Effect of Transcranial Alternating Current Stimulation on Ataxia Symptoms of Spinocerebellar Ataxia Type 3: A Randomized Clinical Trial

doi:10.21203/rs.3.rs-4814671/v1

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Effect of Transcranial Alternating Current Stimulation on Ataxia Symptoms of Spinocerebellar Ataxia Type 3: A Randomized Clinical Trial

https://doi.org/10.21203/rs.3.rs-4814671/v1

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Currently, there are no treatments to alter the natural course of spinocerebellar ataxia type 3 (SCA3). Transcranial alternating current stimulation (tACS) have the sustainable potential to alleviate SCA3. Therefore, we conducted a randomized controlled trial enrolling 158 patients with SCA3 to investigate the safety and efficacy of tACS (NCT05557786). Enrolled participants received Active-tACS or Sham-tACS treatment 5 days/week for 2 weeks. The primary outcome was the proportion of participants whose Scale for the Assessment and Rating of Ataxia score improved by at least 1.5 points compared with baseline on assessments immediately after treatment and at 1-month and 3-month follow-up visits. The primary outcome assessed in the intention-to-treat population was met by 32 of 40 patients in the active-tACS group (80%) and 4 of 40 patients in the sham-tACS group (OR, 2.04[95% CI, 1.75 to 2.38; P < 0.001]). These promising findings motivate additional study to establish guidelines for tACS as a clinically recommended treatment for cerebellar diseases.

Health sciences/Neurology/Neurological disorders/Spinocerebellar ataxia

Health sciences/Diseases/Neurological disorders/Spinocerebellar ataxia

Spinocerebellar ataxia type 3 (SCA3) caused by a pathogenic CAG expansion of the ATXN3 gene, is the most common autosomal dominant form of inherited ataxia worldwide^1-3. The core clinical manifestation of SCA3 is progressive cerebellar ataxia, which presents as unstable walking, progressive dysarthria, dysphagia, and poor movement accuracy^1,2. Non-motor symptoms (cognitive, affective, fatigue, and sleep disorders) also occur^1,4. There are currently no effective treatments that can alter the natural course of the disease, making SCA3 a significant burden on health and social systems^5-7.

Non-invasive brain stimulation (NIBS) interventions are increasingly used to enhance rehabilitation approaches in treatment of a wide range of neurological and psychiatric disorders by modulating neuroplasticity^8-10. Transcranial alternating current stimulation (tACS) is a special kind of NIBS¹¹, which can stimulate cortical neurons with sinusoidal and biphasic alternating currents¹². Recently, several clinical trials have demonstrated that tACS may be effective in treatment of neurological disorders such as Parkinson's disease¹³, Alzheimer's disease¹⁴, epilepsy¹⁵, schizophrenia¹⁶, depression¹⁷, insomnia¹⁸ and stroke¹⁹. Furthermore, related meta-analysis^20,21 and systematic reviews^22,23 also support the use of tACS as a novel treatment for different neurological conditions. However, there is no well-designed, large, randomized, controlled trial investigating tACS for cerebellar diseases, although one recent study in patients with ataxia described temporary functional improvement after a single session of tACS²⁴. However, the potential long-term effects of repeated sessions of tACS on cerebellar disease remain completely unknown.

Recently, studies on cerebellar tACS, which was developed by Mehta and colleagues²⁵, have demonstrated that cerebellar tACS is safe²⁶ and can modulate different human behavior domains²⁷, including affecting motor adaptation^26,28, improving motor posture^29,30, modulating gait rhythm^31,32, modulating motor learning^33,34, improving visuomotor performance^35,36, and improving affection and cognition^27,37. In addition, animal studies have demonstrated that cerebellar tACS can modulate multiunit spike activity and strongly impact Purkinje cell activity^38-41. These findings support cerebellar tACS as a new approach for regulating oscillatory activity connected to cerebellar networks that could be developed as a therapeutic tool for cerebellar diseases.

