Feasibility and Safety of Combined Cerebello-spinal Neuromodulation and Exercise in Spinocerebellar Ataxia Type 3: A 20-session Protocol

Feasibility and Safety of Combined Cerebello-spinal Neuromodulation and Exercise in Spinocerebellar Ataxia Type 3: A 20-session Protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Feasibility and Safety of Combined Cerebello-spinal Neuromodulation and Exercise in Spinocerebellar Ataxia Type 3: A 20-session Protocol Anna Fontes Baptista, Thiago Lemos, Yasmin Carvalho Heiderick, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7437650/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Nov, 2025 Read the published version in The Cerebellum → Version 1 posted 9 You are reading this latest preprint version Abstract Background Spinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder that progressively impairs balance and gait, without effective pharmacological treatments available. Cerebellar and cerebello-spinal transcranial direct current stimulation (tDCS) have shown neuromodulatory potential. However, extended protocols combined with exercise have not yet been tested in these individuals in a public health service. Objective To assess the feasibility and safety of 20 sessions of cerebello-spinal tDCS combined with exercise in individuals with SCA3 in realworld conditions, and to explore preliminary changes in ataxia severity, balance, and mobility. Methods : In this clinical trial, 39 participants (67% female; mean age 46 years) with mild-to-moderate SCA3 completed 20 sessions over four weeks under realworld publichealth conditions. Feasibility was evaluated through adherence and tolerability, and safety was assessed by monitoring adverse events. Secondary outcomes included disease severity (SARA), balance (Berg Balance Scale), and mobility (Timed Up and Go), assessed at baseline, post-intervention, and one-month follow-up. Analyses included standardized individual differences and multiple linear regression adjusted for baseline values. Results : Adherence was 97.3%, with no serious adverse events. Significant improvements were observed in SARA (P < 0.001), BBS (P 0.171). Conclusions : A combination of multiple sessions of cerebello-spinal tDCS and exercise in a public health service was feasible, safe, and may improve ataxia severity, balance, and mobility in individuals with SCA3. Despite the absence of a control group, these findings encourage further investigation of the proposed intervention as a potential rehabilitation strategy for cerebellar neurodegeneration. Machado‑Joseph Disease Transcranial Direct Current Stimulation Exercise Therapy Feasibility Studies Pragmatic Clinical Trials Figures Figure 1 Figure 2 Figure 3 Figure 4 INTRODUCTION Spinocerebellar ataxia (SCA) is a hereditary degenerative disorder of the cerebellum that progressively impairs balance and gait, predominantly affecting individuals in their productive years [ 1 , 2 ]. Type 3 (SCA3, or MachadoJoseph Disease) is the most prevalent worldwide, followed by SCA2 and SCA6[ 3 , 2 ]. Rehabilitation interventions are crucial for this population since there are no effective pharmacological treatments for this condition[ 2 , 4 ]. Interest in cerebellar anodal transcranial direct current stimulation (ctDCS), has grown in recent years. This portable, non-invasive neuromodulation technique has few side effects. It promotes neuroplasticity by modulating cortical excitability in specific brain regions, including damaged cerebellar areas, and may optimize residual function[ 5 , 6 , 7 , 8 , 9 , 10 ] (Chen et al., 2021). These properties make ctDCS a promising approach for SCA. Further advancements include simultaneous cerebellar and spinal tDCS (called cerebello-spinal tDCS). The cerebello-spinal pathway plays a key role in motor control, balance and coordination, functions that are often compromised in cerebellar ataxia [ 11 , 12 ]. Modulation of this pathway involves the application of anodal current to the cerebellum and cathodal current to the spinal region. By targeting circuits distinct from those engaged with cerebellar stimulation alone, cerebellospinal tDCS may provide additional benefits [13]. A study [ 14 ] showed that cerebello-spinal tDCS produced greater clinical benefits compared to their earlier study using ctDCS [ 8 ]. Results showed reductions in ataxia severity scores, 9Hole Peg Test times and 8m walk times compared to sham stimulation in a heterogeneous sample of individuals with neurodegenerative cerebellar ataxia, including SCA. In a subsequent follow-up study, the authors further confirmed the benefits of cerebello-spinal tDCS in a larger cohort (N = 61) of multiple ataxia etiologies [15]. They performed a randomized, double-blind, sham-controlled tDCS trial, with sessions held five days a week for two weeks. Following a three-month washout period, an open-label phase was implemented, maintaining the same schedule of five sessions per week for two weeks. Additionally, significant reductions were observed in disease severity scale scores, along with improvements in quality-of-life measures [15]. However, most of these trials included heterogeneous samples of cerebellar ataxias; there are few studies evaluating tDCS specifically in SCA3, which highlights the need for exploratory trials targeting this population. Combining tDCS with exercise is clinically relevant and has gained importance because it increases motor cortex excitability, improves physical performance and motor learning, and yields greater effects than tDCS alone (for a review, see [ 16 ]. One study, for example, evaluated ctDCS combined with gait training in individuals with cerebellar ataxia [ 10 ]. However, despite preliminary evidence of efficacy, the specific pairing of cerebello-spinal tDCS with progressive balance and gait exercises in longer protocols (e.g., 20 consecutive sessions) still requires investigation in individuals with SCA3. Given the specificity of cerebello-spinal tDCS, the clinical characteristics of individuals with SCA, and the need to better understand its interaction with balance and gait exercises, it is essential to first assess the feasibility and safety of this combined approach over multiple sessions before progressing to large-scale efficacy trials. Thus, the present study aimed to (i) assess the feasibility and safety of 20 consecutive sessions of cerebellospinal tDCS combined with balance and gait exercises in individuals with SCA3; (ii) verify whether the protocol can be implemented in routine clinical practice; and (iii) preliminarily explore the therapeutic effects of this intervention on the severity of ataxia, balance, and mobility. METHODS Design This study was designed with a pragmatic approach, conducted in a public rehabilitation service to reflect real-world conditions while assessing the safety, adherence, and acceptability of the intervention. The trial followed the CONSORT extension for Pragmatic Trials [ 17 ]. To reflect real-world clinical conditions, broad inclusion criteria were adopted, and the intervention was delivered in a routine outpatient rehabilitation setting with minimal restrictions on concurrent treatments. The study was approved by the Comitê de Ética em Pesquisa (CEP) da UNISUAM (process number 70797823.1.0000.5235) and was registered at ClinicalTrials.gov (NCT06267222) on October 11, 2023. All participants provided written informed consent prior to enrollment, in accordance with the Declaration of Helsinki. Sample The individuals with SCA, identified through records from national public hospitals, physician clinics, and physiotherapy facilities, representing a typical outpatient rehabilitation population, were invited to participate in the study. Initially, they were interviewed to research the eligibility criteria. Those who were eligible and agreed to participate signed an informed consent form. Inclusion criteria were: individuals aged 18 to 70, without distinction of gender or ethnicity; with a confirmed diagnosis of any type of spinocerebellar ataxia by a neurologist; with mild to moderate ataxia severity (stage 1–2) as stated by Klockgether (stage 0 = absence of walking difficulties; stage 1 = onset of the disease, defined by the onset of walking difficulties; stage 2 = loss of independent walking; stage 3 = confinement to a wheelchair) [ 18 ]; able to walk 2 meters even when using a walker, cane or crutch; score ≥ 21 [ 19 ] on the Mini-Mental State Examination (MMSE) [210,21]; with no other concomitant neurological diseases. The exclusion criteria were musculoskeletal, neurological, or cardiorespiratory disorders that prevent the tests and exercises from being carried out, and any exclusion criteria for tDCS [ 22 ]. From the 48 invited to participate, 43 met inclusion criteria and were allocated to the intervention: (5 excluded: neurological disorders [n = 1], stage 3 SCA [n = 1], declined participation [n = 2], other reason [n = 1]). Among them, 41 received the intervention, while 1 did not received intervention for personal reasons and 1 discontinued due to COVID-19. Post-intervention assessment was completed by 40 participants (1 lost due to influenza). At follow-up, 39 participants were assessed (1 lost for personal reasons). During data processing, 3 individuals with SCA2, SCA5 and SCA7 were excluded to homogenize SCA3 type. All participants who discontinued or were lost at follow-up were reintroduced in the intention-to-treat analysis, resulting in a final analyzed sample of 39 individuals (see Fig. 1 ). = insert Fig. 1 approximately here = Procedure The eligible participants completed an anamnesis form which contained questions about their sociodemographic data (sex, age, weight, height, year of disease onset, type of SCA, presence of comorbidities, current level of physical activity and use of walking aids). Then they were evaluated (ASSESSMENT 1) by two trained physiotherapists through: the Inventory of non-ataxic signs (INAS); the SARA scale; The Berg Balance Scale (BBS); and Timed up and go (TUG). Then, 20 successive sessions of intervention were applied to the participants. At the end of the 20 sessions (ASSESSMENT 2), all instruments were reapplied, except for INAS (ASSESSMENT 2). One month later, all evaluations were repeated, again excluding INAS (ASSESSMENT 3). The examiners did not join in other parts of the study and all assessments were conducted on the first Monday evening after the end of 20 sessions to standardize factors that could potentially impact performance across groups. Intervention The intervention sessions were performed over four consecutive weeks on weekdays, totaling the 20 sessions. The total duration of each session was 30 minutes in which participants simultaneously received 20 min of anodal cerebellar tDCS and cathodal spinal tDCS and perform a gait and balance training protocol. Given the study’s pragmatic design and focus on feasibility and safety, all participants received real stimulation, and blinding procedures were not implemented. A stimulator (NeuroConnn equipment - DC, Germany) NKL Stimulator offered a continuous-type current through a pair of electrodes of 5x7 cm (35 cm 2 ) which were wrapped in sponges soaked with saline solution. The cerebellar anode electrode was positioned at 2cm under the inion region using adjustable bands. The cathode electrode was positioned over the spinal region, at the level of T8 spinal segment. To find this position, the thoracic spinous processes were palpated, and the point 2cm below the 11th process was located and fixed using adhesive tape. Electrode placement was consistently performed by the same researcher across all sessions. The stimulation intensity was 2mA. Impedance levels were kept below 5 kΩ throughout the stimulation. A ramp-up and ramp-down procedure was applied at the beginning and end of each stimulation session to gradually adjust current intensity, enhancing participant comfort. In the present study, we used a gait and balance exercise program with progressively increasing difficulty, previously tested by our group in older adults [ 23 ] and adapted for individuals with SCA [ 24 ]. Each session was individually supervised by a physiotherapist (one therapist per participant). Feasibility and safety The primary outcomes were the feasibility and safety of the 20 cerebello-spinal tDCS sessions applied alongside progressively challenging exercises in a public health hospital. Feasibility was assessed based on the number of sessions attended (adherence rates), dropout rates and the participants' ability to perform the exercises and their progression in terms of exercise difficulty (session tolerability). Attendance was documented for each session, and the execution of exercises by each participant was closely monitored by a physiotherapist. To ensure safety, the occurrence of adverse events and discomfort reports were recorded. Several outcomes were assessed, such as prolonged muscle soreness (lasting up to 72 hours), syncope, and falls. Also, given the larger number of subsequent sessions of tDCS (20), adverse effects of neuromodulation were examined (skin irritation or redness at the electrode sites, headache, dizziness or lightheadedness, and fatigue, and visual disturbances). For this purpose, participants were interrogated about any adverse effects after each session by using the Brunoni’s questionary. Clinical outcomes SARA is an instrument to evaluate the disease severity through eight tasks including gait, balance, speech, and coordination that produce a total score of 0 (no signs of ataxia) and 40 (more severe ataxia). It was validated for Portuguese [ 25 ]. Balance The BBS measures functional balance and falls risk in 14 tasks. Each item is given a score of 0–4, with a total score between 0 and 56; the higher the score, the better the individual's performance. A score equal to or less than 45 points indicates a greater risk of falls. It was validated for Portuguese [ 26 ]. Mobility TUG assesses mobility, balance, walking ability and the risk of falling. On the command "go", the patient gets up from the chair, walks 3 meters, turns around, returns to the chair, and sits down. The time is calculated in seconds. The longer the time taken, the greater the risk of falling [ 27 ]. Non-Ataxic Signs : The inventory of Non-Ataxic Signs (INAS) is an instrument to detect the presence or absence of 16 non-ataxic signs and symptoms through a clinical physical examination. The INAS assesses the presence of extracerebellar neurological signs [ 28 ]. It was created out of the need to standardize the evaluation of non-ataxic signs in individuals with SCA. The inventory demonstrates high short-term test-retest reliability and consists of 30 items grouped into 16 non-ataxic signs, including: arreflexia, hyperreflexia, plantar extensor response, spasticity, paresis, amyotrophy, fasciculation, myoclonus, rigidity, chorea, dystonia, resting tremor, sensory symptoms, urinary dysfunction, cognitive dysfunction, and brainstem oculomotor signs. Each item is scored from 0 (absence of non-ataxic signs) to 1 (presence of non-ataxic signs). The results can range from a minimum score of 0, indicating no impairment, to a maximum score of 16, indicating severe impairments. Statistical analysis To evaluate the feasibility of the intervention, adherence was defined as session attendance during the intervention period and expressed as the participants’ attendance rate. Session tolerability was documented through qualitative notes regarding each participant’s ability to perform the exercises and their progression in difficulty after sessions. To evaluate safety, the absolute number of reported adverse events were recorded. An intention-to-treat approach was applied. Missing data (8.3% of total data set) were handled using multiple imputations with chained equations (MICE), which iteratively imputes missing values in a dataset using regression models [ 29 ]. MICE was implemented in a Python 3.11.7 environment using the “statsmodels” package, version 0.14.0. To examine individual changes in outcomes (SARA, BBS and TUG), we transformed raw data into standardized individual differences (SID). For each outcome, the SID was computed by subtracting the preintervention score from the postintervention score for each participant and dividing this change by the standard deviation of the change scores across the group [30]. A one-sample t-test was used to compare the SID with zero-value reference to check for significant changes in outcome values after intervention; in this case, no difference from zero-value implies no change. Additionally, to control the potential influence of patient’s pre-intervention clinical status on the outcomes, a multiple linear regression model was applied. The models used SIDs as the dependent variable while adjusting for baseline SARA scores (for BBS and TUG only), INAS scores, and symptom onset time. Each subitem of SARA was also analyzed. Due to the non-normal distribution of this data (Shiapiro-Wilk’s P < 0.021), the Friedman test was used to compare repeated measures across multiple time points, pre-intervention (ASSESSMENT 1), post-intervention (ASSESSMENT 2), and follow-up (ASSESSMENT 3). Post hoc pairwise comparisons were conducted using the Holm correction to control for family-wise error rate, and the Kendall’s W coefficient was computed to assess the effect size. FDR correction was applied to account for multiple comparisons. The statistical threshold was set at 5% and was corrected for multiple comparisons using False Discovery Rate approach (FDR) [ 31 ]. All analysis were performed in Python 3.11.7 environments using “pingouin” 0.5.4 and “statsmodel” 0.14.0 packages. Friedman analysis was made in JASP (version 0.19.3). RESULTS A total of 42 patients were included in the study. However, 39 of them had SCA3 and three had SCA2, SCA5 and SCA7, respectively. To homogenize the data, only the individuals with SCA3 were included in the analyses. The general characteristics of the sample are shown in Table 1 . The patients were classified as being in Klockgether stages 1 (N = 18) and 2 (N = 21). Thirteen patients reported using a walking device, and fourteen patients reported experiencing pain. Additionally, a few patients reported systemic arterial hypertension (N = 8), labyrinthitis (N = 2), and diabetes (N = 1). As a convenience sample was used, a post-hoc analysis was performed based on the findings reported below (G*Power 3.1.9.7, University of Kiel, Germany). Considering the sample size and effect sizes found, the statistical power was always above 82%. Table 1 Sample characteristics. Variables Statistics Sex (F/M) 26/13 (67/33%) Age (years) 46 (23–70) Weight (kg) 71 (49–115) Height (cm) 166 (152–182) BMI (kg/m2) 25.5 (17.5–36.3) Time since diagnosis (years) 8 (1–24) MEMS (score) 26 (19–30) INAS (score) 3 (0–7) Data expresses as mean (min.-max) or absolute (relative) frequency. BMI, body mass index, MEMS, Mini Exam of Mental State; INAS, Inventory of Non-Ataxic Symptoms. = insert Table 1 approximately here = Of the 780 sessions held, participants were absent from 21 of them, which corresponds to a percentage of 2.6% absences. When absences did occur, the sessions were rescheduled for the following Saturday. The mean presence rate of the 39 participants was 97.3%. Two participants took part in the first evaluation session, however, one of them dropped out due to a COVID-19 infection, and another because of personal issues. Relative to safety, no episodes of adverse events such as abnormal pressure response to exercise, fatigue, muscle pain of long duration or syncope occurred during the implementation of the intervention. Regarding falls, 8 episodes of imbalance occurred when the individuals were in a semi-kneeling position and 3 when the patient was in the standing position. The falls occurred during the semi-kneeling position. The participants went to this position to sitting on the heel of the leg resting behind. And in the case of falls from their own height, the individuals were supported during the descent to the ground. There were no adverse consequences of these falls. Most of the patients felt itching around the electrodes, which improved with the addition of saline, or which passed spontaneously with the accommodation of the stimulus. No serious or unexpected effects related to the 20 tDCS sessions occurred. Changes in outcomes after the intervention Comparison between outcomes’ SIDs and zero-value reference revealed significant differences for SARA, BBS, and TUG (Fig. 2 , white circle markers). The results indicate that the intervention promotes significant decreases in SARA scores (Fig. 2 A), increases in BBS scores (Fig. 2 B), as well as decreases in time spent on TUG (Fig. 2 C). = insert Fig. 2 approximately here = Results from the multiple linear regression analysis for post-intervention period were shown in (Table 2 ). A significant model was found only for SID-TUG (R 2 adj = 0.271, P = 0.001). Specifically, the baseline SARA scores emerged as predictors of changes in TUG performance after interventions (P = 0.027), with a negative association between them, i.e., higher baseline SARA scores correspond to reduced changes in TUG after intervention (Fig. 3 A). Table 2 Linear regression models with post minus pre-intervention SIDs. Parameters beta 95%CI, lower 95%CI, upper P-value SID-SARA (score), model R 2 adj = 0.015, F = 0.270, P = 0.765 intercept -0.456 -1.292 0.380 0.276 INAS (score) -0.031 -0.187 0.126 0.693 Onset time of symptoms (years) -0.023 -0.089 0.043 0.483 SID-BBS (score), model R 2 adj = 0.046, F = 0.562, P = 0.644 intercept 0.177 -0.794 1.149 0.713 SARA, baseline (score) -0.016 -0.096 0.066 0.700 INAS (score) 0.114 -0.071 0.299 0.221 Onset time of symptoms (years) 0.023 -0.051 0.096 0.536 SID-TUG (seconds), model R 2 adj = 0.271, F = 4.330, P = 0.011 intercept 0.230 -0.619 1.079 0.586 SARA, baseline (score) -0.080 -0.151 -0.010 0.027 INAS (score) -0.052 -0.214 0.110 0.521 Onset time of symptoms (years) 0.058 -0.006 0.123 0.074 R 2 adj , adjusted coefficient of determination. = insert Table 2 approximately here = = insert Fig. 3 approximately here = Follow-up analysis The SIDs from follow-up minus pre-intervention values were also computed and compared with zero-value. The SIDs from all outcomes assessed in the follow-up were significantly different from zero (Fig. 2 , gray triangle markers), suggesting that the decreases in SARA scores and TUG duration, along with increases in BBS scores, persists in the follow-up assessment. Additionally, follow-up SIDs were compared to those obtained post-intervention through paired t test, and no significant difference between SIDs from post-intervention and those from follow-up was found (all P > 0.171). The multiple linear regression analysis results (Table 3 ) were like those observed for post- minus pre-intervention SIDs: considering follow-up SIDs, the baseline SARA scores also emerged as predictor of changes in follow-up TUG performance (P = 0.004; Fig. 3 B). Moreover, a significant, positive coefficient was found between baseline SARA scores and changes in BBS scores (P = 0.025; Fig. 3 C), despite the lack of significance in this model. Table 3 Table 3 . Linear regression models with follow-up minus pre-intervention SIDs. parameters beta 95%CI, lower 95%CI, upper P-value SID-SARA (score), model R 2 adj = 0.052, F = 0.991, P = 0.381 intercept -0.437 -1.257 0.383 0.287 INAS (score) -0.106 -0.260 0.047 0.168 Onset time of symptoms (years) -0.012 -0.076 0.053 0.714 SID-BBS (score), model R 2 adj = 0.162, F = 2.251., P = 0.100 intercept -0.025 -0.936 0.885 0.955 SARA, baseline (score) 0.087 0.011 0.163 0.025 INAS (score) -0.026 -0.199 0.148 0.767 Onset time of symptoms (years) -0.030 -0.099 0.039 0.390 SID-TUG (seconds), model R 2 adj = 0.251, F = 3.918, P = 0.016 intercept 0.277 -0.583 1.137 0.518 SARA, baseline (score) -0.109 -0.181 -0.037 0.004 INAS (score) 0.038 -0.125 0.203 0.636 Onset time of symptoms (years) 0.048 -0.017 0.113 0.144 R 2 adj , adjusted coefficient of determination. Overall, along the three evaluations, a progressive reduction can be observed in the SARA scores, which is accompanied by increases in BBS scores and a smaller meantime spent on TUG. = insert Table 3 approximately here = SARA subscales analysis The Friedman test revealed significant differences across time points for several SARA subitems (Fig. 4 ). Gait, posture, finger chase, diadochokinesia, heel-shin, and the total SARA score exhibited highly significant changes (P < 0.001), with moderate effect sizes (Kendall’s W ranging from 0.176 to 0.410). Post hoc analysis with Holm correction showed that gait, heel-shin, and the total score differed significantly between pre-intervention and post-intervention, as well as between pre-intervention and follow-up (Fig. 4 A, H, I). Posture and speech exhibited reduced scores after intervention, with no difference between post-intervention and follow-up, suggesting sustained improvement (Fig. 4 B, D). = insert Fig. 4 approximately here = In contrast, finger chase and diadochokinesia displayed a delayed response, with significant differences only between pre-intervention and follow-up but not between pre- and