The frequency and intensity of physical activity, the absence of digital games, and attending sports clubs seem to have the most beneficial effects in terms of academic competence in school children, among other relevant confounders mediating in this complex relationship.Physical activity has beneficial effects on overall academic performance in children. However, there is a lack of evidence regarding how the individual characteristics of physical activity interact with other confounding variables of academic competence. Leisure-time physical activity with potential confounders—such as developmental, behavioral, family, and school factors, predicting overall, mathematical, and reading academic competence—was studied in a random sample of 1520 Slovenian primary school students in grades 4–6 . A structured self-reported questionnaire was used to gather data on the children’s leisure-time physical activity and social-demographic variables, while academic competence was measured by teachers using the SSRS Academic Competence Evaluation Scale. The findings showed that children engage in physical activity most days a week, with moderate-intensity and unorganized activities. It was predicted that engaging in physical activity would lead to an increase in academic performance by 4.2% in males ( Physical activity (PA) is a crucial factor in children’s development and health. Performing 60 min of regular moderate-to-vigorous PA ever day throughout the week, including vigorous aerobic activity and strength exercises for muscles and bones at least 3 days per week, improves physical fitness, cardiometabolic health, bone health, and mental health in children ,2. In adOver the past 20 years, many researchers have attempted to identify the mechanisms that explain the impact of PA on academic performance. PA is a potent stimulator of molecular and cellular components that underlie brain structure and function and, in particular, are responsible for complex cognitive processes ,18. A syHowever, not all studies have reported positive associations between PA and academic performance in primary school children. For example, in a systematic review by Singh et al. , 40% of Current evidence on the relationship between PA and academic performance appears inconclusive and limited. Instead of a growing number of systematic reviews, findings are rarely based on high-quality studies with representative samples, using standardized assessment tools of a valid and reliable measure of PA and academic performance. Moreover, they often do not take into account confounding factors or relevant moderators for academic performance. As a result, many aspects of this relationship remain unclear, including the characteristics of PA  that most favorably affect academic achievement ,18,19,25Using a cross-sectional survey on a representative sample of Slovenian primary school children in grades 4–6 with standardized measured academic competencies and multiple regression analysis, we identified the characteristics of leisure-time PA that may predict academic outcomes in primary school children.This is a non-experimental study with a cross-sectional design.n = 454) were included. We used multistage sampling, i.e., a three-stage random sampling procedure. First, primary schools from all 12 statistical regions of Slovenia were randomly selected according to the size of the region: 3 primary schools from the Central Slovenia region; 2 schools each from the Drava and Savinja regions; and 1 school each from the Mura region, the Carinthia region, the Middle Sava region, the Lower Sava region, the Southeast Slovenia region, the Upper Carniola region, the Inner Carniola-Karst region, the Coastal Karst region, and the Gorizia region. In the second phase, we selected 4th- to 6th-grade classes from the randomly selected schools. These were primary schools where permission to interview the children was obtained from the principal and class teachers of the respective classes. The third stage of sampling included all the children from the selected classes whose parents had signed a written consent to participate in the study and who were present in the school on the day the study was conducted. In total, 2192 Slovenian primary school students in grades 4–6 were invited to participate in the study. Among these, 1782 children participated in the study, but 262 participants were excluded from the analysis due to incomplete responses or other missing data in the assessment. Thus, the data of 1520 children and their class teachers were used in the final analysis.A total of 16 primary schools from the population of all primary schools in Slovenia  when they could do so without interruptions. The time for completing the questionnaires was not limited but varied according to the number of participating children in each class. All teachers voluntarily participated in this study, receiving no funding or other compensation for their participation.The first author, who has expertise in survey methodology and primary education (grades 1–6), conducted all the measurements. She was present during the completion of the questionnaire to help both children and teachers with possible questions.Based on previous studies ,32,33,34The validity of the leisure-time PA questionnaire was tested in a previous study . PrincipThe children’s academic competence was assessed using Gresham and Elliott’s Social Skills Rating System (SSRS) . The SSRThis standardized test consists of three assessment forms—for the student, parent, and teacher—covering three different scales: the Social Skills Scale , the Problem Behavior Scale (parent form and teacher form), and the Academic Competence Scale (teacher form). Only the SSRS teacher form was used to assess the academic competence of school children in this study. The scale included nine dependent variables that reflected each student’s academic functioning from the teacher’s perspective: overall academic performance, reading performance, mathematical performance, reading skills, mathematical skills, child’s motivational level, parental support, overall cognitive functioning, and overall classroom behavior.All variables were scored on a 5-point scale to rank the child’s academic performance compared to the other students in the class. The number 1 indicates the lowest 10% of students in the class, the number 2 the next-lowest 20%, the number 3 the middle 40%, the number 4 the next-highest 20%, and the number 5 the highest 10%. The highest possible score was 45 points, and the lowest possible score was 9 points.Based on the SSRS test, children were placed into one of three academic achievement groups corresponding to developmental norms: below average (9–15 points), average (26–44 points), and above average (45 points). Gresham and Elliott  developeThe reliability of the SSRS was estimated using internal consistency and test–retest . First, not important, important, and critical in terms of behavior for a child’s school success); and (3) revising and reconstructing stage . This rigorous assessment process helped evaluate the selected items and their rating based on the degree to which they are relevant and representative for the target construct of academic competence assessment [academic competence. The items on the scale had high factor loadings, ranging from 0.62 to 0.93, with the highest loadings found for overall academic performance (0.93), intellectual functioning (0.91), reading competence and skills (0.90), and mathematical competence and skills (0.90). Although each of these items was highly correlated with the others, the authors decided to keep all items on the scale because each item seemed to have social validity [Several validation strategies were used to develop the SSRS . First, sessment ,37. Secosessment ,39,40. Cvalidity . Relatedvalidity ,42,43 haControlling for potential confounding variables related to developmental, family, and school characteristics of participants included gathering data reported by children , their teachers , and their parents . In addition, parental encouragement and students’ motivation to succeed academically as confounding variables were extracted from the academic competence assessment tool, evaluated by the teachers.A pilot study tested the PA questionnaire and the SSRS test for validity, reliability, objectivity, and sensitivity. Both measurement instruments were improved and standardized based on the pilot study results for Slovenian primary school children in grades 4–6. In the pilot study, 151 students from one of the selected schools in the Upper Carniola region participated. A high level of internal consistency was calculated for both assessment systems: Cronbach’s α values for children’s academic competence and leisure-time PA were 0.965 and 0.841, respectively.In the pilot study, the SSRS was translated into Slovenian. The first draft was prepared by the first author of this article. Participants in the pilot study were explicitly asked to evaluate the items of the SSRS in terms of clarity, comprehensibility, and cultural sensitivity. Based on their feedback, some linguistic revisions were made to the Academic Competence Scale to improve the transparency of the Slovenian version.The pilot study showed a selection of relevant items in both measurement instruments to determine the dimensions of children’s PA behavior and academic competence.This study is based on the ethical principles for research involving human subjects, as set out in the Declaration of Helsinki. Personal data were collected and protected under the provisions of the Personal Data Protection Act . The ethp ≤ 0.05.Data on children’s leisure-time PA and academic competence were analyzed using IBM SPSS version 28.0 , including descriptive statistics , bivariate statistics using the t-test for independent samples, Pearson’s chi-square test and one-way analysis of variance, and multiple regression analysis. The level of statistical significance was set at t-test for independent samples and Pearson’s chi-square test were performed to detect possible differences in the levels of PA and academic competence between the sexes. Since our bivariate analysis showed that girls and boys differ in terms of leisure-time PA and academic competence, a multiple regression analysis was conducted for girls and boys separately. One-way ANOVA was used to first compare the three groups of students with different levels of academic competence . The three levels were calculated based on the total score of the Academic Competence Scale of the SSRS test (teacher form) according to Gresham and Elliott [The  Elliott . Based oMultiple regression analysis aimed to find a model of the characteristics of leisure-time PA and the potential confounding variables that best predict the academic competence of primary school children in grades 4–6. Five models were applied using Enter multiple regression analysis that included leisure-time PA and the potential confounding variables to predict academic competence . All serThe survey results of Slovenian primary school children in grades 4–6 are presented in three sections: (1) characteristics of the study participants, (2) academic competence of the participants, and (3) associations between PA and academic competence in the studied group.n = 1520, 51.9% female) provided complete data for the analyses. The academic competence of eligible participants was assessed by their class teachers . Of the 2192 Slovenian primary school students in grades 4–6 who were invited to participate in the survey, 69.3% (The results of the participants’ leisure-time PA are presented in p < 0.001)  .Students’ academic competence was measured by their