Effects of transcutaneous vagus nerve stimulation on anxiety and balance under space constraints in Parkinson's disease with anxiety syndrome: A preliminary study

Abstract

Background

Impaired balance and anxiety are critical motor and non-motor symptoms in Parkinson's disease. Space constraints could heighten anxiety and compromise balance, particularly in anxious individuals. Transcutaneous vagus nerve stimulation (tVNS) has potential for modulating anxiety and motor control, but its effects under space constraints in people with Parkinson's disease (PwPD) remain unclear.

Objective

We aimed to investigate the benefits of tVNS on anxiety and dynamic balance under space constraints in anxious PwPD.

Methods

Sixteen anxious PwPD completed a randomized cross-over trial involving active and sham tVNS sessions. Participants conducted mediolateral weight-shifting by coupling the weight-bearing of their more-affected lower extremity to a sinusoidal target in non-constraint, low-constraint, and high-constraint conditions. Weight-shifting tracking error and amplitude, physiological anxiety, and subjective anxiety were assessed.

Results

Under space constraints, tracking error was reduced (low-constraint: p = 0.002; high-constraint: p = 0.001) and weight-shifting amplitudes toward the more-affected side (low-constraint: p < 0.001; high-constraint: p = 0.015) and less-affected side (low-constraint: p < 0.001; high-constraint: p = 0.015) were larger in active tVNS session compared with sham tVNS session. Relative to sham tVNS, active tVNS led to a lower normalized skin conductance level (physiological anxiety) in the low-constraint (p = 0.012) and high-constraint (p < 0.001) conditions. Neither weight-shifting performance nor anxiety levels were affected by tVNS in the non-constraint condition.

Conclusions

This study provides preliminary evidence that tVNS has the potential to improve weight-shifting control and modulate anxiety under space-constraint conditions in anxious PwPD. These findings suggest that tVNS may be a promising non-invasive intervention for space-related balance deficits in this population.

Trial registration

ClinicalTrials.gov, Balance Exercise and Vagus Nerve Stimulation on Weight-shifting Control and Ambulation in Parkinson Disease and Anxiety, https://clinicaltrials.gov/ct2/show/NCT06476912, NCT06476912.

Plain language summary title

Can non-invasive vagus nerve stimulation reduce anxiety and improve balance in people with Parkinson's disease when space is limited?

Plain language summary

People with Parkinson's disease (PwPD) often have problems with balance and anxiety. These problems may become worse when they stand or move in limited spaces, such as narrow walkways or crowded places. In these situations, anxiety may increase and make balance more difficult, which may increase risk of falling. Therefore, it is important to identifying strategies that can help PwPD maintain balance in space-limited situations.

This study examined whether non-invasive transcutaneous vagus nerve stimulation (tVNS) could reduce anxiety and improve balance in PwPD who had anxiety symptoms. tVNS uses mild electrical stimulation applied to the skin of the outer ear to activate the vagus nerve. This nerve helps regulate stress responses and may also be involved in motor control.

Sixteen participants completed two experimental sessions in a randomized order one with active tVNS and one with sham tVNS). In the active tVNS session, participants received mild electrical stimulation on the left cymba conchae, a part of the outer ear that can stimulate the auricular branch of the vagus nerve. In the sham tVNS session, stimulation was applied to the earlobe, which was not expected to activate this nerve. During each session, participants rhythmically shifted their body weight from side to side at a set speed under three conditions: no space restriction, low space restriction, and high space restriction. Their weight-shifting movements and anxiety levels were recorded.

The results showed that active tVNS was linked to larger weight-shifting movements and lower anxiety when anxious PwPD performed the task under low or high levels of space restriction. However, active tVNS did not show clear benefits when there was no space restriction.

These findings suggest that tVNS may help reduce anxiety-related balance problems in PwPD who have anxiety symptoms, especially when they are in limited spaces.

Keywords

Parkinson's disease anxiety tVNS weight-shifting space constraint

Introduction

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive motor and non-motor symptoms. Impaired balance and anxiety have been prioritized as issues that need to be addressed for motor and non-motor symptoms, respectively.¹ Anxiety is one of the most common non-motor symptoms in people with PD (PwPD), affecting up to 40% of patients.² Moreover, anxiety could exacerbate balance control and the development of freezing of gait (FOG).³ For example, anxious PwPD exhibit larger weight-shifting errors and shorter margins of stability than non-anxious PwPD.⁴ In the clinic, PwPD often complain that space constraints (i.e., narrow or crowed spaces) induce higher anxiety and deteriorate their balance. Studies have also reported that PwPD have higher anxiety scale score when they walk on a narrow plank than on a wide plank in a virtual reality environment, and freezers have a decreased step length and increased step length variability when walking through a narrow doorway (67.5 cm wide) compared with normal-size (90 cm wide) and wide (180 cm wide) doorways.^5,6 Although anxiety is often treated with medicines, studies have proposed that pharmacological treatment for anxiety may lead to higher postural instability and fall incidence in PwPD.^7,8 Thus, non-pharmacological interventions, such as cognitive behavioral therapy, physical exercise, and neuromodulation techniques, have been proposed as alternative approaches for anxiety symptoms.⁹