post-intervention (Fig. 4 E, G). Sitting remained stable across assessments (P = 0.301; Fig. 4 C), while nose-finger test showed differences only between pre-intervention and follow-up, with post-intervention not differing from either time point (Fig. 4 F). These findings highlight differential responsiveness of SARA subitems to intervention over time, with some domains showing persistent improvements and others exhibiting delayed or no significant changes. DISCUSSION The main objective of this study was to assess the feasibility and safety of a long-duration protocol combining cerebello-spinal tDCS with progressively challenging gait and balance exercises in individuals with SCA3 in real-world conditions. Secondary objectives included evaluating the potential clinical benefits on disease severity, balance, and mobility, as well as verifying the retention of these effects one month after the intervention. The results showed high feasibility (attendance > 97%, minimal adverse events) and good tolerability under routine conditions. Furthermore, participants showed improvements in ataxia severity, postural control, and functional mobility, which were maintained at one-month follow-up. Nevertheless, because this was a feasibility study without a control group, the clinical improvements should be interpreted cautiously and not considered definitive evidence of efficacy. Feasibility outcomes To our knowledge, this is the first study to examine the feasibility of combining 20 sessions of cerebello‑spinal tDCS with progressively challenging gait and balance exercises in individuals with SCA3. The high adherence rate (97.3%) and minimal rescheduling (21 of 780 planned sessions) suggest that the protocol is feasible in a realworld outpatient rehabilitation setting. Notably, this adherence was achieved without financial incentives or transportation assistance, reinforcing the practical applicability of this protocol. In terms of safety, no serious adverse events occurred; mild skin irritation or itching under the electrodes were transient and easily managed. The few falls observed were minor and resulted in no injuries. These findings indicate that the protocol is safe and well tolerated by people with SCA3. Nonetheless, larger studies with control conditions are needed to confirm these observations and fully establish integration into clinical neurorehabilitation programs. Changes in clinical scores We analysed both the SARA total score and its subitems. SARA total scores showed a significant reduction after the intervention, indicating a decrease in ataxia severity. A study [9] investigated the effects of 10 sessions of ctDCS (2 mA, 20 min) in a homogeneous sample of SCA3 individuals and found no significant changes in SARA scores. On the other hand, another study [8] applied cerebellar-tDCS (2 mA, 20 min) in patients with various cerebellar ataxia syndromes and reported significant improvements in SARA scores, lasting up to three months. The efficacy of 5 consecutive sessions of cerebello-spinal tDCS (2 mA, 20 min, cathode below the 11th thoracic vertebra) [14] in the same patients from their previous study [8] and found reductions in SARA scores. To our knowledge, few studies have examined homogeneous SCA3 cohorts; our findings therefore provide preliminary evidence that longer protocols combined with exercise may produce measurable improvements. These findings suggest that, given the progressive nature of SCA3, protocols longer than 10 sessions, especially when combined with exercise, may be necessary to observe measurable improvements. The SARA subitems showed differential responses: gait and heelshin improved immediately postintervention and were maintained at followup; finger chase and diadochokinesia improved only at followup, suggesting a slower recovery of fine coordination; speech improved early and was maintained; sitting and the nose–finger test showed little change. These findings can be interpreted as as trends or possibilities, as this is an exploratory study. However, it can indicate the importance of considering the symptomatic heterogeneity of ataxia and adapting rehabilitation strategies based on the specific responsiveness of each functional domain. Improvements in BBS scores and TUG performance Postural instability is considered the initial and the most frequently reported symptom of SCA [ 28 , 32 ]. In the present study, BBS scores increased significantly after the intervention, indicating potential benefits in functional balance. The studies that used BBS to assess the impact of tDCS on postural control showed varying results depending on the number of sessions and the protocols applied [ 10 , 14 , 15 ]. A comparison of these studies suggests that short protocols, such as those [ 10 , 14 ], produce immediate but transient benefits; in contrast, studies with 10 or more sessions [ 15 ] and the present study show more lasting improvements. However, differences between protocols (electrode placement, current intensity, exercises applied) make causal attributions difficult. The time required to complete the Timed Up and Go (TUG) test was significantly reduced, reflecting potential improvements in functional mobility. In comparison, significant changes in TUG performance after 10 sessions of cerebellar tDCS alone were not found [ 9 ], suggesting the relevance of combining stimulation with progressive exercises. Follow-up outcomes The follow-up analysis showed that the benefits of the intervention, including reductions in SARA scores, decreased TUG time, and increased BBS scores, were maintained one month after the protocol. No significant differences were found between post-intervention and follow-up outcomes, suggesting the gains were sustained. A study [ 15 ] also reported benefit retention after three months of interventions with 10 sessions of cerebello-spinal tDCS, though in a heterogeneous sample. Despite the small sample and absence of a control group, the present study is the first to demonstrate benefit retention in a homogeneous sample of patients with SCA3. Baseline features influence on outcomes Regression analysis showed that baseline SARA scores, but not INAS scores or symptomonset time, emerged as significant predictors of changes in TUG both postintervention and at followup (Tables 2 and 3 ). Higher baseline ataxia severity was associated with smaller improvements in TUG, suggesting that more severe ataxia may limit gains in functional mobility. Conversely, baseline SARA scores were positively associated with improvements in BBS at followup, indicating that participants with more severe ataxia may exhibit delayed balance gains. These findings corroborate observations [9] that baseline severity influences tDCS outcomes; individuals with severe ataxia may improve balance yet show limited capacity to modify complex behaviors such as walking and turning. Additionally, because the intervention emphasized static balance exercises, this could have biased improvements toward balance measures. The lack of association between INAS scores or symptom onset and outcomes probably reflect the small sample size, which limited statistical power. Larger studies are needed to identify predictors of tDCS efficacy in ataxia. Because no prior studies have explored these predictors with cerebellospinal tDCS, direct comparisons are not available. Study limitations Because there was no control group, the observed improvements cannot be attributed causally to the intervention; future randomized controlled trials are required to confirm these preliminary findings. The pragmatic design deliberately mirrored realworld rehabilitation conditions to maximize applicability, but this approach affords less experimental control than explanatory trials conducted in highly standardized environments. Another limitation is the wide age range of participants. Although the severity of SCA3 does not necessarily correlate with age (some younger individuals may be more severely affected than older ones) agerelated differences in disability and responsiveness could have influenced the outcomes. This heterogeneity may limit the generalizability of the findings yet provides an opportunity to explore how different age groups respond to the protocol. Finally, participants were recruited through a convenience sample, which further restricts generalizability even though it reflects typical clinical practice. Conclusion The results of this study highlight that the combined intervention of cerebello-spinal tDCS and specific exercises is a feasible, safe, and potentially beneficial approach to reduce disease severity and improve balance and mobility in individuals with SCA3. Retention of benefits at onemonth followup suggests durability, but confirmatory randomized trials are needed. Preliminary analyses suggest that patients with higher baseline ataxia may experience greater balance gains, highlighting the need for personalized intervention strategies. These findings provide preliminary support for the clinical utility of this protocol and warrant further investigation in controlled trials. Moreover, future studies should explore the effects of this intervention using biomarkers (e.g., EEG or neuroimaging), patient-reported outcomes, and comparative designs contrasting cerebellar-spinal tDCS alone with combined approaches. This would allow the identification of individual characteristics that may favor more significant responses to the intervention, maximizing its impact and broadening its applicability. Declarations Ethics approval and consent to participate The study was approved by the Comitê de Ética em Pesquisa (CEP) da UNISUAM (process number 70797823.1.0000.5235). All participants provided written informed consent prior to enrollment, in accordance with the Declaration of Helsinki. Clinical trial registration Clinical trial registration: ClinicalTrials.gov Identifier NCT06267222. Registration date: October 11, 2023. Consent for publication Not applicable. This manuscript does not contain any individual person’s data in any form (including individual details, images, or videos). Competing interests The authors declare that they have no competing interests. Funding This study is funded by the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ, No. E-26/211.104/2021) and by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Financial Code 001, No. 88881.708719/2022-01, and No. 88887.708718/2022-00). Author Contribution LASO and AFB: Conceptualization, Methodology, and Writing – original draft preparation; TL and LASO: Formal analysis and Writing – review and editing; TL: prepared figures and Tables; AFB, LASO, YCH, FGA: Investigation and Data Curation LASO: Supervision, and Funding acquisition; LASO, AFB and YCH: Project administration; All authors reviewed the manuscript. Acknowledgement We would like to thank all the undergraduate students from Unisuam and IFRJ who contributed to this study: Marina, Raquel, Jean, Bruna, Maíra, Lucas, Camila, Mônica, Luana, Blendo, Layssa, Thayná, and Roberta. We would also like to thank all the patients who participated in this study. Data Availability Data cannot be shared openly to protect study participant privacy. References Klockgether T, Paulson H, Milunsky JM. Ataxia: review of clinical features and treatment approaches. Lancet Neurol. 2019;18(9):931–45. 10.1016/S1474-4422(19)30277-4 . Ghanekar SD, Kuo SH, Staffetti JS, Zesiewicz TA. Current and emerging treatment modalities for spinocerebellar ataxias. Expert Rev Neurother. 2022;22(2):101–14. 10.1080/14737175.2022.2029703 . Scott SS, de O, Pedroso JL, Barsottini OGP, França-Junior MC, Braga-Neto P. Natural history and epidemiology of the spinocerebellar ataxias: insights from the first description to nowadays. J Neurol Sci. 2020;417:117082. 10.1016/j.jns.2020.117082 . Chien HF, Zonta MB, Chen J, Diaferia G, Viana CF, Teive HAG, et al. Rehabilitation in patients with cerebellar ataxias. Arq Neuropsiquiatr. 2022;80(3):306–15. 10.1590/0004-282X-ANP-2021-0065 . Chen TX, Yang CY, Willson G, Lin CC, Kuo SH. The efficacy and safety of transcranial direct current stimulation for cerebellar ataxia: a systematic review and meta–analysis. Cerebellum. 2021;20(1):124–33. 10.1007/s12311-020-01181-z . Grimaldi G, Oulad Ben Taib N, Manto M, Bodranghien F. Marked reduction of cerebellar deficits in upper limbs following transcranial cerebello-cerebral DC stimulation. Front Syst Neurosci. 2014;8:9. 10.3389/fnsys.2014.00009 . Benussi A, Koch G, Cotelli M, Padovani A, Borroni B. Cerebellar transcranial direct current stimulation in patients with ataxia: a double-blind, randomized, sham-controlled study. Mov Disord. 