CONTROL METHOD FOR A NEUROPROSTHETIC DEVICE FOR THE REDUCTION OF PATHOLOGICAL TREMORS

Abstract

The invention relates to a control method for a neuroprosthetic device, allowing to monitor and reduce pathological tremors in users via the stimulation of the peripheral muscles and modulation of the afferent pathways.

Claims

1. A method for a window-based control of a neuroprosthetic device comprising the steps of: a) obtaining a set of electromyography (EMG) signals from at least one pair of EMG electrodes; b) filtering the EMG signals obtained by using a low-pass filter; c) obtaining envelopes of the filtered EMG signals; d) determining two or more local maxima of the envelopes obtained; e) calculating period and frequency of tremorgenic bursts of each muscle based on said local maxima; f) determining an adaptive EMG threshold of tremor for each EMG signal, which is computed as root mean square (RMS) of the EMG signals obtained in step a) multiplied by a gain between 0.5 and 2; wherein when frequencies of tremorgenic bursts of one or more muscles are in the range of 3-12 Hz, is determined that tremor is present and a stimulation mode is enabled, which further comprises the steps of: i) setting a stimulation time-window, which has a duration inversely proportional to the period of tremorgenic burst, such that the shorter the tremorgenic burst, the longer the stimulation time-window; ii) obtaining one or more updated EMG signals from the EMG electrodes; iii) obtaining an updated RMS value of a measuring time window of each updated EMG signal; iv) comparing each updated RMS value with the adaptive EMG threshold; v) determining the existence of tremor in an agonist muscle if the RMS value of an EMG electrode is above the adaptive EMG threshold, vi) generating an activation signal on the neuroprosthetic device, with respect to the agonist muscle suffering a tremor, and repeating steps (ii) to (v) until the duration of the stimulation time-window is finished.

2. The method according to claim 1, wherein the low-pass filter is a Butterworth filter.

3. The method according to claims 1 and 2, further comprising a step of applying a Hilbert transformation to the envelope obtained in step c) for obtaining an improved envelope.

4. The method according to any of claims 1 to 3, wherein the step a) obtains the EMG signal during a period of 0.5 to 2 seconds.

5. The method according to any of claims 1 to 4, wherein the step ii) obtains the updated EMG signal during 3 to 15 milliseconds.

6. The method according to any of claims 1 to 5, wherein the step v) generates the activation signal during 5 to 20 milliseconds.

7. The method according to any of claims 1 to 6, wherein steps i) to vi) are performed during seconds before repeating step a).

8. The method according to any of claims 1 to 7, further comprising a step of calculating the intensity and duration of the activation signal of the neuroprosthetic device based on the EMG signal and below the motor threshold.

9. A neuroprosthetic system for monitoring and reducing pathological tremors, comprising one or more wearable elements, each wearable element comprising at least one pair of EMG electrodes for obtaining a set of electromyography (EMG) signals, wherein the system further comprises a programmable electronic device adapted to: a) filter the EMG signals obtained by using a low-pass filter; b) obtaining envelopes of the filtered EMG signals; c) determining two or more local maxima of the envelopes obtained; d) calculating period and frequency of tremorgenic bursts of each muscle based on said local maxima; e) determining an adaptive EMG threshold of tremor for each EMG signal, which is computed as root mean square (RMS) of the EMG signals obtained in step a) multiplied by a gain between 0.5 and 2, and wherein the programmable electronic device is further adapted such that when the frequencies of tremorgenic bursts are in the range of 3-12 Hz, determine that a tremor is present and a stimulation mode is enabled.

10. A neuroprosthetic system according to claim 9, further comprising stimulation means for stimulating a patient's affected pathways, and wherein the programmable electronic device is further adapted such that when the stimulation mode is enabled, it performs the following steps: i) setting a stimulation time-window, which has a duration inversely proportional to the period of tremorgenic burst, such that the shorter the tremorgenic burst, the longer the stimulation time-window; ii) obtaining one or more updated EMG signals from the EMG electrodes; iii) obtaining an updated RMS value of a measuring time window of each updated EMG signal; iv) comparing each updated RMS value with the adaptive EMG threshold; v) determining the existence of tremor in an agonist muscle if the RMS value of an EMG electrode is above the adaptive EMG threshold, vi) generating an activation signal on the neuroprosthetic device, with respect to the agonist muscle suffering a tremor, and repeating steps (ii) to (v) until the duration of the stimulation time-window is finished.

