New non‐contrast MRI of endolymphatic hydrops in Ménière's disease considering inversion time

Abstract

Objectives

Three‐tesla MRI with gadolinium‐based contrast agents is important in diagnosing Ménière's disease. However, contrast agents cannot be used in some patients. By using the compositional difference between the inner ear endolymph and perilymph, we performed basic and clinical research focused on potassium ions and protein to find the optimal parameters for visualizing endolymphatic hydrops on MRI without contrast. We then examined the relationship between severity stage and visualization rate of endolymphatic hydrops.

Methods

In phantom experiments simulating the endolymph and perilymph, we explored MRI parameters that could be used to separate endolymph from perilymph by gradually changing the inversion time. We then used these parameters to perform both new non‐contrast MRI and contrast MRI on the same day in Ménière's disease patients, and we compared the visualization rates of endolymphatic hydrops under the two modalities. Fifty patients were selected from 478 patients with Ménière's disease of different severity stages; 12 patients had asthma and allergy to contrast agents.

Results

The higher the disease stage, the higher the endolymphatic hydrops visualization rate. The new non‐contrast MRI gave significantly higher (p < .01) visualization rates of endolymphatic hydrops on the affected side in patients at Stage 3 or above than in Stages 1 and 2 combined.

Conclusion

New non‐contrast MRI with parameters focusing on the endolymph–perilymph difference in the density of protons surrounding the potassium ions and protein can produce images consistent with endolymphatic hydrops. We believe that this groundbreaking method will be useful for diagnosing Ménière's disease in patients.

Evidence Level

Clinical studies are at evidence level 3 in non‐randomized controlled trials.

INTRODUCTION

Ménière's disease is an important inner ear disorder characterized by sudden attacks of vertigo and hearing loss. With increasing severity of the disease, hearing loss, tinnitus, and vertigo attacks impose substantial burdens, not only on patients' personal lives but also on their social lives. Therefore, correct diagnosis of severe disease is extremely important. Ménière's disease was first reported as an inner ear disease in 1861 by Ménière.¹ Hallpike and Cairns² and Yamakawa³ reported in 1938 that the pathological feature of the disease was endolymphatic hydrops. According to the 1995 diagnostic criteria for Ménière's disease of the AAO-HNS (Committee on Hearing and Equilibrium of the American Academy of Otolaryngology—Head and Neck Surgery), a definitive diagnosis of Ménière's disease was made when post-mortem examination of the temporal bone revealed endolymphatic hydrops.⁴ However, the 2015 AAO-HNS criteria for Ménière's disease deleted the pathological confirmation.⁵ The 2015 international diagnostic criteria jointly formulated by several organizations, including the Bárány Society, state that endolymphatic hydrops is frequently observed in Ménière's disease, both pathologically and on contrast-enhanced magnetic resonance imaging (MRI).⁶

In 2007, Nakashima et al. succeeded in detecting endolymphatic hydrops by MRI by injecting a gadolinium-based contrast agent (GBCA) into the middle ear cavity by tympanocentesis and imaging the inner ear the following day.⁷ However, this method had disadvantages, including complications such as otitis media, sequelae such as tympanic membrane perforation, and a long-time interval of 24 h between the injection of a GBCA into the middle ear cavity and imaging.

In 2012, Naganawa et al. successfully obtained clear images of endolymphatic hydrops by MRI of the inner ear 4 h after intravenous administration of a GBCA.⁸ The images were obtained by subtracting a positive endolymph image (PEI) from a positive perilymph image (PPI) by using 3D FLAIR (three-dimensional fluid-attenuated inversion recovery).⁹ This method, which creates a HYDROPS (HYbriD of Reversed image Of Positive endolymph signal and native image of positive perilymph Signal), is an excellent diagnostic technique.^8,9 The method was reported to be very important for understanding the pathogenesis of Ménière's disease¹⁰ and is now valued highly. Detection of endolymphatic hydrops on contrast-enhanced MRI is one of the diagnostic criteria for definitive Ménière's disease in Japan.¹¹ However, contrast MRI is generally contraindicated in patients with allergies to contrast agents or with bronchial asthma or renal insufficiency, and these patients therefore cannot undergo this procedure.

