Transcranial Temporal Interference Stimulation of the Right Globus Pallidus in Parkinson's Disease

Abstract

Background

Invasive deep brain stimulation (DBS) has been shown to be effective in treating patients with Parkinson's disease (PD), yet its clinical use is limited to patients at the advanced stage of the disease. Transcranial temporal interference stimulation (tTIS) may be a novel nonneurosurgical and safer alternative, yet its therapeutic potential remains unexplored.

Objective

This pilot study aims to examine the feasibility and safety of tTIS targeting the right globus pallidus internus (GPi) for motor symptoms in patients with PD.

Methods

Twelve participants with mild PD completed this randomized, double‐blind, and sham‐controlled experiment. Each of them received either 20‐minute or sham tTIS of the right GPi. Before and immediately after the stimulation, participants completed the Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS‐III) in the “medication‐on” state to assess the motor symptoms. The blinding efficacy and side effects were also assessed.

Results

tTIS was well tolerated by participants, with only mild, transient adverse effects reported. tTIS significantly reduced MDS‐UPDRS‐III scores by 6.64 points (14.7%), particularly in bradykinesia (23.5%) and tremor (15.3%). The left side showed more significant alleviation in motor symptoms, particularly bradykinesia, compared to the right side. Participants with severer bradykinesia and tremor before stimulation experienced greater improvement after tTIS.

Conclusion

This pilot study suggests that the tTIS, as a novel noninvasive DBS approach, is feasible and safe for alleviating motor symptoms in mild PD, especially bradykinesia and tremor. Future larger‐scale and more definitive studies are needed to confirm the benefits. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Parkinson's disease (PD) is a progressive neurodegenerative disorder that predominantly affects the motor system. The hallmark symptoms of PD include muscular rigidity, tremors, bradykinesia, and postural instability, ¹ all of which negatively impact patients' quality of life and functional independence. Currently, PD management strategies mainly involve pharmacotherapy, physiotherapy, and neurostimulation techniques. Among these, deep brain stimulation (DBS), an invasive neurostimulation approach, has shown significant success in alleviating some of the most debilitating motor symptoms in advanced PD patients. ² The DBS involves the surgical implantation of electrodes in specific brain areas to reduce symptoms via electrical stimulation that interrupts abnormal neural activities and synchrony in targeted circuits. ³ , ⁴ Studies have demonstrated that DBS targeting areas like the subthalamic nucleus (STN) and globus pallidus internus (GPi) ⁴ is effective at reducing motor symptoms in PD with a typical frequency of 130 Hz. ⁵ , ⁶ Despite its benefits, DBS has limitations such as its invasive nature, possible complications, risk of electrode displacement, and the need for an external controller. It is primarily used for patients in advanced stages of PD in clinical practice. ⁷ , ⁸

In recent years, transcranial temporal interference stimulation (tTIS) has emerged as a promising noninvasive therapeutic alternative for DBS. ⁹ Instead of targeting a brain region with an implanted electrode, tTIS employs dual electric currents at slightly different frequencies, utilizing the interference pattern produced within the brain to create a targeted frequency that stimulates designated brain regions. ⁹ The tTIS may offer several advantages for the treatment of mild PD over DBS, especially the elimination of surgical implants. Studies have demonstrated the positive effect of tTIS on neural functions. For instance, tTIS targeting the hippocampus has been observed to enhance memory function. Additionally, θ‐burst tTIS directed at the striatum has been shown to significantly improve motor learning in older adults, ¹⁰ with the effectiveness being frequency dependent—80‐Hz tTIS targeting the striatum may counteract motor learning improvements. ¹¹ More importantly, a recent study based on the observation of more than 250 sessions of tTIS suggests that tTIS is a tolerable and safe technique for humans and can achieve successful blinding. ¹² These human studies, together with previous animal studies, ¹³ provide evidence that implementing tTIS can safely and effectively modulate the neuronal activities in the subcortical regions. Nevertheless, the effects of tTIS on the motor symptoms in PD have not been well examined.