teachers using nine items on a scale of 1 to 5 . On avern = 1065, 68.8%). A chi-square test confirmed a statistically significant higher level of academic competence in girls compared to boys (p < 0.001)  .The gender differences in leisure-time PA  and acadThe results of one-way ANOVA were used as a criterion for selecting leisure-time PA variables for multiple regression analysis. Only variables that showed statistically significant associations with academic competence were selected for modeling using multiple regression analysis .Three criterion variables, defining overall academic competence, mathematical competence, and reading competence, were used in five different multiple regression models for girls and boys. The models first included the variables for leisure-time PA and then gradually added potential confounding variables as predictor variables for academic competence, as shown in R2 showed the strongest prediction for overall academic competence for girls (3.2–81.1%) and boys (4.2–84.1%). The highest explanatory prediction for overall academic competence was found in model 5 (81.1% for girls and 84.1% for boys), which included the variables for leisure-time PA and all confounding variables. In contrast, model 1, which included only leisure-time PA variables, explained ~3% of the variance in overall academic competence for girls and ~4% for boys. The incremental addition of confounding variables to the models increased their prediction and explanation of factors of academic competence. The lowest prediction was found for mathematical competence. Model 3 explained 43.9% of the mathematical competence, which was the highest prediction for this competence in girls. The models for boys showed stronger predictions than the models for girls.All models for boys and most models for girls showed statistically significant associations between leisure-time PA and academic competence. p = 0.024) and participation in sports clubs among boys (p = 0.002) were statistically significant predictors of academic achievements among Slovenian 9- to 11-year-olds. The resulting β-value suggests that for every 1 SD increase in the frequency of leisure-time PA, girls’ overall academic competence increases by 0.10 SD.Since leisure-time PA variables for predicting academic competence in primary school were the focus of our study, we reported the association between the variables measuring the PA characteristics and overall academic competence in model 1 . The freThat leisure-time PA significantly predicts academic competencies was also found in other models. For girls, spending more time on PA predicted higher overall academic competence after adjusting for confounding factors in model 2 (0.14 SD increase) and model 3 (0.11 SD increase). Similarly, girls’ mathematical competence could be predicted by the frequency of PA (0.10 SD increase) after adjusting for confounding factors in model 2 (0.16 SD increase) and model 3 (0.12 SD increase). Playing digital games was associated with lower reading competence in girls in model 1 (−0.12 SD decrease) and model 2 (−0.09 SD decrease). In contrast, increased frequency of PA, adjusted for confounding variables, predicted an increase in girls’ reading literacy in model 3 (0.08 SD increase) and model 2 (0.11 SD increase).For boys, the overall academic competence could be predicted by the frequency of PA performed alone (0.10 SD increase) and the frequency of activity in a sports club (0.11 SD increase) in model 2 and the intensity of PA in model 4 (0.55 SD increase). Similar results were found for both mathematical competence and reading competence. For mathematical competence, an increase in the frequency of PA in a sports club  and PA performed alone (model 2 = 0.13 SD increase) and a decrease in the intensity of PA (model 2 = −0.10 SD decrease) predicted better performance in mathematics when the overall PA was controlled for the confounding variables of grade level and developmental disability. In contrast, the intensity of daily PA predicted a 0.78 SD increase in boys’ reading competence in fully adjusted model 5 and a 0.83 SD increase in adjusted model 4. In addition, boys’ reading competence could be predicted by the frequency of PA performed alone (0.09 SD increase) in model 2 and membership in a sports club (0.12 SD increase) in model 1.Conducting multiple regression in this study revealed significant associations between leisure-time PA and higher overall academic competence, mathematical literacy, and reading literacy among female and male primary school students in grades 4–6. Students with above-average academic ability meet or exceed some of the WHO recommendations  for PA. Although it is statistically significant, leisure-time PA itself explains only 3% of academic competence in girls and 4% in boys. The prediction becomes much clearer when the model is adjusted for confounding variables, such as developmental, family, and school factors. When confounding factors are added, the model can explain more than 80% of the variance in academic competence. In the following sections, we discuss which confounding variables have the greatest impact on the model and act as mediators between PA and academic competence and which elements or characteristics of PA are most strongly related to academic competence in school-age children. Finally, we present some strengths and limitations of the study.Our results suggest that children’s grade level and developmental handicap, along with the family size and parental encouragement for academic success, play a significant mediating role between PA and academic competence. This is true for all academic competencies and both males and females. Adding the confounding variables from the school environment into the model could reduce the prediction for girls’ mathematical and reading competencies. For boys, however, all models remained significant for all academic competencies, with the prediction increasing when other confounding variables were added, especially classroom behavior and motivation to succeed academically.A positive impact of leisure-time PA on academic competence when controlling developmental, family, and school confounders is consistent with emerging evidence ,27,29,45In this study, conducted on a representative sample of Slovenian primary school students in grades 4–6, the extent and intensity of leisure-time PA were reported according to the recommendations of WHO . On averThe partial coefficients of the multiple regression showed a significant, albeit small, effect size of the predictor variables for academic competence based on the total frequency of PA in leisure time for girls and involvement in sports clubs for boys. Schoolgirls who are more frequently physically active in their leisure time may benefit from better overall academic performance. Similarly, more frequent involvement in organized physical activities, such as sports clubs or sports associations, may lead to better academic performance for boys. Dapp and Roebers  came to In addition, previous studies have shown a significant relationship between the type of PA and the academic performance of school children. For example, a comprehensive meta-analysis by Fedewa and Ahn  found thFinally, notable implications were found for the relationship between academic competence and sedentary behavior. Although the time spent in front of the TV was the most common sedentary activity among the children in this study, it was not a significant predictor of academic competence. On the contrary, playing digital games on a daily basis led to a significant decline in academic performance, especially for girls in their competency in reading. The relationship between academic performance and sedentary behavior is not well established. Nevertheless, Jaruratanasirikul et al.  came to The main strengths of this study were the large and representative sample with a high response rate of participants, which allowed generalization of the results to the entire population of Slovenian primary school students in grades 4–6; the objectively measured academic performance using a standardized assessment instrument; and a comprehensive set of confounding variables controlled for in the multiple regression models of the associations between leisure-time PA and academic competence. This combination of strengths contributes to the justification and credibility of the study’s findings.However, this study also had a few limitations. First, the data collection method to assess children’s leisure-time PA was based on a self-report questionnaire. Data collection was controlled and guided by the principal researcher, with the support of class teachers in the field, to minimize bias due to misunderstanding or socially desirable responses from participants. However, Jurakić et al.  warn thaBased on the frequency, intensity, time, and type of PA (FITT) principle , our stuSecond, the Academic Competence Scale was used to assess different aspects of children’s academic performance and was not limited to one school subject or the overall grade point average, as is common in previous similar studies ,26,46. TThird, previous studies ,47 have Finally, mathematical performance and mathematical skills were found to be the lowest among academic competencies for both genders. Moreover, regression models showed the lowest prediction of mathematical competence among girls. These findings contradict previous studies that demonstrate a significant relationship between PA and mathematical achievement. For example, in a systematic review of high-quality intervention studies, Singh et al.  found stHowever, much remains to be learned about the effects of PA on academic performance. Therefore, qualitative and mixed-methods studies would also help understand how PA and academic performance interact with each other and other potential confounders. Different perspectives of children, their parents, and their teachers should be explored.The findings of this study contribute toward elucidating the relationship between PA and academic performance by showing that sufficient frequency and intensity of leisure-time PA, together with participation in organized activities and limited time spent playing digital games, may significantly contribute to better academic performance in primary school children. However, although significant, the effect size of this relationship is modest when only PA characteristics are considered. The model becomes stronger when adjusted for potential confounding variables. Gender, grade level, developmental disability, family size, and parental encouragement for academic success appear to play the strongest mediating role between PA and academic competence. Therefore, these factors should be carefully considered when developing and implementing new school-based health promotion interventions. Multiple target groups should be addressed in interventions, including children’s families and the school environment, to ensure the sustained impact of PA on a child’s academic performance and overall well-being. It seems that interventions for girls could be effective when focusing on increasing the PA frequency and on decreasing sitting time when playing digital games, while interventions for boys are promising when encouraging their participation in sports clubs and engagement in vigorous PA.The implications of the findings should be combined with established recommendations for PA for school-age children. Further high-quality intervention studies and systematic reviews are strongly recommended to clarify the association between PA and academic performance, considering several factors that mediate this complex relationship.