The dynamic hydration numbers of potassium ions range from 6 to 8, according to an analysis using nuclear magnetic resonance spectroscopy.¹² These numbers are very close to those from analyses using X-ray diffraction or Monte Carlo simulations.^12,13 This means that there are many protons that form water molecules around the K⁺ ions. The K⁺ concentrations differ markedly between the endolymph and the perilymph: the K⁺ concentration of the endolymph is high, at about 150 mEq/L,¹⁴ whereas that of the perilymph is quite low, at about 5 to 9 mEq/L.¹⁵ The concentration of protein is 20 to 30 mg/dL in the endolymph and 70 to 100 mg/dL in the perilymph.^15,16 In other words, there are dense protons surrounding K⁺ in the endolymph, whereas in the perilymph the protons are relatively sparse. As far as we know, there has been no report on the visualization of endolymphatic hydrops in Ménière's disease by using new non-contrast MRI focusing on the composition of the endolymph and the perilymph of the inner ear.

Therefore, with a special focus on the difference in density of the protons surrounding K⁺ in the endolymph and the perilymph, we conducted basic research by MRI of fluids with different concentrations of K⁺ and protein. We used an inversion recovery (IR) pulse sequence to evaluate changes in the signal intensity of the fluids. Furthermore, we prepared artificial endolymph and perilymph to explore the optimal inversion time (TI) values, and we found parameters that could be applied to clinical research. Here, we introduce a new method of MRI without contrast agents (new non-contrast MRI). We also examined the relationship between the severity of Ménière's disease and the visualization rate of endolymphatic hydrops, and we report the results.

METHODS AND SUBJECTS

Basic experiment (phantom experiment using artificial labyrinthine fluid)

Phantom solutions of artificial endolymph and perilymph containing K⁺ and protein were prepared for the basic research (Figure 1). The artificial endolymph had a high concentration of K⁺ (153.8 mEq/L) and a low concentration of protein (3.84 mg/dL), whereas the artificial perilymph had a low concentration of K⁺ (9.6 mEq/L) and a high concentration of protein (73.2 mg/dL). These concentrations were approximated to the reported respective normal K⁺ and protein concentrations in the endolymph and the perilymph.^14–16

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The artificial endolymph was prepared by adding KCL solution (20 mL ampoule; 15 w/v%, 2 mol; 40 mEq potassium: Maruishi Pharmaceutical Co. Ltd., Osaka, Japan, generic name: K.C.L.) and albumin solution (human serum albumin 5%, 12.5 g/250 mL, CSL Behring Co. Ltd., generic name: Albuminer) to pure water. The artificial perilymph was prepared by adding the KCL solution and the albumin solution to 0.9% NaCl solution (physiological saline). These solutions of artificial endolymph and perilymph were used as “normal” reference solutions. To examine changes in the TI values due to increases in the K⁺ and albumin concentrations, artificial endolymph with a K⁺ concentration of 307.6 mEq/L (double concentration) and artificial perilymph with an albumin concentration of 146.4 mg/dL (double concentration) were also prepared.

A 3.0-T Ingenia CX with 32-channel head coils (Philips) was used for the experiment in Figure 1. The parameters used for IR were: repetition time (TR) = 15,000 ms; echo time (TE) = 613 ms; turbo spin echo (TSE) factor = 160; and TI = 2000 to 3500 ms at 100-ms intervals (Table 1A). The phantom temperature was approximately 35 to 36°C.

TABLE 1 MRI systems and parameters.

(A) MRI system: Philips Ingenia CX 3.0-T Head 32-ch coil Phantom Temp: 35–36°C
IR 3D (3.0) T2 weighted 3D IR
TR: 15,000 ms
TI: 2000–3000 ms
TE: 613 ms
TSE factor: 160
(B) New non-contrast MRI system: Philips Ingenia CX 3.0-T Head 32-ch coil for Ménière's disease
PPI (3.0 T) T2-weighted 3D-IR	PEI (3.0 T) T2-weighted 3D-IR
TR: 15,000 ms	TR: 15,000 ms
TI: 3050 ms	TI: 2800 ms
TE: 480 ms	TE: 480 ms
TSE factor: 109	TSE factor: 109
(C) Contrast MRI system: Philips Ingenia CX 3.0-T Head 32-ch coil for Ménière's disease
PPI (3.0 T) T2-weighted 3D-IR	PEI (3.0 T) T2-weighted 3D-IR
TR: 12,000 ms	TR: 12,000 ms
TI: 2250 ms	TI: 2050 ms
TE: 527 ms	TE: 527 ms
TSE factor: 147	TSE factor: 147
(D) New non-contrast MRI setup values for Meniere's disease
Geometry	Non-contrast (Philips)	Contrast (Philips)	Contrast (Siemens)
FOV (mm)	160	200	196
RFOV (%)	100	90	84.4
Matrix scan	240	352	384
Reconstruction	320	640	?
ACQ Voxel MPS (mm)	0.67/0.67/2.0	0.57/0.57/2.0	0.5/0.5/2.0
REC Voxel MPS (mm)	0.5/0.5/1.0	0.31/0.31/1.0	0.5/0.5/1.0
Scan percentage (%)	100	100	100
Sence	2	2	2
Stacks	1	1	1
Slices	55	80	104
Acq slice thickness (mm)	2	2	2
Rec slice thickness (mm)	1	1	1

