Subthalamotomy in parkinsonian monkeys Behavioural and biochemical analysis

Guridi, Jorge; Herrero, M.T.; Luquin, M. R.; Guillén, Javier; Ruberg, Merle; Laguna, Janeth; Vila, Miquel; Javoy‐Agid, F.; Agid, Yves; Hirsch, Étienne C.; Obeso, José A.

doi:10.1093/brain/119.5.1717

Cited by 210 publications

(108 citation statements)

References 59 publications

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“…However, the mechanisms underlying the effects of STN-HFS remain unclear Dostrovsky and Lozano, 2002;McIntyre et al, 2004a). Because STN-HFS effects have been shown to be functionally equivalent to those of STN lesions (Bergman et al, 1990;Aziz et al, 1991;Guridi et al, 1996;Alvarez et al, 2005), it has been suggested that STN-HFS silences STN neurons (Benazzouz et al, 1993). However, recent modeling and in vivo studies have shown that additional mechanisms, such as activation of the STN afferent and efferent pathways, may be involved, leading to distant synaptic inhibitory and excitatory effects in BG output nuclei (Windels et al, 2000(Windels et al, , 2005Salin et We investigated the mechanisms involved further by studying STN stimulation in rats in conditions comparable with those used in clinical practice: parameters, monopolar stimulation, and awake animals.…”

Section: Introductionmentioning

confidence: 99%

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Boulet¹,

Lacombe²,

Carcenac³

et al. 2006

J. Neurosci.

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The neurobiological mechanisms by which high-frequency stimulation of the subthalamic nucleus (STN-HFS) alleviates the motor symptoms of Parkinson's disease (PD) remain unclear. In this study, we analyzed the effects of STN-HFS on motor behavior in intact or hemiparkinsonian rats (6-hydroxydopamine lesion of the substantia nigra pars compacta) and investigated the correlation between these effects and extracellular glutamate (Glu) and GABA levels, assessed by intracerebral microdialysis in the substantia nigra pars reticulata (SNr). STN-HFS at an intensity corresponding to the threshold inducing contralateral forelimb dyskinesia, increased Glu levels in the SNr of both intact and hemiparkinsonian rats. In contrast, STN-HFS at half this intensity did not affect Glu levels in the SNr in intact or hemiparkinsonian rats but increased GABA levels in hemiparkinsonian rats only. STN-HFS-induced forelimb dyskinesia was blocked by microinjection of the Glu receptor antagonist kynurenate into the SNr and facilitated by microinjection of a mixture of the Glu receptor agonists AMPA and NMDA into the SNr. These new neurochemical data suggest that STN-HFS-induced forelimb dyskinesia is mediated by glutamate, probably via the direct activation of STN axons, shedding light on the mechanisms of STN-HFS in PD.

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Section: Introductionmentioning

confidence: 99%

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Boulet¹,

Lacombe²,

Carcenac³

et al. 2006

J. Neurosci.

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“…[3][4][5] In animal models of Parkinson's disease, neuronal activity is increased in the subthalamic nucleus and pars interna of the globus pallidus, 6 and lesions of these structures result in marked improvement in motor function. [6][7][8] These findings have led to the development of surgical procedures for Parkinson's disease that target the subthalamic nucleus and pars interna of the globus pallidus. 9,10 In patients with Parkinson's disease, the creation of lesions in the pars interna of the globus pallidus (pallidotomy) improves contralateral dyskinesia and provides moderate antiparkinsonian benefits.…”

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confidence: 99%

Deep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease

2001

N Engl J Med

1,352

225

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ConclusionsEVODOPA is the mainstay of treatment for Parkinson's disease. 1 However, long-term levodopa treatment is complicated by involuntary movements known as dyskinesia and motor fluctuations in which patients cycle between periods of good mobility ("on" periods) and impaired mobility ("off " periods). 2 These complications result in disability that cannot be satisfactorily controlled by medical therapy in the majority of patients. Advances in understanding of the pathophysiology of the basal ganglia have provided opportunities for new therapeutic strategies to manage these problems. [3][4][5] In animal models of Parkinson's disease, neuronal activity is increased in the subthalamic nucleus and pars interna of the globus pallidus, 6 and lesions of these structures result in marked improvement in motor function. [6][7][8] These findings have led to the development of surgical procedures for Parkinson's disease that target the subthalamic nucleus and pars interna of the globus pallidus. 9,10 In patients with Parkinson's disease, the creation of lesions in the pars interna of the globus pallidus (pallidotomy) improves contralateral dyskinesia and provides moderate antiparkinsonian benefits. 11,12 However, pallidotomy necessitates making a destructive brain lesion and entails the risk of inducing neurologic deficits, particularly with bilateral procedures. 13 The creation of lesions in the subthalamic nucleus also provides benefits to patients, 14 but is associated with the risk of hemiballismus. 15 Accordingly, physicians have been reluctant to perform bilateral pallidotomy or subthalamotomy. 10 High-frequency deep-brain stimulation of specific brain targets simulates the effect of a lesion without deliberately damaging the brain. 16 Deep-brain stimulation of the thalamus has been shown to control tremor 17 but not other, more disabling, features of Parkinson's disease. Studies in small numbers of patients with Parkinson's disease suggest that stimulation of the subthalamic nucleus and pars interna of the globus pallidus can improve the full constellation of parkinsonian motor features. [18][19][20][21][22] We evaluated the results LThe New England Journal of Medicine METHODSWe performed a six-month, prospective, multicenter trial of bilateral deep-brain stimulation of the subthalamic nucleus or pars interna of the globus pallidus in patients with advanced Parkinson's disease. The study included a double-blind, randomized, crossover evaluation of the immediate effects of stimulation three months after implantation of the electrodes; unblinded evaluations of motor function two weeks before and one, three, and six months after implantation; and assessments of motor status with the use of a home diary. PatientsThe ages of the patients ranged from 30 to 75 years. The criteria for inclusion were the presence of at least two cardinal features of parkinsonism (tremor, rigidity, and bradykinesia), a good response to levodopa, a minimal score of 30 points on the motor portion of the Unified Parkinson's Disease Rating S...

