Effects of non-invasive brain stimulation for degenerative cerebellar ataxia: a protocol for a systematic review and meta-analysis

Abstract

Introduction

To date, the medical and rehabilitation needs of people with degenerative cerebellar ataxia (DCA) are not fully met because no curative treatment has yet been established. Movement disorders such as cerebellar ataxia and balance and gait disturbance are common symptoms of DCA. Recently, non-invasive brain stimulation (NIBS) techniques, including repetitive transcranial magnetic stimulation and transcranial electrical stimulation, have been reported as possible intervention methods to improve cerebellar ataxia. However, evidence of the effects of NIBS on cerebellar ataxia, gait ability, and activity of daily living is insufficient. This study will aim to systematically evaluate the clinical effects of NIBS on patients with DCA.

Methods and analysis

We will conduct a preregistered systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We will include randomised controlled trials to assess the effects of NIBS on patients with DCA. The primary clinical outcome will be cerebellar ataxia, as measured by the Scale for Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale. The secondary outcomes will include gait speed, functional ambulatory capacity and functional independence measure, as well as any other reported outcomes that the reviewer considers important. The following databases will be searched: PubMed, Cochrane Central Register of Controlled Trials, CINAHL and PEDro. We will assess the strength of the evidence included in the studies and estimate the effects of NIBS.

Ethics and dissemination

Because of the nature of systematic reviews, no ethical issues are anticipated. This systematic review will provide evidence on the effects of NIBS in patients with DCA. The findings of this review are expected to contribute to clinical decision-making towards selecting NIBS techniques for treatment and generating new clinical questions to be addressed.

PROSPERO registration number

CRD42023379192.

Correspondence to Dr Akiyoshi Matsugi; [email protected]

Strengths and limitations of this study

• This systematic review and meta-analysis will address the effect of non-invasive brain stimulation (NIBS) on widely degenerative cerebellar ataxia (DCA).

• The effect sizes of the repetitive transcranial magnetic stimulation and transcranial electrical stimulation on symptoms of cerebellar ataxia will be calculated and compared.

• This study will provide the parameters of NIBS montages for DCA, based on a systematic review.

• This systematic review may reveal a lack of solid and strong evidence, due to the heterogeneity of intervention parameters and diseases.

Introduction

Degenerative cerebellar ataxia (DCA)¹ is a group of inherited neurodegenerative disorders that are characterised by progressive cerebellar ataxia.² Representative diseases include autosomal dominant spinocerebellar ataxia (ADSCA),³ spinocerebellar ataxia (SCA),^4–6 Friedreich’s ataxia (FA),⁷ multiple system atrophy with cerebellar ataxia (MSA-C),⁸ sporadic adult-onset ataxia of unknown aetiology (SAOA)⁹ and autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS).¹⁰ The pathological hallmark of almost all types of DCA is the loss of neurons such as Purkinje cells in the cerebellum, which leads to its atrophy. In addition, degeneration of other neuronal populations in the cerebellum, brainstem and spinal cord contributes to the wide range of clinical manifestations of DCA. These diseases lack adequate treatment, and the associated movement disorders are progressive and have a significant impact on the patients’ daily living activities and quality of life.¹¹ These diseases are rare, and while treatment methods are being developed, they remain insufficient to meet patients’ medical needs.^12–14

Some pharmacological and non-pharmacological treatments have been recommended in previous systematic research based on clinical studies.¹⁵ One of the treatments for movement disorders and disabilities is neurorehabilitation, including high-intensity physical and occupational therapy.¹¹ Some conventional interventions, such as weighted orthoses and balance training,¹⁶ are applied by clinicians. Additionally, non-invasive brain stimulation (NIBS), such as repetitive transcranial magnetic stimulation (rTMS)^17–22 and transcranial electrical stimulation (tES),^23–29 is also used for neuromodulation.³⁰

