Inter-day and intra-day variations in effective intensity of noisy galvanic vestibular stimulation to improve postural stability in bilateral vestibulopathy

Abstract

BACKGROUND:

The reproducibility of the effective intensity of noisy galvanic vestibular stimulation (nGVS) to improve postural stability is not well known.

OBJECTIVE:

We aimed to investigate inter-day and intra-day variations in effective intensity in patients with bilateral vestibulopathy (BVP).

METHODS:

Thirteen BVP patients were measured for center-of-pressure movements in the standing posture at five time points: morning of the first test day, morning and evening of the second test day, and morning and evening of the third test day. The mean velocity, the envelopment area, and the root mean square were measured in the eyes-closed condition for 30 s during nGVS application ranging from 0 to 1000μA. The effective intensity was defined as the intensity at which all the three parameters measured during the stimulation were simultaneously smaller than the values at baseline (0μA).

RESULTS:

Seven of the 13 patients had a common effective intensity throughout the three test days. Six patients on the second test day and five patients on the third test day had no common effective intensity between morning and evening.

CONCLUSIONS:

The effective intensity of nGVS changes depending on the time during the day as well as between the days.

Keywords

Bilateral vestibulopathy electric stimulation posture

1 Introduction

Noisy galvanic vestibular stimulation (nGVS) delivers zero-mean electrical current noise transcutaneously to the vestibular system through electrodes placed over the bilateral mastoid regions. An optimal level of nGVS has been reported to facilitate the processing of subthreshold stimuli in the neural system as well as in the autonomic, motor and postural control systems [5 , 20]. Stochastic resonance, in which the presence of optimal levels of noise enhances subthreshold signals in nonlinear systems, has been proposed as the mechanism behind these ameliorating effects [14, 17]. Regarding the postural control system, the improvement in standing postural stability and gait performance during the application of an optimal imperceptible level of nGVS has been reported in both healthy subjects and patients with bilateral vestibulopathy (BVP) [8–11 , 19].

Recently, we have reported the long-term effects of nGVS on body balance in healthy subjects and BVP patients toward future clinical application [2 , 5]. In these studies, the current intensity used to evaluate the long-term effect of nGVS was determined for each subject by applying various current intensities for short periods of time (30 s) and searching for the optimal intensity that was most effective in improving the typical parameter values related to center of pressure (COP) movement [2 , 5].

When considering clinical applications of nGVS in the future, it is important to obtain information on the reproducibility of effective intensity. In the present study, we investigated inter-day and intra-day variations in effective intensity of nGVS in patients with BVP patients.

2 Methods

2.1 Standard protocol approvals, registrations, and subject consents

This study was conducted in accordance with the Declaration of Helsinki. This clinical trial was approved by the Institutional Review Board of the University of Tokyo Hospital (P2016-011) and was registered with the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN-CTR: UMIN000028054). Written informed consent was obtained from all subjects.

2.2 Subjects

Thirteen BVP patients (8 males, 5 females, age range 43–83 years, mean age 63.1 [±4.0] years) were enrolled from the Balance Disorder Clinic, Department of Otolaryngology and Head and Neck Surgery, the University of Tokyo Hospital. The etiologies of BVP in the 13 patients were unknown (n = 10), mitochondrial A3243G mutation (n = 2), and bilateral vestibular neuritis (n = 1). All patients showed bilateral catch-up saccades in the horizontal plane in a bed-side head impulse test and bilateral reduced or absent responses in an ice water caloric test (maximum slow phase velocity of nystagmus <10°/s in each ear) [4]. The maximum slow phase velocity of the caloric test for each subject was summarized in Table 1.

Table 1
Maximum slow phase velocity of the subject’s nystagmus in the ice water caloric test

Subject Right (°/s) Left (°/s)

1 0 0

2 0 0

3 0 7

4 0 0

5 9 5

6 0 0

7 7 0

8 5 5

9 8 0

10 0 0

11 0 0

12 3 9

13 8 0

Subject	Right (°/s)	Left (°/s)
1	0	0
2	0	0
3	0	7
4	0	0
5	9	5
6	0	0
7	7	0
8	5	5
9	8	0
10	0	0
11	0	0
12	3	9
13	8	0

2.3 Posturography

Changes in the COP position were measured with a Gravicorder GP-5000 (Anima Inc., Tokyo, Japan) at a sampling frequency of 20 Hz. Subjects performed bipedal standing tasks with or without nGVS with closed eyes. The mean velocity of COP movement (velocity), the area enclosed by the COP movement (area), and the root mean square (RMS) of the COP displacement were measured in the XY plane [5, 11].