Clinical research

In the second stage—the clinical research—both our new non-contrast MRI with the appropriate parameters obtained in the basic research and contrast MRI were performed on the same day. Imaging diagnosis was made by three neuroradiologists who had no conflict of interest with this research. The results were analyzed, and all three doctors made the same diagnosis in the case of patients diagnosed as having endolymphatic hydrops in the inner ear.

The subjects were 50 patients (100 ears) who met the diagnostic criteria for Ménière's disease (No. 1–3) of the Japan Society for Equilibrium Research.¹¹ Thirty-eight of the patients (22 women and 16 men; age 22 to 75 years [mean, 53.3 ± 13.8 years]) underwent both new non-contrast MRI and contrast MRI. The severity classification of Ménière's disease in these 38 patients was Stage 1 in seven, Stage 2 in seven, Stage 3 in 10, Stage 4 in seven, and Stage 5 in seven. The mean disease duration was 5.3 ± 4.8 years. The remaining 12 patients (24 ears) (all women, age 48 to 74 years [mean, 59.8 ± 7.2 years]), who were under treatment for bronchial asthma and were allergic to contrast agents, underwent only new non-contrast MRI. All of them were in Stage 3. Their mean disease duration was 6.2 ± 3.8 years.

These cases of Ménière's disease were classified on the basis of severity¹⁷ (Table 2). This was done by summing up the severity of symptoms for (A) Balance disorder and daily life impairment; (B) Hearing impairment; and (C) Degree of disease progression, and classifying them into five stages. Hearing impairment included reversible low-frequency hearing loss, irreversible high-frequency hearing loss, moderate hearing loss, and severe bilateral hearing loss. All subjects were limited to those who were able to have MRI exam within 1 month after attacks of Ménière's disease.

TABLE 2 Ménière's disease severity classification by symptoms.

A: points	Balance disorder and daily life impairment
0 points	Normal
1 point	Daily activities are sometimes limited (reversible balance disorder)
2 points	Daily activities are often limited (irreversible mild balance disorder)
3 points	Daily activities are always limited (irreversible severe balance disorder)
4 points	Constant limitation of daily activities, difficulty standing and walking in the dark (irreversible bilateral severe balance disorder)
Note	Irreversible bilateral severe balance disorder means that bilateral semicircular canal paralysis is observed in the balance function test
B: points	Hearing impairment
0 points	Normal
1 point	Reversible (hearing loss limited to low frequencies)
2 points	Irreversible (irreversible high-frequency hearing loss)
3 points	Moderate progression (moderate or more irreversible hearing loss)
4 points	Bilateral severe progression (irreversible bilateral severe hearing loss)
Note	Note: Irreversible bilateral severe hearing loss means that the average hearing level is 70 dB or more on both sides and does not improve to less than 70 dB in pure tone audiometry
C: points	Degree of disease progression
0 points	Only lifestyle guidance is given and follow-up observation is performed.
1 point	Conservative treatment is required for reversible lesions.
2 points	Irreversible lesions progress even with conservative treatment.
3 points	Lesions progress severely and resist conservative treatment, and invasive treatment is considered.
4 points	Irreversible lesions progress severely and leave sequelae.
Ménière's disease comprehensive severity classification
Stage 1: Subnormal period A: 0 points; B: 0 points; C: 0 points
Stage 2: Reversible period A: 0–1 points; B: 0–1 points; C: 1 point
Stage 3: Irreversible period A: 1–2 points; B: 1–2 points; C: 2 points
Stage 4: Progressive period A: 2–3 points; B: 2–3 points; C: 3 points
Stage 5: Sequelae period A: 4 points; B: 4 points; C: 4 points

Verbal and written informed consent was obtained from all patients before the series of examinations. Following new non-contrast MRI (see imaging parameters in Table 1B and setup values in Table 1D), contrast MRI was performed 4 h after the administration of GBCA (C₁₈H₃₁GdN₄O₉ Gadovist; Bayer Healthcare Pharmaceuticals, Co. Ltd., Osaka, Japan, generic name: Gadobutrol), at 0.1 mmol/kg. A 3.0-T Ingenia CX with 32-channel head coils (Philips) was used. The imaging parameters used for the contrast MRI are shown in Table 1C. Statistical analysis of the data was performed on a Windows 10 PC by using add-on software (Statcel Ver. 5, Microsoft Excel) dedicated to statistical analysis.