Single-pulse TMS can induce action potentials in the focal cortical site of the brain, resulting in temporal effects on motor and sensory function.³¹ Moreover, rTMS can induce more long-term changes in neural activity and function than single-pulse stimulation.³² rTMS has thus been studied as a potential treatment³³ for mental disorders,³⁴ cognitive dysfunction,³⁵ pain,³⁶ movement disorders after stroke,³⁷ symptoms of Parkinson’s disease,³⁸ multiple sclerosis³⁹ and cerebellar ataxia.¹⁹ These studies have indicated that rTMS can be performed to obtain long-term desirable effects on the symptoms of cerebellar and other neural diseases and in a safe manner in these patients.³²

Recent systematic reviews and meta-analyses have investigated the effects of rTMS on cerebellar ataxia, including patients with DCA and patients who had a stroke.⁴⁰ One review⁴⁰ has reported that rTMS improves scores on the International Cooperative Ataxia Rating Scale (ICARS),⁴¹ the Scale for the Assessment and Rating of Ataxia (SARA),⁴² the Berg Balance Scale and in Timed Up and Go tests.⁴⁰ These findings indicate that rTMS has the potential to improve cerebellar ataxia, balance and gait dysfunction. However, the effect of rTMS may be affected by other conditions, including stroke and degenerative diseases. About 80% of cases with cerebellar ataxia after cerebellar stroke reach an independent level of activity of daily living within 3 months after onset.⁴³ DCA, on the other hand, causes a gradual loss of Purkinje cells in the cerebellar cortex and functional compensations in the deep cerebellar nuclei and cerebral cortex, gradually resulting in significant dynamic changes in the cerebrocerebellar system over time.⁴⁴ Because the pathophysiologies of stroke and DCA differ considerably, there may be too much heterogeneity to unify the effects of rTMS. In addition, the quality and heterogeneity of the studies should be considered. One systematic review on the effect of rTMS on DCA¹⁹ included seven randomised controlled trials (RCTs), but a recent report²¹ that aimed to improve cerebellar ataxia with a novel stimulus parameter of rTMS was not included. The reason this RCT was excluded is that the prior systematic review limited the disease to SCA, that is, it did not cover MSA-C, a neurodegenerative disease that presents with cerebellar ataxia. Therefore, we will estimate the effect of rTMS on cerebellar ataxia in DCA based on recent clinical studies.

Another important use of NIBS is tES for the treatment of DCA. This method,⁴⁵ which includes transcranial direct current stimulation (tDCS),⁴⁶ transcranial alternating current stimulation⁴⁷ and transcranial random noise stimulation,⁴⁸ applies a low-level electrical current to the scalp to modulate the activity of the underlying brain tissue. This technique involves placing one or more electrodes on the scalp and applying a weak direct/alternating/random noise current that flows between the electrodes. The mechanism of tDCS is thought to involve changes in the resting membrane potential of neurons in the brain.⁴⁵ A continuous weak electrical current can depolarise or hyperpolarise neurons, depending on the polarity and intensity of the current. However, despite many reports of its clinical efficacy, the underlying mechanism remains controversial.⁸

The tDCS is most often used in clinical trials for DCA treatment. Recently, two systematic reviews and meta-analyses reported the effects of tES on cerebellar ataxia.^{28 49} These two reports have shown that tDCS dramatically improves symptoms of cerebellar ataxia, including upper/lower limb movement, balance of stance and gait function. The review included four RCTs^{25–27 50} for DCA until 2019, while more recent RCTs^{23 29 51} could not be included. Therefore, we will estimate the effects of tDCS on cerebellar ataxia through a systematic review and meta-analysis including the most recent studies.

The aforementioned previous systematic reviews and meta-analyses about tES and rTMS were appropriately conducted, but they considered each intervention independently. Furthermore, several important, more recent RCTs were published after analysis. In the current study, tES and rTMS are treated as a single NIBS approach same as previous systematic review and meta-analysis,⁵² and their joint effect size will be assessed at the present time. This comprehensive analysis may contribute to estimate whether brain stimulation itself improves DCA symptoms. Moreover, we will create tES and rTMS subgroups and compare their effect sizes on the outcomes. In clinical practice, only one tES or rTMS technique can be employed at a time, and clinicians must have a rationale for choosing one technique over the other. Therefore, an indirect comparison of their effect sizes and new recommendations for their selection may be useful for patients with DCA and clinicians.

