Brief Submotor-Threshold Electrical Stimulation Applied Synchronously Over Wrist Flexor and Extensor Muscles does Not Suppress Essential Tremor, Independent of Stimulation Frequency

Christian Metzner; Adam Stringham; Brenna Hislop; Joseph Bonham; Larrisa Chatterton; Ryan DeFigueiredo; Steven K. Charles

doi:10.5334/tohm.740

Figures & Tables

Table 1

Stimulation parameters used in previous studies. FCR, FCU, ECR represent flexor carpi radialis, flexor carpi ulnaris, and extensor carpi radialis muscles, respectively. ET stands for Essential Tremor, and NA stands for “not available”. Negative tremor change indicates tremor reduction during/following the stimulation.

FIRST AUTHOR	YEAR	STIMULATION PARAMETERS						NUMBER OF PATIENTS	TREMOR CHANGE
FIRST AUTHOR	YEAR	MAGNITUDE	AGONIST-ANTAG. TIMING	FREQ (HZ)	PULSE WIDTH (µS)	DURATION (MIN)	SITE	NUMBER OF PATIENTS	TREMOR CHANGE
Javidan [10]	1992	Above motor threshold	Asynch.	30	100	NA	NA	24 (3 ET)	–73%
Maneski [11]	2011	Above motor threshold	Asynch.	40	250	Intervals of 0.05	Wrist extensors and flexors	7 (3 ET)	–67 ± 13%
Grimaldi [32]	2011	Above motor threshold	Synch.	30	100	0.33	Biceps, Triceps, FCR, ECR	3 (1 ET)	–50%
Widjaja [33]	2011	Above motor threshold	Asynch.	25	200	0.167 × 2	FCU and ECR	1 (1 ET)	–57%
Gallego [13]	2013	Above motor threshold	Synch.	30/40	250/300	0.25	FCU and ECR	6 (4 ET)	–52 ± 25%
Bo [12]	2014	Above motor threshold	Synch.	40	150	Intervals of 0.167–0.833	Wrist, fingers or thumb/index	10 (10 ET)	–60 ± 27%
Dosen [9]	2015	Above motor threshold	Asynch.	100	300	2	Wrist flexor and extensor muscles	6 (2 ET)	–60 ± 14%
Dosen [9]	2015	Below motor threshold	Asynch.	100	300	2	Wrist and finger flexor and extensor muscles	6 (2 ET)	–42 ± 5%
Heo [18]	2015	Below motor threshold	Synch.	100	300	NA	Elbow and wrist muscles	18 (all ET)	–90% (max. tremor reduction)
Heo [19]	2016	Below motor threshold	Synch.	100	300	NA	Elbow and wrist muscles	18 (all ET)	–12–24%
Dideriksen [14]	2017	Below motor threshold	Asynch.	100	400	0.5 × 2	Intramuscular	4 (2 ET)	–54 ± 20%
Dideriksen [14]	2017	Below motor threshold	Asynch.	100	400	0.5 × 2	Surface	5 (2 ET)	–50 ± 41%
Lin [16]	2018	Below motor threshold	Asynch.*	150	650	40	Median and Radial Nerves	10 (all ET)	–60 ± 8.4%
Pahwa [15]	2019	Below motor threshold	Asynch.*	150	650	40	Median and Radial Nerves	40 (all ET)	–59 ± 13%
Isaacson [17]	2020	Below motor threshold	Asynch.*	150	650	40	Median and Radial Nerves	205 (all ET)	–72%
Pascual-Valdunciel [20]	2021	Below motor threshold	Synch.	100	400	0.5	Surface	6 (all ET)	+30 ± 14%
			Synch.	100	200	0.5	Intramuscular	7 (all ET)	+40 ± 40%
			Asynch.	100	400	0.5	Surface	8 (all ET)	–6 ± 16%
			Asynch.	100	200	0.5	Intramuscular	6 (all ET)	–26 ± 6%

[i] * Unlike the other studies that used asynchronous stimulation, in these studies, stimulation was administered over median and radial nerves at the wrist joint (not antagonist muscles), and the timing of the stimulation was not synchronized with the patient’s tremorogenic activity or tremor.

Table 2

Patient information. Patients are ordered from lowest to greatest TETRAS score.