2.4 nGVS

A portable stimulator (112×67×28 mm, 200 g, including batteries) was used to deliver nGVS from electrodes on the bilateral mastoid region [5, 11]. Waveforms were digitally stored and converted from digital to analog at 20 Hz. Zero-mean white noise nGVS in 0.02 to 10 Hz range was used. The white noise waveform had a duration of 204.8 s and was repeated continuously throughout the tests. Vitrode F (Nihon Kohden Co. Ltd., Tokyo, Japan) was used as the electrode. The raw materials of the electrode element are Ag/AgCl, and the raw materials of the adhesive gel are acrylic hydrophilic polymer, glycerin, and water. The surface area of this electrode is 19×36 mm.

2.5 Methods

Subjects were studied for effective intensity of nGVS five different times: 1) on the morning of the first test day, 2) morning and 3) evening of the second test day, and 4) morning and 5) evening of the third test day (Fig. 1A). The interval between each test day was 14 days. To determine the effective intensity, the value of each COP parameter (velocity, area and RMS) without nGVS (0μA) was first measured for 30 s, which were used as the baseline value (Fig. 1B). Next, the value of each COP parameter was measured for 30 s during the application of nGVS with peak amplitudes set at 100, 200, 300, 500, 700, and 1000μA (Fig. 1B). The effective intensity was defined as the intensity at which the measured values during stimulation were simultaneously smaller than the values at baseline for all three parameters above. If a subject felt stimulation at a certain current intensity, that intensity was not adopted as the effective intensity. Tests using current intensities that exceeded the intensity at which the subject felt stimulation (cutaneous sensory threshold) were stopped at the discretion of the experimenters.

Fig. 1

Schedule for measuring the effective intensity of nGVS and the procedure for each test day. (A) Schedule for measuring the effective intensity of nGVS. The circle indicates the measurement time point to evaluate the inter-day variation. The triangle indicates the measurement time point to evaluate the intra-day variation on the second test day. The square indicates the measurement time point to evaluate the intra-day variation on the third test day. (B) Procedure for each test day. RMS = root mean square.

After the effective intensity investigations on the morning of the second and third test day, each subject participated in a study evaluating the long-term effects of nGVS and received nGVS for 30 min [2]. Although we have previously reported on clinical trials evaluating these long-term effects, the purpose of the present study is quite different from previous reports [2 , 5].

2.6 Statistical analyses

We calculated the intraclass correlation coefficient (ICC) for the inter-day and intra-day variation for patients with the effective intensity of nGVS to assess the degree of repeatability. In this study, the optimal intensity used for ICC (two-way, agreement) was defined as the minimum value among the common effective intensity values, if any, or the median value if there was no common effective intensity value. R version 4.2.2 and package irr version 0.84.1 were used for statistical analyses.

3 Results

To examine the inter-day variation in effective intensity of nGVS to improve postural stability in BVP, we compared the effective intensity in 13 patients measured on the morning of the first, second, and third test days (Table 2 and S1). Eleven of the 13 patients (85%) had effective intensity on the first test day whereas all patients (100%) had the effective intensity on the second and third test days. Common effective intensity through the three test days existed in seven patients (54%). In the remaining six patients, five patients (38%) had common effective intensity on two of the three testing days and the remaining one patient (8%) did not have any common effective intensity. These results suggested that the effective intensity of nGVS varied from day to day in nearly a half of BVP patients.

Table 2
Optimal intensity in the morning of each test day

Subject First test day (μA) Second test day (μA) Third test day (μA)

1 No optimal intensity 100, 200, 300, 500, 700 200, 300, 700

2 100, 200, 300, 500, 700 100, 200, 500, 700, 1000 200, 500

3 100, 200, 300, 500, 700, 1000 200, 300, 500, 700, 1000 100, 200, 300, 500, 700, 1000

4 100, 300, 700 100, 200, 300, 500, 700, 1000 300, 700

5 700 700, 1000 100, 500

6 100, 200, 300, 500, 700, 1000 100, 300 200, 300

7 100, 200, 500 200 300

8 100 300 100, 300, 500

9 No optimal intensity 200, 300 700

10 100, 200, 300, 500, 700 300, 500 100, 500, 700

11 100, 200, 300, 700, 1000 200, 300, 500, 700, 1000 100, 200, 300, 500

12 100, 200, 300, 500, 700, 1000 200, 300, 500, 700 100, 200, 300, 500, 700, 1000