2015;30(12):1701–5. 10.1002/mds.26362 . Benussi A, Dell’Era V, Cotelli MS, Turla M, Casali C, Padovani A, et al. Long-term clinical and neurophysiological effects of cerebellar transcranial direct current stimulation in patients with neurodegenerative ataxia. Brain Stimul. 2017a;10(2):242–50. 10.1016/j.brs.2016.11.001 . Maas RPPWM, Teerenstra S, Toni I, Klockgether T, Schutter D, van de Warrenburg BPC. Cerebellar transcranial direct current stimulation in spinocerebellar ataxia type 3: a randomized, double-blind, sham-controlled trial. Neurotherapeutics. 2022;19:1259–72. 10.1007/s13311-022-01216-3 . Brito R, Fabrício JV, Araujo A, et al. Differential effects of cerebellar transcranial direct current stimulation with gait training on functional mobility, balance, and ataxia symptoms. Cerebellum. 2024;23:2457–66. 10.1007/s12311-024-01750-6 . Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain. 1998;121(Pt 4):589–600. Daskalakis ZJ, Paradiso GO, Christensen BK, Fitzgerald PB, Gunraj C, Chen R. Exploring the connectivity between the cerebellum and motor cortex in humans. J Physiol. 2004;557(2):689–700. 10.1113/jphysiol.2003.059808 . Benussi A, Pilotto A, Premi E, et al. The therapeutic potential of non-invasive and invasive cerebellar stimulation techniques. Cells. 2023;12(11):1193. 10.3390/cells12071193 . Benussi A, Dell’Era V, Cantoni V, et al. Cerebello-spinal tDCS in ataxia: a randomized, double-blind trial. Brain Stimul. 2018;11(2):287–9. 10.1016/j.brs.2017.12.005 . Benussi A, Dell’Era V, Cantoni V, et al. Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia. Neurotherapeutics. 2021;18(4):2524–35. 10.1007/s13311-021-01088-7 . Wang CS, Campbell KL, Ross CJ, Boyd LA. Promoting neuroplasticity for motor rehabilitation after stroke: considering the effects of aerobic exercise and genetic variation on brain-derived neurotrophic factor. Phys Ther. 2014;93(12):1707–16. Zwarenstein M, Treweek S, Gagnier JJ, Altman DG, Tunis S, Haynes B, Oxman AD, Moher D, CONSORT Group; Pragmatic Trials in Healthcare (Practihc) Group. Improving the reporting of pragmatic trials: an extension of the CONSORT statement. BMJ. 11 nov 2008;337:a2390. 10.1136/bmj.a2390 Klockgether T, Lüdtke R, Kramer B, Abele M, Bürk K, Schöls L, Riess O, Laccone F, Boesch S, Lopes-Cendes I, et al. The natural history of degenerative ataxia: a retrospective study in 466 patients. Brain. 1998;121(4):589–600. 10.1093/brain/121.4.589 . Castro-Costa E, Fuzikawa C, Uchoa E, Firmo JOA, Lima-Costa MF. Norms for the Mini-Mental State Examination: adjustment of the cut-off point in population-based studies (evidences from the Bambuí health aging study). Arq Neuropsiquiatr. 2008;66(3A):524–8. 10.1590/S0004-282X2008000400013 . Folstein MF, Folstein SE, McHugh PR. Mini-mental state: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12(3):189–98. 10.1016/0022-3956(75)90026-6 . Almeida OP. Mini exame do estado mental e o diagnóstico de demência no Brasil. Arq Neuropsiquiatr. 1998;56(3B):605–12. 10.1590/S0004-282X1998000400013 . Nitsche MA, Cohen LG, Wassermann EM, Priori A, Lang N, Antal A, et al. Transcranial direct current stimulation: state of the art 2008. Brain Stimul. 2008;1:206–23. dos Santos MP, Lemos T, da Silva DCL, Martins CP, Martins JVP, de Oliveira LAS. The effectiveness of progressions of difficulty during an exercise program to improve balance and gait in older individuals: a randomized clinical trial. Braz J Phys Ther. 2025;29:101207. Santos MPG, Martins JVP, Lemos T, Figueiredo FBL, Martins CP, Ferreira AS, Oliveira LAS. Feasibility and safety of a progressive gait and balance training program in spinocerebellar ataxia. Submitted for publication. Braga-Neto P, Godeiro-Junior C, Dutra LA, Pedroso JL, Graziani O, Barsottini P. Translation and validation into Brazilian version of the Scale of the Assessment and Rating of Ataxia (SARA). Arq Neuropsiquiatr. 2010;68(2):228–30. 10.1590/s0004-282x2010000200014 . Miyamoto ST, Lombardi Junior I, Berg KO, Ramos LR, Natour J. Versão brasileira da Balança de Berg. Braz J Med Biol Res. 2004;37(9):1411–21. 10.1590/S0100-879X2004000900017 . Podsiadlo D, Richardson S. The timed Up & Go: a test of basic functional mobility for frail elderly persons. J Am Geriatr Soc. 1991;39(2):142–8. 10.1111/j.1532-5415.1991.tb01616.x . Jacobi H, Rakowicz M, Rola R, et al. Inventory of Non-Ataxia Signs (INAS): validation of a new clinical assessment instrument. Cerebellum. 2013;12:418–28. 10.1007/s12311-012-0457-2 . Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be used for handling missing data in randomised clinical trials – a practical guide with flowcharts. BMC Med Res Methodol. 2017;17:162. 10.1186/s12874-017-0442-1 . Estrada E, Ferrer E, Pardo A. Statistics for evaluating pre-post change: relation between change in the distribution center and change in the individual scores. Front Psychol. 2019;9:2696. 10.3389/fpsyg.2018.02696 . Benjamini Y, Hochberg Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc Ser B. 1995;57(1):289–300. Nanetti L, Alpini D, Mattei V, Castaldo A, Mongelli A, Brenna G, Gellera C, Mariotti C. Stance instability in preclinical SCA1 mutation carriers: a 4-year prospective posturography study. Gait Posture. 2017;57:11–4. 10.1016/j.gaitpost.2017.05.028 . Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7437650","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":508404590,"identity":"59645c01-d411-49c0-a2a7-635120c2ac1a","order_by":0,"name":"Anna Fontes Baptista","email":"","orcid":"","institution":"Graduate Program in Rehabilitation Sciences, Centro Universitário Augusto Motta–UNISUAM","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Fontes","lastName":"Baptista","suffix":""},{"id":508404591,"identity":"2160f493-33ba-41a3-930d-8626b0d19bff","order_by":1,"name":"Thiago Lemos","email":"","orcid":"","institution":"Graduate Program in Rehabilitation Sciences, Centro Universitário Augusto Motta–UNISUAM","correspondingAuthor":false,"prefix":"","firstName":"Thiago","middleName":"","lastName":"Lemos","suffix":""},{"id":508404592,"identity":"e7782bc8-81bf-4c54-b56e-9d93137d8dbb","order_by":2,"name":"Yasmin Carvalho Heiderick","email":"","orcid":"","institution":"Federal Institute of Rio de Janeiro","correspondingAuthor":false,"prefix":"","firstName":"Yasmin","middleName":"Carvalho","lastName":"Heiderick","suffix":""},{"id":508404593,"identity":"77ef664b-5127-467a-8cb9-8a8c3674431c","order_by":3,"name":"Fernanda Guimaraes de Andrade","email":"","orcid":"","institution":"Federal Institute of Rio de Janeiro","correspondingAuthor":false,"prefix":"","firstName":"Fernanda","middleName":"Guimaraes","lastName":"de Andrade","suffix":""},{"id":508404595,"identity":"c7251298-acf0-47bd-95c7-54f1723a49f0","order_by":4,"name":"Laura Alice Santos de Oliveira","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEklEQVRIiWNgGAWjYBACPigtwwYkDjAw2PCwNzAkMDAAuQY4tLBBaR6oljQengPEaoHShxmAWhjwa2E/Y/bhB9A9fBLJBw9X1JyX4ZE+8IDhQ9lhBnPpA9i18OQYz+wBuodNIi3h4Jljt3l4+BISGGecO8xg2ZeAw2E5xkBXHeZh4zljcLCB7TaPPQ9DAjNv22EGgzM4HMb/xpjxD1jL+Q8HG/6d4+EBafmLT4tEjjEz2Bb2HoaDjW0HIFoY8Wp5VswsYwD0C3ubwcHGvmSwloM959J5LHuwa+HnT97M+KbCRk6+mfnxx4ZvdvZAPYkPfpRZy5nzYNcCAahRwJNwgAERU0QB9gOkqB4Fo2AUjILhDwAoN06F+r0STwAAAABJRU5ErkJggg==","orcid":"","institution":"Graduate Program in Rehabilitation Sciences, Centro Universitário Augusto Motta–UNISUAM","correspondingAuthor":true,"prefix":"","firstName":"Laura","middleName":"Alice Santos","lastName":"de Oliveira","suffix":""}],"badges":[],"createdAt":"2025-08-22 23:08:09","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7437650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7437650/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12311-025-01927-7","type":"published","date":"2025-11-18T15:58:34+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":90793789,"identity":"2a717d3c-48db-4d7c-8c38-65ae8c95f37a","added_by":"auto","created_at":"2025-09-08 08:39:17","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":510767,"visible":true,"origin":"","legend":"\u003cp\u003eStudy workflow. MICE, multiple imputations with chained equations.\u003c/p\u003e","description":"","filename":"Picture1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7437650/v1/1530b8320206f02868270931.jpg"},{"id":90793791,"identity":"6c94dd0b-f489-4aba-91be-f8b2e4516b3c","added_by":"auto","created_at":"2025-09-08 08:39:17","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":97584,"visible":true,"origin":"","legend":"\u003cp\u003eComparison between the standardized individual differences (SID) with zero-reference (dotted gray horizontal lines) for SARA (A), BBS (B) and TUG (C). Comparisons were performed for post minus pre-intervention (white circles) and follow-up (flw) minus pre-intervention (gray triangles) SIDs. Data are shown as mean ±SD. P-values and Cohen’s d from a one-sample t test are shown as inset. a.u., arbitrary units.\u003c/p\u003e","description":"","filename":"Picture2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7437650/v1/1fdc7451f5ab84bd54a6fdbf.jpg"},{"id":90793724,"identity":"64ea996b-dff3-4a8d-8701-a724e4251c90","added_by":"auto","created_at":"2025-09-08 08:39:12","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":135002,"visible":true,"origin":"","legend":"\u003cp\u003eAssociation between the standardized individual differences (SID, adjusted for baseline) and baseline clinical measures, for (A-B) TUG performance, and (C) BBS scores. Data are shown for post minus-pre-intervention (circle markers) and follow-up (flw) minus pre-intervention (triangle markers). For illustrative purposes, the linear regression line and the corresponding 95% confidence interval were also shown (gray lines)\u003c/p\u003e","description":"","filename":"Picture3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7437650/v1/ac45f6a5b1dcfb712f209315.jpg"},{"id":90793754,"identity":"62b2bdd9-3ca4-4d98-8719-1e9b37221143","added_by":"auto","created_at":"2025-09-08 08:39:16","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":226902,"visible":true,"origin":"","legend":"\u003cp\u003eBoxplots depicting group-level changes in SARA subscale scores across pre-intervention, post-intervention, and follow-up (flw). Horizontal dotted lines indicate statistically significant pairwise comparisons between time points. Cross markers represent outlier values.\u003c/p\u003e","description":"","filename":"Picture4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7437650/v1/1be4adf2501b6ebfaae45f8c.jpg"},{"id":96650365,"identity":"c5bc52bc-9da4-4683-88c9-6807ac1a3e26","added_by":"auto","created_at":"2025-11-24 16:11:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1838865,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7437650/v1/8afb5083-f7a9-4989-9f19-01b8f237c150.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eFeasibility and Safety of Combined Cerebello-spinal Neuromodulation and Exercise in Spinocerebellar Ataxia Type 3: A 20-session Protocol\u003c/p\u003e","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eSpinocerebellar ataxia (SCA) is a hereditary degenerative disorder of the cerebellum that progressively impairs balance and gait, predominantly affecting individuals in their productive years [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Type 3 (SCA3, or MachadoJoseph Disease) is the most prevalent worldwide, followed by SCA2 and SCA6[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Rehabilitation interventions are crucial for this population since there are no effective pharmacological treatments for this condition[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Interest in cerebellar anodal transcranial direct current stimulation (ctDCS), has grown in recent years. This portable, non-invasive neuromodulation technique has few side effects. It promotes neuroplasticity by modulating cortical excitability in specific brain regions, including damaged cerebellar areas, and may optimize residual function[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] (Chen et al., 2021). These properties make ctDCS a promising approach for SCA.\u003c/p\u003e\u003cp\u003eFurther advancements include simultaneous cerebellar and spinal tDCS (called cerebello-spinal tDCS). The cerebello-spinal pathway plays a key role in motor control, balance and coordination, functions that are often compromised in cerebellar ataxia [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Modulation of this pathway involves the application of anodal current to the cerebellum and cathodal current to the spinal region. By targeting circuits distinct from those engaged with cerebellar stimulation alone, cerebellospinal tDCS may provide additional benefits [13].