Here, this randomized clinical trial investigated the efficacy and safety of tACS, including ataxia severity, quality of life, and adverse events (AEs) in SCA3. We hypothesized that SCA3 patients randomly assigned to receive active-tACS would obtain a greater improvement than sham-tACS.

Study Participants

Between August 2022 and March 2023, we screened 158 participants by phone or in person. Among screened participants, 100 participants met the eligibility requirements, and of these, 18 participants declined to patriciate in the study. The remaining 82 eligible patients were randomized 1:1 into two treatment groups to receive A-tACS or S-tACS. Figure 1 presents the study methodology. The mean (SD) age was 44 (11) years; 29 participants (35.4%) were female, and 53 (64.6%) were male. The mean age at onset of SCA3 was 36 (10) years, and the mean time of disease duration was 8.1 (4.4) years. The mean repeat length of expanded alleles was 75.2 (3.8), and the mean repeat length of short alleles was 20.4 (7.1). The mean baseline functional and mood test scores were as follows: SARA, 10.1 (4.2); EQ-5D, 0.64 (0.23). In baseline gait analysis, mean stride time variability was 0.29 (0.05), mean double-support time variability was 7.44 (2.21), mean toe-out angle variability was 4.63 (3.24), and mean toe-off angle variability was 4.03 (2.51). All baseline demographic and clinical characteristics are provided in Table 1 and were similar between groups. In total, 80 (97.6%) participants finished all treatment sessions (A-tACS, 40 of 41 (97.6%); S-tACS, 40 of 41 (97.6%)).

Table 1

**Baseline characteristics for all randomized participants based on ITT.** Values are expressed as means (SD), count (n), or percentages (%) as appropriate. Abbreviations: SD, standard deviation; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); SARA, Scale for the Assessment and Rating of Ataxia; EQ-5D, The European Quality of Life five-dimension scale; # indicates that a total of 71 participants completed the gait assessment (35 in the A-tACS group and 36 in the S-tACS group); the remaining participants failed to complete the gait assessment because they could not walk independently.
Characteristics	Participants No.
Characteristics	Total (n = 82)	A-tACS (n = 41)	S-tACS (n = 41)
Age, Mean (SD), years	43.72 (10.58)	43.56 (11.14)	43.88 (10.13)
Age at onset, Mean (SD), years	35.67 (10.45)	35.93 (10.98)	35.41 (10.02)
Disease duration, Mean (SD), years	8.05 (4.39)	7.63 (3.95)	8.46 (4.80)
Sex
Male	53 (64.63%)	27 (65.85%)	26 (63.41%)
Female	29 (35.37%)	14 (34.15%)	15 (36.59%)
Repeat length of expanded alleles	75.15 (3.76)	75.12 (3.52)	75.17 (4.03)
Repeat length of short alleles	20.43 (7.14)	20.29 (7.22)	20.56 (7.14)
BMI, Mean (SD), kg/m²	21.80 (3.24)	21.25 (3.36)	22.35 (3.06)
SARA, Mean (SD)	10.14 (4.17)	9.99 (3.73)	10.29 (4.61)
EQ-5D, Mean (SD)	0.64 (0.23)	0.61 (0.24)	0.68 (0.22)
Gait Variability
Stride time variability #	0.29 (0.05)	0.28 (0.05)	0.29 (0.05)
Double-support time variability #	7.44 (2.21)	7.21 (2.03)	7.67 (2.37)
Toe-out angle variability #	4.63 (3.24)	4.4 (3.14)	4.85 (3.35)
Toe-off angle variability #	4.03 (2.51)	3.68 (2.11)	4.37 (2.83)

Primary Outcomes

At T1, both ITT and PP showed that more patients in A-tACS achieved clinical remission rate (80% and 87.5%, respectively) compared with S-tACS (10% and 9.4%, respectively), with odds ratio of 2.04 (95% CI: 1.75, 2.38; P < 0.001) for ITT and 2.18 (95% CI: 1.87, 2.54; P < 0.001) for PP. Sensitivity analyses considered diversified assumptions and using multiple imputation for missing data did not change the conclusion that A-tACS had superior therapeutic effect compared with S-tACS. (Table 2, eTable 1 in Supplement)

