1. 引言
遺傳性脊髓小腦共濟失調 ( SCA ) 是一類罕見的遺傳性神經退化性疾病,具有顯著的臨床和遺傳多樣性。 1–4 這些疾病屬於遺傳性共濟失調的廣義類別,表現出一系列神經系統症狀,主要包括運動功能障礙,如步態不穩、構音障礙、眼球運動不協調以及其他與周圍神經病變、錐體束徵和認知缺陷有關的症狀。 2 3 SCA 亞型的分佈在不同族群中存在地理差異。 5–7 在白種人群中, SCA1 、SCA2 和 SCA3 是最常見的亞型。相較之下,SCA2、SCA3、SCA6 和齒狀核紅核蒼白球路易氏體萎縮 (DRPLA) 更常見於東亞人群,包括日本人和中國人。 8–10 這種地區差異凸顯了在診斷和治療靜息促腎上腺皮質激素(SCAs)時考慮遺傳和人口統計因素的重要性。然而,臨床實務中針對靜止促腎上腺皮質激素(SCA)的有效治療策略仍有限。
多項研究發現神經調節是有效的。 11–13 非侵入性神經調節,例如重複經顱磁刺激 (rTMS),代表著一種有前景的治療 SCA 運動症狀的替代方法,值得進一步研究。 rTMS 是一種安全、非侵入性的腦刺激技術,由於其能夠促進神經可塑性 14 ,並廣泛應用於各種神經和精神疾病的神經康復治療,包括抑鬱症、 15 焦慮症、 16 帕金森病、 17 阿茲海默症, 18 甚至 SCA 患者,作為一種治療共濟失調的方法 ,引起了越來越多的關注。 11 12 不同的 rTMS 方案表現出不同的神經生理機制和治療效果。 低頻 (LF) rTMS 通常以 1 Hz 的頻率發送,可誘發類似長期抑制 (LTD) 的效應,從而導致持續的皮質抑制和 γ-氨基丁酸 (GABA) 能神經傳遞的調節,而高頻 (HF) rTMS (3-5 Hz) 透過類似長期增強 (LTP) 的神經核效應增加並激活原神經下訊號通路。 19–21 在 θ 爆發方案中,cTBS 提供連續的刺激爆發,產生類似 LTD 的效應和皮質抑制,調節 GABA 水平 ,而 iTBS 以 θ 節律 (5 Hz) 提供快速爆發 (50 Hz),從而誘導更強勁的 LTP 可塑性。 20 22 23 儘管 rTMS 具有潛力,但關於 SCA 治療方案的文獻仍然不一致,所報告的方法和結果各不相同。
儘管系統性回顧已評估了 rTMS 對 SCA 患者的效果, 11 12 但在對不同 rTMS 方案(包括 LF、HF 和 θ 爆發刺激 (TBS))的比較分析中仍存在關鍵差距。 11 24–26 這一差距凸顯了需要進一步研究以確定和標準化最有效的 rTMS 方案,以緩解 SCA 的臨床症狀。現有文獻表現出一些方法學上的局限性;值得注意的是,現有的綜述排除了 TBS 方案,儘管其具有良好的治療和節省成本的效果, 27 而對 LF 和 HF 方案的綜述分析通常存在顯著的偏見風險。例如,一項 HF 亞組分析結合了多系統萎縮-小腦型 (MSA-c) 和 SCA3 患者的數據,降低了對 SCA 族群的特異性 。 25 另一項綜述納入了非英語出版物,但沒有進行充分的品質評估,這可能會引入方法學上的異質性。 26 這些不一致之處凸顯了進行嚴格的、針對特定方案的比較研究的必要性,以便確定針對不同 SCA 亞型的最佳神經調節參數。本文旨在系統性地回顧所有現有且符合條件的、研究 rTMS 治療 SCA 的隨機對照試驗(RCT)。透過綜合各種 rTMS 方案的療效,我們評估了它們對改善 SCA 患者臨床症狀的影響。 這項薈萃分析研究的結果提供了寶貴的見解,可以為未來涉及 rTMS 的臨床試驗提供參考並改進實驗設計。
2. 研究策略
在 PubMed、Medline 和 Cochrane 資料庫中檢索以英文發表的、著重於經顱磁刺激(TMS 或 rTMS)在成人身上治療應用的 RCT 和綜述文章。檢索詞包括「脊髓小腦性共濟失調」、「共濟失調」、「經顱磁刺激」、「rTMS」、「TMS」、「θ爆發刺激」、「TBS」和「神經調節」。此外,摘要還進行了系統篩選,以確定符合全文評估條件的文章。