Vagus nerve stimulation (VNS) is a promising neuromodulation technique that bridges emotional and motor systems through afferent projections to the nucleus tractus solitarius and locus coeruleus that involve arousal, attention, and emotional regulation.^10,11 Both animal and human studies have provided evidence that VNS is a promising therapeutic technique for tackling anxiety.^12–14 A pilot trial of implanted VNS in treatment-resistant anxiety disorders showed modest acute effects, with longer-term benefits observed in patients with obsessive-compulsive disorder.¹² Transcutaneous VNS (tVNS) has been proposed as a safer clinical intervention for anxiety.¹⁵ Recent studies have also shown that tVNS may have potential for improved walking in PwPD. Marano and colleagues reported that a single session of tVNS could increase walking speed and stride (or step) length and reduce step variability for PwPD in either an on-medication or off-medication state.^16,17 In addition, after a 7-day tVNS intervention (30 min/session, 2 sessions/day), PwPD had improved walking performance with decreased oxyhemoglobin in the motor and somatosensory cortices.¹⁸ Although tVNS shows potential for reducing anxiety or improving balance, research examining the concurrent benefits of tVNS for anxiety modulation and balance control remains limited. In particular, no study has investigated the effect of tVNS on balance control in anxious PwPD under space constraints. Given the limited evidence in this area, the present study was exploratory in nature and aimed to generate preliminary evidence regarding the effects of tVNS on anxiety and balance control under space constraints in anxious PwPD.

Space-related deterioration of balance and anxiety in PwPD is often observed clinically; however, studies have seldom examined this issue, and those that have done so have primarily focused on walking tasks.^5,6 Moreover, the association between balance control and anxiety symptoms in PwPD remains insufficiently understood. Impairments in weight-shifting have been identified as one of the most common FOG-related postural deficit, and incorrect weight-shifting may increase the risk of falls in PwPD.^19,20 Accordingly, present exploratory study focused on the effects of tVNS on weight-shifting control and related anxiety levels in anxious PwPD, particularly under space constraints. We hypothesized that 1) space constraints would decrease the accuracy and amplitude of weight-shifting movement in anxious PwPD, and 2) tVNS would reduce anxiety levels and improve weight-shifting control in anxious PwPD, especially under space constraints.

Methods

Participants

Sixteen PwPD with anxiety symptoms were included in this study (Table 1). The inclusion criteria were a diagnosis of idiopathic PD according to the United Kingdom PD Society Brain Bank clinical diagnostic criteria,²¹ a Parkinson Anxiety Scale (PAS) score ≥14,²² ability to stand unassisted without an assistive device ≥60 s, PD onset at >40 years of age, and a Mini Mental State Examination (MMSE) score ≥26 points.²³ Participants were excluded when they had a history of brain surgery, other diseases and conditions that could influence balance, or a score >2 on item 3.13 (posture) of the Movement Disorder Society-sponsored Revision of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS). A score >2 on item 3.13 indicates a predominant stooped posture or scoliosis, which may affect weight-shifting performance. We also excluded participants who were currently taking antidepressants or scored >1 on item 1.3 (depression) of the MDS-UPDRS to avoid a possible influence of depression on postural control.²⁴ All participants had normal or corrected-to-normal vision. All procedures were approved by the National Taiwan University Hospital Research Ethics Committee (Clinical Trial Registration No.: NCT06476912), and all participants provided written informed consent.

Table 1.

Demographic and clinical characteristics of study participants (N = 16).

