The aim of the study was to assess serum cathepsin B, D, and L concentrations in women with late-onset preeclampsia.One hundred forty pregnant women were enrolled in the study, of which 100 subjects were preeclamptic and 40 were healthy controls. Serum concentrations of cathepsin B, D, and L were measured and compared between the preeclamptic and control groups.Cathepsin B and D concentrations were significantly higher in the preeclamptic group compared with the control group. There was no statistically significant difference between the groups in terms of cathepsin L concentrations. Cathepsin B concentrations were significantly higher in women with preeclampsia with severe features compared with those with preeclampsia alone.Women with late-onset preeclampsia have significantly higher serum cathepsin B and D concentrations than controls. Cathepsin B and D may be promising biomarkers in women with late-onset preeclampsia. PRECIS: Cathepsin B and D may be promising biomarkers in women with late-onset preeclampsia.. The important roles of cathepsins have been implicated in normal and abnormal placentation; however, research on the serum concentrations of cathepsins in preeclampsia is limited.Cathepsin proteases have been suggested to be involved in a variety of cellular processes such as apoptosis, angiogenesis, cell proliferation, and invasion.Determining late-onset preeclampsia, which is more common than the early-onset preeclampsia, and identification of high risk individuals may be helpful for close monitoring and to minimize adverse outcomes in clinical practice. The aim of the study was to assess serum cathepsin B, D, and L concentrations in women with late-onset preeclampsia and to determine the impact of cathepsins with regard to the presence of severe features.Preeclampsia is one of the leading causes of maternal-fetal morbidity and mortality, affecting approximately 3-5% of all pregnancies.Both cysteine proteases are determined to have critical roles during normal placentation and in the etiology of preeclampsia. Cathepsin D is an aspartic protease that participates in the trophoblast invasion process, and the contribution of cathepsin D is also suggested in the pathogenesis of preeclampsia,5.Cathepsin B and L are cysteine proteases that have important roles in placental development and in the physiology of normal and pathologic conditions. Cathepsin B is reported to be predominantly located in placental and decidual macrophages, which may be important in mediating villous angiogenesis and decidual apoptosis, and cathepsin L is found to be expressed in invasive cytotrophoblastsHowever, there are a limited number of studies that evaluated serum concentrations of cathepsins in preeclamptic women and the studies had small sample sizes. Additionally, to our knowledge this is the first study to evaluate serum cathepsin B, D, and L concentrations in late-onset preeclampsia.After obtaining written informed consent from all participants, one hundred forty pregnant women were enrolled in the study, of which 100 subjects were preeclamptic (late-onset preeclampsia diagnosed at ≥34 weeks gestation) and 40 were healthy controls. The study protocol was approved by the Marmara University Ethics Committee .. The common inclusion criteria for both groups were: singleton pregnancy at ≥34 weeks gestation, normal fetal morphology, non-smoking, and the absence of concomitant disease.Preeclampsia and severe features were defined according to current recommendations based on the 2013 American College of Obstetricians and Gynecologists’ consensus guidelinesSerum concentrations of cathepsin B, D, and L were measured using an enzyme-linked immunosorbent assay (ELISA) by using the human cathepsin B, D,  and L  ELISA kits according to the manufacturer’s instructions and then compared between the preeclamptic and control groups.All data were analyzed using the Statistical Package for the Social Sciences 20.0 for Windows program . The distribution of data was measured using the Kolmogorov-Smirnov test. Data are presented as mean ± standard deviation or n (%). Student’s t-test was used for comparisons of means, and the chi-square test was used to compare categorical variables between the two groups, as appropriate. Pearson’s correlation test was used for the correlation analyses. The receiver operating characteristics (ROC) curve of cathepsin B in predicting severe preeclampsia was analyzed. The results were considered significant if p values were <0.05, and highly significant if p<0.01.One hundred forty pregnant women were enrolled in the study, of which 100 subjects were preeclamptic (late-onset preeclampsia diagnosed at ≥34 weeks’ gestation) and 40 were healthy controls. Twenty-six subjects in the preeclamptic group had severe features.Cathepsin B concentrations were significantly higher in the preeclamptic group compared with the control group . Cathepsin D concentrations were significantly higher in the preeclamptic group compared with the control group . There was no statistically significant difference between the groups in terms of cathepsin L concentrations . There were no statistically significant differences between the groups in terms of age, body mass index, and gestational age. Systolic and diastolic blood pressures and serum uric acid concentrations were significantly higher in the preeclamptic group . The mea,8,9. Although there is growing evidence and there are many theories addressing its heterogeneous nature, the pathogenesis is not yet fully understood,8,9.Preeclampsia is a multifactorial clinical state that adversely affects several vital organs and increases the morbidity and mortality of both the fetus and the motherThe aim of the study was to evaluate cathepsin concentrations in women with late-onset preeclampsia and to determine the impact of cathepsins with regard to the presence of severe features. To our knowledge, this is the first study to emphasize the importance of cathepsin B, D, and L serum concentrations in women with late-onset preeclampsia.In our study, we found significantly higher serum concentrations of cathepsin B and D in the preeclamptic group compared with the control group; however, cathepsin L concentrations were similar between the two groups. Moreover, cathepsin B concentrations were found to be positively correlated with uric acid concentrations in women with preeclampsia. Our data also indicate that cathepsin B concentrations were significantly higher in women with preeclampsia with severe features compared with those with preeclampsia alone, emphasizing the importance of cathepsin B in women with preeclampsia and in the subgroup of preeclamptic women with severe features.,11 and it has been demonstrated that abnormal concentrations and activities may correlate with various physiologic processes and human diseases, such as neurodegenerative disorders, regulation of apoptosis, immune responses, inflammatory diseases, cancer,,14,15 psoriasis, and cardiovascular,18 and kidney diseases.Cysteine cathepsins are lysosomal peptidases that comprise cathepsin B and cathepsin L, which have many physiologic roles in different organs and tissues including cancer progression, tumor proliferation triggers, invasion, and metastasis,. The distribution and abnormal expression concentrations of cysteine cathepsins were also reported in preeclamptic placentas indicating their important roles during normal placentation and in the etiology of preeclampsia.In a study evaluating serum concentrations of cathepsin B and L that included 40 women with preeclampsia and 38 women as controls, higher concentrations of cathepsin B and L were reported in women with preeclampsia; however, no statistically significant difference was reported between women with severe preeclampsia compared with subjects with mild preeclampsia. The differential expression or aberrant release of cathepsin proteases from trophoblasts or other types of cells were suggested to have a key role in the pathophysiology of preeclampsia.Circulating concentrations of cathepsin B and D were determined in a cohort of 72 pregnant women in which 25 were preeclamptic and 47 were normotensive. In accordance with our study, cathepsin B concentrations were found to be significantly increased in preeclamptic women, whereas in contrast to our data, no significant difference was found in cathepsin D concentrations between the preeclamptic and control groups, and no correlation was found between the cathepsin concentrations and the severity of preeclampsia. Few studies have evaluated the impact of cathepsin D in women with preeclampsia. In a study evaluating cathepsin D activity in the umbilical cord, it was reported that preeclampsia was associated with a reduction in the activity of cathepsin D in human umbilical cord. The placentas of preeclamptic subjects were also evaluated by Kim et al., and an overexpression of cathepsin D in the placentas from preeclamptic patients was demonstrated suggesting a trigger of apoptosis. In another study, circulating serum concentrations of cathepsin D were found to be significantly lower in the preeclamptic group (n=15) than in normotensive pregnancies (n=35) and also similar to those in non-pregnant healthy patients (n=20); however, a limited number of preeclamptic cases were included in the study and further studies with larger sample sizes were suggested. In our study, we found that serum cathepsin D concentrations were significantly higher in the preeclamptic group compared with the control group.Cathepsin D is a lysosomal aspartic proteinase that plays a key role in protein degradation and in apoptotic processes that are induced by oxidative stress, cytokines, and agingThe limitation of the study is its small sample size. Further studies with larger sample sizes are needed.This is the first study to demonstrate the impact of cathepsin B, D, and L on late-onset preeclampsia. There are few previously published studies with small sample sizes that have reported conflicting results about the importance of cathepsins in the pathogenesis of preeclampsia. The present study shows that women with late-onset preeclampsia have significantly higher serum cathepsin B and D concentrations than controls, and cathepsin B concentrations are even higher in the subgroup of preeclampsia that has severe features. In summary, the study suggests that cathepsin B and D may be promising biomarkers in women with late-onset preeclampsia. Moreover, cathepsin B may be useful in early identification of preeclamptic women with severe features.


