Pallidal stimulation that improves parkinsonian motor symptoms also modulates neuronal firing patterns in primary motor cortex in the MPTP-treated monkey

Abstract

Deep brain stimulation (DBS), a surgical therapy for advanced Parkinson's disease (PD), is known to change neuronal activity patterns in the pallidothalamic circuit. Whether these effects translate to the motor cortex and, if so, how they might modulate the functional responses of individual neurons in primary motor cortex remains uncertain. A 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkey was implanted with a DBS lead spanning internal and external segments of globus pallidus. During therapeutic stimulation (135 Hz) for rigidity and bradykinesia, neurons in primary motor cortex (M1) exhibited an inhibitory phase-locking (2-5 ms) to the stimulus, an overall decrease in mean discharge rate, and an increase in response specificity to passive limb movement. Sub-therapeutic DBS (30 Hz) still produced entrainment to the stimulation, but the mean discharge rate and specificity to movement were not changed. Lower stimulation intensities (at 135 Hz), which no longer improved motor symptoms, had little effect on M1 activity. These findings suggest that DBS improves parkinsonian motor symptoms by inducing global changes in firing pattern and rate along the pallido-thalamocortical sensorimotor circuit.

Figure 1

In primary motor cortex (M1), single-unit responses during passive joint articulation differed between therapeutic and sub-therapeutic DBS settings. A, For therapeutic settings (1V, 135Hz), population-averaged firing patterns became time-locked to the stimulation, which B, was not present for attenuated DBS voltages (0.5V, 135Hz) that no longer produced a therapeutic effect. C, Lowering the DBS frequency (1V, 30Hz) resulted in a similar initial firing pattern to that observed during therapeutic DBS (inset), but the overall firing probability returned to baseline within 5 ms. The black histograms show population-averaged responses to virtual stimulation epochs, whereas colored histograms correspond to population-averaged responses to actual stimulation pulses. D, A significant decrease in overall rate was observed for therapeutic, but not for sub-therapeutic settings (**p<0.001, *p<0.05). E-H, Therapeutic DBS also modulated the specificity of neuronal discharge to passive movement as shown for a representative cell (responsive to shoulder internal/external rotation, n=20 cycles) before, during, and after stimulation. Horizontal dotted lines indicate mean firing rate, whereas shaded boxes indicate 95% confidence intervals. The curve above the raster scan shows the movement profile compressed into 2D space. I-K, The neuronal discharge specificity ratio, quantified as the ratio of average firing rates between opposing joint articulations, increased during therapeutic but less so during sub-therapeutic DBS. Pie chart inserts represent the proportion of units with DSR changes above +20% (blue), below -20% (yellow), or no change (maroon). The black dot in I (indicated by the arrow) represents the example cell in E-H. L, A statistically significant increase in the recorded population's DSR was only present during therapeutic DBS (*p=0.019, n=55, paired t-test).