13 100, 200, 700, 1000 100, 200, 300, 500, 700, 1000 500

Subject	First test day (μA)	Second test day (μA)	Third test day (μA)
1	No optimal intensity	100, 200, 300, 500, 700	200, 300, 700
2	100, 200, 300, 500, 700	100, 200, 500, 700, 1000	200, 500
3	100, 200, 300, 500, 700, 1000	200, 300, 500, 700, 1000	100, 200, 300, 500, 700, 1000
4	100, 300, 700	100, 200, 300, 500, 700, 1000	300, 700
5	700	700, 1000	100, 500
6	100, 200, 300, 500, 700, 1000	100, 300	200, 300
7	100, 200, 500	200	300
8	100	300	100, 300, 500
9	No optimal intensity	200, 300	700
10	100, 200, 300, 500, 700	300, 500	100, 500, 700
11	100, 200, 300, 700, 1000	200, 300, 500, 700, 1000	100, 200, 300, 500
12	100, 200, 300, 500, 700, 1000	200, 300, 500, 700	100, 200, 300, 500, 700, 1000
13	100, 200, 700, 1000	100, 200, 300, 500, 700, 1000	500

The underlined current values are the optimal intensity matched on all 3 test days.

Next, to examine the intra-day variation in effective intensity of nGVS, we compared the effective intensity of nGVS measured on the morning and evening on the second and third test days. On the second test day, while all the patients (100%) had the effective intensity in the morning, 5 patients (38%) did not have the effective intensity in the evening (Table 3). Six patients (46%) did not have a common effective intensity between the morning and evening (Table 3). On the third test day, while all the patients (100%) had the effective intensity in the morning, 2 patients (15%) did not have the effective intensity in the evening (Table 4). Five patients (38%) did not have a common effective intensity between the morning and evening (Table 4). These results suggest that there is intra-day variation in the effective intensity of nGVS in a part of BVP patients.

Table 3

Optimal intensity in the morning and evening of the second test day

Subject	Moring (μA)	Evening (μA)
1	100, 200, 300, 500, 700	No optimal intensity
2	100, 200, 500, 700, 1000	100, 200, 300, 500, 700
3	200, 300, 500, 700, 1000	300, 500, 700, 1000
4	100, 200, 300, 500, 700, 1000	200, 700, 1000
5	700, 1000	200, 300, 500, 700
6	100, 300	No optimal intensity
7	200	100, 200, 300, 500, 700
8	300	No optimal intensity
9	200, 300	No optimal intensity
10	300, 500	No optimal intensity
11	200, 300, 500, 700, 1000	100
12	200, 300, 500, 700	300, 700
13	100, 200, 300, 500, 700, 1000	100, 300, 500, 700

The underlined current values are the optimal intensity matched in the morning and evening measurements.

Table 4

Optimal intensity in the morning and evening of the third test day

Subject	Moring (μA)	Evening (μA)
1	200, 300, 700	100, 200, 300, 500, 700
2	200, 500	100
3	100, 200, 300, 500, 700, 1000	100, 200, 300, 500, 700, 1000
4	300, 700	300
5	100, 500	300
6	200, 300	No optimal intensity
7	300	300
8	100, 300, 500	500, 700, 1000
9	700	200, 500, 700, 1000
10	100, 500, 700	200, 300, 500
11	100, 200, 300, 500	100, 200, 500, 700, 1000
12	100, 200, 300, 500, 700, 1000	No optimal intensity
13	500	200

The underlined current values are the optimal intensity matched in the morning and evening measurements.

Then, we calculated the ICC of the optimal intensity for the inter-day and intra-day variation for patients with the effective intensity of nGVS (11 for the inter-day variation, 8 for the second test day of the intra-day variation, and 11 for the third test day of the intra-day variation). The ICC for the inter-day variation was 0.662. The ICC for the intra-day variation was 0.759 for the second test day and 0.882 for the third test day, respectively.

The cutaneous sensory threshold of each subject was shown in Table 5. Of the 9 trials that showed no effective intensity, the only trial that could not be performed because the cutaneous sensory threshold was reached was the 1000μA trial on the evening of the second test day of Subject 2 (Table S1). The remaining 8 trials could be performed up to 1000μA, but there were no effective intensities.

Table 5

Intensity at which the subject felt stimulation at 1000μA or less

Subject	First test day	Second test day		Third test day
	Morning (μA)	Morning (μA)	Evening (μA)	Morning (μA)	Evening (μA)
1	N/A	1000	1000	N/A	1000
2	N/A	N/A	1000	700	700
3	N/A	N/A	N/A	N/A	N/A
4	N/A	N/A	N/A	1000	1000
5	N/A	N/A	1000	N/A	700
6	N/A	500	N/A	700	N/A
7	N/A	N/A	N/A	500	N/A
8	N/A	N/A	N/A	N/A	N/A
9	N/A	700	N/A	1000	N/A
10	N/A	N/A	N/A	N/A	N/A
11	N/A	N/A	N/A	700	N/A
12	N/A	N/A	N/A	N/A	N/A
13	N/A	N/A	N/A	N/A	N/A

N/A = Not applicable.