We investigated the distribution of cold hypersensitivity in the hands and feet (CHHF) and examined the association between CHHF and health-related quality of life (HRQOL) among Koreans. Stratified multistage sampling was used for random selection of 2,201 adults. HRQOL was assessed using the Short-Form 12-Item Health Survey (SF-12). Cold hypersensitivity was measured using a new self-report questionnaire to score the extent of cold sensation in their hands, feet, and abdomen using a 7-point scale. The correlation between CHHF and HRQOL was analysed using multiple regression analysis. Cold hypersensitivity was present in the hands of 21.6%, the feet of 23.0%, and the abdomen in 22.5% of participants. Cold hypersensitivity in the hands and feet was observed in 17.9%, at least one body part  in 34.2%, and all three body regions in 12.3% of participants. The prevalence of cold hypersensitivity was significantly higher among women than among men, irrespective of the involved body part. Cold hypersensitivity scores in the hands and feet correlated negatively with body mass index, but not with age. The physical component summary (PCS) and mental component summary (MCS) of the SF-12 were both significantly lower in women with than in those without CHHF. Among men, only the PCS was significantly lower in the CHHF group. Multiple regression analysis, adjusted for sociodemographic variables, age, sex, and body mass index (BMI), confirmed that CHHF had negative effects on PCS and MCS. CHHF is more common in women and in individuals with a lower BMI. CHHF has an independent negative effect on HRQOL. Cold hypersensitivity in the hands and feet (CHHF) is the symptom of sensation of cold in the extremities under conditions that would not typically evoke such a sensation. CHHF is commonly observed in East Asians, especially women, and is a result of the abnormal contraction of blood vessels in the extremities , 2. AlthCHHF is considered more important in Korean medicine and other types of traditional East Asian medicine (TEAM) than in Western medicine. This is because CHHF is an important diagnostic factor in TEAM and is traditionally known to accompany several chronic symptoms and diseases, such as dyspepsia, menstrual pain, fatigue, and infertility , 9. TherAlthough the prevalence of CHHF and its effects on health-related quality of life (HRQOL) are important with regard to health care and policies, studies related to CHHF are insufficient. In Korea, one study investigated the location  and severity of cold hypersensitivity in 362 women visiting the gynaecology outpatient department of one university-affiliated hospital of Korean medicine . AdditioHence, this study aimed to investigate the prevalence of cold hypersensitivity by location , and its effect on HRQOL, using a nationwide survey conducted over two rounds in 2013 and 2015.The participants in this study were adult Korean men and women aged 19 years and over. The questionnaire survey was conducted by petition to a specialist organization . Registered citizen population statistics were used for random extraction of participants using stratified multistage sampling based on region, sex, and age . A total of 1101 participants were surveyed between May 6 and June 14, 2013, and 1100 participants were surveyed between October 1 and October 30, 2015.The survey was conducted through face-to-face interviews by a trained interviewer. The participants responded to structured questionnaires with the assistance of the interviewer. These questionnaires did not include the participants' personal information , and the participants provided verbal consent to participation after receiving an explanation of the objectives of the questionnaires and their use.This survey did not collect personal information on participants. Participants verbally agreed that the questionnaire results could be used for research purposes. This study was approved by the Institutional Review Board of the Semyung University Korean Medicine Hospital (No. 1707-10).The questionnaire about cold hypersensitivity required participants to respond to questions about their hands, feet, and abdomen in everyday life. Each question was scored on a 7-point scale, whereby a score closer to 7 indicated a colder condition, and a score closer to 1 indicated a warmer condition. A score of 5–7 points for one location was defined as cold hypersensitivity of that area, a score of 5–7 points in both the hands and the feet was defined as CHHF, while a score of 1–4 points in both the hands and the feet was defined as non-CHHF.The participants' HRQOL was assessed using the Short-Form 12 Item Health Survey (SF-12 v2). The SF-12 is a health-related questionnaire with established validity and reliability. It is divided into the physical component summary (PCS) and the mental component summary (MCS) and consists of 8 domains. Scores range from 0 to 100 points, with a higher score indicating better health –17. We a t-tests were used to compare data between different time points, cold hypersensitivity prevalence between males and females, and HRQOL scores and anthropometric variables according to CHHF status. The correlations of the cold hypersensitivity score with age and body mass index (BMI) were evaluated for each body part using Pearson's correlation coefficient. A multiple regression analysis was performed to verify whether CHHF acted as an independent factor affecting HRQOL after adjustment for sex, age, BMI, and sociodemographic variables, such as drinking, smoking, marital status, income, occupation, and education, as variables that could affect CHHF and HRQOL. A P value of less than 0.05 was considered statistically significant. SPSS 22.0  was used for all statistical analyses.Participants' general characteristics are expressed as the mean ± SD (standard deviation) and frequency. Chi-square tests and independent2. Mean cold hypersensitivity scores were 3.4, 3.5, and 3.6 for the hands, feet, and abdomen, respectively. Other general characteristics are presented in There were 2201 participants in total, comprising 1090 men (49.5%) and 1111 women (50.5%). The mean age of participants was 46.5 ± 15.4 years and the mean BMI was 23.2 ± 2.9 kg/mCold hypersensitivity scores in the hands and feet were strongly positively correlated, with correlation coefficients exceeding 0.8 in both men and women; there were also moderate positive correlations between cold sensitivity in the abdomen and the hands, and in the abdomen and the feet . Age did not correlate with cold hypersensitivity, but BMI was negatively correlated with cold hypersensitivity in the hands and feet. Abdominal cold hypersensitivity and BMI did not show a significant correlation in women or men, individually, but did show a weak negative correlation across all participants combined .As shown in Cold hypersensitivity of the hands was observed in 21.6%, cold hypersensitivity of the feet was observed in 23.0%, and cold hypersensitivity of the abdomen was observed in 22.5% of participants. Cold hypersensitivity of all three body parts was observed in 17.9% of participants, and 34.2% of participants showed cold hypersensitivity in at least one of the three body parts. The prevalence of cold hypersensitivity was significantly higher in women than in men, irrespective of the body part .The two groups showed no difference in age, but weight and BMI were lower in the CHHF group for both men and women. PCS and MCS were significantly lower in the CHHF group than in the non-CHHF group for women. For men, PCS was significantly lower in the CHHF group, but there was no significant difference between these groups in terms of MCS .In a multiple regression analysis investigating the effects of CHHF on PCS and MCS, CHHF was found to have a statistically significant negative effect on PCS and MCS in all models, including Model 1, which did not use adjustment variables, Model 2, which corrected for age and sex, Model 3, which corrected for age, sex, and BMI, and Model 4, which added sociodemographic variables such as drinking, smoking, marital status, income, occupation, and education .Here, we investigated the prevalence and characteristics of CHHF among Koreans by administering a self-report questionnaire survey to typical Korean adults. Overall, our results have implications for both basic research and clinical applications and suggest that people with CHHF might have poor health.hanjeung; han zheng; 寒證) or yang deficiency  in traditional Korean medicine, but is also considered to be associated with various other symptoms and diseases. Recently, several studies have reported that individuals with CHHF have a higher prevalence of functional dyspepsia , while they have a lower prevalence of metabolic syndrome [CHHF is not only a major factor for diagnosing certain conditions, such as cold syndrome (syndrome , 20.In related work, studies in Japan have investigated subjects with a cold disorder called ‘hiesho', which is a similar concept to CHHF, and reported a higher frequency of symptoms such as shoulder stiffness, fatigue, neck stiffness, eyestrain, knee pain, and abdominal pain , 22. MorTherefore, the public health sector is increasingly recognizing the importance of ascertaining the prevalence and distribution of CHHF. In one study of 3067 elderly individuals aged 65 years or older, 28.6% of women and 23.6% of men were reported to have cold feet and/or legs . AnotherIn Korea, even though a large number of individuals visit medical institutions for CHHF, few studies have investigated the proportion of Koreans with CHHF or other cold disorders, and on the impact of CHHF on HRQOL. Indeed, the majority of studies of cold disorder or CHHF in Korea have only examined particular subject groups , 28, makAs previously mentioned, at an institution of traditional Korean medicine, subjects most frequently complained of cold sensation in their hands, feet, and abdomen . Hence, As shown in Age showed no correlation with cold hypersensitivity scores in either men or women; this differs from the results of Mozaffarieh and colleagues, who reported a negative correlation between CHHF and age in women . HoweverUsing the SF-12, the relationship between CHHF and HRQOL was evaluated in terms of the MCS and PCS. Since previous studies had confirmed a high prevalence of various symptoms and diseases in groups with CHHF, we predicted that similar trends would be observed in the general Korean population , 21, 23.This study has the following limitations. First, because the questionnaire used in this study only assesses the severity of cold sensation in each body part, participants may have differed in their standards for discomfort related to cold hypersensitivity. A more objective instrument will need to be developed in the future to overcome this problem. In addition, because we were unable to survey the duration of symptoms and the time of onset, it was not possible to evaluate the impact of CHHF duration on HRQOL. Second, it is difficult to directly compare the results of this study with those of previous studies, since previous CHHF studies used different evaluation and diagnostic methods. Third, because CHHF is influenced by race, culture, and the environment , 30, it Despite these limitations, this study differs from previous studies that have largely investigated patients at medical institutions. Specifically, we recruited a sample analogous to the general Korean population by stratifying participants by age, sex, and region. Therefore, our study was able to examine the distribution of cold hypersensitivity in Korea more accurately compared with any previous study, so the data on tendency and distribution of CHHF in Koreans collected through this study can be used as a reliable basis for preparing health policies and medical care guidelines for this symptom in the future. In addition, the results of this study on the relationship between CHHF, BMI, and HRQOL suggest that people with CHHF need management of CHHF in order to improve HRQOL, and one of the ways to improve the HRQOL is to avoid low BMI.In conclusion, this study elucidated the distribution of cold hypersensitivity among Korean adults by body part and sex and also demonstrated a clear negative correlation between BMI and CHHF. Finally, we confirmed that CHHF had an independent negative effect on PCS and MCS, even after adjusting for age, sex, BMI, and sociodemographic variables.


