Deep brain stimulation of the globus pallidus internus in the parkinsonian primate: local entrainment and suppression of low-frequency oscillations

Abstract

Competing theories seek to account for the therapeutic effects of high-frequency deep brain stimulation (DBS) of the internal globus pallidus (GPi) for medically intractable Parkinson's disease. To investigate this question, we studied the spontaneous activity of 102 pallidal neurons during GPiDBS in two macaques rendered parkinsonian by administration of MPTP. Stimulation through macroelectrodes in the GPi (> or =200 microA at 150 Hz for 30 s) reduced rigidity in one animal and increased spontaneous movement in both. Novel artifact subtraction methods allowed uninterrupted single-unit recording during stimulation. GPiDBS induced phasic (78% of cells) or sustained (22%) peristimulus changes in firing in both pallidal segments. A subset of cells responded at short latency (<2 ms) in a manner consistent with antidromic driving. Later phasic increases clustered at 3- to 5-ms latency. Stimulation-induced decreases were either phasic, clustered at 1-3 ms, or sustained, showing no peristimulus modulation. Response latency and magnitude often evolved over 30 s of stimulation, but responses were relatively stable by the end of that time. GPiDBS reduced mean firing rates modestly and only in GPi (-6.9 spikes/s). Surprisingly, GPiDBS had no net effect on the prevalence or structure of burst firing. GPiDBS did reduce the prevalence of synchronized low-frequency oscillations. Some cell pairs became synchronized instead at the frequency of stimulation. Suppression of low-frequency oscillations did not require high-frequency synchronization, however, or even the presence of a significant peristimulus response. In summary, the therapeutic effects of GPiDBS may be mediated by an abolition of low-frequency synchronized oscillations as a result of phasic driving.

FIG. 1.

Validation of artifact subtraction method. Ai: a neuronal signal acquired during deep brain stimulation in globus pallidus internus (GPiDBS), but with artifact subtraction disabled, showed large long-duration voltage transients time-locked to delivery of each shock (vertical gray lines; 150 Hz, 400 μA, 200-μs pulse width). Note that extreme voltage values are clipped in this figure to aid comparisons with the processed traces illustrated below. Aii: the same microelectrode signal acquired on a parallel acquisition channel with artifact subtraction working shows no evidence of shock artifacts while action potentials and recording noise are preserved. Action potentials that were completely obscured by artifacts in the unsubtracted data stream were easily detected in the processed data stream (↓). Aiii: action potential waveform snippets aligned on the times of spiking of an individual neuron based on spike sorting of the signal shown in Aii. The snippets are stretched ×2 in time to make waveform shape more apparent. B: off-line test of artifact subtraction efficacy. The mean waveforms of spikes during stimulation (thick black lines; ±SE indicated by gray shading) were required to fall within the 95% confidence interval (CI) for all spikes from nonstimulation periods (dotted lines). The test was performed separately for 4 adjacent peristimulus intervals (indicated by time intervals and horizontal brackets in Bi). Numbers below each mean indicate the number of action potentials contributing to each mean. Bii: for the same neuron, a peristimulus rate histogram (gray bars) is compared with an equivalent perievent rate histogram from nonstimulation periods (thick black line). Note that action potentials approximately coincident with the time of stimulation (time 0, vertical gray line) had mean shapes, SEs, and mean rates of occurrence that were indistinguishable from those during other peristimulus intervals and from those during nonstimulation periods.

FIG. 2.

Histologic confirmation of recording locations and dopamine depletion. A: approximate recording positions (circles) were collapsed across 2 mm in the coronal plane and projected onto atlas-derived line drawings of pallidal nuclear boundaries at 2 positions relative to the anterior commissure (AC). The approximate locations of stimulating electrodes are indicated by diagonal black lines. Results are plotted separately for monkeys E and C (top and bottom rows, respectively). The color and fill of each symbol indicate, respectively, the sign and form of DBS-induced peristimulus responses (see caption and Table 1). Clusters of symbols indicate recording sites where more than one neuron was sampled. The locations of some symbols have been shifted slightly to improve visibility. B: tyrosine hydroxylase (TH-DAB) immunoreactivity in an adjacent coronal section illustrates the MPTP-induced depletion of TH-reactivity in dorsolateral regions of the caudate and putamen (open arrow) and relative preservation of TH-reactive fibers in the ventral medial regions of both nuclei (filled arrowhead).

FIG. 3.

