Extended haplotype with rs41524547-G defines the ancestral origin of SCA10.

Spinocerebellar ataxia type 10 (SCA10) is a rare autosomal dominant ataxia caused by a large expansion of the (ATTCT)n repeat in ATXN10. SCA10 was described in Native American and Asian individuals which prompted a search for an expanded haplotype to confirm a common ancestral origin for the expansion event. All patients with SCA10 expansions in our cohort share a single haplotype defined at the 5'-end by the minor allele of rs41524547, located ~35 kb upstream of the SCA10 expansion. Intriguingly, rs41524547 is located within the miRNA gene, MIR4762, within its DROSHA cleavage site and just outside the seed sequence for mir4792-5p. The world-wide frequency of rs41524547-G is less than 5% and found almost exclusively in the Americas and East Asia-a geographic distribution that mirrors reported SCA10 cases. We identified rs41524547-G(+) DNA from the 1000 Genomes/International Genome Sample Resource and our own general population samples and identified SCA10 repeat expansions in up to 25% of these samples. The reduced penetrance of these SCA10 expansions may be explained by a young (pre-onset) age at sample collection, a small repeat size, purity of repeat units, or the disruption of miR4762-5p function. We conclude that rs41524547-G is the most robust at-risk SNP allele for SCA10, is useful for screening of SCA10 expansions in population genetics studies and provides the most compelling evidence to date for a single, prehistoric origin of SCA10 expansions sometime prior to or during the migration of individuals across the Bering Land Bridge into the Americas.

Characteristics of tandem repeat inheritance and sympathetic nerve involvement in GAA-FGF14 ataxia.

BACKGROUND: Intronic GAA repeat expansion ([GAA] ≥250) in FGF14 is associated with the late-onset neurodegenerative disorder, spinocerebellar ataxia 27B (SCA27B, GAA-FGF14 ataxia). We aim to determine the prevalence of the GAA repeat expansion in FGF14 in Chinese populations presenting late-onset cerebellar ataxia (LOCA) and evaluate the characteristics of tandem repeat inheritance, radiological features and sympathetic nerve involvement. METHODS: GAA-FGF14 repeat expansion was screened in an undiagnosed LOCA cohort (n = 664) and variations in repeat-length were analyzed in families of confirmed GAA-FGF14 ataxia patients. Brain magnetic resonance imaging (MRI) was used to evaluate the radiological feature in GAA-FGF14 ataxia patients. Clinical examinations and sympathetic skin response (SSR) recordings in GAA-FGF14 patients (n = 16) were used to quantify sympathetic nerve involvement. RESULTS: Two unrelated probands (2/664) were identified. Genetic screening for GAA-FGF14 repeat expansion was performed in 39 family members, 16 of whom were genetically diagnosed with GAA-FGF14 ataxia. Familial screening revealed expansion of GAA repeats in maternal transmissions, but contraction upon paternal transmission. Brain MRI showed slight to moderate cerebellar atrophy. SSR amplitude was lower in GAA-FGF14 patients in pre-symptomatic stage compared to healthy controls, and further decreased in the symptomatic stage. CONCLUSIONS: GAA-FGF14 ataxia was rare among Chinese LOCA cases. Parental gender appears to affect variability in GAA repeat number between generations. Reduced SSR amplitude is a prominent feature in GAA-FGF14 patients, even in the pre-symptomatic stage.

Effect of Regional Brain Activity Following Repeat Transcranial Magnetic Stimulation in SCA3: A Secondary Analysis of a Randomized Clinical Trial.

Repetitive transcranial magnetic stimulation (rTMS), a noninvasive neuroregulatory technique used to treat neurodegenerative diseases, holds promise for spinocerebellar ataxia type 3 (SCA3) treatment, although its efficacy and mechanisms remain unclear. This study aims to observe the short-term impact of cerebellar rTMS on motor function in SCA3 patients and utilize resting-state functional magnetic resonance imaging (RS-fMRI) to assess potential therapeutic mechanisms. Twenty-two SCA3 patients were randomly assigned to receive actual rTMS (AC group, n = 11, three men and eight women; age 32-55 years) or sham rTMS (SH group, n = 11, three men and eight women; age 26-58 years). Both groups underwent cerebellar rTMS or sham rTMS daily for 15 days. The primary outcome measured was the ICARS scores and parameters for regional brain activity. Compared to baseline, ICARS scores decreased more significantly in the AC group than in the SH group after the 15-day intervention. Imaging indicators revealed increased Amplitude of Low Frequency Fluctuation (ALFF) values in the posterior cerebellar lobe and cerebellar tonsil following AC stimulation. This study suggests that rTMS enhances motor functions in SCA3 patients by modulating the excitability of specific brain regions and associated pathways, reinforcing the potential clinical utility of rTMS in SCA3 treatment. The Chinese Clinical Trial Registry identifier is ChiCTR1800020133.