To verify whether trade-off ability varies across VWM capacity, we measured each individual’s VWM capacity and then conducted a colour recall task to examine their trade-off ability. By manipulating the task requirement, participants were instructed to memorise either more colours in a low-precision way or fewer colours in a high-precision way. We conducted two experiments by adjusting stimulus duration to be longer than predicted critical value (Experiment 1) and duration shorter than predicted critical value (Experiment 2). While the results of Experiment 1 showed a positive correlation between the VWM capacity and trade-off ability, the results of Experiment 2 showed a lack of such correlation. These results are consistent with the prediction from the two-phase model.The relation between visual working memory (VWM) capacity and attention has attracted much interest. In this study, we investigated the correlation between the participants’ VWM capacity and their ability to voluntarily trade off the precision and number of items remembered. The two-phase resource allocation model proposed by Ye  This system provides a storage space as a buffer to integrate information into continuous visual experience. By maintaining the mental contents after the visual scene disappears, this system plays a role as a gatekeeper between perception and high-level cognition2.Visual working memory (VWM) is a system to actively maintain visual information and provide the information for advanced cognitive processing4. Previous studies also found that VWM capacity differs substantially across different populations, and the VWM impairment is associated with a variety of cognitive disorders, such as Parkinson’s disorder5 and schizophrenia7. Moreover, there are reliable individual differences in VWM capacity even for healthy population8. Some individuals show VWM capacity of four items or above, whereas others show VWM capacity of two or less9. Besides, these individual differences are robustly correlated with many advanced cognitive functions such as fluid intelligence10. Therefore, understanding the relation between VWM capacity and other cognitive constructs is an essential topic in this field.It is well known that VWM capacity develops in childhood, peaks in adulthood, and then declines with age16. A well-established consensus is that individuals with low VWM capacity are poor at exerting attention control over what is being consolidated and maintained in VWM. For example, evidence provided by Vogel, et al.13 clearly illustrated this relationship. They identified a contralateral delay activity (CDA), an ERP component strongly modulated by the number of items in VWM during the maintenance phase and reaches an asymptote once VWM capacity is exhausted. They asked participants to memorise simple targets and ignore distractors. The CDA amplitude was used as an index of whether irrelevant distractors unnecessarily consumed VWM storage. The results suggested that participants with high VWM capacity were able to filter out the distractors, but low VWM capacity participants tended to fail to filter out distractors and involuntarily allocate VWM storage to them. By using a similar technique, a recent study also found that even when social stimuli such as emotional faces acted as distractors in a VWM task, high VWM capacity participants could still filter face distractors entirely, while participants with low VWM capacity automatically stored neutral and angry face distractors into VWM14. These studies have shown that low VWM capacity individuals could not help but orient their attention to distractors11, and thus they ended up storing more distractors in their limited-capacity VWM than high VWM capacity individuals13. Therefore, the individual’s VWM capacity is highly related to the attention efficiency for target selection . Although this individual difference approach successfully clarified the critical relationship between VWM capacity and attention control in the tasks with distractors18, it is still unclear how attention control ability is affected by the VWM capacity in other tasks.Many studies have investigated the relationship between individuals’ VWM capacity and attention control ability28, but the conclusion is still debated.In tasks without distractors, the attention control can be studied in tasks requiring a voluntary trade-off ability in VWM resource allocation. Here, the trade-off ability for VWM precision and number refers to a situation in which individuals adjust the VWM resource allocation voluntarily, while the lack of trade-off ability refers to a situation where individuals can only allocate VWM resource involuntarily. So far in the literature, there have been many studies on whether individuals could voluntarily trade off the VWM precision and number23 investigated whether participants could voluntarily trade off the VWM precision and number when they have enough incentives. In their Experiment 3, they asked participants to memorise four colours and then recall one of the colours. After the response in each trial, feedback would be presented to inform them about their performance. They gave participants different incentives to trade off the VWM precision and number by manipulating the rules of the feedback. In the low-precision condition, participants could get some rewards even when recalling colours with low-precision. On the contrary, in the high-precision condition, only when they reported the colour with high precision, they would be told that they were correct and received more monetary rewards. However, Zhang and Luck23 did not find any evidence to support the voluntary trade-off ability in individuals with their experimental setting. Similarly, Murray, et al.19 asked participants to memorise stimuli in a way that emphasised precision or number, and only observed the null effects. These results support that the resource could only be allocated in a stimulus-driven (involuntary) manner.Zhang and Lucket al.24 asked participants to memorise orientations of items with either low-precision or high-precision. Their results showed that, in low-precision condition, participants could retain three to four items in VWM, but in high-precision condition, participants could only retain two items in VWM. Similarly, Machizawa, et al.20 found that participants could adjust the memory precision when the memory load was low (two items) according to different task requirements. These results suggest that people have a voluntary trade-off ability, and support that the resource could also be allocated in a goal-directed (voluntary) manner.However, the phenomenon of voluntary trade-off has been reported in some other studies. In an ERP study, Gao, et al.21 proposed a two-phase VWM resource allocation model that can explain these two different patterns of results24. In their experiments, they used an orientation recall task. Similar to Experiment 3 and 4b in Zhang and Luck’s23 study, by manipulating the feedback following each trial, Ye, et al.21 asked participants to memorise different numbers of orientations in different precision blocks. The novel aspect of the study is that stimulus exposure duration and set size were systematically manipulated. They found no effect of precision requirement with a high set size and short exposure duration (stored four items with 200 ms exposure duration). However, when the set size was low (stored two items with 200 ms exposure duration) or the exposure duration was long (stored four items with 500 ms exposure duration), participants could trade off the VWM precision and number according to task requirements. These results were interpreted with the two-phase VWM resource allocation model. The model states that in the early phase the VWM resource could only be allocated in a stimulus-driven (involuntary) manner. However, the allocation could enter the late phase after the completion of the first phase. In the late phase, the allocation could be controlled flexibly according to task requirements in a goal-directed (voluntary) manner. In other words, individuals automatically allocate VWM resources in the early phase and create a low-precision representation for each item in the scope of attention. After the low-precision representations have been entirely created or the VWM resources have been completely allocated, the individual can reallocate VWM resources and create high-precision representations according to the requirements of the task. Therefore, for a given set size, it takes a certain amount of consolidation time for an individual to control attention to adjust resources to trade off the memory precision and number in the VWM task without distractors.Recently, Ye, 28. The table also reports whether these experiments support an individual’s voluntary trade-off for VWM precision and number. In 23 out of 25 experiments reported, when the exposure duration per stimulus item equalled or exceeded 100 ms/item, trade-off between the VWM number with precision occurred, however, when the exposure duration per stimulus item was equal or smaller than 50 ms/item, trade-off between the VWM precision with number did not occur. We thus speculate that the different patterns of results in terms of the trade-off between VWM precision and number could be determined by a critical value of the ratio of duration/set size . The two-phase VWM resource allocation model could explain such critical value influencing the trade-off.Table individual’s capacity. Although so far in the literature there have been many studies examining whether individuals could trade off the VWM precision and number28, surprisingly, the impact of individual’s VWM capacity on the trade-off ability of VWM precision and number have not been carefully examined.It is reasonable to argue that the critical value of duration/set size affecting trade-off could be related to individual participants’ VWM capacities. All ten studies described above examined the participants’ performance at a population level (using the mean performance of the sample). An alternative way to identify the critical factor affecting the trade-off is to examine the relation between trade-off tendency and 23, we conducted a similar colour recall task to examine participants’ trade-off ability. In order to verify whether trade-off ability varies across VWM capacity, we first measured each individual’s VWM capacity and then conducted the colour recall task to examine their trade-off ability. By using different feedback to manipulate task requirements, participants were asked to memorise colours in different precision conditions. We conducted two experiments using a ratio of duration/set size higher than the predicted critical value (Experiment 1) and a ratio lower than the predicted value (Experiment 2).The current study takes a novel approach to examine the effect of individual VWM capacity on the underlying process in resource allocation. To be more comparable with Zhang and LuckWe anticipated that, at the population level, with a high ratio of duration/set size provided in Experiment 1, we would find that participants in the high VWM capacity group