Sexual selection influences broad-scale patterns of biodiversity. While a large body of research has investigated the effect of mate competition on sexual selection, less work has examined how pre-adult life history influences sexual selection. We used a mathematical framework to explore the influence of pre-adult survival on sexual selection. Our model suggests that pre-adult male mortality will affect the strength of sexual selection when a fixed number of adult males have an advantageous mate-acquisition trait. When a fixed number of males have an advantageous mate-acquisition trait, sexual selection is expected to increase when pre-adult mortality is relatively low. By contrast, if a fixed proportion (rather than number) of adult males have a mate-acquisition trait, pre-adult male mortality is not expected to affect the strength of sexual selection. Further, if the advantageous mating trait affects pre-adult survival, natural and sexual selection can interact to influence the overall selection on the mating trait. Given that pre-adult mortality is often shaped by natural selection, our results highlight conditions under which natural selection can have cascading effects on sexual selection. This ASs in ASR .Stegastes partitus), larger adult males tend to produce more offspring because larger males retain a nest longer than smaller males, maintain relatively high-quality territories, and receive more eggs from females than smaller males [Pachydiplax longipennis, a trade-off exists between pre-adult survival and the development of a sexually selected ornament, but only when predation risk is relatively high [In addition to influencing which individuals enter the mating pool, selection for pre-adult survival can trade off with sexually selected traits ,37,38, aer males . In addier males . Thus, ter males . Such tra priori hypotheses regarding the conditions under which pre-adult survival will affect sexual selection. To identify the conditions under which pre-adult life history is expected to affect sexual selection, we use a mathematical framework to explore the effect of pre-adult survival on sexual selection.Despite some previous research on the impact of pre-adult survival on sexual selection (described above), most research on sexual selection focuses primarily on mating pool dynamics , and life-history theory and sexual-selection theory have largely been developed independently . In the electronic supplementary material, to illustrate specifically the link between natural selection on pre-adult survival and sexual selection on a male trait, we provide an example of how natural selection could shape a pre-adult survival trait . In the model, we assume that males can mate multiply, whereas females mate only once during a given reproductive episode, such that mate availability only affects male fitness. Males either have or lack a trait that is beneficial in mate acquisition and fertilization success, and only males who have this trait can mate  to explIn the model, we considered an initial population with equal numbers of pre-adult males and females (discussed below). We then quantified the relationship between pre-adult male mortality and the strength of sexual selection on the male mating trait across scenarios in which (i) pre-adult survival was either different or equal between the sexes and (ii) either a fixed proportion or fixed number of males had the mating trait. We specifically considered the following scenarios: males and females have equal pre-adult mortality and a fixed proportion of surviving adult males have the mating trait (Scenario 1); males and females have different pre-adult mortality and a fixed proportion of surviving adult males have the mating trait (Scenario 2); males and females have equal pre-adult mortality and a fixed number (rather than a fixed proportion) of surviving adult males have the mating trait (Scenario 3); males and females have different pre-adult mortality and a fixed number of surviving adult males have the mating trait (Scenario 4). We chose these scenarios as they represent a broad range of possible survival and male-trait distribution scenarios.We considered the following values of pre-adult mortality and male mating-trait distribution: male and female pre-adult mortality is 10%, 40% or 70% across three levels of male-trait distribution  (Scenario 1); female pre-adult mortality is 10% and male pre-adult mortality is 10%, 40% or 70% across three levels of male-trait distribution  (Scenario 2); male and female pre-adult mortality is 10%, 40% or 70% across three levels of male-trait distribution  (Scenario 3); and female pre-adult mortality is 10% and male pre-adult mortality is 10%, 40% or 70% across three levels of male-trait distribution  (Scenario 4). The parameters were chosen as they reflect a broad range of mortalities and male-trait distributions and therefore probably apply to a range of systems. As mentioned above, variation in pre-adult survival could be associated with genetic drift and/or natural selection, and to illustrate how natural selection could impact pre-adult mortality, we provide a scenario in which natural selection acts on a pre-adult survival trait in the electronic supplementary material . Likewise, the adult male mating trait distributions outlined above could be reflective of genetic drift or natural selection on the male mating trait, and whether natural selection affects the mating trait will depend on the initial frequency of the mating trait among pre-adult males (discussed further below).ssex) quantifies the strength of sexual selection on the mating trait and is proportional to the response to sexual selection expected if there is heritable variation associated with the trait and if mating success is correlated with reproductive success. The sexual selection differential was calculated as follows:xmale is the male mating trait value and Wmat is relative mating success [For each level of pre-adult mortality and male-trait distribution associated with each scenario, we assumed that each population initially consisted of 30 pre-adult males and 30 pre-adult females. Individuals who survived the pre-adult stage were assumed to successfully mature and have the potential to reproduce. For each case, only males with the mating trait could receive one or more female mates . As ment success . Only ma success  and the snat, was calculated as follows:xmale is the male mating trait value and Wsurv is relative pre-adult survival success [In addition, because a fixed number or proportion of males have the mating trait as adults (Scenarios 1–4 above), pre-adult survival will in some cases be non-randomly associated with the mating trait. For example, if only males with the mating trait survive to adulthood, there will be positive natural selection associated with the mating trait. Such a pattern might be expected if some males are ‘better’ than others and are both more likely to survive the pre-adult stage and have an advantageous mating trait. By contrast, having the mating trait could be associated with increased pre-adult mortality , in which case natural selection would select against the mating trait. In other cases, males who have the mating trait might be equally likely to survive the pre-adult stage as males who lack the mating trait, in which case there would be no natural selection associated with the mating trait. To explore how natural selection can be associated with the mating trait, we calculated the minimum and maximum possible strength of natural selection  that could be associated with the adult mating trait frequencies outlined in Scenarios 1–4 above. The selection differential,  success . We then success  and the https://doi.org/10.5061/dryad.v41ns1rzk.All data are available at . 3. 3.1a). Sex differences in pre-adult mortality, a pattern documented in a range of animals [b). However, when a fixed proportion of males had the mating trait, the proportion of males with the mating trait, but not pre-adult male mortality, determined the strength of sexual selection . Specifically, the strength of sexual selection increased when a smaller proportion of males had the mating trait. This pattern occurs because there is greater mate monopolization by the few males  with the preferred trait. That is, when a relatively small proportion of males had the mating trait, a relatively large proportion of males remained unmated and those males with the advantageous trait had relatively high mating success, which led to high non-random variation in mating success.Pre-adult mortality will in some—but not all—cases influence sexual selection. When males and females had equal pre-adult mortality and a fixed proportion of adult males had the mating trait (Scenario 1), ASR and OSR were equal to one across pre-adult mortality levels, and the proportion of males with the mating trait, but not pre-adult mortality, determined the strength of sexual selection a. Sex di animals ,47, led c,d). Specifically, sexual selection strength increased when pre-adult male mortality was relatively low and when a relatively small number of males had the preferred trait . This pattern was consistent regardless of whether males and females had the same or different pre-adult survival . In particular, when relatively few males (three in our scenarios) had the advantageous mating trait and when pre-adult male mortality was low , the strength of sexual selection was greatest. This pattern occurs because relatively few males monopolize all female mates under these conditions. Specifically, when a large number of males survive to adulthood but few have the advantageous trait, many males remain unmated; the few that do have the advantageous trait are then able to acquire and monopolize the female mates in the population and as a result have relatively high mating success. Because mating success is then skewed heavily toward the few males with the advantageous mating trait, sexual selection is relatively strong. By contrast, if many males die before reaching adulthood and a fixed number of males have the preferred trait, there is less non-random variation in mating success, which reduces the strength of sexual selection.By contrast, if a fixed number, rather than a fixed proportion, of adult males had the mating trait, both pre-adult male survival and the number of males with the mating trait affected the strength of sexual selection  and as the proportion (figure 3a) or number (figure 3b) of adult males with the mating trait increases. Likewise, when a fixed proportion of adult males have the mating trait, natural selection against the mating trait (i.e. negative selection) has the potential to be strongest when male pre-adult mortality is relatively high and when a relatively small proportion of males have the mating trait (figure 3a). When a fixed number (rather than a fixed proportion) of adult males have the mating trait, pre-adult male mortality and the number of males with the mating trait will interact to determine the maximum possible strength of natural selection that can oppose the mating trait (figure 3b). Specifically, when a fixed number of males have the mating trait, natural selection against the mating trait has the potential to be strongest when pre-adult male mortality is relatively high and relatively few (i.e. only three) adult males have the mating trait . When a greater number (i.e. six or nine) of adult males have the mating trait, natural selection against the mating trait has the potential to be strongest when pre-adult male mortality is intermediate .In our scenarios, there is potential for natural selection to influence the mating trait during the pre-adult stage. If individuals with the mating trait are more or less likely to survive the pre-adult stage relative to individuals who lack the mating trait, natural selection will favour or disfavour the mating trait . The maxfigure 3Importantly, natural selection associated with the mating trait can act in the same direction as sexual selection , but it could also be associated with genetic drift. The above patterns provide a set of election . Our fin


