Efficacy and Safety Analysis of Repetitive Transcranial Magnetic Stimulation in Patients with Persistent Postural Perceptual Dizziness: A Single-Center, Single-Blind, Randomized Placebo-Controlled Trial

Abstract

Introduction

Persistent postural-perceptual dizziness (PPPD) is a chronic functional dizziness often triggered by vestibular, psychological, or environmental factors. Current treatments, including pharmacological and cognitive therapies, show limitations. In recent years, transcranial magnetic stimulation (TMS) has been explored in other neuropsychiatric disorders but has not been studied extensively for PPPD.

Objective

We aimed to evaluate the efficacy and safety of TMS of the left high-frequency dorsolateral prefrontal cortex (DLPFC) in improving dizziness and mood disorders in patients with PPPD in a single-blind, placebo-randomized controlled trial.

Methods

This trial recruited patients from October 8, 2023, to June 30, 2024, with follow-up completed on September 30, 2024, of 80 patients screened from the second affiliated hospital of Chongqing Medical University in China. Totals of 4 patients were excluded and 66 patients were randomized. PPPD patients were randomized to receive either TMS (10 Hz, 20 min) or SHAM-TMS treatments to the left DLPFC over ten sessions within 2 weeks. Dizziness severity, anxiety, and depression quality were assessed at baseline, post-treatment, and 1 and 3 months. Adverse events were also monitored.

Results

Of 66 eligible patients [median (IQR) age, 54.5 (49.8–67.0) years; Of 42 women (63.6%)], 33 were randomized to the TMS group, and 33 were randomized to the SHAM-TMS group. After three months, a total of 52 participants (TMS group [n = 27]; SHAM-TMS group [n = 25)] completed the follow-up. At 2 weeks, 1 month, and 3 months post-treatment, the TMS group exhibited significant reductions in the levels of dizziness and anxiety compared to both their baseline measurements and the SHAM-TMS group at the same time points (all, p < 0.05). In the SHAM-TMS group, dizziness showed a significant improvement only at 2 weeks post-treatment compared to baseline (p < 0.05). Additionally, in the TMS group, Hamilton Depression Rating Scale (HAMD) scores decreased at both 2 weeks and 1 month relative to baseline. In contrast, the SHAM-TMS group displayed no significant changes in HAMD scores during the 3-month follow-up.

Conclusion

TMS targeting the DLPFC significantly alleviated symptoms of dizziness and anxiety in patients with PPPD. This non-invasive treatment may offer a safe and effective therapeutic alternative for managing PPPD symptoms. Further large-scale studies are recommended to confirm these findings.

Trial Registration

ClinicalTrials.gov identifier, CTR2400093690.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40120-025-00733-x.

Key Summary Points

Why carry out this study?

Persistent postural-perceptual dizziness (PPPD) is a chronic vestibular disorder associated with continuous dizziness, unsteadiness, and increased motion sensitivity, often triggered by vestibular, psychological, or environmental factors. The condition significantly impairs daily functioning and quality of life.

Traditional treatments, such as vestibular rehabilitation, cognitive behavioral therapy, and selective serotonin reuptake inhibitors (SSRIs), show limitations.

What was the hypothesis of the study?

Transcranial magnetic stimulation (TMS) of the left dorsolateral prefrontal cortex (L-DLPFC) can effectively reduce dizziness and improve psychological symptoms in patients with PPPD compared to a sham treatment.

What was learned from the study?

The results highlight the importance of neuromodulation techniques in managing PPPD and pave the way for future large-scale trials to further explore TMS efficacy.

