External pallidal stimulation improves parkinsonian motor signs and modulates neuronal activity throughout the basal ganglia thalamic network

Abstract

Deep brain stimulation (DBS) of the internal segment of the globus pallidus (GPi) and the subthalamic nucleus (STN) are effective for the treatment of advanced Parkinson's disease (PD). We have shown previously that DBS of the external segment of the globus pallidus (GPe) is associated with improvements in parkinsonian motor signs; however, the mechanism of this effect is not known. In this study, we extend our findings on the effect of STN and GPi DBS on neuronal activity in the basal ganglia thalamic network to include GPe DBS using the 1-methyl-4-phenyl-1.2.3.6-tetrahydropyridine (MPTP) monkey model. Stimulation parameters that improved bradykinesia were associated with changes in the pattern and mean discharge rate of neuronal activity in the GPi, STN, and the pallidal [ventralis lateralis pars oralis (VLo) and ventralis anterior (VA)] and cerebellar [ventralis lateralis posterior pars oralis (VPLo)] receiving areas of the motor thalamus. Population post-stimulation time histograms revealed a complex pattern of stimulation-related inhibition and excitation for the GPi and VA/VLo, with a more consistent pattern of inhibition in STN and excitation in VPLo. Mean discharge rate was reduced in the GPi and STN and increased in the VPLo. Effective GPe DBS also reduced bursting in the STN and GPi. These data support the hypothesis that therapeutic DBS activates output from the stimulated structure and changes the temporal pattern of neuronal activity throughout the basal ganglia thalamic network and provide further support for GPe as a potential therapeutic target for DBS in the treatment of PD.

Fig 1

a. Histological reconstructions of DBS lead placement within the pallidal complex. Left: Coronal section showing the tissue artifact within the striatum and pallidal complex. Right: Gross histological section with a scaled-down DBS lead superimposed on the tissue artifact that remained after its post-mortem removal, illustrating its course and position relative to the pallidum. Red and blue arrows note the relative location of the cathode and anode used in the current study, respectively. b. Sample sagittal section revealing the location of recording tracks, including at least one track through the STN (arrow). c. Bar graph illustrating the effect of GPe DBS on motor performance. Reach and retrieval times for the affected (left) and non-affected (right) upper extremity during the DBS OFF condition as well as DBS at ineffective, non-therapeutic (2 V) and effective, therapeutic (5.5 V) voltage settings. * Compared to control: t(42) = 5.52, p < 0.001 d. Population post-stimulation time histograms (PSTHs) during effective GPe DBS, where the continuous line represents a smoothed running average of the PSTH data. On the right, each PSTH smoothed running average is superimposed to allow for comparison across the four nodal points examined. For all figures, the x-axis is the time in ms after the stimulation pulse, while the y-axis represents spikes per second (bin width = 0.2 ms). e. Change in mean discharge rate during GPe DBS (“on” minus “off”) for GPi, STN, VPLo and VA/VLo neurons during effective (5.5 V) and ineffective (2.0 V) stimulation (* p < 0.05). VA, ventralis anterior; AC, anterior commissure; OT, optic tract; SNr, substantial nigra pars reticulata.