11. A neuroprosthetic system according to claim 9 or 10, wherein the wearable elements comprise stimulating electrodes for delivering stimulation signals.

12. A neuroprosthetic system according to claim 9 or 10, wherein the wearable elements comprises an electronic device incorporating a micro-controller, and wherein the wearable elements are adapted to be incorporated into clothing or to be worn on a patient's body.

13. A neuroprosthetic system according to any of the claims 9 to 12, wherein the wearable elements comprises an external device incorporating a user interface provided with a display for displaying data, and adapted to access the functionalities of the programmable electronic device of one or more wearable elements.

Description

DESCRIPTION OF THE DRAWINGS

[0063] FIG. 1. Illustration of the selective and adaptive timely stimulation (SATS—the method of the invention) strategy for a pair of tremorgenic muscles controlling the wrist (flexor carpis radialis—FCR, and extensor carpis radialis—ECR). In the recording window (1s), tremor was detected from the EMG signals. When tremor was present, stimulation was enabled during the subsequent 2s. Although grey areas are drawn over tremorgenic burst activity of the recorded muscle, stimulation pulses were delivered to the antagonist muscle to that where tremorgenic activity was detected in short RMS windows. SATS allows co-contraction of both muscles or individual stimulation of on muscle, depending if both muscles present tremorgenic burst at the same time or not.

[0064] FIG. 2. Illustration of the effects of electrical stimulation on segments of wrist flexion-extension amplitude (degrees). Data corresponding to the intramuscular stimulation session with SATS of patient P5. Window 1: Pre-assessment; Window 2: stimulation trial, dark grey areas represent 2s stimulation windows, light grey represents a period when stimulation was turned OFF; Window 3: Post-assessment; Window 4: Assessment 24 h after experimentation.

[0065] FIG. 3. Acute tremor reduction scores on kinematics tremor power for 4 ET patients. Tremor scores between the 30 s OFF period (stimulation turned OFF) and 30 s ON period (stimulation turned ON) for each assessed joint (1-stimulated wrist, 2 ipsilateral elbow, 3 ipsilateral shoulder, 4-contralateral shoulder, 5 contralateral elbow, 6-contralateral wrist). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular SATS stimulation; dashed black bars: surface SATS stimulation; grey bars: intramuscular CON stimulation; dashed grey bars: surface CON stimulation. * Statistical significance between groups (p<0.05);

[0066] FIG. 4. Acute tremor reduction scores on kinematics tremor power for 4 ET patients. Tremor scores between the 30 s OFF period and the 2 s stimulation windows segmented from the ON periods (1-stimulated wrist, 6-contralateral wrist). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular SATS stimulation; dashed black bars: surface SATS stimulation; grey bars: intramuscular CON stimulation; dashed grey bars: surface CON stimulation. * Statistical significance between groups (unpaired T-test, p<0.05); ** Statistical significance from baseline tremor (one-sample T-test, p<0.05).

[0067] FIG. 5. Tremor scores of electrical stimulation on wrist kinematics tremor amplitude for 4 ET patients right after stimulation. Results from the post-ASSESS after the stimulation trials. (1-stimulated wrist, 2 ipsilateral elbow, 3 ipsilateral shoulder, 4-contralateral shoulder, 5 contralateral elbow, 6-contralateral wrist). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular stimulation; grey bars: surface stimulation.

[0068] FIG. 6. Prolonged tremor scores of electrical stimulation on wrist kinematics tremor amplitude for 4 ET patients. Results from the assessment 24 h after stimulation trials. (1—stimulated wrist, 2 ipsilateral elbow, 3 ipsilateral shoulder, 4—contralateral shoulder, 5 contralateral elbow, 6—contralateral wrist). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular stimulation; grey bars: surface stimulation.

[0069] FIG. 7. Effect of electrical stimulation for 9 ET patients (P1-P9) right after stimulation trials. Tremor scores on wrist kinematics after the stimulation trials (post-ASSESS). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular stimulation; grey bars: surface stimulation. P1-P4 received SATS and CON stimulation trials in the same session; P5-P6 received only SATS stimulation; P7-P9 received only CON stimulation.