"Phoenix in Flight": an unique fruit morphology ensures wind dispersal of seeds of the phoenix tree (Firmiana simplex (L.) W. Wight).

BACKGROUND: Many seed plants produce winged diaspores that use wind to disperse their seeds. The morphology of these diaspores is directly related to the seed dispersal potential. The majority of winged diaspores have flat wings and only seeds; however, some angiosperms, such as Firmiana produce winged fruit with a different morphology, whose seed dispersal mechanisms are not yet fully understood. In this study, we observed the fruit development of F. simplex and determined the morphological characteristics of mature fruit and their effects on the flight performance of the fruit. RESULTS: We found that the pericarp of F. simplex dehisced early and continued to unfold and expand during fruit development until ripening, finally formed a spoon-shaped wing with multiple alternate seeds on each edge. The wing caused mature fruit to spin stably during descent to provide a low terminal velocity, which was correlated with the wing loading and the distribution of seeds on the pericarp. When the curvature distribution of the pericarp surface substantially changed, the aerodynamic characteristics of fruit during descent altered, resulting in the inability of the fruit to spin. CONCLUSIONS: Our results suggest that the curved shape and alternate seed distribution are necessary for the winged diaspore of F. simplex to stabilize spinning during wind dispersal. These unique morphological characteristics are related to the early cracking of fruits during development, which may be an adaptation for the wind dispersal of seeds.

Factors Associated with Intergenerational Instability of ATXN3 CAG Repeat and Genetic Anticipation in Chinese Patients with Spinocerebellar Ataxia Type 3.

Spinocerebellar ataxia type 3 (SCA3) is caused by unstable expanded CAG repeats (expCAGs) in ATXN3. Factors associated with intergenerational instability (delta-expCAG) and genetic anticipation in SCA3 have never been reported in Chinese mainland. Here, we demonstrated that unstable transmissions occurred more often in sons than in daughters (91% vs 72%, Fisher's exact test, p = 0.012). The extended delta-expCAG of father-son transmissions was greater than that of mother-son transmissions (3.8 ± 2.3 repeats vs 1.6 ± 1.0 repeats, Mann-Whitney U, p = 0.001). Genetic anticipation was frequently observed between generations but not affected by the delta-expCAG.

Hispanic Spinocerebellar Ataxia Type 35 (SCA35) with a Novel Frameshift Mutation.

Genetic mutations in transglutaminase 6 (TGM6) are recently identified to be associated with spinocerebellar ataxia type 35 (SCA35). We report a Hispanic SCA35 patient, who was confirmed to have a heterozygous, single-nucleotide deletion in TGM6, causing a frameshift mutation with a premature stop codon. An immune-mediated ataxia previously found to be associated with autoantibody reactivity to TG6 may share a similar pathomechanism to SCA35, suggesting a converging role for TG6 in cerebellar function.

Association Between Body Mass Index and Disease Severity in Chinese Spinocerebellar Ataxia Type 3 Patients.

Spinocerebellar ataxia type 3 (SCA3), the most common subtype of SCA worldwide, is caused by mutation of CAG repeats expansion in ATXN3. Body mass index (BMI) is an important modulatory factor in the progression of neurodegenerative disorders such as Huntington disease and amyotrophic lateral sclerosis. However, its relevance in SCA3 is not well understood. In this study, BMI was investigated in 134 molecularly confirmed SCA3 patients and 136 healthy controls from China. The multivariable linear regression models were performed to establish the putative risk factors for BMI, and whether BMI could affect the severity of ataxia. We found that BMI was significantly lower in the case group than that in the control group. The age at onset (positive correlation) and severity of ataxia (negative correlation) were the risk factors affecting BMI. Conversely, BMI along with the disease duration, the age at onset, and the numbers of CAG repeats could also have influence on the severity of ataxia. In conclusion, SCA3 patients had lower BMI than matched controls and BMI is a predictor of disease progression in SCA3. Nutritional intervention to promote weight gain could be a promising strategy to impede SCA3 progression.

Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3), which is the most common subtype of SCA worldwide, exhibits common neuropsychological symptoms such as depression. However, the contribution of depression to the severity of SCA3 has not yet been thoroughly investigated. METHODS: The present study investigated the prevalence of depression using Beck depression inventory in 104 molecularly confirmed SCA3 patients from China. The putative risk factors for depression and whether the depression could affect the severity of ataxia were established by multivariable linear regression models. RESULTS: The frequency of depression in the study subjects was 57.69% (60/104), which was higher than that in SCA3 patients from a subset of other populations. The gender (p = 0.03) and severity (p < 0.01) of ataxia were those risk factors that could affect depression. Conversely, depression (p < 0.01) together with the duration (p < 0.01) of SCA3 could also play a positive role in the severity of ataxia. CONCLUSIONS: The extremely common depression results from motor disability caused by ataxia; it also affects the disease severity of SCA3. These findings suggested that depression was a part of neurodegeneration in SCA3 and necessitated intensive focus and interventions while caring for SCA3 patients.

Disease Progression and Multiparametric Imaging Characteristics of Spinocerebellar Ataxia Type 3 With Spastic Paraplegia.

Background and Objectives: Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia that occurs worldwide. Clinical patterns were observed, including the one characterized by marked spastic paraplegia. This study investigated the clinical features, disease progression, and multiparametric imaging aspects of patients with SCA3. Methods: We retrospectively analyzed 249 patients with SCA3 recruited from the Organization for Southeast China for cerebellar ataxia research between October 2014 and December 2020. Of the 249 patients, 145 were selected and assigned to 2 groups based on neurologic examination: SCA3 patients with spastic paraplegia (SCA3-SP) and SCA3 patients with nonspastic paraplegia (SCA3-NSP). Participants underwent 3.0-T brain MRI examinations, and voxel-wise and volume-of-interest-based approaches were used for the resulting images. A tract-based spatial statistical approach was used to investigate the white matter (WM) alterations using diffusion tensor imaging, neurite orientation dispersion, and density imaging metrics. Multiple linear regression analyses were performed to compare the clinical and imaging parameters between the 2 groups. The longitudinal data were evaluated using a linear mixed-effects model. Results: Forty-three patients with SCA3-SP (mean age, 37.58years ± 11.72 [SD]; 18 women) and 102 patients with SCA3-NSP (mean age, 47.42years ± 12.50 [SD]; 39 women) were analyzed. Patients with SCA3-SP were younger and had a lower onset age but a larger cytosine-adenine-guanine repeat number, as well as higher clinical severity scores (all corrected p < 0.05). The estimated progression rates of the Scale for the Assessment and Rating of Ataxia (SARA) and International Cooperative Ataxia Rating Scale scores were higher in the SCA3-SP subgroup than in the SCA3-NSP subgroup (SARA, 2.136 vs 1.218 points; ICARS, 5.576 vs 3.480 points; both p < 0.001). In addition, patients with SCA3-SP showed gray matter volume loss in the precentral gyrus with a decreased neurite density index in the WM of the corticospinal tract and cerebellar peduncles compared with patients with SCA3-NSP. Discussion: SCA3-SP differs from SCA3-NSP in clinical features, multiparametric brain imaging findings, and longitudinal follow-up progression.

Cognitive impairment associated with cerebellar volume loss in spinocerebellar ataxia type 3.