In this pilot study, we thus explored the potential effects of tTIS on motor symptoms in mild PD. Specifically, we employed tTIS of 130 Hz targeting the right GPi. ¹⁴ We hypothesize that (1) compared to sham stimulation (ie, control), tTIS would significantly alleviate the motor symptom as assessed by the total score of Movement Disorder Society‐Unified Parkinson's Disease Rating Scale (MDS‐UPDRS‐III) and its subscores (eg, bradykinesia, tremor), (2) people with more severe symptom before stimulation may have greater improvement after tTIS, and (3) this tTIS would not induce any severe side effects. The findings of this proof‐of‐concept study will provide novel evidence for the feasibility and safety of tTIS for alleviating motor symptoms in PD, informing a potential therapeutic strategy in future clinical practice.

Patients and Methods

This randomized, double‐blind, sham‐controlled, and within‐subject crossover study was conducted by the World Medical Association's Declaration of Helsinki. The study protocol was reviewed and approved by the Ethics Committee of the Shanghai University of Sport (approval number: 102772023RT063). The trial was registered on the clinical trials platform (registration number: ChiCTR2300077258). All participants were informed of the study's framework and potential risks before the commencement of the trial and provided their informed consent.

Participants and Experimental Protocol

Participants were recruited from the affiliated hospital of Shanghai University of Sport and local community Parkinson's support groups. Inclusion criteria were as follows: (1) diagnosed with idiopathic PD according to Brain Bank criteria in movement disorder clinics, with onset at age 40 or later; (2) responsive to levodopa medication (ie, at least 30% reduction in MDS‐UPDRS‐III scores after medication); (3) total score of MDS‐UPDRS‐III ≥20; (4) Hoehn and Yahr (H&Y) stages 1.5 to 2.5; and (5) regular intake of PD medication in the 4 weeks prior to the study.

Exclusion criteria were as follows: (1) presence of other neurologic diseases affecting the study (eg, epilepsy); (2) worse than mild cognitive impairment (Montreal Cognitive Assessment ≤18) ¹⁵ ; (3) orthopedic conditions that could affect motor symptoms; (4) history of taking antipsychotic drugs, antidepressants, or other drugs that could affect dopamine levels; (5) history of severe psychiatric disorders such as depression or psychosis; (6) metallic implants in the head or heart (eg, DBS, pacemakers); (7) history of electroconvulsive therapy; and (8) cardiovascular risk factors diagnosed by a doctor.

After the screening, eligible participants completed the two study visits during their medication‐effective periods (medication‐on phase), at least 1 hour after taking PD‐related medications, with visits timed consistently across sessions. Each participant received either tTIS or sham stimulation (ie, control) in each of the two visits randomly, and at least a 7‐day interval was provided between visits (Fig. 1). The experimental procedure for each session was completed within 1.5 to 2 hours. The intervention included one session of 20‐minute tTIS targeting the right GPi or sham stimulation. Before and 10 minutes after stimulation, they completed the assessments. Two study staff members administrated and monitored the whole study procedure to ensure the safety of the participants.

FIG. 1.

Visit procedure of the study. tTIS, transcranial temporal interference stimulation; UPDRS‐III, Movement Disorder Society‐revised Unified Parkinson's Disease Rating Scale, Part III. [Color figure can be viewed at wileyonlinelibrary.com]

Randomization and Blinding

Neither the participants nor the study personnel involved in the assessment and data processing were aware of the stimulation condition in this double‐blinded study. A random number generator was used to assign numbers (1 for tTIS, 2 for sham stimulation) to each participant. Only one staff who was not involved in any of those procedures managed the randomization and the settings of the stimulation device. Other members of the research team were unblinded after the statistical analyses of the data.