Characteristic	Values
Age (years)	69.24 ± 6.46
Age range (years)	58.50−79.90
Sex (male/female)	9/7
Disease duration (years)	8.44 ± 5.64
Modified H-Y stage	2.31 ± 0.66
Stage 1.5	3
Stage 2	5
Stage 2.5	2
Stage 3	6
MDS-UPDRS total	29.94 ± 21.71
MDS-UPDRS part I	4.56 ± 4.08
MDS-UPDRS part II	9.38 ± 8.39
MDS-UPDRS part III	15.06 ± 12.48
MDS-UPDRS part IV	0.94 ± 1.48
MMSE score	29.94 ± 5.43
PAS score	19.81 ± 3.47
LEDD (mg)	1163.53 ± 584.92
tVNS intensity (mA)
Active tVNS	2.556 ± 0.167
Sham tVNS	2.563 ± 0.171

Values are presented as the mean ± standard deviation or number of participants unless otherwise noted

H&Y = Hoehn and Yahr; MMSE = Mini-Mental Status Examination; MDS-UPDRS = Movement Disorder Society Unified Parkinson's Disease Rating Scale; PAS = Parkinson Anxiety Scale; LEDD = levodopa equivalent daily dose; tVNS = transcutaneous vagus nerve stimulation.

The sample size was calculated by G*power software. Because prior research specifically examining the interaction between tVNS and space-constraint condition is limited, the required sample size was calculated by independently considering two primary domains: balance performance and anxiety level. For the domain of balance performance, based on a comparable study that investigated the effects of tVNS on walking speed in people with PD,¹⁷ an effect size of dz = 0.81 (α = 0.05, power = 0.80) indicated that 15 participants would be sufficient to detect a tVNS-related effect on balance performance. For the domain of anxiety level, based on a prior VNS research,¹² an effect size of dz = 1.08 (α = 0.05, power = 0.80) indicated that 9 participants would be sufficient to detect a tVNS-related effect on anxiety. Although the final sample size of 16 participants exceeded the estimated requirements for both domains and was considered sufficient to achieve adequate statistical power for detecting the hypothesized effects in our experimental paradigm, the sample size remains relatively small. Therefore, the present study was framed as preliminary.

Experimental setup and data recording

This study used a cross-over design. Each participant underwent two experimental sessions: active tVNS and sham tVNS. The two sessions were held 4 or 5 days apart and the order randomized across all participants (Figure 1). For each participant, both sessions were scheduled at the same time of day, and all examinations were performed in the on-medication state.

Figure 1.

Flow diagram. tVNS = transcutaneous vagus nerve stimulation.

While performing the weight-shifting task, participants stood with feet shoulder-width apart on a level surface. A force plate (9260AA6, Kistler, Switzerland) was placed under the lower limb of the more-affected side, which was identified as the side with higher sum of score when comparing the bilateral scores of the lower extremities from MDS-UPDRS items 3.3 (rigidity), 3.7 (toe tapping), 3.8 (leg agility), and 3.17 (rest tremor amplitude). Participants were asked to track a target signal by controlling their body weight on the force plate. The target signal moved sinusoidally in a mediolateral direction at a speed of 0.25 Hz. This frequency was selected as it approximates the natural frequency of spontaneous postural sway, ensuring stable and precise weight-shifting performance in PwPD while minimizing movement instability.^25,26 The target range was of 10% to 90% of the participant's full body weight on a 22-inch monitor screen. The monitor was positioned at eye level 1.0 m from the participant (Figure 2).

Figure 2.

Schematic representation of the experimental setup.

Three testing conditions were examined in this study: non-constraint, low-constraint, and high-constraint. In the non-constraint condition, participants performed weight-shifting movement without space constraints. In the low-constraint condition, participants performed weight-shifting movements within a low-constraint space (length: 90 cm, width: 90 cm). They were surrounded by light-tight partitions (height: 190 cm) on their left, right and rear sides. In the high-constraint condition, participants performed weight-shifting movements within a high-constraint space (length: 70 cm, width: 70 cm). They were surrounded by the same light-tight partitions as the low-constraint condition. The order of the three testing conditions was randomized across all participants. Each participant completed one practice trial before performing six testing trials in each experimental condition. A rest period of 30 s was provided between trials, with a 1-min break between experimental conditions to minimize the effects of muscle fatigue.

During weight-shifting movements, participants received active tVNS or sham tVNS via a transcutaneous electrical nerve stimulator (TENS; GM3A50TE, Gemore Technology, Taiwan). In the active tVNS session, stimulation electrodes (8 mm diameter; Hometech Co., Ltd, Taiwan) were placed on the left cymba conchae to stimulate the auricular branch of the vagus nerve. In the sham tVNS session, stimulation electrodes were placed on the left earlobe because this area is not innervated by the auricular branch of the vagus nerve.²⁷ The pulse duration and frequency were 250 μs and 25 Hz, respectively. The intensity was individually adjusted below the pain threshold.²⁸ These parameters are recognized as a standard range for effectively modulating the auricular branch of the vagus nerve while maintaining a balance between neural recruitment and participant comfort.