Table 2

**Generalized Estimating Equation Analysis of Primary, Secondary Outcomes and Exploratory analyses based on ITT Population.**
	Time	N	A-tACS	N	S-tACS	OR (95%CI)	P value
Primary Outcome	2 weeks	40	32/40 (80%)	40	4/40 (10%)	2.04 (1.75 to 2.38)	< 0.001
	6 weeks	34	28/34 (82.4%)	33	3/33 (9.1%)	2.17 (1.88 to 2.52)	< 0.001
	14 weeks	32	24/32 (75%)	32	1/32 (3.1%)	2.11 (1.77 to 2.52)	< 0.001
	Time	N	A-tACS	N	S-tACS	Mean Difference (95%CI)	P value
SARA EQ-5D STTD DSSD Toe-out SD Toe-off SD	2 weeks	40	8.06 (3.46)	40	10.20 (4.77)	−1.83 (− 2.31 to − 1.35)	< 0.001
	6 weeks	34	7.79 (3.31)	33	10.03 (5.02)	−1.93 (− 2.50 to − 1.36)	< 0.001
	14 weeks	32	7.75 (3.77)	32	10.72 (4.95)	−2.45 (− 3.15 to − 1.74)	< 0.001
	2 weeks	40	0.79 (0.18)	40	0.66 (0.22)	0.17 (0.13 to 0.22)	< 0.001
	6 weeks	34	0.83 (0.18)	33	0.63 (0.27)	0.25 (0.18 to 0.31)	< 0.001
	14 weeks	32	0.82 (0.14)	32	0.59 (0.29)	0.27 (0.19 to 0.35)	< 0.001
	2 weeks	34	0.25 (0.05)	35	0.27 (0.05)	−0.02 (− 0.03 to − 0.01)	< 0.001
	6 weeks	29	0.24 (0.04)	29	0.28 (0.04)	−0.03 (− 0.04 to − 0.02)	< 0.001
	14 weeks	28	0.24 (0.05)	28	0.28 (0.05)	−0.03 (− 0.05 to − 0.02)	< 0.001
	2 weeks	34	6.79 (1.96)	35	7.85 (2.52)	−0.58 (− 0.76 to − 0.41)	< 0.001
	6 weeks	29	6.53 (1.77)	29	8.00 (2.51)	−0.61 (− 0.78 to − 0.44)	< 0.001
	14 weeks	28	6.57 (1.82)	28	8.09 (2.47)	−0.60 (− 0.79 to − 0.40)	< 0.001
	2 weeks	34	4.19 (3.05)	35	4.86 (3.36)	−0.26 (− 0.37 to − 0.14)	< 0.001
	6 weeks	29	3.87 (2.95)	29	4.98 (3.54)	−0.34 (− 0.50 to − 0.19)	< 0.001
	14 weeks	28	4.01 (2.91)	28	5.08 (3.6)	−0.37 (− 0.55 to − 0.20)	< 0.001
	2 weeks	34	3.48 (1.98)	35	4.31 (2.87)	−0.18 (− 0.32 to − 0.03)	0.015
	6 weeks	29	3.31 (2.14)	29	4.39 (2.44)	−0.31 (− 0.50 to − 0.11)	0.002
	14 weeks	28	3.37 (2.16)	28	4.49 (2.43)	−0.32 (− 0.48 to − 0.17)	< 0.001
Values are expressed as means (SD), count (n), or percentages (%) as appropriate.

