Brain iron deposition and microstructural changes in brain tissue are associated with Parkinson’s disease (PD). However, the correlation between these factors in Parkinson’s disease has been little studied. This study aimed to use quantitative susceptibility mapping combined with diffusion kurtosis imaging to investigate the effects of iron deposition on microstructural tissue alterations in the brain.Quantitative susceptibility mapping and diffusion kurtosis imaging were performed on 24 patients with early PD, 13 patients with advanced PD, and 25 healthy controls. The mean values of magnetic susceptibility and diffusion kurtosis were calculated for the bilateral substantia nigra, red nucleus, putamen, globus pallidus, and caudate nucleus, and compared between the groups. Correlation analyses between the diffusion kurtosis of each nucleus and its magnetic susceptibility parameters in PD patients and healthy controls were performed.The study found a significant increase in iron deposition in the substantia nigra, red nucleus, putamen and globus pallidus, bilaterally, in patients with PD. Mean kurtosis values were increased in the substantia nigra but decreased in the globus pallidus; axial kurtosis values were decreased in both the substantia nigra and red nucleus; radial kurtosis values were increased in the substantia nigra but showed an opposite trend in the globus pallidus and caudate nucleus. In the substantia nigra of patients with PD, magnetic susceptibility was positively correlated with mean and radial kurtosis values, and negatively correlated with axial kurtosis. None of these correlations were significantly different in the control group. In the putamen, magnetic susceptibility was positively correlated with mean, axial, and radial kurtosis only in patients with advanced-stage PD.Our study provides new evidence for brain iron content and microstructural alterations in patients with PD. Iron deposition may be a common mechanism for microstructural alterations in the substantia nigra and putamen of patients with PD. Tracking the dynamic changes in iron content and microstructure throughout the course of PD will help us to better understand the dynamics of iron metabolism and microstructural alterations in the pathogenesis of PD and to develop new approaches to monitor and treat PD. Parkinson’s disease (PD) is characterized clinically by rest tremor, bradykinesia, rigidity, and postural instability. The main pathological change in PD is dopaminergic neuron degenerative death in the nigrostriatal system due to iron deposition . The linDiffusion kurtosis imaging (DKI) is a state-of-the-art method for quantifying non-Gaussian water diffusion . An alteMagnetic susceptibility (MS) , 2020 anAll examinations in this study were performed with the written consent of each participant, and the study was approved by the Ethics Department of the Second Affiliated Hospital of Xiamen Medical College. All processes were conducted in accordance with the principles of the Declaration of Helsinki. In the study, we prospectively assessed 37 patients with PD who attended the Department of Neurology at the hospital between January 2019 and December 2020. All patients were diagnosed with PD by a movement disorder neurologist , underwent MRI, and met British Parkinson’s Disease Association Brain Bank criteria. The following exclusion criteria were applied: atypical or secondary PD, history of other neurological disease e.g., severe head trauma or stroke, poor image quality, or general MRI scan contraindications. All patients were older than 50 years, right-handed, and underwent a thorough neurological examination. Patients and their families provided detailed information on the onset, course, and evolution of PD. Hoehn-Yahr (HandY) stage and Unified Parkinson’s Disease Rating Scale (UPDRS) were used to assess disease severity and motor function .Patients were further categorized into early-stage PD (ESPD)  and advanced stage PD (ASPD)  groups. PD duration was defined as the time difference between first motor symptom development and the study examination date. The mental status of all patients was assessed using the Mini-mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) scores .Since both methods have unique characteristics, we conducted two PD tests for each patient . ClinicaAll participants underwent MRI examinations on a 3 T scanner  equipped with an eight-channel phased array receiver coil. Participants were instructed to relax and avoid any motion during the test. Noise-proof earplugs and foam pads were applied to minimize acoustic scanner noise and motion artifacts, respectively. Auto shimming was employed at the start of each scan to ensure uniformity of the static magnetic field. Before QSM and DKI imaging, routine images, including T1-weighted imaging, T2-weighted imaging, fluid-attenuated inversion recovery (FLAIR) images, and diffusion-weighted imaging (DWI), were acquired. They were used to confirm the absence of structural abnormalities, and to exclude secondary Parkinson’s syndrome caused by severe vascular disease, multisystem atrophy, trauma, or encephalitis.b-values = 0, 1,000 (30 directions), and 2,000 (30 directions) s/mm2; number of slices = 15; total scan time = 3 min 2 s. QSM source images, including magnitude and phase images, were obtained using a three-dimensional multi-echo fast spoiled gradient recalled echo (FSPGR) sequence with the following parameters: TR = 23.7 ms; TE = 3.4/5.8/8.1/10.5/12.8/15.2/17.5/19.9 ms; flip angle = 12°; slice thickness/gap = 1/0 mm; FOV = 256 × 256 mm; matrix size = 256 × 256; NEX = 1; number of slices = 140; total acquisition time = 5 min 1 s. Two experienced neuroradiologists provided diagnostic support. All sequences were acquired in the axial plane parallel to the anterior commissure-posterior commissure (AC-PC) line. All images were carefully reviewed after scanning to ensure image quality, and poor image quality due to motion artifacts prompted rescanning.Diffusion kurtosis imaging images were obtained using a single-shot spin-echo echo-planar imaging (SE-EPI) sequence with the following parameters: repetition time (TR) = 3,000 ms; echo time (TE) = 60 ms; slice thickness/gap = 5/1.5 mm; field of view (FOV) = 240 × 240 mm; matrix size = 128 × 128; number of excitations (NEX) = 1; Raw DKI and QSM data were transferred to the Advantage Workstation 4.6  and post-processed by the FuncTool software. Specifically, DKI parameter maps, including MK, Ka, and Kr, were calculated by using the following equation :S denotes the diffusion encoding direction n and the diffusion signal intensity of the diffusion-weighted b-value, S0 denotes the diffusion signal intensity of b0, and Dij and Wijkl represent the components of the diffusion tensor and the diffusion kurtosis tensor, respectively. We have also used this DKI analysis method in our earlier studies  were delineated three times manually by two independent, double-blinded neuroradiologists with B0 images as references, and values were recorded each time to reduce offset errors . The avet-tests were used to compare demographic information and clinical characteristics among the groups. Average MS values and corresponding 95% confidence intervals of QSM imaging data were calculated for each region, along with MK, Ka, and Kr values from DKI. One-way ANOVA followed by false discovery rate (FDR) correction, as described by the Benjamini–Hochberg method, were used to compare the differences in MS, MK, Ka, and Kr values using the R software package (R for Windows v. 4.0.3)1 in patients with different stages of PD to HCs. For intergroup comparisons of non-normally distributed data, the non-parametric Kruskal–Wallis test was used. Pearson correlation analyses were used to investigate the relationship between the MS of the nucleus and the MK, Ka, and Kr values in patients with PD and HCs. Nuclei with good correlations in prior assessments were further divided to investigate correlations with different PD stages. We performed an FDR correction for multiple correlation tests. Finally, the associations between the QSM and DKI parameters and disease severity in the SN were examined using the Pearson correlation test, with adjustments for age and sex effects. For all analyses, values of P < 0.05 were considered significant.All data were analyzed using SPSS Statistics Package, version 19.0 . The Kolmogorov–Smirnov test was used to confirm the normal distribution of data. One-way analysis of variance (ANOVA) or unpaired p < 0.001). Meanwhile, the UPDRS-total, UPDRS-II, UPDRS-III scores, and the HandY stage of patients with ASPD were significantly greater than those of ESPD (p < 0.05).The demographic and clinical characteristics of the participants are shown in p = 0.003 and p < 0.001, respectively), indicating that the SNs of patients with PD have greater paramagnetism, and thus, greater iron deposition levels than healthy people. We also found that MK and Kr values in the SN in the PD group were higher than that of the control group, while the Ka of the control group was higher than that of the PD group. The MS of the RN was elevated in patients with different stages of PD compared to HCs , while Ka in the ESPD group decreased more than in the HCs (p < 0.001). Although the MS value of the putamen in patients with ASPD was significantly higher than that of the HCs (p < 0.001), diffusion kurtosis did not change significantly. Compared with the HCs, the MS of the GP of ESPD and ASPD patients increased , while MK  and Kr  decreased. No significant differences in Ka were found in this experiment. A slight decrease in the Kr of the caudate nucleus in ESPD, compared