[0070] FIG. 8. Prolonged effect (24 hours) of electrical stimulation for 9 ET patients (P1-P9). Tremor scores on wrist kinematics after the stimulation trials (post 24h-ASSESS). 0.5 represents no change in tremor amplitude, 1 represents 100% tremor reduction and 0 represents 100% tremor aggravation. Black bars: intramuscular stimulation; grey bars: surface stimulation. P1-P4 received SATS and CON stimulation trials in the same session; P5-P6 received only SATS stimulation; P7-P9 received only CON stimulation.

[0071] FIG. 9. Spiral drawings from patient P6, who received SATS stimulation with intramuscular electrodes. 1—Pre-assessment; 2—Post-Assessment; 3—post 24h-assessment.

[0072] FIG. 10. Reciprocal inhibition values measured as the percentage of the unconditioned H-Reflex of a healthy participant. In-phase SATS increased reciprocal inhibition at the POST assessment, while out-of-phase stimulation reduced reciprocal inhibition. Note that decreased values in yy axis mean increased reciprocal inhibition.

EXAMPLES

Participants and Materials

Participants

[0073] Eleven ET were recruited and clinically examined between April 2019 and January 2020. Inclusion criteria included diagnosis of ET with or without family history, according to Tremor Research Investigation Group, regardless of the disease duration and the current or previous treatment, presenting clinically objectionable postural tremor, age between 18-80 years, tremor affecting at least one of the upper limbs, with prominent wrist flexion-extension movement, absence of another neurological pathology that could produce abnormal movements or impaired mobility in the extremities, ability to understand the procedure; and sign the informed consent. Exclusion criteria included coexistence of other diseases that distort movement, mixed or complex tremors, with involvement of multiple muscles; concomitant important medical pathology; anticoagulant treatment.

Materials

[0074] Each patient underwent two different sessions, at different weeks and in randomized order: 1) stimulation with thin-film multichannel intramuscular electrodes; and 2) surface stimulation.

[0075] For the intramuscular stimulation session (IntraStim), two intramuscular electrodes were acutely implanted in the muscle belly of flexor carpis radialis (FCR) and extensorcarpis radialis (ECR) of the most affected side. The insertion of each intramuscular electrode was done with a hypodermic needle (25G, B. Braun AG, Germany) and 5 guided by ultrasonography to guarantee its placement within the muscle belly.

[0076] For the surface stimulation session (SurfStim), round adhesive electrodes (3.2 cm diameter, ValuTrode Cloth, Axelgaard Manufacturing, Denmark) were placed over the median and radial nerves of the most affected side through palpation, as previously 10 described (Pascual-Valdunciel et al., Conf Proc IEEE Eng Med Biol Soc, Vol: 2019, Pages: 6267-6272). For both sessions, a surface ground squared electrode (5×5 cm, ValuTrode Cloth, Axelgaard Manufacturing, Denmark) was placed over the olecranon.

[0077] Stimulation strategies were controlled using a customized embedded processing unit including both an electromyography (EMG) amplifier and voltage electrical stimulator (OT Bioelettronica, Italy). Monopolar (intramuscular) or bipolar (surface) EMG signals were sampled at 1,000 Hz. Stimulation frequency was set at 100 Hz (Dideriksen et al., Front. Neurosci., April 2017, vol. 11: art. 178), with biphasic pulse width and maximum stimulation amplitude of 200 μs and 2.7 mA, and 400 μs and 5 mA, for intramuscular and surface electrodes, respectively (Muceli et al., J. Neural Eng., 2019, vol. 16, n. 2).

[0078] Additionally, bipolar surface electromyography (sEMG) electrodes were placed over the FCR and ECR after cleaning the skin with alcohol (Hermens et al., “European recommendations for surface electromyography: Results of the SENIAM Project,” 1999). sEMG signals were acquired at 2,048 Hz with a biosignal amplifier (Quattrocento, OT Bioelettronica, Italy), which also recorded digital and synchronization signals from the stimulator unit and kinematics measurement system. Wet wristbands were secured around the wrist of the stimulated side and used as reference for all EMG recordings.