我們根據預先定義的資格標準(涵蓋介入、對照、結果和研究框架)選擇了與本綜述相關的文章。要納入薈萃分析,研究必須滿足以下標準:(1)研究必須是利用 rTMS 作為 SCA 患者治療介入的原創研究。 (2)所有納入的 SCA 患者必須具有經基因確診的診斷。 (3)需要使用至少一種運動功能結果測量方法來評估 SCA 治療的有效性,並附上足夠的統計數據來計算獨立的效應大小。 (4)參與者必須年滿 18 歲。 (5)研究必須是 RCT 並發表在同行評審期刊上( 圖 1 )。主要評估著重於評估運動功能結果,尤其是 rTMS 治療後的結果。感興趣的結果是乾預前後(1)共濟失調評估和評定量表(SARA) 28 和(2)國際合作共濟失調評定量表(ICARS) 29 之間的差異,這兩項是測量小腦共濟失調的最常用評定量表。 30 31

圖 1: 研究選擇流程圖。 TMS = 經顱磁刺激。
使用 Review Manager V.5.4 進行薈萃分析。以 I² 統計量評估研究異質性。顯著性閾值設為 p < 0.05。當異質性較低( I² < 50% 或 p > 0.1)時,採用固定效應模型;當異質性較高( I² ≥ 50% 或 p < 0.1)時,採用隨機效應模型。對於連續變量,計算平均差 (MD) 及其 95% 信賴區間 (CI)。當無法進行定量分析時,則對單一研究的結果進行定性匯總。
3.結果
3.1. 納入研究的特徵
我們透過預先定義的關鍵字搜尋對 419 項研究進行了初步篩選,並刪除了 194 項重複研究。在篩選標題和摘要後,169 項研究因不符合人體研究標準而被排除,因此無法以英文全文發表。最終,根據納入標準,選擇了八項研究進行審查( 表 1 )。 32–39 這項回顧共涉及 237 名經基因確診的 SCA 患者;大多數納入的患者被診斷為 SCA3,而其他患者則具有較不常見的亞型,例如 SCA1、SCA2 和 SCA6。這些研究發表於 2000 年至 2024 年之間,主要採用雙對照平行組設計,其中一項研究採用單一對照設計。 36 總共納入了 237 名參與者,其中男性比例(68.35%)高於女性比例(31.65%)。樣本數為 5 至 37 名參與者,rTMS 治療持續時間為 5 至 28 天。刺激部位主要集中在雙側小腦,其中兩項研究分別針對中線蚓部和雙側小腦。 32 35 使用 SARA 和 ICARS 進行的結果評估,以及 rTMS 治療後這些評分的變化,並與假手術組進行了比較。偏倚風險圖及總結如圖 2 所示。
Scroll left or right to view entire table.
雙側小腦目標位置:右側小腦距離枕骨大凸點 4cm,左側小腦距離枕骨大凸點 4cm。
ALFF = 低頻波動幅度;BBS = 伯格平衡評分;bil = 雙側;CCAS = 小腦認知情緒症候群;iBTS = 間歇性 θ 爆發刺激;ICARS = 國際合作共濟失調評定量表;LF = 低頻;MRI = 磁振造影;PRT = PATAMS 反應試驗;RMT = 靜息運動閾值;共濟失調評估和評定量表;SCA = 脊髓小腦性共濟失調;TUG = 計時起立行走測試。
Fig. 2: Risk of bias graph and summary. The bias assessment for each study is presented, with green, yellow, and red indicating low, unclear, and high risk of bias, respectively. One study employed a single-blind design, and some studies raised some concerns due to the lack of clarity regarding allocation concealment. In addition, some studies noted incomplete outcome assessments. Finally, one study had a significant difference between the control and rTMS groups. rTMS = repetitive transcranial magnetic stimulation.