Physiological and subjective anxiety levels were also recorded. The skin conductance level (SCL) was measured by a skin conductance sensor (Q-S222 GSR sensor, Qubit System Inc., Canada) during weight-shifting movements to represent the physiological anxiety level.²⁹ Two disposable tab electrodes were attached to the second knuckles of the index and middle fingers of the participant's left hand to monitor skin conductivity.³⁰ At the end of each trial, participants were asked to rate their subjective anxiety level using the 9-point Self-Assessment Manikin (SAM; 1 = without any anxiety, 9 = greatest anxiety).³¹

Data analysis

For the weight-shifting task, weight-bearing data from the force plate were pre-processed using a zero-phase low-pass filter (cutoff frequency: 6 Hz). The root mean square value of the mismatch between the target weight and the recorded weight was calculated to represent the tracking error. In addition, the weight-shifting amplitudes toward more-affected and less-affected sides were calculated. Weight-shifting amplitude was defined as the peak value of weight shift toward the more-affected and less-affected sides for each weight-shifting cycle, expressed as a percentage of body weight (% body weight).

For analysis of SCL, we recorded the resting-state SCL for 5 min before the main experiment while the participant sat with their eyes closed. The mean value of the 5-min SCL was used to represent the baseline physiological anxiety level. The mean SCL value from the 11th to 60th second during the weight-shifting movement was also calculated. The normalized SCL (nSCL) was calculated as the change from resting-state as follows: nSCL = SCL in weight-shifting period – SCL in resting-state period.²⁹ All weight-shifting performance parameters and anxiety levels were averaged from six testing trials.

In the present study, weight-shifting tracking error and nSCL were designated as the primary outcomes for balance control and anxiety modulation, respectively. Weight-shifting amplitudes and SAM score served as secondary outcomes.

Statistical analysis

Based on the Shapiro-Wilk test, all weight-shifting parameters and nSCL fit a normal distribution. The effects of tVNS (active tVNS vs. sham tVNS) and space (non-constraint, low-constraint, high-constraint) on weight-shifting performance and nSCL were analyzed using two-way repeated-measures analysis of variance (ANOVA). The assumption of sphericity was examined using Mauchly's test for space and tVNS-by-space interaction effects; when this assumption was violated, Greenhouse-Geisser corrections were applied. To minimize the risk of Type I errors, significant main or interaction effects were followed by Bonferroni-adjusted post hoc comparisons. The SAM score was analyzed using nonparametric tests. The Friedman test and Wilcoxon signed-rank test were used to examine the space and tVNS effects. The level of significance was set at p < 0.05. The effect sizes in each variable from the ANOVA, Friedman test, and Wilcoxon signed-rank test were presented as partial eta squared (η_p²), Kendall's W, and r. Signal processing and statistical analyses were performed using MATLAB v. R2024a (MathWorks, MA, USA) and SPSS v. 21 (SPSS Inc., USA). All data are presented as the mean ± standard deviation.

Results

All participants completed the experiment without experiencing any adverse effects or falls.

Behavioral performance

Primary outcome: weight-shifting tracking error

The assumption of sphericity was met for the weight-shifting tracking error, as indicated by Mauchly's test (space effect: p = 0.326; tVNS-by-space interaction effect: p = 0.082). ANOVA revealed significant main effects of tVNS (F_(1,15) = 17.644, p = 0.001, η_p² = 0.541), space (F_(2,30) = 8.274, p = 0.001, η_p² = 0.356), and the tVNS-by-space interaction (F_(2,30) = 7.940, p = 0.002, η_p² = 0.346) on the weight-shifting tracking error (Figure 3A). With Bonferroni adjustment, post-hoc tests showed that space constraints did not significantly affect tracking error when participants received sham tVNS. In contrast, under active tVNS, participants exhibited lower tracking error in the low-constraint (p = 0.002) and high-constraint (p = 0.012) conditions compared with the non-constraint condition, although no significant difference was observed between the low- and high-constraint conditions (p = 0.201). Moreover, compared with sham tVNS, active tVNS led to smaller tracking error values in the low-constraint (p = 0.002) and high-constraint (p = 0.001) conditions. The difference in tracking error between the active tVNS and sham tVNS sessions was not observed in the non-constraint condition (p = 0.831).

Figure 3.

Boxplot of weight-shifting tracking error (A), weight-shifting amplitude toward the more-affected side (B), and weight-shifting amplitude toward the less-affected side (C) under the active tVNS and sham tVNS in the non-constraint, low-constraint and high-constraint conditions. Solid circles represent active tVNS, whereas open circles represent sham tVNS. *p < 0.05, **p < 0.01; ***p < 0.001. BW = body weight.