could trade off the precision and number according to task requirements, but participants in the low VWM capacity group could not. However, with a low ratio provided in Experiment 2, neither high VWM capacity participants nor low VWM capacity participants could trade off the precision and number. Moreover, at the individual level, with a high ratio of duration/set size provided in Experiment 1, we would see a relation between trade-off ability and VWM capacity, as for most participants, they would have completed the early phase and entered the late phase of the two-phase model in which allocation could be controlled voluntarily according to task requirements. In contrast, with a low ratio provided in Experiment 2, we would not see such a relation, as for most participants, the processing would still be in the early phase of the model in which VWM resource could be allocated only by an involuntary manner.et al.21, when 500 ms exposure duration was used for four memory items, participants were able to trade off the VWM precision and number, we adopted this ratio of 125 ms/item in our Experiment 1.Based on the study by Ye, A total of 26 undergraduate students  were recruited from the participant pool at the Minnan Normal University of China. They reported normal or corrected-to-normal vision and no history of neurological problems. Participants gave informed consent before participating in the experiment. All procedures were approved by the Ethics Committee of the Liaoning Normal University, China, to collect data outside the campus , and conducted in accordance with the Declaration of Helsinki (2008).In the change detection task for VWM capacity measurement described below, colour squares (each 0.65° × 0.65°) in the memory array displayed within a 9.8° × 7.3° region around a central fixation cross, with a constraint that the distance between two colours was at least 3.5° (centre-to-centre). The colours were randomly selected from 360 possible colours  in the colour recall task, with colour separated by at least 50 colour steps.29, was used for the recall array. The stimuli showed in the memory array were randomly chosen from the colour palette with a minimum distance of 30° in colour space between stimuli in the array of four colours. The whole experiment was conducted in a dark room, with a 19 inch LCD screen (1280 × 768 pixel) for presenting the stimuli, and the distance between the participant and the screen was approximately 60 cm.In the colour recall task described below, for the memory array, the colour stimuli were four coloured squares (each 0.9° × 0.9°) presented against a grey background. With a fixation cross in the centre, the colour stimuli were presented at the four corners of an imaginary square with an eccentricity of 3.0°. Then, a set palette of 360 colours in a colour wheel , adopted in a prior study by our groupThere were two sessions in the experiment, the VWM capacity measurement session and the colour recall task session. The participants first completed a change detection task to measure their VWM capacities. In this session (VWM capacity measurement), each trial began with a central fixation cross that appeared on the screen for 200 ms. A memory array of six colours was then presented for 500 ms. After a subsequent 1000 ms retention period featuring a blank screen, a test array that lasted for 2500 ms was presented Fig. . A test After the completion of the VWM capacity measurement, participants had a rest of at least five minutes before beginning the second session. In this session, participants needed to complete a colour recall task with two precision conditions Fig. . Each trThere were 100 trials in the VWM capacity measurement session. In the colour recall task session, the order of the precision conditions was counterbalanced across participants. Each precision condition included 280 trials. There were seven 30-second breaks within-blocks and a 2-min break between the low- and high-precision blocks. Before each block, participants needed to finish at least 24 practice trials to understand the rules. The entire experiment lasted for approximately one hour.30. Similar to previous VWM studies31, the median split was used to divide participants into different VWM capacity groups.For each participant in the VWM capacity measurement session, we measured the VWM capacity by using Cowan’s K formula: K = N × (H − F), where K represents the VWM capacity, N represents the number of displayed colours, H represents the hit rate, and F represents the false alarm rateet al.’s21 study, where the first 80 trials in each block were not included because participants need to take a certain amount of time for forming an appropriate strategy based on the task feedback in different conditions. Thus, the results were only calculated based on the last 200 trials. The offset in each trial was calculated by subtracting the recalled colour  from the target colour.In the colour recall task session, it may have taken a certain amount of time for forming an appropriate strategy based on the task feedback in different conditions. The same method was used here as that used in Ye, 32. The mixture model allowed us to estimate the correct memory rate (P) that the target item was correctly recalled from VWM as 1 − G. Data analysis was performed using the MemToolbox33. The standard mixture model was fitted to individual data in different precision conditions, respectively. Since the precision is inversely related to the variance, we used the SD (inversely related to the precision) as the memory precision index and used the P  as the memory number index. Besides, we also used the swap model34 to fit the data, as the outcomes from statistical tests of mixture model parameters and swap model parameters are substantially identical .The data were fitted with the standard mixture model to independently measure the SD  and G (guess rate) of the representations stored in VWMFor the individual level analysis, we defined the voluntary trade-off magnitude in the VWM precision index (SDT) aslow) and SD(high) are the precision index in the low- and high-precision conditions, and P(low) and P(high) are the correct memory rate in the low- and high-precision conditions. If the participants allocated resources flexibly in the high-precision conditions, resulting in remembering fewer items, this would make P(low) > P(high), which would obtain a positive PT. However, the items remembered would be maintained more precisely, meaning SD(low) > SD(high) , which would obtain a positive SDT. By dividing the numerators by the low-precision value, the equations of SDT and PT could minimise the inter-participant variance of the precision and number indexes and indicate the change degree of the indexes in high-precision condition to that in low-precision condition. GT value, a combined measure that contains both precision and number index, is thus the extent to which participant did trade-off according to the task requirements.Then, we merged these two indexes  and calculated a general voluntary trade-off index (GT), which was defined as35. We used the JASP 0.7 statistics package to calculate the Bayes factors36. The suggested default priors from JASP have been chosen for the Bayesian analysis. The Bayes factor  provides a continuous measure of how much more likely the data are under the alternative hypothesis compared with the null hypothesis. In our study, the null hypothesis was that there was no difference between two precision conditions, while the alternative hypothesis was that there was a difference between them. For instance, a BF10 of 0.5 represents that the data are 2 times likely under the null hypothesis than the alternative hypothesis, and a BF10 of 2 represents that the alternative hypothesis is 2 times more likely than the null hypothesis.For the population level analysis, a significance level of p < 0.05 was used for all variables and was introduced as the criterion for the post hoc analysis in the repeated measures ANOVAs. Paired two-tailed t-tests were conducted for comparison in both capacity groups. Also, Bayes factor analysis was conducted to avoid that the null results were observed by chanceFor the individual level analysis, as we mentioned above, we expected that if VWM capacity affects the trade-off ability, there should be a positive correlation between VWM capacity (K) and trade-off ability . Participants with higher VWM capacity should have better trade-off ability. On the contrary, if VWM capacity does not affect the trade-off ability, there should be no correlation between VWM capacity and trade-off ability. Therefore, we used the one-tailed tests in the correlation analysis based on our expectation.Participants were divided into different groups by the median split of their VWM capacity. A high VWM capacity group (K = 3.42 ± 0.56) and a low VWM capacity group (K = 1.89 ± 0.58), resulting in 13 participants in each group.We fitted the mixture model to the aggregate data Fig.  and averF = 13.015, p < 0.01, η2 = 0.352, but the main effect of VWM capacity was non-significant, F = 0.062, p = 0.805, η2 = 0.003. The interaction between the precision condition and VWM capacity was significant, F = 7.097, p < 0.05, η2 = 0.228. For the memory number index (P), the main effect of VWM capacity was significant, F = 4.959, p < 0.05, η2 = 0.171, but the main effect of precision condition was non-significant, F = 0.812, p = 0.377, η2 = 0.033. The interaction between the precision condition and VWM capacity was significant, F = 6.625, p < 0.05, η2 = 0.216.A two-way ANOVA with precision condition (low-precision vs high-precision) and VWM capacity (low VWM capacity vs high VWM capacity) was conducted on the memory precision (SD) and number index (P), respectively. For the precision index (SD), the main effect of precision condition was significant, t(12) = 4.102, p < 0.001, Cohen’s d = 0.86, BF10 = 28.57 for SD. Besides, the memory number in the high-precision condition was less than that in the low-precision condition, t(12) = 2.621, p < 0.05, Cohen’s d = 0.47, BF10 = 3.03 for P. In contrast, for the low-capacity group, there was neither VWM precision difference nor memory number difference between high-precision and low-precision conditions, t(12) = 0.732, p = 0.478, Cohen’s d = 0.11, BF10 = 0.35 for SD; t(12) = 1.117, p = 0.286, Cohen’s d = 0.13, BF10 = 0.47 for P.Follow-up pairwise comparisons showed that, for the high VWM capacity group the VWM precision was higher for the high-precision condition compared to the low-precision condition, In line with our expectation, these results support the hypothesis that VWM capacity affects the trade-off ability. The results suggest that for the high-capacity group, participants memorise fewer colours but with higher precision in the high-precision condition compared to the low-precision condition. However, for the low-capacity group, there was no significant difference in the precision or number between two precision conditions.We measured the relationship between the K (VWM capacity) and SDT (trade-off magnitude in VWM precision) value, K and PT (trade-off magnitude in