One effective cognitive treatment is the rehabilitation of working memory (WM) using an integrated approach that targets the “executive attention” system. Recent neuroscientific literature has revealed that treatment efficacy depends on the presence of various features, such as adaptivity, empathy, customization, avoidance of automatism and stereotypies, and alertness activation. Over the last two decades, an Integrated Cognitive Training (ICT) protocol has been proposed and developed; ICT takes the above-mentioned features and existing literature into account, and has been used to promote the development of reading skills. ICT has been employed in several clinical settings and involves stimulation of a specific deteriorated system  and the improvement of executive attention components, thus also increasing working memory capacity. In this context, we present two experiments. In Experiment 1, participants diagnosed with dyslexia (aged between 8 and 14 years) underwent two ICT sessions a week, with home supplements, for a duration of 7 months. The participants showed a significant improvement in the reading speed of text, words, and non-words, and in the reading accuracy of text and non-words. In Experiment 2, we replicated Experiment 1, but included a comparison between two groups  of young participants with diagnosis of dyslexia. The experimental group was subjected to 18 ICT sessions twice a week and with home supplements, using the same protocol as in Experiment 1. The control group was entrusted to the protocol of compensatory tools and dispense/helping procedures provided by the scholastic Personalized Educational Plan. After training, the experimental group gained about 0.5 syllables per second in text reading, and a marked decrease in error rate. The control group showed no significant improvement in reading skills after the same period. Moreover, the improvement observed in the experimental group remained stable 4 months after ICT had ended. The results of these two experiments support the efficacy of the integrated ICT protocol in improving reading skills in children with dyslexia and its sustained effect. One cognitive treatment that has been shown to be effective is an integrated approach that combines rehabilitation of working memory (WM) with that of the executive attention system. However, models and definitions of such theoretical constructs must be specified considering the numerous versions of the models introduced in neuropsychology over the decades, and the evolution of each model over time. The present study aimed to add to the knowledge on cognitive treatments by highlighting crucial points raised in the existing literature, and thus to increase the efficacy of cognitive treatments.The expression “working memory” can be easily misunderstood due to changes and improvements to the initial models of WM, which have evolved alongside neuroscientific discoveries in the field. This evolution has been mainly characterized by a clearer definition of the executive control system. Indeed, the executive control system was initially described rather vaguely as a “central processor” , and their time course” . Longitudinal studies into macrostructural brain plasticity have found mixed findings regarding the direction of training-induced alterations in gray matter volume or cortical thickness in task-relevant brain regions. For instance, Draganski et al.  found increases in gray matter volume in temporal and parietal regions after 3 months of juggling whilst, Takeuchi et al.  reported reductions of gray matter volume in parieto-frontal cortical regions after working memory training” (p. 48). It is therefore necessary to take into account, as much as is possible, the different variables that affect behavior and plasticity. These include the brain area involved, subjects' age, training duration, administration time, exercise intensity, treatment type, the setting in which treatment is carried out, calibration and difficulty of the exercises, the presence of a skilled operator who is able to motivate participants and regulate emotions . A training is “not adaptive” when the skills required greatly exceed or are inferior to the actual skills of a subject. In this case, the subject remains in an automatic and stereotyped mode for too long. Without attentive awareness, these repetitive exercises can lead to boredom, distraction, and the creation of rigid and closed patterns; even if improvements are achieved, they tend to be unstable over time or cannot be generalized to new contexts. The time spent in automatic or stereotyped mode is a crucial intervening variable that operators should take into account. High levels of non-adaptivity may transform a treatment into a pseudo-treatment, but both may be erroneously classified or analyzed as treatments, particularly in meta-analyses of effect sizes.Unfortunately, the need to overcome automatism during the treatment and learning phases is rarely acknowledged, even by expertsThese results indicate that adaptivity is an important variable to take into account; indeed, the effect of adaptivity seems to have been reported in very different research fields, such as that on memory prediction  of executive attention. ICT protocols have already been applied to patients with head trauma, degenerative diseases, children with developmental disorders, and athletes, as well as to develop learning procedures in the classroom Benso, . In the a. Considering what cognitive neuroscience has revealed about the theoretical models of learning, different aspects of attention and some executive functions are expressed in WMC. Moreover, it is necessary to understand the functional architectures to integrate the underlying trigger to the servo-systems of deteriorated or underdeveloped modular circuits.b. An empathic and motivating operator administering the treatment, who can also control computer software  the ability to vary and recognize attentional states , and understanding the different levels of attention  in a required setting through conscious “here and now” activities and provide immediate feedback. This provides the necessary repetitions that are aimed at creating hyper-learning and expertise, and avoid stereotypical settings.ICT requires these points to be satisfied. Moreover, skilled supervisors play a fundamental role in ICT. Current treatment proposals tend to focus on the instruments of the treatment, such as the increasingly sophisticated automated technologies and software. We recognize their usefulness, particularly when subjects cannot be treated directly and continuously. However, increasing evidence shows that a “human” presence can further enhance the effects of rehabilitation  and their underlying functions . In line with the research already described, the theoretical framework we refer to Benso ,b; BensoAs described above, one of the essential elements of ICT fundamentals is that the subject has to be activated and carried in an attentive set  measures  of ICT, there is first a harmonization of the subject conditions . Second, there is an enhancement of executive cognitive attentional circuits . In a final third phase, ICT can be specifically applied to weak systems , those with neurological pathologies, older people, or on sporting/artistic abilities. The last two phases can be integrated, and certain exercises can be shared and tailored according to the type and severity of a pathology and age of the patient . In the present study, the chosen third-phase treatment was reading. Many of the exercises have also been translated into “cognitive motor activities.”The conditions of the subjects are carefully considered before starting treatment, since it is possible that subjects are not willing to cooperate. For example, children who arrive in the clinical setting in the mid-afternoon, after school hours, might be demotivated, emotionally discharged, distracted, tired, or over-excited. Therefore, in the first 5–10 min, attempts are made to normalize emotional, motivational, attentional, and psychophysical arousal to prepare for the cognitive tasks that follow, which are tailored to the participant.According to the Hebb/Yerkes-Dobson curve, the arousal state should be “centered.” To achieve this, arousal should be activated when it is too low  or calmed down when it is too high In the meantime, the subject can become motivated by receiving clarification of the purposes of the session, and emotional states addressed by creating an empathic relationship, whereby the operator welcomes the child, and demonstrates solidarity with their discomfort and weaknesses. Any chronic emotional disturbance is treated separately.We will now describe the training phases, exercises, and materials used in the ICT protocol, which were tailored to create integrated executive attention-reading training. It is worth underlining that the material itself is interchangeable and can be altered according to the specific needs of a subject; the crucial element is instead the nature of the exercises, which aim to elicit different attentional states that are maintained over time, and to enhance the resources of executive attention and WMC.a) A fast naming (Rapid Automatized Naming task: RAN) task using interference stimuli  on cards and scoreboards, as well as concurrent calibrated tasks  and copying simple gestures.b) Breathing exercises combined with coordinated, slow gestures.a) Potential cards: Updating and divided attention training, multi-tasking processes, shifting activities and executive control with multimodal stimulations, including verbal (fast naming) and motor (gesture) tasks.b) Matrices: Matrices are grids (whose measures have been tailored to each person) with different stimuli . Visual and auditory updating, spatial orientations, generation of mental images, and sustained and focused attention tasks were completed, showing positive effects also on the method of study Benso, . The tasc) The Attention and Executive Processing-10 min (APE 10): Visual and auditory training that in just 10 min triggers different attentive executive functions using cards and scoreboards with n-back tasks. This exercise provides parallel stimulation of the visual-perceptual aspects involved in reading, including attentive focus, crowding and contrast effects, and ocular movements of pursuit and saccades Benso, . The APEa) Spoonerisms  and metaphonological awareness exercises  Tachistoscope and turbo-reader “LEGgo” in the ICT application to reading skills was used. This tool provides reading exercises, from sub-lexical aspects to disappearing text. It was designed to train meta-phonology, with fusion and segmentation exercises, as well as treatment of the crowding effect, and has many linguistic and visuo-spatial aspects that play a role in reading, such as letter-span . The ICT protocol has also been adapted to other different integrated systems, such as executive attention and writing, computation, problem solving, motor control, motor learning, and visuo-spatial processing.via the right cerebral hemisphere) and a second linguistic analysis phase (left hemisphere). The model suggests that, in people with dyslexia, there is an imbalance between the two hemispheres. Using PET, Nicolson et al.  of 4 months.In the first experiment, we evaluated the efficacy of a 7-month ICT on a sample of children with dyslexia. The aim of this experiment was to verify the actual increase in accuracy and speed of reading, measured in syllables per second (syll/s), after administration of the ICT. The speed of reading and accuracy were assessed before and after the treatment period.Twenty children  aged 8–14 years , whose parents opted for a 7-month ICT training for reading disorder, were enrolled in Experiment 1. Participants were admitted to Alassio Salute Medical Center, Italy, and received diagnosis of developmental dyslexia. Children were dignosed with developmental dyslexia by the National Health System, according to the guidelines of the national Consensus Conference . The enrWe employed the MT test  n = 1, 0.64 syll/s; 7th Grade n = 1, 0.96 syll/s. No statistical significative difference was found between QI (Raven Matrices expressed in percentiles) and