Firing Patterns and Correlations of Spontaneous Discharge of Pallidal Neurons in the Normal and the Tremulous 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Vervet Model of Parkinsonism

Abstract

To investigate the role of the basal ganglia in parkinsonian tremor, we recorded hand tremor and simultaneous activity of several neurons in the external and internal segments of the globus pallidus (GPe and GPi) in two vervet monkeys, before and after systemic treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and development of parkinsonism with tremor of 5 and 11 Hz.In healthy monkeys, only 11% (20/174) of the GPe cells and 3% (1/29) of the GPi cells displayed significant 3-19 Hz oscillations. After MPTP treatment, 39% (107/271) of the GPe cells and 43% (26/61) of the GPi cells developed significant oscillations. Oscillation frequencies of single cells after MPTP treatment were bimodally distributed around 7 and 13 Hz. For 10% of the oscillatory cells that were recorded during tremor periods, there was a significant tendency for the tremor and neuronal oscillations to appear simultaneously.Cross-correlation analysis revealed a very low level of correlated activity between pallidal neurons in the normal state; 95.6% (477/499) of the pairs were not correlated, and oscillatory cross-correlograms were found in only 1% (5/499) of the pairs. After MPTP treatment, the correlations increased dramatically, and 40% (432/1080) of the cross-correlograms had significant oscillations, centered around 13-14 Hz. Phase shifts of the cross-correlograms of GPe pairs, but not of GPi, were clustered around 0°.The results illustrate that MPTP treatment changes the pattern of activity and synchronization in the GPe and GPi. These changes are related to the symptoms of Parkinson's disease and especially to the parkinsonian tremor.

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.…”

“…Several authors have pointed out that the pattern of neuronal activity, not just the rate, may be important (Bergman et al, 1994;Nini et al, 1995;Magnin et al, 2000;Montgomery et al, 2000;Obeso et al, 2000;Raz et al, 2000;Brown et al, 2001;Terman et al, 2001Terman et al, , 2002. In particular, numerous experimental studies have demonstrated that neurons within both the STN and GPi show an increased level of synchrony and bursting activity during parkinsonian states (Bergman et al, 1994;Nini et al, 1995;Magnin et al, 2000;Raz et al, 2000;Brown et al, 2001). Using a computational model, we show that while synchronous and patterned output of GPi (corresponding to a parkinsonian state) may disrupt the thalamic ability to relay depolarizing (e.g., sensorimotor) inputs, high-frequency, tonic output of GPi (corresponding to DBS) may restore thalamic relay capabilities.…”

“…Here, I app is a constant and represents input from the striatum. We model GPi neurons very similarly to GPe neurons, using a voltage equation of the form (4) but with Ge replaced with Gi; however, we renormalize certain parameters to reflect the fact that GPi neurons fire faster than GPe (DeLong, 1971;Filion and Tremblay, 1991;Raz et al, 2000;Hashimoto et al, 2003). Moreover, GPe and GPi cells receive different levels of striatal input (Gerfen and Wilson, 1996).…”

“…5. These definitions are based on experimental results revealing corresponding patterns under normal versus parkinsonian conditions (Bergman et al, 1994;Nini et al, 1995;Magnin et al, 2000;Raz et al, 2000;Brown et al, 2001).…”

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

“…The use of DBS electrodes for recording purposes in humans, and in a large number of animal studies [44,152,[322][323][324][325][326], has emphasized that many of the identified electrical disease markers (e.g., oscillatory bursting or phase-amplitude coupling) can be explained by an abnormal level of synchronous neuronal discharge that may ultimately result in increased beta-band oscillations throughout the corticobasal ganglia circuits. Studies in the normal basal ganglia have shown that neighboring neurons tend to fire independently (e.g., [44,45]), perhaps continuing at the cellular level what is readily apparent as circuit segregation at the macroanatomic level [8,10].…”