Introduction

Persistent postural-perceptual dizziness (PPPD) is a chronic vestibular disorder characterized by continuous, non-rotational dizziness, unsteadiness, and increased sensitivity to motion and visual stimuli [1]. The condition often develops following an acute vestibular disorder, with psychological factors, such as anxiety and depression, significantly contributing to its persistence. In an epidemiological study conducted by a Canadian team, it was found that the prevalence of PPPD among patients with chronic dizziness reached 43% [2]; in another study from South Korea, PPPD was identified as the second most common cause of dizziness, following only benign paroxysmal positional vertigo [3]. Patients with PPPD experience symptom exacerbation in response to upright posture, movement, or complex visual environments, leading to significant impairments in daily functioning and quality of life [4]. Traditional treatment options for PPPD include vestibular rehabilitation, cognitive behavioral therapy, and pharmacological treatments such as selective serotonin reuptake inhibitors (SSRIs) [5, 6]. These SSRIs were known to help alleviate dizziness symptoms by addressing the underlying anxiety and depression, which are often present in patients with PPPD [1, 7]. Even so, more than 30%of patients who received SSRI treatment correctly reported no significant benefit [8]. Many non-pharmacological treatment options have already been demonstrated to be effective in the treatment of functional dizziness [9, 10]. Furthermore, an integrated approach combining cognitive behavioral therapy and vestibular rehabilitation has shown longer-lasting positive effects on dizziness symptoms, as well as on accompanying psychiatric dysfunctions such as anxiety and depression [11, 12].

Structural imaging studies, particularly those utilizing voxel-based morphometry, have revealed significant gray matter reductions in several brain areas involved in sensory processing, emotional regulation, and motor control [13]. The longer the duration of PPPD, the more pronounced the gray matter changes observed in the hippocampus, superior temporal gyrus, dorsolateral prefrontal cortex (DLPFC), and cerebellum [14]. At the same time, since PPPD belongs to functional dizziness, we also refer to some early imaging studies in the study of functional dizziness. These studies have highlighted characteristic brain changes in patients with chronic subjective dizziness and phobic postural vertigo (PPV). For instance, Popp et al. and Huber et al. used functional magnetic resonance imaging (fMRI) and structural imaging techniques to observe significant alterations in brain networks associated with sensory processing, emotional regulation, and motor control in PPV patients [15, 16]. These findings further support the neurobiological basis of PPPD, indicating that it may involve both sensory and emotional dysfunctions, and that the observed changes in brain regions could represent maladaptive cortical plasticity in response to chronic vestibular disturbances [14, 17]. Additionally, regions responsible for motor function, such as the precentral gyrus, show structural changes, which could explain the characteristic postural stiffening and increased body sway observed in patients [18–20].

Moreover, longitudinal studies also show that the duration of the disease correlates with the extent of grey matter reductions in regions associated with sensory and motor processing, particularly in the visual cortex and postcentral gyrus [13]. This suggests a progressive alteration in brain structure, reinforcing the hypothesis that PPPD involves long-term maladaptive mechanisms due to heightened visual dependence and diminished vestibular function. These neuroimaging findings emphasize that PPPD is not solely a vestibular disorder but also involves significant changes in brain regions related to emotional processing and sensory integration. This underscores the importance of considering both sensory and emotional components when developing treatment strategies for PPPD [21]. A study by Eren et al. found that short-term non-invasive vagus nerve stimulation significantly improved the quality of life in patients with PPPD [22]. An open-label pilot study in patients with PPV showed that five sessions of transcranial direct current stimulation (tDCS) had a significant impact on reducing dizziness symptoms [23]. However, another double-blind placebo-controlled study of tDCS in patients with PPPD did not find effective relief of dizziness symptoms by stimulating the dorsolateral prefrontal area [24]. A recent double-blind study showed that repetitive TMS (rTMS) is a beneficial addition to patients with PPPD [25]. In conclusion, an increasing number of clinical studies in recent years have confirmed the effectiveness of non-invasive neuromodulation techniques as adjunctive treatments for PPPD [4, 26].

Advances in neuromodulation techniques in recent years, particularly transcranial magnetic stimulation (TMS), have provided promising results for a variety of neurological and psychiatric disorders including depression and anxiety, both of which are common comorbidities of PPPD [9]. TMS is a non-invasive procedure that delivers magnetic pulses to specific brain regions to modulate neural activity [27]. The latest depression treatment guidelines recommend the left DLPFC (L-DLPEC) as a target for therapy [28]. The DLPFC is a brain area involved in emotional regulation and cognitive control, and has long been a key target in the treatment of anxiety and depression. Imaging studies related to functional dizziness [14, 15] and non-invasive neuromodulation research in PPPD [24, 25] also suggest that targeting the DLPFC could be a potentially valuable approach for TMS interventions in treating PPPD. Despite the success of TMS in other conditions, its application in PPPD remains underexplored, and few randomized controlled trials have evaluated its effectiveness in treating the condition.