speed increase of reading: N = 20, Spearman's rho = 0.022, p = 0.926.The analyses were performed using SPSS statistical software version 20.0. Raw and standard scores were analyzed. Standard Z-scores were used to rule out the effect of age covariance, since participants were in different school grades. For the “errors” parameter, and since the MT test provides a qualitative report, performance ranges were converted into numerical values to obtain quantitative data. The MT results were scored as follows: Request for Immediate Intervention = 0; Warning Request = 1; Sufficient Performance = 2; Criterion Completely Reached = 3. The children's IQ ranged from 30 to 75, with a mean value of 52.7 ± 14.3. The numerosity for each school grade and reading speed increase were: 2nd Grade (7 years old) p = 0.493, skewness = 0.233, kurtosis = −0.346; Text errors: Kolmogorov-Smirnov p = 0.731, skewness = 0.203, kurtosis = −0.308; Reading speed of words: Kolmogorov-Smirnov p = 0.539, skewness = 0.651, kurtosis = 0.163; Errors of words: Kolmogorov-Smirnov p = 1.026, skewness = 0.901, kurtosis = 2.703; Reading speed of non-words: Kolmogorov-Smirnov p = 0.446, skewness = −0.169, kurtosis = −0.878; Errors of non-words: Kolmogorov-Smirnov p = 0.759, skewness = 0.054, kurtosis = −0.702; Analyses of standard scores showed similar values). However, given the small sample size, non-parametric tests were executed and reported along with parametric tests.After verifying the significance of the Kolmogorov-Smirnov test and that skewness and kurtosis values were not between 1 and −1, all dependent variables were deemed to be normally distributed , reading accuracy (number of errors), for the conditions text reading, words and non-words reading. The observed raw values (means and SD) of the dependent variables and the corresponding Z-scores (weighted for school grade) measured at pre- and post-treatment are reported in Z = −3.58; p < 0.001, r = 0.56; reading speed of words: Z = −3.59; p < 0.001, r = 0.57; reading speed of non-words: Z = −3.21; p < 0.001, r = 0.51; reading accuracy of text: Z = 3.22; p < 0.001; r = 0.58; reading accuracy of non-words: Z = −3.55; p < 0.001, r = 0.56). Analyses of the raw scores revealed the same results as those obtained using the Wilcoxon test . All the effect sizes (r) were large, according to Cohen's classification. As seen in t-test. T-test analyses of standard scores (Z scores) showed improvements in the reading speed of text , words , and non-words , and also revealed improvements in the reading accuracy of text . There were no significant differences in reading accuracy of words  and non-words We also verified the results using a parametric test, and therefore took advantage of the robustness of the To examine possible differences associated with disease severity, we also analyzed the results by splitting participants into mild and moderate dyslexia groups. The mild dyslexia group comprised 13 children with a −2 < Z-score < −1.5 in at least two parameters among speed and accuracy in the three tasks for text, words, and non-words reading. The moderate dyslexia group included 7 children with −3 < Z-score ≤ −2, in at least two of the above-cited parameters. None of the children had severe dyslexia.Z = −1.625, p = ns), words , or non-words . No significant between-group differences were found in reading accuracy  of text , words , or non-words .A Mann-Whitney test revealed no significant difference between moderate and mild dyslexia groups in the pre-post training comparisons on reading speed (syll/s post- minus pre-training) of text , sex , IQ The speed and accuracy of reading were evaluated before and after the treatment period using the MT test . However, given the small sample size (N < 20), non-parametric tests were used to analyze the data.After verifying the significance of the Kolmogorov-Smirnov test and that the skewness and kurtosis values were not between 1 and −1, the data distributions were considered to be normally distributed , and between-group analyses were carried out using Mann-Whitney tests for independent samples (mainly on standardized scores). Effect sizes were calculated, and Corbetta and Shulman  guidelinn Glass,  was alsoTo assess the efficacy of ICT, a comparison was made with the estimated measure of natural change (without treatment) of the control group and the level achieved by the experimental group.p > 0.05; see In the pre-test phase (T0) no significant between-group difference in reading skills was found using the Mann-Whitney test for two independent samples  and accuracy  of text reading. The differences had a large effect size (r) in the MT text reading speed on standard scores (r = 0.49) and MT text reading error performance (r = 0.51). There were no significant differences in the two parameters of non-word reading. See The comparison between the experimental and control groups at T1 see  using thZ = −2.41; p < 0.05, r = 0.47), MT text reading error performance , non-word reading syll/s , non-word reading errors .As shown in p > 0.05; see Z = −0.94; p = ns), MT text reading error performance , non-word reading syll/s standard score , non-word reading errors standard score .The control group showed no increases between pre- and post-treatment evaluation , text reading accuracy , and non-word reading speed . The Wilcoxon test results  and accuracy of text reading , and for the speed of non-word reading .To verify the robustness of the ICT-induced improvements, reading skills were retested 4 months after the end of treatment (T2 phase) in 6 participants in the experimental group. The longitudinal study of the three phases T0, T1, T2 clarified the ICT-induced improvement trend and its retention after 4 months. As seen in ults see , 8 reveap-values for every assessment trial were >0.05. Furthermore, the Wilcoxon test performed using standard scores revealed no significant differences in MT reading speed , reading accuracy , non-word reading speed , or non-word reading accuracy . Thus, the subjects retested in October (T2) retained reading skills that had been achieved at the end of treatment . The Wilcoxon test performed using raw data did not reveal improvements in MT reading speed , MT reading accuracy , non-word reading speed , or non-word reading accuracy . The Wilcoxon test analyses, reported in The results of Experiment 2 demonstrate the efficacy of ICT. We found that ICT was associated with a gain of about 0.5 syll/s after 18 sessions in children with dyslexia, and this effect was stable in a group of 6 experimental participants evaluated 4 months after treatment. Participants in the control group that had access to the scholastic Personalized Educational Plan did not exhibit any appreciable changes in either reading speed or accuracy.The data of Tressoldi et al.  on the nWe hypothesized that the multi-component ICT on the reading module would be effective. This hypothesis was supported by the significant improvements exhibited by participants in Experiment 1 (1.08 syll/s in text reading after 7 months) and by the experimental group in Experiment 2. Experiment 1 showed that ICT was associated with a significant improvement of both reading speed and accuracy. In Experiment 1, the assessment tools revealed a significant improvement between pre- and post-treatment phases in the reading speed of text, words, and non-words, and in reading accuracy of text and non-words.In Experiment 2, the experimental group showed significant improvements in both speed and accuracy for text and non-word reading between pre-training T0 and retest T1. The effect sizes  were “large,” according to Corbetta and Shulman . The samDespite the positive results of the ICT, a longer treatment period is recommended (considering that of Experiment 2). As an alternative, we could suggest more cycles of the same duration, with a possible break between them. These studies are necessary to further support the efficacy of the ICT methodology that we have shared in the present paper, which is based on research spanning over more than two decades. At the same time, in light of new advances in neuroscience, the ICT protocol has been improved upon over time, and has been found to be effective in various areas, such as people with dyslexia , and avoided stereotyped and automatic modes of administration, thus ensuring that the training was “adaptive”  would be appreciable. Furthermore, the attentional networks  that we consider in the present study have been theorized to be involved in the cyclical phases of mindfulness  and that the selected operators complied with the essential criteria of the ICT protocol. Therefore, the experimental results of skills improvement/acquisition and their stability over time offer additional data in favor of the ICT efficacy. Previous work has proposed that learning stabilization is obtained and reinforced by the stimulation of isolated neural circuits , to improve planning and organization skills in everyday life and, as far as self-perception is concerned, family members reported an increase in self-esteem and perceived self-efficacy. We can suggest that these results are due both to the targeted training of weaknesses and to the enhancement of the method of study that emerges during the course of ICT.Limitations of this work primarily concern experimental elements rather than the cognitive training itself. Specifically, there was no age-matched control group in Experiment 1; however, the improvements observed exceeded those predicted by the normal developmental rate, and pre-post significant differences were calculated on age-standardized Z scores.decrease/not decrease as a dichotomous variable, we have the probability of 1/2. To evaluate the probability that an event that has a p-value of 0.5 repeats itself 6 times in succession in the same way, we can use the formula of the binomial calculus (see below). The results was p = 0.0156, and this significance would be the probability that such event is due to the case.One limitation of Experiment 2 is the small number of participants who completed the Retest 2 phase (T2), which was due to a lack of availability. However, the conclusion of a maintenance of reading levels acquired after ICT treatment is supported by a binomial distribution made on the minimum number of 6 subjects. In the experimental group, no children exhibited a decrease in the reading rate or accuracy. Hence, if we consider Furthermore, for both experiments, considering the executive attention treatments and WM training, it would have been interesting to measure any increases in these skills, as has been reported in our previous work. Considering the sample size, possible influence of differences in socio-demographic and educational levels on ICT outcomes has not been evaluated and can hence be addressed in new experimental protocols.In the future, it will be necessary to replicate this work with more consistent experimental groups and controls, which would also enable subgroup analyses and elucidate the involvement of specific learning and executive attention systems. Furthermore, inspired by various protocols for sports activities that we have developed in collaboration with researchers in motor science, and given the importance of motivational and emotional systems, we would like to evaluate developmental indices both in the assessment and treatment phases. For example, future work could evaluate stress values in addition to cognitive measurement and treatment  using physiological indicators (for example heart rate variability, e.g., Gazzellini et al., We are confident that by applying the principles highlighted to construct a more effective training protocol, we could apply the ICT to pathologies and conditions that have limited effective interventions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.FB and SM conceived and designed the experiments. EB, SM, and VB performed the experiments. FB and EA analyzed the data. FB, SM, EB, EA, and SG contributed materials/analysis tool. FB, EB, SM, VB, EA, and SG contributed to the writing of the manuscript. All authors contributed to the article and approved the submitted version.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.


