Parkinson's disease is characterized by degeneration of nigral dopaminergic neurons, leading to a wide variety of psychomotor dysfunctions. Accumulated evidence suggests that abnormally synchronized oscillations in the basal ganglia contribute to the expression of Parkinsonian motor symptoms. However, the mechanism that generates abnormal oscillations in a dopamine-depleted state remains poorly understood. We addressed this question by examining basal ganglia neuronal activity in two 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated Parkinsonian monkeys. We found that systemic administration of l-3,4-dihydroxyphenylalanine (l-DOPA; dopamine precursor) decreased abnormal neuronal oscillations (8-15 Hz) in the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) during the ON state when Parkinsonian signs were alleviated and during l-DOPA-induced dyskinesia. GPi oscillations and parkinsonian signs were suppressed by silencing of the STN with infusion of muscimol (GABA(A) receptor agonist). Intrapallidal microinjection of a mixture of 3-(2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP; N-methyl-d-aspartate receptor antagonist) and 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulfonamide (NBQX; AMPA/kainate receptor antagonist) also decreased the oscillations in the GPi and the external segment of the globus pallidus (GPe). Neuronal oscillations in the STN were suppressed after intrasubthalamic microinjection of CPP/NBQX to block glutamatergic afferents of the STN. The STN oscillations were further reduced by muscimol inactivation of the GPe to block GABAergic inputs from the GPe. These results suggest that, in the dopamine-depleted state, glutamatergic inputs to the STN and reciprocal GPe-STN interconnections are both important for the generation and amplification of the oscillatory activity of STN neurons, which is subsequently transmitted to the GPi, thus contributing to the symptomatic expression of Parkinson's disease.
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To understand how the information derived from different motor cortical areas representing different body parts is organized in the basal ganglia, we examined the neuronal responses in the subthalamic nucleus (STN), and the external (GPe) and internal (GPi) segments of the globus pallidus (input, relay and output nuclei, respectively) to stimulation of the orofacial, forelimb and hindlimb regions of the primary motor cortex (MI) and supplementary motor area (SMA) in macaque monkeys under the awake state. Most STN and GPe/GPi neurons responded exclusively to stimulation of either the MI or SMA, and one-fourth to one-third of neurons responded to both. STN neurons responding to the hindlimb, forelimb and orofacial regions of the MI were located along the medial-lateral axis in the posterolateral STN, while neurons responding to the orofacial region of the SMA were located more medially than the others in the anteromedial STN. GPe/GPi neurons responding to the hindlimb, forelimb and orofacial regions of the MI were found along the dorsal-ventral axis in the posterolateral GPe/GPi, and neurons responding to the corresponding regions of the SMA were similarly but less clearly distributed in more anteromedial regions. Moreover, neurons responding to the distal and proximal forelimb MI regions were found along the lateral-medial axis in the STN and the ventral-dorsal axis in the GPe/GPi. Most STN and GPe/GPi neurons showed kinaesthetic responses with similar somatotopic maps. These observations suggest that the somatotopically organized inputs from the MI and SMA are well preserved in the STN and GPe/GPi with partial convergence.
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