3.2. Meta-analysis
We studied SARA and ICARS as the primary motor function outcome after rTMS treatment. For the SARA scores, six studies including 190 patients were considered to report changes in total SARA scores. The results indicated a significant reduction, with an MD of −1.56 (95% CI, −2.88 to −0.24; p = 0.02) in the rTMS stimulation condition compared to sham condition. The I² statistic showed uniformity across the studies, with no evidence of heterogeneity (I2 = 0%; Fig. 3A). Outcomes assessed using the ICARS were reported in five studies involving 201 participants. The meta-analysis demonstrated a significant therapeutic benefit of rTMS in SCA patients, with an MD of −3.16 (95% CI, −3.93 to −2.39; p < 0.001) over sham stimulation and low heterogeneity (I2 = 28%; Fig. 3B). In conclusion, our meta-analysis results showed that both SARA and ICARS scores improved after the rTMS stimulation compared to the sham group. No obvious adverse events were noted in these RCTs.
Fig. 3: Forest plot for meta-analytic estimates of post-rTMS changes in scale for the SARA and ICARS. A, The results of post-rTMS changes in scale for the SARA, (B) the results of post-rTMS changes in scale for the ICARS. ICARS = International Cooperative Ataxia Rating Scale; rTMS = repetitive transcranial magnetic stimulation; SARA = Scale for Assessment and Rating of Ataxia.
3.3.Subgroup analysis: Different rTMS protocol comparison
In the SARA subgroup analysis, we evaluated the effects of different rTMS protocol parameters, including LF, HF, and TBS. The overall pooled analysis revealed a statistically significant improvement of SARA scores (MD, −1.67; 95% CI, −2.22 to −1.11; p < 0.001) with low heterogeneity (χ² = 0.31, df = 6, p =1.00, I2 = 0.00%) between the overall rTMS stimulation group and the sham group. Regarding the subgroup analysis, the LF protocol showed a significant change compared with the sham group, with an MD of −1.60 (95% CI, −3.06 to −0.13; p = 0.03) and no heterogeneity (χ² = 0.26, df = 3, p = 0.97, I² = 0%). The HF protocol, assessed in a single study, yielded a reduced but nonsignificant change (MD, −1.52; 95% CI, −6.34 to 3.30; p = 0.54) when compared with the sham group. For iTBS, although only two studies were included after inclusion criteria, a significant change was observed, with an MD of −1.68 (95% CI, −2.29 to −1.08; p < 0.001) and no heterogeneity (χ² = 0.04, df = 1, p = 0.85, I² = 0%) when compared with the sham group (Fig. 4). Notably, as no studies utilized continuous theta burst stimulation (cTBS) for SCA patients, we only enrolled iTBS in our meta-analysis.
Fig. 4: Forest plot for meta-analytic estimates of post-rTMS changes in SARA subgroup: LF, HF, and iTBS. The results of post-rTMS changes in scale for the SARA subgroup according to LF (1.1.1), HF (1.1.2), and iTBS (1.1.3) as well as the overall effect of rTMS. HF = high-frequency; iTBS = intermittent theta burst stimulation; LF = low-frequency; rTMS = repetitive transcranial magnetic stimulation; SARA = Scale for Assessment and Rating of Ataxia.
In the ICARS subgroup analysis, we evaluated the effects of different rTMS protocol parameters, including LF and HF. Notably, no studies utilizing TBS were identified, and only one study was identified in the HF subgroup. The total pooled analysis revealed a statistically significant improvement of ICARS scores (MD, −3.34; 95% CI, −4.47 to −2.22; p = 0.007) with low heterogeneity (τ² = 0.45, χ² = 5.59, df = 4, p = 0.23, I² = 28%) between the overall rTMS stimulation group and the sham group. Regarding the subgroup analysis, the LF protocol showed a significant change with an MD of −3.37 (95% CI, −4.63 to −2.11; p = 0.01) and low heterogeneity (τ² = 0.68, χ² = 5.35, df = 3, p = 0.15, I² = 44%). The HF protocol, assessed in a single study, yielded a reduced but nonsignificant change (MD = −5.90, 95% CI, −16.99 to 5.19, p = 0.30; Fig. 5).
Fig. 5: Forest plot for meta-analytic estimates of post-rTMS changes in ICARS subgroup: LF and HF. The results of post-rTMS changes in scale for the ICARS subgroup according to LF (1.2.1), HF (1.2.2), and iTBS (1.2.3) as well as the overall effect of rTMS. HF = high-frequency; ICARS = International Cooperative Ataxia Rating Scale; iTBS = intermittent theta burst stimulation; LF = low-frequency; rTMS = repetitive transcranial magnetic stimulation.