Noninvasive DBS

We employed a simulation protocol following previous studies using a highly detailed and precise standard head model. ¹⁶ The stimulation montage (ie, current intensity and placement of electrodes) was determined by constructing the head model using the SimNIBS framework. Specifically, we segmented tissues and assigned conductivities, placed electrodes following the standard 10‐10 EEG system of 64 channels, performed finite element meshing, and then calculated the electric field. More detailed information is provided in Supporting Materials. The right GPi was the region of interest for the simulated electric field stimulation, and the goal of the modeling was thus to develop an electrode placement scheme inducing a 130‐Hz interfering electric field in this region. According to the simulation results (Fig. 2), the first electrode pair (I1) was positioned in CP3 and CP6, whereas the second electrode pair (I2) was positioned in F3 and F6 of the 10‐10 EEG system. The currents applied for I1 and I2 were 2.5 and 2 mA (AC peak to baseline), respectively, with frequencies of f1 = 1300 Hz and f2 = 1430 Hz, resulting in an interfering electric field frequency Δf = 130 Hz. The intensity of the electric field on target was 0.63 V/m. The total stimulation duration was 20 minutes, including a 30‐second current ramp‐up at the beginning and a 30‐second ramp‐down at the end. Sham stimulation had only 30 seconds of current ramping‐up and ramping‐down at the beginning and end of the stimulation, respectively, to simulate the sensation of actual stimulation.

FIG. 2.

Concept map of electrode placement and electric field modeling with the GPi (globus pallidus internus) montage. The colors show the transcranial temporal interference exposure (electric field modulation magnitude). [Color figure can be viewed at wileyonlinelibrary.com]

The tTIS was delivered using a Soterix Medical's interferential neuromodulation system (Soterix Medical Inc, Incwoodbridge, NJ). Before the stimulation, all preparation was completed, including fitting a 64‐lead electrode cap based on head size, reducing impedance through scalp abrasion with abrasive paste, applying conductive gel, and positioning electrodes to ensure device resistance was under 15 kΩ. Then, a 20‐minute stimulation session was conducted.

During and after stimulation, if participants experienced intolerable adverse reactions, such as severe flashing lights, unbearable pain, or palpitations, researchers would immediately cease the stimulation and stop the assessments. After each tTIS session, participants were asked to fill out a questionnaire regarding blinding effectiveness and adverse events that is widely used in transcranial electrical stimulation. ¹⁷ The severity and their relevance to the stimulation were recorded.

The Assessment of Motor Symptoms in PD

To assess the motor symptoms, participants completed the official Chinese version of MDS‐UPDRS‐III before and 10 minutes after the stimulation. The MDS‐UPDRS‐III includes 33 items, with scores ranging from 0 to 132. The subscores of MDS‐UPDRS‐III, including (1) rigidity (item 3.3), (2) bradykinesia (items 3.2, 3.4–3.8, and 3.14), (3) tremor (items 3.15–3.18), and (4) axial signs (items 3.9–3.13), were also used as the secondary outcomes in the following analyses.

Additionally, we calculated the scores of left and right sides separately, which allowed us to explore if this unilateral stimulation induced unilateral effects. The score for each side ranged from 0 to 44, ¹⁸ which was derived from the sum of scores for rigidity, bradykinesia, and tremor items for each side.

Statistical Analysis

Statistical analysis was performed using IBM SPSS software, version 25.0. Continuous variables were described using mean ± standard deviation (SD). Fisher's test was used to evaluate the blinding efficacy of the two stimulation conditions. The normality of the data was assessed using the Shapiro–Wilk test. When the data were normally distributed, we used separate analysis of variance (ANOVA) models. Specifically, to examine if the outcomes before stimulations were different between two visits, one‐way ANOVA models were used, and the model factor was visit (ie, visits 1 and 2). When the data were not normally distributed, Wilcoxon signed‐rank tests were used to examine if there were differences in the baseline between the two visits.

To examine the effects of tTIS on the primary outcome, when the data were normally distributed, we used a two‐by‐two ANOVA model. The model factors were stimulation condition (ie, tTIS, sham stimulation), time (ie, pre, post), and their interaction. The dependent variable was the total score of MDS‐UPDRS‐III. When a significant interaction was observed, Tukey's post hoc analysis was used to explore where the significance was. Age, sex, and history of PD were included as the covariates in the model. Similar models were also used for secondary outcomes. The significance level was set at P < 0.05 for primary outcome and at P < 0.0125 for secondary outcomes after the Bonferroni correction for multiple comparisons (n = 4).