Intrahepatic cholestasis of pregnancy (ICP) is a common pregnancy-related liver disease and is associated with an increased risk of adverse neonatal outcomes. Ursodeoxycholic acid (UDCA) is the most effective treatment. This study was aimed at investigating the adverse outcomes of ICP and evaluating the effects of treatment with UDCA in patients with ICP.  We included 114 women with ICP and 3725 women without ICP (no-ICP group) who delivered in our hospital between September 2017 and August 2019. The prevalence of ICP in this study was 3.15%. We matched each woman with ICP to five controls. Of all the 114 women with ICP, 73 (64.04%) received UDCA while 41 (35.96%) did not. Logistic multivariate regression analysis was used to compare the adverse outcomes between those with ICP and matched controls as well as between those who received UDCA (UDCA group) and those who did not (non-UDCA group).  Compared with controls, women with ICP were more likely to have preeclampsia , cesarean section , and preterm birth . Administration of UDCA reduced the rate of preterm birth .  ICP increased the risk of preeclampsia, cesarean section, and preterm birth. UDCA could reduce the rate of preterm birth. Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder , 2. Clinμmol/l , an165,136) . In addi165,136) . In our μmol/l [μmol/l, partially explaining the absence of stillbirth in our study. Nonetheless, the risk of stillbirth seems to increase after 37 weeks [Stillbirth is the most severe outcome that could be induced by ICP. In our study, no stillbirth was observed, which is not surprising as this outcome is very rare according to previous reports . In a reμmol/l . In our 37 weeks . To prev37 weeks , obstetrUDCA is the mainstay of treatment for ICP. In an 8-year case-control study in France, UDCA was administered to 43.6% of women with ICP and its prescription rate increased with the severity of bile acid elevation . Our stuThis study has several strengths including the comparison of comprehensive maternal and neonatal outcomes of ICP and the evaluation of UDCA in decreasing the adverse outcomes. Moreover, we explored the correlation of TBA with adverse pregnancy outcomes in the no-ICP group. However, it also has some limitations. First, this study is retrospective. Second, we did not distinguish emergency from elective cesarean section. Lastly, this is a single-center study, and the number of subjects was small. Hence, further prospective studies with a larger sample size are warranted to further explore the effect of TBA and ICP during pregnancy.In conclusion, ICP could result in preeclampsia, cesarean section, and preterm birth. Furthermore, UDCA could decrease the preterm birth rate. Further larger prospective studies are required to determine the adverse effect of ICP during pregnancy and the efficacy of UDCA.


Purpose: The purpose of this study was to evaluate whether clinical findings in children with ileocolic intussusception differ based on age and duration of symptoms and to assess the clinical characteristics of diagnosed and undiagnosed patients to determine which symptoms make diagnosis more difficult.Methods: We reviewed 536 medical records of <15-year-old children diagnosed with ileocolic intussusception between 2008 and 2019. We divided the children into three categories according to age . The children were also divided into two groups based on whether symptoms lasted for more or <6 h. Diagnosed and undiagnosed children were assessed separately during for the initial evaluation.Results: Following analysis of the three age groups, bloody stool, post-enema bloody stool, diarrhea, vomiting, poor oral intake, and lethargy were more frequent in children aged <1 year. In children aged ≥2 years, non-specific abdominal pain was more frequent and the undiagnosed rate was higher. Following analysis of the duration of symptoms, paroxysmal pain was significantly more frequent in the early group (<6 h), and bloody stool and fever were significantly more frequent in the late group (≥6 h). Nonspecific abdominal pain was more frequent and the door-to-diagnosis time was significantly longer in the undiagnosed group than in the diagnosed group.Conclusions: Clinical findings of ileocolic intussusception vary depending on the age and duration of symptoms. Younger children with paroxysmal pain, vomiting, bloody stool, poor oral intake, or lethargy should be suspected of having intussusception. In older children, non-specific abdominal pain without bloody stool may be a symptom of intussusception. Glycerin enema is helpful in diagnosing intussusception in children with no typical symptoms. Intussusception is the most common cause of acute intestinal obstruction in infants and young children and is a potentially life-threatening condition that is commonly seen in the emergency room (ER) , 2. The Untreated intussusception may lead to bowel necrosis and perforation, and even death , 7, 8. EThe primary objective of this study was to evaluate whether clinical findings in children with ileocolic intussusception differ based on age and duration of symptoms. The secondary objective was to evaluate the clinical characteristics of diagnosed and undiagnosed patients to determine which symptoms make diagnosis more difficult.We retrospectively reviewed the medical records of children aged 0 to 15 years with discharge diagnoses of intussusception  between January 2008 and December 2019 . All casThe following factors were extracted: demographic details and clinical features . The evaluation of patients and recording of data in the pediatric ER of our hospital were performed by pediatric residents, pediatric faculty members, emergency medicine residents, and emergency medicine faculty members. They used a standardized form, which consisted of historical and physical examination variables. Initial assessments were completed before any advanced diagnostic imaging  was conducted. When the clinical signs and symptoms signaled the presence of intussusception, an US was performed. The diagnosis of intussusception was confirmed when a target sign or doughnut sign was noted on the US; ileocolic intussusception was confirmed using air contrast enema. All diagnostic imaging findings were validated by a pediatric radiologist. The final diagnosis was based on the diagnosis of the hospitalized patient at discharge.We defined fever as a temperature ≥38°C measured at home or in the ER. Paroxysmal pain was defined as severe, cyclic, and cramping abdominal pain, or episodic irritability. Non-specific abdominal pain was defined as non-severe and non-periodic abdominal pain that was not the typical paroxysmal pain. We defined bloody stool as grossly bloody spontaneously passed stool visualized by parents at home. Post-enema bloody stool was defined as the absence of stool until the ER visit with grossly bloody stool after glycerin enema in the ER. The classic triad included typical paroxysmal pain, bloody stool, and vomiting, but does not include post-enema bloody stool. The duration of symptoms was defined as the time from the onset of symptoms as determined by the parents to the ER visit. Door-to-diagnosis time was defined as the time from the ER visit to diagnosis by US/air contrast enema.We performed an analysis by dividing all children into three categories according to age: <1 year, 1–2 years, and >2 years. The duration of symptoms was analyzed by dividing it into early and late groups, <6 h and ≥6 h, respectively. Based on initial assessment by the initial attending physician, the children were assigned to either the diagnosed or undiagnosed group. The undiagnosed group included patients who were discharged from the ER, admitted on the suspicion of other diseases, and patients who were diagnosed with intussusception based on the US or CT scanning after suspecting other diseases  in the ER.t-test or one-way analysis of variance was applied for continuous variables. Categorical variables were reported using frequencies and proportions and were compared using the Pearson χ2 or Fisher's exact test, as appropriate, or by linear association. The data were analyzed by using the Statistical Program for the Social Sciences . A P-value of <0.05 was considered to be statistically significant.Continuous variables are presented as medians with ranges or means ± standard deviations. An independent Student's A total of 536 patients were included in this study. The median age was 19 months  and 345 (64.4%) patients were male. The classic triad of paroxysmal pain, vomiting, and bloody stool was encountered in 50/536 cases (9.3%). The median duration of symptoms was 11 h  and the median door-to-diagnosis time was 2 h .P < 0.05). In children ≥2 years, non-specific abdominal pain was significantly more frequent (P < 0.001), and the rate of undiagnosed intussusception was higher (P = 0.012). The duration of symptoms and door-to-diagnosis time were significantly longer in the group ≥2 years old than the groups <1 year and 1–2 years .P < 0.001). Bloody stool and fever were significantly more frequent in the late group than in the early group .In a large proportion of patients (33.8%), the duration of symptoms was <6 h; in only 16.8% of patients, it exceeded 24 h . Table 2P < 0.05) (P < 0.001). There was no difference in the duration of symptoms in the two groups, but the door-to-diagnosis time was significantly longer in the undiagnosed than in the diagnosed group (P < 0.001). Of the patients included in this study, 108 were transferred from another hospital with a confirmed diagnosis of intussusception. A total of 428 patients were divided into diagnosed and undiagnosed groups according to the initial assessment and were compared. Of these, 367 were suspected of intussusception and 61 were not diagnosed with intussusception. In the diagnosed group, paroxysmal pain, bloody stool, post-enema bloody stool, and abdominal mass were significantly more frequent than in the undiagnosed group ( < 0.05) . In the Intussusception is notoriously difficult to diagnose because of the lack of sensitive or specific clinical indicators. However, it is a potentially dangerous disease that can lead to death if left untreated, and it is therefore imperative to prevent underdiagnoses of patients with suspected intussusceptions. This study showed differences in clinical features of ileocolic intussusception with the duration of symptoms