Secondary outcome: weight-shifting amplitudes

Mauchly's test indicated that the assumption of sphericity was violated for the weight-shifting amplitude toward the more-affected side (space effect: p = 0.003; tVNS-by-space interaction effect: p < 0.001); therefore, Greenhouse–Geisser corrections were applied. There were significant main effects of tVNS (F_(1,15) = 5.559, p = 0.032, η_p² = 0.270) and space (F_{(1.272,19.086)} = 7.245, p = 0.010, η_p² = 0.326), as well as a significant tVNS-by-space interaction (F_{(1.197,17.957)} = 5.779, p = 0.023, η_p² = 0.278) for the weight-shifting amplitude toward the more-affected side (Figure 3B). With Bonferroni adjustment, post hoc tests showed that participants exhibited a smaller weight-shifting amplitude in the low-constraint (p = 0.027) and high-constraint (p = 0.048) conditions than in the non-constraint condition under sham tVNS. However, the weight-shifting amplitudes were not significantly different between the low-constraint and high-constraint conditions (p = 0.231). In contrast to sham tVNS, space constraints did not deteriorate the weight-shifting amplitude toward the more-affected side under active tVNS. In addition, participants had a larger weight-shifting amplitude when receiving active tVNS than sham tVNS in the low-constraint (p < 0.001) and high-constraint (p = 0.015) conditions; this difference was not observed in the non-constraint condition (p = 0.508).

The assumption of sphericity was met for the weight-shifting amplitude toward the less-affected side, as indicated by Mauchly's test (space effect: p = 0.711; tVNS-by-space interaction effect: p = 0.563). The weight-shifting amplitude was significantly affected by tVNS (F_(1,15) = 19.262, p = 0.001, η_p² = 0.562), space (F_(2,30) = 4.218, p = 0.024, η_p² = 0.219), and their interaction (F_(2,30) = 7.009, p = 0.003, η_p² = 0.318) (Figure 3C). Under sham tVNS, post hoc tests with Bonferroni correction showed that the weight-shifting amplitude toward the less-affected side did not change significantly across the three testing conditions. Under active tVNS, participants had a larger weight-shifting amplitude in the low-constraint condition than in the non-constraint condition (p = 0.009). The weight-shifting amplitude in the high-constraint condition did not significantly differ from that of the low-constraint (p = 0.141) or non-constraint (p = 0.657) conditions. The participants had larger weight-shifting amplitudes toward the less-affected side when they received active tVNS than when they received sham tVNS in the low-constraint (p < 0.001) and high-constraint (p < 0.001) conditions, but not in the non-constraint condition (p = 0.881).

Anxiety level

Primary outcome: nSCL

The absolute SCL values in the resting state and each weight-shifting condition are represented in Supplementary Table 1. In addition, representative raw SCL traces under active and sham tVNS across testing condition are shown in Supplementary Figure 1. For nSCL, Mauchly's test indicated that the assumption of sphericity was violated for the main effect of space (p = 0.016), whereas it was met for the tVNS-by-space interaction effect (p = 0.646). Therefore, the Greenhouse–Geisser correction was applied to the main effect of space. ANOVA revealed significant main effects of tVNS (F_(1,15) = 24.556, p < 0.001, η_p² = 0.621), space (F_{(1.381,20.711)} = 5.563, p = 0.020, η_p² = 0.271), and their interaction (F_(2,30) = 5.280, p = 0.011, η_p² = 0.260) on the nSCL (Figure 4A). With Bonferroni adjustment, post hoc tests showed that participants exhibited higher nSCL values in the high-constraint condition than in the non-constraint condition (p = 0.011) under sham tVNS, whereas no significant difference was observed between the non-constraint condition and low-constraint condition (p = 0.101). The nSCL exhibited a marginal significant difference between the low-constraint and high-constraint conditions (p = 0.059). Under active tVNS, the nSCL did not differ significantly among the three testing conditions. In addition, the nSCL values were lower in the low-constraint (p = 0.012) and high-constraint (p < 0.001) conditions when participants received active tVNS compared with sham tVNS, with no significant difference in the non-constraint condition (p = 0.831).

Figure 4.

Boxplot of normalized skin conductance level (A) and the self-assessment manikin score (B) under the active tVNS and sham tVNS in the non-constraint, low-constraint and high-constraint conditions. Solid circles represent active tVNS, whereas open circles represent sham tVNS. *p < 0.05, ***p < 0.001, ⁺p = 0.059.

