Lesion of the centromedian thalamic nucleus in MPTP‐treated monkeys

Abstract

The caudal intralaminar nuclei are a major source of glutamatergic afferents to the basal ganglia. Experiments in the 6-hydroxydopamine rat model have shown that the parafascicular nucleus is overactive and its lesion alleviates basal ganglia neurochemical abnormalities associated with dopamine depletion. Accordingly, removal of this excitatory innervation of the basal ganglia could have a beneficial value in the parkinsonian state. To test this hypothesis, unilateral kainate-induced chemical ablation of the centromedian thalamic nucleus (CM) has been performed in MPTPtreated monkeys. Successful lesions restricted to the CM boundaries (n = 2) without spreading over other neighboring thalamic nuclei showed an initial, short-lasting, and mild change in the parkinsonian motor scale but no effect against levodopa-induced dyskinesias. The lack of significant and persistent motor improvement leads us to conclude that unilateral selective lesion of the CM alone cannot be considered as a suitable surgical approach for the treatment of PD or levo-dopa-induced dyskinesias. The role of the caudal intralaminar nuclei in the pathophysiology of movement disorders of basal ganglia origin remains to be clarified. HHS Public Access Author Manuscript Author ManuscriptAuthor Manuscript Author ManuscriptThe centromedian-parafascicular thalamic complex (CM-Pf) is one major source of glutamatergic innervation of several basal ganglia nuclei, including the striatum, 1-15 the subthalamic nucleus (STN), 4,7,[12][13][14][15][16][17][18][19][20][21] the globus pallidus, and the substantia nigra. 15,21,22 Projections arising from the caudal intralaminar nuclei are excitatory and use glutamate as neurotransmitter. [23][24][25] In recent years, a number of studies have suggested a possible role for the CM-Pf complex on the pathophysiology of movement disorders. 26,27 In rats, Pf neurons that innervate the STN 28,29 and the striatum 25 are known to be hyperactive after unilateral midbrain dopaminergic lesion with 6-hydroxydopamine (6-OHDA). Indeed, the chemical ablation of Pf in rodents is highly effective in reversing the increases on STN metabolic activity typically observed after dopamine depletion. 30 Interestingly, early observations considered the CM/Pf as a target by deep brain stimulation (DBS) for the treatment of levodopainduced dyskinesias in Parkinson's disease, [31][32][33] and this has recently been proposed in combination with DBS of the globus pallidus pars interna (GPi). 34 On the other hand, important cell loss has been described in the CM-Pf of PD patients 35 as well as in rodents after nigrostriatal damage. 25,36 To further assess the relevance of the CM/Pf as a potential therapeutic target for parkinsonism and levodopa-induced dyskinesias, we have performed chemical ablation of the caudal intralaminar nuclei in MPTP-treated monkeys and determined its impact on parkinsonian motor signs and dyskinesias. SUBJECTS AND METHODSA total number of five young adult male Macaca fascicularis primates (body weight ranging fr...

Glutamatergic and cholinergic pedunculopontine neurons innervate the thalamic parafascicular nucleus in rats: changes following experimental parkinsonism

“…Moreover, the caudal intralaminar nuclei in humans have been considered as a surgical candidate for DBS, particularly when dealing with levodopa-induced dyskinesia (Caparrós-Lefebvre et al 1994Krauss et al 2002). However, the unilateral lesion of the caudal intralaminar nuclei in MPTP-treated primates failed to induce a long-lasting motor improvement and had no effect on levodopa-induced dyskinesia (Lanciego et al 2008). This led us to conclude that the caudal intralaminar nuclei can no longer be considered as a feasible surgical candidate.…”

The basal ganglia in Parkinson's disease: Current concepts and unexplained observations

“…93 However, we found neither antiparkinsonian benefit nor amelioration of L-dopa-induced dyskinesias after chemical ablation of the CM nucleus in MPTP-treated monkeys. 94 This casts doubts on the likelihood that this intralaminar nucleus plays an important role in the pathophysiology of PD. It is still possible, though, that the CM is involved in more complex aspects of movement and behavioral control.…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…The CM/Pf-striatal system is seen as providing sensory and salience information to the basal ganglia, which may assist in procedural and reinforcement learning and action selection (see below) [56,57]. Lesions of CM, the motor portions of CM/Pf, have little or no effect in relieving akinesia/ bradykinesia in the MPTP-treated primate [58], although DBS of CM in patients with PD has been reported to be beneficial for dyskinesias in limited studies [59].…”