Given the role of abnormal sensory processing and psychological comorbidities in PPPD, TMS targeting the DLPFC holds the potential for modulating the dysfunctional neural circuits responsible for the condition. This exploratory study aims to address this gap by evaluating the safety and efficacy of TMS in reducing dizziness and psychological symptoms in patients with PPPD. By providing a comprehensive assessment of clinical outcomes in a randomized, placebo-controlled trial, this study offers valuable insights into the feasibility of using TMS as a novel treatment for PPPD.

Materials and Methods

Study Design

This trial was a randomized, single-blind, placebo-controlled study. Patients from the Dizziness Outpatient Clinic and the Inpatient Department of Neurology at the Second Affiliated Hospital of Chongqing Medical University were recruited between October 8, 2023, and June 30, 2024, and followed for up to 3 months after randomization. Follow-up was completed on September 30, 2024. After initial screening and baseline evaluation, participants were randomly assigned to either the TMS group or the SHAM-TMS group using a computer-generated randomization process. The randomization procedure was conducted by researchers who were not involved in patient care or data collection. The randomization process was carried out using a randomization website that generates numbers based on an algorithm. While the operators who performed the treatments knew the group assignments, they were not involved in the clinical evaluation of participants. Patients underwent ten treatment sessions within 2 weeks. Clinical evaluations were performed at baseline, at the end of the treatment, and at follow-up visits 1 month and 3 months post-treatment (Fig. 1). Patients in both groups were unaware of the type of treatment they received, and participants were evaluated blindly after treatment ended. Adverse events during and after treatment were also documented in detail. The SHAM-TMS group received a placebo treatment that mimicked the TMS protocol regarding equipment setup and duration, but did not deliver magnetic pulses to the brain. All participants received financial support covering assessment and treatment costs during the study. Additionally, participants in the SHAM-TMS group were offered free active TMS treatment upon completion of the trial as compensation. This study adhered to the Consolidated Standards of Reporting Trials (CONSORT) guidelines [29] and the ethical principles of the 1964 Declaration of Helsinki. The study protocol was approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University and registered with the Chinese Clinical Trial Registry (registration number: CTR2400093690). Written informed consent was obtained from all participants, including patients, parents/legal guardians, or legally authorized representatives, in accordance with local regulations prior to study participation.

Fig. 1.

Flow of patients through the trial

Participants

The trial used Dizziness Handicap Inventory (DHI) scores as the primary outcome indicator [30–33]. According to previous studies, the average DHI score in the control group was 54.25 ± 14.73 points, while the average DHI score in the experimental group was expected to be lower by 12.34 points. For a significance level of α = 0.05 (bilateral) and a power of 90%, the sample size was calculated as: n = (2 × zα + zβ)² × σ²)/δ². The sample size for each group is estimated to be n = 30. Considering the 1:1 distribution ratio and allowing for a 10% follow-up loss, 66 participants were eventually included in the study. This study enrolled 80 patients diagnosed with PPPD according to the criteria established by the Barany Society [1]. All participants were screened by at least two senior physicians with long-term experience managing vestibular disorders. The inclusion criteria required participants to be between 18 and 80 years old, right-handed, and have no prior history of TMS treatment. Participants must have experienced at least 3 months of non-rotational dizziness and unsteadiness, with heightened sensitivity to motion and visual stimuli. The exclusion criteria included the following: dizziness due to trauma, surgery, tumor, encephalitis, cerebrovascular malformation, or other neurological causes of central dizziness; contraindications to rTMS, including intracranial placement of metallic foreign bodies, cardiac pacemakers, cochlear implants, traumatic brain injury with increased intracranial pressure, signs of brain abnormality, and epilepsy; clinically relevant psychiatric disorders, medical conditions, or neurological diseases; alcoholism or substance abuse; head trauma with a history of loss of consciousness or pregnancy; history of loss of consciousness or pregnancy; and involvement in other research projects. Prior to enrollment, all participants were required to discontinue the use of SSRIs/SNRIs for at least 3 weeks to eliminate potential pharmacological confounders. Throughout the treatment and follow-up periods, patients who resumed or initiated any antidepressant medications (including SSRIs/SNRIs) were excluded from the final analysis to maintain protocol adherence. This exclusion criterion ensured that observed therapeutic effects could be attributed to TMS intervention rather than concomitant pharmacotherapy. Details of eligibility criteria are provided in Table S1.