Secondary outcomes

Therapeutic benefit was also observed at the T2 and T3. The proportion in A-tACS (ITT, 82.4%; PP, 84.4%) was significantly higher than that in S-tACS (ITT, 9.1%; PP, 9.4%) with odds ratio of 2.08 (95% CI: 1.77, 2.44; P < 0.001) for ITT and 2.17 (95% CI: 1.88, 2.52; P < 0.001) for PP at T2. At T3, the proportion was 75% and 3.1% in A-tACS and S-tACS, respectively, for both ITT and PP, resulting in a mean between-group difference of 2.11 (95% CI: 1.77, 2.52; P < 0.001) for both analyses (Fig. 2). Sensitivity analyses considered diversified assumptions and using multiple imputation for missing data did not change the conclusion that A-tACS had superior therapeutic effect compared with S-tACS. (Table 2, eTable 1 in Supplement)

For ataxia symptoms, compared with the S-tACS group, the A-tACS group demonstrated significantly greater reductions in SARA scores (T1: mean difference of − 1.83 [95% CI: −2.31, − 1.35; P < 0.001]; T2: −1.93 [95% CI: −2.5, − 1.36; P < 0.001]; and T3: −2.45 [95% CI: −3.15, − 1.74; P < 0.001]). In addition, we also observed statistically significant within-group improvements in symptoms at each follow-up time point compared with T0 in the A-tACS group, with mean differences of − 1.96 (95% CI: −2.54, − 1.38; P < 0.001) at T1, − 2.11 (95% CI: −2.77, − 1.46; P < 0.001) at T2, and − 2.08 (95% CI: −2.86, − 1.3; P < 0.001) at T3 for SARA scores. However, no statistically significant within-group improvement was noted in SARA scores over time in the S-tACS group (Fig. 3, and Table 2, and eTable 2 in Supplement).

Exploratory analyses

Quality of life measured by EQ-5D showed significantly better improvement in A-tACS compared with S-tACS at all time points with the mean differences of 0.17 points (95% CI: 0.13, 0.22; P < 0.001) at T1, 0.25 points (95% CI: 0.087, 0.301; P < 0.001) at T2, and 0.27 points (95% CI: 0.19, 0.35; P < 0.001) at T3. Whereas no significant improvement was noted in the S-tACS group across time points. In addition, we also observed statistically significant within-group improvements in quality of life at each follow-up time point compared with T0 in the A-tACS group, however, no statistically significant within-group improvement was noted in SARA scores over time in the S-tACS group (Fig. 3, and Table 2, and eTable 2 in Supplement).

For gait variability, both stride time standard deviation (STSD) and double support-time standard deviation (DSSD), showed significantly better improvement in the A-tACS group compared with the S-tACS group at each time point, with mean difference of − 0.02 (95% CI: −0.03, − 0.01; P < 0.001) at T1, − 0.03 (95% CI: −0.04, − 0.02; P < 0.001) at T2, and − 0.03 (95% CI: −0.05, − 0.02; P < 0.001) at T3 for STSD and − 0.58 (95% CI: −0.76, − 0.41; P < 0.001) at T1, − 0.61 (95% CI: −0.78, − 0.44; P < 0.001) at T2, and − 0.60 (95% CI: −0.79, − 0.40; P < 0.001) at T3 for DSSD. Meanwhile, in other measures of gait variability, the A-tACS group had also demonstrated greater improvement in Toe Out Angle Standard Deviation (Toe-Out SD) and Toe Off Angle Standard Deviation (Toe-Off SD) compared with the S-tACS group at each time point, with mean difference of − 0.26 (95% CI: −0.37, − 0.14; P < 0.001) at T1, − 0.34 (95% CI: −0.50, − 0.19; P < 0.001) at T2, and − 0.37 (95% CI: −0.55, − 0.20; P < 0.001) at T3 for Toe-Out SD and − 0.18 (95% CI: −0.32, − 0.03; P = 0.015) at T1, − 0.31 (95% CI: −0.50, − 0.11; P = 0.002) at T2, and − 0.32 (95% CI: −0.48, − 0.17; P < 0.001) at T3 for Toe-Off SD. (Fig. 3, and Table 2). In addition, we also observed statistically significant within-group improvements at each follow-up time point compared with T0 in the A-tACS group, however, no statistically significant within-group improvement was noted in SARA scores over time in the S-tACS group (Fig. 3, and Table 2, and eTable 2 in Supplement).