and age of the children. In addition, this study analyzed the diagnosed and undiagnosed patients, as determined by the initial attending physician. We also identified cases in which it was difficult to diagnose intussusception and noted various symptoms that are important in preventing underdiagnoses.P < 0.001).In our study, the most common symptom of intussusception was paroxysmal pain, which was observed in 77.4% of patients, regardless of age. Previous studies have reported abdominal pain in 13–22% of patients . Our resn = 247). Vomiting was significantly more common in younger children (P < 0.001), similar to previous studies  of all patients had bloody stool, and it was more common in younger children . This result was comparable with that of previous studies (P = 0.0001) (P < 0.001), and children older than 2 years tended to have a normal stool (no blood in the stool) even after glycerin enema (77.1%). Bloody stool may occur as a result of the compression of the mesenteric vessels, mucosal edema, hemorrhage, and ischemia of the bowel, and may not be detected in early cases (P = 0.023). This indicates that bloody stool is highly specific for intussusception, but an absence of bloody stool cannot exclude the probability of the presence of intussusception.Bloody stool, though a key feature of intussusception, was less common than other symptoms. Its frequency varied considerably between studies, with reported rates ranging from 9 to 36% –18. In o studies , 20. Yam 0.0001) . In our ly cases , 19. BloP < 0.001)  , but in < 0.001) , 15, 16.In this study, poor oral intake and lethargy were significantly higher in younger children than in older children. Vomiting and decreased oral intake can lead to severe dehydration and shock, as well as neurological symptoms such as altered mentality, lethargy, and seizures that may appear as the initial presentation. In our study, two children were misdiagnosed with meningitis due to mental changes without gastrointestinal symptoms and were later diagnosed with intussusception. Dominguez-Carral et al. reported that fewer than 3% of children with intussusception initially presented with isolated neurological symptomatology (lethargy being the most common symptom) out of 351 cases . MaldonaIn the current study, children older than 2 years had a longer duration of symptoms and door-to-diagnosis time than the other two groups, and were more likely to be undiagnosed. Turner et al. and Kim et al. also reported that children older than 2 years were prone to receiving a delayed diagnosis , 25. OldP < 0.001). This finding suggests that glycerin enema also helps diagnose intussusception in children without the typical triad of symptoms. A negative post-enema bloody stool cannot exclude intussusception but shows that it as a significant positive predictor. Door-to-diagnosis time in the undiagnosed group was significantly longer than that in the diagnosed group (P < 0.001), showing how important it is to suspect intussusception for timely diagnosis treatment.When comparing the diagnosed group with the undiagnosed group, the decision to perform an additional image study was easy when there was paroxysmal pain, bloody stool, and abdominal mass, indicative of intussusception. Conversely, in the case of non-specific abdominal pain, other diseases were considered first. When 146 children who did not spontaneously pass bloody stool underwent glycerin enema in the ER, 64 in the undiagnosed group and more in the diagnosed group had bloody stool (For early detection of intussusception, a few recent studies have suggested that bedside US by radiologists and emergency physicians can be an effective diagnostic modality , 27. HowThis study had some limitations. First, this was a retrospective study, and the quality of data collected was dependent on medical records. A standardized form consisting of historical and physical examination variables was used, but data might not be complete or accurate. Second, we divided the diagnosed and undiagnosed groups, based on the clinical suspicion of the attending physician in the ER. Clinical suspicion and assessment can be subjective, as there are multiple attending physicians and clinical experience varies from person to person. This may have affected the analysis of the diagnosed and undiagnosed groups. Finally, this study had no control group, so our data are presented only as absolute numbers and percentages. We cannot comment on the sensitivity, specificity, or positive and negative predictive values of our findings.In conclusion, the clinical findings of ileocolic intussusception may vary depending on the duration of symptoms and age of the children. If children, especially those under 1 year, have paroxysmal pain, vomiting, bloody stool, poor oral intake, or lethargy, intussusception should be suspected. It is important to keep in mind that in older children, non-specific abdominal pain without bloody stool may be a symptom of intussusception. Glycerin enema also helps in diagnosing intussusception in children with no typical symptoms. Diagnosis of intussusception is still difficult, but carefully identifying and considering all symptoms is essential for timely diagnostic treatment in children. We hope that this study will aid in the timely and appropriate treatment of children of various ages with varying symptoms.mjtolord@hanmail.net.The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to The studies involving human records were reviewed and approved by Ulsan University Hospital Human Research Ethics Committee.MC: study conception and design, critical revision, drafting of the manuscript. IP and MC: analysis, data interpretation, and data acquisition. All authors: contributed to the article and approved the submitted version.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.


Background: Increasing evidence from modern neuroimaging has confirmed that cervical dystonia (CD) is caused by network abnormalities. Specific brain networks are known to be crucial in patients suffering from CD. However, changes in network homogeneity (NH) in CD patients have not been characterized. Therefore, the purpose of this study was to investigate the NH of patients with CD.Methods: An automated NH method was used to analyze resting-state functional magnetic resonance (fMRI) data from 19 patients with CD and 21 gender- and age-matched healthy controls (HC). Correlation analysis were conducted between NH, illness duration and symptom severity measured by the Tsui scale.Results: Compared with the HC group, CD patients showed a lower NH in the right superior medial frontal gyrus. No significant correlations were found between abnormal NH values and illness duration or symptom severity.Conclusion: Our findings suggest the existence of abnormal NH in the default mode network (DMN) of CD patients, and thereby highlight the importance of the DMN in the pathophysiology of CD. Cervical dystonia (CD) is a disorder of the nervous system characterized by involuntary sustained contractions of the cervical musculature, causing an abnormal and involuntary rotation or tilt of the head in specific directions . The heaIt is widely accepted that deficient motor control in dystonia is related to basal ganglia dysfunction, ultimately resulting in a systems-level loss of inhibitory function –12. ReceThrough the developments of neuroimaging techniques, it is now possible to investigate details of structural changes and neuronal activity in the brain that are potentially involved in the pathophysiology of CD. For example, several structural neuroimaging studies have reported micro-structural changes in specific brain regions of CD patients, including the basal ganglia, thalamus, cerebellum, motor cortex, and supplementary motor cortices –21. FuncOver recent years, a methods to analyze resting-state fMRI data have provided a new way to study the previously neglected field of intrinsic network organization . The metIn this study, we used the NH method to study patients with CD. Previously, we have used Global-brain functional connectivity (GFC), voxel-mirrored homotopic connectivity (VMHC) and ReHo to analyze fMRI data of patients with CD. Results showed that the GFC and the VMHC in the supplementary motor area (SMA) were significantly decreased , 31. FurThis study, which was approved by the ethics committee of the First Affiliated Hospital, Guangxi Medical University, China, was performed in an outpatient setting in the Department of Neurology of The First Affiliated Hospital. Patients were diagnosed based on the 2011 EFNS  guideline on the diagnosis and treatment of primary dystonias. Patients who matched the following criteria were included in the study: (1) idiopathic cervical dystonia; (2) no history of botulinum toxin treatment, related drug therapy, or operation in the previous 3 months; (3) no history of serious physical or neuropsychiatric disorders; and (4) right-handedness.Healthy controls (HC) were simultaneously recruited from the community. They were group-matched in gender, age, and were all right-handed. The exclusion criteria for HC individuals were as follows: (1) diagnosis of secondary spasmodic torticollis; (2) any history of severe physical or neuropsychiatric disorders; and (3) any family history of psychiatric or neurological diseases in their first-degree relatives. Only subjects who had no contraindications for MRI or exhibited no abnormalities in conventional MRI scans were included.The Tsui scale  was usedResting-state image acquisition was performed on a Siemens 3.0 T scanner . All subjects underwent scans with foam padding and earplugs to minimize head movement and reduce scanner noise. Every participant was asked to lie still and relax, eyes closed, and remain awake but avoid thinking of anything in particular. Subsequently, we confirmed that each subject had not fallen asleep during the session. For each subject, the following parameters were used for echo-planar imaging sequence acquisition: repetition time/echo time (TR/TE) = 2,000/30 ms, slice thickness = 4 mm, flip angle = 90°, gap = 0.4 mm, matrix = 64 × 64, FOV = 24 × 24cm, number of volumes = 250.Data pre-processing was performed using Matlab  Mathwor. The priAfter data pre-processing, we performed NH analysis on Matlab  Mathwor. Brieflyt-test was used to compare quantitative variables (p < 0.05). The NH analysis were completed