\u003c/p\u003e\u003cp\u003eA study [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] showed that cerebello-spinal tDCS produced greater clinical benefits compared to their earlier study using ctDCS [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Results showed reductions in ataxia severity scores, 9Hole Peg Test times and 8m walk times compared to sham stimulation in a heterogeneous sample of individuals with neurodegenerative cerebellar ataxia, including SCA. In a subsequent follow-up study, the authors further confirmed the benefits of cerebello-spinal tDCS in a larger cohort (N\u0026thinsp;=\u0026thinsp;61) of multiple ataxia etiologies [15]. They performed a randomized, double-blind, sham-controlled tDCS trial, with sessions held five days a week for two weeks. Following a three-month washout period, an open-label phase was implemented, maintaining the same schedule of five sessions per week for two weeks. Additionally, significant reductions were observed in disease severity scale scores, along with improvements in quality-of-life measures [15]. However, most of these trials included heterogeneous samples of cerebellar ataxias; there are few studies evaluating tDCS specifically in SCA3, which highlights the need for exploratory trials targeting this population.\u003c/p\u003e\u003cp\u003eCombining tDCS with exercise is clinically relevant and has gained importance because it increases motor cortex excitability, improves physical performance and motor learning, and yields greater effects than tDCS alone (for a review, see [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. One study, for example, evaluated ctDCS combined with gait training in individuals with cerebellar ataxia [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. However, despite preliminary evidence of efficacy, the specific pairing of cerebello-spinal tDCS with progressive balance and gait exercises in longer protocols (e.g., 20 consecutive sessions) still requires investigation in individuals with SCA3. Given the specificity of cerebello-spinal tDCS, the clinical characteristics of individuals with SCA, and the need to better understand its interaction with balance and gait exercises, it is essential to first assess the feasibility and safety of this combined approach over multiple sessions before progressing to large-scale efficacy trials.\u003c/p\u003e\u003cp\u003eThus, the present study aimed to (i) assess the feasibility and safety of 20 consecutive sessions of cerebellospinal tDCS combined with balance and gait exercises in individuals with SCA3; (ii) verify whether the protocol can be implemented in routine clinical practice; and (iii) preliminarily explore the therapeutic effects of this intervention on the severity of ataxia, balance, and mobility.\u003c/p\u003e"},{"header":"METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eDesign\u003c/h2\u003e\u003cp\u003eThis study was designed with a pragmatic approach, conducted in a public rehabilitation service to reflect real-world conditions while assessing the safety, adherence, and acceptability of the intervention. The trial followed the CONSORT extension for Pragmatic Trials [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. To reflect real-world clinical conditions, broad inclusion criteria were adopted, and the intervention was delivered in a routine outpatient rehabilitation setting with minimal restrictions on concurrent treatments. The study was approved by the \u003cem\u003eComit\u0026ecirc; de \u0026Eacute;tica em Pesquisa (CEP) da UNISUAM\u003c/em\u003e (process number 70797823.1.0000.5235) and was registered at ClinicalTrials.gov (NCT06267222) on October 11, 2023. All participants provided written informed consent prior to enrollment, in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eSample\u003c/h3\u003e\n\u003cp\u003eThe individuals with SCA, identified through records from national public hospitals, physician clinics, and physiotherapy facilities, representing a typical outpatient rehabilitation population, were invited to participate in the study. Initially, they were interviewed to research the eligibility criteria. Those who were eligible and agreed to participate signed an informed consent form. Inclusion criteria were: individuals aged 18 to 70, without distinction of gender or ethnicity; with a confirmed diagnosis of any type of spinocerebellar ataxia by a neurologist; with mild to moderate ataxia severity (stage 1\u0026ndash;2) as stated by Klockgether (stage 0\u0026thinsp;=\u0026thinsp;absence of walking difficulties; stage 1\u0026thinsp;=\u0026thinsp;onset of the disease, defined by the onset of walking difficulties; stage 2\u0026thinsp;=\u0026thinsp;loss of independent walking; stage 3\u0026thinsp;=\u0026thinsp;confinement to a wheelchair) [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]; able to walk 2 meters even when using a walker, cane or crutch; score\u0026thinsp;\u0026ge;\u0026thinsp;21 [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] on the Mini-Mental State Examination (MMSE) [210,21]; with no other concomitant neurological diseases. The exclusion criteria were musculoskeletal, neurological, or cardiorespiratory disorders that prevent the tests and exercises from being carried out, and any exclusion criteria for tDCS [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. From the 48 invited to participate, 43 met inclusion criteria and were allocated to the intervention: (5 excluded: neurological disorders [n\u0026thinsp;=\u0026thinsp;1], stage 3 SCA [n\u0026thinsp;=\u0026thinsp;1], declined participation [n\u0026thinsp;=\u0026thinsp;2], other reason [n\u0026thinsp;=\u0026thinsp;1]). Among them, 41 received the intervention, while 1 did not received intervention for personal reasons and 1 discontinued due to COVID-19. Post-intervention assessment was completed by 40 participants (1 lost due to influenza). At follow-up, 39 participants were assessed (1 lost for personal reasons). During data processing, 3 individuals with SCA2, SCA5 and SCA7 were excluded to homogenize SCA3 type. All participants who discontinued or were lost at follow-up were reintroduced in the intention-to-treat analysis, resulting in a final analyzed sample of 39 individuals (see Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e= insert Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e approximately here =\u003c/p\u003e\n\u003ch3\u003eProcedure\u003c/h3\u003e\n\u003cp\u003eThe eligible participants completed an anamnesis form which contained questions about their sociodemographic data (sex, age, weight, height, year of disease onset, type of SCA, presence of comorbidities, current level of physical activity and use of walking aids). Then they were evaluated (ASSESSMENT 1) by two trained physiotherapists through: the Inventory of non-ataxic signs (INAS); the SARA scale; The Berg Balance Scale (BBS); and Timed up and go (TUG). Then, 20 successive sessions of intervention were applied to the participants. At the end of the 20 sessions (ASSESSMENT 2), all instruments were reapplied, except for INAS (ASSESSMENT 2). One month later, all evaluations were repeated, again excluding INAS (ASSESSMENT 3). The examiners did not join in other parts of the study and all assessments were conducted on the first Monday evening after the end of 20 sessions to standardize factors that could potentially impact performance across groups.\u003c/p\u003e\n\u003ch3\u003eIntervention\u003c/h3\u003e\n\u003cp\u003eThe intervention sessions were performed over four consecutive weeks on weekdays, totaling the 20 sessions. The total duration of each session was 30 minutes in which participants simultaneously received 20 min of anodal cerebellar tDCS and cathodal spinal tDCS and perform a gait and balance training protocol. Given the study\u0026rsquo;s pragmatic design and focus on feasibility and safety, all participants received real stimulation, and blinding procedures were not implemented.\u003c/p\u003e\u003cp\u003eA stimulator (NeuroConnn equipment - DC, Germany) NKL Stimulator offered a continuous-type current through a pair of electrodes of 5x7 cm (35 cm\u003csup\u003e2\u003c/sup\u003e) which were wrapped in sponges soaked with saline solution. The cerebellar anode electrode was positioned at 2cm under the inion region using adjustable bands. The cathode electrode was positioned over the spinal region, at the level of T8 spinal segment. To find this position, the thoracic spinous processes were palpated, and the point 2cm below the 11th process was located and fixed using adhesive tape. Electrode placement was consistently performed by the same researcher across all sessions. The stimulation intensity was 2mA. Impedance levels were kept below 5 kΩ throughout the stimulation. A ramp-up and ramp-down procedure was applied at the beginning and end of each stimulation session to gradually adjust current intensity, enhancing participant comfort.\u003c/p\u003e\u003cp\u003eIn the present study, we used a gait and balance exercise program with progressively increasing difficulty, previously tested by our group in older adults [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e] and adapted for individuals with SCA [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Each session was individually supervised by a physiotherapist (one therapist per participant).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFeasibility and safety\u003c/strong\u003e\u003cp\u003eThe primary outcomes were the feasibility and safety of the 20 cerebello-spinal tDCS sessions applied alongside progressively challenging exercises in a public health hospital. Feasibility was assessed based on the number of sessions attended (adherence rates), dropout rates and the participants' ability to perform the exercises and their progression in terms of exercise difficulty (session tolerability). Attendance was documented for each session, and the execution of exercises by each participant was closely monitored by a physiotherapist. To ensure safety, the occurrence of adverse events and discomfort reports were recorded. Several outcomes were assessed, such as prolonged muscle soreness (lasting up to 72 hours), syncope, and falls. Also, given the larger number of subsequent sessions of tDCS (20), adverse effects of neuromodulation were examined (skin irritation or redness at the electrode sites, headache, dizziness or lightheadedness, and fatigue, and visual disturbances). For this purpose, participants were interrogated about any adverse effects after each session by using the Brunoni\u0026rsquo;s questionary.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eClinical outcomes\u003c/strong\u003e\u003cp\u003eSARA is an instrument to evaluate the disease severity through eight tasks including gait, balance, speech, and coordination that produce a total score of 0 (no signs of ataxia) and 40 (more severe ataxia). It was validated for Portuguese [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eBalance\u003c/strong\u003e\u003cp\u003eThe BBS measures functional balance and falls risk in 14 tasks. Each item is given a score of 0\u0026ndash;4, with a total score between 0 and 56; the higher the score, the better the individual's performance. A score equal to or less than 45 points indicates a greater risk of falls. It was validated for Portuguese [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e].\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMobility\u003c/strong\u003e\u003cp\u003eTUG assesses mobility, balance, walking ability and the risk of falling. On the command \"go\", the patient gets up from the chair, walks 3 meters, turns around, returns to the chair, and sits down. The time is calculated in seconds. The longer the time taken, the greater the risk of falling [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cem\u003eNon-Ataxic Signs\u003c/em\u003e: The inventory of Non-Ataxic Signs (INAS) is an instrument to detect the presence or absence of 16 non-ataxic signs and symptoms through a clinical physical examination. The INAS assesses the presence of extracerebellar neurological signs [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. It was created out of the need to standardize the evaluation of non-ataxic signs in individuals with SCA. The inventory demonstrates high short-term test-retest reliability and consists of 30 items grouped into 16 non-ataxic signs, including: arreflexia, hyperreflexia, plantar extensor response, spasticity, paresis, amyotrophy, fasciculation, myoclonus, rigidity, chorea, dystonia, resting tremor, sensory symptoms, urinary dysfunction, cognitive dysfunction, and brainstem oculomotor signs. Each item is scored from 0 (absence of non-ataxic signs) to 1 (presence of non-ataxic signs). The results can range from a minimum score of 0, indicating no impairment, to a maximum score of 16, indicating severe impairments.