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      Optimal target localization for subthalamic stimulation in patients with Parkinson disease

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          Abstract

          Objective:

          To further determine the causes of variable outcome from deep brain stimulation of the subthalamic nucleus (DBS-STN) in patients with Parkinson disease (PD).

          Methods:

          Data were obtained from our cohort of 309 patients with PD who underwent DBS-STN between 1996 and 2009. We examined the relationship between the 1-year motor, cognitive, and psychiatric outcomes and (1) preoperative PD clinical features, (2) MRI measures, (3) surgical procedure, and (4) locations of therapeutic contacts.

          Results:

          Pre- and postoperative results were obtained in 262 patients with PD. The best motor outcome was obtained when stimulating contacts were located within the STN as compared with the zona incerta (64% vs 49% improvement). Eighteen percent of the patients presented a postoperative cognitive decline, which was found to be principally related to the surgical procedure. Other factors predictive of poor cognitive outcome were perioperative confusion and psychosis. Nineteen patients showed a stimulation-induced hypomania, which was related to both the form of the disease (younger age, shorter disease duration, higher levodopa responsiveness) and the ventral contact location. Postoperative depression was more frequent in patients already showing preoperative depressive and/or residual axial motor symptoms.

          Conclusion:

          In this homogeneous cohort of patients with PD, we showed that (1) the STN is the best target to improve motor symptoms, (2) postoperative cognitive deficit is mainly related to the surgery itself, and (3) stimulation-induced hypomania is related to a combination of both the disease characteristics and a more ventral STN location.

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          Most cited references26

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          Electrical stimulation of the subthalamic nucleus in advanced Parkinson's disease.

          In many patients with idiopathic Parkinson's disease, treatment with levodopa is complicated by fluctuations between an "off" period, when the medication is not working and the motor symptoms of parkinsonism are present, and an "on" period, when the medication is causing improved mobility, often accompanied by debilitating dyskinesias. In animal models of Parkinson's disease, there is overactivity in the subthalamic nucleus, and electrical stimulation of the subthalamic nucleus improves parkinsonism. We therefore sought to determine the efficacy and safety of electrical stimulation of the subthalamic nucleus in patients with Parkinson's disease. We studied 24 patients with idiopathic Parkinson's disease in whom electrodes were implanted bilaterally in the subthalamic nucleus under stereotactic guidance with imaging and electrophysiologic testing of the location. Twenty were followed for at least 12 months. Clinical evaluations included the Unified Parkinson's Disease Rating Scale, a dyskinesia scale, and timed tests conducted before and after surgery, when patients were off and on medications. After one year of electrical stimulation of the subthalamic nucleus, the patients' scores for activities of daily living and motor examination scores (Unified Parkinson's Disease Rating Scale parts II and III, respectively) off medication improved by 60 percent (P<0.001). The subscores improved for limb akinesia, rigidity, tremor, and gait. In the testing done on medication, the scores on part III improved by 10 percent (P<0.005). The mean dose of dopaminergic drugs was reduced by half. The cognitive-performance scores remained unchanged, but one patient had paralysis and aphasia after an intracerebral hematoma during the implantation procedure. Electrical stimulation of the subthalamic nucleus is an effective treatment for advanced Parkinson's disease. The severity of symptoms off medication decreases, and the dose of levodopa can be reduced with consequent reduction in dyskinesias.
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            The organization of prefrontal-subthalamic inputs in primates provides an anatomical substrate for both functional specificity and integration: implications for Basal Ganglia models and deep brain stimulation.