VWM number) value, K and GT  value. The SDT, PT, GT values were plotted as a function of each’s VWM capacity in Fig. r = 0.333, p < 0.05, one-tailed): low VWM capacity participants showed low trade-off magnitude in VWM precision, and high VWM capacity participants produced much higher trade-off magnitude in VWM precision. There was a small positive correlation trend between the K and PT, but it was not statistically significant . More importantly, the VWM capacity and GT were positively correlated : low VWM capacity participants showed low general trade-off magnitude, and high VWM capacity participants produced much higher general trade-off magnitude.The K and SDT were positively correlated  as suggested by the two-phase model. We used the same procedure as Experiment 1 but reduced the exposure duration from 500 ms to 200 ms (the set size remained as four), generating a ratio of duration/set size of 50 ms/item. It is expected that participants could not voluntarily trade off for the small ratio of duration/set size as they need more time to enter the late allocation phase.Twenty-six new undergraduate students  were recruited from the participant pool at the Minnan Normal University. All procedures were approved by the Ethics Committee of the Liaoning Normal University, China, to collect data outside the campus , and conducted in accordance with the Declaration of Helsinki (2008).Except that the exposure duration of the memory array in the colour recall task decreased from 500 ms to 200 ms, the procedure and data analysis of Experiment 2 was identical with that of Experiment 1.As in Experiment 1, we divided 26 new participants based on their VWM capacity estimated in Experiment 2 into two different groups, a high VWM capacity (K = 3.24 ± 0.59) and a low-capacity group (K = 1.81 ± 0.48), resulting in 13 participants in each group respectively.Again, the mixture model was fitted to the aggregate data Fig.  and averF = 0.883, p = 0.357, η2 = 0.035, and VWM capacity, F = 0.129, p = 0.722, η2 = 0.005, were non-significant. Also, there was no significant interaction effect between the precision condition and VWM capacity, F = 0.053, p = 0.820, η2 = 0.002. For the memory number index (P), similar to the result pattern of memory precision index, no significant main effect was found neither for precision condition, F = 0.002, p = 0.967, η2 = 0.000, nor for VWM capacity, F = 1.604, p = 0.218, η2 = 0.063. Also, the interaction effect between the precision condition and VWM capacity was non-significant, F = 1.827, p = 0.189, η2 = 0.071.A two-way ANOVA with precision condition (low-precision vs high-precision) and VWM capacity (low VWM capacity vs high VWM capacity) was conducted on the memory precision (SD) and number index (P), respectively. For the memory precision index (SD), the main effects of precision condition, The results suggest that for both high and low VWM capacity group, participants maintained the same number of VWM representations with the same precision in different precision conditions. In line with our expectation, that is, with a small ratio of duration/set size, both low- and high-capacity groups did not show a trade-off ability as it appeared in Experiment 1. In other words, with a smaller ratio, most people can only allocate VWM resource in a stimulus-drive (involuntary) manner regardless of their VWM capacity.F = 4.135, p < 0.05, η2 = 0.079, but no other significant main effect nor interaction was found . For the memory number index (P), the main effect of VWM capacity was significant, F = 6.025, p < 0.05, η2 = 0.112, and there was a significant interaction effect across precision condition, VWM capacity and experiment, F = 5.909, p < 0.05, η2 = 0.110, but neither other significant main effects nor interaction was found .In addition, a mixed-factor ANOVA was conducted respectively for on the memory precision (SD) and number index (P), with the precision condition (low-precision vs high-precision) as a within-subject factor, and the VWM capacity (low VWM capacity vs high VWM capacity) and experiment (Experiment 1 vs Experiment 2) as between-subject factors For the memory precision index (SD), a significant main effect of precision condition was found, The results of ANOVA across experiments showed that there was a significant interaction between two precision conditions, VWM capacity and experiment for the number index, but no significant interaction for the precision index. However, in Experiment 1 there was a significant positive correlation between VWM capacity and trade-off magnitude in precision, but no significant positive correlation between VWM capacity and trade-off magnitude in number. These different result patterns may be due to the different variability of number index and precision index, the difference of number index was more evident in the population level analysis, on the contrary, the difference of precision was more evident in the individual level analysis. Therefore, we respectively reported the results of the population level analysis and individual level analysis. It would help us to have a more comprehensive understanding of the relationship between VWM capacity and voluntary trade-off ability.r = −0.080, p = 0.348, one-tailed), K and PT , K and GT .Again, we measured the relationship between the K (VWM capacity) and SDT (trade-off magnitude in VWM precision) value, K and PT (trade-off magnitude in VWM number) value, K and GT  value. The SDT, PT, GT values were plotted as a function of each’s VWM capacity in Fig. et al.’s21 study only because of insufficient exposure duration. Thus, the result further verifies the two-phase model.The results of both population level and individual level analyse in Experiment 2 suggest that regardless of the VWM capacity, participants could not voluntarily trade off the VWM precision and number under a small ratio of duration/set size condition. The present evidence supports that the voluntary trade-off failed in Experiment 1 of Ye, 13, our work showed that VWM capacity is also related to attention control in VWM task in allowing a voluntary trade-off between VWM precision and number, that is, the ability of voluntary VWM resource allocation. Although many previous studies have explored whether individuals can voluntarily trade off the VWM precision and number23, based on our knowledge, the current study provides the first evidence that there is a correlation between the ability of voluntary trade-off and the VWM capacity when the value of duration/set size is large enough . For participants with low VWM capacity who showed a weaker trade-off ability, the resource allocation is mainly in the form of a stimulus-driven manner, while for participants with high VWM capacity, they can take extra effort to allocate resource to trade off the precision and number voluntarily. In contrast, in Experiment 2, when the ratio of duration/set size was only 50 ms/item , the results showed that regardless of the VWM capacity, most participants could not voluntarily trade off the VWM precision and number. In this case, there was no relation between VWM capacity and voluntary trade-off ability.Experiment 1 showed, with a high ratio of duration/set size, that high VWM capacity participants were able to adjust memory precision flexibly according to task requirements, while low VWM capacity participants failed. More importantly, the VWM capacity of the individual was positively correlated with the ability of voluntary trade-off when most participants, for a given set size, have enough consolidation time to trade off the VWM precision and number. Following the previous demonstration that the individual’s VWM capacity could affect the ability of attention control to filter distractors28, but also the results of the individual level analysis by merging precision and number index. The population level analysis for the precision index did not reach significance in a between-experiment analysis . This may reflect some potential problems of the population level analysis, such as the relying solely on a median split to divide capacity groups for data analysis (while useful for illustrative purposes) might be problematic from a statistical standpoint. Thus, the continuous measure of performance  may be a more appropriate approach here. The discussion below is mainly based on the correlation results within the separate experiments.In the present study, we not only reported the results of the population level analysis on the memory precision and number index respectively as previous studieset al.21, suggesting that for a given set size, when the consolidation time is extremely short, regardless of VWM capacity, individuals cannot allocate resources voluntarily. However, when the consolidation time is long enough, individuals can allocate resources voluntarily, and the ability to allocate resources is highly related to their VWM capacity.In general, the results from the current study are consistent with the two-phase model proposed by Ye, 26, but most of the studies using colour materials failed to find evidence that participants could trade off voluntarily25. Therefore, one might think that the stimulus property (orientation vs colour) might be the determining factor for the patterns of the results. After all, orientation is a boundary feature while the main property of a colour stimulus is its surface feature37. The consolidation mechanisms for the orientation and colour materials could be different. For example, a series of studies have shown that the memory consolidation bandwidth is different between colour and orientation feature43. Thus, there is a possibility that individuals could show a lack of voluntary trade-off ability for colour materials. However, the results of our Experiment 1 showed that there was a voluntary trade-off for colour materials . These results suggest that, regardless of the stimulus property, the individuals could voluntarily trade off the VWM precision and number with long exposure duration. Moreover, it should be noted that, as it showed in our Experiment 2, with a small ratio of duration/set size, the individuals could not trade off voluntarily in the condition. Therefore, although the two-phase model was proposed in the study using orientation materials as stimulus21, the combined results of our Experiment 1 and 2 suggest that the model is also suitable for colour materials.In previous studies about the voluntary trade-off between VWM precision and number, many studies supported the voluntary trade-off used the orientation as the stimuluset al.’s26 study. Although the two-phase model could well predict the results of their Experiment 1 and 2 (which could trade off the VWM precision and number when participants memorize five colours at 1200 ms exposure duration), they conducted a quick supplementary experiment and found that participants could also trade off the VWM precision and number when they needed to memorize five colours at 200 ms. Thus, their study suggested that participants could trade off VWM precision and number without being affected by the length of exposure duration. The second contrary evidence was Experiment 