BACKGROUND: Many neuroscience and neurology studies have forced a reconsideration of the traditional motor-related scope of cerebellar function, which has now expanded to include various cognitive functions. Spinocerebellar ataxia type 3 (SCA3; the most common hereditary ataxia) is neuropathologically characterized by cerebellar atrophy and frequently presents with cognitive impairment. OBJECTIVE: To characterize cognitive impairment in SCA3 and investigate the cerebellum-cognition associations. METHODS: This prospective, cross-sectional cohort study recruited 126 SCA3 patients and 41 healthy control individuals (HCs). Participants underwent a brain 3D T1-weighted images as well as neuropsychological tests. Voxel-based morphometry (VBM) and region of interest (ROI) approaches were performed on the 3D T1-weighted images. CERES was used to automatically segment cerebellums. Patients were grouped into cognitively impaired (CI) and cognitively preserved (CP), and clinical and MRI parameters were compared. Multivariable regression models were fitted to examine associations between cerebellar microstructural alterations and cognitive domain impairments. RESULTS: Compared to HCs, SCA3 patients showed cognitive domain impairments in information processing speed, verbal memory, executive function, and visuospatial perception. Between CI and CP subgroups, the CI subgroup was older and had lower education, as well as higher severity scores. VBM and ROI analyses revealed volume loss in cerebellar bilateral lobule VI, right lobule Crus I, and right lobule IV of the CI subgroup, and all these cerebellar lobules were associated with the above cognitive domain impairments. CONCLUSIONS: Our findings demonstrate the multiple cognitive domain impairments in SCA3 patients and indicate the responsible cerebellar lobules for the impaired cognitive domain(s).

Short-term efficacy of repetitive transcranial magnetic stimulation in SCA3: A prospective, randomized, double-blind, sham-controlled study.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant ataxia globally. No effective treatment is currently available for SCA3. Repetitive Transcranial Magnetic Stimulation (rTMS) is a non-invasive form of brain stimulation, demonstrated to improve symptoms in patients with neurodegenerative cerebellar ataxias. The present study investigated whether treatment with rTMS over the cerebellum for 15 consecutive days improved measures of ataxia in SCA3 patients. METHODS: A double-blind, prospective, randomized, sham-controlled trial was carried out on 44 SCA3 patients. Participants were randomly assigned to two groups: real or sham stimulation. Each participant underwent 30 minutes of 1Hz rTMS stimulation (a total of 900 pulses) for 15 consecutive days. The primary outcome measure was the score on the International Cooperative Ataxia Rating Scale (ICARS), and secondary outcomes were from the Scale for the Assessment and Rating of Ataxia (SARA) and the Berg Balance Scale (BBS). RESULTS: Nausea was the only adverse effect reported by 2 participants from the sham and real group. After 15 days of treatment, there was a significant improvement in all performance scores in both real and sham stimulation groups. However, compared to the sham group, the improvements were significantly larger in the real group for the ICARS (P = 0.002), SARA (P = 0.001), and BBS (P = 0.001). INTERPRETATION: A 15 days treatment with rTMS over the cerebellum improves the symptoms of ataxia in SCA3 patients. Our results suggest that rTMS is a promising tool for future rehabilitative approaches in SCA3.

Altered brain white matter structural motor network in spinocerebellar ataxia type 3.

OBJECTIVES: Spinocerebellar ataxia type 3 is a disorder within the brain network. However, the relationship between the brain network and disease severity is still unclear. This study aims to investigate changes in the white matter (WM) structural motor network, both in preclinical and ataxic stages, and its relationship with disease severity. METHODS: For this study, 20 ataxic, 20 preclinical SCA3 patients, and 20 healthy controls were recruited and received MRI scans. Disease severity was quantified using the SARA and ICARS scores. The WM motor structural network was created using probabilistic fiber tracking and was analyzed using graph theory and network-based statistics at global, nodal, and edge levels. In addition, the correlations between network topological measures and disease duration or clinical scores were analyzed. RESULTS: Preclinical patients showed increasing assortativity of the motor network, altered subnetwork including 12 edges of 11 nodes, and 5 brain regions presenting reduced nodal strength. In ataxic patients assortativity of the motor network also increased, but global efficiency, global strength, and transitivity decreased. Ataxic patients showed a wider altered subnetwork and a higher number of reduced nodal strengths. A negative correlation between the transitivity of the motor network and SARA and ICARS scores was observed in ataxic patients. INTERPRETATION: Changes to the WM motor network in SCA3 start before ataxia onset, and WM motor network involvement increases with disease progression. Global network topological measures of the WM motor network appear to be a promising image biomarker for disease severity. This study provides new insights into the pathophysiology of disease in SCA3/MJD.

Effects of cerebellar transcranial alternating current stimulation in cerebellar ataxia: study protocol for a randomised controlled trial.