GPiDBS reduced elbow rigidity and increased postural transients. A: the elbow was moved through a constant ±20° sinusoidal displacement at 1 Hz (thin line) with a servo-controlled torque motor. The torques required to move the arm (thick line) were reduced within 1 s of the onset of GPiDBS (gray shading; 150 Hz, 400 μA, 200-μs pulse width). B: torque–angle plots from the same data set illustrated in A. GPiDBS (gray line) reduced the slope of the torque–angle relationship (i.e., elastic stiffness) and reduced areas defined by the torque–angle hysteresis loop (i.e., work). C: elbow rigidity (measured as cycle-by-cycle work) was reduced consistently during GPiDBS. The plot shows mean cycle-by-cycle work averaged across eight 30-s-long presentations of GPiDBS (gray shading). Rigidity was reduced for the duration of GPiDBS and recovered slowly after stimulation ended. D: the GPiDBS-induced reduction in rigidity scaled with the intensity of stimulation (current). Mean values (±SE) are shown for 13 stimulation sessions collected on 1 day in monkey C (all but one error bar fell within the bounds of the filled symbols). E: postural transients (*) occurred more frequently during GPiDBS. Raw reactive torque records (thick black traces) are plotted aligned on the onset of GPiDBS stimulation blocks (gray shading) in an exemplar data set from monkey C. The shape and timing of the transients varied substantially between stimulation blocks. No significant transients occurred during blocks 4 and 7. F: for the data set shown in E, the mean fraction of torque cycles containing significant postural transients (black histogram) was zero prior to stimulation onset, but increased markedly during GPiDBS. Rigidity (mean cycle-by-cycle work; dark gray line) was reduced during the 2 stimulation blocks that did not contain significant postural transients (i.e., during blocks 4 and 7, E). G: GPiDBS at currents ≥200 μA increased the frequency of postural transients in both animals. Symbols reflect the mean (±SE) change in occurrence of postural transients attributable to GPiDBS during stimulation at different currents in monkeys C and E (data points with no error bars indicate currents that were used one time).

FIG. 4.

Exemplar neuronal recording during GPiDBS. A: a raw microelectrode signal is shown as acquired during 400 s of collection including four 30-s-long episodes of GPiDBS (gray shading; 150 Hz, 1,000 μA, 200-μs pulse width). There was no obvious effect of GPiDBS on the quality of recording (i.e., stimulation artifacts were not evident). The compressed timescale of the figure obscures individual action potentials. B: an expanded representation of 5 s of the record resolves individual action potentials and illustrates how the onset of one block of GPiDBS (*) was associated with a modest reduction in mean spike rate. There was no apparent stimulation-induced change in spike amplitude or deterioration in recording quality. One short-duration artifact coincided with the onset of GPiDBS (*). The times of individual GPiDBS stimuli are marked by vertical gray lines. Ci: further expansion around the onset of GPiDBS (*) confirmed that recording quality was similar before and during GPiDBS. Action potentials had similar shapes before and during GPiDBS, even when spikes were coincident (↓) with the times of individual stimuli (vertical gray lines). Cii: the waveforms of individual action potentials are shown in expanded format. Di: unprocessed microelectrode recording aligned on 1,000 successive stimuli (data are from the period indicated by the horizontal gray bar at the bottom right of A). The times of stimulus delivery are indicated by vertical gray bars and * (2 stimuli were delivered within the 8-ms-long epochs plotted). Action potentials tended to cluster at 0–1.5 and 3.5–4 ms after stimulus delivery. Dii: from the whole 400-s-long data record, the shapes of spike waveforms during GPiDBS (black lines and gray areas showing means ± SE, respectively) fell within the 95% CIs for spike waveforms sorted from control (nonstimulation) periods (dotted lines). Spike waveforms were also virtually identical across the 4 peristimulus epochs. Horizontal brackets above indicate the peristimulus interval from which each waveform mean (±SE) is derived. Numbers below indicate the number of sorted waveforms contributing to each mean. Voltage scales indicate 0.1 mV throughout the figure.

FIG. 5.