3 in Ramaty and Luria’s28 study. Ramaty and Luria28 conducted a follow-up study of Fougnie, et al.26’s study, but they found different results from Fougnie, et al.’s26 study. In Ramaty and Luria’s28 study, they firstly repeated that participants could trade off the VWM precision and number when they need to memorise five items at 1200 ms exposure duration (Experiment 1). Then they found that this trade-off disappeared when the exposure duration decreases from 1200 ms to 300 ms (Experiment 2). Although the results mentioned above (the first two experiments in Ramaty and Luria’s28 study) could be predicted by the two-phase model, Experiment 3 in Ramaty and Luria’s28 study showed that the trade-off disappeared when participants need to memorise five items at 1200 ms exposure duration with an articulatory suppression. Thus, they suggested that an effective trade-off between VWM precision and number was due to verbal encoding instead of VWM processing, and the verbal encoding was mediated by long encoding durations. Unlike the present study, both of these studies28 asked participants to conduct a standard task (for the high-precision condition) and a get-them-all task (for the low-precision condition) to induce a trade-off. In the standard task, participants were asked to report only one colour out of five colours that appeared in the memory array, but in the get-them-all task, participants were asked to report all five colours. Compared with the standard task, participants had more motivation to maintain all five colours simultaneously in the get-them-all task. Because memorising five colours are beyond the average of individual VWM capacity, participants were not able to merely use the VWM encoding to complete the get-them-all task, which leads to the participants may use verbal encoding as a strategy to improve the performance, thus producing a stronger trade-off effect. However, the verbal encoding hypothesis could not explain our current results because of the following reasons. Firstly, in our study, the response requirements were the same in low- and high-precision conditions. Even if the verbal encoding can assist memory, participants should use verbal coding to help to memorise under both conditions. Thus, the effect of verbal encoding should be counteracted by calculating trade-off indexes. Secondly, if the trade-off was caused by using verbal encoding to memorise items strategically, we should be able to observe that low VWM capacity participants could also trade off effectively as high VWM capacity participants in our Experiment 1. Thirdly, verbal encoding requires a long retention interval or exposure duration. For example, in Experiment 4 of Souza and Skora’s44 study, they found that the articulatory suppression impaired the performance of the VWM task when the four colours were present at a 250 ms exposure duration followed by a 3000 ms retention interval. However, the articulatory suppression did not affect the performance of the VWM task when the four colours were present at a 250 ms exposure duration followed by a 1000 ms retention interval. In Vogel, et al.’s45 study, they found that there was no difference in the memory performance between the 100 ms exposure duration and 500 ms exposure duration when the participants needed to memorise four colours. Moreover, the VWM performance did not change because of the additional verbal working memory load. This evidence suggests that verbal encoding has a limited impact on VWM performance in our study, which used 500 ms or less exposure duration and 1000 ms retention interval. Therefore, the trade-off in the present study is mainly caused by the reallocation of VWM resources, instead of verbal encoding.It is important to point out that, as mentioned in the introduction, there were still two pieces of contrary evidence (2/25 experiments) which did not correspond to the predictions of the two-phase model. The first contrary evidence was the result of a supplementary experiment in Fougnie, et al.’s21 study demonstrated the importance of the critical value of duration/set size as a factor in determining whether voluntary trade-off would occur. The current results showed that when a ratio of 125 ms/item was adopted for presenting stimuli, participants with high VWM capacity could flexibly adjust the trade-off according to task requirements. However, participants could not voluntarily adjust the trade-off regardless of the VWM capacity when the ratio of 50 ms/item was adopted. According to the two-phase model, whether individuals can start the late resource allocation phase is mainly depends on their early consolidation processing. The consolidation process, the initial formation of VWM representations, has been studied for decades49. Vogel, et al.’s48 study showed that the VWM consolidation rate of the colour stimulus was about 50 ms/item48. A recent study by our group found similar results that participants spent an average of 60 ms to consolidate a colour stimulus into their VWM38. Thus, these results imply that the rate of duration/set size allowing individuals to trade off voluntarily is probably related to the time spent on VWM consolidation of the stimuli, and the voluntary trade-off between quality and quantity only occur when the ratio for presenting stimuli is much larger than the rate of consolidation.Both the current results and results found in Ye, 26.It is important to point out that the trade-off of precision and number can take place in two forms. Participants can opt to increase memory precision by sacrificing the number of items remembered. A more interesting question would be whether participants can increase the VWM number by sacrificing precision. It is still under debate if such an increase in VWM number can go beyond an upper limit of normal memory capacity50. However, a more recent revision of such a model, called slot + average model, states that when the number of stored items did not reach the maximal number of slots, a single item could be stored in multiple slots, leading to an increase in precision of that item32. In contrast, flexible resource model suggests a flexible allocation of limited cognitive resources. Allocating more resources to an item will allow greater precision. The trade-off between precision and number can be in two directions: an increase in precision on a small number of items or increase in memory number by sacrificing precision. More importantly, the resource models do not impose an upper limit on memory number54. There have been studies supporting each of the two classes of models mentioned above. The current study was not designed to provide direct support for either model. Instead, we offered a novel perspective suggesting that, for a given set size, the stimulus duration is the determining factor for the voluntary trade-off. The current study utilised the set size of four, which is likely for most participants within their VWM capacity. Future work may introduce tasks requiring participants to memorise a large number of the items above estimated average memory capacity to seek an answer for the question whether there is a limit in storing more items by scarifying precision.For the nature of VWM resource, there are two classes of models: “slot” model and “resource” model. The classical slot model proposes that the number of available resources (considered as “slots”) in VWM is limited. The slots can only be used to keep a limited set of discrete items. It means that when all those slots are fully occupied in VWM, no additional items can be further stored into these slots, and the memory precision could not be affected by the number of memory items13. However, the attention mechanism invoked in the studies about attention filtering may not be entirely the same as the attention that is invoked in the present study. The mental process involved in ignoring distractors might be primarily contributed by selective attention, which has been widely studied in the interaction between VWM and attention58. This kind of attention can be classified as external attention58. In addition to this, another kind of attention called internal attention also affects VWM performance, which is used by participants in the present study to reallocate resource to achieve a voluntary trade-off between VWM quality and quantity. The impact of internal attention on VWM processing has been generating considerable interest. For example, recent studies suggested that more internal attention resources enable individuals to allocate VWM resources more effectively, thereby improving VWM performance59. In addition, individuals can use internal attention to flexibly allocate VWM resources to even a particular dimension of representations60. Thus, the present study provides an important supplement to the research on the relation between attention and VWM.The present study showed that when participants were able to trade off the VWM precision and number voluntarily, the individual’s VWM capacity is positively related to the voluntary trade-off ability for VWM precision and number. This result is consistent with the results found in VWM task involving distractors, which suggests that there is a positive correlation between VWM capacity and attention filtering ability28, according to our knowledge, all of them analysed the precision and number index respectively. In the present study, we used GT as a measure to merge the precision and number index to quantify the magnitude of voluntary trade-off. We did not use this paper to argue that the equation of GT is an ideal solution to the trade-off issue in the field, but we believe that future studies on trade-off can further improve the equation of GT to take into account the change of both precision and number. For example, future research could further explore the relationship between individual trade-off ability and attentional filtering ability with a method similar to the GT equation. Therefore, the setup of the combined measure in this paper is a new beginning to quantify the individual’s trade-off ability.It is worth noting that although there have been many studies on trade-off using a mixture model (or other models) fittingData fitting results of swap model


