
Caparros-Lefebvre, Pollak P: History of surgery for movement disorders, in
Germano IM (ed): Neurosurgical Treatment of Movement Disorders. Park
Ridge, IL: AANS, 1998, pp 19­36 Burchiel KJ, Anderson VC, Favre J, et al:
Comparison of pallidal and subthalamic nucleus deep brain stimulation for
advanced Parkinson's disease: results of a randomized, blinded pilot
study. Neurosurgery 45:1375­1384, 1999 Caparros-Lefebvre D, Blond S,
Feltin MP, et al: Improvement of levodopa induced dyskinesias by thalamic
deep brain stimulation is related to slight variation in electrode
placement: possible involvement of the centre median and parafascicularis
complex. J Neurol Neurosurg Psychiatry 67:308­314, 1999 Cotzias CG,
Papavasiliou PS, Gellene R: Modification of parkinsonism—chronic 
treatment
with L-dopa. N Engl J Med 280: 337­354, 1969 The Deep-Brain Stimulation
for Parkinson's Disease Study Group: Deep- brain stimulation of the
subthalamic nucleus or the pars interna of the globus pallidus in
Parkinson's disease. N Engl J Med 345:956­963, 2001 Eskandar EM, 
Flaherty
A, Cosgrove GR, et al: Surgery for Parkinson disease in the United States,
1996 to 2000: practice pat terns, short-term outcomes, and hospital
charges in a nationwide sample. J Neurosurg 99:863­871, 2003 Esselink 
RAJ,
di Bie RMA, de Haan RJ, et al: Unilateral pallidotomy versus bilateral
subthalamic nucleus stimulation in PD: a randomized trial. Neurology
62:201­207, 2004 Ghika J, Villemure JG, Fankhauser H, et al: Efficiency
and safety of bilateral contemporaneous pallidal stimulation (deep brain
stimulation) in levodopa- responsive patients with Parkinson's disease
with severe motor fluctuations: a 2-year follow-up re view. J Neurosurg
89:713­718, 1998 Giron LT Jr, Koller WC: Methods of managing
levodopa-induced dyskinesias. Drug Saf 14:365­374, 1996 Gross C, Rougier
A, Guehl D, et al: High-frequency stimulation of the globus pallidus
internalis in Parkinson's disease: a study of seven cases. J Neurosurg
87:491­498, 1997 Jankovic J, Lang AE: Classification of movement
disorders, in Germano IM (ed): Neurosurgical Treatment of Movement Dis
orders. Park Ridge, IL: AANS, 1998, pp 3­18 Kleiner-Fisman G, Fisman 
DN,
Sime E, et al: Long-term follow up of bilateral deep brain stimulation of
the subthalamic nucleus in patients with advanced Parkinson disease. J
Neurosurg 99:489­495, 2003 Krack P, Batir A, Van Blercom N, et al:
Five-year follow-up of bilateral stimulation of the subthalamic nucleus in
advanced Parkinson's disease. N Engl J Med 349:1925­1934, 2003 Krack P,
Fraix V, Mendes A, et al: Postoperative management of subthalamic nucleus
stimulation for Parkinson's disease. Mov Disord 17 (Suppl 3):S188­S197,
2002 Krack P, Pollak, P, Limousin P, et al: Opposite motor effects of
pallidal stimulation in Parkinson's disease. Ann Neurol 43: 180­192, 1998
Krack P, Pollak P, Limousin P, et al: Stimulation of subthalamic nucleus
alleviates tremor in Parkinson's disease. Lancet 350: 1675, 1997 Krack P,
Pollak P, Limousin P, et al: Subthalamic nucleus or internal pallidal
stimulation in young onset Parkinson's disease. Brain 121:451­457, 1998
Kumar R: Methods for programming and patient management with deep brain
stimulation of the globus pallidus for the treatment of advanced
Parkinson's disease and dystonia. Mov Disord 17 (Suppl 3):S198­S207, 2002
Kumar R, Lozano AM, Montgomery E, et al: Pallidotomy and deep brain
stimulation of the pallidum and subthalamic nucleus in advanced
Parkinson's disease. Mov Disord 13 (Suppl 1): 73­82, 1998 Loher TJ,
