High-frequency stimulation (HFS) of the subthalamic nucleus (STN) or internal segment of the globus pallidus is a clinically successful treatment for the motor symptoms of Parkinson's disease. However, the mechanisms by which HFS alleviates these symptoms are not understood. Whereas initial studies focused on HFS-induced changes in neuronal firing rates, recent studies suggest that changes in patterns of neuronal activity may correlate with symptom alleviation. We hypothesized that effective STN HFS reduces the disorder of neuronal firing patterns in the basal ganglia thalamic circuit, minimizing the pathological activity associated with parkinsonism. Stimulating leads were implanted in the STN of two rhesus monkeys rendered parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Action potentials were recorded from neurons of the internal and external globus pallidus and the motor thalamus (ventralis anterior, ventralis lateralis pars oralis, and ventralis posterior lateralis pars oralis) during HFS that reduced motor symptoms and during clinically ineffective low-frequency stimulation (LFS). Firing pattern entropy was calculated from the recorded spike times to quantify the disorder of the neuronal activity. The firing pattern entropy of neurons within each region of the pallidum and motor thalamus decreased in response to HFS (n > or = 18 and P < or = 0.02 in each region), whereas firing rate changes were specific to pallidal neurons only. In response to LFS, firing rates were unchanged, but firing pattern entropy increased throughout the circuit (n > or = 24 and P < or = 10(-4) in each region). These data suggest that the clinical effectiveness of HFS is correlated with, and potentially mediated by, a regularization of the pattern of neuronal activity throughout the basal ganglia thalamic circuit.
Deep brain stimulation (DBS) in the subthalamic nucleus (STN)is an effective tool for the treatment of advanced Parkinson's disease. The mechanism by which STN DBS elicits its beneficial effect, however, remains unclear. We previously reported STN stimulation increased the rate and produced a more regular and periodic pattern of neuronal activity in the internal segment of the globus pallidus (GPi). Here we extend our observations to neurons in 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 during STN DBS. Stimulation parameters that produced improvement in rigidity and bradykinesia resulted in changes in the pattern and power of oscillatory activity of neuronal activity that were similar in both regions of the motor thalamus. Neurons in both VA/VLo and VPLo tended to become more periodic and regular with a shift in oscillatory activity from low to high frequencies. Burst activity was reduced in VA/VLo, but was not significantly changed in VPLo. There was also a significant shift in the population of VA/VLo neurons that were inhibited during STN DBS, whereas VPLo neurons tended to be activated. These data are consistent with the hypothesis that STN DBS increases output from the nucleus and produces a change in the pattern and periodicity of neuronal activity in the basal ganglia thalamic network, and that these changes include cerebellar pathways likely via activation of adjacent cerebello-thalamic fiber bundles.
Theoretical and experimental analyses of deep brain stimulation (DBS) in the subthalamic nucleus (STN) show both excitatory and inhibitory effects on the neural elements surrounding the electrode. Given these observations, the mechanism underlying the therapeutic effect of STN DBS on parkinsonian motor signs remains under debate. One hypothesis suggests that abnormal levels of bursting activity in the pallidum play a key role in the development of parkinsonian motor signs and that STN DBS may exert its beneficial effect by modifying this type of activity. We quantified the changes in bursting activity of globus pallidus internus (GPi) and externus (GPe) neurons before and during ineffective (subtherapeutic) and effective (therapeutic) STN DBS in two monkeys rendered parkinsonian by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared to pre-stimulation control values, the population mean firing rate increased during therapeutic stimulation significantly in both GPe (from 41.7 Hz+/-2.8 to 71.4 Hz+/-7.8) and GPi (from 58.8 Hz+/-4.2 to 71.5 Hz+/-6.2). The burst rate, however, increased significantly in GPe (from 80.1 bursts/min+/-10.0 to 103.1 bursts/min+/-11.1) and decreased significantly in GPi (from 104.2 bursts/min+/-8.3 to 75.8 bursts/min+/-10.8). Although both animals showed improvement in parkinsonian motor signs, changes in rate and bursting activity in GPi were significant only in one animal. These data suggest that while changes in rate and bursting activity may contribute to the improvement in PD motor signs during STN DBS, one cannot explain the therapeutic effects of stimulation in all cases solely on changes in these parameters. Other physiological changes that contribute to its therapeutic effect must also occur.
Methodologies for stereotactic neurosurgery and neurophysiological microelectrode recordings (MER) in non-human primate research typically rely on brain atlases that are not customized to the individual animal, and require paper records of MER data. To address these limitations, we developed a software tool (Cicerone) that enables simultaneous interactive 3D visualization of the neuroanatomy, neurophysiology, and neurostimulation data pertinent to deep brain stimulation (DBS) research studies in non-human primates. Cicerone allows for analysis of co-registered magnetic resonance images (MRI), computed tomography (CT) scans, 3D brain atlases, MER data, and DBS electrode(s) with predictions of the volume of tissue activated (VTA) as a function of the stimulation parameters. We used Cicerone to aid the implantation of DBS electrodes in two parkinsonian rhesus macaques, targeting the subthalamic nucleus in one monkey and the globus pallidus in the other. Cicerone correctly predicted the anatomical position of 79% and 73% of neurophysiologically defined MER sites in the two animals, respectively. In contrast, traditional 2D print atlases achieved 61% and 48% accuracy. Our experience suggests that Cicerone can improve anatomical targeting, enhance electrophysiological data visualization, and augment the design of stimulation experiments.
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