The most common inherited peripheral neuropathy is Charcot‐Marie‐Tooth disease (CMT), with a prevalence of 1/2500. Other symptoms can be associated to the condition, such as hearing loss. Currently, no global hearing impairment assessment has been determined, and the physiopathology is not well known.The aim of the study was to analyze among a French series of 3,412 patients with inherited peripheral neuropathy (IPN), the ones who also suffer from hearing loss, to establish phenotype‐genotype correlations. An NGS strategy for IPN one side and nonsyndromic hearing loss (NSHL) on the other side, were performed.PRPS1; MPZ; SH3TC2; NEFL; and ABHD12. Two patients with PMP22 variant, had also an additional variant in COCH and MYH14 respectively. No pathogenic variant was found at the DFNB1 locus. Genotype‐phenotype correlations do exist, especially with SH3TC2, PRPS1, ABHD12, NEFL, and TRPV4.Hearing loss (HL) was present in only 44 patients (1.30%). The clinical data of 27 patients were usable. Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. HL varied from mild to profound. Five cases of auditory neuropathy were noticed. Diagnosis was made for 60% of these patients. Seven novel pathogenic variants were discovered in five different genes: PMP22 is not enough to explain hearing loss in patients suffering from IPN. HL can be due to cochlear impairment and/or auditory nerve dysfunction. HL is certainly underdiagnosed, and should be evaluated in every patient suffering from IPN.Involvement of  CMT has a wide range of phenotypes and is genetically heterogeneous. Almost 10% of the French population suffers from hearing loss, which can be sensorineural, conductive, or mixed. Sensorineural hearing loss can be due to a virus , environment (e.g. noise exposure), or genetic factors. Congenital hearing loss represents more than 50% of sensorineural hearing loss. More than 100 genes have been identified to be responsible for NSHL, and more still for syndromic hearing loss. Genetic hearing loss is most of the time a monogenic disease.The aim of the study was to analyze a French series of patients suffering from inherited peripheral neuropathy associated with hearing loss, in order to establish phenotype‐genotype correlations.22.1A French series of 3,412 patients suffering from IPN has been analysed thanks to medical records and a clinical questionnaire, so as to identify patients presenting IPN and hearing loss. The 3,412 patients had been selected on clinical and inheritance criterion, and all have been genetically screened.Phenotypes were screened on the basis of clinical data and electroneuromyograms (ENMG) for IPN, and audiograms, OtoAcoustic Emissions (OAE), and Auditory Brainstem Responses (ABR) for hearing loss.Peripheral blood samples of the patients were collected on EDTA tubes after giving their informed consent. The protocol was in accordance with French ethical legislation and Helsinki declaration.2.2http://exac.broadinstitute.org), dbSPN135 , ClinVar (www.ncbi.nlm.nih.gov/clinvar), and HGMD (www.hgmd.cf.ac.uk) were also screened. In silico studies were performed thanks to Polyphen‐2 (http://genetics.bwh.harvard.edu/pph2/), SIFT (https://sift.bii.a-star.edu.sg), UMD‐Predictor (http://umd-predictor.eu/), and Mutation Taster (http://www.mutationtaster.org/). Pathogenic variants of interest were verified by Sanger sequencing using forward and reverse primer pairs. Data have been submitted into a freely accessible public database, namely LOVD at https://databases.lovd.nl/shared/genes/DMD.Genomic DNA was extracted by standard methods . For neuropathy screening, a Next Generation Sequencing (NGS) strategy was implemented using a 92‐gene custom panel designed for CMT and associated neuropathies diagnosis Table . It inclGJB2 and GJB6 were performed for all the deaf patients. A NGS strategy was performed on a 63‐gene custom panel designed for hearing loss in 8 selected patients . The clinical data of 27 patients, 15 women and 12 men, were usable for this study. The clinical description is presented in Table Demyelinating neuropathy was diagnosed in 15 cases and axonal neuropathy in 12 cases. Age at onset varied from 2 to 73 years. In case of early onset, both demyelinating and axonal forms were observed .n = 8 cases), HL was severe to profound in four cases .Hearing loss varied from mild to profound, could be progressive, and five cases of auditory neuropathy (AN) were related . Endocochlear involvement was also present with absence of Otoacoustic Emissions as in case of patient XIV. Age at onset varied from 1 to 68. One patient has successful cochlear implantation (Patient XIV) and one patient has recently been assessed for a cochlear implant (Patient XII). They both suffered from AN. In case of early onset , or bilateral laryngeal nerve paresis (n = 1). Neurological features such as cerebellar ataxia (n = 3), proprioceptive balance disorders (n = 4), urinary incontinence (n = 2) and pain (n = 2) were observed. Ophthalmological conditions like cataracts (n = 3) or retinal detachment (n = 1) were also present. Scoliosis was present in three cases. The other major symptoms observed were linked to other cranial nerve disorder such as optic neuropathy n = , or bila3.2Thirteen sporadic and 14 familial cases were noted. Inheritance mode was in favour of an autosomal dominant (AD) way in 13 cases, and an autosomal recessive (AR) one in 1 case.PMP22 (n = 5), SH3TC2 (n = 4), MPZ (n = 2), NEFL (n = 2), PRPS1 (n = 1), TRPV4 (n = 1), ABHD12 (n = 1) : PMP22 duplication of 1.5Mb in three cases, PMP22 deletion of 1.4Mb in one case, PMP22 variant p.(Leu145Argfs*9), SH3TC2 variants c.2642A>G, p.(Asn881Ser); c.2860C>T, p.(Arg954*); c.3325C>T, p.(Arg1109Ter); c.3596G>A, p.(Trp1199*), NEFL variant c.293A>C, p.(Asn98Ser) and TRPV4 variant c.694C>T, p.(Arg232Cys).The already known variants were: PRPS1, MPZ, SH3TC2, NEFL and ABHD12. These variants were all absent from the different databases, and in silico studies were in favour of pathogenic variants  in ‐MPZ: these two variants were present in patients XI and XVI respectively. Autosomal dominant transmission was suspected in one case. Family segregation was concordant as seen on pedigrees in Figure c.437T>C, p. and c.418T>C, p.(Ser140Pro) in ‐SH3TC2: patient XVII developed an autosomal recessive form of demyelinating neuropathy and was associated with the known variant c.2860C>T, p.(Arg954*). Family segregation could not have been performed because parents’ DNA was not available.c.3377T>C, p.(Leu1126Pro) and c.3617C>A, p.(Ala1206Asp) in ‐SH3TC2: Patient XX had an autosomal recessive form of demyelinating neuropathy associated with moderate hearing loss. His sister only developed peripheral neuropathy, but her DNA was not available.c. 3617C>A, p.(Ala1206Asp) in ‐NEFL: patient XIX had an autosomal dominant form of axonal neuropathy. Family segregation was concordant in the son presenting this pathogenic variant associated with IPN and hearing loss.‐c.269A>G, p.(Glu90Gly) in ‐ABHD12: patient XXVI presented that homozygous variant. Family segregation was concordant, each asymptomatic parent presenting the heterozygous pathogenic variant.c.379_385delAACTACTinsGATTCCTTATATACCATTGTAGTCTTACTGCTTTTGGTGAACACA, p.(Asn127Aspfs*23) in As a consequence, seven novel variants, that could be classified as pathogenic or probably pathogenic, were discovered in five different genes s Tables .‐c.202AMYH14, c.1067C>T, p.(Thr356Met) was found in patient XII, already as being carrier of a 1.4Mb deletion of PMP22. MYH14 was found once in ExAc. The patient had presented a tomacular neuropathy since the age of 20. Severe auditory neuropathy started at the age of 5. Although family segregation was not possible, this variant seems to be potentially pathogenic.Another rare heterozygous variant in SPTCL1, c. ‐35delCCGCTTCCTTCCGGAAGGCGGGTCACAAG, located in the promotor that could prevent SPTLC1 expression. However, segregation analysis was not possible, and we cannot conclude for this patient. For patient VI, we found a variant of uncertain significance: c.1250C>T, p. in DNMT1. It was not present in ExAc. However, this variant involves a residue which is not well conserved among species, and seems to be likely benign.Two additional variants were classified as variants of unknown significance (VUS): patient I presented a novel variant in No other potential pathogenic variant was identified in any other screened genes.Analysis at the DFNB1 locus did not reveal any pathogenic variant in the 27 patients.PMP22, MPZ and NEFL). This revealed a known pathogenic variant in COCH, c.326T>C, p.(Ile109Thr) . This female patient developed both demyelinating sensori‐motor neuropathy and progressive severe to profound auditory neuropathy at 50. Balance disorders were also reported. Family segregation was concordant, as her sister presented only hearing loss, associated with the COCH pathogenic variant.In addition, NGS of the HL‐gene panel was performed in eight selected patients  carrying IPN and rearrangements in genes frequently involved , NEFL (n = 2), MPZ (n = 1), TRPV4 (n = 1). By contrast, hearing impairment was profound to severe in one case of 1.4Mb deletion PMP22, in cases of variants in PRPS1 and in ABHD12.Hearing loss was mild or moderate in one case of PRPS1 (n = 1), NEFL (n = 2), MPZ (n = 1), TRPV4 (n = 1); or at a distance in some cases of variants in SH3TC2 (n = 2) and ABHD12 (n = 1). Hearing loss occurrence varied widely with PMP22.Hearing loss could develop simultaneously with neuropathy, in some patients with pathogenic variants in PMP22 , one case due to TRPV4 and one case due to ABHD12. For patient II, no pathogenic variant was identified. Endocochlear hearing loss was observed in patients with variants in PRPS1, MPZ, SH3TC2, NEFL and PMP22 (duplication).In our series, auditory neuropathy was found in five cases: three cases of SH3TC2 seems to be the most frequent cause (n = 4). This corresponds to CMT4C or AR‐CMTde‐SH3TC2 . The frequent association with deafness and/or scoliosis in CMT4C may be a clue for the diagnosis.In case of AR demyelinating IPN, PRPS1. PRPS1 pathogenic variants lead to CMTX5, a rare condition with only seven variants already reported. Our variant c.202A>T, p.(Met68Leu) is novel.Patients who develop polyneuropathy associated with sensorineural hearing loss and optic atrophy during childhood, with an X‐linked inheritance, such as Patient IV, should be assessed for NEFL responsible for CMT are rare and associated to various phenotypes. However, hearing loss is often linked to neuropathy, up to 64% of cases, especially with the pathogenic variants p.(Glu90Lys) and p.(Asn98Ser) , which is a neurodegenerative disease including demyelinating Polyneuropathy, Hearing loss, cerebellar Ataxia, Retinis pigmentosa and early‐onset Cataract (PHARR). Patient XVI presented demyelinating Polyneuropathy, Hearing loss with auditory neuropathy, Ataxia and Cataracts.TRPV4 is responsible for CMT2C or AD‐dHMN‐TRPV4. The phenotype is characterized by association with vocal cord and/or diaphragm paresis, and hearing loss  is statistically different from that in the general population, showing that the pathogenic variant in SH3TC2 is directly responsible for hearing loss. We report two novel variants, c.3377T>C, p.(Leu1126Pro) associated with the already known variant, c.2860C>T, p.(Arg954*) and c.3617C>A, p.(Ala1206Asp).In our study, ABHD12, hearing loss is almost constant and is the first clinical sign, starting in the late teens. It is progressive and varies from moderate to profound. IPN is the most variable symptom.For PRPS1 is linked to three different phenotypes, always associated with hearing loss: CMTX5, DFNX1 and Arts syndrome. These three clinical presentations tend to overlap . This variant is predicted as pathogenic.NEFL, hearing loss is associated with IPN in case of the following variants: (p.(Glu90Lys), p.(Asn98Ser), p.(Asn98Thr), p.(Leu268Pro), p.(Cys322_Asn326del), p.