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.

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.

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.

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.

Quantitative assessment of postural instability in spinocerebellar ataxia type 3 patients.

OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3) is one of the most common hereditary neurodegenerative diseases, with balance instability as main symptom. Balance quantification is crucial for evaluating the efficacy of therapeutic interventions. However, balance evaluation in SCA3 is often subject to bias. Here, we aimed to quantitatively evaluate postural instability and investigate the relationship between postural instability and clinical characteristics in SCA3 patients. METHODS: Sixty-two SCA3 patients and 62 normal controls were recruited, and their postural balance was measured using a posturographic platform. Principal component analysis was performed as data reduction to identify postural instability factors. Multivariable linear regression was used to investigate potential risk factors for postural instability and to explore whether postural instability predicts the severity and progression of ataxia in SCA3 patients. RESULTS: We found SCA3 patients experience postural instability characterized by significant impairment in static and dynamic stability. The condition without visual feedback was the most sensitive measure in differentiating SCA3 from controls. Regression analyses revealed that ataxia severity predicted both static (P = 0.014) and dynamic stability (P = 0.001). Likewise, along with expanded CAG repeats (P < 0.001), both static (P < 0.001) and dynamic stability (P < 0.001) predicted ataxia severity, but not ataxia progression. INTERPRETATION: Our findings demonstrate the validity of using the Pro-kin system for assessing postural instability in SCA3 patients. This type of quantitative assessment of balance dysfunction can contribute to clinical trials and balance rehabilitation in SCA3 patients.

Ataxic Severity Is Positively Correlated With Fatigue in Spinocerebellar Ataxia Type 3 Patients.

Background: Spinocerebellar ataxia type 3 (SCA3) is an inherited form of ataxia that leads to progressive neurodegeneration. Fatigue is a common non-motor symptom in SCA3 and other neurodegenerative diseases, such as Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS). Although risk factors to fatigue in these diseases have been thoroughly studied, whether or not fatigue can affect clinical phenotypes has yet to be investigated. Methods: Ninety-one molecularly confirmed SCA3 patients and 85 age- and sex-matched controls were recruited for this study. The level of fatigue was measured using the 14-item Fatigue Scale (FS-14), and the risk factors to fatigue and how fatigue correlates with clinical phenotypes were studied using multivariable linear regression models. Results: We found that the severity was significantly higher in the SCA3 group than in the control group (9.30 ± 3.04% vs. 3.94 ± 2.66, P = 0.000). Daytime somnolence (ß = 0.209, P = 0.002), severity of ataxia (ß = 0.081, P = 0.006), and poor sleep quality (ß = 0.187, P = 0.037) were found to have a positive relationship with fatigue. Although fatigue had no relationship with age at onset or ataxic progression, we found that it did have a positive relationship with the severity of ataxia (ß = 7.009, P = 0.014). Conclusions: The high level of fatigue and the impact of fatigue on the clinical manifestation of SCA3 patients suggest that fatigue plays a large role in the pathogenesis of SCA3, thus demonstrating the need for intervention and treatment options in this patient cohort.

The influence of initial symptoms on phenotypes in spinocerebellar ataxia type 3.

BACKGROUND: Spinocerebellar ataxia type 3 (SCA3) is a rare, inherited form of ataxia that leads to progressive neurodegeneration. The initial symptoms could affect clinical phenotypes in neurodegenerative diseases, such as Parkinson's disease and amyotrophic lateral sclerosis. However, the contribution of initial symptoms to the phenotypes of SCA3 has been scarcely investigated. METHODS: In the present study, 143 SCA3 patients from China were recruited and divided into two groups of gait-onset and non-gait-onset. For determining the influences of initial symptoms on age at onset (AAO), the severity and progression of ataxia, and the possible factors affecting the initial symptoms, multivariable linear regression, and multivariate logistic regression were performed. RESULTS: We found that the frequency of gait-onset was 87.41%, and the frequency of non-gait-onset was 12.59% (diplopia: 7.69%, dysarthria: 4.20%, dystonia: 0.70%). Compared to the non-gait-onset group, the gait-onset group had significantly more severe ataxia (p = 0.046), while the initial symptoms had no effect on AAO (p = 0.109) and progression of ataxia (p = 0.265). We failed to find the existence of any factors affecting initial symptoms. CONCLUSION: These findings collectively suggested that initial symptoms influenced phenotypes in SCA3 and that neurodegeneration in different parts of brain may induce different disease severity in SCA3.