Comparison of the effects of transcranial direct current stimulation and transcutaneous tibial nerve stimulation on the urgency and frequency of women with overactive bladder syndrome: study protocol of a randomized clinical trial

Abstract

Background

Overactive bladder syndrome is common, with a prevalence of 12–17% among adults. Posterior tibial nerve stimulation is the primary nonpharmacological and conservative treatment for overactive bladder syndrome. While several human brain imaging studies have shown the involvement of supraspinal centers in bladder control, a literature review has found that no research has specifically investigated cortical stimulation through transcranial direct current stimulation as a treatment for overactive bladder syndrome in women. Therefore, this study aims to assess the potential benefits of transcranial direct current stimulation (tDCS) and compare them with the effects of posterior tibial nerve stimulation on overactive bladder syndrome.

Methods/design

The random allocation method will be used to divide the participants into two groups. Group 1 (n = 19) will undergo pelvic floor muscle training and transcutaneous tibial nerve stimulation. Group 2 (n = 19) will undergo pelvic floor muscle training and transcranial direct current stimulation. The transcranial direct current stimulation for group 2 will consist of 12 sessions occurring thrice a week, each lasting for 20 min. Anodal tDCS will be administered to FPz targeting the medial prefrontal cortex (mPFC) for 12 sessions, with the cathode electrode positioned between Oz and inion at an intensity of 2 mA for 20 min.

Discussion

It is believed that utilizing an approach involving non-invasive electrical stimulation of the cortex could lead to a more efficient treatment for individuals with overactive bladder. Additionally, it is theorized that combining the effects of tDCS and pelvic floor muscle training could present an innovative technique for alleviating the negative impacts of overactive bladder syndrome. Ultimately, this new method could provide help for patients who have not responded to conventional therapy.

Trial registration

Iranian Registry of Clinical Trials (IRCT) ID: IRCT20090301001722N26, registration date: May 17, 2023. https://en.irct.ir/.

Background

Overactive bladder syndrome (OAB) is characterized by a set of symptoms defined by the International Society of Continence and the International Society of Urogynecology as follows: “a Sudden urge to urinate, with frequency and nocturia with or without urinary incontinence, in the absence of pathological causes or neurological disorders” [1].

The syndrome’s prevalence is significant, impacting 12–17% of adults, and can significantly diminish adults’ quality of life [2, 3].

Pelvic floor muscle training and posterior tibial nerve stimulation are the recommended first-line treatments for OAB due to minimal invasiveness and side effects. Although PFMT is recommended as the first-line treatment for overactive bladder syndrome, some patients may experience slight improvement due to poor adherence to exercise or the inability to contract pelvic floor muscles correctly. Therefore, combining these exercises with other methods, such as electrical stimulation, may be necessary. The known electrical stimulation for overactive bladder syndrome is the tibial nerve stimulation, introduced by Stoller in 1999 [4].

The tibial nerve is a mixed nerve that originates from roots L5 through S3, the same roots responsible for parasympathetic innervation to the bladder. As a result, stimulating the posterior tibial nerve, known as retrograde stimulation, has an inhibitory effect on the bladder’s detrusor muscle [5, 6].

The mechanism of tibial nerve stimulation’s operation was previously discussed. This technique addresses the OAB syndrome at the sacral level, while studies using brain imaging techniques in healthy individuals have clearly shown the involvement of supraspinal centers in bladder control [7,8,9,10].

The medial prefrontal cortex plays a crucial role in the neural control of urination [7]. Research has demonstrated its significance in bladder control, mainly inhibitory control during decision-making and emotional responses [11]. Damage to the medial prefrontal cortex has been shown to have long-term clinical effects on bladder function, potentially leading to reduced inhibitory control and overactive bladder (OAB) symptoms [12, 13]. Studies comparing incontinent women to controls have indicated reduced prefrontal cortex activity in those with urge incontinence, highlighting dysfunction in this area. Additionally, prefrontal cortex lesions can lower the voiding reflex threshold, resulting in involuntary voiding as bladder volume increases [9]. Several tomographic studies have revealed decreased activity in the medial prefrontal cortex in women with overactive bladder syndrome [12, 14].

