The subthalamic nucleus (STN) is the most common target for the treatment of Parkinson's disease (PD) with deep brain stimulation (DBS). DBS of the globus pallidus internus (GPi) is also effective in the treatment of PD. The output fibers of the GPi that form the lenticular fasciculus pass in close proximity to STN DBS electrodes. In turn, both STN projection neurons and GPi fibers of passage represent possible therapeutic targets of DBS in the STN region. We built a comprehensive computational model of STN DBS in parkinsonian macaques to study the effects of stimulation in a controlled environment. The model consisted of three fundamental components: 1) a three-dimensional (3D) anatomical model of the macaque basal ganglia, 2) a finite element model of the DBS electrode and electric field transmitted to the tissue medium, and 3) multicompartment biophysical models of STN projection neurons, GPi fibers of passage, and internal capsule fibers of passage. Populations of neurons were positioned within the 3D anatomical model. Neurons were stimulated with electrode positions and stimulation parameters defined as clinically effective in two parkinsonian monkeys. The model predicted axonal activation of STN neurons and GPi fibers during STN DBS. Model predictions regarding the degree of GPi fiber activation matched well with experimental recordings in both monkeys. Only axonal activation of the STN neurons showed a statistically significant increase in both monkeys when comparing clinically effective and ineffective stimulation. Nonetheless, both neural targets may play important roles in the therapeutic mechanisms of STN DBS.

Deep brain stimulation (DBS) is an established therapy for the treatment of Parkinson's disease and shows great promise for numerous other disorders. While the fundamental purpose of DBS is to modulate neural activity with electric fields, little is known about the actual voltage distribution generated in the brain by DBS electrodes and as a result it is difficult to accurately predict which brain areas are directly affected by the stimulation. The goal of this study was to characterize the spatial and temporal characteristics of the voltage distribution generated by DBS electrodes. We experimentally recorded voltages around active DBS electrodes in either a saline bath or implanted in the brain of a non-human primate. Recordings were made during voltage-controlled and currentcontrolled stimulation. The experimental findings were compared to volume conductor electric field models of DBS parameterized to match the different experiments. Three factors directly affected the experimental and theoretical voltage measurements: 1) DBS electrode impedance, primarily dictated by a voltage drop at the electrode-electrolyte interface and the conductivity of the tissue medium, 2) capacitive modulation of the stimulus waveform, and 3) inhomogeneity and anisotropy of the tissue medium. While the voltage distribution does not directly predict the neural response to DBS, the results of this study do provide foundational building blocks for understanding the electrical parameters of DBS and characterizing its effects on the nervous system.

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.

1. We quantitatively compared the effects of eye position within the orbit on saccadic eye movements electrically elicited from two oculomotor areas of the macaque monkey's frontal lobe cortex: the frontal eye field (FEF) and the supplementary eye field (SEF). 2. The effect of eye position on electrically elicited saccades was studied by delivering 70-ms trains of intracortical microstimulation while the monkeys fixated a spot of light. Tests of different fixation points located across a rectangular array were randomly intermixed. Complete experiments were carried out on 38 sites in three FEFs of two monkeys and 59 sites from three SEFs of the same two monkeys. Stimulation currents for the array experiments were usually 10-20 microA above the site threshold; the average current used was 36 microA for FEF and 49 microA for SEF. 3. The magnitude of effect of the initial eye position on the elicited saccade's dimensions was quantified at each site by computing the linear regression of saccadic eye movement displacement on the eye position within the orbit when stimulation was applied. This computation was done separately for the horizontal and vertical axes. We call the resulting pair of regression coefficients "orbital perturbation indexes." Indexes of 0.0 represent elicited saccades that do not change their trajectory with different initial eye positions (constant-vector saccades), whereas indexes of -1.0 represent elicited saccades that end at the same orbital position regardless of initial eye position (goal-directed saccades). 4. The effect of eye position varied across sites. In both FEF and SEF, the orbital perturbation indexes were distributed between approximately 0.0 and -0.5, with the horizontal and vertical indexes highly correlated across sites. 5. The average orbital perturbation indexes were small for both eye fields and were not significantly different. The mean horizontal indexes were -0.13 and -0.16 for SEF and FEF, respectively. The mean vertical indexes were -0.16 and -0.13. Neither SEF versus FEF difference was statistically significant. 6. In both SEF and FEF, sites yielding larger-amplitude saccades generally had larger orbital effects than sites yielding smaller saccades. This relationship accounted for the majority of the variability of the orbital perturbation indexes across sites in both SEF and FEF. 7. These results indicate that SEF and FEF are not distinguished from each other by the orbital dependence of their electrically elicited saccades. Thus they do not confirm the previously hypothesized dichotomy that FEF codes constant-vector saccades and SEF codes goal-directed saccades.(ABSTRACT TRUNCATED AT 400 WORDS)

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.