            The identification of a hyperdirect cortico-subthalamic nucleus connection highlighted the important role of the subthalamic nucleus (STN) in regulating behavior. However, this pathway was shown primarily from motor areas. Hyperdirect pathways associated with cognitive and motivational cortical regions are particularly relevant given recent data from deep brain stimulation, both for neurologic and psychiatric disorders. Our experiments were designed to demonstrate the existence and organization of prefrontal-STN projections, help delineate the "limbic" STN, and determine whether convergence between cortico-STN fibers from functionally diverse cortical areas exists in the STN. We injected anterograde tracers in the ventromedial prefrontal, orbitofrontal, anterior cingulate, and dorsal prefrontal cortices of Macaca nemestrina and Macaca fascicularis to analyze the organization of terminals and passing fibers in the STN. Results show a topographically organized prefrontal hyperdirect pathway in primates. Limbic areas project to the medial tip of the nucleus, straddling its border and extending into the lateral hypothalamus. Associative areas project to the medial half, motor areas to the lateral half. Limbic projections terminated primarily rostrally and motor projections more caudally. The extension of limbic projections into the lateral hypothalamus, suggests that this region be included in the STN. A high degree of convergence exists between projections from functionally diverse cortical areas, creating potentially important interfaces between terminal fields. Taken together, the results provide an anatomical substrate to extend the role of the hyperdirect pathway in models of basal ganglia function, and new keys for understanding deep brain stimulation effects on cognitive and motivational aspects of behavior.
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              Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease.

              Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double-blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio.
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                Author and article information

                Contributors
                Journal
                Neurology
                Neurology
                neurology
                neur
                neurology
                NEUROLOGY
                Neurology
                Lippincott Williams & Wilkins (Hagerstown, MD )
                0028-3878
                1526-632X
                15 April 2014
                15 April 2014
                : 82
                : 15
                : 1352-1361
                Affiliations
                From the Université Pierre et Marie Curie-Paris 6 (M.-L.W., M.S., V.C., C.K., S.F.-V., J.-L.G., A.H., V.M., F.P., Y.W., D. Grabli, D. Galanaud, D.D., M.V., L.M., E.B., J.Y., Y.A.), Centre de Recherche de l'Institut du Cerveau et de, la Moelle épinière, UMR-S975, Paris; Inserm (M.-L.W., M.S., V.C., C.K., S.F.-V., A.H., V.M., F.P., Y.W., D. Grabli, D. Galanaud, D.D., M.V., L.M., E.B., J.Y., Y.A.), U975, Paris; CNRS (M.-L.W., M.S., C.K., S.F.-V., A.H., V.M., F.P., Y.W., D. Grabli, D. Galanaud, D.D., M.V., L.M., E.B., J.Y., Y.A.), UMR 7225, Paris; Centre d'Investigation Clinique (M.-L.W., M.S., C.K., G.S., A.H., V.M., F.P., Y.W., P.Z., D. Grabli, A.-M.B., M.V., Y.A.), Département de Neurologie (M.-L.W., V.C., A.W., A.H., V.M., D. Grabli, A.-M.B., M.V., Y.A.), IM2A (V.C., F.P.), Service de Neurochirurgie (C.K., S.N., P.C., H.B.), Department of Clinical Neurophysiology (B.P.), and Service de Neuroradiologie Diagnostique et Fonctionnelle (D. Galanaud, D.D.), Hôpitaux Universitaires Pitié-Salpêtrière/Charles Foix, Assistance Publique-Hôpitaux de Paris, France; Department of Neurology (M.S.), University Hospital, Bern, Switzerland; Centre de Neuroimagerie de Recherche (S.F.-V., D. Galanaud, D.D.), Hôpitaux Universitaires Pitié-Salpêtrière/Charles Foix, Paris, France; Département de Biostatistiques et Information Médicale (J.-L.G.), Hôpitaux Universitaires Pitié-Salpêtrière/Charles Foix, Assistance Publique-Hôpitaux de Paris, ER4 (ex EA3974) Modélisation en Recherche Clinique, Paris, France; Department of Neurology (P.Z.), 251 Hellenic Air Force General Hospital, Athens, Greece; and Department of Neurology (J.-L.H.), CHU Poitiers, France.
                Author notes
                Correspondence to Dr. Welter: marie-laure.welter@ 123456psl.aphp.fr

                Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

                Article
                NEUROLOGY2013545384
                10.1212/WNL.0000000000000315
                4001189
                24647024
                4944c3d2-41c7-456e-b7f5-2a2b4025c9d1
                © 2014 American Academy of Neurology

                This is an open access article distributed under the terms of the Creative Commons Attribution-Noncommercial No Derivative 3.0 License, which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                : 27 August 2013
                : 10 December 2013
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