Transcranial Magnetic Stimulation

We used a figure-eight-shaped coil to give focused magnetic pulses (S-100 Ultimate; Yingchi, Shenzhen, China). The L-DLPFC was located at the F3 site according to the International 10/20 electroencephalogram system [34, 35]. For the TMS session, the coil was parallel to the scalp, while, for the SHAM-TMS session, the coil was at a 90° angle to the scalp [36, 37]. Each participant’s resting motor threshold was measured from their motor cortex (the C3), with the intensity being defined as 50% of the pulses that reliably produced thumb twitches [38]. In the TMS group, a frequency of 10 Hz was delivered for 20 min per session, with each session consisting of 40 trains of 50 pulses, with an inter-train interval of 30 s. The total number of pulses per session was 2000. In the SHAM-TMS group, the coil was placed at the exact location, with the stimulation coil rotated 90°, but the device was adjusted to avoid delivering any active stimulation in order to significantly reduce the magnetic field strength reaching the target area, while still emitting the typical clicking sounds associated with the TMS group, ensuring that the appearance and working sounds were identical to the TMS group, thus maintaining blinding.

Clinical Assessments

The primary outcome measure was the change in dizziness severity, assessed using the Dizziness Handicap Inventory (DHI), a 25-item questionnaire designed to measure the functional, emotional, and physical impact of dizziness on patients’ lives. Secondary outcome measures included Visual Analog Scale (VAS), anxiety, and depression, which were evaluated using the Hamilton Anxiety Rating Scale (HAMA-14) and the Hamilton Depression Rating Scale (HAMD-17), respectively. Assessments were conducted at four time points: baseline (before the first TMS session), immediately after the completion of the 2-week treatment protocol, and at the 1-month and 3-month follow-up visits. Safety assessments included monitoring for adverse effects such as headaches, transient dizziness, scalp discomfort, and other potential side effects commonly associated with TMS. At the end of the study, we assessed the effectiveness of blinding by conducting a questionnaire to determine whether patients had guessed their assigned treatment group.

Statistical Analysis

The statistical analysis was conducted using SPSS version 25.0 (IBM). To ensure the validity of the comparison between the data, we conducted a preliminary test to evaluate the normal distribution of the data and the homogeneity of the variance. For data that follow a normal distribution, the mean (standard deviation) has been used. For data that do not follow a normal distribution, the median (quartile range) has been used and rank sum tests performed to compare baseline features. For categorical variables, the data are expressed as frequency and percentage and compared by the chi-square test. If the normal distribution hypothesis was satisfied, we performed a t test to compare the baseline features of the TMS group and the SHAM-TMS group. A repeated measures ANOVA of 2 (TMS group, SHAM-TMS group) × 4 (baseline, week 2, month 1, month 3) design was used to assess changes in in-group and intergroup clinical outcomes (DHI, HAMA, and HAMD) over time, and to calculate the effect sizes (η²) of major effects and interactions. η² criteria: small effect (0.01~0.059), medium effect (0.06~0.137), and large effect (> 0.137). When a significant main effect was detected, post hoc pairwise comparisons were performed using Bonferroni correction. When Mauchly’s sphericity test was significant (p < 0.05), Greenhouse–Geisser correction was performed on the statistical results. If significant interaction effects were found, a simple effect analysis was performed. Adverse effects were compared between groups using Fisher’s exact test, and any differences in the occurrence of side effects were noted. Additionally, power calculations were conducted to ensure the sample size was sufficient to detect meaningful differences. This enhanced the robustness of the findings and ensured that the study was adequately powered.

