To date, several meta-analyses clearly demonstrated that resistance and plyometric training are effective to improve physical fitness in children and adolescents. However, a methodological limitation of meta-analyses is that they synthesize results from different studies and hence ignore important differences across studies . Therefore, we aimed at examining comparative intervention studies that assessed the effects of age, sex, maturation, and resistance or plyometric training descriptors  on measures of physical fitness while holding other variables constant.To identify relevant studies, we systematically searched multiple electronic databases  from inception to March 2018. We included resistance and plyometric training studies in healthy young athletes and non-athletes aged 6 to 18 years that investigated the effects of moderator variables  on components of physical fitness .Our systematic literature search revealed a total of 75 eligible resistance and plyometric training studies, including 5,138 participants. Mean duration of resistance and plyometric training programs amounted to 8.9 ± 3.6 weeks and 7.1±1.4 weeks, respectively. Our findings showed that maturation affects plyometric and resistance training outcomes differently, with the former eliciting greater adaptations pre-peak height velocity (PHV) and the latter around- and post-PHV. Sex has no major impact on resistance training related outcomes . In terms of plyometric training, around-PHV boys appear to respond with larger performance improvements  compared with girls. Different types of resistance training  are effective in improving measures of muscle strength  in untrained children and adolescents. Effects of plyometric training in untrained youth primarily follow the principle of training specificity. Despite the fact that only 6 out of 75 comparative studies investigated resistance or plyometric training in trained individuals, positive effects were reported in all 6 studies .The present review article identified research gaps  that should be addressed in future comparative studies. For many years, the effects of resistance and plyometric training in youth and its potential benefits and harms were among the most debated research topics in exercise science and physiology. During the 1970s and 80s, researchers and scientific societies postulated an increased risk of sustaining injuries when conducting resistance training because of the immaturity of the skeletal system . In addiDespite today’s compelling evidence for the effectiveness and safety of youth resistance and plyometric training, there is still inconclusive evidence regarding the effects of different moderator variables on physiological adaptive processes following resistance and plyometric training programs in youth. Previous meta-analyses tried to address this question by means of meta-regressions and subgroup analyses. For example, a previously published meta-analysis revealed that resistance training induced strength gains only slightly increased with chronological age . The samThe difficulty in identifying relevant moderator variables from meta-analyses may reflect the inherent flaws of this methodological approach. A common limitation of meta-analyses is that a wide variety of participants, interventions, and outcome measures are included in one analysis, often denoted as “mixing oranges and apples”. Even though random effects models adjust for some of the resulting statistical heterogeneity, important dissimilarities between studies get lost and may lead to erroneous conclusions. Additionally, research limitations  as demonstrated by Ramirez-Campillo et al. for plyometric training research, further hamper the identification of these moderator variables  . By contIn the present systematic literature review, the term ‘children’ refers to boys and girls who are pre-PHV, whereas ‘adolescents’ refers to around- and post-PHV boys and girls. The term ‘youth’ includes both children and adolescents. The terms ‘trained’ and ‘untrained’ refer to the training history of each individual or the respective exercise group. In this context and in accordance with Rhea et al. , ‘untraiTo identify relevant studies, two investigators  independently performed a systematic literature search between September 2017 and March 2018 using the electronic databases PubMed (1966), Web of Science (1945), and Google Scholar from their inception until March 2018. We applied a Boolean search strategy using the operators AND, OR, NOT in combination with the following keywords and truncation technique using asterisks: child*, adolescent*, youth, boy*, girl*, maturity, athlete*, strength, resistance, weight, plyometric*, weight-bearing, training, and exercise. Additionally, reference lists of identified studies, reviews, and meta-analyses were examined to identify further relevant studies. Any discrepancies regarding eligibility of studies to be included in this systematic review were resolved by a third investigator (UG). Only studies were included for further analyses if participants were healthy trained or untrained children and/or adolescents (mean age under 18 years). Of note, studies were eligible for inclusion if the study design included a comparison of different training regimes, or the same training was applied to different cohorts . Further, the included studies had to examine a physical fitness component before and after the training intervention. Additionally, comparative studies that examined the effects of complex training were excluded from this review because with complex training it is not possible to ascribe the observed training effects to either resistance or plyometric exercises. In addition, our search retrieved a small number of complex training studies which did not allow independent sub-analysis according to moderator variables.Relevant information from the included studies, such as participant characteristics, training protocols, and study outcomes