(Glu396Lys)) . Hearing loss frequency does not seem to be statistically different from that in the general population, suggesting that pathogenic variants in MPZ may not be the real cause of hearing loss in these patients who are susceptible to carry additional pathogenic variants in HL genes.Interestingly in our series of 3,412 IPN patients, 60 patients were mutated in PMP22 gene  and we had information on associated hearing loss in only 5 of them (0.05%), presenting duplications (n = 3), a large deletion (n = 1) or 1 basepair deletion (n = 1). This 0.05% proportion is statistically different from the rate in the general population, with 10% of hearing loss. Nevertheless, the IPN and CMT populations are younger. It seems difficult to conclude that variations in PMP22 could protect from hearing loss. We therefore think it is probably underdiagnosed. The rarity of severe hearing loss in families with PMP22 pathogenic variants could rather suggest that most PMP22 pathogenic variants have minimal or no effects on hearing loss occurrence. As a consequence, hearing loss in that population could be due to other genes, as we started to point out for two of our patients, with a pathogenic variant in COCH and a suspected one in MYH14.Hearing loss has also been described in association with duplication, deletion or point pathogenic variants of the COCH gene is responsible for DFNA9, which consists in post‐lingual progressive hearing loss with vestibular dysfunction, such as Meniere‐like diseases , that could potentially explain hearing loss, was found in addition to the 1.4Mb deletion of PMP22 that explains the IPN. That is in accordance with our hypothesis that PMP22 is not responsible for hearing loss. MYH14 could nevertheless be also responsible for IPN. Actually, only one case has been reported with IPN and hearing loss , one case due to TRPV4 and one case due to ABHD12 (molecular diagnosis was not made for the last one); and endocochlear hearing loss was observed in patients with variants in PRPS1, MPZ, SH3TC2, NEFL and PMP22 (duplication). That was also demonstrated by Kovach et al.  by Postelmans et al., To our knowledge, only three patients suffering from IPN and AN received a cochlear implant  and a large NGS screening could help to find the gene involved and so to improve the care of the patient. This is for instance the case of Perrault syndrome type II (MIM# 233400), a rare autosomal recessive condition, characterized by sensorineural hearing loss, gonadic dysgenesis in males and females, and neurological features such as developmental delay or intellectual disability, cerebellar ataxia, motor and sensory peripheral neuropathy. As in patients suffering from IPN and hearing loss, the delay between the onset of the two or more symptoms can be up to 40 years, which leads to underdiagnose this phenotype if the involved genes are not tested in “hearing loss” NGS screening (Lerat et al., GJB2 and GJB6. Analysis at the DFNB1 locus did not reveal any pathogenic variant for all diagnosed and known deaf patients. It is also the first time that HL NGS was tested on this population. However, only eight cases could be tested by HL‐NGS because of availability of the analysis. It would have been more significant to test all the 27 patients suffering from IPN and HL by HL‐NGS so as to give better genotype‐phenotype correlations.To our knowledge, it is the first time that hearing loss screening has been carried out by MLPA and Sanger sequencing for Another possibility to explain both IPN and hearing loss is the presence of modifier genes that will induce that particular phenotype. That is why, for unsolved cases, WES could be very useful to identify new candidate genes for IPN and hearing loss, so as to improve diagnosis and patient care.In addition, to better understand the physiopathology of neuropathies associated with hearing loss, animal models e.g. in rats and mice, should be developed. Indeed, it could be interesting to perform a biopsy of the auditory nerve and cochlea of wild‐type and affected animals in order to localize accurately, for example by immunochemistry the proteins involved in those two features. However, murine phenotype might be different as the organization differs.5PMP22, and in a lesser proportion MPZ, involvement is not enough to explain hearing loss in patients suffering from hereditary peripheral neuropathy. Hearing loss can be due to cochlear impairment and/or auditory nerve dysfunction. As HL is certainly underdiagnosed in IPN patients, we suggest that audiologic tests should be systematically performed in these patients and their DNA should be screened with large NGS panels. This would enhance the diagnosis, help to better understand the physiopahology of IPN + HL and eventually improve patient's care.Through an NGS strategy, we have been able to establish a molecular diagnosis in almost 60% of the cases presenting IPN associated with HL. As a consequence, a precise description of the phenotype can help molecular investigations. None. Click here for additional data file. Click here for additional data file.


CMTX5 is characterized by peripheral neuropathy, early‐onset sensorineural hearing impairment, and optic neuropathy. Only seven variants have been reported and no genotype‐phenotype correlations have yet been established. PRPS1 has a crystallographic structure, as it is composed of three dimers that constitute a hexamer.Next‐generation sequencing (NGS) was performed using a custom 92‐gene panel designed for the diagnosis of Charcot‐Marie‐Tooth (CMT) and associated neuropathies.PRPS1 gene, c.202A > T, p.(Met68Leu) was found. This change is predicted to lead to an altered affinity between the different subunits in the dimer, thereby may prevent the hexamer formation.We report the case of a 35‐year‐old male, who had presented CMT and hearing loss since childhood associated to bilateral optic neuropathy without any sign of retinitis pigmentosa. A new hemizygous variant on chromosomic position X:106,882,604, in the PRPS1 exists. Patients who developed polyneuropathy associated to sensorineural deafness and optic atrophy during childhood should be assessed for PRPS1.CMTX5 is probably under‐diagnosed, as an overlap among the different features due to  All four are X‐linked recessively inherited and in two of them, the males affected display variable degrees of central and peripheral nervous system involvement. Hearing loss is the only feature common to all four disorders and the only symptom observed in DFNX1 or DFN2.Phosphoribosyl pyrophosphate synthetase (PRS) I deficiency is a rare medical condition caused by missense variants in PRPS1. Phenotype‐genotype correlation of these specific features have been looked for thanks to a review of the literature.CMTX5 is characterized by peripheral neuropathy, early‐onset sensorineural hearing impairment, and optic neuropathy. Hypotonia, gait disturbances, and loss of deep tendon reflexes with an onset between 10 and 12 years of age have also been reported , dbSNP135 , Clin Var (www.ncbi.nlm.nih.gov/clinvar), and HGMD professional (www.hgmd.cf.ac.uk), were also screened. Pathogenic variants of interest were verified by Sanger sequencing using forward and reverse primer pairs. The PRPS1 variant was submitted to the corresponding LOVD database at http://databases.lovd.nl/shared/variants/0000438212 (patient ID00207340).Genomic DNA was extracted using standard methods . Next‐generation sequencing (NGS) was performed using a custom 92‐gene panel designed for the diagnosis of CMT and associated neuropathies Table . It inclGJB2 and GJB6 were performed to screen for hearing loss.MLPA and Sanger sequencing of 2.3https://www.rcsb.org)  Li, .2.4https://www.ncbi.nlm.nih.gov/pubmed) and all published articles reporting pathogenic variants of PRPS1 and neuropathies were collected. Seven variants have already been reported for PRPS1 and CMTX5.A review of the literature was performed, based on PubMed  of 20–30 m/s on electromyogram, associated to polyphasic responses and an amplitude of 400 µV. At the age of 28, there was an absence of sensory activity in the four limbs. The motor activity was slumped down in the four limbs, all below 11 mV, associated with very slow down NCV in the lower limbs, in a more moderate way in the upper limbs. At the age of 30, results were similar for sensory activity, motor amplitudes were even lower with very slow NCV. Sural nerve biopsy did not show any demyelinating characteristic, in childhood. No mental retardation was observed. Profound bilateral sensorineural hearing loss had been diagnosed before one year of age. Auditory Brainstem Responses (ABR) could not be carried out. CT‐scan and MRI of the petrous bones were normal. There was no tinnitus but gait disturbances were present. Hearing aids were inefficient and were removed at the age of 15. Communication was based on sign language, but with some difficulties due to reduced hand mobility. Bilateral optic neuropathy without any sign of retinitis pigmentosa was also present. He was a sporadic case and came from a non‐consanguineous family.3.2NGS revealed the detection of the hemizygous variant on chromosomic position X:106,882,604, c.202A>T, p.(Met68Leu) , located on the head of the protein, in the dimerization region.Phosphoribosyl pyrophosphate synthetase 1 (PRSP1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis, as it catalyzes the phosphoribosylation of ribose 5‐phosphate and ATP to 5‐phosphoribosyl‐1‐pyrophosphate Becker, . It actsPRPS1 gene contains seven exons. Missense variants in PRPS1 are rare and may result in increased or decreased PRS‐I activity , enzyme activity had been tested and was not detectable in the male index patient, was reduced in the symptomatic carrier sister and normal in the asymptomatic carrier mother , Arts syndrome and X‐linked deafness (DFNX1); or PRS superactivity, which can induce gout  bilateral profound sensorineural hearing loss. Homogeneity is observed between the different patients, especially for age at onset and severity. Mixed sensory motor polyneuropathy before the age of 10, prelingual severe to profound sensorineural hearing loss, optic atrophy during teen ages Table . In our et al described a male with an intermediate phenotype between CMTX5 and Arts syndrome and a carrier female affected with DFN2 due to X‐chromosome inactivation skewing  supplements in patients with Arts syndrome help to replenish ATP and GTP concentrations to some extent, thereby slowing the progression of sensorineural hearing loss and alleviating some of the neurological symptoms (Mittal et al., 5PRPS1 exists. Patients who developed polyneuropathy associated to sensorineural deafness and optic atrophy during childhood should be assessed for PRPS1. Here, we report the first novel pathogenic variant in the French population. Moreover, it is located at the center of the dimerization zone, between two homopolymers. We hypothesize that change may induce an absence of dimerization, and then an absence of hexamer creation.CMTX5 is a rare condition, with only seven pathogenic variants already reported. However, it is presumably under‐diagnosed, as an overlap among the different features due to The authors declare no conflict of interest. Click here for additional data file.