We performed exploratory analyses to examine if the unilateral tTIS induced unilateral effects (ie, on the left or right side) across all the participants. Similar models that were used for primary and secondary outcomes were used. The significance level was set at P < 0.05 for unilateral total score and at P < 0.017 for three subscores after the Bonferroni correction for multiple comparisons.

To examine the relationship between the pre‐stimulation of motor symptoms and the change in the symptoms from pre‐ to poststimulation, we used Pearson's correlation analysis. The changes in the outcomes that were significantly changed by tTIS were calculated and included in the analysis. The significance level was set as P < 0.05 for the correlation analysis.

Results

Fifteen participants were recruited. Two of them were excluded during the thorough screening process, one of whom had primary tremor with moderate cognitive impairment, and the other concealed a previous DBS surgery during the preliminary online visit. Another participant was withdrawn due to personal reasons (unrelated to the stimulation project) before completing the second visit. A total of 12 participants (7 women; age [mean ± SD]: 71.92 ± 4.23 years; 66–80, median: 72 years) then successfully completed this study. The demographic and clinical characteristics are presented in Table 1. The average duration of illness was 9.75 ± 5.07 years (range: 4–23 years, median duration: 9 years). All participants were on dopamine‐based medication for PD. All the outcomes were normally distributed except for the right‐side rigidity score post‐tTIS. One‐way ANOVA models revealed that there were no significant differences in symptom outcomes before the stimulation between the two visits (P = 0.38–0.86).

TABLE 1.

Characteristics of study participants

Patient ID	Sex	Age (y)	Height (cm)	Weight (kg)	Side of worse symptoms	Disease duration (y)	H&Y	MoCA	FoG	Baseline MDS‐UPDRS‐III
1	M	68	168	62.0	R	5	2.5	28	N/A	41
2	M	73	165	66.4	R	8	1.5	25	18	33
3	M	66	177	80.0	L	8	1.5	30	7	39
4	F	69	158	56.6	L	9	1.5	27	7	45
5	F	74	156	51.6	L	23	2.5	27	14	36
6	F	69	164	63.4	L	6	2	25	N/A	45
7	M	69	172	83.8	L	4	2	26	7	43
8	F	72	160	49.1	R	9	2.5	27	N/A	53
9	M	79	168	72.3	B	11	2	28	N/A	35
10	F	72	152	51.6	R	10	2	29	N/A	46
11	F	72	153	55.0	B	15	2	26	N/A	39
12	F	80	156	60.4	B	9	2.5	26	17	46

Abbreviations: H&Y, Hoehn and Yahr stages; MoCA, Montreal Cognitive Assessment; FoG, freezing of gait; MDS‐UPDRS, Movement Disorder Society‐revised Unified Parkinson's Disease Rating Scale; M, male; R, right; L, left; F, female; B, bilaterally affected; N/A, not applicable.

No moderate or severe adverse events were reported by any of the study participants during or after the stimulation. Six participants (50%) reported mild discomfort related to the active tTIS period, including tolerable sensations of pricking (or itching); additionally, 1 reported a sensation of head warmth, 1 reported slight pain, and 1 reported visual flash toward the end. During sham stimulation, 5 participants (42%) reported mild discomfort, also including tolerable pricking (or itching) sensations; of these, 2 experienced visual flashes, and 1 reported tinnitus. Importantly, none of the participants discontinued the experiment due to an inability to tolerate the electrical stimulation, indicating the procedure's overall tolerability within this cohort.

The Effects of tTIS on Motor Symptoms in PD

The primary two‐way ANOVA model demonstrated a significant interaction between the two factors in the total score of MDS‐UPDRS‐III (P = 0.02) but no significant main effects of stimulation condition and time (P = 0.17–0.34). Tukey's post hoc analysis showed that the score post‐tTIS was significantly lower compared to that in any other three conditions (ie, pre‐tTIS, pre‐ and post‐sham) (Fig. 3; Table 2), suggesting an improvement in the motor symptoms after tTIS.

FIG. 3.

