Identifying and modulating distinct tremor states through peripheral nerve stimulation in Parkinsonian rest tremor

Abstract

Background: Resting tremor is one of the most common symptoms of Parkinson's disease. Despite its high prevalence, resting tremor may not be as effectively treated with dopaminergic medication as other symptoms, and surgical treatments such as deep brain stimulation, which are effective in reducing tremor, have limited availability. Therefore, there is a clinical need for non-invasive interventions in order to provide tremor relief to a larger number of people with Parkinson's disease. Here, we explore whether peripheral nerve stimulation can modulate resting tremor, and under what circumstances this might lead to tremor suppression.

Methods: We studied 10 people with Parkinson's disease and rest tremor, to whom we delivered brief electrical pulses non-invasively to the median nerve of the most tremulous hand. Stimulation was phase-locked to limb acceleration in the axis with the biggest tremor-related excursion.

Results: We demonstrated that rest tremor in the hand could change from one pattern of oscillation to another in space. Median nerve stimulation was able to significantly reduce (- 36%) and amplify (117%) tremor when delivered at a certain phase. When the peripheral manifestation of tremor spontaneously changed, stimulation timing-dependent change in tremor severity could also alter during phase-locked peripheral nerve stimulation.

Conclusions: These results highlight that phase-locked peripheral nerve stimulation has the potential to reduce tremor. However, there can be multiple independent tremor oscillation patterns even within the same limb. Parameters of peripheral stimulation such as stimulation phase may need to be adjusted continuously in order to sustain systematic suppression of tremor amplitude.

Keywords: Non-invasive; Parkinson’s disease; Peripheral stimulation; Phase-locked stimulation; Tremor oscillation patterns.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1

An illustration of the triaxial accelerometer, peripheral stimulation electrodes, and EMG surface electrodes placed on participant’s upper limb. A Participant’s hand was hanging over the armrest of the chair which supported the forearm. A triaxial accelerometer was placed on the dorsum of the most tremulous hand, a wristband containing stimulation electrodes was attached to the wrist, and EMG surface electrodes were placed on the participant’s hand and forearm. EMG 1 recorded signals from the forearm finger extensors; EMG 2, from the forearm finger flexors; and EMG 3, from the abductor pollicis brevis. B An illustration of the ventral surface of the study participant’s forearm and hand, showing the placement of the stimulation electrodes and EMG 2 and 3 surface electrodes

Fig. 2

Data collection and analysis pipeline. Tremor signals were collected from the most tremulous hand using a triaxial accelerometer. The power spectral density of the three axes was computed, the dominant tremor axis was identified as the one with the largest peak at the frequency of the tremor and was subsequently band-pass filtered between 2 and 8 Hz. The tremor phase was extracted from the filtered signal in real time. Stimulation was phase-locked to one of 12 randomly assigned phases from 0 to 330° with a 30° resolution. To evaluate the effect of phase-locked peripheral nerve stimulation, Hilbert transform was applied to band-pass filtered accelerometer signals, from which change in tremor severity within 5-s epochs was computed by subtracting the average of the tremor envelope during the first 1 s of stimulation (indicated in green) from the average envelope during the last 1 s (indicated in blue) and then dividing the result by the average of the first 1 s (indicated in green). The phase-amplitude profiles were derived as the medians for all the changes at a given phase.

Fig. 3

An example of how cluster representation in serial 5-s periods changes over time in the signals without stimulation. A Dominant cluster label (orange or green) obtained from the first principal component coefficients is shown for the median accelerometer signal amplitude and B for the median rectified EMG in each channel per 5-s period. C The first principal component coefficients corresponding to the three accelerometer axes. D The labels for the time segments assigned to each of the two clusters. E The corresponding three-dimensional cluster division from the first principal component coefficients

Fig. 4

Example phase-amplitude profiles for one study participant, showing the median change in tremor severity at each phase for the three accelerometer axes and two clusters. Significant median change in tremor severity was identified with respect to the tremor variability during the without stimulation condition following Bonferroni correction for 12 comparisons

Fig. 5

A Example of the Fisher-corrected correlations for each cluster combination in one study participant. B Mean between and within clusters of the Fisher-corrected correlation across participants

Fig. 6

Rose plots indicating the number of phase bins for which there was significant tremor suppression or significant tremor amplification at each of the 12 equally spaced stimulation phases. Rayleigh test for departure from circular uniformity resulted in p = 0.7204 for suppression and p = 0.2347 for amplification

Fig. 7

A Rose plots indicating the probability of significant tremor suppression or tremor amplification at each of the 12 equally spaced stimulation phases where the minimum suppression and maximum amplification angles were realigned to 180°. Rayleigh test resulted in p = 2e−8 for suppression and p = 0.0002 for amplification. B Rose plots indicating the probability of tremor suppression or tremor amplification at each of the 12 equally spaced stimulation phases, regardless of whether tremor modulation was significant, where the minimum suppression and maximum amplification angles in all phase-amplitude profiles were realigned to 180°. Rayleigh test resulted in p = 6e−6 for suppression and p = 0.0334 for amplification. C Rose plots generated from surrogate phase-amplitude profiles indicating the probability of tremor suppression or tremor amplification at each of the 12 equally spaced stimulation phases where the minimum suppression and maximum amplification angles were realigned to 180° regardless of whether tremor modulation were significant. D Rose plots displaying the ratio between the real (B) and surrogate (C) probabilities of suppression or amplification in all phase-amplitude profiles, such that ratios significantly greater than 1 after FDR correction are shown in red, ratios significantly smaller than 1 are shown in green, and ratios that are not significant after FDR correction are shown in grey. Precise p-values given in Table 3