were extracted by two independent reviewers . We decided not to apply a risk of BIAS scale in this systematic review due to various reasons. First, Cochrane Collaboration recently recommended not to use these scales . Second,To investigate the effect of the moderator variable maturity, an adequate classification is mandatory. Since chronological age does not account for biological changes associated with maturational processes , differeInitially, our search syntax identified 2,459 potentially relevant studies see . Five huIn the past, it has been discussed intensively whether trainability of physical fitness changes with maturation of children and adolescents ,106. EspIt is well-documented that during maturation, natural strength development largely differs between boys and girls ,113. DurOur systematic literature search identified eight studies that examined the effects of the moderator variable sex on resistance training-related physical fitness outcomes. For instance, Vom Heede et al. reported similar gains (with one exception) in several strength and power outcomes  for both sexes (age 10.6 years) after resistance training, which focused on the development of muscular endurance or speed strength . UnfortuControversial results were observed by Muehlbauer et al., who studied the effects of high velocity resistance training on proxies of strength and power in (estimated) post-PHV boys and girls . In termIn summary, the majority of the identified studies indicate that resistance training induced adaptations are similar between males and females of the same age group –43,45. TTraining descriptors that specify the exercise stimulus are known to have a significant effect on specific physical fitness outcomes . TherefoIt has previously been reported that low-intensity high-repetition protocols  produce While the majority of the above cited studies ,49,51 exOf the above-cited studies, four examined the effects of resistance training on measures of muscular endurance. Two studies conducted by Faigenbaum and co-workers ,48 showeIn summary, the identified studies that examined the effects of different intensities, repetitions and volumes in resistance training with youth show conflicting results. Thus, there is no conclusive evidence from comparative studies in terms of optimal intensity-volume relations that are needed to improve maximal strength in youth. Interestingly, there is currently no comparative study available that observed larger training-related improvements with high intensities compared to low intensities in youth. This is contrary to the results of a recent meta-analysis. These aIt has previously been reported that children and adolescents show faster recovery between sets of resistance training  and may From adult research, it is known that training frequency plays an important role for the design of resistance training programs. For instance, training twice per week is superior to training once per week to induce muscle hypertrophy . In addiIn youth, the role of training frequency is less clear. Out of six identified studies that examined training frequencies, four compared one versus two training sessions per week. Three of the identified studies reported larger gains in physical fitness  in children and adolescents for two compared to one training session per week ,54,55. UTaken together, two resistance training sessions per week appear to produce larger training-related gains in physical fitness  than one session per week, particularly in untrained youth. However, further research is needed to investigate if more than two sessions produce additional effects. Unfortunately, all of the identified studies did not report the maturational status of the enrolled subjects which is why results have to be interpreted with caution.Another important training descriptor in resistance training is the application of appropriate and performance enhancing periodization models. This has previously been shown in a meta-analysis on the effects of periodization in strength and power training on measures of muscle strength and power in adults. The study revealed that periodized training programs are more effective than non-periodized programs, irrespective of sex, training background, or chronological age . HoweverFour studies examined the impact of different resistance training modes  and forms  on measures of muscle strength in youth. In terms of exercise mode, Shields et al. compared an eight week resistance training, that was either conducted in isokinetic or isotonic mode, on maximal isometric leg strength and muscle endurance in adolescents . SimilarIn terms of exercise type, Bulgakova et al. examined the effects of a machine-based resistance training program versus a sport-specific conditioning program (tethered swimming) in (estimated) pre-PHV swimmers . It was Flanagan and co-workers compared machine-based resistance training to resistance training that was conducted with the own body weight in untrained male and female children . They obFrom the above mentioned studies, it is evident that different training types  are capable of improving measures of strength or power in youth. It appears that the type of exercise mode  does not influence strength gains in youth. Since adult research has shown that eccentric contraction seem to elicit greater strength adaptations than concentric contractions , eccentrSupervision during youth resistance training is important to ensure appropriate exercise technique and to avoid injuries . There iThe literature search revealed a total of five studies that examined the effects of plyometric training in general and the influence of the moderator variable maturation in specific on physical fitness outcomes. For instance, Moran et al. compared a 6-week plyometric training with either pre- or around-PHV boys and detected larger training-induced improvements in 10-m sprint time for the around PHV-group . In contTaken together, the results of