A polyphasic response to GPiDBS. A: raw microelectrode signal during 4 blocks of GPiDBS (conventions as in Fig. 4A). B: each block of GPiDBS induced a moderate sustained reduction in mean firing rate (spike density function [SDF]; top), which was the product of a polyphasic pattern of increases and decreases in firing (bottom). Time-resolved perievent histograms (0.2-ms bins), constructed from consecutive 2-s epochs around either sham events (during control periods) or real stimulation events (gray shading), are plotted vs. the time from the beginning of recording (0–400 s). The color scale (right) represents firing rate. The horizontal gray line indicates perievent time 0 (i.e., the time of stimulation delivery during GPiDBS blocks). C, left: a mean time-resolved perievent histogram summarizes the time-dependent nature of the short-latency responses to GPiDBS (color scale same as in B). C, right, i–v: Pericontrol and peristimulus change histograms (PCtH and PStH, respectively), formed from 10-s epochs of the mean stimulation block (indicated by brackets labeled i–v, in C, left bottom), were used for quantitative assessment of response magnitude, timing, and significance. The histograms illustrate peristimulus changes from the cell's baseline firing rate (60.2 spikes/s). D: changes in firing induced by stimulation were highly significant relative to the deviations detected in control histograms. The areas of all deviations from baseline firing are plotted for 2 PCtHs (i and ii) and 3 PStHs (iii–v). A threshold for significance (horizontal black line) was derived from the mean and SD (black circle and error bar, respectively) of all PCtH areas. Red and blue symbols indicate areas of increases and decreases, respectively. For significant deviation areas (filled circles), character labels correspond with matching labels next to the PStHs in C, right.

FIG. 6.

Characteristic responses to GPiDBS. A: a monophasic increase in firing in a neuron sampled from GPe. The only significant stimulation-induced change began 3 ms after stimulation and lasted roughly 3.5 ms. The latency of the response did not shift significantly, although its magnitude declined across the 30-s block of stimulation (baseline rate = 64.3 spikes/s). B: a polyphasic response that included brief fixed-duration driving at about 1-ms latency (baseline rate = 47.4 spikes/s). C: a typical sustained-type response in a neuron sampled from GPe (baseline rate = 44.1 spikes/s). Each panel of the figure shows: left: a mean SDF and mean time-resolved perievent histogram aligned on stimulation onset (*) across multiple 30-s blocks of GPiDBS (gray shading). Color plots in A–C use the scale found at the right of the time-resolved histogram in A (in spikes/s). Text to the top right of the SDF identifies the neuron and the number of GPiDBS blocks contributing to the data shown. Top right: results from analysis of waveform isolation across the peristimulus interval. Horizontal and vertical scales indicate 1 ms and 0.1 mV, respectively. Bottom right: mean PStHs derived from the indicated epochs of the time-resolved histogram (i–iii). Otherwise, the figure follows the conventions outlined for Fig. 5.

FIG. 7.

Summary of effects of GPiDBS on pallidal firing. A: population mean PStHs averaged across all phasic- and sustained-type cells from external globus pallidus (GPe) and GPi (left and right panels, respectively). Gray shading and thin dotted lines indicate ±SE for phasic- and sustained-type responses, respectively. Box-and-whisker plots (to the right of each population PStH) indicate the median and range of GPiDBS-induced changes in mean firing rate. The horizontal ends of each box indicate upper and lower quartile values. Whiskers extend to the most extreme value 1.5-fold the interquartile range. Outliers are displayed as +'s. Notches in the sides of each box display the 95% CI of the median. B: color plot of all PStHs (one row per cell) classified as phasic (top) or sustained (bottom). Colors along each horizontal band indicate the significant changes in firing rate of one cell induced by stimulation (red–yellow = increases; blue–cyan = decreases; firing rate scale at far right). Black = no significant change in a PStH. Individual phasic PStHs are sorted top to bottom by a response's score on the first principal component across all phasic PStHs. C: peristimulus distributions of increase maxima (above zero) and decrease minima (inverted below zero) as a percentage of all phasic-type cells. Times of individual maxima and minima were collected into 1-ms bins to aid visualization. (Statistical comparisons were performed on cumulative distributions of the raw latency values.) Scales are the same for right and left columns of the figure unless noted otherwise.

FIG. 8.

Latency and magnitude shifts in responses. A: an example of gradual shifts in response latency across the stimulus block in a cell recorded from GPe. Results from the timing analysis are overlaid on a time-resolved peristimulus change histogram [30 histograms (0.1-ms bins), one histogram for each second of the mean stimulation block]. Dashed lines plot the latencies of peak changes across the 30 histograms (green and magenta for increases and decreases, respectively). Solid lines show the best piecewise linear fit to each dashed line. Color scale (right) in spikes/s: red–yellow = increases; blue–cyan = decreases, both from a baseline firing rate of 47.4 spikes/s. B: slopes of temporal shifts (ms shift/s of stimulation, derived from the best-fit function) are plotted vs. the initial latency of all responses. Filled symbols indicate responses with significant latency shifts that asymptoted within the stimulation block (black) or did not asymptote (red). A histogram (right) summarizes the distribution of slopes. C: slopes of shifts in response magnitude (measured as spikes/s shift/s of stimulation) are plotted vs. the initial latency of responses. Filled symbols indicate magnitude shifts that asymptoted within the stimulation block (black) or did not asymptote (red). Note that the ordinates of the plots in B and C are split to provide greater resolution for points clustered close to a slope of zero.