In conclusion, the LF inhibitory stimulation showed a significant effect for both SARA and ICARS motor outcomes for SCA patients whereas the HF excitatory stimulation showed an improving trend without significance due to finding only one RCT. Regarding the TBS, although only two qualified randomized studies of iTBS excitatory stimulation were pooled into our meta-analysis, the results showed the potential effects for the motor functions mainly in SCA3 patients. In addition, no adverse events were reported across these trials, consistent with the well-established safety profile of rTMS when administered according to standard protocols.
4. DISCUSSION
This study presents a systematic review and meta-analysis evaluating the effects of rTMS as a treatment for SCA patients. Our findings demonstrate that rTMS has a significant impact on improving motor outcomes in SCA patients. The results highlight rTMS as a promising therapeutic approach for mitigating motor symptoms in hereditary SCA. Our study is the first systematic review of different TBS protocols in SCA patients and included the latest studies within 1 year.32,38,39 However, the annual progression rate of SARA scores varies across SCA subtypes due to genetic heterogeneity,8,10,40–42 necessitating careful consideration of subtype-specific responses to rTMS. Among the studies included in our analysis, most patients were diagnosed with SCA3, which has an annual SARA progression rate of 0.65 to 1.61.8,40,42,43 Notably, our meta-analysis revealed a mean reduction of 1.56 points in SARA scores following rTMS, exceeding the natural progression rate. This suggests that rTMS alleviates motor symptoms of disease progression.
The cerebellum, traditionally regarded as controlling the motor coordination function, is now recognized as playing a significant role in cognitive processes. Functional imaging studies44–46 and clinical observations47–50 have found that patients with cerebellar damage experience impairments in executive function, spatial awareness, emotions, and language, leading to the definition of the cerebellar cognitive affective syndrome (CCAS).47,51 Despite this expanded understanding, most clinical studies on SCA continue to rely on motor-centric outcome measures, such as the SARA and the ICARS scores. To fully capture the spectrum of SCA symptoms, non-motor outcome assessments like the CCAS scale47,51 or the Cerebellar Impulsivity–Compulsivity Assessment scale (CIA)52 can be incorporated into future clinical trials. Indeed, future clinical studies on SCA should prioritize the development and integration of more sensitive tools for assessing both motor and non-motor symptoms to provide a comprehensive evaluation of therapeutic efficacy.
Our findings demonstrated that both inhibitory LF stimulation and excitatory iTBS may improve motor function in SCA patients, particularly SCA3. LF stimulation is typically associated with LTD in the cerebellum,53 whereas HF stimulation and iTBS promote LTP in presynaptic neurons.54,55 Interestingly, motor-evoked potential (MEP) responses, modulated by the dentato-thalamo-cortical (DTC) pathway, differ based on the stimulation protocol: MEPs exhibit distinct responses to different stimulation protocols, decreasing after continuous cTBS but increasing with LF or iTBS.56–59 These outcomes are closely tied to the function of Purkinje cells, which govern the DTC pathway. By coordinating the firing patterns of cerebellar nuclei cells, Purkinje cells establish precise timing that is critical for effective motor control and modulation.60,61 These results support the concept of cerebellar plasticity,62 highlighting the cerebellum’s capacity for adaptation and reorganization in response to external stimulation. Despite these insights, the specific mechanisms through which rTMS protocols modulate activity in the cerebellum and its connected networks remain unclear. To address this gap, future research should combine rTMS with advanced neuroimaging techniques, such as magnetic resonance spectroscopy (MRS), and electrophysiological tools to deepen our understanding of cerebellar function in SCA and elucidate the mechanisms underlying rTMS effects.63,64
Our studies have some limitations. The first limitation is the small sample size of the enrolled randomized controlled studies: only one RCT for the HF group and two RCTs for the iTBS group. However, the number of enrolled studies in previous meta-analyses on the same topic is less than our study.11,12,65,66 Second, most of the patients are SCA3; we should cautiously apply this result to all the SCA subtypes. Third, the treatment duration is variable from 5 to 28 days, and most of the studies only measured the short-term effect. Long-term effects of rTMS should be considered in future study designs. Fourth, this study did not incorporate wearable sensors, which is a possible clinical assessment for SCA patients.67,68 Finally, the lack of non-motor outcome measures in the included studies limited our ability to capture the full clinical spectrum of SCA symptoms. Future research should incorporate assessments such as the CCAS,47,51 CIA scores,52 and the PROM-ataxia69 to better evaluate non-motor symptoms.