Regarding the safety and tolerability of rTMS¹⁹ and tES²⁸ in patients with DCA, no severe harmful side effects and only minimal unfavourable events were recorded. In contrast, additional investigations are necessary to ascertain the most suitable NIBS parameters and evaluate their influence on the clinical outcomes of patients with DCA. More specifically, the polarity of tES, the frequency (high or low) of rTMS and the site of stimulation (cerebellum itself or other sites) are also important. The effects of these stimulus parameters on efficacy should also be examined in this systematic review and meta-analysis.

This study will aim to systematically review the available data on the use of NIBS, including rTMS or tES, as a therapeutic intervention for cerebellar ataxia in patients with DCA. This review will address the following research questions: (1) What is the impact of rTMS and tES on the degree of ataxia; (2) Which rTMS and tES stimulation parameters have been used in previous studies, and how these have impacted the results; and (3) What must be evaluated in future research.

Methods and analysis

This systematic review will be conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) statement (see online supplemental file ‘PRISMA-P-checklist’).⁵³ This protocol has been registered in the International Prospective Register of Systematic Reviews (PROSPERO) database.

Patient and public involvement

None.

Participants

We will include studies involving patients with DCA and exclude studies involving individuals with ataxia other than DCA. DCA encompasses a large number of diagnoses,¹ which typically are ADSCA,³ SCA,^4–6 FA,⁷ MSA-C,⁸ SAOA⁹ and ARSACS.¹⁰ SCA is most typically of the SCA1, 2, 3, 6 and 31 subtypes, among others.⁵⁴ These diseases mainly arise with a later onset, being even rarer in patients less than 18 years old. Therefore, the age range covered in this systematic review is restricted to above 18 years old.⁵⁴ Pharmacological treatment and rehabilitation therapies are standard treatments⁵⁵ and are usually preferred over NIBS. Since most of the cases treated with NIBS also receive these two treatments concurrently, they will be included in both the intervention and comparator groups.

Interventions

NIBS, namely rTMS and tES, will be included as interventions for cerebellar ataxia. Transcranial alternating current stimulation, tDCS, and transcranial random noise electrical stimulation will be included as tES types.

Comparators

No intervention and active control interventions, such as sham stimulation or treatment, will be included as comparators. However, physical therapy, occupational therapy and pharmacotherapy will not be included solely as control treatments for NIBS. These therapies will be included in both the intervention and comparator groups.

Outcomes of interest

The primary clinical outcome will be cerebellar ataxia, as measured by SARA⁴² and ICARS scores.⁴¹ The use of these scales is recommended for assessment of cerebellar ataxia as a clinician-reported outcome measure.⁵⁶ The secondary outcomes will include gait speed, functional ambulatory capacity (FAC)⁵⁷ and functional independence measure (FIM),⁵⁸ as well as any other reported outcomes that the reviewer considers important. The weighted mean difference and the mean and SD will be used for continuous data. The standard mean difference will be used to summarise multiple measures of the same outcome items.

Study design

The inclusion criteria for the studies are single-blind or double-blind RCTs published in English with full-text availability. Only peer-reviewed articles will be included. The exclusion criteria are review articles, conference abstracts and letters to the editor.

Information sources and search strategy

The following databases will be searched: PubMed, Cochrane Central Register of Controlled Trials, CINAHL and PEDro. The searches will be restricted to English and human participants. Abstract and conference proceedings will not be included. The main search words are set to be the following: ‘cerebellum’, ‘spinocerebellar degeneration’, ‘ataxia’, ‘transcranial magnetic stimulation’, ‘transcranial electrical stimulation’ and ‘clinical trial’. A draft of the search strategy for the above databases is provided in the supplementary file (online supplemental appendix 1). The review will encompass all eligible studies published from database inception until the present time.

Data extraction (selection and coding)

The search will be performed by one independent reviewer using the databases, and four other reviewers will confirm the initial list of papers. The search terms will consist of a combination of medical subject heading (MeSH) terms and free text search terms in the database, based on author consensus. Rayyan and EndNote V.20 will be used to manage the studies across databases.