RESULTS

Results of basic research

An important feature of this phantom experiment is that images of the perilymph with normal and double albumin concentrations were compared and those of endolymph with normal and double K⁺ concentrations were also compared. There was no difference in TI values at the null point between normal artificial perilymph and endolymph, both being 2600 ms. However, the TI values of artificial perilymph with double the albumin concentration were 2500 to 2600 ms and those of artificial endolymph with double the K⁺ concentration were 2700 to 2800 ms.

In other words, the TI value at the null point was the same between the artificial endolymph with normal K⁺ concentration and the artificial perilymph with normal albumin concentration. When the K⁺ concentration was increased in the artificial endolymph, the TI value at the null point was prolonged; when the albumin concentration was increased in the perilymph, the TI value at the null point was shortened. The IR longitudinal magnetization recovery process (T1 relaxation) can be assumed from the changes in the TI values at the null point (Figure 2). The T1 values were shortened with increasing albumin concentration; in contrast, the T1 values were prolonged with increasing K⁺ concentration. This suggested the possibility of separating the images of perilymph and endolymph.

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These results suggest that, if increased K⁺ in the endolymph and increased protein in the perilymph are involved in the pathogenesis of Ménière's disease, then subtracting the PEI with high K⁺ and low protein concentrations from the PPI with low K⁺ and high protein concentrations could provide new parameters for new non-contrast MRI.

Results of clinical research

From the results of the basic research over many years, we pursued the null point of the PPI with a high albumin concentration and that of the PEI with a high K⁺ concentration in our clinical research. The null point of the PPI was eventually found to be 3050 ms and that of the PEI was found to be 2800 ms (Table 1B).

We created schematic diagrams of the contrast and new non-contrast-enhanced MRI imaging methods used for endolymphatic hydrops (Figure 3). The upper row shows the contrast MRI imaging method, in which images are obtained by subtracting the PEI from the PPI 4 h after intravenous administration of the GBCA (HYDROPS).^8–10 The bottom row shows the new non-contrast MRI imaging method, in which images are obtained by subtracting the PEI from the PPI. The TI values of the PPI and the PEI differed markedly between contrast MRI and the new non-contrast MRI. The other imaging parameters of MRI set up values (Geometory) were also substantially different (Table 1D).

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Here, we present clinical cases of patients with Ménière's disease who underwent the contrast or new non-contrast MRI, or both, using above mentioned parameters. Figure 4 shows an image of GBCA contrast-enhanced MRI and an image of the new non-contrast MRI created in a patient with Ménière's disease by subtracting the PEI from the PPI using the parameters in Table 1B,C. Patient 1 was a 49 year-old man with Stage 3, right-sided Ménière's disease who had right-sided hearing loss and had the disease for 2 years and 10 months. Lesions with decreased signal intensity are apparent in the new non-contrast MRI; they are consistent with images considered to be endolymphatic hydrops in the right vestibule and cochlea.

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Figure 5 shows contrast and new non-contrast MRI of Patient 2. Patient 2 was a 25-year-old man with Stage 4 left-sided Ménière's disease who had left-sided severe hearing loss and had the disease for 3 years and 7 months. Lesions with decreased signal intensity are apparent in the new non-contrast MRI; they are consistent with images considered to be endolymphatic hydrops in the left vestibule and cochlea.

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Figure 6 shows contrast and new non-contrast MRI of Patient 3, who was a 34-year-old woman with Stage 3 right-sided Ménière's disease. Lesions with decreased signal intensity are apparent in the new non-contrast MRI; they are consistent with images considered to be endolymphatic hydrops in the left vestibule and cochlea.

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Figure 7 shows new non-contrast MRI of Patient 4. Patient 4 was a 61-year-old woman with Stage 3 right-sided Ménière's disease and asthma, with allergy to contrast agents. Patient 4 had moderate left low- to middle-tone hearing loss and had the disease for 8 years and 5 months. Lesions with decreased signal intensity consistent with symptoms are evident on the new non-contrast MRI, consistent with imaging and symptoms of possible endolymphatic hydrops of the right vestibule and cochlea.