using REST with a two-sample t-test. Multiple comparisons were conducted using a Gaussian random field (GRF) correction , and the level of significance was set at the corrected p < 0.05.Demographic and clinical information, such as sex and age were recorded. The Chi-square test was used to compare qualitative variables, whereas the two-sample p < 0.05) were performed. Correlation analysis of mean NH values of clusters and patient age were performed using Pearson's correlations, and correlation analysis of illness duration and Tsui total score were performed using Spearman's correlations.Moreover, the mean NH values of brain regions that were defined as regions of interest (ROIs) that showed abnormal NH were extracted. Subsequently, further correlation analysis between these NH values and illness duration and Tsui scores in the patient group . Consequently, a total of 19 two-sample t-tests, p = 0.220) or age . There were no difference in head motion of the residual patients and HCs. The detail results were listed in There were no subject excluded due to any contraindications for MRI or shown changes under conventional MRI scans. No participants were excluded due to falling asleep during image acquisition. Two patients were excluded due to excessive head movement. Therefore, 19 patients and 21 HCs were included in this study. As listed in Compared with HCs, CD patients showed a lower NH in the right superior medial frontal gyrus. None of the brain regions showed a significantly increased NH in CD patients compared with those of HCs. Group comparisons of NH values are shown in ; Table 3Considering the small sample size of our study, we used split-half and leave-one-out validations to assess the reproducibility of our results.The results of split-half replicated those of the full sample .The results indicated a highly reproducible pattern of NH alteration across these tests, as well as in the overall analysis .The abnormal NH in the right superior medial frontal gyrus of CD patients was defined as the ROI, from which mean NH values were extracted. Linear correlations were calculated between these NH values and the illness duration or Tsui score in the patient group. No significant correlation was detected between these NH values and illness duration or Tsui score.The abnormality found for NH values in the right superior medial frontal gyrus of CD patients was further validated by the ROC method. The results supported that the NH values in the right superior medial frontal gyrus could be applied to differentiate patients from controls with optimal specificity  and sensitivity  ; Table 4Previous fMRI studies in CD patients were mostly task-based, which have limitations compared with resting-state fMRI. First, the introduction of tasks is likely to cause activation in brain regions associated with the completion of tasks and mask abnormal spontaneous activities in regions associated with the pathogenesis of the disease. In addition, it is difficult to choose tasks related to CD symptoms based on MRI scans. Thus, we used the resting-state fMRI method to study CD patients. NH analysis is a new method to evaluate the NH of a distributed and meaningful network based on the level of a voxel-wise comparison. This study used the NH method to analyze the fMRI data of CD patients and HCs. Compared with the HC group, CD patients showed lower NH values in the right superior medial frontal gyrus. No brain region had higher NH values in the CD group compared with those of the HC group. Furthermore, no significant correlations were found between abnormal NH values and age, illness duration, or symptom severity.The right superior medial frontal gyrus is a primary region of the SMA , 36. TheOf the 19 CD patients we included, 17 patients showed “sensory tricks”. Neurophysiological evidence suggests that sensory tricks work by reducing abnormal facilitation. Moreover, this is associated with established dystonia pathogenesis, leading to the hypothesis that sensory tricks reduce abnormally increased facilitation-to-inhibition ratios in brains with dystonia . NaumannThe right superior medial frontal gyrus was suggested as a key node of the DMN . BesidesWe observed asymmetric activity patterns in CD that were primarily involved in the right-hemispheric dystonia-related connectivity pattern. It is important to note that the asymmetric activity patterns were not an accidental finding, as we have noted in other studies in patients with CD . This phStrikingly, no significant correlations were found between abnormal NH brain regions and CD clinical data such as illness duration and severity of symptoms. This suggests a corollary that the abnormality of this region is an inherent abnormality of dystonia. The most likely reason is that abnormalities in the cortex and not only the basal ganglia are a cause for this disorder. Thus, we suggest that abnormalities in the right superior medial frontal gyrus are intrinsic to CD. In addition, as presented in There are several limitations to our study. First, the sample size was small. Second, dystonic posturing was minimal in the supine position or absent during scanning in all patients. To confirm whether this was a specific sensory trick is challenging. Therefore, the influence of a sensory trick on the analysis could not be fully eliminated. Moreover, physiological noises including respiratory and heart rhythms could not be eliminated despite the use of a low sampling rate (TR = 2s). Lastly, given the small sample size, patients were not subdivided into different groups according to head rotation. Hence, research using a larger sample size is required to expand our findings.Our findings suggest that abnormal NH of the DMN is a key feature of CD patients, which further highlights the importance of the DMN in the pathology of CD. The DMN may be exploited as a potential biomarker to diagnose CD patients.luoshuguang@stu.gxmu.edu.cn.SL had access to all the data in the study and had final responsibility for decision to submit for publication. The data will be available upon request to SL, The studies involving human participants were reviewed and approved by the Ethics Committee of The First Affiliated Hospital, Guangxi Medical University. All participants were given information regarding study procedures and subsequently provided written informed consent to participate in this study.SL and WG: conceived and designed the study. SW, XC, YX, WJ, QY, CL, LY, JW, YL, WL, and JT: collected the original imaging data. WG: managed and analyzed the imaging data. SW and XC: wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.This study was supported by grants from the National Key R&D Program of China (Grant No. 2016YFC1307100), National Natural Science Foundation of China (Grant No. 81771447), Natural Science Foundation of Hunan (Grant No. 2020JJ4784), Guangxi Appropriate Technology for Medical and Health Research and Development Project (Grant No. S2020028), and Guangxi Appropriate Technology for Medical and Health Research and Development Project (Grant No. S2019002).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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background: Congenital amusia (CA) is a rare disorder characterized by deficits in pitch perception, and many structural and functional magnetic resonance imaging studies have been conducted to better understand its neural bases. However, a structural magnetic resonance imaging analysis using a surface-based morphology method to identify regions with cortical features abnormalities at the vertex-based level has not yet been performed.Methods: Fifteen participants with CA and 13 healthy controls underwent structural magnetic resonance imaging. A surface-based morphology method was used to identify anatomical abnormalities. Then, the surface parameters' mean value of the identified clusters with statistically significant between-group differences were extracted and compared. Finally, Pearson's correlation analysis was used to assess the correlation between the Montreal Battery of Evaluation of Amusia (MBEA) scores and surface parameters.Results: The CA group had significantly lower MBEA scores than the healthy controls (p = 0.000). The CA group exhibited a significant higher fractal dimension in the right caudal middle frontal gyrus and a lower sulcal depth in the right pars triangularis gyrus  compared to healthy controls. There were negative correlations between the mean fractal dimension values in the right caudal middle frontal gyrus and MBEA score, including the mean MBEA score , scale score , contour score , interval score , rhythmic score , meter score , and memory score . There was a significant positive correlation between the mean sulcal depth in the right pars triangularis gyrus and the MBEA score, including the mean score , scale score , interval score , rhythmic score , meter score , and memory score .Conclusion: Individuals with CA exhibit cortical morphological changes in the right hemisphere. These findings may indicate that the neural basis of speech perception and memory impairments in individuals with CA is associated with abnormalities in the right pars triangularis gyrus and middle frontal gyrus, and that these cortical abnormalities may be a neural marker of CA. Music is a fundamental element in interpersonal and social communication. However, 1.5–4% of the general population exhibits lifelong impairments in music production, perception, and memory , in the Several imaging studies have been conducted to understand the neurobiological mechanisms underlying pitch disorders in people with CA. Previous functional magnetic resonance imaging (fMRI) studies have indicated that abnormal activity in the right frontotemporal network , 9 and/oFurthermore, these anatomical abnormalities associated with amusia cannot fully explain the clinical manifestations of CA. It has been reported that individuals with CA have impairments that extend to other domains, including speech perception –22, emotSurface-based morphology (SBM) and VBM are common methods by which to learn about structural abnormalities . VBM is In the current study, we systematically investigated brain structural abnormalities in individuals with CA and HCs using SBM. We hypothesized that individuals with CA would show alterations in SBM metrics in brain regions associated with language, memory, and/or