This study describes the development and application of an ASE analysis pipeline on a unique cohort of 87 well phenotyped and RNA sequenced patients from the Maastricht Cardiomyopathy Registry with dilated cardiomyopathy (DCM), a complex genetic disorder with a remaining gap in explained heritability. Regulatory processes for which ASE is a proxy might explain this gap. We found an overrepresentation of known DCM-associated genes among the significant results across the cohort. In addition, we were able to find genes of interest that have not been associated with DCM through conventional methods such as genome-wide association or differential gene expression studies. The pipeline offers RNA sequencing data processing, individual and population level ASE analyses as well as group comparisons and several intuitive visualizations such as Manhattan plots and protein–protein interaction networks. With this pipeline, we found evidence supporting the case that cis-regulatory variation contributes to the phenotypic heterogeneity of DCM. Additionally, our results highlight that ASE analysis offers an additional layer to conventional genomic and transcriptomic analyses for candidate gene identification and biological insight.Allele-specific expression (ASE) analysis detects the relative abundance of alleles at heterozygous loci as a proxy for  Differential gene expression (DGE) studies in turn, while offering more mechanistic insight, fail to distinguish between cis- and trans-regulatory variation1. In addition, allelic dosage compensation can hide mono-allelic downregulation from DGE analysis. Using RNA-sequencing data, allele-specific expression (ASE) determines the relative expression of individual alleles to find allelic imbalance caused by cis-acting regulatory mechanisms3. These include cis-acting expression and splicing quantitative trait loci (eQTLs and sQTLs), nonsense-mediated decay (NMD), X-inactivation, imprinting, and RNA interference through non-coding RNAs (ncRNA)5. The detection of allelic imbalance can be performed on a per-sample basis, which allows for the discovery of variants with low minor allele frequencies (MAF)3. Thus, ASE analysis enables researchers to find regulatory genomic differences regardless of total gene expression or direct variant-phenotype correlations. In complex phenotypes with low explained heritability and inter-individual differences in pathophysiology, this could contribute to the identification of causal mechanisms and therapeutic targets.Genome-wide association studies (GWAS) of complex phenotypes often identify non-coding variants and fail to distinguish causal variants from commonly co-inherited variants associated through linkage disequilibrium7. Around 15–30% of DCM cases are familial, but the currently known relevant genes and variants still fail to explain 70–80% of all cases8. Family members of affected patients often show no evidence for familial DCM and are diagnosed with sporadic DCM10. Previous studies have shown eQTL enrichment for GWAS hits in two separate DCM cohorts, indicating regulatory mechanisms play a role in this phenotype11. The unexplained heritability and assumed regulatory mechanisms make DCM a fitting case for ASE analysis.Dilated cardiomyopathy (DCM) is a complex genetic disorder characterized by dilation of the left ventricle and impaired systolic functioncis-regulatory processes involved in the development of complex genetic disorders. We find evidence supporting the case that cis-regulatory variation contributes to the phenotypic heterogeneity of DCM, discover new candidate genes, and show the benefit of performing ASE analysis in addition to GWA and differential gene expression studies.In this study, we have developed and applied an open-source ASE analysis pipeline in R that performs ASE analysis on the individual and population level as well as group comparisons. The aim of this pipeline is to enable the analyses of, often readily available, RNA-sequencing data in novel ways that help elucidate https://github.com/macsbio/AlleleSpecificExpression). We chose to represent ASE as the absolute deviation from a heterozygous biallelic frequency of 0.5, as per the standard guidelines3.The pipeline consists of three steps, starting with RNA sequencing data preprocessing using the Genome Analysis Toolkit (GATK), followed by the general ASE score statistics and the analyses for biological interpretation Fig.   determined an ASE score of 0.966 as the optimal threshold to distinguish between true heterozygous loci and RNA sequencing errors. The total number of heterozygous and homozygous loci was 167,329 and 719,769 respectively . In this paragraph the results and visualizations for the group comparisons are described following the Mann–Whitney U test between each phenogroup and the others as well as the Kruskal–Wallis test results between all combinations of phenogroups  setting.We have shown that allele-specific expression analysis is able to pinpoint disease-relevant genes under cis-regulatory variation. Our analysis on a unique DCM cohort shows that allelic imbalances are detected in known DCM genes; furthermore, imbalances detected in novel DCM genes, while not yet experimentally or clinically linked to development of DCM, may ultimately be shown to reflect novel disease-relevant processes. Our ASE analysis pipeline can be applied at the individual and the population level and thereby play a role in research on both rare and common complex phenotypes.29. All patients were diagnosed according to World Health Organization criteria and the current European Society of Cardiology guidelines. Patients with a left ventricular ejection fraction of < 50% in the absence of obstruction of > 50% of a major coronary artery branch, pericardial diseases, congenital heart diseases, cor pulmonale, and active myocarditis were included. Unless contraindicated, patients received guideline-directed medical therapy titrated to the maximally tolerated dose and defibrillator device therapy. Endomyocardial biopsies were obtained in routine diagnostic care for each patient. All RNA was isolated from spare biopsies and sequenced using the TruSeq mRNA sample preparation kit  and the NextSeq 500 sequencing chip . All patients received genetic counseling and testing using a cardiomyopathy-associated gene panel with either single molecule molecular inversion probes or whole-exome sequencing. Whole-exome sequencing data was available for 35 patients, obtained with the Affymetrix GW6 platform . In addition, they were assigned classification labels based on a machine learning algorithm that performs clustering on DCM patients based on 28 distinct clinical features11. This resulted in four phenotypically distinct patient clusters (phenogroups) with increasing disease severity. Phenogroup 1 was mainly characterized by a moderate ejection fraction with low creatine levels and overall mild disease symptoms, phenogroup 2 by high creatine levels and an overrepresentation of auto-immune disease diagnoses, phenogroup 3 by the presence of atrial fibrillation, and phenogroup 4 by a low ejection fraction and other end-stage symptoms. All patients gave written informed consent before inclusion and the relevant guidelines and regulations were strictly adhered to29.The data set consists of a group of 87 RNA sequenced DCM patients from the Maastricht Cardiomyopathy Registry30. The fraction of reference and alternative allele reads was calculated for all loci. As a means of standardization, the ASE scores were set as the absolute deviation of the allelic read fraction from 0.5 to 1.0 as commonly done by others  for variant calling and read counting. All following steps were performed in R version 4.0.231. Next, Youden’s J statistic was applied to find the threshold that maximizes the distance to the ROC diagonal31. Due to unequal sample sizes between homozygous and heterozygous loci, resampling was applied. The mean ASE score threshold was then used to filter out likely homozygous loci within the non-genotyped subset.The subset of samples with available whole-exome sequencing data was used to determine a homozygosity threshold based on the ASE score since the true zygosity for these samples was known. A receiver operating characteristic (ROC) analysis was performed using a model of zygosity  as a function of the ASE score32. For the group comparisons, a Wilcoxon rank-sum test was applied to calculate the statistical significance of differential imbalance between pairs of phenogroups. To investigate ASE variation between all four phenogroups, we performed the Kruskal–Wallis Rank-Sum Test. Non-parametric tests were chosen due to the non-normality of the ASE scores as well as the sparse measurements per SNP across the samples.Statistical tests were performed on the ASE scores on a per sample basis as well as between phenogroups. Within-sample ASE significance was determined using a binomial test, where the expected probability of finding a certain allele in the total read count at a particular locus was set to be the median of all median ASE values per sample (0.647). Multiple testing correction was performed for the binomial test results using the Benjamini–Hochberg method33. For genes with multiple ASE measurements, the SNP with the lowest p-value was taken to represent the gene for that individual, since several of the potential underlying mechanisms of ASE, such as splicing and transcript truncation (followed by NMD), are position-specific and cannot be accurately aggregated with imbalances in other exons10. Ensembl Gene Ontology data and SNP-to-gene mapping were subsequently used to perform biological interpretation. The R-package topGO was used to perform Gene Ontology enrichment analysis using the parent–child for all significant gene hits from each analysis35. A gene was considered statistically significant if the lowest q-value for an ASE event within that gene was < 0.05. Genes with a SNP showing statistically significant differential imbalance between the four phenogroups were visualized as a network connecting functionally related genes including their representative SNPs with median ASE scores indicated per cluster. This network was created by taking the related genes of differentially imbalanced SNPs and, after translating gene identifiers to protein identifiers, using the STRING database to find protein–protein interactions with a cut-off of 0.936.All SNP identifiers in the output results were mapped to Ensembl gene identifiers (ENSG IDs) and HUGO Gene Name Committee (HGNC) symbols29. An independent Medical Ethics Committee of the Maastricht University Medical Center (MUMC+) has approved this registry.All patients gave written informed consent before inclusionSupplementary Legends.Supplementary Information 2.