Results

Subjects

Of a total of 80 patients who were enrolled or assessed, of whom 66 were considered eligible and participated in the study, made up on 33 in the TMS group and 33 in the SHAM-TMS group. Baseline characteristics, such as age, gender, duration of symptoms, and baseline scores on the DHI, HAMA-14, and HAMD-17, were similar between the two groups, with no statistically significant differences (all, p > 0.05; Table 1). At the end of 3 months of follow-up, five patients were lost to follow-up, one in the TMS group and four in the SHAM-TMS group. Nine participants did not complete ten treatment sessions, five in the TMS group and four in the SHAM-TMS group. Therefore, these patients were excluded from the 3-month evaluation. A PP (compliance protocol) analysis was performed on 52 participants in the TMS group (n = 27) and the SHAM-TMS (n = 25). At the same time, all participants were included in the intention-to-treat (ITT) analysis, and we found that significant differences remained between the TMS and SHAM-TMS groups (p < 0.05). Since the gap between PP analysis and ITT analysis was small, the data presented in this paper are presented as the result of the PP analysis. The details of the study participants are shown in Fig. 1.

Table 1.

Demographic and clinical characteristics of the patients at baseline

Characteristic	Overall (n = 66)	TMS group (n = 33)	SHAM-TMS group (n = 33)	p value
Age, years	54.5 (49.8–67.0)	54.1 (15.8)	56.2 (12.1)	0.55
Female, n (%)	42 (63.6)	20 (60.6)	22 (66.7)	0.80
Duration, month	11 (3.0–24.0)	14 (3.5–36.0)	7 (3.0–16.0)	0.06
Education, years	12.0 (9.0–16.0)	12.0 (9.0–16.0)	12.0 (9.0–12.0)	0.89
Exercise intensity, n (%)
Low	16 (24.2)	7 (21.2)	9 (27.3)	0.92
Moderate	35 (53.0)	19 (57.6)	16 (48.5)
High	11 (16.7)	5 (15.2)	6 (18.2)
Others	4 (6.1)	2 (6.1)	2 (6.1)
Medical history, n (%)
Smoking	14 (21.2)	7 (21.2)	7 (21.2)	1.00
Drinking	16 (24.2)	7 (21.2)	9 (27.3)	0.56
Hypertension	27 (40.9)	14 (42.4)	13 (39.4)	0.80
Diabetes	15 (22.7)	6 (18.2)	9 (27.3)	0.38
Hyperlipidemia	17 (25.8)	8 (24.2)	9 (27.3)	0.78
Clinical evaluation
DHI score	53.4 (13.9)	52.1 (15.5)	54.7 (12.2)	0.46
VAS score	5.0 (1.2)	4.9 (1.4)	5.5 (0.9)	0.30
HAMA score	16.6 (8.3)	17.0 (8.6)	16.3 (8.1)	0.73
HAMD score	10.7 (6.4)	11.4 (6.9)	10.0 (6.0)	0.37

Satisfies normal distribution mean (SD), not normal distribution median (IQR), and categorical variables use frequency (%). p > 0.05 indicates no significant difference. Smoking and drinking include current or past

DHI Dizziness Handicap Inventory, HAMA Hamilton Anxiety Rating Scale, HAMD Hamilton Depression Rating Scale, VAS Visual Analog Scale

Clinical Outcomes

This study aimed to investigate the effects of TMS and time on DHI. A two-way repeated measures ANOVA was conducted with a sample of 52 participants. The analysis revealed a significant main effect of group, indicating that DHI was significantly reduced in the TMS group compared to the SHAM-TMS group. Moreover, the interaction effect between group and time (F = 27.34, η² = 0.30, p < 0.01; Table S2) was also significant, suggesting that the effect of the group on DHI varied significantly across different time points. Therefore, simple effects analyses were conducted. The DHI scores of the TMS group and SHAM-TMS group at different time points are shown in Table 2. Post hoc analyses using Bonferroni correction showed significant differences in DHI scores at 2 weeks, 1 month, and 3 months compared to the baseline in the TMS group (p < 0.01; Fig. 2A). At the end of the 2-week treatment period, the TMS group demonstrated a mean reduction of 25.4% in DHI scores, while the SHAM-TMS group exhibited a reduction of only 17.6%. These findings suggest that TMS was effective in relieving dizziness in patients with PPPD.