For each study, a pair of two independent reviewers randomly assigned from a group of five reviewers (AM, HO, KB, YKo and YKi) will screen the study title and abstract for determining whether the study meets the inclusion criteria. Studies that cannot be judged only by the title and abstract will be evaluated by referring to the full text. During the initial evaluation, the identity of the other reviewer is blinded to the pair. If the decisions of the two reviewers are inconsistent, a third reviewer will participate in the discussion and make the final decision. At this stage, the pair is informed about the identity of the reviewer assessing the applicable study.

Data extraction will be performed by two independent reviewers to obtain precise information on the study design and methodology, participant demographics and baseline characteristics, sample size and effect measurements. Discrepancies will be resolved by the participation of a third reviewer in the discussion. We will contact study authors for any missing data, if needed. If the authors do not respond to our request or refuse to provide data, we will analyse only the available data. Data extraction will be performed using Microsoft Excel spreadsheets.

Risk of bias in individual studies

The risk of bias will be assessed using the Cochrane risk of bias tool (RoB 2.0). Two of the five independent reviewers will critically evaluate the included studies. The evaluation items include the following: (1) bias arising from the randomisation process; (2) bias due to deviation from the intended intervention; (3) bias due to missing outcome data; (4) bias in the measurement of outcomes; (5) bias in the selection of reported results. For each item, we will evaluate each study as having a low, uncertain or high risk of bias. Any discrepancies will be discussed and resolved by a third reviewer, if necessary.

Data synthesis

If more than two randomised (or quasi-randomised) controlled trials report the same outcome, such as SARA and ICARS scores, FAC gait speed or FIM, a meta-analysis will be performed. RevMan V.5.4 software will be used for the meta-analysis and to calculate the weighted mean difference, and the mean and SD will be used for continuous data. The standard mean difference will be used to summarise multiple measures of the same outcome items. Random effect models will be used to obtain pooled estimates, and the results will be described using forest plots. The I² test will be used to evaluate heterogeneity; if the I² value exceeds 50%, heterogeneity will be judged to be high, and a subgroup analysis will be performed. A summary table of the published results will be prepared. If a quantitative synthesis is not appropriate, we will provide a summary table about NIBS montage, stimulation parameters, patient diagnosis, effect size of the intervention on outcomes and main findings in individual studies.

Analysis of subgroups or subsets

First, to examine the effects of NIBS, one meta-analysis will be conducted without separating tES and rTMS. Next, a subgroup analysis will be performed based on the type of intervention such as polarity of tES, frequency and location of rTMS. Furthermore, a subgroup analysis will be performed based on participant characteristics, such as sex and diagnosis (such as DCA or multiple system atrophy), and use of control (no intervention or active control) if there was more than one arm in each trial. Z-tests will be used to elucidate the differences in NIBS (tES and rTMS).³⁸

Assessment of strength of evidence

The Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework will be employed to assess the overall quality of evidence across all outcomes. This will involve evaluating the individual risk of bias, meta-bias, precision, consistency, directedness and magnitude of effect. These indicators are used to determine the level of certainty associated with the estimated effect, which is classified as ‘very low’, ‘low’, ‘high’ or ‘very high’.

Ethics and dissemination

There will be no requirement for ethical approval because this systematic review will not include original data from human beings. The results will be disseminated through peer-reviewed publication.

Discussion

The present review will aim to summarise the available evidence on the effects of rTMS and tES in the treatment of DCA. The review will encompass all eligible studies published from inception until the present time and will assess the quality of the studies and analyse outcome data. One strength of this study is the expansion of the target population to patients with DCA, as in the past the study population was limited to patients with SCA and MSA. Another strength is the calculation and comparison of the effect sizes of tES and rTMS in the same systematic review and meta-analysis study, as they have been difficult to compare in the past. Furthermore, with the publication of several new RCTs since the latest systematic review, a better estimation of the effect size of NIBS is expected. The findings generated by this systematic review and meta-analysis may contribute to the clinical decision-making regarding the use of NIBS and the choice of NIBS technique for treating an individual patient with DCA.