Despite these limitations, our study provides valuable insights into the efficacy of rTMS protocols for treating SCA. These findings contribute to the growing body of evidence supporting the use of rTMS as a therapeutic option and underscore the need for further studies to refine and expand its application in SCA management.
Our study informs stratified treatment approaches based on genetic subtypes, with SCA3 patients potentially prioritized for rTMS interventions. Future clinical protocols should consider personalized stimulation parameters, with the potential for optimization based on individual cerebellar network connectivity patterns assessed through functional neuroimaging. Critically, magnetic resonance imaging (MRI)–guided neuronavigation should be incorporated into treatment protocols, as it has been demonstrated to be the most precise method for localizing and positioning rTMS coils to targets,70 with evidence suggesting it contributes to improved clinical response rates.71,72 The implementation of rTMS in standard care pathways would require the development of standardized protocols addressing stimulation parameters (frequency, intensity, duration), treatment schedules (daily vs intermittent), and maintenance regimens to sustain therapeutic benefits. Furthermore, our findings highlight the need for specialized neuromodulation facilities with expertise in cerebellar stimulation techniques for SCA patients.
In conclusion, to assess the therapeutic potential of rTMS in SCA patients, we conducted a systematic review and meta-analysis. Our analysis revealed statistically significant improvements in motor function following rTMS compared to sham interventions. These results support the potential of rTMS as a therapeutic strategy for mitigating motor symptoms in patients with hereditary SCA. These findings align with the concept of cerebellar plasticity,62 supporting the idea that the cerebellum can adapt and reorganize in response to external stimulation. Further research is required to elucidate the underlying neural mechanisms63 and their relationship with cerebellar neuromodulation, which may pave the way for novel therapeutic applications.
ACKNOWLEDGMENTS
This study was supported by the National Science and Technology Council (Taiwan) (113-2410-H-A49-066-MY2, 113-2321-B-A49-015, 112-2926-I-A49A-502-G, 112-2321-B-A49-008, 111-2410-H-A49-057-MY2, 111-2321-B-A49-003, 110-2321-B-101-004, 109-2917-I-010-002, 108-2410-H-010-007-MY3, 108-2321-B-010-010-MY2), the International Collaboration Project of Brain Science, and the Brain Research Center (112W32101) National Yang Ming Chiao Tung University, Taiwan, under The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan.
REFERENCES
1. Soong BW, Morrison PJ. Spinocerebellar ataxias. Handb Clin Neurol. 2018;155:143–74.
2. Kuo SH. Ataxia. Continuum (Minneap Minn). 2019;25:1036–54.
3. Sullivan R, Yau WY, O’Connor E, Houlden H. Spinocerebellar ataxia: an update. J Neurol. 2019;266:533–44.
4. Klockgether T, Mariotti C, Paulson HL. Spinocerebellar ataxia. Nat Rev Dis Primers. 2019;5:24.
5. Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol. 2004;3:291–304.
6. Ruano L, Melo C, Silva MC, Coutinho P. The global epidemiology of hereditary ataxia and spastic paraplegia: a systematic review of prevalence studies. Neuroepidemiology. 2014;42:174–83.
7. Soong BW, Paulson HL. Spinocerebellar ataxias: an update. Curr Opin Neurol. 2007;20:438–46.
8. Lin YC, Lee YC, Hsu TY, Liao YC, Soong BW. Comparable progression of spinocerebellar ataxias between Caucasians and Chinese. Parkinsonism Relat Disord. 2019;62:156–62.
9. Maruyama H, Izumi Y, Morino H, Oda M, Toji H, Nakamura S, et al. Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients. Am J Med Genet. 2002;114:578–83.
10. Jacobi H, Bauer P, Giunti P, Labrum R, Sweeney MG, Charles P, et al. The natural history of spinocerebellar ataxia type 1, 2, 3, and 6: a 2-year follow-up study. Neurology. 2011;77:1035–41.
11. Qiu M, Wang R, Shen Y, Hu Z, Zhang Y. Efficacy and safety of repetitive transcranial magnetic stimulation in spinocerebellar ataxia type 3: a systematic review and meta-analysis of randomized controlled trials. Cerebellum. 2024;23:1604–13.
12. Liu Y, Ma Y, Zhang J, Yan X, Ouyang Y. Effects of non-invasive brain stimulation on hereditary ataxia: a systematic review and meta-analysis. Cerebellum. 2024;23:1614–25.