[0079] Kinematics of upper limbs joints were assessed through seven Inertial Measurements Units (IMUs) (Technaid S.L., Spain): two IMUs were placed over dorsal side of each hand, two over dorsal sides of each forearm, two were placed over the lateral side of each arm and one over the chest, which worked as reference. Raw quaternions data were sampled at 50 Hz and stored for offline analysis.

Procedures

[0080] For each different experimental session (each one on different weeks), IntraStim or SurfStim was delivered on each patient. The order of the sessions were randomized. At the beginning of each session, patients were instrumented with EMG and stimulation electrodes, as well as IMUs.

[0081] Subjects were asked to keep their arms pronated and outstretched, or with their elbows flexed and pronated facing both hands, for each trial. For each subject, the position that elicited higher tremor amplitude at wrist was selected. To assess basal tremor (pre-ASSESS trial), each participant was then asked to hold their upper limbs in the same posture that would elicited higher tremor amplitude, for 60 seconds, while IMUS and EMG data were recorded.

[0082] Then, stimulation parameters were calibrated. For IntraStim, a similar procedure to that described in Muceli et al., (J. Neural Eng., 2019, vol. 16, n. 2) was applied to find motor threshold (MT) and perception threshold (PT) of both ECR and FCR. The total current delivered by the three stimulating points never exceeded 2.7 mA, for safety reasons. In the case of SurfStim, MT and PT were also identified, and maximum current delivered over nerves was 5 mA maximum. For both types of stimulation, intensity delivered in stimulation trials was usually 0.1 mA below MT or the maximum current allowed for each type of stimulation (2.7 mA for intramuscular and 5 mA for surface stimulation), for those cases where MT was higher than maximum allowed stimulation.

[0083] After setting stimulation parameters, the session proceeded with several stimulation trials, each one lasting 60 seconds. For each of these trials, subjects were asked to keep the same posture as in pre-ASSESS. Stimulation trials started with 10 seconds of tremor recording, followed by two 30-seconds windows in which a different stimulation strategy was turned ON or OFF (randomly assigned order). During ON periods, a given stimulation condition was delivered to the patient, whereas no stimulation was applied during OFF periods. Each patient completed at least six stimulation trials and was blinded to the stimulation condition applied. In some cases, patients did not feel any sensation when stimulation was delivered.

[0084] The two different stimulation strategies applied in this study were selective and adaptive timely stimulation (SATS— the method of the invention) and continuous stimulation (CON): [0085] SATS was based on alternating EMG recording with electrical stimulation time windows (FIG. 1). It started with the analysis of 1s windows of FCR and ECR EMG data, demodulation of both signals to extract the main frequency of tremor, as a simplification of a previous method (Dideriksen et al., Front. Neurosci., April 2017, vol. 11: art. 178). If signals' frequencies were in the range 3-12 Hz, tremor was detected and the stimulation was enabled for the next 2 seconds. During this window, RMS of 10 ms EMG epochs was computed for both FCR/ECR and, if any of the RMS values exceeded the adaptive threshold, then a short stimulation burst would be delivered to the antagonist muscle. This method considers that both antagonists can be in-phase and, therefore, be stimulated at the same time (Puttaraksa et al., J. Neurophysiol. 2019, vol. 122, no. 5, pp. 2043-2053). After the stimulation burst, the short RMS recording windows were consecutively computed and stimulation would be delivered if tremorgenic activity was detected. Once the 2s stimulation window was past, 1s recording window was activated again to assess tremorgenic status and the same cycle repeated again. [0086] CON stimulation consisted of 1s recording EMG window followed by 2s simultaneous stimulation of both antagonists.

[0087] The first four patients enrolled for the study received SATS intermingled with CON stimulation, in randomized order, for both sessions. Two other patients underwent SATS while the other three underwent CON stimulation trials alone in each session, seeking to discriminate the effects of each stimulation condition. At the end of each 30 session, the effect of stimulation on kinematics was assessed through IMUs (post-ASSESS), with patients holding their upper limbs as in pre-ASSESS. A final assessment (post 24-ASSESS) was also performed 24 h after each session to assess possible prolonged effects on tremor.