Additionally, a 2015 review study highlighted those patients who are unresponsive to pelvic floor muscle training with biofeedback exhibit strong deactivation of the medial prefrontal cortex on fMRI images. These results suggest that a ceiling effect, causing complete deactivation of the medial prefrontal cortex, may impede improvements in therapeutic outcomes [8]. According to the studies above, using electrical stimulation to activate the medial prefrontal cortex can alleviate symptoms in women with overactive bladder syndrome. TDCS is a noninvasive method widely recognized for modulating brain activity by altering neuronal excitability through sustained depolarization or hyperpolarization of targeted brain regions. TDCS operates by applying a low-intensity electrical current through electrodes on the scalp. This current induces a slight shift in the resting membrane potential of neurons under the electrodes [15]. Depending on the polarity (anodal or cathodal), tDCS can increase (anodal) or decrease (cathodal) neuronal excitability. These changes can persist beyond the stimulation period, potentially influencing neural plasticity and functional connectivity in the brain [16]. The primary aim of this study is to evaluate the effectiveness of tDCS in treating OAB by modulating the activity of the mPFC. Specifically, we aim to understand whether tDCS can enhance the inhibitory control exerted by the mPFC over bladder function, improving urinary continence and reducing symptoms of OAB.

Methods/design

Research sites

The study will be conducted at the Neuromusculoskeletal Research Center, Firoozgar Hospital.

Ethics

This research is a superiority trial aiming to demonstrate that tDCS is more effective than PTNS in improving urinary continence and reducing symptoms of OAB. The study has been approved by the Tehran University of Medical Sciences Ethics Committee in Iran (IR.TUMS.FNM.REC.1401.210) and registered in the Iranian Clinical Trials Registry (IRCT) under the number IRCT20090301001722N26, https://fa.irct.ir/. All participants will be required to sign an informed consent form and receive detailed explanations of the research objectives, their freedom to participate in the study, and the anonymity of their information from the physical therapist responsible for their treatment.

Sample size

The preliminary data from a research study by Jacomo et al. is used to calculate the sample size. This study demonstrated a significant enhancement with TTNS and an effect size of 1.8. By utilizing their primary outcome measure (ICIQ-OAB), which will also be the main outcome of this investigation, we are able to estimate the necessary sample size in our study [17].

The sample size will be determined based on the following assumptions using the G-Power 3.1.9.2 software: test family = F tests, statistical test = ANOVA: repeated measures, between factors α = 0.05, power = 0.8, effect size = 0.39, number of groups = 2, and number of measurements = 3. According to these assumptions, the total sample size of N = 38 will be required. An additional 10% of participants will be added, resulting in a total of 42 women (21 in each group) to be included in this study to account for potential losses due to follow-up and treatment interruption.

Study design

The study protocol follows the SPIRIT checklist and outlines a two-arm, parallel, randomized, controlled clinical trial with a 1:1 allocation ratio. It is designed within a superiority framework and involves two physiotherapy intervention groups. The study also includes a 1-month follow-up period (Fig. 2).

Blinding

In this protocol study, the patients will be assigned to group 1 and group 2 (TTNS and PFMT; tDCS and PFMT, respectively). Because of the nature of the interventions, patients will be aware of the type of treatment they are receiving. As a result, they will not be blinded to their specific treatment protocol. An independent and blinded physiotherapist will collect baseline and follow-up questionnaires and measure the pelvic floor muscle training strength before and after treatment. Besides, data analysts will not be involved in the measurement process.

Eligibility criteria/subjects

Inclusion criteria

Target population is women aged 18–65 with the self-reported urge or mixed urinary incontinence. Participants meeting the criteria for OAB syndrome, including symptoms such as nocturia, frequency, and urge incontinence, regardless of the severity of incontinence, will be included in this study [18,19,20].

Exclusion criteria

• Diagnosed with neurological or psychological disorders

• History of pelvic or brain surgeries

• History of diabetes

• Presence of a cardiac pacemaker

• Pregnancy

• History of brain tumor

• Taking of anticholinergic medications in the last month

Withdrawal criteria

• Sensitivity to electrical stimulation (patient-reported discomfort and adverse nerve response)

• Occurrence of urinary tract infection during the treatment period (based on urinalysis results)

• Non-cooperation

• Leaving the intervention for more than two sessions

Recruitment

Women will be recruited in this study through the physical therapy department of Firoozgar Hospital with complaints of OAB symptoms by the physiotherapist responsible for the treatment.

Female participants will be recruited from Firoozgar Hospital’s physical therapy department to participate in a study focusing on overactive bladder (OAB) symptoms. Participants will be individuals who spontaneously report OAB symptoms. Before the study, all participants will receive detailed information about the significance of attending treatment sessions and completing the entire treatment program. Each participant will be provided with a personalized treatment plan. Any participant can choose to withdraw from the study at any time without explaining.

One month after completing the treatment, the physiotherapist will request the participants to send paper questionnaires via WhatsApp. The study will assess participants at three crucial time points: before the intervention begins, immediately after the 12th intervention session, and 30 days post-intervention. Evaluations will involve administering the ICIQ-LUTSqol and ICIQ-OAB questionnaires and a 3-day bladder diary. Pelvic floor strength will be evaluated both before and after the 12th session.

