Comparison of MPTP-induced changes in spontaneous neuronal discharge in the internal pallidal segment and in the substantia nigra pars reticulata in primates

Abstract

The basal ganglia are currently viewed as components of segregated corticosubcortical reentrant circuits. One of these circuits, the "motor" circuit, is critically involved in the development of parkinsonian motor signs. Current pathophysiologic models postulate that parkinsonism is associated with increased activity in the basal ganglia output nuclei. The neuronal activity in the motor portion of one of these output nuclei, the internal segment of the globus pallidus (GPi), has been characterized in detail in intact and parkinsonian animals, but the neuronal activity in the second major basal ganglia output nucleus, the substantia nigra pars reticulata (SNr), has received far less attention. This study in primates represents a comparison of the effects of parkinsonism, induced by injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), on the neuronal discharge in the GPi and SNr. These electrophysiologic recording experiments were carried out in three African green and two rhesus monkeys. One hundred and twenty-four neurons were recorded in the GPi before treatment with MPTP, and 93 neurons thereafter. In the SNr, 55 cells were recorded before treatment with MPTP, and 41 cells thereafter. MPTP induced a non-significant increase in the average discharge rate and a significant decrease in the median interspike interval length (ISI) in the GPi (by 13%), whereas no changes were detected in either parameter in the SNr. The average ISI distributions were markedly asymmetric in both structures, and could be modeled by a logarithmic normal distribution. With the MPTP treatment, the mode of the ISI distribution fell by 24% in the GPi (P< or =0.01), whereas it did not change significantly in the SNr. An algorithm that detects burst discharges in the raw ISI data (based on the method by Legendy and Salcman) detected a significant increase in the proportion of action potentials that participated in bursts of discharge in both structures (increase by 257% in the GPi, and by 67% in the SNr). Power spectral and autocorrelation analysis revealed that treatment with MPTP increased the proportion of cells with oscillatory burst patterns at 3-8 Hz in both structures (from 0.8% to 27% of all neurons in the GPi, and from none to 10% in the SNr). The results show that neuronal discharge in the SNr is affected in parkinsonism, but that the changes in the SNr are less pronounced then those seen in the GPi.

High Frequency Stimulation of the Subthalamic Nucleus Eliminates Pathological Thalamic Rhythmicity in a Computational Model

“…While our focus is on modulation of thalamic firing by GPi, the interacting STN and GPe network is crucial in our model in that its signals (both from STN to GPi and from GPe to GPi) interact with intrinsic GPi currents to generate patterns of of GPi activity that are consistent with experimental data (DeLong, 1971;Filion and Tremblay, 1991;Wichmann et al, 1999;Raz et al, 2000;Hashimoto et al, 2003). We assume that the thalamus receives two sources of input.…”

“…One argument is that because the clinical effects of DBS are similar to those of ablative surgeries, the mechanisms underlying these treatments must be similar Olanow et al, 2000Olanow et al, , 2001Benabid et al, 2001c). Experimental studies have demonstrated that in PD, the output nuclei of the basal ganglia, such as GPi, become overactive (Filion and Tremblay, 1991;Wichmann et al, 1999), thereby increasing the level of inhibition sent onto the thalamus. This may in turn inhibit the thalamus from passing along sensorimotor signals to the cortex.…”

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

“…Metabolic studies suggested [140,141], and microelectrode recording studies demonstrated, a reduction of neuronal discharge in GPe, and increased activity in the STN, leading to increased excitatory drive upon the basal ganglia output nuclei, GPi, and SNr [142][143][144][145], all strongly implicating increased activity over the indirect pathway in the pathophysiology of PD. Based on this evidence, models were developed positing that akinesia/bradykinesia results from excessive inhibitory output from GPi [13,15,16], and emphasizing the role of increased GPi output in hypokinetic and decreased output in hyperkinetic disorders.…”

“…In contrast, interventions directed at the PPN have revealed significant motoric effects in animal experiments [55]. Thus, PPN inactivation in normal primates reduces body movements of arms, trunk, and legs [142][143][144][145][146], and PPN injection of a GABA-A receptor antagonist, or low-frequency stimulation of PPN, alleviates experimental akinesia in monkeys, presumably by increasing PPN activity [146][147][148][149][150][151][152][153][154][155][156]. This constellation of findings suggests the possibility that the descending basal ganglia projections to the brainstem may play a greater role in the pathophysiology of akinesia/bradykinesia and movement than is commonly assumed.…”

Mechanisms of Deep Brain Stimulation in Movement Disorders as Revealed by Changes in Stimulus Frequency

“…Motor symptoms including tremor, bradykinesia, and rigidity are associated with increased neuronal synchronization and low-frequency rhythmic oscillation, 49 -51 and bursts and oscillations parallel the appearance of motor symptoms in PD. [52][53][54] A comparison of single unit GPi activity in subjects with PD versus Huntington's disease (HD) highlights the importance of the patterns of neuronal activity in addition to the rate of neuronal activity in movement disorders. The classical rate model of the basal ganglia divides the basal ganglia into the direct and indirect pathways (i.e., activity in the direct pathway initiates movements while activity in the indirect pathway inhibits movements).…”