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“…Lesion of the STN increases striatal glutamate levels in normal rats 83 and decreases 6-hydroxydopamine (6-OHDA)-induced elevation of glutamate. 16,83 Moreover, STN ablation in normal primates decreases pallidal 2-deoxyglucose uptake 43 and expression of the gene for glutamic acid decarboxylase 67; 24 together, these observations indicate decreased cellular activity in STN efferent structures.…”

Section: Discussionmentioning

confidence: 94%

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

Jourdain

Morin

Grégoire

et al. 2015

JNS

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abbreviatioNs AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; GP = globus pallidus; GPe = GP externus; GPi = GP internus; LID = levodopa-induced dyskinesia; mGlu = metabotropic glutamate; MPTP = 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; NMDA = N-methyl-d-aspartate; PD = Parkinson disease; STN = subthalamic nucleus; 6-OHDA = 6-hydroxydopamine. obJect Unilateral subthalamotomy is a surgical procedure that may be used to alleviate disabling levodopa-induced dyskinesias (LIDs) in patients with Parkinson disease (PD). However, the mechanisms involved in LID remain largely unknown. The subthalamic nucleus (STN) is the sole glutamatergic nucleus within the basal ganglia, and its lesion may produce changes in glutamate receptors in various areas of the basal ganglia. The authors aimed to investigate the biochemical changes in glutamate receptors in striatal and pallidal regions of the basal ganglia after lesion of the STN in parkinsonian macaque monkeys. methods The authors treated 12 female ovariectomized monkeys with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce PD-like symptoms, treated 8 of these animals with 3,4-dihydroxy-l-phenylalanine (L-DOPA; levodopa) to induce LID, and performed unilateral subthalamotomy in 4 of these 8 monkeys. Four additional monkeys were treated with saline only and were used as controls. The MPTP monkeys had previously been shown to respond behaviorally to lower doses of levodopa after the STN lesion. Autoradiography of slices from postmortem brain tissues was used to visualize changes in the specific binding of striatal and pallidal ionotropic glutamate receptors (that is, of the α-amino-3-hydroxy 5-methyl-4-isoxazole propionate [AMPA] and N-methyl-d-aspartate [NMDA] NR1/NR2B subunit receptors) and of metabotropic glutamate (mGlu) receptors (that is, mGlu2/3 and mGlu5 receptors). The specific binding and distribution of glutamate receptors in the basal ganglia of the levodopa-treated, STN-lesioned MPTP monkeys were compared with those in the saline-treated control monkeys and in the saline-treated and levodopa-treated MPTP monkeys. results The autoradiographic results indicated that none of the pharmacological and surgical treatments produced changes in the specific binding of AMPA receptors in the basal ganglia. Levodopa treatment increased the specific binding of NMDA receptors in the basal ganglia. Subthalamotomy reversed these increases in the striatum, but in the globus pallidus (GP), the subthalamotomy reversed these increases only contralaterally. Levodopa treatment reversed MPTPinduced increases in mGlu2/3 receptors only in the GP. mGlu2/3 receptor-specific binding in the striatum and GP decreased bilaterally in the levodopa-treated, STN-lesioned MPTP monkeys compared with the other 3 groups. Compared with mGlu5 receptor-specific binding in the control monkeys, that of the levodopa-treated MPTP monkeys increased in the dorsal putamen and remained unchanged in the caudate nucleus and in the GP. coNclusioNs These results implicate glutamate recepto...

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Subthalamotomy in parkinsonian monkeys Behavioural and biochemical analysis

Cited by 210 publications

References 59 publications

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Subthalamic Stimulation-Induced Forelimb Dyskinesias Are Linked to an Increase in Glutamate Levels in the Substantia Nigra Pars Reticulata

Deep-Brain Stimulation of the Subthalamic Nucleus or the Pars Interna of the Globus Pallidus in Parkinson's Disease

Changes in glutamate receptors in dyskinetic parkinsonian monkeys after unilateral subthalamotomy

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