to HCs, was observed (p = 0.02).The results of the ICC analysis of the QSM and DKI parameter values for the left and right ROIs of HCs and patients with PD are shown in p = 0.0305), a positive correlation between Kr and UPDRS III (p = 0.0355), and a negative correlation between MK and MMSE and MoCA . MS was positively correlated with HandY staging and UPDRS III , and negatively correlated with MMSE and MoCA scores . The remaining identified correlations were not statistically significant.The results of our regression analysis are summarized in Maps of diffusion kurtosis and MS at the midbrain level were successfully constructed. We used DKI to identify microstructural changes in brain tissue associated with brain iron deposition in patients with PD. We found, for the first time, that microstructural alterations in the SN and putamen have unique characteristics and may be associated with brain iron deposition. In addition, we found that in ESPD, changes in kurtosis correlated with paramagnetism exclusively in the SN. We performed an etiological analysis of these interesting results, which are described below.QSM data, shown in Mean kurtosis elevation in the SN may be due to a combination of several factors. First, following dopaminergic neuronal injury and apoptosis , damagedAs iron accumulates, microglia activate to release reactive oxygen species, causing neurotoxicity, and eventually, fluid accumulation in the myelin sheath, causing edema. Because myelin travels directionally, water molecules within myelin do not diffuse freely in each direction, elevating Kr .in vivo high-resolution positron emission tomography study revealed that synaptic density was significantly reduced in the SN, RN, and locus coeruleus in PD  is inhibited, which manifests as structural changes of axonal atrophy . Recentlus in PD . Second,us in PD .As shown in Our data showed that in the SN of patients with PD, MS correlated positively with HandY staging, and, most significantly, UPDRS III scores, and negatively with cognitive test (MMSE and MoCA) scores, which is consistent with a prior report . It has An interesting phenomenon was observed in the SN of patients with PD, in which Ka was positively correlated with MMSE scores; Kr was positively correlated with UPDRS III scores, and MK was negatively correlated with MMSE and MoCA scores. We hypothesize that some specific microstructural alterations may be associated with clinical symptoms. The presence of a relationship between neuropsychological symptoms and imaging indicators should be investigated at more sites in future studies. Therefore, QSM and DKI parameter abnormalities are clinically significant and likely reflect PD symptom severity.The RN is composed of dense cells and small myelinated axons with a complex microstructure . The venThroughout neuronal degeneration, the number of major histocompatibility complex class II-positive microglia increased in both the SN and putamen . A prospAutopsy results of GP iron levels are controversial. Our results and those of The study has some limitations. First, iron in the SN initially accumulates in the dorsal pars compacta; however, in the present study, the entire SN was assessed, which reduced sensitivity. Second, according to Braak’s stage, iron deposition initially occurs in the dorsal IX/X motor nucleus and/or intermediate reticular zone, and gradually accumulates in the coeruleus–subcoeruleus complex. By Braak’s stage III, a lesion forms in the SN, by which time clinical motor symptoms are already present. The present study assessed the correlation between iron deposition and tissue microstructure in the major gray matter nuclei. The association should be comprehensively studied in the future, considering all voxels from the medulla oblongata to the neocortex. Finally, most of the patients with PD included in the study were clinically symptomatic, with disease that was more severe than Braak stage III. It is not clear whether brain iron deposition in patients with PD with pre-Braak stage III disease will have a different kurtosis index profile. To address this problem, a study with a greater sample size, with preclinical patients with PD, is needed.In recent years, many efforts have been made to examine brain iron levels and their effects on patients with PD. Our study provides new insights into iron overload and associated microstructural alterations from a neuroimaging perspective, which has the potential to integrate previous findings. Tracking the dynamic changes in iron content and microstructure throughout the course of PD will help us to better understand the dynamics of iron metabolism and microstructural alterations in the pathogenesis of PD and to develop new approaches to monitor and treat PD. First, we found that iron deposition in the SN and putamen may have an impact on changes in brain microstructure in patients with PD. Increased SN iron deposition was positively correlated with MK and Kr, and negatively correlated with Ka. Increased iron deposition in the putamen was positively correlated with MK, Ka, and Kr. This was especially true for the SN in which correlations were observable during early-stage PD. In addition, magnetic sensitivity was significantly higher in patients with PD, especially in the SN, RN, putamen, and GP. Finally, we confirmed that iron deposition in the SN affects brain microstructure, and, potentially, motor function in PD.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Department of the Second Affiliated Hospital of Xiamen Medical College. The patients/participants provided their written informed consent to participate in this study.LY, YC, YS, and YX: conceptualization, organization, and execution of research projects. JN, JG, YR, YJ, and ZZ: design, execution, and review of statistical analyses. LY, GY, and RW: wrote and reviewed the manuscript. All authors contributed to this article and approved the final 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.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.


Chronic kidney disease (CKD) in women is often accompanied by hormone disorders such as sex hormones, and most women with CKD are in the post-menopausal age group. Due to the close relationship between menopause and sex hormones, we aimed to explore the association between early menopause and CKD in post-menopausal women, and the influence of early menopause on longevity in the CKD population.Information regarding 4,945 post-menopausal women was extracted from the database of the National Health and Nutrition Examination Survey (NHANES) 1999–2014, and then divided into 4 groups according to the type of menopause  and early menopause (menopause at age <45) or not. The association between early menopause and CKD prevalence was examined using multivariable logistic regression, while we used multivariable Cox proportional hazards models to investigate the possible relationship between early menopause and all-cause mortality in CKD and non-CKD populations. The differences in the levels of sex hormones between women with and without CKD were also explored.Compared with women with natural menopauseat age ≥45, women experiencing early natural menopause had a higher risk of CKD [OR = 1.26 (1.01–1.56)]. Similarly, as compared to women with surgical menopause at age ≥ 45, women in the early surgical menopause group were more likely to have CKD [OR = 1.38 (1.05–1.81)]. In addition, early surgical menopause was associated with higher mortality in the non-CKD group [HR = 1.62 (1.06–2.49)], but not in the CKD group. Women with CKD had a higher level of luteinizing hormone and follicle-stimulating hormone, combined with a lower level of testosterone and estradiol than the non-CKD women.Both early natural and surgical menopause were associated with a higher risk of CKD. Early surgical menopause was a hazard factor for survival in the non-CKD group, but not in the CKD group. Further research is required to understand the mechanisms. Chronic kidney disease (CKD), mainly manifested by decreased GFR and proteinuria , is a maPrevious studies have shown that early menopause, both natural and surgical, is associated with many diseases, including cardiovascular disease, diabetes, and osteoporosis –11. ConsWe hypothesized that early menopause might be a risk factor of CKD and associated with higher mortality among women with CKD. We examined the National Health and Nutrition Examination Survey (NHANES) database from1999 to 2014 to evaluate the effect of early natural menopause and surgical menopause on CKD prevalence as well as all-cause mortality among women with CKD respectively. The differences in the levels of sex steroid hormone between women with and without CKD were also explored.All data in this study were from NHANES, a representative cross-section survey. It was designed to get information about civilian residents' health and nutritional status in the United States, using a multistage-stratified sample. The NHANES is a periodic survey conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). The NCHS Research Ethics Review Board reviewed and approved the NHANES and all participants provided written informed consent. The NHANES Reproductive Health questionnaire surveys females to provide personal interview data on menstrual history, pregnancy history, lactation, oral contraceptive, and other related conditions. These questions were administered at the mobile examination center by trained interviewers, using the Computer-Assisted Personal Interviewing system as part of the Mobile Examination Center (MEC) interview.We merged the data from the 1999 to 2014 NHANES strictly following the analytical guidelines. 