Secondary outcome: SAM score

For subjective anxiety (Figure 4B), the Friedman test indicated a significant space effect on the SAM score when participants received sham tVNS (χ² = 7.508, p = 0.023, W = 0.751) but not when they received active tVNS (χ² = 1.501, p = 0.591, W = 0.150). In the sham tVNS session, the Wilcoxon signed-rank test revealed that the high-constraint condition had a higher SAM score than the non-constraint (Z = −2.488, p = 0.013, r = 0.622) and low-constraint (Z = −2.044, p = 0.041, r = 0.511) conditions, but the SAM scores did not differ significantly between the non-constraint and low-constraint conditions (Z = −1.708, p = 0.088). For the effect of tVNS, the Wilcoxon signed-rank test indicated that the SAM scores were not significantly different between active tVNS and sham tVNS sessions in the non-constraint (Z = −0.625, p = 0.532, r = 0.156), low-constraint (Z = −0.595, p = 0.552, r = 0.149), or high-constraint (Z = −0.909, p = 0.363, r = 0.227) condition.

Discussion

In the present study, space constraints were associated with anxiety modulation and changes in weight-shifting movement in PwPD, particularly in weight-shifting amplitude. Under both low-constraint and high-constraint conditions, anxious PwPD showed less tracking error, larger weight-shifting amplitudes, and lower anxiety levels with active tVNS than with sham tVNS. On the other hand, the potential benefits of tVNS for weight-shifting control and anxiety relief were not observed in the non-constraint condition. To our knowledge, this study is the first to provide preliminary evidence that tVNS may help reduce anxiety and improve weight-shifting performance in anxious PwPD, particularly under space-constraint conditions.

Effect of space constraints on anxiety and weight-shifting control

Our findings suggest that, during the sham tVNS session, space constraints may adversely affect weight-shifting performance in anxious PwPD, particularly reduced shifting amplitude. Compared with the non-constraint condition, space-constraint conditions were associated with smaller weight-shifting amplitudes toward the more-affected side and higher anxiety levels. Weight-shifting is fundamental to the initiation of forward stepping.³² In particular, mediolateral weight-shifting is essential to daily activities, such as stepping, gait initiation, or turning.³³ The smaller weight-shift amplitudes under space constraints may be due to several reasons. First, high anxiety could influence the perception of affordance and the person may underestimate their action capabilities for action range, showing a withdrawal behavior.³⁴ Second, biomechanical findings in PwPD have demonstrated that patients with higher fear of falling—a psychological manifestation of anxiety—exhibit increased muscle stiffness and reduced pelvic and knee range of motion, limiting movement flexibility and constraining postural adjustment.³⁵ Third, visuospatial or body schema deficits may contribute to the reduced weight-shift amplitudes under space constraints.^36,37 When moving through a narrow space, the perceived relationship between one's own body and environmental objects is impaired in PwPD; they perceive distances as smaller and their own body as larger, reflecting a constriction of the representation of extrapersonal space.³⁶ The phenomenon of space misjudgment may be due to abnormalities in fronto-parietal connectivity.³⁸ Our findings suggest that misjudgment of available space may be more prominent on the more-affected side in anxious PwPD. However, greater spatial restriction did not appear to be associated with further reductions in weight-shifting amplitude, as the high-constraint condition did not produce greater impairment than the low-constraint condition. Nevertheless, participants showed a trend toward higher physiological and subjective anxiety levels as the degree of space constraints increased. Further studies are warranted to investigate fronto-parietal connectivity under space-constraint conditions, particularly in the hemisphere responsible for the more-affected side.

Effect of tVNS on anxiety and weight-shifting control

As expected, tVNS appeared to exert beneficial effects on anxiety modulation primarily under space-constraint conditions, whereas no such effect was observed in the non-constraint condition. Moreover, the anxiolytic effects of tVNS were more evident in physiological anxiety than in subjective anxiety, as reflected by lower nSCL values under active tVNS than under sham tVNS in both the low- and high-constraint conditions. One possible explanation for the lack of a tVNS effect in the non-constraint condition is a floor effect, in which the relatively low baseline anxiety in the non-constraint condition limited the potential for further reduction. This interpretation is supported by the raw SCL traces shown in Supplementary Figure 1. Accordingly, the anxiolytic effects of tVNS may be more readily detectable when physiological stress is heightened under space-constraint conditions. Although no significant difference in subjective anxiety (i.e., SAM score) was observed between the active tVNS and sham tVNS sessions under space-constraint conditions, subjective anxiety remained at similar levels across the space-constraint and non-constraint conditions during active tVNS. In contrast, space constraints were associated with higher subjective anxiety levels during sham tVNS. Mechanistically, tVNS activates brainstem nuclei, notably the nucleus of the solitary tract, which modulates autonomic tone and emotional regulation via projections influencing the amygdala and prefrontal cortex.¹¹ Studies have reported tVNS can immediately reduce anxiety or fear intensity when people are under stressful conditions. For example, during fear extinction, healthy adults who receive active tVNS quickly experience a decrease in anxiety levels compared with those who receive sham tVNS.³⁹ Our study provides preliminary evidence that tVNS may help counteract increases in anxiety under space-constraint conditions in PwPD with anxiety symptoms. Notably, the finding of significant tVNS effect on nSCL but not on SAM score, may be due to the different nature of these two assessments. SCL primarily reflects physiological anxiety or arousal^29,40 and is regulated by the autonomic nerve system.⁴¹ In contrast, SAM scores reflect subjective and consciously perceived anxiety. Because tVNS targets the vagus nerve and may influence autonomic regulation,⁴² these findings may imply that tVNS primarily modulates autonomic anxiety (or arousal) rather than consciously perceived anxiety.