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Figure 8 shows new non-contrast MRI of Patients 5 and 6. Patient 5 was a 47-year-old woman with Stage 3 right-sided Ménière's disease who had moderate right-sided low- to high-tone hearing loss and had the disease for 3 years and 7 months. Patient 6 was a 51-year-old woman with Stage 3 left-sided Ménière's disease who had moderate left low- to middle-tone hearing loss and had the disease for 4 years and 2 months. Both patients underwent only new non-contrast MRI, because they had asthma and were allergic to contrast media. Lesions in Patients 5 and 6 with decreased signal intensity are apparent in the new non-contrast MRI; they are consistent with images considered to represent endolymphatic hydrops in the vestibule and cochlea.

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Figure 9 shows new non-contrast MRI of Patient 7. Patient 7 was a 52-year-old woman with Stage 3 right-sided Ménière's disease who had moderate left-sided low- to high-tone hearing loss and had the disease for 4 years and 9 months. Patient 7 underwent only new non-contrast MRI, because she had asthma and was allergic to contrast media. Lesions with decreased signal intensity are apparent in the new non-contrast MRI; they are consistent with images considered to represent endolymphatic hydrops in the vestibule and cochlea.

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Table 3 shows the visualization rates of endolymphatic hydrops in the cochlea and the vestibule of 38 patients (76 ears) who underwent both novel non-contrast MRI and contrast MRI. The visualization rate of endolymphatic hydrops in the cochlea was very low on novel non-contrast MRI (28.9%) compared with that on contrast MRI (71.1%). The visualization rate in the vestibule was 65.8% on novel non-contrast MRI and 84.2% on contrast MRI. However, there was no significant difference in the visualization rate of endolymphatic hydrops between contrast MRI and the novel non-contrast MRI, or between the cochlea and the vestibule (2 × 2 contingency table: Chi-square test for independence).

TABLE 3 Visualization rates of endolymphatic hydrops in the cochlea and the vestibule of 38 patients with Ménière's disease.

	Cochlea	Vestibule
Contrast MR	75.5%	81.8%
New non-contrast MRI	27.3%	63.6%

Next, we plotted the visualization rates of endolymphatic hydrops with contrast MRI and the new non-contrast MRI by stage of disease severity (Figure 10). There was no significant difference in the visualization rates of endolymphatic hydrops between Stages 1 and 2 (n.s. by the chi-square test) or among Stages 3 to 5 (n.s. by the chi-square test). However, the visualization rate for Stages 3 to 5 as a group was significantly greater than that for Stages 1 and 2 as a group (chi-square test for independence, p < .01). Also, the visualization rate of endolymphatic hydrops in patients at all stages was significantly greater with contrast MRI than with the new non-contrast MRI (m × n contingency table: chi-square test for independence, p < .01).

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DISCUSSION

Endolymphatic hydrops in patients with Ménière's disease has been demonstrated by non-contrast MRI using T2 preparations (T2Preps) technique.¹⁸ However, problems of artifacts and noise with the technique have been pointed out.^19,20 As a preliminaries test to our study, on the basis of that report,¹⁸ we verified the technique in six normal controls and five patients with Ménière's disease. That results showed no significant difference in the vestibular images between normal controls and patients with Ménière's disease, and no clear difference between the affected and healthy sides. Therefore, an alternative non-contrast-agent method was required.

The pathogenesis of Ménière's disease is still mostly unknown. However, we have been studying the autonomic nervous system in detail in these patients for over 10 years. We have found that overexcitation of sympathetic nerves on the affected side occurs immediately before an attack of Ménière's disease, and we recently reported this finding.²¹ Overexcitation of the sympathetic nervous system, which is closely related to stress, causes contraction of arterioles distributed in the inner ear. This generates shear stress in the blood vessels, leading to increased K⁺ in the blood vessels and increased vascular permeability.²² Increased vascular permeability causes extravascular leakage of albumin.²³ Increased K⁺ in the perilymph leads to increased K⁺ in the endolymph by the potassium ion cycle,²⁴ and the resulting neurotoxicity can be assumed to cause hearing impairment, nystagmus, and vertigo.^21,25,26 Furthermore, increased K⁺ leads to a decrease in hydration kinetics (negative hydration),^27,28 resulting in the prolongation of T1 values; in contrast, increased albumin leads to an increase in hydration kinetics (positive hydration),²⁹ resulting in the shortening of T1 values. Therefore, this difference in T1 values enables us to separate the endolymph and perilymph.