the above mentioned studies indicate a better trainability of plyometrics in the pre-PHV phase. This is partly in line with a recent meta-analysis reporting that plyometric training is moderately effective during the pre- and post PHV periods and less effective during the around-PHV period in improving countermovement jump performance . InteresTo date, four studies examined sex-related effects following plyometric training. Three studies investigated (estimated) pre-PHV children ,69,72 anTaken together, the trainability of plyometrics in pre-PHV children appears not to be affected by sex-specific effects, with the exception of one tested parameter (twitch torque) in one study . In contAnyhow, since three out of four studies show major limitations, conclusions for the general youth population are not possible. Additionally, post-PHV boys and girls have not been examined yet. Since sensitivity to plyometric training programs may change differently according to sex over time/maturation, future studies should elucidate sex-specific adaptational differences following plyometric training in pre-, around-, and post-PHV cohorts separately. Also, the possible influence of the menstrual cycle needs to be taken into account when investigating around- and post-PHV females.Comparative studies on plyometric training volume show diverse results. A recent study compared protocols with either low (50–60 contacts per session) or high volume (110–120 contacts per session) and found that both protocols resulted in similar increases in measures of speed and power (10m sprint and CMJ) in prepubertal soccer players . RamírezWith regards to plyometric training for the upper body, Marques et al. compared the effects of a training program using throwing exercises conducted in the stretch shortening cycle . While oDifferent intensities in plyometric training have recently been investigated . Elite sTaken together, the above mentioned studies suggest that low-to-moderate volume of lower body plyometric training might be sufficient and more time efficient to induce improvements in physical fitness  compared to high volume training. However, training surface  has to be taken into account and might affect training-related outcomes as well. Studies with adults have shown that plyometric exercises performed under unstable conditions can result in performance decrements  and altePlyometric training intensities can be modified in different ways . Additional training loads seem to be beneficial ,82, wherRegarding plyometric training in the adult population, data for optimal rest periods between plyometric sets do not exist, but an inter-day rest of 48 to 72 hours was previously recommended . InteresPlyometric training in youth populations has been shown to be effective with different training frequencies  of two weekly sessions compared to four weekly sessions . UnfortuPlyometric training programs vary in several parameters, such as exercise selection and execution. Thomas et al. found the jump and change of direction performance to be improved in adolescent males to the same extent by either countermovement or drop jump (40 cm height) training, while sprint time was not affected . Steben Taken together, plyometric training outcomes seem to follow the principle of training specificity, and hence training has to mimic the demands of everyday or sport-specific activities.Differences between different types of training, such as strength, power, plyometric and complex training on training-induced physical fitness performance have been examined in several studies. For instance, Lephart et al. could not observe differences in strength outcomes  after either eight weeks of resistance  training or four weeks of resistance  followed by four weeks of plyometric and resistance training in female adolescents . HoweverTraining for muscular power (Olympic weight lifting) has also been compared with traditional resistance training (“power lifting”) in male adolescents . Even thEscamilla and co-workers examined the impact of either strength (throwers ten), power (pneumatic resistance) or plyometric training  and found all training types to be equally effective in increasing the throwing velocity in adolescent baseball players .Adding a power/plyometric training to resistance training in male adolescent baseball players has been shown to further increase strength gains , specific to the additional stimulus  . Also FaThe comparison of strength, plyometric and power training, suggests that power training might lead to the best outcomes if a single training type is practiced, since no inferior effects compared to strength and plyometric training have been observed. A recent review and meta-analysis that compared the effects of traditional resistance training with “power” training (plyometrics) in youth population , observeA growing body of literature indicates that alternative training stimuli, such as whole body vibration , neuromuFor instance Mahieu et al. compared whole body vibration training with an equivalent resistance training in young  male and female alpine skiers . The resNeuromuscular electrical stimulation (NMES) has only scarcely been applied in youth. In one study, Deley et al. investigated its effect on different performance parameters in prepubertal gymnasts, and this study revealed promising results  . HoweverA recent meta-analysis  on the uTaken together all of the above mentioned modern training types have been sparsely investigated in youth population and might be promising alternative resistance training methods for improving physical fitness in children and adolescents. Future research needs to determine their safety and effects on youth populations.In line with previous reviews ,12 and mThe analysis of comparative studies further indicated that maturity affects strength and plyometric training adaptations differently, with the former showing smaller and the latter showing larger effects during the