4 Discussion

Application of an optimal intensity of nGVS that was most effective in improving body balance has been investigated as a potential treatment for refractory persistent balance disorders caused by peripheral vestibulopathy [2 , 11]. Considering the prolonged daily use of nGVS as a treatment, reproducibility of the effective intensity of nGVS is an important factor. The results of the present study suggest that both inter-day and intra-day variations in the effective intensity of nGVS exist in some BVP patients. These results provide important information for the clinical application of nGVS. We also calculated ICC of the optimal intensity for the inter-day and intra-day variation to assess the degree of repeatability. However, care is needed to be taken in interpretation because cases without the effective intensity of nGVS were excluded from the analysis. Therefore, it might be better to interpret the ICC as the best value, such as the ICC among patients who always had optimal intensities regardless of inter- or intra-day variation.

It is currently unknown why inter-day and intra-day variations in the effective intensity of nGVS occur. One possibility is that the effect of changes in electrical resistance of the skin and subcutaneous content since the skin impedance has the intra-and inter-individual variations [12]. Furthermore, the electrical properties of the skin show marked changes after application of iontophoretic current [12]. Another possibility is the effect of the intra- and inter-day changes in subjects’ postural stability [1 , 15]. Several previous studies have shown that postural stability is affected by the time of day at which it is measured [1 , 15]. In this study, baseline values of each COP parameter tended to be lower in the evening session than in the morning session (Table S1), and the effective intensity observed in the morning was not observed in the evening in a portion of patients. In another feasibility study we conducted, in healthy subjects, the group with effective intensity had higher baseline values than the group without for each COP parameter [3]. The lack of effective intensity in some patients in the evening in this study may be due to a lower baseline value in the evening for each COP parameter.

After the effective intensity investigations on the morning of the second and third test day, each subject participated in a study evaluating the long-term effects of nGVS and received nGVS for 30 min [2]. The velocity of the BVP patients who received the 30 min of nGVS improved significantly for 6 h after the stimulus cessation [2]. This post-stimulation ameliorating effect may affect the baseline values of velocity in the evening session, and may be one possible reason for the lack of effective intensity in the 6 patients in the evening session. On the other hand, no significant post-stimulation ameliorating effects were observed in terms of area and RMS. The reasons for the lack of effective intensity in the 6 patients in the evening session are unclear in the present study and require further investigation.

The present study has some limitations. First, the present study did not have a placebo control group. Therefore, it was not possible to assess the effects of subject habituation due to repeated measurements on COP parameter values. Second, the order of sham and nGVS presentation was not randomized. Since sham stimulation was always tested first, the possibility that the improvement in subsequent standing trials was due to a habituation effect cannot be excluded. Third, the small number of female patients did not allow us to evaluate gender differences. Fourth, it is difficult to quantify the extent to which transcutaneous currents actually stimulate the vestibular system.

5 Conclusions

In conclusion, there were substantial degree of inter-day and intra-day variations in the effective intensity of nGVS in a portion of BVP patients.

Footnotes

Acknowledgments

We thank Masato Koizumi (Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo) and the members of the Clinical Research Promotion Center, The University of Tokyo Hospital for experimental support. We also thank all of the members of Department of Otolaryngology and Head and Neck Surgery, Graduate School of Medicine, The University of Tokyo for helpful discussions.

Funding

This work was supported by the Japan Agency for Medical Research and Development [grant number 18dk0310061h0003].

Declaration of competing interest

None.

The supplementary material is available in the electronic version of this article: .

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Inter-day and intra-day variations in effective intensity of noisy galvanic vestibular stimulation to improve postural stability in bilateral vestibulopathy

Abstract

BACKGROUND:

OBJECTIVE:

METHODS:

RESULTS:

CONCLUSIONS:

Keywords

1 Introduction

2 Methods

2.1 Standard protocol approvals, registrations, and subject consents

2.2 Subjects

Table 1 Maximum slow phase velocity of the subject’s nystagmus in the ice water caloric test Subject Right (°/s) Left (°/s) 1 0 0 2 0 0 3 0 7 4 0 0 5 9 5 6 0 0 7 7 0 8 5 5 9 8 0 10 0 0 11 0 0 12 3 9 13 8 0

2.4 nGVS

2.5 Methods

3 Results

5 Conclusions

Footnotes

Acknowledgments

Funding

Declaration of competing interest

References

Table 1
Maximum slow phase velocity of the subject’s nystagmus in the ice water caloric test

Subject Right (°/s) Left (°/s)

1 0 0

2 0 0

3 0 7

4 0 0

5 9 5

6 0 0

7 7 0

8 5 5

9 8 0

10 0 0

11 0 0

12 3 9

13 8 0