There are potential concerns in the interpretation of the results in the current systematic review and meta-analysis. One concern is that stimulation methods for tES and rTMS have evolved over time. For example, attention should be paid to probing placement and stimulation duration in electrical stimulation, and coil geometry and pulse intervals in magnetic stimulation. It is important to note that these technological developments may lead to differences in the size of NIBS effects on the outcomes. We plan to report a detailed summary of the intervention methods for each study and discuss their impact on outcomes. Furthermore, we should note that the effects of rTMS and tES may differ due to differences in the areas that can be stimulated. Moreover, the price of the equipment and the cost of the application of rTMS and tES may differ. Additionally, while patients can receive tES at home, this is more difficult with rTMS treatment. Therefore, recommendations should consider the effectiveness as well as the accessibility of the devices. Moreover, the anticipated limitations to the study include the scarcity of high-quality trials and an insufficient homogeneity of data to allow quantitative analysis. We should also pay attention to the heterogeneity and diverse baseline severity of the included diseases. These concerns may have to be addressed in future clinical studies, and a future research agenda will be proposed accordingly.

The treatment of DCA aims to reduce symptoms associated with ataxia, including gait disturbance. The use of NIBS for treating these symptoms is still in the research stage and has not yet been implemented in clinical practice. To establish optimal clinical practices, evidence regarding stimulation parameters is critical. These parameters include not only the stimulation site of the brain but also factors such as polarity and intensity in tES, as well as frequency in rTMS. Taken together, we believe that the results of our systematic review and meta-analysis study will provide valuable insights that will help patients with DCA and healthcare professionals make decisions regarding the selection of NIBS as a treatment approach. If our systematic review and meta-analysis do not provide sufficient insights regarding clinical use, we will propose specific clinical questions regarding research on the impact of these parameters on treatment outcomes.

We appreciate Ms. Tomoko Morimasa and Ms. Asako Baraki, librarians at Showa University, for their support in developing the search strategies. We would like to thank Editage (www.editage.jp) for the English language editing.

Ethics statements

Patient consent for publication

Not applicable.

Footnote

Twitter @matsu__aki, @Hiroyuki Ohtsuka, @kyota_bando, @studious_kick

Contributors AM, HO, KB, YKo and YKi conceptualised the study. AM and HO designed the protocol. AM and HO defined the search items, data extraction process and statistical analysis. AM drafted the initial manuscript. All authors have appraised the whole methodology, and revised and approved the final manuscript.

Funding This study was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number, 20K11298) and the Institute of Health Sciences at Shijonawate Gakuen University (grant number, IHSS2301).

Competing interests None declared.

Patient and public involvement Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.

Provenance and peer review Not commissioned; externally peer reviewed.

Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

References

¹ Coarelli G, Wirth T, Tranchant C, et al. The inherited cerebellar ataxias: an update. J Neurol 2023; 270: 208–22. doi:10.1007/s00415-022-11383-6

² Maas RPPWM, Helmich RCG, van de Warrenburg BPC. The role of the cerebellum in degenerative ataxias and essential tremor: insights from noninvasive modulation of cerebellar activity. Mov Disord 2020; 35: 215–27. doi:10.1002/mds.27919

³ Müller U. Spinocerebellar ataxias (SCAs) caused by common mutations. Neurogenetics 2021; 22: 235–50. doi:10.1007/s10048-021-00662-5

⁴ Opal P, Ashizawa T, et al. Spinocerebellar ataxia type 1. In: Adam MP, Everman DB, Mirzaa GM, eds. GeneReviews((R)). Seattle (WA), 1993.

⁵ Saucier J, Al-Qadi M, Amor MB, et al. Spinocerebellar ataxia type 31: a clinical and radiological literature review. J Neurol Sci 2023; 444: 120527. doi:10.1016/j.jns.2022.120527

⁶ Casey HL, Gomez CM, et al. Spinocerebellar ataxia type 6. In: Adam MP, Everman DB, Mirzaa GM, eds. GeneReviews((R)). Seattle (WA), 1993.