Adverse Events

Two serious adverse events were determined by the principal investigator to be unrelated to any study procedure during the study. One died from severe pneumonia caused by SARS-CoV‐2 in A-tACS, and one suffered a cervical vertebral fracture after a cycling accident in S-tACS. All study-related AEs were mild and transient, and were reported with similar frequency by the two groups. (Table 3)

Table 3

**Reported adverse events during the study.**
	Treatment, No. (%) of Participants		p Value
	A-tACS (n = 41)	S-tACS (n = 41)	p Value
Adverse events
Optical illusion	14 (34.1)	11 (26.8)	0.632
Scalp pain	7 (17.1)	9 (22.0)	0.781
Erythema	8 (19.5)	8 (19.5)	1
Itches	5 (12.2)	4 (9.8)	1
Dizziness	3 (7.3)	2 (4.9)	1
Serious adverse events	1 (2.4)	1 (2.4)	1

This randomized clinical trial showed the efficacy and safety of tACS in SCA3 patients. TACS yielded significant and meaningful improvements in ataxia severity, and quality of life, and the treatment effects persisted for up for 3 months in 75% patients in A-tACS group. Results of this trial support our hypothesis that 2 weeks of tACS treatment could improve ataxia symptoms for 3 months.

The pathophysiological mechanisms activated by non-invasive stimulation of the cerebellar cortex remain incompletely understood. TACS seems to induce an excitatory tone on Purkinje cells and change the activity pattern in the deep cerebellar output nuclei. The oscillating electric fields generated by tACS can bias neural spike timing through locking to their frequency and phase, which can change local neural oscillatory power as well as alter cross-frequency and cross-area coherence^12,42,43. This results in an enhanced physiological inhibitory effect of Purkinje neurons on cerebellar nuclei and increases the excitability of the cerebellar cortex, which subsequently excites the ventrolateral motor thalamus and then the motor cortex^12,44,45.

This study represents the first application of cerebellar tACS to SCA3 patients. There is no established stimulation protocol for this procedure; therefore, we designed the protocol on the basis of several considerations. First, gamma oscillations are fundamental for organizing temporal neural activity patterns for large-scale brain networks related to behaviors, computations, and codes^46,47. In the molecular layer of cerebellum, inhibitory interneurons, which are connected to Purkinje cells, are active in the gamma frequency band (30–80 Hz)⁴⁸. Thus, we selected 70 Hz tACS in SCA3. Second, we selected a novel montage of tACS based on the combination of computational modelling (eFigure.6 in Supplement 2) using SimNIBS and experimental data^49,50, with the goal of minimizing side effects and maximizing treatment effects. Finally, previous studies showed temporary functional improvement after a single session of tACS in patients with neurodegenerative diseases^24,51,52 and long-term functional improvement after 2 weeks of treatment with 40-min sessions^53,54, and we mirrored this approach to study long-term effects of tACS in SCA3^17,18.

Strengths and Limitations

A strength of the trial was conducted a triple-blinded, sham-controlled, randomized, parallel-group study design, enrolled plenty of patients to provide adequate statistical power to detect treatment effects in cerebellar disease. Another advantage was that we prospectively evaluated a single genetically determined group of patients with SCA3. Furthermore, lots of diverse assessments including ataxia, non-motor symptoms, quality of life, wearable sensors, voice device. Finally, we detected a clinically meaningful effect of tACS at multiple follow-up time points to demonstrate long-term effects. One limitation was that it was a single-center study, and multicenter studies should be performed to validate our findings. Another limitation was that we only evaluated a single frequency, current, and stimulation location. Furthermore, functional magnetic resonance imaging and electroencephalogram should be fully considered for the interpretation of brain neural networks and electrophysiological mechanisms in future studies. Also, the COVID-19 pandemic limited access to the study and increased the number of participants who were lost to follow-up.