Table 2.

Efficacy and safety outcomes between TMS-group and SHAM-TMS group

	TMS-group (n = 27)	SHAM-TMS group (n = 25)	t value	p value
DHI
2 week	33.9 (13.2)	45.0 (10.4)	− 3.8	< 0.01
1 month	29.8 (12.1)	47.09 (11.0)	− 6.1	< 0.01
3 month	37.0 (12.3)	49.33 (10.4)	− 4.2	< 0.01
VAS
2 week	3.2 (1.5)	4.1 (1.0)	− 3.1	< 0.05
1 month	2.7 (1.1)	4.2 (1.3)	− 5.4	< 0.01
3 month	3.7 (1.4)	4.2 (1.3)	− 3.2	< 0.05
HAMA
2 week	9.6 (5.7)	12.4 (6.0)	− 2.0	< 0.05
1 month	8.8 (5.2)	12.1 (6.1)	− 3.4	< 0.05
3 month	9.9 (5.0)	13.7 (6.1)	− 2.7	< 0.05
HAMD
2 week	6.4 (4.3)	7.8 (4.4)	− 1.3	0.20
1 month	6.4 (4.6)	8.1 (4.6)	− 1.6	0.12
3 month	7.7 (4.0)	7.9 (3.8)	− 0.2	0.82

p value represents significant difference compared with the TMS-group and the SHAM-TMS group

Fig. 2.

Comparison of within-group baseline and between-group efficacy in the TMS and SHAM-TMS groups: Dizziness Handicap Inventory (DHI) scores (A), Visual Analog Scale (VAS) scores (B), Hamilton Anxiety Rating Scale (HAMA) scores (C), and Hamilton Depression Rating Scale (HAMD) scores (D) for the TMS group and the sham-TMS group at baseline, after 2 weeks of treatment, 1 month, and 3 months. The data are presented as means (SD), and simple effects tests with LSD as default adjustment was used for pairwise comparison. *p < 0.05 versus SHAM-TMS group, #p < 0.05 versus baseline

In terms of VAS score, dizziness symptoms in the TMS group improved significantly after 2 weeks of treatment (p < 0.05; Fig. 2B), showing a trend from moderate to severe dizziness to mild to moderate dizziness. Unfortunately, at the 1-month and 3-month follow-ups, patients’ VAS showed an aggravating trend and eventually remained between 3 and 4 points (3.70 ± 1.38, p < 0.05; Fig. 3).

Fig. 3.

Distribution of scores on the VAS at 3 months among patients. Figures indicate percentage share, and the dotted line denotes the proportion of VAS scores of 4 or less

The HAMA-14 and HAMD-17 scores were significantly lower in the TMS group immediately after treatment and at follow-up points (p < 0.01), whereas the SHAM-TMS group exhibited only marginal improvements (p > 0.05). At the end of the 2-week treatment period, the TMS group demonstrated a mean reduction of 44% in HAMA-14 and HAMD-17 scores, while the SHAM-TMS group exhibited a reduction of only 24% and 22%, respectively. Notably, although the HAMD scores in the TMS group showed variability compared to those at baseline (p < 0.05; Fig. 2C), no significant differences were seen in HAMD intergroup comparisons during the follow-up period (p > 0.05; Table 2).

Based on the results of the correlation analysis, we found a significant positive correlation between DHI, HAMA, and HAMD, suggesting that the level of vertigo is correlated with the level of anxiety and depression (the Pearson correlation coefficient between DHI and HAMA was r = 0.650, p < 0.01, and the Pearson correlation coefficient between DHI and HAMD was r = 0.575, p < 0.01). Meanwhile, the correlation between HAMA and HAMD was highly significant (r = 0.889, p < 0.01, Table S3), indicating that anxiety levels are highly correlated with depression levels.