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eStatistical analysis\u003c/span\u003e\u003c/h2\u003e\u003cp\u003eTo evaluate the feasibility of the intervention, adherence was defined as session attendance during the intervention period and expressed as the participants\u0026rsquo; attendance rate. Session tolerability was documented through qualitative notes regarding each participant\u0026rsquo;s ability to perform the exercises and their progression in difficulty after sessions. To evaluate safety, the absolute number of reported adverse events were recorded.\u003c/p\u003e\u003cp\u003eAn intention-to-treat approach was applied. Missing data (8.3% of total data set) were handled using multiple imputations with chained equations (MICE), which iteratively imputes missing values in a dataset using regression models [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. MICE was implemented in a Python 3.11.7 environment using the \u0026ldquo;statsmodels\u0026rdquo; package, version 0.14.0.\u003c/p\u003e\u003cp\u003eTo examine individual changes in outcomes (SARA, BBS and TUG), we transformed raw data into standardized individual differences (SID). For each outcome, the SID was computed by subtracting the preintervention score from the postintervention score for each participant and dividing this change by the standard deviation of the change scores across the group [30]. A one-sample t-test was used to compare the SID with zero-value reference to check for significant changes in outcome values after intervention; in this case, no difference from zero-value implies no change. Additionally, to control the potential influence of patient\u0026rsquo;s pre-intervention clinical status on the outcomes, a multiple linear regression model was applied. The models used SIDs as the dependent variable while adjusting for baseline SARA scores (for BBS and TUG only), INAS scores, and symptom onset time.\u003c/p\u003e\u003cp\u003eEach subitem of SARA was also analyzed. Due to the non-normal distribution of this data (Shiapiro-Wilk\u0026rsquo;s P\u0026thinsp;\u0026lt;\u0026thinsp;0.021), the Friedman test was used to compare repeated measures across multiple time points, pre-intervention (ASSESSMENT 1), post-intervention (ASSESSMENT 2), and follow-up (ASSESSMENT 3). Post hoc pairwise comparisons were conducted using the Holm correction to control for family-wise error rate, and the Kendall\u0026rsquo;s W coefficient was computed to assess the effect size. FDR correction was applied to account for multiple comparisons.\u003c/p\u003e\u003cp\u003eThe statistical threshold was set at 5% and was corrected for multiple comparisons using False Discovery Rate approach (FDR) [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. All analysis were performed in Python 3.11.7 environments using \u0026ldquo;pingouin\u0026rdquo; 0.5.4 and \u0026ldquo;statsmodel\u0026rdquo; 0.14.0 packages. Friedman analysis was made in JASP (version 0.19.3).\u003c/p\u003e\u003c/div\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 42 patients were included in the study. However, 39 of them had SCA3 and three had SCA2, SCA5 and SCA7, respectively. To homogenize the data, only the individuals with SCA3 were included in the analyses. The general characteristics of the sample are shown in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The patients were classified as being in Klockgether stages 1 (N\u0026thinsp;=\u0026thinsp;18) and 2 (N\u0026thinsp;=\u0026thinsp;21). Thirteen patients reported using a walking device, and fourteen patients reported experiencing pain. Additionally, a few patients reported systemic arterial hypertension (N\u0026thinsp;=\u0026thinsp;8), labyrinthitis (N\u0026thinsp;=\u0026thinsp;2), and diabetes (N\u0026thinsp;=\u0026thinsp;1). As a convenience sample was used, a post-hoc analysis was performed based on the findings reported below (G*Power 3.1.9.7, University of Kiel, Germany). Considering the sample size and effect sizes found, the statistical power was always above 82%.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSample characteristics.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"3\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStatistics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSex (F/M)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26/13 (67/33%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e46 (23\u0026ndash;70)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight (kg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e71 (49\u0026ndash;115)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeight (cm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e166 (152\u0026ndash;182)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI (kg/m2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.5 (17.5\u0026ndash;36.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTime since diagnosis (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (1\u0026ndash;24)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMEMS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e26 (19\u0026ndash;30)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3 (0\u0026ndash;7)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c2\" namest=\"c1\"\u003e\u003cp\u003eData expresses as mean (min.-max) or absolute (relative) frequency. BMI, body mass index, MEMS, Mini Exam of Mental State; INAS, Inventory of Non-Ataxic Symptoms.\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"1\" nameend=\"c3\" namest=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e= insert Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e approximately here =\u003c/p\u003e\n\u003ch3\u003e\u003c/h3\u003e\n\u003cp\u003eOf the 780 sessions held, participants were absent from 21 of them, which corresponds to a percentage of 2.6% absences. When absences did occur, the sessions were rescheduled for the following Saturday. The mean presence rate of the 39 participants was 97.3%. Two participants took part in the first evaluation session, however, one of them dropped out due to a COVID-19 infection, and another because of personal issues.\u003c/p\u003e\u003cp\u003eRelative to safety, no episodes of adverse events such as abnormal pressure response to exercise, fatigue, muscle pain of long duration or syncope occurred during the implementation of the intervention. Regarding falls, 8 episodes of imbalance occurred when the individuals were in a semi-kneeling position and 3 when the patient was in the standing position. The falls occurred during the semi-kneeling position. The participants went to this position to sitting on the heel of the leg resting behind. And in the case of falls from their own height, the individuals were supported during the descent to the ground. There were no adverse consequences of these falls. Most of the patients felt itching around the electrodes, which improved with the addition of saline, or which passed spontaneously with the accommodation of the stimulus. No serious or unexpected effects related to the 20 tDCS sessions occurred.\u003c/p\u003e\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eChanges in outcomes after the intervention\u003c/h2\u003e\u003cp\u003eComparison between outcomes\u0026rsquo; SIDs and zero-value reference revealed significant differences for SARA, BBS, and TUG (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, white circle markers). The results indicate that the intervention promotes significant decreases in SARA scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA), increases in BBS scores (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), as well as decreases in time spent on TUG (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e= insert Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e approximately here =\u003c/p\u003e\u003cp\u003eResults from the multiple linear regression analysis for post-intervention period were shown in (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). A significant model was found only for SID-TUG (R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.271, P\u0026thinsp;=\u0026thinsp;0.001). Specifically, the baseline SARA scores emerged as predictors of changes in TUG performance after interventions (P\u0026thinsp;=\u0026thinsp;0.027), with a negative association between them, i.e., higher baseline SARA scores correspond to reduced changes in TUG after intervention (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eLinear regression models with post minus pre-intervention SIDs.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eParameters\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003ebeta\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95%CI, lower\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95%CI, upper\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-SARA (score), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.015, F\u0026thinsp;=\u0026thinsp;0.270, P\u0026thinsp;=\u0026thinsp;0.765\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.456\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.292\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.380\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.276\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.031\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.126\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.693\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.089\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.043\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.483\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-BBS (score), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.046, F\u0026thinsp;=\u0026thinsp;0.562, P\u0026thinsp;=\u0026thinsp;0.644\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.794\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.149\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.713\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSARA, baseline (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.016\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.096\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.066\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.700\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.114\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.071\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.299\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.221\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.023\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.051\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.096\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.536\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-TUG (seconds), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.271, F\u0026thinsp;=\u0026thinsp;4.330, P\u0026thinsp;=\u0026thinsp;0.011\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.230\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.619\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.079\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.586\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSARA, baseline (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.080\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.151\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.010\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.027\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.052\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.214\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.110\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.521\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.006\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.123\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.074\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e, adjusted coefficient of determination.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e= insert Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e approximately here =\u003c/p\u003e\u003cp\u003e= insert Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e approximately here =\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eFollow-up analysis\u003c/h2\u003e\u003cp\u003eThe SIDs from follow-up minus pre-intervention values were also computed and compared with zero-value. The SIDs from all outcomes assessed in the follow-up were significantly different from zero (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, gray triangle markers), suggesting that the decreases in SARA scores and TUG duration, along with increases in BBS scores, persists in the follow-up assessment.