other domains. We also hypothesized that some of these abnormalities would be correlated with clinical parameters, such as the MBEA score.via advertisements and campus screening between November 2018 and August 2019. First, we conducted a structured clinical interview to collect basic information . All subjects spoke Mandarin and were right-handed. Second, the Wechsler Intelligence Scale and a pure tone audiometary test were used to exclude the possibility of hearing and/or intellectual deficits. The specific inclusion criteria were as follows: (1) a Wechsler Intelligence Scale score of more than 85, which indicates normal intelligence, and (2) the ability to hear at least 25 decibels, as measured by pure tone audiometry. The exclusion criteria were as follows: (1) hearing loss, (2) the presence of a neurological or psychiatric disorder, (3) drug use history in the past 6 months, (4) had received musical training, and (5) contraindications to MRI examination. The HCs were recruited from the same universities as the individuals with CA; they fulfilled the same exclusion criteria and were matched to the CA group for age, sex, handedness, and education. Third, all participants completed the MBEA face to face to assess ability in the temporal dimension (rhythm and meter) and melodic dimension , and in musical memory  or Class B  . In our Hit rate = hit number/(hit number + miss number); false alarm rate = false alarm number/d' = Z(HR)-Z(FAR)c = −0.5·[Z(HR)+Z(FAR)]All MRI data were collected on a 3.0-T Siemens Skyra MRI scanner  using a 20-channel head coil. Participants' heads were immobilized in the scanner with foam cushions and earplugs were worn to reduce the noise. Our protocol included a T1-weighted high-resolution three-dimensional sagittal Magnetization Prepared Rapid Acquisition Gradient Echo sequence with the following acquisition parameters: repetition time = 1,900.0 ms, echo time = 2.03 ms, flip angle = 9°, 176 slices, slice thickness = 1 mm, slice spacing = 1 mm, field of view = 256 × 256 mm, acquisition matrix = 64 × 64 mm, voxel size = 1.0 × 1.0 × 1.0 mm.www.fil.ion.ucl.ac.uk) and the Computational Anatomy Toolbox  in the MATLAB environment . All images were transformed to a Nifti-format using dcm2nii (http://www.nitrc.org/projects/mricrogl) and were visually inspected for structural abnormalities, artifacts, and apparent head motion before preprocessing. Next, all images were manually reoriented to have the same point of origin (anterior commissure) and spatial orientation.Image data processing was performed using Statistical Parametric Mapping 8  T1-weighted Magnetization Prepared Rapid Acquisition Gradient Echo images were normalized and further segmented into gray matter volume, white matter volume, and cerebrospinal fluid volume. (2) In CAT12, projection-based thickness was used to estimate cortical thickness and create the central cortical surface for the left and right hemispheres . Surfacet-tests were used to assess between-group differences for normally distributed data . The Fisher's exact test was used to perform between-group comparisons of categorical variables . To eliminate artifacts and slight head motion, such as pulsatile effects from the vasculature and partial volume effects in boundary regions, subjects with any slight head motion  were excluded. The cortical thickness and other surface parameter maps of the left and right hemispheres were separately assessed within a brain mask using voxel-wise two-sample t-tests in SPM8 and the CAT12 toolbox. All statistical maps were assigned thresholds at p < 0.001 (voxel level), and the false discovery rate was corrected to p < 0.05 at the cluster level for multiple comparisons. The surviving clusters are reported in the following results. We also used a regions-of-interest tools module in the CAT12 toolbox to extract the mean values within regions of interest defined using the Desikan–Killiany–Tourville atlases. The mean cortical thickness and additional surface parameters of clusters with statistically significant between-group differences were obtained. Finally, Pearson's correlation analysis was applied to assess the correlation of the MBEA global score and subscores with surface parameters. Statistical significance was defined as a p-value < 0.05.Statistical analysis was performed using SPSS v25.0 . The Shapiro–Wilk test was used to assess normality. Unpaired Student's p = 0.274), sex (p = 0.266), or years of education (p = 0.892). There were significant between-group differences in each MBEA subscore, whereby the CA group had significantly lower scores on all MBEA subtests compared to the HCs (p = 0.000).After checking MRI images and head motion, eight subjects were excluded (three from the CA group and five from the HC group). One participant from the HC group was excluded due to slight head motion, and all other excluded participants were excluded due to artifacts. Finally, 15 participants with CA  and 13 HCs  were included in our study. The average MBEA score ranged from 16.33 to 21.5 in the CA group, and from 26.33 to 29 in the HC group. t = 2.520, p = 0.018) and rhythm subtest  , interval subtest , contour subtest , rhythm subtest , and memory subtest   and global c score . Finally, the mean minus one standard deviation of global d' value in the HC group (2.29 = 2.865–0.575) was taken as cutoff to identify CA. On this diagnostic criteria, 13 subjects were diagnosed as HCs and 15 were diagnosed with CA, which was similar with the results of MBEA. Therefore, these subjects were included in subsequent studies.SDT analyses were conducted in order to verify the results of the MBEA test. The mean and standard deviation of d' and c were calculated for every subtest. The skew and kurtosis of d' suggested that the d' value on every subtest basically is normally distributed . There w= 0.020) ; Table 4= 0.000) ; Table 5p < 0.05; false discovery rate-corrected at the cluster level). The cluster size and peak value in the two brain regions are shown in p = 0.001), and the mean fractal dimension values of significantly increased clusters in the right caudal MFG were significantly larger in the CA group (p = 0.002).We found significant increases of fractal dimension in the right caudal middle frontal gyrus MFG;  and a der = −0.5398, p = 0.0030), scale score , contour score , interval score , rhythmic score , meter score , and memory score , scale score , interval score , rhythmic score , meter score , and memory score   .The present structural MRI study was conducted to identify regions with cortical feature abnormalities at the vertex-based level in individuals with CA. The CA group exhibited a lower sulcal depth in the right pars triangularis gyrus and higher fractal dimension in the right caudal MFG. Furthermore, the MBEA score and subscores were negatively correlated with the mean fractal dimension value in the right caudal MFG. There was also a positive correlation between performance on the MBEA (except for the contour subtest) and sulcal depth in the right pars triangularis gyrus.To our knowledge, this is the first study to investigate structural abnormalities using SBM in individuals with CA, and is also the first to report structural abnormalities in the right MFG in patients with CA. The MFG, which is located anterior to the premotor cortex and posterior to the dorsolateral prefrontal cortex , is an iMoreover, we found significant decreases of sulcal depth in the right pars triangularis gyrus in the CA group compared with HCs, and a positive correlation between sulcal depth in the right pars triangularis gyrus and the mean MBEA score and subscores. These results revealed anatomical abnormalities in the IFG in patients with CA, and we assumed that this structural abnormality could represent the anatomical basis of mild speech perception impairment reported in those with CA. There are some reasons for this assumption. First, the right pars triangularis gyrus is located in the IFG and is known as the right homologue of Broca's area ; it is aOur correlation analysis also showed that fractal dimension in the MFG and the sulcal depth in the right pars triangularis gyrus were associated with the mean MBEA score. The MBEA has a good sensitivity and validity , is currFinally, all the identified brain regions were located in the right hemisphere. In right-handed healthy humans, the right hemisphere is more specialized in musical and non-verbal processing, such as pitch discrimination, timbre detection, and musical structure processing, while the left hemisphere is more dedicated to linguistic and verbal processing, such as the processing of spoken words, digits, and syllables . CA mainDespite the novel discoveries of the present study, it has some limitations that should be noted. First, the final sample from which structural MRI data were obtained was relatively small due to the rarity of the disease. Given that our study had a small sample size, we focused on detecting structural abnormities, but did not investigate the link between the right MFG and right pars triangularis gyrus, and did not evaluate the relationship between scores of a detailed language and memory scale and abnormal brain anatomy. Future work should use larger sample sizes, refine behavioral materials, and explore the relationship between behavior and neurobiology in pitch disorders.Our findings indicate that CA is associated with cortical morphological changes. Our findings may suggest that the neural basis of speech perception and memory impairments in those with CA is associated with abnormality in the right pars triangularis gyrus and MFG, and that the cortical abnormality in these two brain regions may represent a neural marker of CA.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of the Second Xiangya Hospital, Central South University. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.DW, ZJ, and JL designed the project. ZJ, JS, and XL collected the data. Data analysis and manuscript writing were conducted by XL. The manuscript revision was conducted by XL and JL. All authors approved the final version of the manuscript.This work was supported by the National Natural Science Foundation of China , the Clinical Research Center for Medical Imaging in Hunan Province (Grant No. 2020SK4001).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. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.