Currently, there are various shoe lateral upper support designs  available in the market, but scientific guidelines are not well established. This study examined the location effect of lateral shoe upper supports on the ground reaction forces, as well as ankle kinematics and moments during the change of direction maneuvers using a statistical parametric mapping approach. The forefoot support shoe had a reduced eversion moment in between ~25–95% across all change of directions. The forefoot upper support shoe had increased ankle inversion between ~8–14% (complete turns) and ~96–100% of contact time , and increased inversion velocity in side-cuts. The rearfoot upper support shoes reduced inversion velocity in lateral shuffle compared to no support. These findings suggest that lateral upper support location on basketball shoes can influence coronal plane ankle mechanics, but not ground reaction forces.t-tests between all shoe conditions. The coronal ankle results revealed that the forefoot support shoe had a reduced eversion moment that varied between ~25–95% across all change of directions (p < 0.05). However, the forefoot upper shoe had increased ankle inversion between ~8–14% (complete turns) and ~96–100% , and increased inversion velocity in side-cuts than the other shoes (p < 0.05). Compared to the control, the rearfoot support shoes reduced inversion velocity in side-cut between ~78–92% (p < 0.05). These findings suggest that a forefoot upper support induced most changes in ankle mechanics during basketball cutting maneuvers, with only inversion angle in the complete turn being influenced during the initial period where ankle injury may occur. Future research should examine if these coronal ankle mechanics influence change-of-direction performance and injury risk with regular wear.This study examined the location effect of lateral shoe upper supports on the ground reaction forces, as well as ankle kinematics and moments during the change of direction maneuvers using a statistical parametric mapping approach. University basketball athletes performed side-cuts, complete turns and lateral shuffle maneuvers with their maximum-effort in four shoe conditions with varying shoe upper support locations: full-length, forefoot, rearfoot, none (control). The statistical parametric mapping repeated measures ANOVA test was applied to compare differences between the shoe conditions, followed-up with post-hoc statistical parametric mapping paired  Acceleration, cutting and turning are increasingly executed in basketball, soccer and other team sports ,2, as plPrevious studies have identified that type/design of footwear could be related to ankle sprain, ACL injury and foot pain during sports ,10,11. ATo date, most basketball footwear research has focused on the midsole, whereas the construction of the upper support has received little attention. Some recent studies investigated the effect of shoe fit configurations (lacing or wrap structure) on performance and joint biomechanics in four agility-based movements, including lateral skater jump, countermovement jump, triangle drop step drill and anterior-posterior drill ,18. TheiFurthermore, the increased frequency and intensity of lateral movements can lead to instability of the forefoot/midfoot regions of shoe upper in basketball shoes . While tHence, the purpose of this study was to examine the effects of the lateral shoe upper support location on the ground reaction forces, as well as ankle kinematics and moments in basketball-specific cutting maneuvers . It was hypothesized that lateral shoe upper support would increase ankle stability as indicated by a reduced ankle inversion angle and inversion velocity during basketball-specific cutting maneuvers. It was also hypothesized that an upper support across the full lateral shoe length would increase the ankle moments. A priori power calculation was calculated in G-Power software with an alpha of 0.05 and power of 0.8. Based on the previously reported large effect size between a 45° side-cut and complete turn observed in the peak lower-limb moments and contact time , we inpuFour identical pairs of basketball shoes a, which To replicate a realistic shoe–ground interface, a 1.2 × 1.2 m force platform  and its surrounding ground was covered with the standard basketball court surface. Participants were instructed to perform the side-cut, complete turn and lateral shuffle with their maximum effort b, which For all tested maneuvers, the starting point was set five meters away from the force platform. Photoelectric timing gates  were placed three meters before and after the force platform to measure performance time and to encourage maximum cut velocity. The ellipse time between the starting and exit timing gates indicated the overall cutting performance time across maneuvers. For the side-cut, participants were instructed to sprint forward, plant their right foot on the platform and continue sprinting towards the endpoints at 45 degrees b. For thAfter anthropometrical measurements taken, twenty-one reflective markers (ø = 14 mm) were attached over the pelvis (left and right ASIS and PSIS) and the right lower-limb on the medial and lateral femoral epicondyles, the medial and lateral malleoli and the first and fifth metatarsal heads. Four markers on rigid clusters were attached to the right shank and thigh, and an additional three markers on the superior, inferior and lateral heel counter were used to track the movement trials  6]. The. The6]. http://www.random.org, assessed at 10 October 2019) across participants.After a 10-min warm-up, including self-selected stretching, jogging and familiarization with each of the tested maneuvers, the participants were instructed to tighten their shoelaces as they would in regular training. They were required to perform the tasks as fast as possible, plant their right foot on the force platform and change direction to the respective endpoints b. To ensA spline interpolation was performed for missing marker trajectories using three frames of data before and after the missing data . Data weContact time between initial foot contact to toe-off was defined using a 20N threshold of the vertical ground reaction force. The resultant horizontal ground reaction force was calculated by the square root of the sum of the squared antero-posterior and medial-lateral grounds reaction forces. Sagittal and coronal plane ankle kinematics angles, velocities and moments were assessed where the sequence of rotations (+/−) was along the medio-lateral X-axis (flexion/extension) and antero-posterior Y-axis (ankle inversion/eversion). Inverse dynamics was used to calculate the internal joint moments  using the resultant approach. Ankle moments were resolved into the proximal segment (shank) coordinate system using Dempster’s inertial parameters .https://spm1d.org/Downloads.html (accessed on 2 April 2022) and the SPM repeated measures ANOVA test was applied to compare differences between the shoe conditions. Significance was determined by the SPM(F) value exceeding the critical threshold, which is calculated by random field theory on equivalent random smooth data [t-tests between all shoe conditions. The alpha level for all tests was 0.05, and no adjustments were made for the multiple comparisons because this study was exploratory in nature. The null hypothesis was that there would be no differences in the kinetic and kinematic parameters tested during the change of the direction step. The group mean and standard deviation were calculated from the three trials for statistical analyses. For all kinematic and kinetic parameters in each participant and shoe condition, the mean time-normalized curves were computed to 101 data points during the ground contact phase. Most cutting-related studies investigated discrete variables that were zero-dimensional (0D) ,28,33,38oth data . SignifiThe contact phase of cuts has commonly been divided into the braking and propulsion phases ,11,27,31The SPM repeated measures ANOVA revealed no differences in the vertical ground reaction force or resultant horizontal shear force during the change of direction step in any of the cutting maneuvers . p > 0.05). There was a main effect in the frontal plane ankle angle in side-cut, turn and lateral shuffle  and full-length support shoes (44–48% and 94–97%). In addition, the control had a significantly reduced eversion moment compared to the rearfoot support shoe between 81–85% of ground contact. In the lateral shuffle, post-hoc analysis revealed a significantly reduced eversion moment in forefoot support shoes compared to rearfoot support shoes between 20–38% and 41–75% of contact time. This study examined the influence of lateral shoe upper support  on the ground reaction forces, and ankle kinematics and moments during side-cuts, complete turns and lateral shuffle maneuvers. The SPM results from the present study provided insights across the entire change of direction step, which enabled us to assess the effects of lateral upper support locations without any bias about what time points might provide differences. This was suitable for this exploratory analysis, as no prior data on lateral supports suggested we should limit our study to certain time points ,41. The present results indicated that both vertical and horizontal shear ground reaction forces are robust to different lateral shoe upper support constructions in all of the tested maneuvers. This suggests that the lateral upper support had a little to minimal effect on the ground reaction forces, which have been reported to be affected by other shoe construction features, such as midsole hardness and shear-reduction structure ,31,42.While sagittal plane motion appears to have an influence on ankle stability and inversion sprains, they were not influenced by the shoe lateral upper support in the present study. Yet, we found that the upper support structure played a role in the changes in coronal ankle variables including the inversion angle, inversion velocity and eversion moment in most of the change of direction maneuvers. The reduced ankle inversion angle and velocity during the braking phase of change-of-direction movements was suggested to reduce the risk of ankle sprain injury ,43. The On the other hand, the larger inversion velocity found in later contact phase may also allude to performance benefits, as it could promote better/faster support for inversion to push-off. It is appeared that the forefoot support shoes were increasing from middle (weight acceptance) to later phase (acceleration/push-off) of ground contact. This is explained by a coping effect between forefoot and midfoot/ankle. The previous studies have shown that medially or laterally lifting the forefoot through orthotics can cause subject-specific changes with a lateral shift of the center-of-pressure under the forefoot and, consequently, affect the loading of the knee joint in running ,45. RegaSeveral efforts, such as shoe collars, heel counters, taping and foot inserts, have been developed to restrict large amounts of ankle inversion during cutting and turning tasks, which may be considered important for basketball ankle sprain injury prevention ,10,43. WThere are some limitations when interpreting our results. First, trained male athletes were recruited in this study and our data may not be generalizable to other playing levels or gender. It is known that females might be exposed to increased injury risks than males; moreover, future studies should examine the relationship between landing posture and lateral upper support structures to understand the underlying mechanism associated with ankle inversion injuries in basketball. Furthermore, an in-shoe robotic device could be considered to simulate various boundary conditions for better prediction of the calcaneal movement and ligamentous loading at the ankle. Lastly, we did not measure the knee and hip mechanics as well as muscle activation. Restriction of foot and ankle motion may lead to some compensations of knee motion. A future study should investigate this to confirm this association.The lateral upper support of basketball shoes affects the coronal ankle mechanics, but not for ground reaction forces during maximum-effort cutting maneuvers. The forefoot lateral upper support shoes reduced the eversion moment but increased ankle inversion angle/velocity. The rearfoot lateral upper support may reduce the eversion moment and inversion velocity during propulsion compared to no upper support. These differences were found from early loading to late propulsion during the change of direction step, but were dependent on the cutting maneuver. The findings from this study may guide recommendations for how basketball shoes can be selected to alter ankle mechanics, and thus, optimize the cutting-related performances and injury risks for basketball players.