\u003c/p\u003e\u003cp\u003eAdditionally, follow-up SIDs were compared to those obtained post-intervention through paired t test, and no significant difference between SIDs from post-intervention and those from follow-up was found (all P\u0026thinsp;\u0026gt;\u0026thinsp;0.171).\u003c/p\u003e\u003cp\u003eThe multiple linear regression analysis results (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) were like those observed for post- minus pre-intervention SIDs: considering follow-up SIDs, the baseline SARA scores also emerged as predictor of changes in follow-up TUG performance (P\u0026thinsp;=\u0026thinsp;0.004; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Moreover, a significant, positive coefficient was found between baseline SARA scores and changes in BBS scores (P\u0026thinsp;=\u0026thinsp;0.025; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eC), despite the lack of significance in this model.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Linear regression models with follow-up minus pre-intervention SIDs.\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eparameters\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ebeta\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e95%CI, lower\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e95%CI, upper\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003eP-value\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-SARA (score), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.052, F\u0026thinsp;=\u0026thinsp;0.991, P\u0026thinsp;=\u0026thinsp;0.381\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.437\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-1.257\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.383\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.287\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.106\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.260\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.047\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.168\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.012\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.076\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.053\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.714\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-BBS (score), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.162, F\u0026thinsp;=\u0026thinsp;2.251., P\u0026thinsp;=\u0026thinsp;0.100\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.025\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.936\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.885\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.955\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSARA, baseline (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.087\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.011\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.163\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.025\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.026\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.199\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.148\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.767\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.030\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.099\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.039\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.390\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003eSID-TUG (seconds), model R\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e\u0026thinsp;=\u0026thinsp;0.251, F\u0026thinsp;=\u0026thinsp;3.918, P\u0026thinsp;=\u0026thinsp;0.016\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eintercept\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.277\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.583\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1.137\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.518\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSARA, baseline (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.109\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.181\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.037\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.004\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eINAS (score)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.038\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.125\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.203\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.636\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOnset time of symptoms (years)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.048\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e-0.017\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.113\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.144\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e\u003ccolgroup cols=\"1\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eR\u003csup\u003e2\u003c/sup\u003e\u003csub\u003eadj\u003c/sub\u003e, adjusted coefficient of determination.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eOverall, along the three evaluations, a progressive reduction can be observed in the SARA scores, which is accompanied by increases in BBS scores and a smaller meantime spent on TUG.\u003c/p\u003e\u003cp\u003e= insert Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e approximately here =\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSARA subscales analysis\u003c/h2\u003e\u003cp\u003eThe Friedman test revealed significant differences across time points for several SARA subitems (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Gait, posture, finger chase, diadochokinesia, heel-shin, and the total SARA score exhibited highly significant changes (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with moderate effect sizes (Kendall\u0026rsquo;s W ranging from 0.176 to 0.410). Post hoc analysis with Holm correction showed that gait, heel-shin, and the total score differed significantly between pre-intervention and post-intervention, as well as between pre-intervention and follow-up (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eA, H, I). Posture and speech exhibited reduced scores after intervention, with no difference between post-intervention and follow-up, suggesting sustained improvement (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eB, D).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003e= insert Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e approximately here =\u003c/p\u003e\u003cp\u003eIn contrast, finger chase and diadochokinesia displayed a delayed response, with significant differences only between pre-intervention and follow-up but not between pre- and post-intervention (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eE, G). Sitting remained stable across assessments (P\u0026thinsp;=\u0026thinsp;0.301; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eC), while nose-finger test showed differences only between pre-intervention and follow-up, with post-intervention not differing from either time point (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003eF). These findings highlight differential responsiveness of SARA subitems to intervention over time, with some domains showing persistent improvements and others exhibiting delayed or no significant changes.\u003c/p\u003e\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe main objective of this study was to assess the feasibility and safety of a long-duration protocol combining cerebello-spinal tDCS with progressively challenging gait and balance exercises in individuals with SCA3 in real-world conditions. Secondary objectives included evaluating the potential clinical benefits on disease severity, balance, and mobility, as well as verifying the retention of these effects one month after the intervention. The results showed high feasibility (attendance\u0026thinsp;\u0026gt;\u0026thinsp;97%, minimal adverse events) and good tolerability under routine conditions. Furthermore, participants showed improvements in ataxia severity, postural control, and functional mobility, which were maintained at one-month follow-up. Nevertheless, because this was a feasibility study without a control group, the clinical improvements should be interpreted cautiously and not considered definitive evidence of efficacy.\u003c/p\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eFeasibility outcomes\u003c/h2\u003e\u003cp\u003eTo our knowledge, this is the first study to examine the feasibility of combining 20 sessions of cerebello‑spinal tDCS with progressively challenging gait and balance exercises in individuals with SCA3. The high adherence rate (97.3%) and minimal rescheduling (21 of 780 planned sessions) suggest that the protocol is feasible in a realworld outpatient rehabilitation setting. Notably, this adherence was achieved without financial incentives or transportation assistance, reinforcing the practical applicability of this protocol. In terms of safety, no serious adverse events occurred; mild skin irritation or itching under the electrodes were transient and easily managed. The few falls observed were minor and resulted in no injuries. These findings indicate that the protocol is safe and well tolerated by people with SCA3. Nonetheless, larger studies with control conditions are needed to confirm these observations and fully establish integration into clinical neurorehabilitation programs.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eChanges in clinical scores\u003c/h2\u003e\u003cp\u003eWe analysed both the SARA total score and its subitems. SARA total scores showed a significant reduction after the intervention, indicating a decrease in ataxia severity. A study [9] investigated the effects of 10 sessions of ctDCS (2 mA, 20 min) in a homogeneous sample of SCA3 individuals and found no significant changes in SARA scores. On the other hand, another study [8] applied cerebellar-tDCS (2 mA, 20 min) in patients with various cerebellar ataxia syndromes and reported significant improvements in SARA scores, lasting up to three months. The efficacy of 5 consecutive sessions of cerebello-spinal tDCS (2 mA, 20 min, cathode below the 11th thoracic vertebra) [14] in the same patients from their previous study [8] and found reductions in SARA scores. To our knowledge, few studies have examined homogeneous SCA3 cohorts; our findings therefore provide preliminary evidence that longer protocols combined with exercise may produce measurable improvements. These findings suggest that, given the progressive nature of SCA3, protocols longer than 10 sessions, especially when combined with exercise, may be necessary to observe measurable improvements.\u003c/p\u003e\u003cp\u003eThe SARA subitems showed differential responses: gait and heelshin improved immediately postintervention and were maintained at followup; finger chase and diadochokinesia improved only at followup, suggesting a slower recovery of fine coordination; speech improved early and was maintained; sitting and the nose\u0026ndash;finger test showed little change. These findings can be interpreted as as trends or possibilities, as this is an exploratory study. However, it can indicate the importance of considering the symptomatic heterogeneity of ataxia and adapting rehabilitation strategies based on the specific responsiveness of each functional domain.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eImprovements in BBS scores and TUG performance\u003c/h2\u003e\u003cp\u003ePostural instability is considered the initial and the most frequently reported symptom of SCA [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. In the present study, BBS scores increased significantly after the intervention, indicating potential benefits in functional balance. The studies that used BBS to assess the impact of tDCS on postural control showed varying results depending on the number of sessions and the protocols applied [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. A comparison of these studies suggests that short protocols, such as those [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e], produce immediate but transient benefits; in contrast, studies with 10 or more sessions [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] and the present study show more lasting improvements. However, differences between protocols (electrode placement, current intensity, exercises applied) make causal attributions difficult.