Tremor varies as a function of the temporal regularity of deep brain stimulation

Abstract

The frequency of stimulation is one of the primary factors determining the effectiveness of deep brain stimulation (DBS) in relieving tremor. DBS efficacy, however, may depend not only on the average frequency of stimulation, but also on the temporal pattern of stimulation. We conducted intraoperative measurements of the effect of temporally irregular DBS (nonconstant interpulse intervals) on tremor. As the coefficient of variation of irregular high frequency DBS trains increased, they became less effective at reducing tremor (mixed effects regression model, P<0.04). These data provide evidence that the effects of DBS are dependent not only on the average frequency of DBS, but also on the regularity of the temporal spacing of DBS pulses.

Fig.1

Effects of stimulus train regularity on relief of postural tremor by deep brain stimulation (DBS). (a) Sample stimulus trains with mean interpulse interval (IPI)=7.7ms (mean frequency=130 Hz), and varying coefficients of variation (CVs). (b) Probability density functions for IPI distributions with a mean IPI=7.7ms (IPI step size of 0.25ms). (c–f) Sample accelerometer recordings (left) and power spectral densities (right) for tremor recorded in patient C during 10 s pre-DBS, 20 s DBS, and 5 s post-DBS. Accelerometer (c) and power spectral densities (d) for regular 130Hz DBS. Accelerometer (e) and power spectral densities (f) for DBS with an average rate of 130Hz and CV=0.6. Scale bars in (c) apply to (e). Log scale axis on power spectral density plots should be noted.

Fig. 2

Effects of deep brain stimulation (DBS) frequency and regularity on tremor suppression. (a, b) Log percent tremor power as a function of stimulus frequency in patient C (a) and in all four patients (b). (c, d) Log percent tremor power as a function of stimulus train regularity [coefficient of variation (CV) of the interpulse intervals (IPIs)] in patient C (c), and in all four patients (d). (a, c) The individual tremor measurement replicates are displayed along with their mean. Data represent log₁₀ of 100 times the ratio of tremor power during DBS to tremor power before the application of DBS. (b, d) Means of two to four trials collected with a randomized block design for each patient. Lines represent linear mixed-effects regression model for each patient. (b) The effectiveness of constant IPI DBS in suppressing tremor improved as a function of stimulus frequency (P<0.01, two-sided test on significance of frequency regression coefficient). All lines have the same slope (−0.0034/Hz), but different intercepts [patient A: 2.13, patient B: 2.27, patient C: 2.08, patient D: 2.10 (unitless)]. (d) Although all trains in each patient had the same mean IPI (5.4 ms in patient A, 7.7 ms in patients B–D), the trains with irregular IPIs were less effective at reducing tremor than constant IPI (CV=0) stimulation (P<0.04, two-sided test on significance of CVregression coefficient). All lines have the same slope [0.74 (unitless)], but different intercepts [patient A:1.54, patient B:1.94, patient C: 0.72, patient D:1.61 (unitless)]. Tremor data presented for DBS ‘off’ were not included in the regression model. Legends in (a, b) apply to (c, d), respectively.