PT #	SEX	AGE	AGE OF ONSET	TREMOR DURATION (YEARS)	WRIST TESTED	HT (CM)	WT (KG)	FAMILYHISTORY	TREMOR SEVERITY (TETRAS)*	ON MEDICATION
6	F	58	39	19	L	165	88	Yes	0.3	No
15	F	27	12	15	L	160	84	Yes	1.2	Yes
5	F	59	15	44	R	152	64	No	1.5	Yes
9	M	66	56	10	R	191	134	Yes	1.5	Yes
19	F	55	23	32	R	155	109	Yes	1.7	No
12	M	19	16	3	R	180	66	No	1.9	Yes
7	M	30	10	20	R	191	82	No	2.3	No
11	M	74	54	20	R	180	70	No	2.3	Yes
14	F	41	14	27	R	175	64	Yes	2.3	No
4	F	71	10	61	R	160	75	Yes	2.5	Yes
10	M	82	62	20	R	165	62	Yes	2.5	No
16	F	57	22	35	L	163	72	Yes	2.5	Yes
17	M	74	15	59	R	168	75	No	2.5	No
20	F	57	30	27	R	168	73	Yes	2.5	No
1	M	64	48	16	L	196	125	No	2.7	Yes
2	F	80	65	15	L	157	61	No	2.7	Yes
18	F	68	54	14	L	168	79	No	2.7	Yes
8	F	67	58	9	R	165	94	Yes	2.8	Yes
13	M	70	10	60	L	178	104	Yes	2.9	No
3	F	55	20	35	R	160	65	Yes	3.4	Yes

[i] * Average of scores related to upper-limb tremor; scores of 2, 3, and 4 are associated with mild, moderate, and severe tremor, respectively.

Experimental setup. Subjects rested their forearm on supports proximally and distally, allowing the hand to move freely. Subjects were instrumented with an inertial measurement unit and a laser pointer on the hand (under the blue/red wrap), TENS electrodes straddling the extensor carpi radialis longus and brevis (visible in lower photo) and flexor carpi radialis (not visible), and sEMG sensors over the extensor carpi radialis and ulnaris (visible in both photos) and over the flexor carpi radialis and ulnaris (not visible). Subjects were asked to point at the target in front of the subject (visible in top photo).

Average motor (red) and sensory (blue) thresholds of extensor carpi radialis (solid) and flexor carpi radialis (dashed). Bars indicate ± 1 standard error.

Table 3

Effect of stimulation on motor and sensory thresholds.

SOURCE	THRESHOLDS
SOURCE	DF	DFDEN	F RATIO	PROB > F
Flexor vs. Extensor	1	272.1	32.867	<.0001*
Sensory vs. Motor Threshold	1	264.6	1051.2	<.0001*
Stimulation Frequency	3	268.2	11.230	<.0001*

Data processing for a representative subject (subject 12 with 60 Hz stimulation) with no change in tremor after stimulation. A. Raw acceleration in each axis and the detrended magnitude of the acceleration vector (left) and the linear envelope of sEMG (right). The BASE phase (30s) was followed by the STIM phase (45s) and then the REST phase (60s). The STIM phase in the right subfigure is greyed out because the sEMG data was dominated by the stimulation. B. Spectrogram of acceleration (left) and processed sEMG (right). C. Power spectral density for acceleration (left) and for processed sEMG (right) for each phase.

Hand acceleration power (left column) and sEMG power (right column) over time for three representative subjects and trials: Subject 12 with 60 Hz stimulation **(A)**, subject 10 with 120 Hz stimulation **(B)**, and Subject 11 with 60 Hz stimulation **(C)**.

Least-squares means plots by phase (BASE, STIM, REST) for hand acceleration and sEMG data. A. Log-transformed power in acceleration (left) and sEMG (right). B. Peak frequency of acceleration (left) and sEMG (right). Bars indicate ±1 standard error.

Table 4

Stimulation effect on acceleration-derived tremor power and frequency in BASE, STIM, and REST.

SOURCE	ACCELERATION-DERIVED LOG(TREMOR POWER)				ACCELERATION-DERIVED TREMOR FREQUENCY
SOURCE	DF	DFDEN	F RATIO	PROB > F	DF	DFDEN	F RATIO	PROB > F
Stimulation Frequency	14	264	1.8853	0.0281*	14	264.8	0.4851	0.9401
Phase	2	30.29	1.2877	0.2906	2	30.76	0.1354	0.8738
Stimulation Frequency*Phase	28	416.4	0.8492	0.6900	28	414.4	0.8840	0.6394
Sex	1	14.99	4.9650	0.0416*	1	15.01	0.3178	0.5813
Age	1	15	2.6693	0.1231	1	15.02	6.0244	0.0268*
TETRAS Score	1	14.97	14.4631	0.0017*	1	15	5.1202	0.0389*
Medication	1	14.98	1.1456	0.3014	1	15.01	0.0162	0.9004
Sex*Phase	2	30.35	0.0019	0.9981	2	31.12	0.8142	0.4522
Age*Phase	2	30.73	0.2289	0.7968	2	31.38	0.0677	0.9347
TETRAS Score*Phase	2	30.02	0.6660	0.5212	2	31.06	1.5925	0.2196
Medication*Phase	2	30.25	0.1404	0.8696	2	31.04	0.2903	0.7501
SexStimulation FrequencyPhase	28	416.5	1.0604	0.3842	28	414.8	1.1118	0.3195
AgeStimulation FrequencyPhase	28	416.7	0.4141	0.9969	28	413.7	0.5557	0.9694
TETRAS ScoreStimulation FrequencyPhase	28	416.2	0.5848	0.9568	28	415.9	1.0143	0.4475
MedicationStimulation FrequencyPhase	28	416.4	1.0978	0.3364	28	415.2	1.0083	0.4560