In addition to modulating anxiety, tVNS also influence weight-shifting control, especially under space-constraint conditions. Less tracking error and larger amplitudes of weight-shifting were observed in both low-constraint and high-constraint conditions when participants received active tVNS than when they received sham tVNS (Figure 3). In addition, with active tVNS, the tracking error was even smaller and weight-shifting amplitude toward the less-affected side larger in the low-constraint condition than the non-constraint condition. The space in the low-constraint condition was 90 cm for the width, which is the size of regular doors.6 The observed improvement in fine-tuned weight-shifting control may be partly attributable to reduced anxiety. In the present study, the participants had to track a rhythmic trajectory with a specific rate by meticulously controlling the weight-bearing of the more-affected side, which consumed attentional resources and working memory.⁴ People with high anxiety would direct greater attentional resources to threat-related processing, hindering multiple levels of cognition, such as perception, attention, working memory, and executive function.⁴³ Lower anxiety induced by active tVNS may reduce excessive working memory and free up attentional resources for of the regulation of motor execution, thereby potentially contributing to more precise and resilient movements under pressure.⁴⁴

Some studies have proposed that tVNS could exert motor improvements in PwPD, particularly for patients with comorbid anxiety or emotional dysregulation.^45,46 In Zhang et al.'s study, anxious PwPD had reduced anxiety symptoms and improved verbal fluency performance after receiving 30 min of tVNS for 14 days.⁴⁵ tVNS could activate brain regions involved in motor control, such as the motor cortex, and increase corticospinal excitability, which are inherently deficient in PwPD.⁴⁷ A study of transcranial magnetic stimulation (TMS) showed that tVNS immediately decreases short interval intracortical inhibition over the motor cortex, leading to enhanced cortical excitability.⁴⁸ Another plausible explanation for improved weight-shifting control that tVNS may enhance perceptual processing.⁴⁹ In one study, healthy young adults showed greater accuracy in a random-dot motion task and increased pupil dilation when they received active tVNS compared with sham tVNS.⁴⁹ Sensory gating is impaired in PwPD due to basal ganglia dysfunction,⁵⁰ which may contribute to difficulties in correcting postural trajectories based on visual feedback.⁵¹ Therefore, the reduced tracking error and larger weight-shifting amplitudes observed under active tVNS may be partly reflect enhanced perceptual processing during adjustment of the weight-shifting trajectory. However, because no cortical data were analyzed in the present study, this interpretation remains speculative and should be examined in further tVNS studies incorporating cortical measurement.

The transfer of body weight between legs (i.e., weight-shifting) forms the basis of locomotion. Inadequate scaling and timing of weight-shifting control would cause FOG, especially in narrow spaces.¹⁹ When performing continuous weight-shifting, freezers present smaller mediolateral weight-shifting amplitudes than non-freezers.³³ Studies have demonstrated that tVNS is a safe and effective way to stimulate the vagus nerve.^48,52 Taken together, our findings provide preliminary evidence that tVNS delivered using a TENS device may have potential to reduce anxiety and improve weight-shifting control in narrow spaces for anxious PwPD. Considering that TENS is relatively affordable and widely available in clinical settings, this approach may represent a feasible and accessible adjunctive option for supporting dynamic balance control in this population. However, these potential clinical implications should be interpreted cautiously until they are confirmed by future studies with larger sample sizes.

