Pallidal stimulation suppresses pathological dysrhythmia in the parkinsonian motor cortex

Abstract

Although there is general consensus that deep brain stimulation (DBS) yields substantial clinical benefit in patients with Parkinson's disease (PD), the therapeutic mechanism of DBS remains a matter of debate. Recent studies demonstrate that DBS targeting the globus pallidus internus (GPi-DBS) suppresses pathological oscillations in firing rate and between-cell spike synchrony in the vicinity of the electrode but has negligible effects on population-level firing rate or the prevalence of burst firing. The present investigation examines the downstream consequences of GPi-DBS at the level of the primary motor cortex (M1). Multielectrode, single cell recordings were conducted in the M1 of two parkinsonian nonhuman primates (Macaca fasicularis). GPi-DBS that induced significant reductions in muscular rigidity also reduced the prevalence of both beta (12-30 Hz) oscillations in single unit firing rates and of coherent spiking between pairs of M1 neurons. In individual neurons, GPi-DBS-induced increases in mean firing rate were three times more common than decreases; however, averaged across the population of M1 neurons, GPi-DBS induced no net change in mean firing rate. The population-level prevalence of burst firing was also not affected by GPi-DBS. The results are consistent with the hypothesis that suppression of both pathological, beta oscillations and synchronous activity throughout the cortico-basal ganglia network is a major therapeutic mechanism of GPi-DBS.

Keywords: MPTP; Parkinson's disease; deep brain stimulation; globus pallidus; nonhuman primate; primary motor cortex.

Fig. 1.

Histology and intracortical mapping. Ai: cresyl violet stained slide, showing a coronal section through the electrode implanted hemisphere, which highlights the gliosis mark produced by placement of the stimulating electrode (black arrow). Aii: tyrosine hydroxylase was depleted throughout the dorsal caudate (Cd) and putamen (Pu) but preserved in the limbic regions of the ventral caudate (black arrow). GPi, globus pallidus internus; GPe, globus pallidus externus. B: chamber schematic showing the areas of the chamber sampled for primary motor cortex (M1) recording and microexcitable sites at which intracortical microstimulation elicited movement of specific body parts (filled shapes). OF, orofacial.

Fig. 2.

Stimulation artifact rejection and behavioral response to deep brain stimulation (DBS). Ai: neuronal signal from M1 acquired just before and during GPi-DBS, but with artifact subtraction disabled. Note the presence of large voltage transients during DBS (black) preventing discrimination of single unit spikes. Aii: expanded view of a short time period during DBS showing the large voltage transients that occurred time locked to the delivery of the stimulation pulse (vertical dashed lines; 150-Hz, 1-mA, 200-μs pulse width). Aiii: 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. (Note the different voltage scales in Aii and Aiii.) Action potentials that were completely obscured by artifacts in the unsubtracted data stream were easily detected in the processed data stream. Aiv: peristimulus sweeps (n = 4,500) of the recorded signal (top trace) demonstrate that it was possible to record and discriminate action potentials across the entire peristimulus period, including times close to stimulus pulse delivery (time zero). The bottom traces show statistical tests of the efficacy of the artifact rejection. The mean waveforms of spikes discriminated during DBS (thick black lines; ±SE indicated by light gray shading) were required to fall within the 95% confidence interval for all spikes discriminate during nonstimulation periods (dark gray shading). The test was conducted separately for four 2-ms epochs, defined by the vertical dashed lines. Bi: clinical testing using the torque motor. The figure shows one unprocessed record of constant angular displacement (gray trace) ±20° at 1 Hz and corresponding torque trace (black trace) off- and on-stimulation. Bii: measure of elbow rigidity calculated as cycle-by-cycle work derived from the integrated resistive torque (i.e., “work”) required to move the elbow joint through a ± 20° cycle at 1 Hz from one recording session that consisted of ten 30-s long periods of stimulation. Note the large reduction of work during application of GPi-DBS and the persistence of the effect after stimulation has stopped. Biii: postural transients (*) increased in frequency during GPi-DBS. This particular example shows raw torque (black traces) for 7 successive blocks of GPi-DBS (gray shading) sampled from monkey C.

Fig. 3.

Stimulation induced modulation of firing rates in M1. Exemplar raw data from 2 neurons whose firing rate increased (A) and decrease (B) with GPi-DBS. C and D: peri-DBS histograms (PdbsHs) and raster plots for the units shown in A and B. Vertical dashed line: time of onset of GPi-DBS. Gray shading: the period DBS was active. Horizontal solid and dashed lines: mean and 99% confidence level for firing rates from the pre-DBS control period. E, top: color plot of PdbsHs for all cells recorded in the study (1 horizontal row for each cell) aligned to stimulation (DBSon). Firing rates have been normalized by subtracting the mean firing rate computed from the 30 s before DBSon. Vertical dashed lines: 10 s-long analysis epochs. The on-stimulation period corresponded to epochs 4–6. E, bottom: box and whisker plot for each analysis epoch showing median and range of firing rates. The horizontal ends of each box indicate the upper and lower quartile range. The whiskers extend to 1.5× the interquartile range, while outliers are displayed as +'s.

Fig. 4.

Burst properties and firing patterns in M1 during stimulation. Raster plots of spike times (black tics) and burst events (red arrows) for 2 neurons in which GPi-DBS decreased the rate of burst firing (Ai) and increased burst firing (Aii). B: cell-by-cell measures of burst firing during DBSon were well predicted by the same measures from the no stimulation (DBSoff) condition. This was true both for the number of bursts/s and the %spikes in burst. Biii: GPi-DBS did not alter the time-magnitude structure of bursts. Population mean firing rates aligned on the time of burst onset under DBSoff (black) and DBSon (gray) conditions (dashed lines: SE). Inset: P values from t-tests comparing DBSoff vs. DBSon population mean periburst firing rates. D: for most cells, firing rate variability [coefficient of variation (CV) of interspike intervals] was also highly similar under DBSon and DBSoff conditions.

Fig. 5.

Firing pattern and spectral properties in M1 during stimulation. A: exemplar autocorrelation function and its change during GPi-DBS. In the DBSoff condition (black trace), the cell tended to spike at regular intervals, revealed as significant peaks and valleys in its autocorrelation function, within the beta-frequency range. During stimulation (gray trace), the cell's autocorrelation function flattened and lost the characteristic peaks and valleys observed off-stimulation. B: power spectra for the same exemplar data used in A under DBSoff and DBSon conditions. A prominent spectral peak at 14.8 Hz (*) was abolished during stimulation. Dashed horizontal line: threshold for significance. C: fraction of cells with one or more significant spectral peak under DBSoff and DBSon conditions (black and gray bins, respectively). Note that the prevalence of cells showing oscillatory activity in the beta-frequency range was reduced significantly during stimulation (*).

Fig. 6.

Suppression of synchronized spiking during GPi-DBS. A: spike activity of a pair of simultaneously recorded M1 neurons was synchronized at 15.6 Hz (*) in the DBSoff condition (black trace). That coherent activity was suppressed completely during GPi-DBS (gray trace). B: GPi-DBS reduced the prevalence of low-frequency synchronized rhythmic firing in the M1 population. The bar plot indicates the fraction of cell pairs with 1 or more significant coherence peak in the indicated frequency ranges during control periods (DBSoff) and stimulation (DBSon). Note the elevated prevalence of significant coherent firing in the beta frequency band in the absence of stimulation (black bins) and the significant reduction in that prevalence during stimulation (marked by an *).