BRCA1 and BRCA2 mutation carriers face an elevated lifetime risk of developing ovarian cancer. Oral contraceptives have been shown to significantly decrease the risk of ovarian cancer by approximately 50% in this high-risk population. Changes in contraceptive formulations and patterns of use over time have introduced lower hormonal dosages, different steroid types and non-oral routes of administration. Specifically, there has been a considerable shift in patterns of contraceptive use and the increase in the uptake of non-oral, long-acting, reversible contraception  has corresponded to a decline in oral contraceptive pill use. Whether or not these other methods confer a protective effect against ovarian cancer in the general population is not clear. To our knowledge, there have been no such studies conducted among BRCA mutation carriers. Furthermore, the impact of these changes on the risk of developing ovarian cancer is not known. In this article, we will review the existing epidemiologic evidence regarding the role of contraceptives and the risk of ovarian cancer with a focus on women with a BRCA1 or BRCA2 mutation. We will discuss recent findings and gaps in the knowledge while extrapolating from studies conducted among women from the noncarrier population. BRCA1 and BRCA2 tumour suppressor genes encode nuclear protein products that maintain genome integrity through various roles, including DNA repair, cell-cycle regulation and apoptosis [BRCA1 and BRCA2 are ubiquitously expressed in cells of the human body, pathogenic germline mutations in these genes confer significantly elevated risk of developing various cancers, notably, cancers of the breast and ovary [The nd ovary . The prend ovary , 5.TableBRCA1 mutation and between 17 to 21% for those with a BRCA2 mutation [BRCA1 mutation and age 40–45 for women with a BRCA2 mutation [BRCA mutation [The lifetime risk of developing ovarian and/or fallopian tube cancer (referred to as ovarian cancer hereafter) has been estimated to be between 44 to 49% for women with a mutation , 7. Givemutation . This ismutation .BRCA1 or BRCA2 mutation [Several hormonal and reproductive factors, including oral contraceptive use, early age at menopause, breastfeeding and parity have also been associated with a decreased risk of ovarian cancer among both women in the average-risk and high-risk population , 14. Oramutation –17. Collmutation . This prmutation . In factmutation –21.BRCA mutation. We will discuss recent findings and gaps in the knowledge while extrapolating from studies conducted among women from the noncarrier population.Changes in contraceptive formulations and patterns of use over time have introduced lower hormonal dosages, different steroid types and non-oral routes of administration. The impact of these changes on the risk of developing ovarian cancer is not known. In this article, we will review the available observational evidence regarding the role of combined oral contraceptives as well as long-acting reversible contraceptives and the risk of ovarian cancer with a focus on women with a Over the past five decades, the estrogen and progestin content of oral contraceptive pills has decreased rapidly in an effort to reduce the incidence of undesirable side-effects such as thrombosis and cardiovascular events without compromising contraceptive efficacy , 23. LowBRCA mutation carriers and 253 cases, Antoniou et al., reported a potential increase in risk with formulations initiated after 1975, when low-dose pills dominated the market, compared to those initiated before 1975, when high-dose pills dominated the market in both BRCA1 and BRCA2 mutation carriers combined  [, reported a significantly reduced risk of ovarian cancer for formulations initiated pre-1975  and a suggestively reduced risk for formulations initiated post-1975 compared to never use  for BRCA1 mutation carriers [BRCA2 mutation carriers, formulations initiated pre-1975 trended towards a protective effect  whereas post-1975 use conferred a significant risk reduction . Both studies were limited by lack of data on the specific hormonal content of contraceptives. More research is needed to clarify the impact of hormonal dose and potency of oral contraceptives on BRCA-associated ovarian cancer risk.To our knowledge, only two reports have attempted to evaluate the impact of formulation on risk in the carrier population, using year as a proxy for hormone dose. In a retrospective cohort study of 3319 carriers . For BRCIn addition to oral administration, various injectable, implantable and intrauterine devices have been developed over the years for effective, long-acting reversible contraception (LARC) that require no maintenance after insertion. LARC methods can be classified into those that provide systemic delivery versus local delivery of progestin. Contraceptive implants and injections provide a continued release of progestin into the surrounding tissues that is absorbed into systemic circulation. Intrauterine devices (IUDs) provide continued local administration of levonorgestrel (LNG) to the uterus to avoid systemic effects . The thrContraceptive implants consist of progestin-only subdermal rods or capsules inserted under the skin of the upper arm. They are available as LNG systems  or etonogestrel systems . Whereas etonogestrel implants consistently inhibit ovulation, about one-third of all cycles are ovulatory among users of LNG implants . To mainThe most widely distributed contraceptive injection is depot medroxyprogesterone acetate , which delivers a 150 mg bolus of medroxyprogesterone intramuscularly. This results in serum drug concentrations sufficient for ovulation inhibition over a period of three months .An IUD utilizes a polyethylene, T-shaped frame and releases either copper or a synthetic progestin into the uterine cavity for contraceptive action. The first and most widespread hormonal IUD is the 52 mg LNG-bearing IUD (LNG IUD), commercially marketed as Mirena, Liletta or Levosert . The LNG2 to 380 mm2 of exposed copper wire to enhance spermicidal effect. Similar to the hormonal IUD, the copper IUD inhibits fertilization by impeding sperm transport and the capacity of sperm to fertilize an ovum. The inflammatory reaction of the foreign body reaction is enhanced by the continuous release of copper ions into the luminal fluids of the genital tract [Various inert and metal-coated IUDs have been historically available. The most extensively distributed non-hormonal IUD is the copper-bearing IUD (ParaGard) that contains 200 mmAlongside changes in the formulation and potency of oral contraception, use of LARC methods is increasing worldwide. In 2019, IUDs and oral contraceptive pills were among the most popular methods of reversible contraception globally, adopted by 17 and 16% of reproductive-aged contraceptive users, respectively . From 20BRCA-associated ovarian cancer. Available studies that have evaluated the relationships between LARCs and risk of ovarian cancer in the general population have generally suggested a mitigating effect for the use of injections and potentially contraceptive implants, while the role of IUDs is mixed [Given the growing uptake of LARC methods, it is of interest to understand whether LARCs confer a similar level of ovarian cancer risk reduction. To our knowledge, there are no studies that have reported on the relationship between use of IUDs, implants or injectables and is mixed –48.In a recent pooled analysis of seven case-control studies by the Ovarian Cancer Association Consortium, the authors concluded a reduced risk of ovarian cancer with use of depot-medroxyprogesterone acetate (DMPA) injections , which is in line with the majority of other retrospective data , 49, 50., conducted a systematic review and meta-analysis of IUD use and the development of ovarian cancer, including nine case-control studies and two cohort studies published through 2018 [BRCA mutation carriers.A greater number of studies have explored associations between IUD use and ovarian cancer risk in the average-risk population. Wheeler et al.ugh 2018  . Authorugh 2018  A total ugh 2018 . Populatugh 2018 , 54. Theugh 2018 . Conversugh 2018 . Interesugh 2018 . CurrentSeveral underlying mechanisms may mediate the protective role of these contraceptive methods on ovarian cancer, including inhibition of ovulation and high levels of exogenous progestogens , 56. OraIt has been hypothesized that the protective association between IUD use and ovarian cancer is related to two additional mechanisms: first, the inhibition of retrograde menstruation and second, the foreign body reaction. Hormonal IUDs are associated with decreased menstrual blood loss and amenorrhea in 20% of users . This isBRCA1 mutation carriers [BRCA1 mutation carriers [BRCA2 mutation carriers, a nonsignificant increased risk was reported for oral contraceptive ever users based on a meta-analysis of retrospective data  [BRCA1 mutation carriers , although a moderately increased risk was observed in the left-truncated retrospective analysis  [BRCA2 mutation carriers, oral contraceptives increased the risk of breast cancer in the prospective  and full-cohort retrospective models , but there was no association in the left-truncated retrospective analysis . The discrepancy between prospective and retrospective findings may indicate survival bias or a true association for younger women who were underrepresented in the prospective analysis.The growing uptake of LARC products has raised questions about progestin exposure and the possible increased risk of breast cancer. Evidence from epidemiologic and experimental studies indicate an emerging role of progestogen signalling in breast carcinogenesis. Progesterone upregulates the nuclear factor κB (RANK)/ RANK ligand (RANKL) signalling pathway, which has been shown to drive mammary epithelial cell proliferation, mammary stem cell expansion and carcinogenesis in mice –67 and mcarriers –70. In lcarriers . Specifi89–2.10) . In cont06–1.51) . For BRCBRCA-associated breast cancer cannot be excluded and represents an important avenue of investigation.Whether progestin-only contraceptives pose an increased breast cancer risk is less clearly defined. Limited data from the average-risk population is mixed regarding the association between injections and implants and the risk of breast cancer –75. AlthAlthough hormonal contraception is not a replacement for preventive surgery, established guidelines conflict regarding the prescription of oral contraceptives purely for reduction in ovarian cancer risk among women with a hereditary predisposition –81. The BRCA mutation carriers face a very high lifetime risk of developing ovarian cancer, and non-invasive preventive approaches have been limited to date. The epidemiologic evidence strongly supports a significant protective effect of oral contraceptive use on the risk of developing ovarian cancer among women with a BRCA1 or BRCA2 mutation [mutation , 16, 34.