Data Analysis

[0088] Raw data from IMUs (quaternions) were converted into Euler angles and filtered in the tremor band [3-12 Hz], which allowed calculation of angle displacement for wrist, elbow and shoulder. Power Spectral Density (PSD) method (2s Hamming window and 50% segment overlap) was applied to quantify tremor amplitude in the assessments and stimulation trials. For the wrists, PSD for flexion-extension was assessed, whereas averaged PSD for the 2 and 3 degrees of freedom was computed for elbows and shoulders, respectively. PSD values were used to compute different tremor scores, depending on the pairs of conditions compared, according to the following equation:

[00001]$\begin{array}{cc}\mathrm{Tremor}\mathrm{score}=0.5+0.5\times \frac{\mathrm{condition}A-\mathrm{condition}B}{\max \left(\mathrm{condition}A;\mathrm{condition}B\right)}& \left(\mathrm{Equation}1\right)\end{array}$

where condition A and B represent PSD of two conditions being compared. According to Equation I, a score equal to 1 would correspond to 100% tremor reduction, a score equal to 0.5 would correspond to no tremor change, and a score equal to 0 would correspond to 100% tremor aggravation. Equation I was applied to compare different conditions, such as the different assessments, ON/OFF periods, among others, through kinematics.

Statistical Analysis

[0089] One-sample t-tests were computed to compare the effects of each type of stimulation on acute tremor reduction. Independent samples t-tests where applied to compare differences on acute tremor reduction scores between stimulation conditions (SATS IM vs SATS SF, SATS IM vs CON IM, SATS SF vs CON SF) for each joint. Statistical significance was set with p-value <0.05.

Example 1—Acute Effects

[0090] Wrist flexion/extension angles during pre-ASSESS, during SATS (the method of the invention) stimulation trial and during post-ASSESS and pos 24-ASSESS of a representative patient are depicted in FIG. 2. Acute tremor reduction for this specific subject can be observed in FIG. 2 (see block 2 compared to block 1). Regarding all patients assessed in this study, acute tremor reduction scores (representing the ratio between tremor on the 30-second windows OFF and tremor on the 30-second windows ON across trials) for all joints are presented in FIG. 3. SATS IntraStim was the only condition achieving significant acute tremor reduction (0.63±0.03; p<0.01; equivalent to 26% tremor reduction) at the stimulated wrist, which was significantly higher compared to the other 3 conditions (SATS SurfStim, CON IntraStim and CON SurfStim; p<0.05 for the three comparisons). Another interesting observation was that tremor reduction score was significantly higher (p<0.01) for SATS SurfStim (0.53±0.08) than CON SurfStim strategy (0.35±0.07). In fact, CON strategy not only did not acutely reduce tremor amplitude at the stimulated wrist or any other joint, but it also aggravated wrist tremor during surface stimulation (p<0.05 for CON SurfStim session).

[0091] SATS IntraStim also achieved, on average, acute tremor reduction on the ipsilateral (stimulated) elbow (0.60±0.10) and shoulder (0.58±0.08) (FIG. 3-2,3), although these values were not significantly higher than 0.5 (p-value=0.06). On the other hand, there was no significant acute tremor reduction for any of the contralateral (non-stimulated side) joints (FIGS. 3-4,5,6).

[0092] FIG. 4 represents the ratio between tremor during OFF period of each trial and tremor during stimulation (2-second time windows when stimulation bursts were delivered during the 30-second ON period) of each trial. Also for this specific analysis, the highest acute tremor reduction was registered for the stimulated wrist with SATS IntraStim combination (0.66±0.09; p<0.05). None of the CON combinations achieved acute tremor reduction (FIG. 4).

Example 2-24 Hours Effect

[0093] Four patients (P01-P04) underwent random trials of SATS and CON stimulation for both stimulation sessions (IntraStim and SurfStim) and post-ASSESS showed an effect on the stimulated wrist at the end of the session (FIG. 5 and FIG. 2). Despite the reduced sample size (n=4) and variability of tremor, mean tremor reduction in the stimulated wrist was higher after IntraStim sessions (0.82±0.2) compared to after SurfStim sessions (0.57±0.39). Tremor score was on average higher than 0.5 at the end of both sessions (post-ASSESS) and all assessed joints (FIG. 5).