13. Ciricugno A, Oldrati V, Cattaneo Z, Leggio M, Urgesi C, Olivito G. Cerebellar neurostimulation for boosting social and affective functions: implications for the rehabilitation of hereditary ataxia patients. Cerebellum. 2024;23:1651–77.
14. Jannati A, Oberman LM, Rotenberg A, Pascual-Leone A. Assessing the mechanisms of brain plasticity by transcranial magnetic stimulation. Neuropsychopharmacology. 2023;48:191–208.
15. Rizvi S, Khan AM. Use of transcranial magnetic stimulation for depression. Cureus. 2019;11:e4736.
16. Cox J, Thakur B, Alvarado L, Shokar N, Thompson PM, Dwivedi AK. Repetitive transcranial magnetic stimulation for generalized anxiety and panic disorders: a systematic review and meta-analysis. Ann Clin Psychiatry. 2022;34:e2–e24.
17. Chou YH, Hickey PT, Sundman M, Song AW, Chen NK. Effects of repetitive transcranial magnetic stimulation on motor symptoms in Parkinson disease: a systematic review and meta-analysis. JAMA Neurol. 2015;72:432–40.
18. Chou YH, Ton That V, Sundman M. A systematic review and meta-analysis of rTMS effects on cognitive enhancement in mild cognitive impairment and Alzheimer’s disease. Neurobiol Aging. 2020;86:1–10.
19. Di Lazzaro V, Dileone M, Pilato F, Capone F, Musumeci G, Ranieri F, et al. Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation. J Neurophysiol. 2011;105:2150–6.
20. Funke K, Benali A. Cortical cellular actions of transcranial magnetic stimulation. Restor Neurol Neurosci. 2010;28:399–417.
21. Luo J, Zheng H, Zhang L, Zhang Q, Li L, Pei Z, et al. High-frequency repetitive transcranial magnetic stimulation (rTMS) improves functional recovery by enhancing neurogenesis and activating BDNF/TrkB signaling in ischemic rats. Int J Mol Sci. 2017;18:455.
22. Lee CW, Chu MC, Wu HF, Chung YJ, Hsieh TH, Chang CY, et al. Different synaptic mechanisms of intermittent and continuous theta-burst stimulations in a severe foot-shock induced and treatment-resistant depression in a rat model. Exp Neurol. 2023;362:114338.
23. Huang YZ, Edwards MJ, Rounis E, Bhatia KP, Rothwell JC. Theta burst stimulation of the human motor cortex. Neuron. 2005;45:201–6.
24. Brunoni AR, Sampaio-Junior B, Moffa AH, Aparicio LV, Gordon P, Klein I, et al. Noninvasive brain stimulation in psychiatric disorders: a primer. Braz J Psych. 2019;41:70–81.
25. Yin L, Wang X, Chen L, Liu D, Li H, Liu Z, et al. Repetitive transcranial magnetic stimulation for cerebellar ataxia: a systematic review and meta-analysis. Front Neurol. 2023;14:1177746.
26. Qiu YT, Chen Y, Tan HX, Su W, Guo QF, Gao Q. Efficacy and safety of repetitive transcranial magnetic stimulation in cerebellar ataxia: a systematic review and meta-analysis. Cerebellum. 2024;23:243–54.
27. Mendlowitz AB, Shanbour A, Downar J, Vila-Rodriguez F, Daskalakis ZJ, Isaranuwatchai W, et al. Implementation of intermittent theta burst stimulation compared to conventional repetitive transcranial magnetic stimulation in patients with treatment resistant depression: a cost analysis. PLoS One. 2019;14:e0222546.
28. Schmitz-Hubsch T, du Montcel ST, Baliko L, Berciano J, Boesch S, Depondt C, et al. Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology. 2006;66:1717–20.
29. Salci Y, Fil A, Keklicek H, Cetin B, Armutlu K, Dolgun A, et al. Validity and reliability of the International Cooperative Ataxia Rating Scale (ICARS) and the Scale for the Assessment and Rating of Ataxia (SARA) in multiple sclerosis patients with ataxia. Mult Scler Relat Disord. 2017;18:135–40.
30. Chen ML, Lin CC, Rosenthal LS, Opal P, Kuo SH. Rating scales and biomarkers for CAG-repeat spinocerebellar ataxias: implications for therapy development. J Neurol Sci. 2021;424:117417.