Conventional transcranial electrical stimulation (tES) is a non-invasive method to modulate brain activity and has been extensively used in the treatment of Parkinson’s disease (PD). Despite promising prospects, the efficacy of conventional tES in PD treatment is highly variable across different studies. Therefore, many have tried to optimize tES for an improved therapeutic efficacy by developing novel tES intervention strategies. Until now, these novel clinical interventions have not been discussed or reviewed in the context of PD therapy. In this review, we focused on the efficacy of these novel strategies in PD mitigation, classified them into three categories based on their distinct technical approach to circumvent conventional tES problems. The first category has novel stimulation modes to target different modulating mechanisms, expanding the rang of stimulation choices hence enabling the ability to modulate complex brain circuit or functional networks. The second category applies tES as a supplementary intervention for PD hence amplifies neurological or behavioral improvements. Lastly, the closed loop tES stimulation can provide self-adaptive individualized stimulation, which enables a more specialized intervention. In summary, these novel tES have validated potential in both alleviating PD symptoms and improving understanding of the pathophysiological mechanisms of PD. However, to assure wide clinical used of tES therapy for PD patients, further large-scale trials are required. Parkinson’s disease (PD) is the second most common neurodegenerative disorder . The dimThe most recent decades were marked by extensive research efforts in developing novel pharmacological and physical therapies to ameliorate symptoms of PD. Levodopa has been widely used in PD treatment and proved to be extremely effective in alleviating motor symptoms during early disease stages. Nevertheless, levodopa has fell short treating non-motor impairments, which are especially common during the late stages of PD . FurtherOver the past decades various neuromodulation techniques have been trialed, including deep brain stimulation (DBS), transcranial magnetic stimulation (TMS), and transcranial electrical stimulation (tES). DBS has now been clinically tested in late-stage PD. However, DBS surgery involves implantation of electrodes into deep brain regions, with significant safety risk . Non-invAlthough conventional tDCS has shown some encouraging results in alleviating both motor and non-motor symptoms , in pracConventional tES might modulate the neuronal pathways that are not the main drivers of disease pathology or specific symptoms. Recently, the view that distinct pathologic pathways might be responsible for different PD symptoms has emerged. For example, PD symptoms can be recognized by impaired functional brain networks, which involve multiple brain regions . HoweverAdditionally, improvements in behavior solely resulting from tES are often too subtle for accurate recording , therefoBesides, tES efficacy highly depends on the subjects’ condition and considerable discrepancies have been observed following identical stimulation inter or intra- subject. Therefore, the individualization of tES  is also gaining increasing interests owing to its “specialized to neuron response” characteristic. While conventional tDCS cannot automatically respond to these changes, novel stimulation approaches might give real-time individualized responses.In this review, novel stimulation patterns are discussed and categorized into three groups: novel stimulation approaches, tES combination therapy with other interventions, and closed-loop stimulation. We will first discuss novel stimulation approaches with different modulation mechanisms toward PD. Then, the integrations of existing stimulation approaches with other types of PD intervention strategies will be introduced, and finally, we will analyze the closed-loop stimulation strategy that aims to achieve individualized self-adaptive parameters of stimulation. A detailed method and results of existing novel tES studies toward PD were summarized in Conventional tDCS usually target at one specific brain region, thereby excite or inhibit the activity within that region. The most frequently targeted regions for tES in PD studies are summarized in Multielectrode tES is an improved version of tES with shared mechanism but multielectrode montages. Currently, multielectrode tES consists of multitarget tES and high-definition tES (hd-tES). Multitarget can modulate multiple regions of interest , while hFreezing of gait (FOG) is a characteristic symptom in PD patients and is usually seen as a target disability in PD tES studies. Stemming from both cognitive (failed at decision making) and motor impairments (failed at action) , early FHowever, skepticism still exists in the assumption that multitarget tDCS would improve FOG performance, as a subsequent clinical trial with a subject population of 70 PD patients revealed the opposite results. After 2 weeks of intense treatment containing 10 stimulation sessions and 5 weeks of mild treatment with 5 stimulation sessions, despite some secondary performance improvements, no significant differences in FOG provoking test and FOG severity score were found .In addition, the abovementioned studies did not assess the changes in functional connectivity. It is now generally accepted that the brain consists of many functionally connected networks. The communications and interplays among brain regions are fundamental for complex behaviors . MultitaTranscranial alternating current stimulation provides a sinusoidal external current stimulation that could either synchronize or desynchronize with the internal cortical rhythm . DissimiParkinson’s disease patients suffer from pathological changes in internal brain oscillation frequency ranges. Higher theta (4–8 Hz), delta (less than 4 Hz) activities and lower alpha (8–12 Hz), beta (12–30 Hz) activities in the basal ganglia were detected in PD patients . AdditioOne of the earliest experiments applying tACS toward PD used 77.5 Hz 15 mA current, with the stimulation electrode placed over the forehead and references at mastoids. The total off-medication Unified Parkinson’s Disease motor rating scale (UPDRS) of this experiment exhibited no significant difference in scores between early PD patients and sham patients . NeverthAdditionally, tACS can be applied to probe and detect the causal relationship between behavior and neuron activity. In a randomized crossover tACS study, the associations between bradykinesia and abnormally altered beta/gamma oscillations in primary motor cortex (M1) were exposed when 1 mA tACS at 20 Hz or 7 Hz was delivered to patients. The stimulation electrode was centered over the first dorsal interosseous hotspot, while the return electrode was centered over the PZ according to the EEG 10–20 system. As a result, the increased beta power led to aggravated bradykinesia, while gamma synchronization entrained by tACS mitigated these symptoms .To clarify how this aberrantly increased beta power is linked with bradykinesia, Krause et al. hypothesized that an increase in beta power contributed to decreased cortico-muscular coupling (CMC); a critical linkage between neurological activity and motor performance that subsequently leads to bradykinesia and akinesia. Ten PD patients and 10 healthy control subjects were recruited for this study. Each participant received three sessions of 1 mA current stimulation targeted at M1, randomly applying 15 min of 10 Hz tACS, 20 Hz tACS, and sham. To determine the effects of each stimulus, the behavior performance of PD was assessed after each session. Only after 20 Hz stimulation did PD patients reveal a more rigid motor performance and a significant reduction in beta band CMC amplitude, while healthy controls experienced no significant difference in CMC and behavioral performance after either 10 or 20 Hz stimulation .Despite these positive results, tACS might induce phosphene, namely, the feeling of flickering lights. Phosphene could affect subjects’ performance during tasks and impair the reliability of double-blind studies. Even if the phosphene threshold could be increased to 80 Hz when targeting brain regions far from the retina, it was found that maximum phosphene levels could occur between 14 and 20 Hz under an occiput–vertex electrode montage . Thus, sDifferent from conventional tDCS, tPCS provides discontinuous direct current interrupted by either short or long periodical inter-pulse intervals , thus adIn a Parkinsonian study, a combined tPCS and treadmill strategy was applied for 10 PD freezing of gait(FOG) patients, with both pulse duration and inter-pulse interval of tPCS being 33.3 μs. The tPCS targeted M1 provided 20 min of stimulation with or without concurrent treadmill training. The gait speed and gait amplitude, however, were found to be improved after a single tPCS session but not in the combined group or treadmill alone group . HoweverThere was a study toward healthy population implicated that the duration of tPCS was not aligned with the lasting time of aftereffects . Thus, tTranscranial random noise stimulation delivers alternating currents of random frequencies and amplitudes within a specific range of the spectrum . tRNS haIn order to assess the potential of tRNS toward PD, a study has combined tRNS with intermittent theta burst stimulation (iTBS) to detect neuron activity alterations. In this study, PD patients who received a maximum 640 Hz 0.5 mA tRNS over M1 showed an adverse effect on the excitability of M1. In contrast, in healthy controls, M1 cortical excitability was enhanced after stimulation, while PD patients exhibited decreased cortical activity . This stIn a double-blind study specific to PD with major cognitive impairment (PD-MCI), Monastero et al. applied 1.5 mA tRNS oscillating randomly between 100 and 600 Hz on M1 to 10 PD-MCI subjects. In this study, 10 patients went through two randomized stimulation sessions, one of them being an active tRNS session and the other being sham. As a result, the total UPDRS score of subjects was significantly increased only after the active tRNS session . Again, Although promising results were shown by these novel approaches of tES, some studies revealed adverse results. For example, identical multitarget hd-tDCS stimuli resulted in controversial responses in two studies, possibly attributed to the different scales of subjects. In the future, numerous studies with larger sample sizes are needed to prove the prevalence of their efficacy toward PD. In addition, due to the substantial variabilities between populations, even if studies have revealed positive results toward healthy subjects or other homologous disorders, the stimulation parameters should be carefully reconsidered when applied to PD patients.The investigation of tES mechanisms can not only provide insight into finding optimized tES parameters but also help to explore the neurological process behind specific symptoms. Many studies have employed novel tES to investigate the causal relationship between specific oscillation patterns and behaviors. The understanding of behavior mechanisms can in turn help the design of effective interventions, forming a virtuous circle.Conventional tDCS separates the whole brain into individual functional regions and neglects the brain’s functional networks, while novel modes of tES provide the possibility to modulate the communications between regions. Future studies should focus on stimulating the functional connectivity within brain networks.Although the mechanisms behind tRNS and tPCS are yet uncertain, future exploration of their mechanisms might be extremely advantageous to optimize parameter settings, that will encourage more tRNS and tPCS studies. Therefore, the adjustment of stimulation would be quite challenging and might lead to contradictory results.In addition, tPCS and tACS both face phosphene problems. Although there are solutions such as masking flicker stimuli to offset the phosphene , new metRecently, the tolerability and feasibility of remotely supervised tDCS (rs-tDCS) has been validated in PD patients, and promising therapeutic improvements were shown by rs-tDCS targeted at the DLPFC paired with cognitive training . This reSingle session tES usually experienced shorter aftereffects, while repetitive sessions of stimulation would harvest longer