28,688 women answered the reproduction health questionnaire during this period. 10,064 post-menopause women were selected according to the negative response to the question “Have you had at least one menstrual period in the past 12 months? .” We then excluded women who reported their menopause status as attributable to pregnancy, breastfeeding, usually irregular period. For the surgical menopause group, 1,515 participants reported binary oophorectomy and the surgery time is the same as age at the last period were included. For the natural menopause group, according to the questions “What is the reason that you have not had a period in the past 12 months?” “Have you had a hysterectomy, including a partial hysterectomy, that is, surgery to remove your uterus or womb?” and “Have you had at least one of ovaries removed (either when had the uterus removed or at another time)?” we excluded 2,430 women with a history of hysterectomy, unilateral oophorectomy, or women who reported menopause are due to other medical treatments. Because no data were available on age at menopause, 404 women were excluded. Since this is a questionnaire survey, considering that participants may not be clear about the question, a lot of them reported the age of menopause was the same as age at screening, and most of the participants reported extreme values to have incomplete information. To ensure the accuracy of data, we ruled out 216 women with extreme age at menopause (<30 years old or >60) and 253 women younger than 50 years old at screening consistent with the past study . Both grFor the lack of sex hormone data of women in 1999–2012 NHANES, these laboratory data were from Sex Steroid Hormone—Serum data file in 2013–2016 NHANES. 1,754 women were included to explore the difference in the level of sex hormones between women with CKD and without CKD in the present study.Natural menopause was defined as physiological amenorrhoea longer than 12 months and does not interfere with other causes, such as surgery or medical treatment . SurgicaData related to eGFR calculation are accessed from NHANES. Serum Cr was calibrated for the 1999–2000 and 2005–2006 participants. The recalibration equations for 1999–2000 and 2005–2006 NHANES surveys were applied: standard serum Cr (mg/dl) = 0.147 + 1.013 × uncalibrated serum Crw (mg/dl) and standard serum Cr (mg/dl) = −0.016 + 0.978 × uncalibrated serum Cr (mg/dl). Estimating glomerular filtration rate (eGFR) was calculated by the CKD Epidemiology Collaboration equation:2 or urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g, and CKD patients were classified into stages according to GFR categories and albuminuria categories by the Kidney Disease: Improving Global Outcomes (KDIGO) organization  . Relevannization .Public-use Linked Mortality Files are available for continuous NHANES 1999–2014. These files provide mortality data from the date of survey enrollment through December 31, 2015. The survival time data we use are the number of Person-Months of follow-up from NHANES Interview date, with a mean follow-up time of 89.5 months. Mortality source and cause of death were determined using death certificates similar to previous studies , 25.2, 25 to <30 kg/m2, ≧30 kg/m2), triglycerides , total cholesterol , high-density lipoprotein cholesterol , coronary heart disease, congestive heart failure, stroke, cancer were also included in this analysis. Lifestyle factors included smoking status  and alcohol consumption .Clinical covariates were classified as demographics, medical conditions, and lifestyle factors. We used the information at screening from the survey in these analyses. Demographic factors included age, race/ethnicity, and marital status. Medical conditions included hypertension , diabetes . Obesity , p = 0.011], the result remained the same as the further adjusted model. However, when we explored the relationship between early menopause and CKD-G1/2 and CKD-G3~5 respectively  and luteinizing hormone , but a lower level of testosterone  and estradiol . For sex hormone-binding globulin (SHBG), CKD and non-CKD groups made no difference.To find out the connection between the CKD prevalence and early menopause in women, we compared the hormone level of CKD and the non-CKD group . SeveralIn the present study, both early natural menopause and early surgical menopause were associated with statistically significant increased risk of CKD, with persistent relation observed after adjusted for conventional factors. In our study, when we treated the CKD stage as a covariate, both early natural menopause and surgical menopause were risk factors for survival, but the results had some differences when we divided the participants into CKD and non-CKD. Early natural menopause was independent of longevity in the non-CKD group. However, in the CKD group, the regression results of the age of menopause as a continuous variable and early menopause as a categorical variable are different. As for surgical menopause, bilateral oophorectomy before age 45 years increased the all-cause mortality in the non-CKD group, but such finding was not observed in the CKD group. Our study also revealed the apparent differences in sex hormone levels between CKD and non-CKD participants.Our study revealed women with early menopause, both natural and surgical, had a higher percentage of current smoking and having cardiovascular disease including stroke and congestive heart failure. Studies have reported that smoking is associated with an earlier age of menopause, and a later age of menopause could reduce the risk of cardiovascular diseases . Our stuOur study suggested that early menopause, both natural and surgical, was associated with a higher risk of CKD and early natural menopause is mainly associated with CKD-G3~5. A study based on the multiethnic Women's Health Initiative cohort had mentioned early natural menopause occurred more among women with CKD , but theThe difference in sex hormone levels between the CKD group and the non-CKD group in this study proved that sex hormones may play crucial roles in the association between early menopause and CKD. As CKD develops, an inadequate cyclic release of gonadotropin-releasing hormone (GnRH) by the hypothalamus leads to loss of normal pulsatile gonadotropin secretion by the pituitary including FSH and LH –34. In tIn our study, early natural menopause did no effect on mortality in the non-CKD group. In the CKD group, there was a negative result when we take early menopause as a categories variable, however, when we treated age at menopause as a continuous variable, we found early natural menopause was associated with higher mortality. The relation between age at natural menopause and mortality is controversial. A study based on the Health, Well-Being and Aging study found women with early menopause had a 48% higher risk of all-cause mortality compared to the women with menopause at normal age , but a TBilateral oophorectomy undertaken before age 45 years is thought to increase mortality in the general population , 45, theThere are still many limitations in our study. First, the criterion of menopause was only 1 year without menstruation after excluding some special conditions, without considering the issue of hormone levels. Second, most of the data were from the questionnaire, including the time of menopause. Although some abnormal data had been screened out, the accuracy of the data was still lacking. As for women with surgical menopause, there are no specific reasons for women to undergo bilateral oophorectomy in the NHANES, and we can only speculate it according to other studies, that might interfere with the outcome. Additionally, there were inevitable censorings in the follow-up, which may have an influence on the results. Finally, because we can't get information about when the participants developed CKD, the sequence of CKD and menopause is unknown and the causal relationship between early menopause and CKD is not clear and requires further cohort studies. Despite these limitations, our study has the merit of using a representative national sample, and we have found evidence in support of the association between early menopause and CKD prevalence and all-cause mortality, and their difference between CKD and non-CKD patients.Both early natural and surgical menopause were associated with a higher risk of CKD. In our study, early surgical menopause was a hazard factor for survival in the non-CKD group, but not in the CKD group. The mechanisms behind these associations need further research.The original contributions presented in the study are included in the article/The NHANES is a periodic survey conducted by the National Center for Health Statistics (NCHS) of the Centers for Disease Control and Prevention (CDC). The NCHS Research Ethics Review Board reviewed and approved the NHANES and all participants provided written informed consent. NCHS Ethics Review Board Protocol Number: Protocol #98-12, Protocol #2005-06 and Protocol #2011-17.GX: conceptualization. DQ and Z-fW: data curation and writing—original draft. Z-fW: formal analysis. S-WG: methodology and writing—review and editing. DQ: resources and software. Y-cC and RL: validation. All authors contributed to the article and approved the submitted version.This work was financially supported by the International  Cooperation and Exchange Projects (NSFC-DFG Grant No. 81761138041), National Natural Science Foundation of China (Grant No. 81570667), Major Research Plan of the National Natural Science Foundation of China (Grant No. 91742204), and the National Key R&D Program of China (Grant No. 2018YFC1314003-1).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.