Background: Cerebellar ataxia (CA) is a movement disorder that can affect balance and gait, limb movement, oculomotor control, and cognition. Multiple system atrophy-cerebellar type (MSA-C) and spinocerebellar ataxia type 3 (SCA3) are the most common forms of CA, for which no effective treatment is currently available. Transcranial alternating current stimulation (tACS) is a non-invasive method of brain stimulation supposed to alter cortical excitability and brain electrical activity, modulating functional connectivity within the brain. The cerebellar tACS can modulate the cerebellar outflow and cerebellum-linked behavior and it is a proven safe technique for humans. Therefore, the aim of this study is to 1) examine whether cerebellar tACS improves ataxia severity and various non-motor symptoms in a homogeneous cohort of CA patients consisting of MSA-C and SCA3, 2) explore the time course of these effects, and 3) assess the safety and tolerance of cerebellar tACS in all participants. Methods/design: This is a 2-week, triple-blind, randomised, sham-controlled study. 164 patients (MSA-C: 84, SCA3: 80) will be recruited and randomly assigned to either active cerebellar tACS or sham cerebellar tACS, in a 1:1 ratio. Patients, investigators, and outcome assessors are unaware of treatment allocation. Cerebellar tACS (40 min, 2 mA, ramp-up and down periods of 10s each) will be delivered over 10 sessions, distributed in two groups of five consecutive days with a two-day break in between. Outcomes are assessed after the tenth stimulation (T1), and after 1 month (T2) and 3 months (T3). The primary outcome measure is the difference between the active and sham groups in the proportion of patients with an improvement of 1.5 points in the Scale for the Assessment and Rating of Ataxia (SARA) score after 2 weeks of treatment. In addition, effects on a variety of non-motor symptoms, quality of life, and autonomic nerve dysfunctions are assessed via relative scales. Gait imbalance, dysarthria, and finger dexterity are objectively valued via relative tools. Finally, functional magnetic resonance imaging is performed to explore the possible mechanism of treatment effects. Discussion: The results of this study will inform whether repeated sessions of active cerebellar tACS benefit CA patients and whether this form of non-invasive stimulation might be a novel therapeutic approach to consider in a neuro-rehabilitation setting.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05557786; https://www.clinicaltrials.gov/ct2/show/NCT05557786.

Association of Common Variants in the Glucocerebrosidase Gene with High Susceptibility to Parkinson's Disease among Chinese.

The genetic variants in glucocerebrosidase (GBA) gene have been previously examined as potential susceptibility factors for Parkinson's disease (PD). Although of great interest, possible role of GBA gene in PD has not been well investigated in eastern Chinese population. To explore this association, we conducted a genetic screen of three common GBA variants (p.L444P, p.N370S, and p.R120W) in a casecontrol cohort comprised of 638 subjects of Chinese ethnicity. In order to provide a more precise estimate of this association, a meta-analysis was performed. We found that the GBA p.L444P allele was significantly more frequent (P = 0.001) in the PD patients (6/195 = 3.08%) than in the controls (0/443). The p.L444P mutation, but not p.N370S and p.R120W, was found to be associated with PD. Combined analysis including all previously published ancestral Chinese data yielded a highly significant association between the GBA gene and an increased risk for PD (OR = 8.13, 95% CI, 4.43-14.92, P < 0.00001). Our study suggests that the GBA gene may be a susceptibility gene for PD in the Chinese population. Efforts to elucidate in detail this interesting and biologically plausible genetic association are warranted.

Functional Differentiation of Floral Color and Scent in Gall Midge Pollination: A Study of a Schisandraceae Plant.

Gall midges are among the most host-specific insects. Their interactions with plants likely date back to the Cretaceous period. Plants from at least seven families are involved in gall midge pollination; however, little is known about the pollination signals of gall midges. In this study, we used a Resseliella-Schisandra model to investigate the roles of floral scent and color in attracting gall midges. Field observations, behavioral bioassays via Y-tubes, and "flight box" experiments were performed. The results demonstrated that gall midges may be attracted by both floral scent and color and that two flower signals are more effective in promoting insect flower-landing than either alone. In the field, gall midges visited male flowers effectively at night but almost always visited female flowers during the day. Thus, during the Resseliella-Schisandra interactions, female flowers predominantly employed visual cues over scent to attract midges during the day; in contrast, olfactory cues were more functional for male flowers to export pollen in the dark. In this study, we first identified the roles of floral color and the functional differentiation of visual and olfactory cues during gall midge pollination.

