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Tremor varies as a function of the temporal Merrill J. Birdnoa, Alexis M. Kuncela, Alan D. Dorvala, Dennis A. Turnerb and Warren M. Grilla aBiomedical Engineering, Duke University and bNeurosurgery and Neurobiology, Duke University Medical Center, Durham, North Carolina, USA Correspondence to Dr Warren M. Grill, PhD, Duke University, Department of Biomedical Engineering, Hudson Hall, Room 136, Box 90281, Received10 January 2008; accepted 24 January 2008 The frequency of stimulation is one of the primary factors deter- high frequency DBS trains increased, they became less e¡ective at mining the e¡ectiveness of deep brain stimulation (DBS) in reliev- reducing tremor (mixed e¡ects regression model, Po0.04). These ing tremor. DBS e⁄cacy, however, may depend not only on the data provide evidence that the e¡ects of DBS are dependent not average frequency of stimulation, but also on the temporal pattern only on the average frequency of DBS, but also on the regularity of stimulation. We conducted intraoperative measurements of of the temporal spacing of DBS pulses. NeuroReport 19:599^ 602 the e¡ect of temporally irregular DBS (nonconstant interpulse c 2008 Wolters Kluwer Health | Lippincott Williams & Wilkins.
intervals) on tremor. As the coe⁄cient of variation of irregular Keywords: basal ganglia, deep brain stimulation, movement disorders, subthalamic nucleus, thalamus, tremor, ventral thalamic nuclei valproic acid, gabapentin, and azathioprine through the Deep brain stimulation (DBS) is an established therapy for course of the experiment, and patient D did not withhold the treatment of movement disorders, including essential diazepam. Some patients reported transient paresthesias for tremor and Parkinson’s disease. Although the clinical some stimulus settings, but there were no adverse events benefits of DBS are well documented, the mechanisms of action remain unclear. The stimulation frequency has astrong impact on outcomes, and maximal reductions in tremor are typically observed only when the frequency is We measured tremor in the limb contralateral to the side of Z90 Hz [1–5]. Recent studies suggest that regularization of stimulation during unilateral stimulation. Stimuli were neuronal firing underlies the effectiveness of high frequency delivered with an isolated stimulator (bp isolator, FHC DBS [6–10], and we hypothesized that temporally irregular Inc., Bowdoin, Maine, USA) and pulses were controlled by a stimulus trains would be less effective at suppressing high-speed digital-to-analog converter through LabView tremor than regular high frequency trains. Here we report software (National Instruments, Austin, Texas, USA). The tremor responses to DBS trains with the same average regulated voltage waveform was an asymmetric, charge- frequency but with varying degrees of temporal irregularity.
balanced, biphasic pulse with a large-amplitude short-duration cathodic phase followed by a low-amplitude(10% of cathodic amplitude) and long-duration (10 times the cathodic duration) anodic recharge phase, similar to that used in the IPG. Charge densities were below the We conducted experiments on four individuals with DBS- manufacturer’s recommended limit of 30 mC/cm2/phase responsive tremor who were having their implantable pulse (using conservative estimate of impedance¼500 O).
generator (IPG) surgically replaced due to depleted batteries We tested eight stimulation patterns in each patient: (Table 1). Irregular stimulus trains cannot be delivered using stimulation ‘off’, four constant interpulse interval (IPI¼1/ the IPG (Medtronic Soltera Model 7426 and Kinetra Model instantaneous frequency) trains (Table 1), and three tempo- 7428, Metronic Inc., Minneapolis, Minnesota, USA), and we rally irregular trains with the same mean IPI (Table 1), but used an external stimulator, connected to the implanted DBS with different degrees of irregularity (Fig. 1a and b).
lead extension at the time of IPG replacement. Patients Irregular trains were constructed by drawing IPIs from a participated on a volunteer basis with written informed Gaussian distribution, such that the coefficients of variation consent, and the study protocol was approved by the Duke (CVs) of the IPI distributions were 0.1, 0.3 and 0.6 University Institutional Review Board. Patients B and C (CV¼standard deviation of the IPIs/mean of the IPIs).
withheld dopaminergic and/or antitremor medications Any random IPIs shorter than the combined duration of the overnight before the experiment. Patient A did not withhold cathodic and anodic phases were lengthened to ensure that c Wolters Kluwer Health | Lippincott Williams & Wilkins Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Table 1 Demographic characteristics and stimulation settings for each patient IPI, interpulse interval; MDS, myoclonus-dystonia syndrome; MS, multiple sclerosis; PW, pulse width; STN, subthalamic nucleus; Vim, ventral intermediatenucleus of thalamus.