Effects of transcranial temporal interference stimulation on motor symptoms. (A) Total score of MDS‐UPDRS‐III. (B) The score of bradykinesia. (C) The score of tremor. tTIS, transcranial temporal interference stimulation; MDS‐UPDRS‐III, Movement Disorder Society‐revised Unified Parkinson's Disease Rating Scale, Part III; *significant difference. [Color figure can be viewed at wileyonlinelibrary.com]

TABLE 2.

Outcome measures before and after transcranial temporal interference stimulation

Outcome	Active tTIS			Sham tTIS			P‐value
	Pre	Post	Pre vs. post (95% CI)	Pre	Post	Pre vs. post (95% CI)
MDS‐UPDRS‐III
Total	45.18 ± 5.25a	38.55 ± 4.55b	6.64 (1.01–12.26)	45.18 ± 9.09a	46.40 ± 6.26a	−1.22 (−6.99 to 4.55)	0.02
Rigidity	7.09 ± 1.51	6.73 ± 1.56	0.36 (−1.16 to 1.89)	6.18 ± 2.18	6.08 ± 1.73	0.98 (−1.39 to 1.59)	0.49
Bradykinesia	17.64 ± 3.67a	13.45 ± 2.84b	4.18 (0.04 to 8.32)	16.58 ± 6.69a	17.82 ± 4.89a	−1.24 (−5.29 to 2.82)	0.01
Axial	8.67 ± 1.00	7.73 ± 1.49	0.94 (−0.26 to 2.14)	7.30 ± 1.34	7.73 ± 1.35	−0.43 (−1.60 to 0.74)	0.88
Tremor	13.08 ± 3.94a	11.08 ± 2.91b	2.00 (−0.79 to 4.79)	14.82 ± 4.02a	14.20 ± 2.20a	0.62 (−2.37 to 3.60)	0.01
MDS‐UPDRS‐III left side
Total	17.90 ± 3.99a	14.30 ± 2.95b	3.60 (0.66–6.54)	16.09 ± 3.39a	16.60 ± 2.41a	−0.51 (−3.38 to 2.36)	0.05
Rigidity	3.33 ± 1.44	3.33 ± 1.23	0.00 (−0.75 to 0.75)	2.67 ± 1.50	2.67 ± 0.98	0.00 (−0.75 to 0.75)	1.00
Bradykinesia	8.40 ± 1.96a	5.45 ± 1.75b	2.95 (1.09–4.80)	7.00 ± 2.49a	7.64 ± 2.11a	−0.64 (−2.45 to 1.17)	<0.01
Tremor	5.33 ± 2.27	4.75 ± 1.60	0.58 (−0.49 to 1.66)	5.92 ± 2.02	5.08 ± 1.88	0.83 (−0.24 to 1.91)	0.83
MDS‐UPDRS‐III right side
Total	15.45 ± 3.45	12.82 ± 2.56	2.64 (−1.22 to 6.49)	16.55 ± 6.24	15.91 ± 4.76	0.64 (−3.22 to 4.49)	0.46
Rigidity	3.45 ± 1.13	3.18 ± 0.75	0.27 (−0.64 to 1.18)	3.09 ± 1.14	3.25 ± 1.14	−0.16 (−1.05 to 0.73)	0.50
Bradykinesia	6.82 ± 1.78	5.27 ± 1.19	1.55 (−0.82 to 3.91)	6.75 ± 4.11	6.73 ± 2.80	0.02 (−2.30 to 2.34)	0.36
Tremor	5.54 ± 1.70	5.00 ± 2.05	0.46 (−1.03 to 1.94)	6.27 ± 2.33	6.20 ± 1.14	0.07 (−1.41 to 1.55)	0.71

Different letters (a and b) were used to identify where the significance is.

Abbreviations: tTIS, transcranial temporal interference stimulation; 95% CI, 95% confidence interval; MDS‐UPDRS, Movement Disorder Society‐revised Unified Parkinson's Disease Rating Scale.