Impaired Lower Limb Proprioception in Spinocerebellar Ataxia Type 3 and Its Affected Factors.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases. Postural control dysfunction is the main symptom of SCA3, and the proprioceptive system is a critical sensory component of postural control. Accordingly, proprioception quantification assessment is necessary in monitoring the progression of SCA3. OBJECTIVE: We aimed to quantitatively assess lower limb proprioception and investigate the relationship between proprioception and clinical characteristics in patients with SCA3. METHODS: A total of 80 patients with SCA3 and 62 health controls were recruited, and their lower limb proprioception was measured using the Pro-kin system. Clinical characteristics of the SCA3 patients were collected. Multivariable linear regression was used to investigate potential affected factors for lower limb proprioception. RESULTS: We found that the patients with SCA3 experience poorer lower limb proprioception characterized by significant impairment in the average trace error (ATE) and time to carry out the test time execution (TTE) compared to controls (P < 0.05). Moreover, there were significant differences in TTE between the right and left lower limbs (P < 0.05) of the patients. Regression analyses revealed that increasing age at onset (AAO) predicts poorer lower limb proprioception for both ATE (ß = 2.006, P = 0.027) and TTE (ß = 1.712, P = 0.043) and increasing disease duration predicts poorer lower limb proprioception for ATE (ß = 0.874, P = 0.044). AAO (ß = 0.328, P = 0.019) along with the expanded alleles (ß = 0.565, P = 0.000) could affect the severity of ataxia. By contrast, ATE (ß = 0.036, P = 0.800) and TTE (ß = -0.025, P = 0.862) showed no significant predictors. CONCLUSIONS: Lower limb proprioception in patients with SCA3 is significantly impaired when compared to healthy controls. Increasing AAO and disease duration are related to impaired lower limb proprioception.

Effects of Repetitive Transcranial Magnetic Stimulation on Cerebellar Metabolism in Patients With Spinocerebellar Ataxia Type 3.

Background: Spinocerebellar ataxia type 3 (SCA3) is the most common autosomal dominant hereditary ataxia, and, thus far, effective treatment remains low. Repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of spinal cerebellar ataxia, but the mechanism is unclear; in addition, whether any improvement in the symptoms is related to cerebellar metabolism has not yet been investigated. Therefore, the purpose of this study was to investigate the effects of low-frequency rTMS on local cerebellar metabolism in patients with SCA3 and the relationship between the improvement in the symptoms and cerebellar metabolism. Methods: A double-blind, prospective, randomized, sham-controlled trial was carried out among 18 SCA3 patients. The participants were randomly assigned to the real stimulation group (n = 9) or sham stimulation group (n = 9). Each participant in both the groups underwent 30 min of 1 Hz rTMS stimulation (a total of 900 pulses), differing only in terms of stimulator placement, for 15 consecutive days. To separately compare pre- and post-stimulation data (magnetic resonance spectroscopy (MRS) data and the International Cooperative Ataxia Rating Scale (ICARS) score) in the real and sham groups, paired-sample t-tests and Wilcoxon's signed-rank tests were used in the analyses. The differences in the ICARS and MRS data between the two groups were analyzed with independent t-tests and covariance. To explore the association between the changes in the concentration of cerebellar metabolism and ICARS, we applied Pearson's correlation analysis. Results: After 15 days of treatment, the ICARS scores significantly decreased in both the groups, while the decrease was more significant in the real stimulation group compared to the sham stimulation group (p < 0.001). The analysis of covariance further confirmed that the total ICARS scores decreased more dramatically in the real stimulation group after treatment compared to the sham stimulation group (F = 31.239, p < 0.001). The values of NAA/Cr and Cho/Cr in the cerebellar vermis, bilateral dentate nucleus, and bilateral cerebellar hemisphere increased significantly in the real stimulation group (p < 0.05), but no significant differences were found in the sham stimulation group (p > 0.05). The analysis of covariance also confirmed the greater change in the real stimulation group. This study also demonstrated that there was a negative correlation between NAA/Cr in the right cerebellar hemisphere and ICARS in the real stimulation group (r = - 0.831, p = 0.02). Conclusion: The treatment with rTMS over the cerebellum was found to induce changes in the cerebellar local metabolism and microenvironment in the SCA3 patients. The alterations may contribute to the improvement of the symptoms of ataxia in SCA3 patients.