This randomized clinical trial showed that multiple sessions of cerebellar tACS are safe, effective, well-tolerated, painless, and easy to perform. Given the paucity of treatments for this disease, these findings offer hope for a new effective intervention to improve ataxia and other clinical manifestations of SCA. Our study supports use of a 2-week course of treatment with tACS for rehabilitation of patients with cerebellar diseases.

Study Design and Participants

The study protocol and statistical analysis plan can be found in Supplement 1. This study was performed in accordance with the Declaration of Helsinki. The local ethics committee of The First Affiliated Hospital of Fujian Medical University, Fuzhou, China (MRCTA, ECFAH of FMU [2022]399), approved the protocol, consent form, and study documents prior to study commencement. This study adhered to the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines⁵⁵. The safety and quality of the study were assessed by an independent data safety monitoring board. ClinicalTrials.gov registration: NCT05557786.

Randomization and Blinding

Eligible patients were randomized to either active-tACS (A-tACS) or sham-tACS (S-tACS) in a 1: 1 ratio based on permuted block randomization. Randomization was stratified by ataxia severity to prevent an imbalance between groups in baseline ataxia severity (Mild: 3 to 7 on the SARA score; Moderate: 8 to 14 on the SARA score; Severe: more than 14 on the SARA score)⁵⁶, which was accomplished using permuted blocks of varying size (block size randomly varying between two, four and six) based on permuted block randomization. Randomization numbers were generated by the R program (blockrand function in the package ‘blockrand’). Randomization was performed by an independent statistician who was neither involved in enrolling patients nor in assessing participants. Physicians assigned a specific code to each participant before the first intervention by giving them a sealed, opaque envelope, which determined treatment group. This maintained blinding of participants, investigators, and outcome assessors throughout the study. The treatment type (A-tACS vs S-tACS) was encoded in the in-house software and was masked for both patients and the researchers. Researchers only needed to enter a patient name and session number to start stimulation, but the technician confirmed whether an A-tACS or S-tACS stimulation was delivered after each treatment was done.

TACS intervention

Physicians assigned the participants to 2 weeks of A-tACS or S-tACS intervention using the same conditions for each session. TACS was delivered via three 0.9% NaCl-soaked surface sponge electrodes (5 × 7 cm) on a current stimulator (Neustim NSS18, Neuracle, Changzhou, China). The return electrode was positioned 2 cm below the inion, and the two active electrodes were positioned over the bilateral buccinator muscles⁴⁹. Electrodes were fixed using elastic gauze and coated with conductive gel to reduce contact resistance (< 5 kΩ).

An alternating sinusoidal current of 2 mA peak-to-peak at a frequency of 70 Hz was used throughout the A-tACS treatment session (40 min), based on previous studies^17,18. The S-tACS stimulation used the same electrode placement, but the current was gradually decreased to no current 40 s after stimulus onset to simulate the experimental stimulus; this approach kept patients blinded regarding their treatment group assignment^34,51.

Procedures and Outcome Measures

Participants provided demographic and general clinical history data by telephone or in person. After screening visit to assess eligibility, participants were asked to attend in-person visits at baseline (T0), 2 weeks (T1), 6 weeks (T2) and 14 weeks (T3) follow-up visits^53,54. Detailed procedures are provided in Supplement 1.

The primary outcome was the clinical remission rate, defined as the proportion of participants with at least a 1.5-point reduction in Scale for the Assessment and Rating of Ataxia (SARA) from T1 to T0⁵⁷.

The secondary outcomes included: the clinical remission rate (defined as the proportion of participants with at least a 1.5-point reduction in Scale for the Assessment and Rating of Ataxia (SARA) from T2 or T3 to T0) at T2 and T3, the changes at T1, T2, or T3 from T0 in SARA. The exploratory analyses included EuroQol 5-dimensional questionnaire (EQ-5D), and gait analysis evaluated with the state-of-the-art wearable sensors.

Adverse Events

At each treatment session, participants were assessed for AEs, discomfort ratings using a commonly used questionnaire in tACS trials, and vital signs. During follow-up, participants were called every 2 weeks to report all AEs experienced.