aftereffects duration. A single session tDCS or tACS  usually In addition to the novel stimulation approaches discussed above, the combination of existing tES with another PD therapy can also be recognized as a novel stimulation method.Since one limitation of pharmacologic therapy is side effects, it is intriguing to discuss whether the combination of tES and drugs would optimize improvements and lessen side effects at the same time.In contrast to tDCS experiments where medication is controlled as baseline, in the study of Ferrucci et al., tDCS was provided as a supplementary intervention of levodopa to eliminate L-dopa-induced cognitive and motor impairments. M1 tDCS, cerebellar tDCS, and sham sessions are randomized for each subject, and each session was at least 1 month separated from another. Anodal tDCS (2 mA) was applied for 20 min in 5 consecutive days in each active stimulation session. Although no other cognitive or motor improvements were observed, both M1 and cerebellar tDCS led to a decrease in levodopa-induced dyskinesias in PD patients .Transcranial electrical stimulation can also be combine with TMS to boost the benefits of intervention. Recently, a dual mode tDCS scheme applied anodal tDCS together with repetitive transcranial magnetic stimulation (rTMS). The stimulation electrode of tDCS was placed over the lDLPFC, while TMS targeted M1. This stimulation scheme demonstrated a significant improvement in the executive functions of PD patients under dual-mode stimulation conditions .Similarly, tACS delivered at gamma frequency combined with intermittent theta burst stimulation (iTBS) can also repair the damaged brain activity of PD patients. iTBS is a novel rTMS that provides more tolerable and robust action than conventional rTMS . In PD pMotor and cognitive training can effectively ameliorate PD symptoms . Hence iIn PD-MCI patients, tDCS combined with physical training showed steady cognitive improvements, but no significant additional effects of tDCS was found . In lineIn contrast, in another sham-controlled, double-blind crossover study, Kaski et al. applied tDCS at M1 and the premotor cortex, and together with physical training, PD patients were found to have improved gait and balance performance . AnotherFor cognitive training, another study combined computer-based cognitive training (CT) with 2 mA tDCS targeted at the DLPFC. This combined intervention was administered 4 times a week for 4 weeks, and at the week 16 follow-up survey, the impairment in executive skill and attention in PD-MCI patients was ameliorated and the immediate memory skill ability increased . A laterSince different interventions act through distinct mechanisms to alleviate PD symptoms, combined interventions can modulate multiple pathways with higher efficiency. Future studies might be able to provide individualized combination schemes according to patients’ symptoms and pathogenic factors, leading to maximized improvements and minimized side-effects in individuals.Nevertheless, some limitations in combined interventions need to be considered.First, TMS itself has already faced the problems of tolerability and unblinding toward patients and adding on TMS might worsen the situation.In addition, although many have applied combination interventions for PD, few of them include control groups to assess the improvement of dual therapy interventions compared to single intervention. Therefore, in some studies, it is uncertain whether these combinations are better, more studies and a larger number of subjects are required for further validation of their effects.Moreover, determining the framework of combined intervention is also challenging, since several combined stimulation studies have focused on the yet elusive mechanisms. The combination of interventions might support or interact with each other, forming complex response networks. Therefore, it is difficult to decide the dose and timing of interventions. Should these interventions be given together, or which takes precedence? How can the dose be decided to optimize the efficacy while at the same time not resulting in unpleasant feelings or even damage? These questions need to be solved for a better understanding toward PD.It is generally accepted that discrepancies in effects can emerge between individuals when receiving identical stimulation. Similarly, several studies have witnessed deviations in neuronal feedback between different circumstances undergone by the same subject. To date, most tES research on PD has focused on open-loop schemes, providing constant predefined stimulation during the whole experimental process. However, due to these irremovable inter- and intra-subject variabilities, side effects, and low effect sizes may occur during clinical applications . TherefoClosed loop tES can provide self-adaptive stimulation according to the feedback of brain activity, forming a feedback-control close loop between input and output signals. To be more specific, when a predefined signal is detected(could be both behavior or brain activity) by the sensor, closed loop system should immediately receive the feedback from the sensor and select the corresponding stimulation parameters, then pass to the stimulator to provide real-time control.Brittain et al. explored a closed loop tACS strategy toward rest tremor, a dominant motor symptom of PD unresolved by dopaminergic therapy. First, the patient-specific tremor frequencies were recorded, then tACS at tremor frequency was applied to M1 at original or double tremor frequencies. The amplitude of tremor was found to be minimized when the tremor signal and tACS were in phase and when stimulation was set at tremor frequency. Then, subjects were stimulated for 30 s at individual optimal tACS phases with arbitrary input. By alignment of internal and external oscillations, the phase of this pathogenic cortical oscillation would be canceled out, hence inhibiting an average of 42% of resting tremors . This clIdeally, optimized closed-loop tES should be able to recognize diverse circumstances and select symptom-specific tES parameters, in which case the specificity of stimulation would be improved, like methodology discussed above against rest tremor.Additionally, an ideal closed loop tES should also automatically switch on when symptoms evoked and switch off when symptoms disappear, reducing the effect of overtreatment, and the financial cost of stimulation. For instance, A research group have designed a closed-loop EEG-tDCS system. They predefined an EEG threshold for automatic stimulation initiation, which in this study was when subjects were performing Stroop test. After the stimulation session, the sensor would again search for any above-threshold event and prepared to initiate another tDCS session. This closed loop EEG-tDCS system had achieved this system achieved 100% correct activation of tDCS in healthy population .A recent DBS study on primates verified improved efficiency of closed-loop methodology. By using an adaptive GPi-DBS scheme that responds to signal changes in M1, the improvements in parkinsonian symptoms were greater than normalized DBS at a lower firing rate of GPi . There aCurrent studies applying closed-loop schemes toward PD are mostly focused on DBS, given the preliminary encouraging results, however, conducting a closed-loop tES scheme seems a very promising field in neuronal modulation of PD. Although few closed-loop tES studies focused on PD treatment, the applicability and efficacy of closed- loop tES has been validated in epilepsy  and sleeThere are two possible strategies in conducting closed loop tES studies. First, like DBS, tES might be able to track the internal oscillation of the brain, and if any abnormal oscillations were detected, tES would be activated and initiated the stimulation. On the other hand, closed loop tES can monitor the behavior of subjects and apply stimulation corresponding to subjects’ performance. For example, in the above study of resting tremors, the amplitude and frequency of tremors were recorded to deliver specific stimulation. These external behavior data would serve as an indicator for stimulation settings. Recently, a study assessed the capability of a smartwatch to track the time when PD patients suffer severe resting tremor outbreaks. In the future, this kind of device might be adopted in a closed-loop PD intervention study, providing precise behavioral data .Although no other tES closed-loop study has focused on PD, researchers are trying to investigate novel tES equipment that can satisfy the demands of closed-loop stimulation. For example, a brain-machine interface system that integrate frequency-domain near infrared spectroscopy (fdNIRS) input and tDCS output was designed to enable the application of closed loop tDCS . In addiAlthough closed-loop tES studies toward PD are few, adaptive stimulation schemes have gained vast attention since they can deliver individual- or circumstance-specific modulation. Self-adaptive individualized closed-loop scheme can achieve higher efficacy; and closed-loop tES schemes in the future might also be able to automatically switch on when symptoms occur, like closed-loop DBS.Another serious technical problem for closed loop tES is the time delay between detection of changes in brain conditions and the response to stimulus. For symptoms with a short provoking duration, the time delay in response might just miss the period of symptoms and become ineffective. Future studies might employ machine learning to predict the occurrence of symptoms so that more precise stimulation could be provided. In addition, using a brain machine interface (BMI) can provide a quicker stimulation response. For example, in a chronic pain study that used BMI in mice to monitor and stimulate the brain, the time delay between characteristics detected and stimulation response was minimized; thus, the pain could be released even when recognizing acute pain signals .Many studies have proposed numerous novel adaptive tACS and tDCS systems that proved to be safe and tolerable in healthy people . BuildinNovel tES has proven their potential in preventing both motor and cognitive symptoms in PD and has been clinically translated as a supplementary intervention.Overall, these novel patterns seek to achieve better performance and safety based on achievements made by conventional tES. These three novel tES methods is complementary with each other in a progressive manner. Novel tES approaches provide the possibility to stimulate the brain as functional networks instead of individual regions and have been proved to be effective in most of the PD studies, enhancing current understanding of PD pathology. The development of novel tES modes expanded the choice for combining tES with other intervention strategies and promote the possibility in obtaining the ideal multi-pathway-targeted combination, achieving a “1 + 1 > 2” improvement in efficacy as well as a reduced side-effect. Furthermore, considered as the most promising tES strategy, closed loop tES could take individual differences into consideration and adapt to the patient’s response, further optimizing therapeutic specificity. Nevertheless, closed-loop tES requires knowledge of pathological mechanisms and optimized stimulation pattern for each symptom, thus help the recognition of symptom-related activity and matching corresponding stimulation for recognized symptom.Nevertheless, the results between some of the novel tES studies remain inconsistent, which might be resulted from the small sample size in most of the studies. To put novel tES into clinical use, more clinical trials with larger participant numbers are required. In addition, future studies should recognize the brain as a cohort of many functional networks and utilize tES to modulate functional connectivity between functional regions during PD symptoms. Apart from the study design, there should be more studies that investigate closed loop tES, providing higher specificity of stimulation with the lower consumption of energy. Moreover, efforts should be devoted to the invention of novel tES devices with higher operability that can provide in-home stimulation, making this therapy more convenient and available for patients, for example, rs-tES.Currently, tES strategies lead to undesirable sensations of stimulation that hinder wider applications. Many tES studies are now focusing on temporal interference