Table 5

Stimulation effect on sEMG-derived tremor power and frequency in BASE and REST.

SOURCE	sEMG-DERIVED LOG(TREMOR POWER)				sEMG-DERIVED TREMOR FREQUENCY
SOURCE	DF	DFDEN	F RATIO	PROB > F	DF	DFDEN	F RATIO	PROB > F
Stimulation Frequency	14	264	1.8081	0.0375*	14	265.1	0.3293	0.9899
Phase	1	15.08	31.9547	<.0001*	1	14.72	0.0290	0.8671
Muscle	3	56.99	27.4877	<.0001*	3	56.64	1.0141	0.3933
Stimulation Frequency*Phase	14	1893	1.6053	0.0705	14	1833	1.0849	0.3663
Stimulation Frequency*Muscle	42	1891	0.8859	0.6800	42	1831	0.8000	0.8171
Phase*Muscle	3	1891	56.9466	<.0001*	3	1834	2.1451	0.0926
Sex	1	15	1.0686	0.3176	1	15.01	1.9409	0.1839
Age	1	15.01	0.8733	0.3648	1	15.03	0.5542	0.4681
TETRAS Score	1	15	1.4125	0.2531	1	15.01	12.3494	0.0031*
Medication	1	15	0.0430	0.8385	1	15.01	0.0059	0.9398
Sex*Phase	1	15.12	5.5390	0.0325*	1	14.75	0.0006	0.9813
Age*Phase	1	15.41	2.8455	0.1118	1	15.02	0.6729	0.4249
TETRAS Score*Phase	1	14.87	0.0109	0.9181	1	14.76	0.0455	0.8340
Medication*Phase	1	15.05	1.9325	0.1847	1	14.77	0.2070	0.6557
SexStimulation FrequencyPhase	14	1893	2.2029	0.0061*	14	1834	1.2260	0.2488
AgeStimulation FrequencyPhase	14	1894	0.6494	0.8247	14	1836	1.2298	0.2460
TETRAS ScoreStimulation FrequencyPhase	14	1891	1.0095	0.4404	14	1839	1.4619	0.1175
MedicationStimulation FrequencyPhase	14	1893	1.7275	0.0445*	14	1836	1.3433	0.1738

Least-squares means plots by phase (BASE, STIM, REST) for hand acceleration-derived tremor power, compared across control variable values, including sex **(A)**, medication state **(B)**, TETRAS score **(C)**, and age **(D)**. C. Note the difference in the scales of the vertical axes; TETRAS scores of 2, 3, and 4 are associated with mild, moderate, and severe tremor, respectively. Bars indicate ±1 standard error.

Table 6

Mechanistic hypotheses explaining how submotor peripheral stimulation could suppress tremor along with the required timing strategy and expected tremor effects.

HYPOTHESIS	MECHANISM OF TREMOR SUPPRESSION	STIMULATION TIMING REQUIRED FOR TREMOR SUPPRESSION	EXPECTED STIMULATION EFFECTS ON TREMOR
Supraspinal	Submotor stimulation disrupts central tremorgenic oscillators via afferent signal modulation	Irrelevant (synchronous or asynchronous)	Long-duration tremor suppression
Supraspinal		Irrelevant (synchronous or asynchronous)	Possible tremor frequency changes
Spinal Circuit	Submotor stimulation partially cancels tremor signals via well-timed activation of reciprocal inhibition reflex	Only asynchronous	Instantaneous tremor suppression
Spinal Circuit		Only asynchronous	No tremor frequency changes

Brief Submotor-Threshold Electrical Stimulation Applied Synchronously Over Wrist Flexor and Extensor Muscles does Not Suppress Essential Tremor, Independent of Stimulation Frequency