aTremor type was based on presurgical clinical evaluation and posture was adjusted to maximize tremor in the stimulation ‘o¡’ condition.
bAmplitudes in parentheses indicate clinically programmed amplitudes in cases in which they di¡ered from amplitudes used during experiments.
cMean IPI speci¢es the mean of the IPI distribution used for the irregular IPI trains, with CV¼0, 0.1, 0.3, and 0.6.
charge balancing was complete before the onset of the next incomplete blocks (one patient) were included to provide pulse (B0–2% of IPIs for CV¼0.3 and 4–15% of IPIs for the best estimate of the mean for each stimulus condition.
CV¼0.6 needed to be lengthened). This caused the effective Data were analyzed using two linear mixed-effects regres- CVs of the IPIs to decrease slightly in the most irregular sion models, with patient identity as the random effect. The trains (CV¼0.52–0.56, rather than 0.6). In each block, the first model included frequency as the fixed effect, and stimulation patterns were presented in randomized order, included only tremor measurements recorded during regular and the patient was blinded to the stimulation parameters.
(constant IPI) stimulation. The second model included CV of Each patient completed two to four blocks in a single 30–60- IPIs as the fixed effect, and included only tremor measure- ments made during stimulation with the same mean IPI, but Postural tremor was measured with the wrist extended varying regularity (CV¼0, 0.1, 0.3, 0.6). Individual patient and/or elbow flexed (Table 1). Rest tremor was measured intercepts were computed using best linear unbiased pre- with the elbow supported and the hand unsupported.
dictors from the mixed effects regression model ( JMP: SAS Intention tremor was measured as the patients moved their Institute, Cary, North Carolina, USA). Two-sided tests were index finger between their nose and an experimenter’s performed on the significance of regression coefficients and hand. Tremor was recorded continuously during each trial statistical significance was defined at a¼0.05.
including 5–10 s before turning DBS ‘on’, 10–30 s with DBS‘on’, and an additional 1–5 s after DBS was switched ‘off’.
The patient then relaxed for approximately 30–60 s beforethe next trial began.
Tremor was measured using an accelerometer taped to the We measured changes in tremor in four patients in response dorsum of the hand (Crossbow CXL04LP3; 5V/4g sensitiv- to regular DBS at different frequencies and to irregular ity, San Jose, California, USA), and quantified by combining DBS with the same average pulse frequency, but different degrees of irregularity in the IPIs. Tremor depended on both ffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffiffi the average frequency of stimulation and the regularity of stimulation. Sample accelerometer recordings and power density of |a|, which quantifies the power as a function of spectra illustrate that tremor was suppressed more during signal frequency, using the power spectral density (PSD) stimulation with regular DBS than during stimulation with function (Welch’s averaged periodogram, Hanning window, FFT length¼5000) in MATLAB (Mathworks Inc., Natick, Tremor suppression by DBS increased as a function of Massachusetts, USA). We then defined tremor power as the frequency (Fig. 2a and b). A linear mixed-effects model of sum of the power spectral density between 2 and 20 Hz, log percent tremor as a function of frequency revealed a chosen to include the primary and first harmonics of the significant negative correlation between stimulus frequency tremor and to exclude steady state acceleration due to gravity.
and tremor (Po0.01, two-sided test on significance of slope,R2¼0.42, Fig. 2b).
Tremor suppression by high frequency DBS decreased as Tremor during DBS was analyzed as log10 of the percent of the stimulus train became more irregular (Fig. 2c and d).
tremor power in the period preceding DBS onset.