The secondary models demonstrated significant interactions between the two factors in the scores of bradykinesia (P = 0.01) and tremor (P = 0.01) but not in the scores of rigidity (P = 0.49) and axial (P = 0.88), and no significant main effects of stimulation condition and time (P = 0.14–0.85). Tukey's post hoc analysis showed that the scores of both bradykinesia and tremor were significantly lower compared to any other three conditions, suggesting that tTIS induced improvement in bradykinesia and tremor symptoms (Fig. 3; Table 2).

In the exploratory analysis, we observed significant interactions between the two factors in the total score (P = 0.05) and bradykinesia score (P = 0.008) on the left side, but no significant interactions or main effects were observed on the left‐side rigidity and tremor scores, or on any measures on the right side. Tukey's post hoc analysis showed that the total scores and bradykinesia scores on the left side were significantly lower than those in other conditions, suggesting that tTIS targeting the right GPi were effective in improving motor symptoms on the left side, particularly bradykinesia (Table 2).

The Association between Motor Symptom Scores at Pre‐stimulation and Their Changes as Induced by tTIS

As presented earlier, the scores of MDS‐UPDRS‐III, bradykinesia, and tremor were significantly reduced by tTIS. We thus calculated the change in each of them from pre‐ to post‐tTIS. The primary Pearson's correlation analysis showed that the MDS‐UPDRS‐III scores pre‐tTIS were not significantly associated with its change from pre‐ to post‐tTIS (R = −0.56, P = 0.057, Fig. 4A). However, the secondary analysis showed that those with a greater bradykinesia score had a greater reduction after tTIS (R = −0.65, P = 0.021, Fig. 4B). Similarly, a significant association was observed between the tremor score pre‐stimulation and its change (R = −0.65, P = 0.012, Fig. 4C).

FIG. 4.

Relation between improvement in motor symptoms and symptoms before tTIS. (A) Total score of MDS‐UPDRS‐III. (B) The score of bradykinesia. (C) The score of tremor. tTIS, transcranial temporal interference stimulation; MDS‐UPDRS‐III, Movement Disorder Society‐revised Unified Parkinson's Disease Rating Scale, Part III. [Color figure can be viewed at wileyonlinelibrary.com]

The Blinding Efficacy

After tTIS, 7 participants (58%) believed they had received active stimulation, whereas 4 participants (33%) claimed they were uncertain. After sham stimulation, 6 participants (50%) thought they had received active stimulation, with 3 participants (25%) stating they were uncertain. The result of Fisher's test indicated that there was no significant difference in the correctness of participants' guesses after the two stimulations (P = 0.67), suggesting a satisfactory blinding efficacy.

Discussion

To the best of our knowledge, this is the first systematic study to explore the effects of tTIS on motor symptoms in PD. In line with expectations, a single session of 130‐Hz tTIS targeting the right GPi showed significant improvements in motor symptoms, particularly in bradykinesia and tremor, compared to the control group. Importantly, no severe side effects or adverse events were reported from this treatment. These findings indicate that tTIS is highly promising as a novel, noninvasive therapeutic approach for alleviating motor symptoms in PD, offering a nonsurgical alternative.

The observations reveal that unilateral tTIS targeting the right GPi notably reduced both total and bradykinesia scores on the left side of the body. This lateralized therapeutic effect aligns with the established neuroanatomical principle of contralateral brain control, ¹⁸ , ¹⁹ informing the appropriate design of the stimulation protocol by considering the side‐related severity of symptoms. Moreover, the data imply that the severity of preexisting symptoms may correlate with the extent of positive response to tTIS.

There is an ongoing discussion about whether tTIS, being a subthreshold stimulation, can directly activate neurons or if it requires co‐activation or pre‐activation of the target area. Previous study applying 80‐Hz tTIS to the human striatum, rather than 20 Hz, eliminated benefits for motor learning and altered functional connectivity between the striatum and cortical areas related to motor learning. ¹¹ Additionally, single‐neuron recordings in primate brains have shown that tTIS can alter the timing of neuronal discharge, ¹³ indicating that tTIS may influence neural synchrony or disrupt local oscillatory activity by adjusting the interference field frequency. tTIS is hypothesized to be an ideal noninvasive strategy for disrupting pathological oscillatory activity in deep brain regions. In PD, excessive neuronal synchrony in the basal ganglia, including the GPi, is a common pathological feature, and 130‐Hz DBS is believed to mitigate this over‐synchronization. ³ , ⁴ The results of our study support the notion that subthreshold stimulation, such as tTIS, can have observable or perceptible effects in PD patients. Although our preliminary study focused only on clinical outcomes, we underscore the importance of future research to delve into the underlying mechanisms.