stimulation, which seems to be almost imperceptible to healthy subjects . Future In conclusion, novel tES patterns have harvested encouraging improvements in both motor and cognitive symptoms of Parkinson’s disease despite flaws.JB, RN, LY, YZu, YY, and QM designed the study. RN compiled and analyzed the data and wrote the manuscript. JB and RN were closely involved in the definition of the manuscript structure. JB, ZC, and YZo provided critical feedback on all the tables and text. JB, WY, and RN provided support for the methodical work and supervision. All authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Anxiety disorders are the most common mental diseases. Anxiety and the associated physical symptoms may disturb social and occupational life and increase the risk of somatic diseases. The pathophysiology of anxiety development is complex and involves alterations in stress hormone production, neurosignaling pathways or free radical production. The various manifestations of anxiety, its complex pathophysiological background and the side effects of available treatments underlie the quest for constantly seeking therapies for these conditions. Melatonin, an indolamine produced in the pineal gland and released into the blood on a nightly basis, has been demonstrated to exert anxiolytic action in animal experiments and different clinical conditions. This hormone influences a number of physiological actions either via specific melatonin receptors or by receptor-independent pleiotropic effects. The underlying pathomechanism of melatonin’s benefit in anxiety may reside in its sympatholytic action, interaction with the renin–angiotensin and glucocorticoid systems, modulation of interneuronal signaling and its extraordinary antioxidant and radical scavenging nature. Of importance, the concentration of this indolamine is significantly higher in cerebrospinal fluid than in the blood. Thus, ensuring sufficient melatonin production by reducing light pollution, which suppresses melatonin levels, may represent an endogenous neuroprotective and anxiolytic treatment. Since melatonin is freely available, economically undemanding and has limited side effects, it may be considered an additional or alternative treatment for various conditions associated with anxiety. Anxiety disorders are the most common mental diseases. The prevalence of anxiety varies from 2.5–7%, while around 63% of patients are females . ConditiThe treatment of anxiety disorders includes various approaches ranging from psychotherapies, such as cognitive behavioral therapy or exposure therapy, neurostimulation strategies, such as transcranial magnetic stimulation, to pharmacotherapies. Examples of approved drugs used in anxiety disorders include selective serotonin reuptake inhibitors (SSRIs), serotonin–norepinephrine reuptake inhibitors (SNRIs) and benzodiazepines. SSRIs and SNRIs are the first-line treatments for PD, GAD and SAD. Some of the adverse effects include jitteriness or agitation, especially at the beginning of the treatment, nausea, restlessness, headache, fatigue, changed appetite or weight, tremor or sweating . BenzodiSince pathologic anxiety negatively influences a broad spectrum of common daily activities, is manifested in various clinical forms and the current therapy is of limited effectiveness and exerts significant side effects, there is a constant, ongoing search for novel approaches for treating anxiety. Although there are some clinical trials testing novel anxiolytics, the results are not convincing . This reThe stress response is a reaction to physical or psychological stressors that disrupt the homeostasis mediated by an interplay of the sympathetic nervous system (SNS), the hypothalamus–pituitary–adrenal (HPA) axis and the immune system . The SNSThe activated SNS seems to participate significantly in anxiety. The secretion of salivary alpha-amylase (sAA), a digestive enzyme produced by the salivary glands, increases after SNS stimulation . Thus, sAccordingly, the blockade of SNS reduces anxiety levels. After a social defeat in Sprague Dawley rats, pretreatment with propranolol and nadolol increased the time spent in the lit area of a light/dark box (LDB) and in the open arms of an elevated plus maze (EPM)  that is When a stressor is recognized, the PVN of the hypothalamus activates the HPA axis response. First, CRF is released from the PVN, subsequently stimulating the synthesis and release of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH acts on the cortex of the adrenal glands, resulting in glucocorticoid synthesis and secretion . GlucocoIn PD patients, the plasma and salivary cortisol  and ACTHThe blockade of the glucocorticoid effect by mifepristone, a non-selective antagonist to the glucocorticoid receptor, exerts various effects on anxiety . For exaStress, via increased SNS activity, enhances renin activity, initiating the cascade of the renin–angiotensin–aldosterone system (RAAS). In turn, angiotensin II (Ang II) stimulates catecholamine release from the central locus coeruleus and peripheral adrenal medulla . During The RAAS plays a role not only in stress response but also in subsequent anxiety development. The I/D polymorphism of the angiotensin I-converting enzyme (ACE) gene is more common in male patients with panic disorder , and priThe role of the RAAS is supported by findings that the blockade of the RAAS mediates the anxiolytic effect in humans and animals ,52. PatiHigh oxygen consumption coupled with modest antioxidant defense predisposes the brain to generate reactive oxygen species (ROS), while brain overexpression of neuronal and inducible nitric oxide synthase (nNOS and iNOS) contributes to reactive nitrogen species (RNS) production. ROS/RNS may damage nucleic acids, proteins and neuronal lipid membranes and thus underlie the altered neuronal function considered in the pathogenesis of various neurodegenerative or neuropsychiatric diseases ,67.Several data also indicate a role of oxidative and nitrosative stress in the pathophysiology of anxiety. Hovatta et al. classified six mouse strains by anxiety and found that the brain expression of glutathione reductase 1 and glyoxalase 1—enzymes involved in antioxidant defense mechanisms—was higher in more anxious strains . The oveL-ascorbic acid (vitamin C) is a water-soluble antioxidant that is essential to several mammals, including humans. The high intracellular concentration of vitamin C in neurons suggests its essential role in neuroprotection via its potent antioxidant and free radical scavenging properties . As reviFurthermore, oxidative/nitrosative stress induced by buthionine-S,R-sulfoximine (BSO) treatment was associated with increased anxiety-like behavior in both rats and mice ,80. In c2C receptors within the amygdala was found to enhance fear and anxiety [1A receptor stimulation was associated with anxiolysis [Serotonin  is a significant neurotransmitter modulating various physiological functions  . Seroton anxiety . On the xiolysis . Most anxiolysis   is the main inhibitory neurotransmitter in the CNS of humans and rodents. The GABAergic system is a complex network encompassing several CNS areas, while having multiple reciprocal connections with other neurotransmitter systems . GABAergDysfunctional neurotransmitters and receptors in the dopaminergic system in the mesolimbic, mesocortical and nigrostriatal areas interfering with the glutamatergic system in the medial prefrontal cortex are involved in anxiety . DopaminN-acetyl-5-methoxytryptamine) is the principal secretory product of the pineal gland which is a major source of this indolamine [Melatonin  to the medullar intermediolateral cell column, which innervates sympathetic ganglia generating a sympathetic tone enhancing the peripheral vascular tone and cardiac contractility with a blood pressure increase . SimultaThe constant excitatory output of the PVN is intermittently inhibited by GABAergic innervation from the SCN . MelatonThe melatoninergic sympatholytic effects have been confirmed in a number of experiments. In spontaneously hypertensive rats (SHRs), acute melatonin administration reduced BP and norepinephrine serum levels . The antThe available data indicate that the melatoninergic system may interact with the RAAS:(1) Angiotensin II and melatonin seem to have opposite roles in cardiovascular pathophysiology. While Ang II increases BP and pathologic remodeling of a hypertensive and failing heart , melaton(2) In patients with non-dipping BP, the reduced excretion of 6-sulfatoxymelatonin in the urine was observed . The chr(3) In 53 patients with chronic kidney disease (CKD), impaired night-time excretion of melatonin metabolite urinary 6-sulfatoxymelatonin tightly correlated with altered urinary excretion of angiotensinogen , previouThese prevailing protective effects of melatonin in relation to the RAAS may supposedly participate in the anxiolytic impacts of melatonin.Melatonin’s blunting effect on glucocorticoid actions was suggested to be associated with its putative anxiolytic properties. In fact, melatonin was shown to reduce density, affinity or nuclear translocation of glucocorticoid receptors in different tissues, including the brain ,211. FurMelatonin and its derivates are considered to be potent free radical scavengers and broad-spectrum antioxidants ,217. MorSeveral studies showed that melatonin supplementation reduces oxidative/nitrosative stress, improves antioxidant defense and reduces lipid peroxidation markers in health and disease . Indeed,−/− [−/− [DRN serotonergic neuronal activity shows variations during light–dark periods. Since MT1 receptors are present on DRN serotonergic neurons and MT2 receptors in other neuronal populations projecting to serotonergic neurons , melaton−/−  as well −/− [−/− ,171 knoc−/− [−/− . The syn−/− [−/− .Effects of melatonin involve GABAergic signaling facilitation via GABA receptor stimulation ,227. TheDopamine release appears predominantly during the day and seems to be a counterpart to melatonin released during the night . ThroughAnxiety disorders are the most common mental diseases. They afflict a large proportion of the population and may disturb social and occupational life and various areas of functioning. Moreover, it is generally accepted that anxiety and cardiovascular diseases  or other


To explore the effects of training with and without vibrotactile SA, we compared the changes in performance achieved after participants completed each six-week block of training. Among the seven participants who completed both blocks of training, the change in the SARA scores and SARAposture&gait sub-scores following training with vibrotactile SA was not significantly different from the change achieved following training without SA  with inherited forms of cerebellar ataxia were recruited to participate in a 12-week crossover study during which they completed two six-week blocks of balance and coordination training with and without vibrotactile SA. Participants were instructed to perform balance and coordination exercises five times per week using smartphone balance trainers that provided written, graphic, and video guidance and measured trunk sway. The pre-, per-, and post-training performance were assessed using the Scale for the Assessment and Rating of Ataxia (SARA), SARA Hereditary cerebellar ataxia are a group of neurological disorders characterized by the degeneration of the cerebellum and its associated pathways. The cerebellum is primarily responsible for adaptation and motor learning. Individuals with degenerative cerebellar ataxia have progressive impairments in motor coordination ,2 and sePhysical therapy with balance and coordination training is currently the mainstay of treatment for impaired balance and mobility in individuals with hereditary cerebellar ataxia ,14. BalaSmall, preliminary studies suggest that balance and coordination rehabilitation programs lead to improvements in measures of motor performance in participants with hereditary cerebellar ataxia ,25,26,27A study by Ilg et al.  examinedChallenges associated with home-based balance and coordination training include the lack of supervision and feedback. Prior studies have found that supervised training led to improved outcomes compared to home-based training in participants with vestibular disorders  and oldeSA devices for balance and coordination training applications typically include sensors and a