Safety Outcomes

Both the TMS and SHAM-TMS treatments were well tolerated, with no serious adverse events reported in either group. The most common side effects in the TMS group included dizziness (18.2%), mild scalp discomfort (15.2%), transient headaches (12.1%), and neck pain (9.1%). All these side effects were resolved without intervention. Similar side effects were reported in the SHAM-TMS group, with transient dizziness being the most frequent (9.1%). No significant differences in the incidence of side effects were observed between the groups (p > 0.05; Table 3), and no long-term complications were noted during the 3-month follow-up period. Overall, TMS was found to be a safe and feasible treatment option for patients with PPPD. In the blind evaluation of the two groups of participants, the questionnaire was divided into three options: experimental group, control group, and uncertainty. Finally, it was found that there was no significant difference in the blind evaluation of the subjects who completed the 2-week treatment (p > 0.05; Table 4).

Table 3.

The occurrence of adverse effects in the study groups

Side effects	TMS group (n = 33)	SHAM-TMS group (n = 33)	p value
Dizziness	6 (18.2)	3 (9.1)	0.29
Headache	4 (12.1)	2 (6.1)	0.40
Scalp discomfort	5 (15.2)	2 (6.1)	0.23
Neck pain	3 (9.1)	2 (6.1)	0.64

The chi-square test was used to compare proportions. The number represents frequency (%)

Table 4.

Blind evaluation in the study groups

	Experimental group	Control group	Uncertain	p value
TMS-group (n = 31)	14 (45.2)	6 (19.4)	11 (35.5)	0.22
SHAM-TMS group (n = 30)	8 (26.7)	5 (16.7)	17 (56.7)

The chi-square test was used to compare proportions. The number represents frequency (percentage)

Discussion

These results suggest that TMS applied to the left DLPFC could significantly reduce dizziness and anxiety symptoms in patients with PPPD. TMS, as a non-invasive treatment option, was usually well tolerated. In our study, the most common adverse events were transient dizziness and mild scalp discomfort, and no serious adverse events were observed. These findings highlighted the potential of TMS as a new, non-invasive treatment option for PPPD.

This study is the first to evaluate the efficacy of high-frequency TMS targeting L-DLPFC in patients with PPPD, providing valuable insights for future related studies. While TMS is well known for the treatment of psychiatric disorders, its use for vestibular disorders, particularly PPPD, is a novel therapeutic approach. Direct comparisons with existing pharmacological treatments (e.g., SSRIs) have shown that, while both approaches target anxiety and depression, TMS has additional advantages in addressing sensory processing dysfunction associated with dizziness. Additionally, the rate of improvement in dizziness with TMS compared to SSRIs and vestibular rehabilitation warrants further exploration to determine if TMS achieves higher rates of relief.

Notably, there was a significant improvement in DHI scores in the TMS group. Dizziness in patients with PPPD is multifactorial and associated with vestibular dysfunction, sensory sensitivity, and psychological distress. The reduction in dizziness severity may be due to TMS modulating cortical circuits involved in sensory integration and emotion regulation. It is well known that the DLPFC, a brain region involved in emotion regulation and cognitive control, plays a key role in processing anxiety and sensory inputs, which explains the widespread therapeutic effects of TMS. By modulating these circuits, transcranial magnetic stimulation may help to alleviate the abnormal sensory processing and emotional factors which contribute to the persistence of Parkinson’s disease symptoms. In addition, the reduction in anxiety and depression in the TMS group of patients is consistent with previous studies showing the efficacy of TMS in treating psychiatric disorders. Anxiety and depression are common complications of PPPD, and these emotional states may exacerbate dizziness and other symptoms. By targeting DLPFC associated with anxiety and depressive disorders with TMS, the psychological burden which contributes to the persistence of dizziness may be reduced. This not only improves the patient's mood but also breaks the vicious cycle of psychological distress exacerbating vestibular symptoms.