A linear mixed-effects model of log percent tremor as a function of stimulus irregularity (CV of the IPIs) revealed a significant positive correlation between stimulus irregular- ity and tremor power (Po0.03, two-sided test on signifi-cance of slope, R2¼0.83, Fig. 2d). The magnitude of the slope Measurements made across multiple blocks within the same [0.83 (unitless); 95% confidence interval: 0.10–1.55 (unitless)] patient were averaged, and measurements from trials in indicated that as the CV of the stimulus increased from Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
E¡ects 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 [coe⁄- cient of variation (CV) of the interpulse intervals (IPIs)] in patient C (c),and in all four patients (d). (a, c) The individual tremor measurement re- Fig. 1 E¡ects of stimulus train regularity on relief of postural tremor by plicates are displayed along with their mean. Data represent log10 of 100 deep brain stimulation (DBS). (a) Sample stimulus trains with mean inter- times the ratio of tremor power during DBS to tremor power before the pulse interval (IPI)¼7.7 ms (mean frequency¼130 Hz), and varying application of DBS. (b, d) Means of two to four trials collected with a ran- coe⁄cients of variation (CVs). (b) Probability density functions for IPI dis- domized block design for each patient. Lines represent linear mixed-ef- tributions with a mean IPI¼7.7 ms (IPI step size of 0.25 ms). (c^ f) Sample fects regression model for each patient. (b) The e¡ectiveness of constant accelerometer recordings (left) and power spectral densities (right) for IPI DBS in suppressing tremor improved as a function of stimulus fre- tremor recorded in patient C during 10 s pre-DBS, 20 s DBS, and 5 s post- quency (Po0.01, two-sided test on signi¢cance of frequency regression DBS. Accelerometer (c) and power spectral densities (d) for regular coe⁄cient). All lines have the same slope (À0.0034/Hz), but di¡erent in- 130 Hz DBS. Accelerometer (e) and power spectral densities (f) for DBS tercepts [patient A: 2.13, patient B: 2.27, patient C: 2.08, patient D: 2.10 with an average rate of 130 Hz and CV¼0.6. Scale bars in (c) apply to (e).
(unitless)]. (d) Although all trains in each patient had the same mean IPI Log scale axis on power spectral density plots should be noted.
(5.4 ms in patient A, 7.7 ms in patients B^D), the trains with irregular IPIswere less e¡ective at reducing tremor than constant IPI (CV¼0) stimula- 0 to 0.6, there was a 3.1-fold increase in the median tion (Po0.04, two-sided test on signi¢cance of CVregression coe⁄cient).
percent tremor (not logged), approximately the same as All lines have the same slope [0.74 (unitless)], but di¡erent intercepts[patient A: 1.54, patient B: 1.94, patient C: 0.72, patient D: 1.61 (unitless)].
the proportional increase in the median percent tremor Tremor data presented for DBS ‘o¡’ were not included in the regression that occurred between 130 Hz DBS and DBS ‘off’ in the model. Legends in (a, b) apply to (c, d), respectively.
bursting, but rather pauses between spikes in trains of thalamic input that exceed 20 ms (o50 Hz) lead to burst Our results demonstrate that tremor reduction by DBS responses in thalamus. Bursting in the thalamus has been depends not only on the rate, but also on the temporal associated with both essential tremor and Parkinson’s regularity of stimulation. High frequency stimulation disease [13,14], and DBS-induced rebound bursts may provided better symptom relief than low frequency stimula- tion [1–5], and the effectiveness of high frequency DBS Second, the decreased effectiveness of irregular DBS in decreased as the degree of irregularity of stimulation relieving tremor may be due to long IPIs providing an increased. These results reinforce the importance of the opportunity for intrinsic pathological activity to recover and pattern of neuronal firing in movement disorders, and propagate through the thalamus before the arrival of the support the hypothesis that regularization of neuronal firing next stimulus pulse. Such a mechanism explains the similar is required for effective DBS [6–10].
ineffectiveness of the irregular stimulus trains and regular We theorize three candidate mechanisms for why the temporally irregular stimulation was less effective than Third, the decreased effectiveness of irregular DBS in regular stimulation. First, the decreased effectiveness of relieving tremor may be due to the irregularity, per se, of the irregular DBS in relieving tremor may be due to long IPIs in stimulation patterns. Under this hypothesis, even if irregu- the trains inducing burst responses in thalamus. Computa- lar DBS is able to override pathological bursting [14,15], it tional [11] and experimental [12] results indicate that may be unable to drive regular firing patterns, and thus is irregular stimulus trains, per se, do not lead to thalamic clinically ineffective. Neurons downstream of the stimulated Copyright Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
nucleus may adapt to ignore regularized inputs from the stimulated nucleus, because constant rate firing provides no This study was supported by NIH R21-NS055320, NIH new information to the downstream neurons. Such an explanation provides a basis for understanding the similar Graduate Research Fellowship. Authors report no conflicts effects of high frequency DBS and surgical lesioning of the A limitation of this study is the heterogeneity of the patient population. Although the specific mechanism(s) by which DBS exerts its effects may vary across the diseases 1. Ushe M, Mink JW, Revilla FJ, Wernle A, Schneider Gibson P, McGee- and target nuclei examined in this study, it is nonetheless Minnich L, et al. Effect of stimulation frequency on tremor suppression in remarkable that the effects of stimulus rate and regularity essential tremor. Mov Disord 2004; 19:1163–1168.
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