feedback display to provide body-motion cues . WearablTo date, a limited number of studies have investigated the effects of balance and coordination training with SA among individuals with hereditary cerebellar ataxia. In a preliminary study by Čakrt et al. , seven pThe goal of this preliminary study was to examine the effects of home-based balance and coordination training with and without vibrotactile SA on postural stability, gait, and coordination in individuals with hereditary cerebellar ataxia.Ten individuals diagnosed with hereditary cerebellar ataxia  were recIn this study, we used a 2 × 2 crossover experimental design such that each participant served as their own control to maximize statistical power given the limited sample size. We did not include a washout period because an appropriate length for a washout period for this population and intervention had not been established; prior work has shown evidence of sustained training effects for up to a year with continued home-based training following four weeks of intensive balance and coordination training . ParticiAll participants wore a smartphone balance trainer during home-based balance and coordination training sessions regardless of whether they received vibrotactile SA. The balance trainer, described in detail in Bao et al. , comprisThe sensing unit measured trunk angular velocities via tri-axial gyroscopes embedded in the waist-mounted Apple iPod (50 Hz sampling frequency). Tilt angles (angular displacements) were estimated based on gravitational outputs  following methods described by Lee et al.  in four Participants were instructed to perform the prescribed balance and coordination exercises five times per week for 12 weeks . Each session lasted approximately 30 min and included exercises from five different categories .Vibrotactile SA was only provided for static standing, standing on a compliant surface, arm-raises, and weight-shifting exercises. Vibrotactile SA was not provided during gait exercises since pre-defined thresholds did not exist for individuals with hereditary cerebellar ataxia and non-intended, less natural gait patterns were observed when SA was used with gait exercise in prior studies .Participants performed six repetitions of six unique exercises per session: one from each of the first four categories and two from the fifth (gait) category. Each exercise was performed for 30 s . For sessions involving vibrotactile SA, vibrotactile cues were provided during four (randomly selected) out of the six repetitions per exercise, as prior research reported that a reduced frequency of feedback enhanced motor learning ,59. UponInitial (A1), intermediate (A2), and final (A3) balance and coordination assessments were performed within a laboratory setting to assess performance prior to starting the home-based training protocol and following each six-week block of training .posture&gait sub-score, a sum of the gait, stance, and sitting components of the SARA [The primary clinical outcome measure was the Scale for the Assessment and Rating of Ataxia (SARA) score. The SARA is a clinically validated 0–40 rating scale specifically designed to capture disability that results from cerebellar dysfunction . The SARthe SARA ,63, was Additional clinical outcome measures included: modified Clinical Test of Sensory Interaction in Balance (mCTSIB) , measuriIn addition to laboratory-based clinical outcome measures, a single wearable inertial measurement unit (IMU)  was placed on participants’ lower backs, approximately at the level corresponding to the L4/L5 spinal segment, a commonly used IMU placement to assess postural stability during standing , to measMultiple kinematic features were calculated from the IMU data, as outlined in All statistical analyses were performed using R-studio  and sigTo assess the effect of each block of training, we computed a two-way analysis of variance (ANOVA) for each of the clinical outcome measures and the kinematic data collected during the laboratory-based assessments . In addition, a two-way ANOVA was used to assess the changes in outcome measures at the start of each six-week block of intervention.posture&gait, TUG, TUG-m, 5xSST, mCTSIB, and DGI), as well as the kinematic features extracted for each of the four exercises performed in the mCTSIB outcIn addition, we assessed whether training with vibrotactile SA had an effect on the outcomes of training. We computed a two-way ANOVA to examine the effects of the type of intervention received  and group assignment (two levels: Group 1 and Group 2) on the change in outcome measures achieved after each block of training (Equation (3)).The participants’ initial, intermediate, and final assessment scores for the clinical outcome measures are shown in posture&gait, SARA, TUG, TUG-m, 5xSST, mCTSIB, and DGI). The results of this analysis indicated no statistically significant main effect of training. No statistically significant differences (p ≥ 0.05) were found when comparing the pre- and post-training scores for any of the clinical outcome measures  The results of this analysis indicated that there was a statistically significant increase (p ≥ 0.05) were found when comparing the pre- and post-training scores for the other outcome measures  , inset, measures . No signposture&gait score changes following six weeks of training without vibrotactile SA for both groups; while some participants  improved (by decreasing their SARAposture&gait scores after six weeks of training without vibrotactile SA), others  showed an increase in scores, and some  maintained the same scores.posture&gait, SARA, TUG, TUG-m, 5xSST, mCTSIB, and DGI). The results of this analysis indicated that there was a statistically significant decrease in SARA scores (posture&gait scores (p ≥ 0.05) were found when comparing the pre-  on the change in clinical outcome measures achieved after each six-week block of training. The results from this ANOVA indicated no significant effect of intervention type on the change in outcome measures observed. We saw an estimated improvement in the SARA scores when participants trained with vibrotactile SA compared to when they trained without vibrotactile SA (p ≥ 0.05) were found  for there found  for any re found .Balance and coordination training is currently a standard of care when treating individuals with hereditary cerebellar ataxia . The goaposture&gait, TUG, TUG-m) over the 12 weeks of training, supporting the recommendation that intensive balance and coordination training should be part of a rehabilitation program for individuals with hereditary cerebellar ataxia [Our results showed some evidence of the effectiveness of balance and coordination training in general. Although no statistically significant improvements were detected, the participants maintained (and showed trends of improvement in) balance and coordination outcome measures  was not statistically significant. A decreasing trend in the SARA and SARAposture&gait scores was still observed in this analysis, possibly indicating that training with vibrotactile SA may provide additional benefit compared to training without vibrotactile SA, but this difference did not reach the threshold for statistical significance due to the limited statistical power of this experimental study. This finding was in agreement with a previous study by Bunn et al. [posture&gait scores showed similar trends of improvement in participants with hereditary cerebellar ataxia after eight weeks of training compared to a control group that did not train, statistical significance was not achieved for a minimal detectable difference in scores of 0.8 with a similarly small sample size. Bunn et al. estimated that a sample size of 64 participants or more would be needed to achieve statistical significance with a parallel study design [posture&gait with our study’s 2 × 2 crossover design, we estimated that a sample size of 15 participants in total would be needed .We examined the effect of the type of intervention (training with versus without vibrotactile SA) on the changes in the outcome measures achieved in each six-week block. When we compared the improvements achieved when the participants trained with vibrotactile SA to the changes achieved when the participants trained without SA, we observed a mean decrease (−1.21 points (SD = 1.60)) in the SARAn et al. , which ry design . To achiposture&gait scores significantly decreased following training with vibrotactile SA . By contrast, the participants’ SARA and SARAposture&gait scores did not change significantly after training without vibrotactile SA (compared to their assessment scores immediately preceding the six weeks of training without vibrotactile SA). Therefore, only training with vibrotactile SA showed statistically significant improvements in participants’ performance on the SARA and SARAposture&gait compared to their assessment scores immediately preceding that particular training block. These findings provide preliminary evidence of the potential benefits of enhancing home-based balance and coordination training with vibrotactile SA. This improvement in performance was only statistically significant for the SARA, an instrument developed specifically to capture cerebellar dysfunction, and not for the other, more nonspecific, clinical outcome measures of posture and gait performance. These findings were in alignment with previous studies investigating the effects of balance training with vibrotactile SA compared to training alone in community-dwelling healthy older adults [Participants’ SARA and SARAr adults ,76 and ir adults ; signifiThe results from this study also showed a statistically significant increase in DGI scores after six weeks of training without vibrotactile SA compared to pre-training scores , indicating an improvement in performance on gait tasks. Notably, participants did not receive vibrotactile SA during any of the gait tasks throughout either six-week training block. Therefore, it is unclear why participants did not show similar improvements in their DGI scores after completing the other six-week training block . Consistent with a subset of these findings, Keller et al.  found thposture&gait scores, indicating that untapped or latent cerebellar reserves could still be present in individuals with hereditary cerebellar ataxia and that cerebellar motor learning remains intact.The mechanism(s) underlying improved balance and coordination performance as a result of intensive balance and coordination training in individuals with hereditary cerebellar ataxia is/are not fully understood. One possibility is that it involves better utilization of the functionally intact cerebellum; another is that other unaffected portions of the brain are recruited to improve stability . The curThe analysis of the IMU-based kinematic data suggested no significant changes in any of the metrics computed, indicating that the participants’ postural sway was, on average, maintained throughout the study. A previous study from Čakrt et al.  reportedThe limitations of this study included the small sample size (seven study participants completed the 12-week protocol), which limited our ability to draw generalizable conclusions and obtain statistically significant results due to the limited statistical power. Larger sample sizes were challenging to obtain due to the low incidence rate of hereditary cerebellar ataxia and challenges with compliance due to the multi-week intensive study protocol. Future studies should aim to include larger numbers of participants to further assess the effects of vibrotactile SA during balance and coordination training. In addition, our study only included participants with minimal-to-moderate dependence or deficit (SARA score ≤ 14.25) . Future posture&gait scores, indicating an improvement in performance. While the findings from this study indicate some motor learning and postural stability improvements among participants with hereditary cerebellar ataxia following training with vibrotactile SA, further research with larger sample sizes is needed to assess the significance and generalizability of these findings.This study provided preliminary evidence of the effectiveness of vibrotactile SA during home-based balance and coordination training for individuals with hereditary cerebellar ataxia. Home-based balance and coordination training with vibrotactile SA for six weeks resulted in decreased SARA and SARA