Despite these encouraging results, there are some limitations to consider. Firstly, although screening was performed and basic information was matched between the two groups, residual bias may still be present. Additionally, while the observed improvements in the TMS group are promising, potential contributions from placebo effects or the natural progression of PPPD cannot be entirely ruled out. However, the randomized placebo-controlled design and blinded assessment protocol aimed to minimize the influence of placebo effects. Secondly, due to the limited sample size, we were unable to perform comprehensive covariate analyses for potential confounding factors such as age, gender, educational background, and medical history. These variables may influence treatment response and should be rigorously controlled in future large-scale studies. In addition, despite the pre-calculated sample size and reliable results, the relatively short follow-up period and premature termination of the study restrict our ability to assess long-term outcomes and potential late adverse effects. While early termination was necessitated by ethical concerns over symptom exacerbation in a subset of patients, future studies should prioritize extended follow-up intervals (e.g., 6–12 months) to better characterize the durability of TMS effects. Consequently, larger multicenter trials with long-term follow-up are needed to confirm the efficacy of TMS in a broader population of patients with PPPD. The outcome indicators are mainly scale-rated and may have subjectivity. However, in the case of functional dizziness disorders, there is a lack of objective measures. Future studies should explore whether TMS protocols should be modified, such as targeting different brain regions or adjusting stimulation parameters. Finally, the therapeutic mechanism of TMS for PPPD remains unclear. Although it has been hypothesized that cortical networks involved in sensory processing and emotion regulation play a role, further studies using neuroimaging techniques such as fMRI or electroencephalography are needed to elucidate the specific changes induced by TMS in brain activity in patients with PPPD.

TMS holds promise as a treatment option for PPPD which addresses both the vestibular and psychological factors that contribute to exacerbations. While larger, more definitive studies are necessary to confirm these findings, the current findings provide a foundation for further exploration of TMS as a clinically viable and accessible treatment for PPPD. Attention must be paid to the changes observed after treatment. Pharmacological treatments usually require 6 months of continuous medication to achieve the expected efficacy. In contrast, the present study found that TMS can be effective in the short term for patients with PPPD and that, in the future, it may be possible to combine TMS with existing treatments such as SSRIs, vestibular rehabilitation, or cognitive behavioral therapy to see if the overall treatment effect can be improved. Due to its non-invasiveness, safety, and potential for sustained symptom relief, TMS could be incorporated into the standard of care for patients with PPPD, ultimately improving their outcomes and quality of life.

Conclusion

This exploratory randomized controlled trial has demonstrated that TMS applied to the left DLPFC is a safe and effective treatment option for patients with PPPD. The significant improvements in dizziness severity, as well as reductions in anxiety and depressive symptoms, suggest that TMS may provide a novel therapeutic approach for managing this chronic and often treatment-resistant condition.

Supplementary Information

Below is the link to the electronic supplementary material.

Author Contributions

Wenze Li: writing—original draft; writing—review and editing; conceptualization; methodology; validation; investigation. Chang Liu: writing—original draft; writing—review and editing; conceptualization; methodology; validation; investigation. Yuqing Zhang: review and editing; methodology. Maolin Peng: investigation. Xiuhang Luo: investigation. Hongfa Zhang: review and editing. Hairong Lan: investigation. Zhipeng Li: review and editing. Yankun Chen: review and editing. Zhen Li: investigation. Zhimin Xiao: methodology; review and editing. Linyan Tong: Conceptualization; methodology; supervision; validation; writing—review and editing. Yangmei Chen: Conceptualization; methodology; supervision; validation; writing—review and editing.

Funding

This work and the journal’s Rapid Service Fee were supported by NSFC. The authors gratefully acknowledge support from The National Natural Science Foundation of China (82471474).

Data Availability

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Declarations

Conflict of Interest

Wenze Li, MD, Chang Liu, MD, Yuqing Zhang, PhD, Maolin Peng, B.Med, Xiuhang Luo, B.Med, Hongfa Zhang, MD, Hairong Lan, B.Med, Zhipeng Li, MD, Yankun Chen, MD, Zhen Li, MD, Zhimin Xiao, MD, Linyan Tong, MD, and Yangmei Chen, MD have nothing to disclose.

Ethical Approval

The study protocol was reviewed and approved by the Ethics Committee of the Second Affiliated Hospital of Chongqing Medical University and the Chinese Clinical Trial Registry with registration number CTR2400093690. Written informed consent was obtained from the patients, parents/legal guardians, or legally authorized representatives before study participation, in accordance with local regulations and the Declaration of Helsinki. https://www.chictr.org.cn/showproj.html?proj=218764

Consent to Participate

Patients/participants provided written informed consent to participate in this study. The individual's written informed consent has been obtained for the publication of any potentially identifiable images or data contained herein.