Purpose: This retrospective observational study aimed to investigate the self-reported prevalence of seizure clusters (SCs) in patients with epilepsy (PWE) and its relationship with clinical characteristics.Methods: We retrospectively analyzed data from consecutive PWE from our hospital in northeastern China. Data were collected from the databank of a tertiary epilepsy center. Logistic regression models were employed to investigate the relationships between the individual patient demographic/clinical variables and the occurrence of SC.Results: In total, 606 consecutive PWE were included in the final analysis, and 268 (44.2%) patients experienced at least one seizure cluster. In multivariate logistic regression models, age , seizure frequency , multiple seizure types , number of current anti-seizure medications (ASM) , drug-resistant epilepsy , and a history of status epilepticus  were independent variables associated with a history of SC in PWE.Conclusion: Seizure clusters (SCs) are common occurrences at our study center. The occurrence of SC in individuals with epilepsy, to some extent, is determined by the epilepsy severity. Epilepsy is one of the most common serious brain disorders, affecting more than 70 million patients worldwide . ApproxiMany researchers have paid attention to the potential factors contributing to SC in PWE and they also estimated the patients' risk of SC , 6, 10. The prevalence of SC in Chinese adults with epilepsy has yet to be investigated, and knowledge about factors associated with SC in PWE is also scarce in mainland China. Thus, our study aimed to answer the following questions: (1) How many Chinese adults with epilepsy have experienced a history of SC defined as ≥3 seizures in 24 h? (2) Which demographic or clinical characteristics are associated with a history of SC? (3) Are the potential risk factors for SC vary by epilepsy type?We conducted a retrospective observational study of PWE in an epilepsy management program at the epilepsy center in the First Hospital of Jilin University. A clinical databank was established for PWE in our center. The databank included demographic and clinical information on the PWE who were treated and followed up at our hospital. A standardized questionnaire was used to collect data during the interview when they visited their neurologist at the center. We recorded the demographic data such as name, age, and gender. The recorded clinical information consisted of the diagnosis, 24-h video electroencephalogram (EEG), neuroimaging, epilepsy type, seizure frequency, and medication profile. The establishment of the databank was approved by the Human Research Ethics Committees of our hospital, and participants provided written informed consent before we collected the data.We retrospectively reviewed the medical records of patients in the databank from January 2020 to July 2021. Individuals were included in our analysis if they had the following criteria: (1) had a definite diagnosis of epilepsy in accordance with the International League Against Epilepsy (ILAE) ; (2) hadTo evaluate the history of SC, we defined SC as three or more seizures occurring within 24 h, which is the habitual pattern that has been widely used by previous studies , 6, 15. U-tests were used for continuous variables, while Chi-square/Fisher's exact tests were used for categorical variables. We employed logistic regression models to investigate the relationships between the individual patient demographic/clinical variables and the history of SC. Variables achieving significance at p < 0.05 in the univariate analyses were entered into multivariate logistic regression models. The results were presented as odds ratios (ORs) with the corresponding 95% CIs. The type of epilepsy was classified as focal epilepsy or non-focal epilepsy, including unknown classification. The same logistic regression analyses were also performed based on epilepsy type. All p-values were two-sided, and statistical significance was set at p < 0.05. All data were analyzed in SPSS 26.0 .Data are described as percentages for categorical variables and as medians [interquartile ranges (IQRs)] for continuous variables. For group comparisons, Mann–Whitney In total, 606 consecutive PWE were included in the final analysis, with a median age of 35 years and a male percentage of 53.5%. The demographic and clinical characteristics are shown in p = 0.021), have a longer epilepsy duration (P < 0.001), reported a family history of epilepsy (p = 0.041), and experienced a higher seizure frequency over the last six months (P < 0.001) than those without a history of SC. Multiple seizure types were more frequent in patients with a history of SC (p < 0.001), and their number of present ASMs were higher (p < 0.001). Patients who experienced SC were more likely to have a known etiology of epilepsy (p = 0.002), abnormal MRI (p = 0.011), and drug-resistant epilepsy (P < 0.001). There was an increased risk of the presence of status epilepticus in the SC group (P < 0.001) for details (see Patients with a history of SC were more likely to be older (ails see .p = 0.021), duration of epilepsy , family history of epilepsy , seizure frequency , multiple seizure type , number of present ASMs , known etiology of epilepsy , abnormal MRI , drug-resistant epilepsy , and history of status epilepticus . The ten variables that were significant in the unadjusted univariate analysis were entered into the multivariate logistic regression analysis. In the multivariate logistic regression models, age , seizure frequency , multiple seizure type , number of present ASMs , drug-resistant epilepsy , and history of status epilepticus  were independent variables associated with a history of SC in PWE for details , number of present ASMs , drug-resistant epilepsy , and a history of status epilepticus . In the non-focal epilepsy group, the only variable associated with an increased OR for SC was seizure frequency  for details , duration of epilepsy, seizure frequency, localization , MTS, remote symptomatic epilepsy, posttraumatic epilepsy, CNS infection, cortical dysplasia, and status epilepticus , 18–25. To date, it remains unclear why seizures cluster. The neurobiological underpinnings of SC were not addressed in our investigation. However, prior evidence indicated that this may be because endogenous hormone fluctuations can lead to periods of enhanced seizure susceptibility and other periods with greater resistance to seizure recurrences . PeriodsPrior researchers identified focal epilepsy as a risk factor for SC in PWE . HoweverSeveral limitations should be acknowledged in the current study. First, this study is limited by its retrospective observational nature. Data were collected based on patient self-reports, and thus, there may be recall bias. Second, the data were restricted to PWE in a tertiary epilepsy center, which may also cause a strong sampling bias toward people with refractory epilepsy. Another inherent bias of this study is that patients who died from SC cannot be included. Third, some factors that might be associated with the occurrence of SC in epilepsy  were noSeizure clusters are common occurrences at our study center and were reported by 44.2% of this PWE population. The occurrence of SC in persons with epilepsy, to some extent, is determined by epilepsy severity. Factors associated with the occurrence of SC included older age, higher seizure frequency, multiple seizure types, more current ASMs, drug-resistant epilepsy, and history of status epilepticus.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Human Research Ethics Committees of the First Hospital of Jilin University. The patients/participants provided their written informed consent to participate in this study.RZ and WL conceived of and designed the study. RZ, QC, and XZ were involved in data acquisition. RZ and QC analyzed the data and wrote the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by a grant from the Programme of Jilin University First Hospital Clinical Cultivation Fund (LCPYJJ2017006).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: There are few standardized measures available to assess executive function (EF) in a naturalistic setting for children. The Children’s Cooking Task (CCT) is a complex test that has been specifically developed to assess EF in a standardized open-ended environment (cooking). The aim of the present study was to evaluate the internal consistency, inter-rater reliability, sensitivity and specificity, and also convergent and divergent validity of the Norwegian version of CCT among children with pediatric Acquired Brain Injury (pABI) and healthy controls (HCs).Methods: The present study has a cross-sectional design, based on baseline data derived from a multicenter RCT. Seventy-five children with pABI from two university hospitals with parent-reported executive dysfunction and minimum of 12 months since injury/completed cancer therapy, as well as 59 HCs aged 10–17 years, were assessed with CCT using total errors as the main outcome measure. The pABI group completed tests assessing EF  on the impairment level within the ICF framework , and on the participation level (questionnaires). In addition, they completed tests of intellectual ability, processing speed, attention, learning, and memory. Finally, overall functional outcome  was evaluated for the children with pABI.Results: Acceptable internal consistency and good inter-rater reliability were found for the CCT. Children with pABI performed significantly worse on the CCT than the HCs. The CCT identified group membership, but the sensitivity and specificity were overall classified as poor. Convergent validity was demonstrated by associations between the CCT and performance-based tests assessing inhibition, cognitive flexibility, and working memory, as well as teacher-reported executive dysfunction (questionnaires). Divergent validity was supported by the lack of association with performance-based measures of learning and memory, attention, and verbal intellectual ability. However, there was a moderate association between the CCT and performance-based tests of processing speed. Lastly, better performance on the CCT was associated with a better functional outcome.Conclusion: Our study with a relatively large sample of children with pABI and HC’s demonstrated good psychometric properties of the CCT. CCT performance was associated with the overall level of disability and function, suggesting that CCT is related to the level of activity in everyday life and participation in society. Hence, our study suggests that the CCT has the potential to advance the assessment of EF by providing a valid