⁷ Keita M, McIntyre K, Rodden LN, et al. Friedreich ataxia: clinical features and new developments. Neurodegener Dis Manag 2022; 12: 267–83. doi:10.2217/nmt-2022-0011

⁸ Poewe W, Stankovic I, Halliday G, et al. Multiple system atrophy. Nat Rev Dis Primers 2022; 8: 56. doi:10.1038/s41572-022-00382-6

⁹ Klockgether T. Sporadic adult-onset ataxia of unknown etiology. Handb Clin Neurol 2012; 103: 253–62. doi:10.1016/B978-0-444-51892-7.00015-2

¹⁰ Aly KA, Moutaoufik MT, Zilocchi M, et al. Insights into SACS pathological attributes in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)☆. Curr Opin Chem Biol 2022; 71: 102211. doi:10.1016/j.cbpa.2022.102211

¹¹ Miyai I, Ito M, Hattori N, et al. Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 2012; 26: 515–22. doi:10.1177/1545968311425918

¹² Hadjivassiliou M, Manto M, Mitoma H. Rare Etiologies in immune-mediated cerebellar ataxias: diagnostic challenges. Brain Sci 2022; 12: 1165. doi:10.3390/brainsci12091165

¹³ Kearney M, Orrell RW, Fahey M, et al. Pharmacological treatments for Friedreich ataxia. Cochrane Database Syst Rev 2016; 2016: CD007791. doi:10.1002/14651858.CD007791.pub4

¹⁴ Mills RJ, Yap L, Young CA. Treatment for ataxia in multiple sclerosis. Cochrane Database Syst Rev 2007; 2007: CD005029. doi:10.1002/14651858.CD005029.pub2

¹⁵ Yap KH, Azmin S, Che Hamzah J, et al. Pharmacological and non-pharmacological management of spinocerebellar ataxia: a systematic review. J Neurol 2022; 269: 2315–37. doi:10.1007/s00415-021-10874-2

¹⁶ Matsugi A, Bando K, Kikuchi Y, et al. Rehabilitation for Spinocerebellar ataxia. In: Ambrosi PB, ed. Neurological physical therapyspinocerebellar ataxia - concepts, particularities and generalities: IntechOpen. 2022. doi:10.5772/intechopen.87421

¹⁷ França C, de Andrade DC, Silva V, et al. Effects of cerebellar transcranial magnetic stimulation on ataxias: a randomized trial. Parkinsonism & Related Disorders 2020; 80: 1–6. doi:10.1016/j.parkreldis.2020.09.001

¹⁸ Manor B, Greenstein PE, Davila-Perez P, et al. Repetitive transcranial magnetic stimulation in spinocerebellar ataxia: a pilot randomized controlled trial. Front Neurol 2019; 10: 73. doi:10.3389/fneur.2019.00073

¹⁹ Qiu Y-T, Chen Y, Tan H-X, et al. Efficacy and safety of repetitive transcranial magnetic stimulation in cerebellar ataxia: a systematic review and meta-analysis. Cerebellum 6, 2023. doi:10.1007/s12311-022-01508-y

²⁰ Sikandar A, Liu X-H, Xu H-L, et al. Short-term efficacy of repetitive transcranial magnetic stimulation in SCA3: a prospective, randomized, double-blind, sham-controlled study. Parkinsonism Relat Disord 2023; 106: 105236. doi:10.1016/j.parkreldis.2022.105236

²¹ Song P, Li S, Wang S, et al. Repetitive transcranial magnetic stimulation of the cerebellum improves ataxia and cerebello-fronto plasticity in multiple system atrophy: a randomized, double-blind, sham-controlled and TMS-EEG study. Aging (Albany NY) 2020; 12: 20611–22. doi:10.18632/aging.103946

²² Xia Y, Wang M, Zhu Y. The effect of cerebellar rTMS on modulating motor dysfunction in neurological disorders: a systematic review. Cerebellum 26, 2022. doi:10.1007/s12311-022-01465-6

²³ Ahn JH, Lee D, Kim M, et al. M1 and cerebellar tDCS for MSA-C: a double-blind, randomized, sham-controlled, crossover study. Cerebellum 2023; 22: 386–93. doi:10.1007/s12311-022-01416-1

²⁴ Benussi A, Cantoni V, Manes M, et al. Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia. Brain 2021; 144: 2310–21. doi:10.1093/brain/awab157

²⁵ Benussi A, Dell’Era V, Cantoni V, et al. Cerebello-spinal tDCS in ataxia: a randomized, double-blind, sham-controlled, crossover trial. Neurology 2018; 91: e1090–101. doi:10.1212/WNL.0000000000006210

