Pallidal stimulation: effect of pattern and rate on bradykinesia in the non-human primate model of Parkinson's disease

Abstract

Deep brain stimulation (DBS) involves the delivery of continuous, fixed-frequency electrical pulses to specific brain regions; however the reliance of therapeutic benefit on the fixed-frequency nature of the stimulation pattern is currently unknown. To address this, we investigated the effect of changes in the pattern and frequency of DBS in the internal segment of the globus pallidus (GPi) on bradykinesia in a single, hemi-parkinsonian monkey. Therapeutic parameters (i.e., contacts, pulse width, amplitude) were established for fixed-frequency stimulation at 135 Hz based on improved movement times during a reach and retrieval task. Thereafter, the pattern and frequency of stimulation were varied to assess the effect of variability, bursting and oscillatory patterns of stimulation on bradykinesia. During fixed-frequency stimulation, performance improved as a function of increasing pulse rate (P<0.01). Using a temporally irregular pattern at the same average frequency failed to alter therapeutic benefit relative to the fixed-frequency condition. Introducing an 80 Hz burst pattern (20 bursts/s at 4 pulses/burst) improved bradykinesia (P<0.01) relative to both "OFF" and 80 Hz fixed-frequency conditions, yielding results comparable to fixed-frequency stimulation at 135 Hz with 40% less current drain. Compared to burst and fixed-frequency stimulations, oscillatory patterns at 4 and 8 Hz were less effective. These results suggest that lower frequency stimulation delivered in a regular bursting pattern may be equally effective and require lower energy than higher frequency continuous patterns of stimulation, thereby prolonging battery life and call into question the role of bursting activity in the pathogenesis of bradykinesia.

Figure 1

Effect of varying frequency and pattern on reach and retrieval task performance in the MPTP NHP. A) Temporally regular deep brain stimulation of the internal segment of the globus pallidus was associated with frequency specific improvements in bradykinesia in the MPTP monkey. Reach and retrieval times improved as a function of increasing stimulation frequency, however the trend of improved motor performance between the 80 Hz and 135 Hz was not found to be significant. B) The temporal regularity of the pulse train delivered during deep brain stimulation of the internal segment of the globus pallidus did not influence the motor improvements observed at any of the three levels of stimulation frequency. The series of box plots compare motor performance between the temporally regular and irregular pattern for average frequencies of 50 Hz (top), 80 Hz (middle) and 135 Hz (bottom). The bar chart to the right of each box plot shows an example inter-pulse interval histogram during the irregular stimulation condition. C) Burst pattern stimulation with an average frequency of 80 Hz improved reach and retrieval performance relative to temporally regular stimulation at 80 Hz regardless of whether the burst pattern was temporally regular or irregular. Regular and irregular burst stimulation improved median motor performance by 35.4% and 33.6%, respectively, relative to the DBS OFF condition and by 16.5% and 14.2%, respectively, relative to the temporally regular stimulation at 80 Hz. In both instances, burst pattern stimulation produced motor effects comparable to that observed during temporally regular stimulation at 135 Hz. *Significant differences from the DBS OFF condition. ^#Significant differences from temporally regular DBS at 80 Hz. D) Arrangement of the pulse sequence into an oscillating pattern reduced the efficacy of GPi DBS relative to temporally regular stimulation at the same average frequency. For both the 135 Hz (top) and 80 Hz (bottom) condition, the effect on motor performance was dependent upon modulation frequency such that lower frequencies were associated with an increase in mean reach and retrieval time. *Significant differences from the temporally regular DBS condition. For all figures, the y-axis represents movement time in seconds. *p < 0.05