analysis of real-world performance. Nevertheless, further research is needed on larger samples, focusing on predictors of task performance, and evaluating the ability of CCT to detect improvement in EF over time. The patterns of error and problem-solving strategies evaluated by the CCT could be used to inform neuropsychological rehabilitation treatmentand represent a more valid outcome measure of rehabilitation interventions. Self-control is imperative for optimal functioning in everyday life  working memory (the ability to hold information in mind and manipulate it); (b) cognitive flexibility ; and (c) inhibition  association between performance-based neuropsychological tests; and (2) self- or parent reports about everyday EF such as the Behavior Rating Inventory of Executive Functions  is a complex test specifically developed to assess EF in a standardized naturalistic open-ended environment (cooking). It is designed to require task setting and evaluation of goal maintenance and involves multi-tasking abilities, in addition to providing minimal external control and structure. The behavioral rating is based on error analysis in accordance with Lezak’s cognitive model where execution errors are thought to reflect dysfunction in planning, goal direction, and task monitoring . Other studies found associations between total errors on CCT and EF questionnaires in children with pABI  regarding internal consistency, test-retest reliability  internal consistency and inter-rater reliability; (2) sensitivity and specificity i.e., the ability to discriminate between typically developed children and children with pABI, as well as age-related differences in task performance; (3) convergent validity by including three assessment levels; standardized performance-based tests of EF, other ecologically sensitive tests of EF, parental and teacher reports of EF in daily life, and measures of overall disability and functioning in everyday life ; and (4) divergent validity by comparing CCT-performance to IQ, processing speed, memory, and learning. We hypothesized that we would confirm findings from earlier studies reporting good internal consistency and inter-rater reliability  age 10–17 years; (ii) a diagnosis of pABI; (iii) a period of at least 12 months since injury/illness diagnosis, or 12 months since completion of cancer treatment; and (iv) executive dysfunction in daily life as determined by a semi-structured interview. Exclusion criteria were as follows: (i) injury acquired before 2 years of age; (ii) cognitive, sensory, physical, or language impairment affecting the capacity to attend regular school ; (iii) pre-injury neurological or developmental disease, severe (neuro)psychiatric disorder and/or use of stimulant medication; (iv) recently detected brain tumor relapse; (v) not fluent in Norwegian; and (vi) food allergy interfering with the ability to complete the CCT.For the healthy control (HC) group, typically developed children aged 10–17 years were included. Exclusion criteria were: (i) previous head injury with loss of consciousness >5 min, stroke, other brain injuries, brain diseases or developmental condition; (ii) severe (neuro)psychiatric disorder or substance abuse; (iii) cognitive, sensory, physical, or language impairment affecting the capacity to attend mainstream school; (iv) not fluent in Norwegian; and (v) food allergy interfering with the ability to complete the CCT.Data were collected between 2017 and 2019 at St. Olav’s Hospital, Trondheim University Hospital, and Oslo University Hospital. Participants were recruited from the trauma referral centers for the Central, South-Eastern, and Northern regions of Norway. Seventy-seven participants with pABI who met inclusion and exclusion criteria and completed baseline assessment in the RCT study were included in this study. For a full description of recruitment procedures, see Hypher et al.  and Brann = 59) was recruited from local public schools. Written informed consent was required from potential participants (≥16 years) or primary caregivers (participants <16 years). The HC’s were designed to recruit an equal number of boys and girls, and with an age span evenly distributed across three age groups .The healthy control group  and magnetic resonance imaging (MRI) taken during the first year post injury or disease onset.n = 2). Additionally, the Processing Speed Index (PSI) was derived from the Coding and Symbol Search subtests for children with pABI.We employed two measures of IQ from the Wechsler Intelligence Scales for Children, 5th edition  and subsequently rates the errors. The CCT allows for a two-step error rating where descriptive errors are rated first, and a second step where errors are reconsidered in terms of the reason why they occurred . Subclassification of errors on the descriptive level provides an overview of the number of additions, omissions, comments, and questions, substitutions-sequence errors, and estimation errors. The total number of errors is calculated as the total of those five types of errors. Subclassification of errors based on neuropsychological concepts provides an overview of the number of control errors, context neglect, environmental adherence, purposeless actions and displacements, dependency, and inappropriate behavior. In addition, the test provides qualitative measures . Norms are not yet available. The total number of errors was used as the primary outcome in analyses of reliability and validity, and the total number of errors without comments or questions was used as a secondary outcome .The English version was translated (double-translation and reconciliation procedure) and adapted into Norwegian according to the ITC Guidelines for Translating and Adapting Tests  by two independent raters.All performance-based tests described below have demonstrated adequate validity and reliability, and most have been recommended by McCauley et al.  as commoEF Inhibition include time score (raw score) from the Color-Word Interference Test—condition 3 . For raw scores on Coding, Symbol Search, and CWIT a higher score indicates poorer function. For raw scores on CAVLT and T-scores on C-CPT-III, a higher score indicates better function.Although recognizing that the complex nature of the CCT may implicate integration of non-executive functions, and that measures of cognitive functions such as working memory, attention, and learning may require the integration of all these functions, we chose nevertheless to categorize the following measures as assessing non-executive function : Processing speed  from the Coding and Symbol Search subtests from WISC-V, time raw score from condition 1 and 2 from CWIT, and time raw score from condition 2 from TMT, total Learning , immediate and delayed recall from the Children’s Auditory Verbal Learning Test 2nd . The day was divided into four blocks . Participants were randomly allocated to each of the blocks for assessment. As such, the order of test administration varied between the participants. The assessment was limited to 1 day to prevent unnecessary use of the participants’ time and the burden of additional travel, as we recruited from the whole country with long travel distances. To alleviate tiredness, participants were given frequent breaks and a one-hour lunch break. To compensate for variation associated with multiple assessors, a Standard Operating Procedure (SOP) described the protocol and procedures for assessment, and the test administrators received training from an experienced clinical neuropsychologist. Participants, their parents, and teachers completed the BRIEF .Study procedures and monitoring were performed according to ICH Guideline for Good Clinical Practice and Norwegian procedures and regulations for Clinical Trials, described by the Norwegian Clinical Studies Infrastructure Network. Written informed consent was signed by participants (>16 years) or primary caregivers (<16 years). The study was approved by the Regional Committees for Medical and Health Research Ethics, Norway (2017/772/REK), and conducted in accordance with principles of the Helsinki Declaration and the standards for Ethical Research Involving Children . Clinical Trial Registration No.: NCT03215342.standard deviation, SD) for normally distributed data, and otherwise as median with interquartile range (IQR). All data analyses were conducted using IBM-SPSS version 27  was considered too conservative in the current study given its exploratory nature . As data were non-normally distributed, we evaluated the sensitivity and specificity of the different error types on CCT by calculating a Receiver Operator Characteristic (ROC) Curve and calculated the area under the ROC (AUROC). AUROC between 0.9 and 1.0 were considered Very good, 0.8–0.9 were considered Good, 0.7–0.8 were considered Fair, 0.6–0.7 were considered Poor, and 0.5–0.6 would be considered as Fail.For non-normally distributed data, nonparametric statistics were employed. Proportions were compared using the chi-square test, the unconditional t-test. To explore the clinical significance of the differences between groups, the effect size was calculated (r) for comparisons using Mann-Whitney U-test, and Glass’ delta (d) for comparisons using t-tests , consistency-agreement, and a two-way random-effects model for the intraclass correlation , by first entering all error types from the CCT in the analysis, and then observing the stability of the measure by removing each individual error type from the model. Inter-rater reliability for total errors on the CCT was assessed by using single-rating  was used to estimate the association between the primary and secondary outcome measures in CCT and performance-based tests and questionnaires.t(128) = −5.75, p < 0.001, Glass’ d: −1.0) and visual IQ composite score (t(131) = −5.23, p < 0.001, Glass’ d: −0.99).Demographic and background characteristics are presented in t(131.8) = 5.871, p < 0.001, Glass’ d: 0.92) and their parents reported less EF problems on the DEX-C (t(130.1) = −7.576, p < 0.001, Glass’ d: −1.13). Mean and SD is given in the tables below.Comparing the pABI group and the HCs on selected measures of EF examined for both groups, we found that HC had better performance on BADS-C overall scaled score (α = 0.85) when entering all scores for the different types of error in the analysis. Internal consistency was relatively stable between α = 0.82 and 0.86 when each individual error type was removed from the model.Internal consistency of the CCT was acceptable (k = 2), consistency-agreement, two-way random-effects model for the intraclass correlation . Inter-rater reliability estimate varied between 0.529 (estimation errors) and 