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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. 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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: [log in to unmask] 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 -------------------------------------------------------------------------- ------ Best, Bob ********************************************** Robert A. Fink, M. D., F.A.C.S., P. 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