FIG. 9.

Two examples of antidromic-like activation. Ai and Bi: action potentials at a short fixed latency following stimulation delivery (vertical dotted line). Aii and Bii: collision-like phenomena in which stimulation failed to evoke action potentials when spontaneous spikes occurred immediately prior to stimulation delivery.

FIG. 10.

Burst firing during GPiDBS. Ai: raster representation of a typical 4-s period of neuronal activity off-GPiDBS (the peristimulus response of this neuron is illustrated in Fig. 6B). Black vertical ticks indicate times of individual action potentials. Horizontal blue bars show times of bursts as determined by the Legendy surprise method (Legendy and Salcman 1985; Wichmann and Soares 2006). Aii: an exemplar spike train from the same neuron during GPiDBS (gray shading). The incidence of bursting increased during GPiDBS and burst duration decreased. Aiii: an expanded section of the same spike train during GPiDBS illustrates how bursts persisted during GPiDBS because of multistimulus periods of response failure. Gray vertical ticks show times of individual GPiDBS shocks. B and C: a summary of measures of neuronal burstiness under control and GPiDBS conditions (“OFF” and “ON” stimulation, respectively, plotted on abscissae and ordinates). Subpanels plot 2 measures of burstiness (left: fraction of total time spent in bursts; right: fraction of total spikes found in bursts). Each subpanel plots one symbol for each neuron recorded from GPe and GPi (B and C, respectively). The shape of the symbol reflects the neuron's general response to GPiDBS (see legend at left). Neurons with identical measures of burstiness OFF and ON stimulation have symbols on the line of unity (diagonal dotted line). Confidence ellipses (computed to encompass 50% of the points assuming Gaussian distributions) illustrate the similarity of the population's burst measures under OFF and ON conditions. D and E: mean SDFs (“burst-triggered averages”; ±95% CI) aligned on burst onset times for all bursts detected off- and on-GPiDBS (black and red traces, respectively). Mean preburst firing rate has been subtracted from each average to aid comparison of the burst characteristics. In D (from the same GPe cell as used in A), GPiDBS significantly increased intraburst firing frequency but reduced burst duration (baseline rate = 47.4 spikes/s). E: compares the burst characteristics of a GPi cell that responded phasically to stimulation (inset peristimulus histogram) (baseline rate = 58.6 spikes/s). F and G: mean burst-triggered averages for all GPe and GPi cells, respectively. The mean burst characteristics were remarkably similar during off- and on-GPiDBS conditions for both GPe and GPi populations.

FIG. 11.

Effects of GPiDBS on oscillatory firing. A: autocorrelation (top) and power spectrum (bottom) from a GPe neuron that responded phasically to GPiDBS. Left column: detail for short lags and low frequencies. The autocorrelation from control periods (thin black line) showed distinct peaks and valleys indicative of oscillatory firing. Oscillatory firing was confirmed by the presence of significant peaks in the power spectrum at 5.9 and 12.7 Hz (*). Horizontal dotted line: threshold for a significant elevation of spectral power. During GPiDBS, low-frequency oscillations were replaced by a highly significant peak at the frequency of stimulation (†, right). Note the different scales for top and bottom halves of the spectra ordinates. Inset: the same neuron's phasic peristimulus response following the conventions of Fig. 6 (baseline rate = 40.8 spikes/s). B: DBS-induced suppression of oscillatory activity did not require a peristimulus response. Spectra are shown for a GPi neuron that had no significant peristimulus response to stimulation (inset). The peak at 13.7 Hz was reduced significantly during GPiDBS (*) (baseline rate = 52.6 spikes/s). C: DBS-induced suppression of synchronized oscillations. Coherence spectra are shown for a pair of GPe neurons, both of which had significant polyphasic responses to stimulation (inset). The coherence peak at 10.7 Hz was suppressed completely during GPiDBS (*) (baseline rates = 45.8 and 68.4 spikes/s). D: GPiDBS reduced the prevalence of low-frequency oscillations. The bar plot indicates the fraction of cells with one or more significant peaks in the indicated frequency ranges during control periods (Off DBS) and after 20 s of stimulation (On DBS). E: GPiDBS reduced the prevalence of LF synchronized oscillations. The bar plot indicates the fraction of cell pairs with one or more significant coherence peaks in the indicated frequency ranges during control periods (Off DBS) and after 20 s of stimulation (On DBS). *P < 0.05; **P < 0.005 (χ² test).