Outcome measures

This study will assess one primary outcome and three secondary outcomes. The primary outcome will be the change in scores on the International Consultation on Incontinence Questionnaire Overactive Bladder Module (ICIQ-OAB) immediately after completing the 12 treatment sessions. The ICIQ-OAB has been translated into Persian and validated. This questionnaire is a brief tool designed to evaluate the overactive bladder (OAB) and its effects on the quality of life (QOL). It aims to assess urinary frequency, urgency, urge incontinence, and nocturia symptoms. The questionnaire comprises four questions, with question 3a focusing on urinary frequency, question 4a on nocturia, and questions 5a and 6a covering urgency and urge incontinence (UUI), respectively. The scoring system ranges from 0 to 16, with higher scores indicating greater symptom severity. Additionally, bother scales are utilized to demonstrate the impact of individual symptoms on the patient, although they are not factored into the overall score.

Secondary outcome measures

The secondary outcome measures for this study will involve the use of the International Consultation on Incontinence Questionnaire Lower Urinary Tract Symptoms Quality of Life Module (ICIQ-LUTSqol), assessment of pelvic floor muscle strength, and 3-day bladder diary. The ICIQ-LUTSqol is a reliable patient-completed questionnaire used worldwide to assess the quality of life (QoL) in individuals with urinary incontinence. It is an adaptation of the King’s Health Questionnaire (KHQ) within the ICIQ system. It measures the impact of urinary incontinence on quality of life, particularly in social aspects. The scores on this questionnaire range from 19 to 76, with higher scores indicating more severe symptoms. Bother scales are not included in the total score but indicate the impact of particular symptoms on the patient. Previous studies have demonstrated the reliability and validity of the ICIQ-LUTSqol questionnaire, showing a strong correlation with urodynamic findings (also, this questionnaire was validated in the Persian language) [21, 22].

A 3-day bladder diary is a tool for gathering detailed information about urinary habits over 3 days. It defines nighttime and daytime based on the subject’s “time to go to sleep” and “time to wake up.” This diary captures data on daytime frequency, nocturia, and urinary incontinence [23].

The strength of the pelvic floor muscles will be objectively measured using a perineometer (Cardio Design Pty Ltd, Oakleigh, Victoria, Australia) with a diameter of 28 mm and a length of 108 mm. Pressure will be measured in centimeters of water. To conduct this method, a pressure perineometer covered with a sterile latex sleeve will be inserted into the vagina. A separate sleeve will be used for each patient and discarded after a single use. The patient will be requested to relax the pelvic floor muscle to facilitate easy insertion of the probe. Subsequently, the patient will be instructed to contract her pelvic floor muscle as if stopping the midstream of urine. Three maximal contractions will be performed, and the highest reading will be recorded as the strength.

Randomization

As mentioned, an independent individual will randomly assign the participants to group 1 (control) or group 2 (intervention) through sealed envelopes. The control group (n = 19) will receive PFMT and TTNS, while the intervention group (n = 19) will receive PFMT and tDCS (see Fig. 1). The allocation of the participants to the control or intervention group will use random block sizes of four, maintaining a 1:1 ratio. A computer program will generate a random sequence in blocks before the study starts, and an independent individual will manage it. The treatment codes will be placed in sealed and sequentially numbered envelopes to conceal group assignments. The sequence will be kept hidden until a participant is assigned to a group. After allocation, the data analyses and outcome assessors will be blinded to interventions.

Fig. 1

Study flow diagram demonstrating recruitment, study design, and timing of data collection

Interventions

After the initial assessment, participants will receive information about OAB symptoms and be educated about their treatment procedures. Both groups of participants will undergo pelvic floor muscle training (Fig. 2).

Fig. 2

Schedule of enrolment, interventions, and assessments (according to SPIRIT)

The pelvic floor muscle training will be carried out by the patients following these steps:

• 1. Locate the anal sphincter and try to lift the anus from the chair without contracting the muscles of the abdomen, thighs, and buttocks.

• 2. Find the levator ani muscles and try to lift the vagina from the chair without contracting the abdominal, thigh, and hip muscles.

• 3. Contract the anal sphincter.

• 4. Contract the levator ani muscle.

• 5. Perform these contractions while resting, sitting, standing, and walking [24].

Patients are expected to contract the muscles for 10 s, with a rest of 10 s between each contraction. They should perform 10 contractions 5 times. Women in both groups should exercise pelvic floor muscles at home for 4 weeks. They will be given a pelvic floor muscle exercise diary to monitor treatment adherence to record their exercises.