0.931 (context neglect errors) for the different error scores  compared to the HC : 2%–21%; the exact unconditional z-pooled test: p = 0.05). In addition, a larger proportion of children with pABI needed intervention from an adult to complete the task  compared to the HC . There was no difference between the groups with regard to the occurrence of dangerous behavior (pABI: n = 9 vs. HC: n = 12).For the qualitative scores, a larger proportion of children with pABI failed to achieve the overall goal of the task . We found that younger children with pABI made more additions , omissions , estimation errors , and had more inappropriate behavior .Exploring the effect of age on total errors on CCT, we observed that lower age at assessment was associated with more errors on the CCT in the pABI group .In the HC group, there was no significant association between the age at assessment and the total number of errors on CCT, although younger age at assessment was associated with a higher number of omissions .p = 0.007) among children with pABI.A higher number of total errors on CCT was associated with lower functional outcomes , Cognitive flexibility , and the Working memory domain (Picture memory) when applying adjusted alpha. There was a trend toward a significant association between the total number of errors on CCT and the CPT-III Commissions from the Inhibition domain, the composite score of Working memory, and Digit span from the Working memory domain. Performance on CCT was not associated with any of the tests assessing Planning  nor with other EF subtests. Effect sizes were in the moderate to small range.Furthermore, fewer total errors on the CCT were associated with better overall performance on the ecologically sensitive BADS-C test. Among the BADS-C battery, worse performance on some subtests was also significantly associated with more errors on the CCT . Effect sizes were in the moderate to small range.Notably, fewer total errors with or without comments and questions on the CCT were associated with better perceived daily life EF (DEX-C and BRIEF)—but only through teacher reports, with effect sizes in the moderate range. No associations were observed for self- or parent-report.sr = 0.314, p = 0.007).Lastly, we investigated the association between CCT and level of disability and functional outcomes. We found that better performance on the CCT was associated with less disability and better functional outcome . However, a moderate association was found between total errors on the CCT and the Visual IQ Composite score . For the HC group, we found no association neither between total errors on CCT and the VCI score , nor the VSI .Tests of divergent validity in the pABI group is summarized in Converting the raw scores in For the pABI group, we found that better performance on the CCT was associated with better processing speed—both on the composite score and most of the individual tests. However, there was no significant association between performance on the CCT and performance on tests in the Domain Attention or the Domain Learning and Memory. Nevertheless, there was a trend toward an association between total errors on CCT and performance on CWIT2, CPT-III Detection t score, and CPT-III Hit Reaction Time SD t score, but the effect sizes were small.The main aim of this study was to evaluate the psychometric properties of the Norwegian adaptation of CCT. Overall, our findings provide evidence for good internal consistency, inter-rater reliability, as well as discriminant, convergent and divergent validity.Our study demonstrated good internal consistency for the different error types of the CCT, which is in line with findings in previous studies on children with pABI  prior to inclusion. Although the average parent reported GEC on the BRIEF in the pABI group in our study was significantly worse than the normative average (T-score of 60), they reported fewer executive problems than in the study by Fogel et al.  the significant association with performance-based tests assessing the EF domains of Cognitive flexibility and Working memory in the pABI group; (2) significant association with the ecologically sensitive BADS-C battery for both groups; and (3) significant association with teacher reported executive dysfunction on the BRIEF and DEX-C in the pABI group.In the present study, a higher total number of errors on CCT was related to poorer ability to accurately switch between task sets (Cognitive flexibility), and poorer ability to add relevant and omit non-relevant information from working memory (Working memory). Furthermore, the error types that differentiated best between the pABI group and HCs were errors that could be classified within the same construct of Cognitive flexibility and Working memory. This supports the developmental model of EF proposed by Diamond, arguing that EF could to some extent be divided into separable EF processes. Chevignard et al.  detectedContrary to our hypothesis, no significant associations were observed between the performance on CCT and the composite scores of Inhibition. However, we did find that a higher number of errors on CCT were associated with poorer performance on CWIT Inhibition and there was a trend toward an association between CCT and CPT-III Commissions. This suggests that to some extent, performance on CCT relies on the ability to resist making automatic responses and control actions, as well as ignore distractions. Furthermore, we did not find any association between performance on CCT and tests assessing Planning. This is in contrast to the study by Chevignard et al. , where tThe associations between the CCT and the performance-based tests ranged from small to moderate, which is in accordance with previous findings from both children . Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin for participants under 16 years of age, or by the participant themselves if they were 16 years or older.TF, SA, MC, AB, RH, KR, TR, and JS have developed the study protocol for this study. TF, AB, and JS conceived the original idea for the study design, and together with MC and SA selected outcome measures. TF, JS, and RH have been involved in the translational process of the outcome measures. TF, GJ, and AB have adapted the CCT material. TF has been responsible for the recruiting process, training of assessors, developing the Norwegian manual for CCT, and developing and inserting data into the webCRF. GJ has contributed to the recruiting process, developing the manual for CCT, assessed the participants, conducted the IRR, and inserted data into the webCRF. Finally, all authors have agreed to be accountable for all aspects of the work. 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.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.


This might be due to a lack of proof for its efficacy. We searched electronic databases  for randomized controlled trials (RCTs) examining predefined BPT interventions. A total of 2,180 references were screened, of which 113 studies were scrutinized in detail and 18 RCTs finally included. The observed effect size (ES) demonstrated medium effects of BPT on primary outcomes psychopathology and psychological distress. In case of significant statistical heterogeneity, exploratory subgroup analyses revealed diagnosis and the degree of control group activity as noteworthy moderators. For secondary outcomes, evidence was scarce, and an improvement could be demonstrated only for coping abilities. The identified evidence indicates that BPT is beneficial for a wide spectrum of psychic suffering. There is a strong need for high-quality studies with bigger samples and for well-defined diagnostic entities to underpin its effectiveness.Despite the growing relevance and applicability of elements based on and derived from the  Feeling and connecting to one's own body plays a central role in psychotherapy since its beginning: the founders of psychoanalytic therapy regarded somatic tensions as an expression of mental conflicts , 2, and In psychotherapy, an ambiguity toward bodily experiences becomes apparent that stems from the phenomenological consideration of the body as subject as opposed to the body as object: whereas the former means the experience of the body as constituting the first-person perspective from which an individual encounters the world, the latter refers to the objectified body that natural science examines on different levels  –13. AlthIn case of pathology, Weizsäcker's model of the “Gestaltkreis”  offers abody therapy and BPT. The former technique focuses on the experienced body to increase the person's physical and psychological well-being. BPT fulfills, in addition, the standards of a verbal psychotherapy following Strotzka  addressed intersubjective body experience in the above-described manner, enframed in psychotherapeutic measures; (2) had a two-factorial design  with randomized group allocation; (3) publications had to indicate descriptive statistics such as mean and standard deviation or frequencies suitable for the determination of effect sizes; (4) had to be written in English or German and their abstract had to be available via scientific data bases; and (5) the included participants had to be adult (18+ years) and required a diagnosed psychiatric disorder or significant psychic suffering proven by reliable measures . There were no restrictions regarding setting (outpatient or inpatient), format , dose, and quality of activity applied in the control group.