Image analysis focusing on K⁺ in the endolymph could be important for determining the cause of the disease. By using the results of our basic research, we explored in detail the parameters that could be used to separate the endolymph from the perilymph on MRI. In other words, we tried to reduce image artifacts and noise to increase the resolution as much as possible. We finally found parameters by which the new non-contrast MRI differed markedly from contrast MRI (Table 1D). This enabled us to create images that could separate the endolymph from the perilymph (Table 1C; Figures 2 and 3).

The values for the null point for PPI and PEI—the point at which the artificial endolymph and perilymph could be separated—were lower than those in the actual clinical setting (PPI: 3050 ms; PEI: 2800 ms) (see Figure 2 and Table 1B). This was likely because, unlike in the artificial setting, (i) the core body temperature is around 37°C; (ii) the inner ear has a hard bony capsule and surrounding mastoid air cells; (iii) there is a flow in the inner ear lymph^30–32; and (iv) the endolymph and perilymph contain electrolytes other than K⁺ at different concentrations.^14,15 In our clinical research, comparison of the visualization rates of endolymphatic hydrops in the cochlea and the vestibule by using the new non-contrast MRI and contrast MRI showed that the visualization rates of endolymphatic hydrops in the cochlea tended to be lower with the former than with the latter (see Table 3). This may have been due to the presence of the hard bony capsule around the cochlea and the small volume of the endolymph.

In patients with severe Ménière's disease (Stages 3 to 5), visualization rates of endolymphatic hydrops on the affected side increased with increasing stage (see Figure 10). Endolymphatic hydrops was not visualized on the healthy side in these patients. These findings are extremely important for understanding the pathophysiology of Ménière's disease. Our new non-contrast MRI used parameters focusing on changes in the K⁺ concentration of endolymph and changes in the protein concentration of perilymph; therefore, our results may have suggested that there was an increased K⁺ concentration in the endolymph on the affected side and an unchanged K⁺ concentration on the healthy side. Another reason for the non-visualization of endolymphatic hydrops on the healthy side by our method may have been that the volume of endolymphatic hydrops was too small on that side.

This new method of new non-contrast MRI will make it easier, not only to follow up patients with severe Ménière's disease at higher stages immediately after an attack and thereafter, but also to understand changes in the pathophysiology of the inner ear. Further studies are important and necessary. Because the resolution of our new non-contrast MRI is currently relatively low, classification by using the quantitative analysis of endolymphatic hydrops visualized by using contrast-enhanced MRI³³ cannot yet be applied.

Although we used a 3.0-T MRI scanner with 32-channel head coils in our clinical research, within our research group we have confirmed that, with the use of the same parameters, the same MRI scanner model with 20-channel head and neck coils can provide images of a quality comparable to that of images obtained with a 3.0-T MRI scanner with 32-channel head coils. Use of the same parameters as we have used here will enable the use of other manufacturers' models to visualize endolymphatic hydrops. We consider this to be a future task.

CONCLUSIONS

We devised a new non-contrast MRI method with parameters focusing on protein and protons closely surrounding K⁺ to visualize endolymphatic hydrops in Ménière's disease. The method enabled us to visualize endolymphatic hydrops at high rates in patients at Stage 3 or higher, consistent with the symptomatic, affected side. Therefore, this new non-contrast MRI method will be useful and helpful in patients with clinically problematic Stage 3 or higher Ménière's disease who have restrictions on, or contraindications for, the use of contrast agents. We expect that improvement and enhancement in MRI signal processing will provide greater diagnostic power. Our new non-contrast MRI method has the potential to help us understand the pathophysiological changes that occur immediately after a Ménière's attack and thereafter.

ACKNOWLEDGMENTS

We sincerely thank Dr. Kazuya Nakamoto, Chief Director of the Ochanomizu Clinic, for his unwavering support during this study. We also thank Dr. Seishi Sawano, Clinical Director of AIC Yaesu Clinic, and Mr. Tatsuya Otsuka, Secretary General of the Yaesu Clinic, for their support with ethics and equipment.

AUTHOR CONTRIBUTIONS

HT, RA, Y Kanai, MYand MI initiated and designed the study and RA, Y Kanai and MI collected data. RA, Y Kanai, and MI conducted the data analysis, and MI wrote the main manuscript text. HT, RA, Y Kanai, Y Kato, YI, FM, MY, GI, and AI reviewed the manuscript.

CONFLICT OF INTEREST STATEMENT

The authors declare no conflicts of interest.

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