[0094] Tremor reduction was still observed 24 h after experimentation in 3 out of these 4 patients, with an average post 24-ASSESS ipsilateral wrist tremor reduction score of 0.85±0.22 for IntraStim session and 0.63±0.45 for Surf Stimulation (FIG. 6 and representative example in FIG. 2).

[0095] In the other five patients, we applied just one simulation strategy (IntraStim orSurfStim) to discriminate the effect of each stimulation strategy on prolonged effects. There was tremor reduction at the stimulated wrist of the two patients that only received SATS during IntraStim session (average tremor score 0.76±0.07%—FIG. 7), while the three patients receiving CON during IntraStim session showed tremor aggravation (average 0.35±0.2—FIG. 7).

[0096] Regarding the 24h effect, except for one of the 2 patients that received SATS SurfStim, all other patients aggravated tremor 24 h after sessions. However, in general CON strategy alone aggravated tremor compared to SATS strategy 24 h after sessions (FIG. 8). Spiral drawings also demonstrated improvements right after and 24 h after SATS IntraStim (FIG. 9).

[0097] Additional results from the study with ET patients showed an acute and a short-term tremor reduction which could imply plastic changes at the nervous system. Thus, the application of the control method for the reduction of pathological tremors was tested in healthy volunteers in order to explore the potential neuromodulatory effects at the spinal level.

Participants

[0098] Three healthy subjects were recruited for this study. The participants gave their informed consent to participate in the experiments. Procedures were approved by a local ethical committee and were conducted in accordance with the Declaration of Helsinki. The participants were comfortably seated on an arm chair, with their dominant arm relaxed and supinated on a table.

Materials

[0099] Bipolar surface EMG electrodes were placed over the muscle belly of the Flexor Carpi Radialis (FCR) and Extensor Carpi Radialis (ECR). EMG signals were acquired at 2,000 Hz using a customized embedded unit including a biosignal amplifier and a stimulation stage (EAST, OT Bioelettronica, Italy).

[0100] Surface round stimulation electrodes were placed over the median nerve in the cubital fossa, and the radial nerve in the spiral groove.

[0101] A bipolar current stimulator (Digitimer DS8R, Hertfordshire, UK) was used to deliver single electrical pulses (1 ms, squared pulses).

Procedures

[0102] The intervention consisted of the application of 20 minutes of SATS stimulation while the subject was mimicking wrist flexion/extension tremor at 4-6 Hz with the arm resting on the table. Two strategies were randomly tested in two different experimental sessions on separate days: in-phase and out-of-phase. In-phase SATS stimulation consists of the synchronized stimulation of the nerve innervating the agonist muscle activated in the tremorgenic burst; while out-of-phase SATS stimulation implies the stimulation of the nerve innervating the antagonist muscle to the tremorgenic activity. Biphasic electrical squared pulses 100 Hz frequency and 400 us pulse width were applied with an intensity below motor threshold.

[0103] Assessment of the spinal excitability was measured prior the stimulation intervention (PRE), immediately after the intervention (POST) and 30 minutes after the intervention (POST30′). Disynaptic reciprocal inhibition (RI) was measured by conditioning the FCR H-Reflex through synchronized radial nerve stimulation. The H-reflex response was evoked by applying single stimuli to the median nerve. The electrical stimuli were delivered at different inter stimulus intervals (ISIs) in order to find the optimal synchronization between median and radial nerves stimulation. RI was evoked by stimulating the radial nerve at −1,0 and +1 ms with respect to the median nerve. In each assessment, 10 H-Reflex tests of each condition were applied in a random order.

Data Analysis

[0104] The peak to peak amplitude of the conditioned H-Reflex was measured and averaged per each stimulation condition and relativized to the unconditioned basal H-Reflex.

Results

[0105] The in-phase SATS stimulation increased RI in the POST assessment compared to out-of-phase SATS stimulation, which elicited the opposite effect (decreased RI). At the POST30′ assessment reciprocal inhibition values (FIG. 10) were similar to the PRE assessment for both conditions. If we extrapolate these results to those obtained in ET patients, it is possible that the spinal excitability was subliminally decreased during out-of-phase SATS, which may explain, at least in part, the observed acute and a short-term tremor reduction.