31. Brooker SM, Edamakanti CR, Akasha SM, Kuo SH, Opal P. Spinocerebellar ataxia clinical trials: opportunities and challenges. Ann Clin Transl Neurol. 2021;8:1543–56.
32. Zhou M, Qiu M, Jin Y, Li D, Tao C, Lou D, et al. Effectiveness of high-frequency repetitive transcranial magnetic stimulation in patients with spinocerebellar ataxia type 3. J ECT. 2024;40:15–9.
33. Chen XY, Lian YH, Liu XH, Sikandar A, Li MC, Xu HL, et al. Effects of repetitive transcranial magnetic stimulation on cerebellar metabolism in patients with spinocerebellar ataxia type 3. Front Aging Neurosci. 2022;14:827993.
34. Sikandar A, Liu XH, Xu HL, Li Y, Lin YQ, Chen XY, 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.
35. Manor B, Greenstein PE, Davila-Perez P, Wakefield S, Zhou J, Pascual-Leone, . Repetitive transcranial magnetic stimulation in spinocerebellar ataxia: a pilot randomized controlled trial. Front Neurol. 2019;10:73.
36. Shi Y, Zou G, Chen Z, Wan L, Peng L, Peng H, et al. Efficacy of cerebellar transcranial magnetic stimulation in spinocerebellar ataxia type 3: a randomized, single-blinded, controlled trial. J Neurol. 2023;270:5372–9.
37. Franca C, de Andrade DC, Silva V, Galhardoni R, Barbosa ER, Teixeira MJ, et al. Effects of cerebellar transcranial magnetic stimulation on ataxias: a randomized trial. Parkinsonism Relat Disord. 2020;80:1–6.
38. Grobe-Einsler M, Bork F, Faikus A, Hurlemann R, Kaut O. Effects of cerebellar repetitive transcranial magnetic stimulation plus physiotherapy in spinocerebellar ataxias—a randomized clinical trial. CNS Neurosci Ther. 2024;30:e14797.
39. Liu X, Zhang L, Xu HL, Liu XH, Sikandar A, Li MC, et al.; Members of the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR). Effect of regional brain activity following repeat transcranial magnetic stimulation in SCA3: a secondary analysis of a randomized clinical trial. Cerebellum. 2024;23:1923–31.
40. Jacobi H, du Montcel ST, Bauer P, Giunti P, Cook A, Labrum R, et al. Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: a longitudinal cohort study. Lancet Neurol. 2015;14:1101–8.
41. Yasui K, Yabe I, Yoshida K, Kanai K, Arai K, Ito M, et al. A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan. Orphanet J Rare Dis. 2014;9:118.
42. Ashizawa T, Figueroa KP, Perlman SL, Gomez CM, Wilmot GR, Schmahmann JD, et al. Clinical characteristics of patients with spinocerebellar ataxias 1, 2, 3 and 6 in the US: a prospective observational study. Orphanet J Rare Dis. 2013;8:177.
43. Peng Y, Peng L, Chen Z, Peng H, Wang P, Zhang Y, et al. The natural history of spinocerebellar ataxia type 3 in Mainland China: a 2-year cohort study. Front Aging Neurosci. 2022;14:917126.
44. Stoodley CJ, Schmahmann JD. Functional topography in the human cerebellum: a meta-analysis of neuroimaging studies. Neuroimage. 2009;44:489–501.
45. Bernard JA, Seidler RD, Hassevoort KM, Benson BL, Welsh RC, Wiggins JL, et al. Resting state cortico-cerebellar functional connectivity networks: a comparison of anatomical and self-organizing map approaches. Front Neuroanat. 2012;6:31.
46. Buckner RL, Krienen FM, Castellanos A, Diaz JC, Yeo BT. The organization of the human cerebellum estimated by intrinsic functional connectivity. J Neurophysiol. 2011;106:2322–45.
47. Schmahmann JD, Sherman JC. The cerebellar cognitive affective syndrome. Brain. 1998;121 (Pt 4):561–79.
48. Jacobi H, Faber J, Timmann D, Klockgether T. Update cerebellum and cognition. J Neurol. 2021;268:3921–5.
49. Amokrane N, Viswanathan A, Freedman S, Yang CY, Desai NA, Pan MK, et al. Impulsivity in cerebellar ataxias: testing the cerebellar reward hypothesis in humans. Mov Disord. 2020;35:1491–3.