²⁶ Benussi A, Dell’Era V, Cotelli MS, et al. Long term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia. Brain Stimul 2017; 10: 242–50. doi:10.1016/j.brs.2016.11.001

²⁷ Benussi A, Koch G, Cotelli M, et al. Cerebellar transcranial direct current stimulation in patients with ataxia: a double-blind, randomized, sham-controlled study. Mov Disord 2015; 30: 1701–5. doi:10.1002/mds.26356

²⁸ Chen TX, Yang C-Y, Willson G, et al. The efficacy and safety of transcranial direct current stimulation for cerebellar ataxia: a systematic review and meta-analysis. Cerebellum 2021; 20: 124–33. doi:10.1007/s12311-020-01181-z

²⁹ Maas RPPWM, Teerenstra S, Toni I, et al. Cerebellar transcranial direct current stimulation in spinocerebellar ataxia type 3: a randomized, double-blind, sham-controlled trial. Neurotherapeutics 2022; 19: 1259–72. doi:10.1007/s13311-022-01231-w

³⁰ França C, de Andrade DC, Teixeira MJ, et al. Effects of cerebellar neuromodulation in movement disorders: a systematic review. Brain Stimul 2018; 11: 249–60. doi:10.1016/j.brs.2017.11.015

³¹ Klomjai W, Katz R, Lackmy-Vallée A. Basic principles of transcranial magnetic stimulation (TMS) and repetitive TMS (rTMS). Ann Phys Rehabil Med 2015; 58: 208–13. doi:10.1016/j.rehab.2015.05.005

³² Lefaucheur J-P, Aleman A, Baeken C, et al. Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): an update (2014-2018). Clin Neurophysiol 2020; 131: 474–528. doi:10.1016/j.clinph.2019.11.002

³³ Lefaivre SC, Brown MJN, Almeida QJ. Cerebellar involvement in Parkinson’s disease resting tremor. Cerebellum Ataxias 2016; 3: 13. doi:10.1186/s40673-016-0051-5

³⁴ Somaa FA, de Graaf TA, Sack AT. Transcranial magnetic stimulation in the treatment of neurological diseases. Front Neurol 2022; 13: 793253. doi:10.3389/fneur.2022.793253

³⁵ Saitoh Y, Hosomi K, Mano T, et al. Randomized, sham-controlled, clinical trial of repetitive transcranial magnetic stimulation for patients with Alzheimer’s dementia in Japan. Front Aging Neurosci 2022; 14: 993306. doi:10.3389/fnagi.2022.993306

³⁶ Hosomi K, Seymour B, Saitoh Y. Modulating the pain network--neurostimulation for central poststroke pain. Nat Rev Neurol 2015; 11: 290–9. doi:10.1038/nrneurol.2015.58

³⁷ Dionísio A, Duarte IC, Patrício M, et al. The use of repetitive transcranial magnetic stimulation for stroke rehabilitation: a systematic review. J Stroke Cerebrovasc Dis 2018; 27: 1–31. doi:10.1016/j.jstrokecerebrovasdis.2017.09.008

³⁸ Zhang X, Jing F, Liu Y, et al. Effects of non-invasive brain stimulation on walking and balance ability in Parkinson’s patients: a systematic review and meta-analysis. Front Aging Neurosci 2022; 14: 1065126. doi:10.3389/fnagi.2022.1065126

³⁹ Zhang M, He T, Wang Q. Effects of non-invasive brain stimulation on multiple system atrophy: a systematic review. Front Neurosci 2021; 15: 771090. doi:10.3389/fnins.2021.771090

⁴⁰ Wang Y, Zhang D, Wang J, et al. Effects of transcranial magnetic stimulation on cerebellar ataxia: a systematic review and meta-analysis. Front Neurol 2023; 14: 1049813. doi:10.3389/fneur.2023.1049813

⁴¹ Trouillas P, Takayanagi T, Hallett M, et al. International cooperative ataxia rating scale for pharmacological assessment of the cerebellar syndrome. Journal of the Neurological Sciences 1997; 145: 205–11. doi:10.1016/S0022-510X(96)00231-6