Burgunder JM, Pohle T, et al: Long-term pallidal deep brain stimulation in
patients with advanced Parkinson disease: 1-year follow-up study. J
Neurosurg 96:844­853, 2002 Loher TJ, Krauss JK, Burgunder JM, et al:
Chronic thalamic stimulation for treatment of dystonic paroxysmal
nonkinesigenic dyskinesia. Neurology 56:268­270, 2001 Miyawaki E, Lyons 
K,
Pahwa R, et al: Motor complications of chronic levodopa therapy in
Parkinson's Disease. Clin Neuro pharmacol 20:523­530, 1997 Nutt JG,
Rufener SL, Carter JH, et al: Interactions between deep brain stimulation
and levodopa in Parkinson's disease. Neurology 57:1835­1842, 2001 Oh 
MY,
Abosch A, Kim SH, et al: Long-term hardware-related complications of deep
brain stimulation. Neurosurgery 50: 1268­1276, 2002 Saint-Cyr JA, Hoque 
T,
Pereira LC, et al: Localization of clinically effective stimulating
electrodes in the human subthalamic nucleus on magnetic resonance imaging.
J Neurosurg 97: 1152­1166, 2002 Simuni T, Jaggi JL, Mulholland H, et al:
Bilateral stimulation of the subthalamic nucleus in patients with
Parkinson disease: a study of efficacy and safety. J Neurosurg 96:666­672,
2002 Skalabrin EJ, Laws ER Jr, Bennett JP Jr: Pallidotomy improves motor
responses and widens the levodopa therapeutic window in Parkinson's
disease. Mov Disord 13:775­781, 1998 Stowe RL, Wheatley K, Clarke CE, 
et
al: Surgery for Parkinson's disease: lack of reliable clinical trial
evidence. J Neurol Neurosurg Psychiatry 74:519­521, 2003 Tasker RR, 
Munz
M, Junn FS, et al: Deep brain stimulation and thalamotomy for tremor
compared. Acta Neurochir Suppl 68: 49­53, 1997 Umemura A, Jaggi JL, 
Hurtig
HI, et al: Deep brain stimulation for movement disorders: morbidity and
mortality in 109 patients. J Neurosurg 98:779­784, 2003 Visser-Vandewalle
V, van der Linden C, Temel Y, et al: Long-term motor effect of unilateral
pallidal stimulation in 26 patients with advanced Parkinson disease. J
Neurosurg 99: 701­707, 2003 Vitek JL: Deep brain stimulation for
Parkinson's Disease. A critical re- evaluation of STN versus Gpi DBS.
Stereotact Funct Neurosurg 78:119­131, 2002 Voges J, Volkman J, Allert N,
et al: Bilateral high-frequency stimulation in the subthalamic nucleus for
treatment of Parkinson disease: correlation of therapeutic effect with
anatomical electrode position. J Neurosurg 96:269­279, 2002 Volkman J,
Fogel W, Krack P: Postoperative Patient Management: Stimulation of the
Subthalamic Nucleus for Park inson's Disease. Minneapolis, MN: Medtronic
Neurological, 2001 Wu YR, Levy R, Ashby P, et al: Does stimulation of the
GPi control dyskinesia by activating inhibitory axons? Mov Disord
16:208­216, 2001 Reprint Address

Kenneth A. Follett, M.D., Ph.D., Department of Neurosurgery 1842 JPP,
University of Iowa Hospitals and Clinics, Iowa City, Iowa 52242. email:
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Abbreviation Notes

DBS = deep brain stimulation; GP = globus pallidus; GPi = GP internus; PD
= Parkinson disease; STN = subthalamic nucleus




Kenneth A. Follett, M.D., Ph.D., Department of Neurosurgery, University of
Iowa Hospitals and Clinics, and Iowa City Veterans Administration Medical
Center, Iowa City, Iowa

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Best,

Bob

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Robert A. Fink, M. D., F.A.C.S., P. C.
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Telephone:  510-849-2555   FAX:  510-849-2557
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