50. Lin YC, Hsu CH, Wang PN, Lin CP, Chang LH. The relationship between zebrin expression and cerebellar functions: insights from neuroimaging studies. Front Neurol. 2020;11:315.
51. Schmahmann JD. Disorders of the cerebellum: ataxia, dysmetria of thought, and the cerebellar cognitive affective syndrome. J Neuropsychiatry Clin Neurosci. 2004;16:367–78.
52. Lin CR, Amokrane N, Chen S, Chen TX, Lai RY, Trinh P, et al. Cerebellar impulsivity-compulsivity assessment scale. Ann Clin Transl Neurol. 2023;10:48–57.
53. Hirano T. Long-term depression and other synaptic plasticity in the cerebellum. Proc Jpn Acad Ser B Phys Biol Sci. 2013;89:183–95.
54. Wang DJ, Su LD, Wang YN, Yang D, Sun CL, Zhou L, et al. Long-term potentiation at cerebellar parallel fiber-Purkinje cell synapses requires presynaptic and postsynaptic signaling cascades. J Neurosci. 2014;34:2355–64.
55. Guerra A, Suppa A, Bologna M, D’Onofrio V, Bianchini E, Brown P, et al. Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation. Brain Stimul. 2018;11:734–42.
56. Celnik P. Understanding and modulating motor learning with cerebellar stimulation. Cerebellum. 2015;14:171–4.
57. Miterko LN, Baker KB, Beckinghausen J, Bradnam LV, Cheng MY, Cooperrider J, et al. Consensus paper: experimental neurostimulation of the cerebellum. Cerebellum. 2019;18:1064–97.
58. Popa T, Russo M, Meunier S. Long-lasting inhibition of cerebellar output. Brain Stimul. 2010;3:161–9.
59. Chen Y, Wei QC, Zhang MZ, Xie YJ, Liao LY, Tan HX, et al. Cerebellar intermittent theta-burst stimulation reduces upper limb spasticity after subacute stroke: a randomized controlled trial. Front Neural Circuits. 2021;15:655502.
60. Gassmann L, Gordon PC, Ziemann U. Assessing effective connectivity of the cerebellum with cerebral cortex using TMS-EEG. Brain Stimul. 2022;15:1354–69.
61. Tremblay S, Austin D, Hannah R, Rothwell JC. Non-invasive brain stimulation as a tool to study cerebellar-M1 interactions in humans. Cerebellum Ataxias. 2016;3:19.
62. Mitoma H, Buffo A, Gelfo F, Guell X, Fuca E, Kakei S, et al. Consensus paper. Cerebellar reserve: from cerebellar physiology to cerebellar disorders. Cerebellum. 2020;19:131–53.
63. Hawkes R. Purkinje cell stripes and long-term depression at the parallel fiber-Purkinje cell synapse. Front Syst Neurosci. 2014;8:41.
64. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, et al. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513:532–41.
65. Billeri L, Naro A. A narrative review on non-invasive stimulation of the cerebellum in neurological diseases. Neurol Sci. 2021;42:2191–209.
66. Wang Y, Zhang D, Wang J, Ma J, Lu L, Jin S. Effects of transcranial magnetic stimulation on cerebellar ataxia: a systematic review and meta-analysis. Front Neurol. 2023;14:1049813.
67. Shah VV, Rodriguez-Labrada R, Horak FB, McNames J, Casey H, Hansson Floyd K, et al. Gait variability in spinocerebellar ataxia assessed using wearable inertial sensors. Mov Disord. 2021;36:2922–31.
68. Zhou H, Nguyen H, Enriquez A, Morsy L, Curtis M, Piser T, et al. Assessment of gait and balance impairment in people with spinocerebellar ataxia using wearable sensors. Neurol Sci. 2022;43:2589–99.
69. Schmahmann JD, Pierce S, MacMore J, L’Italien GJ. Development and validation of a patient-reported outcome measure of ataxia. Mov Disord. 2021;36:2367–77.
70. Sack AT, Cohen Kadosh R, Schuhmann T, Moerel M, Walsh V, Goebel R. Optimizing functional accuracy of TMS in cognitive studies: a comparison of methods. J Cogn Neurosci. 2009;21:207–21.
71. Downar J, Daskalakis ZJ. New targets for rTMS in depression: a review of convergent evidence. Brain Stimul. 2013;6:231–40.
72. Burns MR, Hermiller MS. Quantifying and reporting the precision of transcranial magnetic stimulation targeting. Brain Res. 2025;1849:149350.