Methodological concerns and study limitations

This study has some limitations. First, the present study only investigated slow weight-shifting, which corresponds to a slow walking pace and may limit the generalizability of the findings to more dynamic functional mobility tasks, such as turning. This relatively slow movement speed may also help explain why performance did not further deteriorate under the high-constraint condition. Situations with fast speed demand (e.g., under time constraints) have been proposed as a critical factor decreasing weight-shifting amplitude and triggering high anxiety in PwPD.^33,53 Future studies should consider faster weight-shifting movement to better understand the effect of tVNS in PwPD under a condition combining space constraints and time constraints. Second, although participants were not informed which stimulation site was presumed to be effective, formal blinding effectiveness was not assessed in the present study, for example by using a blinding index.⁵⁴ Therefore, expectancy effects, particularly with respect of subjective anxiety, cannot be entirely excluded. Third, this study only examined the immediate effects of tVNS under space constraints, which allowed us to isolate acute anxiety modulation and balance control without confounding from learning effects. Longitudinal studies on balance training combined with tVNS should be conducted to test whether the immediate effects translate into long-term improvements. Fourth, although our findings indicated that tVNS has a positive impact on weight-shifting control and anxiety modulation, further investigation of the neurophysiological mechanisms, such as electroencephalography for regional activation and functional connectivity⁵⁵ or cortical evoked potentials for visual sensory gating,⁵⁶ is needed to elucidate the underlying effects of tVNS on motor control and emotional regulation at the neurophysiological level. Finally, given the exploratory nature of this study, these findings provide important multi-dimensional insights into tVNS effects and serve to generate robust hypotheses for future large-scale confirmatory trials. Furthermore, as a preliminary study, participants were assessed only in the ON-medication state to preserve dopaminergic function necessary for encoding threat-related prediction errors and processing spatiotemporal information.^57–59 Assessing participants in the ON-medication state also reflects typical daily functioning in individuals with PD, thereby enhancing the ecological validity of the findings. Nevertheless, future research with larger sample sizes conducted under OFF-medication conditions is needed to further clarify the clinical applicability of tVNS for balance control.

Conclusion

This study provides preliminary evidence that space constraints may aggravate anxiety and impair weight-shifting control in PwPD with comorbid anxiety. In addition, active tVNS appeared to modulate physiological anxiety (or arousal) and improve weight-shifting performance under space-constraint conditions, although no significant reduction in subjective anxiety was observed. These findings suggest that tVNS may serve as a potential non-invasive strategy to alleviate space-constraint-induced anxiety and balance impairment in anxious PwPD. Additional research is needed to elucidate the underlying neural mechanisms and to determine whether coupling tVNS with motor training could enhance long-term anxiety relief and balance improvements in this population.

Supplemental Material

sj-docx-1-pkn-10.1177_1877718X261465238 - Supplemental material for Effects of transcutaneous vagus nerve stimulation on anxiety and balance under space constraints in Parkinson's disease with anxiety syndrome: A preliminary study

Supplemental material, sj-docx-1-pkn-10.1177_1877718X261465238 for Effects of transcutaneous vagus nerve stimulation on anxiety and balance under space constraints in Parkinson's disease with anxiety syndrome: A preliminary study by Yu-Ting Hung, Ruey-Meei Wu and Cheng-Ya Huang in Journal of Parkinson's Disease

Supplemental Material

sj-docx-2-pkn-10.1177_1877718X261465238 - Supplemental material for Effects of transcutaneous vagus nerve stimulation on anxiety and balance under space constraints in Parkinson's disease with anxiety syndrome: A preliminary study

Supplemental material, sj-docx-2-pkn-10.1177_1877718X261465238 for Effects of transcutaneous vagus nerve stimulation on anxiety and balance under space constraints in Parkinson's disease with anxiety syndrome: A preliminary study by Yu-Ting Hung, Ruey-Meei Wu and Cheng-Ya Huang in Journal of Parkinson's Disease

Footnotes

Acknowledgements

We thank the physicians and nurses at the National Taiwan University Hospital Centre for Parkinson and Movement Disorders for their support and assistance in this study.

ORCID iDs

Yu-Ting Hung

Cheng-Ya Huang

Ethics approval and consent to participate

This study was approved by the Institutional Review Board of National Taiwan University Hospital (approval number: 202301082RIND). All participants provided written informed consent prior to participation in the study.

Consent for publication

Not applicable. This manuscript does not contain any individual person's identifiable data.

CRediT authorship contribution statement

Conceptualization: Y.T.H. and C.Y.H. Methodology: Y.T.H., R.M.W. and C.Y.H. Formal analysis: Y.T.H. and C.Y.H. Writing-original draft preparation: Y.T.H. and C.Y.H. Writing-review and editing: Y.T.H., R.M.W. and C.Y.H. Funding acquisition: C.Y.H.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Science and Technology Council, (grant number NSTC 112-2314-B-006-116-MY3).

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Datasets/data availability statement

The data supporting the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

Supplemental material

Supplemental material for this article is available online.

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