Sample Size

We expected that 25% of participants in S-tACS and 60% in A-tACS would meet the clinical remission rate, on the basis of Romano and colleagues’ report⁴⁷. Calculation was performed using PASS version 15.0. With an attrition rate of 10%, we determined that a sample size of 80 participants (40 per group) had 80% power and an α value of 5% to detect a statistically significant between-group difference.

Statistical Analysis

The primary study statistician remained blinded to treatment group assignments until after the primary analysis. We described baseline characteristics using descriptive statistics to summarize the demographics, health conditions, and clinical outcomes of the participants, means and standard deviations (SD) for continuous variables, and proportions for categorical variables. We used generalized estimating equation (GEE) models to analyze primary and secondary outcomes, which can adequately account for associations induced by repeated measurements within participants and automatically handle any missing data with the method of maximum likelihood, which assumes that data were missing at random. Independent variables included groups (2 levels: A-tACS and S-tACS), times (3 levels: T1, T2, T3) and group-by-time interaction, with the baseline as the covariable. Measurements closer in time were considered more associated than measurements further apart; thus, we assumed a first-order autoregressive structure. For efficacy outcome, primary analysis involved the intention-to-treat (ITT) with known status, with a secondary analysis in the per-protocol (PP) of participants who completed 3-month follow-up as assigned. Bonferroni tests were used for the comparison between-group (T1, T2 and T3) and within-group at different times (T1, T2 and T3 compared with T0). In addition, we performed a sensitivity analysis assessing the sensitivity of the results to the missing at random assumption (eTable 1 in Supplement). All analyses were performed using SPSS Statistics version 26 (IBM). Statistical significance was set at P < 0.05 (two-sided).

Acknowledgements:

We are grateful to all the patients who agreed to participate in the study, the study staff delivering the intervention, and the clinicians who helped with patient recruitment. We also thank the members of the independent safety monitoring board for their guidance and support. We thank Gong - Hua Wu and Jie Ma for reviewing and analyzing assistance with the data independently.

Author Contributions:

X.C., X.L., and S.G. formulated the research questions and developed the study protocol. R.Y., Z.Y., X.Y.C., and B.C. were responsible for patient recruitment and obtaining informed consent signatures. S.H., and L.Q. were responsible for the random allocation of patients. W.L., H.Z., X.C., W.Z., Y.H., Y.Z., Z.W., X.W. and Q.S. collected and extracted the data, with J.N., N.W., and Y.F., providing supervision. X.L., S.H., L.Q., and D.W. analyzed the data. X.L., and X.C. wrote the manuscript. S.G., X.C., and Y.F. revised the manuscript. All authors had full access to all the data in the study, reviewed the manuscript, and had final responsibility for the decision to submit for publication.

Competing interests

The authors declare no competing interests

Funding/Support:

This study was supported by the Joint Funds for the Innovation of Science and Technology, Fujian Province (No.2021Y9088), the National Natural Science Foundation of China (No.82230039) and the National Natural Science Foundation of China (No.81971082).

Role of the Funder/Sponsor:

The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Group Information:

The Investigators for the OSCCAR trial: The following investigators take authorship responsibility for the study results: Xinyuan Chen, MM; Xia Liu, MD; Wei Lin, MM; Lin Zhang, MM; Xiaoping Cheng, MS; Ziqiang Huang, MM; Wanli Zhang, MS; Huating Zeng, MM; Yanhua Lian, MS; Mengcheng Li, MM; Naping Chen, MM; Zhaodi Wang, MS; Xichen Wang, MS; Zhenyi Liu, MM; Qikui Sun, MM; Ruying Yuan, MD; Xuanyu Chen, PhD; Zhixian Ye, MD; Bi Cheng, MM; Qunlin Chen, MBBS; Jianping Hu, MD, PhD; Ying Fu, MD, PhD; Ning Wang, MD, MD; Shirui Gan, MD, PhD;

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Effect of Transcranial Alternating Current Stimulation on Ataxia Symptoms of Spinocerebellar Ataxia Type 3: A Randomized Clinical Trial

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