⁴² Schmitz-Hübsch T, du Montcel ST, Baliko L, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 2006; 66: 1717–20. doi:10.1212/01.wnl.0000219042.60538.92

⁴³ Yamauchi K, Kumagae K, Goto K, et al. Predictive validity of the scale for the assessment and rating of ataxia for medium-term functional status in acute ataxic stroke. J Stroke Cerebrovasc Dis 2021; 30: 105631. doi:10.1016/j.jstrokecerebrovasdis.2021.105631

⁴⁴ Mitoma H, Buffo A, Gelfo F, et al. Consensus paper. Cerebellar Reserve: from cerebellar physiology to cerebellar disorders. Cerebellum 2020; 19: 131–53. doi:10.1007/s12311-019-01091-9

⁴⁵ Krause MR, Vieira PG, Pack CC. Transcranial electrical stimulation: how can a simple conductor orchestrate complex brain activity PLoS Biol 2023; 21: e3001973. doi:10.1371/journal.pbio.3001973

⁴⁶ Li LM, Uehara K, Hanakawa T. The contribution of Interindividual factors to variability of response in transcranial direct current stimulation studies. Front Cell Neurosci 2015; 9: 181. doi:10.3389/fncel.2015.00181

⁴⁷ Takeuchi N. Pain control based on oscillatory brain activity using transcranial alternating current stimulation: an integrative review. Front Hum Neurosci 2023; 17: 941979. doi:10.3389/fnhum.2023.941979

⁴⁸ Potok W, van der Groen O, Bächinger M, et al. Transcranial random noise stimulation modulates neural processing of sensory and motor circuits, from potential cellular mechanisms to behavior: a scoping review. ENeuro 2022; 9: ENEURO.0248-21.2021. doi:10.1523/ENEURO.0248-21.2021

⁴⁹ Wang S-M, Chan Y-W, Tsui Y-O, et al. Effects of Anodal cerebellar transcranial direct current stimulation on movements in patients with cerebellar Ataxias: a systematic review. Int J Environ Res Public Health 2021; 18: 10690. doi:10.3390/ijerph182010690

⁵⁰ Barretto TL, Bandeira ID, Jagersbacher JG, et al. Transcranial direct current stimulation in the treatment of cerebellar ataxia: a two-phase, double-blind, auto-matched, pilot study. Clin Neurol Neurosurg 2019; 182: 123–9. doi:10.1016/j.clineuro.2019.05.009

⁵¹ Maas R, Schutter D, Toni I, et al. Cerebellar transcranial direct current stimulation modulates timing but not acquisition of conditioned eyeblink responses in SCA3 patients. Brain Stimul 2022; 15: 806–13. doi:10.1016/j.brs.2022.05.013

⁵² Chen J-M, Li X-L, Pan Q-H, et al. Effects of non-invasive brain stimulation on motor function after spinal cord injury: a systematic review and meta-analysis. J Neuroeng Rehabil 2023; 20: 3. doi:10.1186/s12984-023-01129-4

⁵³ Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71. doi:10.1136/bmj.n71

⁵⁴ Paulson HL. The spinocerebellar ataxias. J Neuroophthalmol 2009; 29: 227–37. doi:10.1097/WNO0b013e3181b416de

⁵⁵ Zesiewicz TA, Wilmot G, Kuo S-H, et al. Comprehensive systematic review summary: treatment of cerebellar motor dysfunction and ataxia: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology. Neurology 2018; 90: 464–71. doi:10.1212/WNL.0000000000005055

⁵⁶ Klockgether T, Synofzik M, AGIwgo Coa. Consensus recommendations for clinical outcome assessments and registry development in ataxias: ataxia global initiative (AGI) working group expert guidance. Cerebellum 5, 2023. doi:10.1007/s12311-023-01547-z

⁵⁷ Holden MK, Gill KM, Magliozzi MR, et al. Clinical gait assessment in the neurologically impaired. Physical Therapy 1984; 64: 35–40. doi:10.1093/ptj/64.1.35

⁵⁸ Heinemann AW, Linacre JM, Wright BD, et al. Relationships between impairment and physical disability as measured by the functional independence measure. Arch Phys Med Rehabil 1993; 74: 566–73. doi:10.1016/0003-9993(93)90153-2