In this study, the adverse events encountered were mild and tolerable, encompassing sensations such as needle‐like pricking (itching), visual flashes, mild discomfort, warmth in the head, and tinnitus. These reactions are congruent with those documented in prior research on electrical stimulation of cortical regions (eg, transcranial direct current stimulation, transcranial alternating current stimulation). ²⁰ , ²¹ This study presents new evidence supporting the safety and efficacy of blinding in individuals with neurological conditions, aligning with previous findings from research on healthy cohorts. ¹² Given the potential complications associated with DBS stimulation over a certain time course, ²² , ²³ , ²⁴ the comprehensive assessments to cognitive and sensory function and neuropsychiatric and vegetative change are critical to confirm the safety of tTIS in future studies using repeated sessions of tTIS.

Several critical considerations must be noted in the ongoing development and evaluation of tTIS as a treatment for PD. (1) We here used a group‐based montage for tTIS as determined using neuro‐modeling technique. Although the results suggested that this group‐based montage is of great promise to benefit patients with PD, the variance in the brain structure may induce the diffusion of the on‐target current, leading to the variance in stimulation effects between individuals. It is thus highly essential to develop the personalized tTIS protocols using neuroimaging techniques (eg, magnetic resonance imaging [MRI]) to improve the focality of the stimulation ²⁵ and to examine its benefits for PD. (2) We examined only the immediate effects of one session of tTIS. Future studies are thus needed to explore the longer‐term effects of repeated sessions of tTIS and potential long‐term complications via recording the patient's diaries and concurrent effects on medication efficacy. ²⁶ (3) We primarily focused here on the clinical improvement in PD, and studies using neuroimaging techniques (eg, functional MRI) are needed to explore the neurophysiological changes within the brain as induced by tTIS and its relationships to the observed clinical improvement, which will ultimately provide insights into the mechanisms underlying the benefits of tTIS. ²⁷ Additionally, more efforts are needed to explore the influences of the parameters of the tTIS protocols (eg, target, frequency, and lateralization ¹⁰ ) on its effects on PD. For example, studies have shown that the modulation of STN and pedunculopontine can also help alleviate the motor symptoms in PD, ⁴ , ⁵ which may also serve as promising stimulation targets of tTIS. It should also be noted that for the safety assessment of this novel technique, we here leverage the questionnaire that has been widely used in other noninvasive brain stimulation techniques. Future research should delve into the long‐term clinical application of tTIS and assess the potential risks in different patient groups. This will ultimately contribute to establishing a reference framework for its clinical use.

In summary, the results of this pilot study are promising and provide a new direction for noninvasive treatment of PD. However, our study involved only patients with mild PD, and therefore, caution should be exercised in generalizing the conclusions.

Conclusion

This pilot study indicates the feasibility and safety of a novel noninvasive DBS technique, tTIS targeting GPi, for treating the motor symptoms in patients with mild PD, especially in bradykinesia and tremor. The comprehensive understanding of the effectiveness, safety, and optimal clinical application methods of tTIS still requires further research.

Author Roles

Conceptualization: Y.L., C.Z., J.L., J.Z.; data acquisition: C.Y., Y.X., X.F., B.W., Y.D., K.W.; data interpretation: C.Y., C.Z., N.C.; methodology: J.L., Z.Q.; writing—original draft: C.Y.; statistical analysis: C.Y., J.Z., C.Z.; writing—review and editing: C.Y., Y.X., C.Z., L.H., J.Z., Y.L.; project administration: Y.L., Z.W.

Supporting information

Data S1. Checklist.

Data S2. Supporting Information.

Data Availability Statement

The corresponding author can provide the data for this study upon reasonable request. The data from this study are not publicly available due to privacy and ethical constraints.