Patients in the intervention group will receive transcranial direct current stimulation (tDCS) and pelvic floor muscle training. To carry out this procedure, a battery-powered stimulator will administer a steady current of 2 mA to the targeted area using a pair of sponge electrodes for of 20 min (25 cm² electrodes; current density of approximately 0.08 mA/cm²). Electrodes will be soaped in normal saline to facilitate electrical current flow and kept in place with elastic bands. The “active” anodal electrode will be positioned over the mPFC on the Fpz area in accordance with the international 10-20 nomenclature for electroencephalography (EEG) electrode placement. The “reference” electrode will be positioned over an area between inion and Oz. The current will ramp up and down over the first and last 10 s of stimulation in the cathodal currents [25].

In both groups, electrical stimulation (tDCS and TTNS) will be applied three times a week on non-consecutive days for 12 sessions. In the control group, the electrical stimulation parameters will be as follows: a wavelength of 200 µs, a frequency of 10 Hz, and an application time of 20 min. The intensity will gradually increase until the big toe flexes, and then it will be lowered slightly to avoid any motor response. In this method, the active electrode will be placed three fingerbreadths cranial to the medial malleolus, and the other electrode will be placed on the medial surface of the ipsilateral calcaneus. Before the second treatment session, assessments for contact dermatitis, reactions to electrical stimulation, and worsening of urinary symptoms will be carried out. Additionally, a face-to-face consultation will be conducted with each patient regarding their symptoms and adverse events before each treatment session. If side effects continue and the patient does not adapt well to electrical stimulation, treatment sessions will be stopped before the full treatment period is completed, and the patient will be referred to the relevant specialist. Patients are requested to refrain from other conservative treatments for OAB syndrome during the 4-week treatment period. While urinary incontinence medications are discouraged, they are permitted during the study.

Data management and analysis

The patient’s symptoms will be assessed using relevant questionnaires, and the strength of the pelvic floor muscles will be evaluated before and after the treatment. After each evaluation, the physical therapist will review the questionnaires to identify missing data. If any data is missing, the patient will be contacted on the same day to complete the questionnaire. The questionnaires will be kept in a secure, locked location accessible only to authorized research personnel. Unique identification codes will be used instead of personal identifiers to protect participant anonymity. The questionnaire data will be entered into a Microsoft Excel database every week in a secure, private environment. The electronic data will be stored on password-protected computers, and only authorized personnel will have access to these files. Statisticians who are blind to the group allocation and have no involvement in the research will conduct the statistical analysis. Descriptive statistics, including mean and standard deviation, will be used. A statistical professional will analyze all study data using the intention-to-treat method. Multiple imputations will be used to handle missing data.

Statistical analysis

All data will be analyzed using SPSS 21.0 software (SPSS Inc., Chicago, IL, USA) and IBM SPSS Statistics (Armonk, NY, USA). The significance level is set at 5%. The Shapiro-Wilk test will be used to evaluate the normality of the samples. Depending on the distribution of the data, we will use either a one-way repeated measures ANOVA or the Friedman test to compare changes within the groups. If we find significant differences using either the one-way repeated measures ANOVA or the Friedman test, we will conduct post hoc tests to pinpoint specific differences between the time points. To control for type I error, we will perform pairwise comparisons with Bonferroni correction for ANOVA and use Wilcoxon signed-rank tests with Bonferroni correction for the Friedman test. To compare the effectiveness of two treatment methods between groups, we will initially assess the groups’ comparability. When the parametric assumptions are met, we will use an independent t-test to compare the mean outcomes of the two groups. If the data does not meet parametric assumptions, we will use the Mann-Whitney U test for non-parametric comparison. To assess the interaction effects between the treatment methods and types of treatment, we will utilize two-way repeated measures ANOVA.

Discussion

OAB is a prevalent syndrome with significant economic implications due to its impact on the social lives of those affected. Our study represents the first attempt to assess the effectiveness of tDCS on the mPFC in women with OAB in a clinical context. This pioneer randomized, controlled clinical trial aims to compare the effects of tDCS and TTNS in alleviating symptoms in women with overactive bladder syndrome. Based on the literature, TTNS involves retrograde stimulation of the nerve fibers of the sacral plexus, which can subsequently modulate detrusor muscle over activity. Recent fMRI and imaging studies have identified the crucial role of supracentral centers in regulating urinary function in healthy women. It is hypothesized that dysfunction in these centers may contribute to overactive bladder syndrome in women.

In this research, upon completion of the interventions, the collected data will be analyzed statistically and published in international, peer-reviewed journals.

Trials status

Recruitment for study IRCT20090301001722N26 commenced on September 20, 2023, and is scheduled to conclude on October 19, 2024. The latest protocol is version 1, dated March 8, 2024.