*] with . In addition, reference lists of the identified review articles and of the European Body Psychotherapy Association were scrutinized to include further studies. An updated hand search until April 30, 2021 did not detect recent relevant studies. Study selection was carried out by SR and HS, applying a short checklist for the abovementioned criteria. Doubtful cases were discussed between the authors and discrepancies solved by Delphi method, if necessary, under consultation of CL.Relevant articles were identified by searching PubMed (MEDLINE), PsycInfo, and PSYNDEX on November 4, 2018. We cross-referenced  based on the random-effects model between groups on the primary and secondary outcomes. In this way, we accounted for the plausible variability of effects among studies. In case an outcome of interest was reported by more than one scale within a study, we integrated those using z-transformation to avoid multiple testing . Per conp ≤ 0.20). As a quantitative measure, I2 indicates the percentage of variance that is attributable to study heterogeneity.As primary outcomes, we chose measures of psychopathology and psychological distress. Whereas, the former depicts the main characteristic(s) of the psychic suffering, the latter describes the overall functional impairment due to mental or bodily symptoms. As secondary outcomes, measures of coping abilities, quality of life, body experience, and interpersonal difficulties were analyzed. Confidence intervals (95%) of effect sizes were estimated for significance tests using the Z-statistic  . PositivSubgroup analyses were carried out in case of significant heterogeneity for these dimensions: year of publication, sample size, diagnosis, bodily active control, and dose of therapy. Data management and statistical analyses were executed with the open-source online platform Covidence and the Review Manager 5.3 of the Cochrane Collaboration.Concerning dropout, as a convention, sample size was fixed to the smallest available number of participants per dimension. For categorial data, odds ratios (and their SE) were calculated and transformed into SMD (and corresponding SE).The literature search yielded 2,657 publications in three databases, whereof 2,180 remained after duplicates were removed. From these, 84 did meet the inclusion criteria. Another 32 records were identified by additional measures, whereof 3 records were not attainable in full text. One hundred thirteen publications were scrutinized in detail. Finally, 23 records from 18 studies were selected for meta-analysis see . Eight rThe characteristics of the included studies are summarized in g = 0.56 [95% CI ], Z = 5.33, p < 0.001} with a moderate to high degree of heterogeneity .Changes in psychopathology as the most frequently examined outcome dimension were reported for 18 studies . The majg = 0.52, 95% CI , Z = 3.99, p < 0.001], again with moderate to high heterogeneity . Moreover, the corresponding within-group effects on the primary outcomes are statistically significant .For psychological distress , includeg = 0.68, 95% CI , Z = 5.42, p < 0.001]. As the effects on primary outcomes, this effect relies on a more pronounced amelioration of the intervention groups. At the same time, an effect of BPT on quality of life could not be demonstrated  in seven included studies, although five of these studies revealed an at least slight improvement  in this dimension. In four studies reporting data for body experience, an improvement for BPT could not be demonstrated . As to interpersonal conflicts, the four analyzed studies suggested a small effect size, indicating a benefit of BPT compared to CG bordering statistical significance .Data on coping abilities, quality of life, body experience, and interpersonal difficulties were available for a restricted number of studies only see . On copiPost-hoc, we performed subgroup analyses on within-group effects in primary outcomes . As to dose, a smaller number of intervention hours corresponded to a larger effect.g = 0.41, 95% CI , Z = 2.99, p < 0.01] with 10 included studies . However, for psychological distress, the effect remained quite stable with g = 0.47  induced from eight studies , with both effects statistically significant.To estimate long-term stability of the effects, we integrated catamnestic data. On average, follow-up was conducted 7 months  post-intervention. For psychopathology, the long-term total effect-size slightly decreased to a small to medium effect [In order to account for possible publication bias, we generated funnel plots on primary outcomes see . As for This systematic review and meta-analysis aimed to give an overview of existing randomized controlled trials on BPT. In summary, we found moderate effect sizes for BPT on the selected primary outcomes psychopathology and psychological distress, which are characterized by substantial statistical heterogeneity of the included studies. This may reflect the wide variety of the examined interventions, study designs, and included diagnoses. However, for the dimensions investigated, nearly all studies reported effects in favor for BPT. Exploratory subgroup analyses suggest potential influences especially of study design and diagnosis.g = 0.34–0.46) on symptomatology. In comparison, for mindfulness-based interventions  led to smaller between-group effects of BPT on primary outcomes than comparisons with inactive controls. Because of the small number of studies, we did not differentiate between exercise only and body therapy  as control conditions. A medium effect of exercise could be found on depressive symptoms ; yoga miSurprisingly, BPT interventions with smaller dose (hours of therapy) produced larger effects than those with higher dose, an observation that cannot be confirmed by other meta-analyses , 79. As Secondary outcomes were tested to analyze potential mediators of BPT. The large, homogeneous effect on coping abilities should not be granted as a general effect because of the small number of studies that it relies on. Nevertheless, this finding might be seen as a positive indicator that BPT targets emotion regulation. While other meta-analytic data on coping is rare, an evaluation on psychosocial group interventions that addressed coping reported no amelioration . ConsequConsidering quality of life, both groups benefited equally, which contradicts meta-analyses on other types of psychotherapy . When coNeither did we find a difference concerning body experience, where comparable evidence is rare as well. In this regard, the distinction between body schema and body image by Gallagher  might beGeneral concerns regarding meta-analysis potentially limit the usefulness of the applied meta-analytic approach when informing patient care . In partThe evidence identified in this study suggests that BPT often was applied as adjunct therapy rather than an alternative to single psychotherapy. Accordingly, BPT often was examined in  treatment programs for following an additive research design. This issue might result in some benefit for external validity. Moreover, the most commonly used group setting may improve efficacy and economical implementation of these approaches.This study scrutinizes psychotherapeutic approaches providing psychological and bodily interventions simultaneously, studies that accordingly could be characterized as implementing an “embodiment” perspective. The analysis could demonstrate at least some non-neglectable evidence for the effectiveness of BPT: the meta-analytic integration of the observed effect sizes revealed moderate effects of BPT on the chosen primary outcomes psychopathology and psychological distress, indicating that the examined studies provided potentially efficacious measures.For a better understanding of the mechanisms under question, we carried out subsequent subgroup analyses. Most evidently, the good performance of, in particular, active control groups should not be underestimated. As a consequence, BPT and related approaches appear as good candidates to further develop disorder-specific treatment approaches. However, the potential occurrence of negative side effects of BPT, for example, on trauma, should not be neglected further. Reflecting the rich variety of applied therapeutic approaches in very heterogeneous domains of psychic suffering and variegated treatment settings, there seems to be a strong need for future, high-quality studies with bigger samples to elucidate conditions for the effective use of BPT. We emphasize that those studies should report data on safety aspects, adverse events, acceptability, and patients' preferences, too.The original contributions presented in the study are included in the article/All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Introduction: Aging has many effects on the cardiovascular system, including changes in structure  and function . Mouse models are often used to gain insight into vascular aging and mechanisms of disease as they allow invasive assessments that are impractical in humans. Translation of results from murine models to humans can be limited, however, due to species-specific anatomical, biomechanical, and hemodynamic differences. In this study, we built fluid-solid-interaction (FSI) models of the aorta, informed by biomechanical and imaging data, to compare wall mechanics and hemodynamics in humans and mice at two equivalent ages: young and older adults.Methods: For the humans, 3-D computational models were created using wall property data from the literature as well as patient-specific magnetic resonance imaging (MRI) and non-invasive hemodynamic data; for the mice, comparable models were created using population-based properties and hemodynamics as well as subject-specific anatomies. Global aortic hemodynamics and wall stiffness were compared between humans and mice across age groups.Results: For young adult subjects, we found differences between species in pulse pressure amplification, compliance and resistance distribution, and aortic stiffness gradient. We also found differences in response to aging between species. Generally, the human spatial gradients of stiffness and pulse pressure across the aorta diminished with age, while they increased for the mice.Conclusion: These results highlight key differences in vascular aging between human and mice, and it is important to acknowledge these when using mouse models for cardiovascular research. Aging is a primary risk factor for numerous cardiovascular diseases . Even inin vivo. Rather, the gold standard method to estimate the structural stiffness of the aorta clinically is to measure the pulse wave velocity (PWV). PWV increases with natural aging as well as with many related co-morbidities and has been linked clinically to hypertension and other cardiovascular diseases  than in mice (6.3 × 108), which is expected to impact mechanical fatigue-induced loss of elastic fiber integrity , can be used to quantify and compare hemodynamic quantities that are difficult to infer experimentally in humans and mice. In this study, FSI models were built for young and old female adult humans and mice to compare multiple hemodynamic and biomechanical effects of aging on the two species. For the humans, representative computational models for young and old adult subjects were defined using imaging data, non-invasive pressure measurements, and population-specific arterial wall properties. For the mice, representative population-based computational models for young and old adults were obtained using 1 suggests that a 13–27 weeks old mouse is similar to a 20–30 years old human, and an 81–108 weeks old mouse is similar to a 56–69 years old human. Imaging and brachial cuff pressure data were obtained for young adult (31 years old) and older adult (81 years old) female human subjects. This study was approved by the University of Michigan Board of Review (HUM00041514). In vivo imaging and ex vivo biomechanical testing data were obtained for young adult (20 weeks old) and older adult (100 weeks old) female mice. All animal procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Yale University. The mice had a mixed C57BL/6 × 129/SvEv background, generated as +/+Fbln5 by breeding +/–Fbln5 heterozygous pairs  was performed on human subjects at the University of Michigan Medical Center. These exams were performed on 3T MRI scanners  using a 32-channel torso coil. A non-contrast MRA was performed spanning the thoraco-abdominal aorta using a 3D balanced turbo field echo sequence with navigator-based respiratory compensation .As described previously , mice we40-phase, 2D phase-contrast MRI (PC-MRI) images were acquired in planes orthogonal to the human aorta at the levels of the mid-ascending aorta and distal descending aorta at the diaphragm . Brachial artery blood pressure was measured with a standard non-invasive cuff method, averaged from patient data dating back 2 years . It is important to note that the older human was considered healthy and free of cardiovascular diseases and medication, except for long-term, low-dose diuretic (hydrochlorothiazide) to control blood pressure which resulted in a reduction of blood pressure from 140/85 mmHg prior to medication to the 111/55 mmHg used in this study.n = 10 young adult and n = 10 old adult mice.As described previously , mice westructural stiffness, the product of the intrinsic material properties and wall thickness, which dictates the hemodynamic response to an artery under pulsatile flow. A four-fiber family constitutive model was used to quantify the biaxial material stiffness of the arterial wall, both human and murine. This model contains 8 parameters to capture the macroscopic behavior resulting from the contributions of elastic fibers, collagen fibers, and additional matrix ],Mi represents the orientation of the fiber families  was iteratively adjusted until the mean pressure [estimated as Pmean = (2Pdias + Psys)/3 from cuff measurements] corresponded with the in vivo mean diameter [estimated as Dmean = (2Ddias + Dsys)/3 from PC-MRI images] on the pressure diameter curve , and IAA] and a CCA with a computer-controlled custom biaxial testing device (z)  and cyclic axial extension tests at four fixed values of transmural pressure   . Best-fiult mice .FSI models were built with the open source computational hemodynamics platform CRIMSON . Data frThe CRIMSON GUI was used to create 3D models of the aorta and main branches. Centerline paths were determined for each vessel of interest and circular contours were added perpendicular to the centerline with discrete spacing to represent the vessel lumen. 3D volumes resulted by lofting between contours and applying a union function to blend the aorta and main branching vessels. For the humans, the 3D representation was based on MRA images. For the mice, the 3D representation was based on μCTA images. Furthermore, for the mice, 9 sets of intercostal arteries were added based on the location of the ribs.6 tetrahedral elements and 2 × 105 nodes for the young adult and 2.6 × 106 tetrahedral elements and 5 × 105 nodes for the old adult. For the mice, meshes had 1.7 × 106 tetrahedral elements and 3 × 105 nodes for the young adult and 2.9 × 106 tetrahedral elements and 5 × 105 nodes for the old adult.Field-driven mesh adaptation techniques were used to create finite-element meshes refined on regions of high velocity gradients. For the humans, meshes had 1.4 × 100Mb with Υ being the quantity of interest , Υ0 the normalized quantity from experimental data, M the body mass, and b a scaling constant. Linear regression of log-log plots of the quantify of interest versus body mass was used to determine the coefficients  and total arterial compliance (CTOT) were estimated. RTOT was estimated from Pmean/CO for both species. For the humans, CTOT was estimated from (maxQ − minQ/systoleP − diastoleP)tΔ  = P0exp (−t/RTOTCTOT)] Δt . For theOTCTOT)] . FurtherTOT and CTOT can be separated into 3D  and peripheral portions. The 3D portion is set by the anatomy and stiffness of the central vasculature; the peripheral portion can be estimated iteratively. Once RTOT and the distal portion of CTOT are obtained, they must be distributed among the outflow branches of each computational model to ultimately specify proximal resistance (Ci), and distal resistance (i) as described previously , distal DTA (dDTA), SAA, IAA, and one CCA based on in vitro testing. The same values for the four-fiber family parameters were used for both sections of the DTA, but because of differences in diameter, linearization was performed at different in vivo circumferential stretch for the proximal and distal portions. Upper branches  were assigned the same stiffness and thickness as the tested CCA. Middle branches  were assigned the same stiffness matrix as the SAA and the thickness of the CCA. Iliac and tail arteries were assigned the stiffness and thickness of the IAA.For the mice,  testing . In vivos) and damping (cs) coefficients were applied to all vessels to represent the pressure (Pext) from tissues surrounding the vasculature  to the iliac artery (directly after the iliac bifurcation), which is different from the common carotid-femoral PWV (cfPWV) which fails to include the ATA, a region of particular change in aging . PWV wasAnatomical models of the aorta and main branches of humans and mice can be seen in θθθθ) and axial (Czzzz) material stiffness and wall thickness (h) prescribed based on available data . Humans and mice demonstrated differing patterns of aortic stiffness. Human subjects exhibited increased material stiffness down the aorta with peak values occurring in the IAA. In contrast, mice exhibited peak circumferential stiffness in the pDTA that then decreased distally. Nevertheless, both species experienced an increase in circumferential stiffness with age in all aortic regions with the exception of the human IAA. This increase in stiffness was larger in the mouse than the human with the largest increase (550%) occurring in the mouse pDTA. Humans had the greatest increase in circumferential and axial stiffness  from young to old in the ATA. For the mouse, axial stiffness increased with age in all aortic regions except for the IAA. Wall thickness increased in the human subjects with age, while in the mouse it remained relatively constant, except for in the IAA.TOT and CTOT between the central (3D) and peripheral components. RTOT was of similar magnitude for mice and humans, but CTOT was three orders of magnitude smaller for the mice. The young adult human had smaller total resistance and larger total compliance than the older. Conversely, mice experienced a decrease in resistance and an increase in compliance with age. Humans had most of their total compliance in the central vasculature, while mice, particularly the older mice, had a majority in the periphery. For both species, there was a decrease in central and increase in peripheral compliance with age.Computational results for peak systolic blood velocity as well as regional  blood pressure and flow waveforms are shown in Hemodynamic results were validated against experimental data. For the humans, averaged blood pressure cuff measurements were compared with the simulated (not imposed) left subclavian artery pressure , resultiNotwithstanding all that has been learned about vascular biology, mechanics, and physiology via the use of diverse animal models, mice have emerged as the primary model of choice in contemporary vascular research, including studies of the effects of hypertension and aging on the cardiovascular system . NeverthThe representative healthy human subjects in this study showed a decrease in CO with aging, which is consistent with trends found in the literature. Fbln5–/–), which capture some aspects of aortic aging in humans  and population-based data for the mice. In this work, we do not present any population-based statistics. Statistical significance would be important to address for different patient cohorts or for different mouse groups, but with greater numbers of subjects. The key focus here is not on group-to-group differences, but rather on similarities and differences between representative subjects of the species, human and murine in particular. Furthermore, in both species, non-linear material properties were population based. All results were for females, and cardiovascular aging likely differs for males. Similar studies comparing young and old males and contrasting aged males and females would be interesting as well. Because we used population-based data for a particular mouse colony, our results hold for the C57BL/6 × 129/SvEv strain, with expected differences for pure C57BL/6 and 129/SvEv mice cf. . Previouest data . ComputaTo our knowledge, this study is the first comparison of the differences in hemodynamics, wall properties, and vascular anatomy as a function of age between mice and humans. We identified key differences between the human and murine central vasculature such as patterns in aortic stiffness, pulse amplification, amount and distribution of arterial resistance and compliance, and changes in CO, stiffening, and resistance and compliance with age, which question many uses of naturally aged mouse models for understanding certain aspects of cardiovascular aging in humans. Conversely, there are also key similarities between the species, as, for example, a global increase in aortic stiffness, increase in ATA pulse pressure, decrease in mean arterial pressure, reverse flow in older subjects, and increase in PWV. Furthermore, genetic manipulation of mouse models may lessen the differences by capturing broader population diversity, which is a critical step toward personalized medicine. For example, there are mouse models that effect elastin structure and content , which mThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the University of Michigan Board of Review. The patients/participants provided their written informed consent to participate in this study. The animal study was reviewed and approved by the Institutional Animal Care and Use Committee (IACUC) of Yale University, New Haven, CT, United States.FC, NB, JH, and CF: conceptualization. FC, JF, and NB: data collection. SH, FC, JF, SR, JH, and CF: formal analysis. JH and CF: funding acquisition, supervision, and overall responsibility. SH and CF: writing of original draft. SH, FC, JF, NB, SR, JH, and CF: writing—review and editing and final approval 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.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.