\u003c/p\u003e\u003cp\u003eThe time required to complete the Timed Up and Go (TUG) test was significantly reduced, reflecting potential improvements in functional mobility. In comparison, significant changes in TUG performance after 10 sessions of cerebellar tDCS alone were not found [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], suggesting the relevance of combining stimulation with progressive exercises.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eFollow-up outcomes\u003c/h2\u003e\u003cp\u003eThe follow-up analysis showed that the benefits of the intervention, including reductions in SARA scores, decreased TUG time, and increased BBS scores, were maintained one month after the protocol. No significant differences were found between post-intervention and follow-up outcomes, suggesting the gains were sustained. A study [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e] also reported benefit retention after three months of interventions with 10 sessions of cerebello-spinal tDCS, though in a heterogeneous sample. Despite the small sample and absence of a control group, the present study is the first to demonstrate benefit retention in a homogeneous sample of patients with SCA3.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec19\" class=\"Section2\"\u003e\u003ch2\u003eBaseline features influence on outcomes\u003c/h2\u003e\u003cp\u003eRegression analysis showed that baseline SARA scores, but not INAS scores or symptomonset time, emerged as significant predictors of changes in TUG both postintervention and at followup (Tables\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Higher baseline ataxia severity was associated with smaller improvements in TUG, suggesting that more severe ataxia may limit gains in functional mobility. Conversely, baseline SARA scores were positively associated with improvements in BBS at followup, indicating that participants with more severe ataxia may exhibit delayed balance gains. These findings corroborate observations [9] that baseline severity influences tDCS outcomes; individuals with severe ataxia may improve balance yet show limited capacity to modify complex behaviors such as walking and turning. Additionally, because the intervention emphasized static balance exercises, this could have biased improvements toward balance measures.\u003c/p\u003e\u003cp\u003eThe lack of association between INAS scores or symptom onset and outcomes probably reflect the small sample size, which limited statistical power. Larger studies are needed to identify predictors of tDCS efficacy in ataxia. Because no prior studies have explored these predictors with cerebellospinal tDCS, direct comparisons are not available.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec20\" class=\"Section2\"\u003e\u003ch2\u003eStudy limitations\u003c/h2\u003e\u003cp\u003eBecause there was no control group, the observed improvements cannot be attributed causally to the intervention; future randomized controlled trials are required to confirm these preliminary findings. The pragmatic design deliberately mirrored realworld rehabilitation conditions to maximize applicability, but this approach affords less experimental control than explanatory trials conducted in highly standardized environments. Another limitation is the wide age range of participants. Although the severity of SCA3 does not necessarily correlate with age (some younger individuals may be more severely affected than older ones) agerelated differences in disability and responsiveness could have influenced the outcomes. This heterogeneity may limit the generalizability of the findings yet provides an opportunity to explore how different age groups respond to the protocol. Finally, participants were recruited through a convenience sample, which further restricts generalizability even though it reflects typical clinical practice.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe results of this study highlight that the combined intervention of cerebello-spinal tDCS and specific exercises is a feasible, safe, and potentially beneficial approach to reduce disease severity and improve balance and mobility in individuals with SCA3. Retention of benefits at onemonth followup suggests durability, but confirmatory randomized trials are needed. Preliminary analyses suggest that patients with higher baseline ataxia may experience greater balance gains, highlighting the need for personalized intervention strategies. These findings provide preliminary support for the clinical utility of this protocol and warrant further investigation in controlled trials. Moreover, future studies should explore the effects of this intervention using biomarkers (e.g., EEG or neuroimaging), patient-reported outcomes, and comparative designs contrasting cerebellar-spinal tDCS alone with combined approaches. This would allow the identification of individual characteristics that may favor more significant responses to the intervention, maximizing its impact and broadening its applicability.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\u003cp\u003eThe study was approved by the Comit\u0026ecirc; de \u0026Eacute;tica em Pesquisa (CEP) da UNISUAM (process number 70797823.1.0000.5235). All participants provided written informed consent prior to enrollment, in accordance with the Declaration of Helsinki.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eClinical trial registration\u003c/h2\u003e\u003cp\u003eClinical trial registration: ClinicalTrials.gov Identifier NCT06267222. Registration date: October 11, 2023.\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003ch2\u003eConsent for publication\u003c/h2\u003e\u003cp\u003eNot applicable. This manuscript does not contain any individual person\u0026rsquo;s data in any form (including individual details, images, or videos).\u003c/p\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThis study is funded by the Carlos Chagas Filho Foundation for Research Support of the State of Rio de Janeiro (FAPERJ, No. E-26/211.104/2021) and by the Coordination for the Improvement of Higher Education Personnel - Brazil (CAPES) - Financial Code 001, No. 88881.708719/2022-01, and No. 88887.708718/2022-00).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eLASO and AFB: Conceptualization, Methodology, and Writing \u0026ndash; original draft preparation; TL and LASO: Formal analysis and Writing \u0026ndash; review and editing; TL: prepared figures and Tables; AFB, LASO, YCH, FGA: Investigation and Data Curation LASO: Supervision, and Funding acquisition; LASO, AFB and YCH: Project administration; All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eWe would like to thank all the undergraduate students from Unisuam and IFRJ who contributed to this study: Marina, Raquel, Jean, Bruna, Ma\u0026iacute;ra, Lucas, Camila, M\u0026ocirc;nica, Luana, Blendo, Layssa, Thayn\u0026aacute;, and Roberta. We would also like to thank all the patients who participated in this study.\u003c/p\u003e\u003ch2\u003eData Availability\u003c/h2\u003e\u003cp\u003eData cannot be shared openly to protect study participant privacy.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eKlockgether T, Paulson H, Milunsky JM. Ataxia: review of clinical features and treatment approaches. Lancet Neurol. 2019;18(9):931\u0026ndash;45. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/S1474-4422(19)30277-4\u003c/span\u003e\u003cspan address=\"10.1016/S1474-4422(19)30277-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGhanekar SD, Kuo SH, Staffetti JS, Zesiewicz TA. Current and emerging treatment modalities for spinocerebellar ataxias. 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J R Stat Soc Ser B. 1995;57(1):289\u0026ndash;300.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eNanetti L, Alpini D, Mattei V, Castaldo A, Mongelli A, Brenna G, Gellera C, Mariotti C. Stance instability in preclinical SCA1 mutation carriers: a 4-year prospective posturography study. Gait Posture. 2017;57:11\u0026ndash;4. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.gaitpost.2017.05.028\u003c/span\u003e\u003cspan address=\"10.1016/j.gaitpost.2017.05.028\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Machado‑Joseph Disease, Transcranial Direct Current Stimulation, Exercise Therapy, Feasibility Studies, Pragmatic Clinical Trials","lastPublishedDoi":"10.21203/rs.3.rs-7437650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7437650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpinocerebellar ataxia type 3 (SCA3) is a hereditary neurodegenerative disorder that progressively impairs balance and gait, without effective pharmacological treatments available. Cerebellar and cerebello-spinal transcranial direct current stimulation (tDCS) have shown neuromodulatory potential. However, extended protocols combined with exercise have not yet been tested in these individuals in a public health service.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo assess the feasibility and safety of 20 sessions of cerebello-spinal tDCS combined with exercise in individuals with SCA3 in realworld conditions, and to explore preliminary changes in ataxia severity, balance, and mobility.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: In this clinical trial, 39 participants (67% female; mean age 46 years) with mild-to-moderate SCA3 completed 20 sessions over four weeks under realworld publichealth conditions. Feasibility was evaluated through adherence and tolerability, and safety was assessed by monitoring adverse events. Secondary outcomes included disease severity (SARA), balance (Berg Balance Scale), and mobility (Timed Up and Go), assessed at baseline, post-intervention, and one-month follow-up. Analyses included standardized individual differences and multiple linear regression adjusted for baseline values.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Adherence was 97.3%, with no serious adverse events. Significant improvements were observed in SARA (P \u0026lt; 0.001), BBS (P \u0026lt; 0.001), and TUG (P = 0.011). Improvements were maintained at one month (P \u0026gt; 0.171).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: A combination of multiple sessions of cerebello-spinal tDCS and exercise in a public health service was feasible, safe, and may improve ataxia severity, balance, and mobility in individuals with SCA3. Despite the absence of a control group, these findings encourage further investigation of the proposed intervention as a potential rehabilitation strategy for cerebellar neurodegeneration.\u003c/p\u003e","manuscriptTitle":"Feasibility and Safety of Combined Cerebello-spinal Neuromodulation and Exercise in Spinocerebellar Ataxia Type 3: A 20-session Protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 08:39:03","doi":"10.21203/rs.3.rs-7437650/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-21T06:20:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-19T03:33:48+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T08:57:21+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"308468600160012322074402384077729135687","date":"2025-08-29T20:37:45+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"199139101321376555381416622702841114278","date":"2025-08-28T07:30:09+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-27T19:58:15+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-27T07:20:54+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-27T07:20:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Cerebellum","date":"2025-08-22T22:55:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6f462f4e-5ddb-405e-8c35-387e01794bbd","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-11-24T16:07:04+00:00","versionOfRecord":{"articleIdentity":"rs-7437650","link":"https://doi.org/10.1007/s12311-025-01927-7","journal":{"identity":"the-cerebellum","isVorOnly":false,"title":"The Cerebellum"},"publishedOn":"2025-11-18 15:58:34","publishedOnDateReadable":"November 18th, 2025"},"versionCreatedAt":"2025-09-08 08:39:03","video":"","vorDoi":"10.1007/s12311-025-01927-7","vorDoiUrl":"https://doi.org/10.1007/s12311-025-01927-7","workflowStages":[]},"version":"v1","identity":"rs-7437650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7437650","identity":"rs-7437650","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}