Figures & Tables

Table 1

Table 2

Figure 1

Figure 2

Table 3

Figure 3

Figure 4

Figure 5

Table 4

Table 5

Figure 6

Table 6

Paradigm

My account

PT #	SEX	AGE	AGE OF ONSET	TREMOR DURATION (YEARS)	WRIST TESTED	HT (CM)	WT (KG)	FAMILYHISTORY	TREMOR SEVERITY (TETRAS)*	ON MEDICATION
6	F	58	39	19	L	165	88	Yes	0.3	No
15	F	27	12	15	L	160	84	Yes	1.2	Yes
5	F	59	15	44	R	152	64	No	1.5	Yes
9	M	66	56	10	R	191	134	Yes	1.5	Yes
19	F	55	23	32	R	155	109	Yes	1.7	No
12	M	19	16	3	R	180	66	No	1.9	Yes
7	M	30	10	20	R	191	82	No	2.3	No
11	M	74	54	20	R	180	70	No	2.3	Yes
14	F	41	14	27	R	175	64	Yes	2.3	No
4	F	71	10	61	R	160	75	Yes	2.5	Yes
10	M	82	62	20	R	165	62	Yes	2.5	No
16	F	57	22	35	L	163	72	Yes	2.5	Yes
17	M	74	15	59	R	168	75	No	2.5	No
20	F	57	30	27	R	168	73	Yes	2.5	No
1	M	64	48	16	L	196	125	No	2.7	Yes
2	F	80	65	15	L	157	61	No	2.7	Yes
18	F	68	54	14	L	168	79	No	2.7	Yes
8	F	67	58	9	R	165	94	Yes	2.8	Yes
13	M	70	10	60	L	178	104	Yes	2.9	No
3	F	55	20	35	R	160	65	Yes	3.4	Yes

PT #	SEX	AGE	AGE OF ONSET	TREMOR DURATION (YEARS)	WRIST TESTED	HT (CM)	WT (KG)	FAMILYHISTORY	TREMOR SEVERITY (TETRAS)*	ON MEDICATION
6	F	58	39	19	L	165	88	Yes	0.3	No
15	F	27	12	15	L	160	84	Yes	1.2	Yes
5	F	59	15	44	R	152	64	No	1.5	Yes
9	M	66	56	10	R	191	134	Yes	1.5	Yes
19	F	55	23	32	R	155	109	Yes	1.7	No
12	M	19	16	3	R	180	66	No	1.9	Yes
7	M	30	10	20	R	191	82	No	2.3	No
11	M	74	54	20	R	180	70	No	2.3	Yes
14	F	41	14	27	R	175	64	Yes	2.3	No
4	F	71	10	61	R	160	75	Yes	2.5	Yes
10	M	82	62	20	R	165	62	Yes	2.5	No
16	F	57	22	35	L	163	72	Yes	2.5	Yes
17	M	74	15	59	R	168	75	No	2.5	No
20	F	57	30	27	R	168	73	Yes	2.5	No
1	M	64	48	16	L	196	125	No	2.7	Yes
2	F	80	65	15	L	157	61	No	2.7	Yes
18	F	68	54	14	L	168	79	No	2.7	Yes
8	F	67	58	9	R	165	94	Yes	2.8	Yes
13	M	70	10	60	L	178	104	Yes	2.9	No
3	F	55	20	35	R	160	65	Yes	3.4	Yes

PT #	SEX	AGE	AGE OF ONSET	TREMOR DURATION (YEARS)	WRIST TESTED	HT (CM)	WT (KG)	FAMILYHISTORY	TREMOR SEVERITY (TETRAS)*	ON MEDICATION
6	F	58	39	19	L	165	88	Yes	0.3	No
15	F	27	12	15	L	160	84	Yes	1.2	Yes
5	F	59	15	44	R	152	64	No	1.5	Yes
9	M	66	56	10	R	191	134	Yes	1.5	Yes
19	F	55	23	32	R	155	109	Yes	1.7	No
12	M	19	16	3	R	180	66	No	1.9	Yes
7	M	30	10	20	R	191	82	No	2.3	No
11	M	74	54	20	R	180	70	No	2.3	Yes
14	F	41	14	27	R	175	64	Yes	2.3	No
4	F	71	10	61	R	160	75	Yes	2.5	Yes
10	M	82	62	20	R	165	62	Yes	2.5	No
16	F	57	22	35	L	163	72	Yes	2.5	Yes
17	M	74	15	59	R	168	75	No	2.5	No
20	F	57	30	27	R	168	73	Yes	2.5	No
1	M	64	48	16	L	196	125	No	2.7	Yes
2	F	80	65	15	L	157	61	No	2.7	Yes
18	F	68	54	14	L	168	79	No	2.7	Yes
8	F	67	58	9	R	165	94	Yes	2.8	Yes
13	M	70	10	60	L	178	104	Yes	2.9	No
3	F	55	20	35	R	160	65	Yes	3.4	Yes