pre-PHV period. Sex does not seem to impact resistance training outcomes differently. The impact of sex on plyometric training related outcomes is less clear. Pre-PHV boys and girls seem to respond equally, whereas around-PHV boys appear to show larger jump performance improvements than girls. However, research is scarce and this needs further clarification.With regards to training descriptors in resistance training, no final conclusions can be drawn from comparative studies in terms of the optimal dose-response relations in training intensity and volume. While low training intensity / volume were recommended for beginners and untrained youth to begin with , more reComparative studies have shown that different types of strength and plyometric training can be effective. They seem to follow the principle of training specificity and should therefore be designed with respect to the children’s/ young athletes’ needs. When comparing these training types against one another, no clear picture evolves. Nevertheless, a combination of training types will likely result in the largest training-induced improvements in physical fitness. Recently, Behm et al. postulated that resistance training should be incorporated at an early age and prior to power/plyometric training in order to establish an adequate foundation of strength for power training activities .Finally, we identified several research gaps in the literature which were further described in detail in each section. More specifically, training descriptors , as well as modern alternative training types  need to be addressed in future comparative studies. Finally, to allow a context-related and meaningful interpretation of the reported data, comparative studies in pediatric research should (i) always report data on maturity status, (ii) modulate a single training protocol variable only in the experimental compared to the (active) control group only , (iii) provide a detailed description of the applied exercise stimulus , (iv) always report participants’ training history and status.S1 Checklist(DOC)Click here for additional data file.


The application potential of wearable electronics in the healthcare field has been of great interest over the past several decades. Flexible and wearable devices based on skin-friendly soft elastic materials can be snugly attached to the surface of human skin, so that a series of vital health information such as wrist pulse, body temperature, and blood glucose can be extracted and analyzed to help the patient maintain physical fitness. Here, we outlined the most common types of wearable electronics for monitoring human health information, including force sensors, temperature sensors, physiological biochemical sensors, and multifunctional sensors. Their general working principles and structural innovations are reviewed. Then, we discussed two functional modules that make the wearable sensors more applicable in real life—self-powered module and signal processing module. The challenges and future research directions are also proposed to develop wearable electronics for monitoring human health information. Since the 1950s, the rise of silicon-based semiconductor technology has greatly promoted the development of the information technology industry, making people’s lives change dramatically. However, with the acceleration of the world informationization and the development of the Internet of Things (IoT), conventional silicon-based electronics with high Young’s modulus are facing new challenges. Over the past few decades, flexible and wearable electronics have drawn increasing interest and become a hot topic in the science world. In contrast with rigid silicon-based electronic devices, flexible electronics exhibit many unique superior characteristics, such as high flexibility, ultralight weight, and conformality, which enable flexible and wearable electronics to be used in a wider range of application.In particular, there has been a growing interest in flexible and wearable medical device for regular and continuous monitoring human health information. New devices are being invented to continuously monitor vital signs as comfortably as possible. These wearable medical electronic devices can measure various health indicators such as heart rate, pulse, body temperature, blood glucose, etc. noninvasively in real time by simply attaching them to the human body surface. Real-time monitoring of vital signs can alert users and health care providers to further medical care when an individual’s physical health indicators are abnormal, avoiding the situation where the best treatment time is missed. Also, flexible electronics can be deformed at will and detect various signals with extremely high sensitivity, thus can be used in artificial electronic skin, motion detection, telemedicine, and in-home healthcare. There is no doubt that next-generation flexible and wearable electronics will lead to a revolution in human way of life.Considerable efforts have been devoted to the production and development of wearable electronics and exciting advancements have been made in new materials, new process, and sensing mechanism during the past few years. As shown in Fig. The force sensor is a sensing device that can detect the values of mechanical forces such as tension, pressure, torque, stress, and strain and convert them into electrical signals. The various physical stimuli generated by regular physiological activity of human body contain many important health information, for instance, heart beat rate, muscle movement, respiration rate, and blood pressure. Most of traditional force sensors are bulky and heavy because they are mostly based on metal and semiconductor materials, and they are not applicable to wearable electronics for monitoring vital signs of human body due to their greatly limited portability and flexibility. Compared with traditional force sensors, flexible force sensors using plastic and elastomeric substrates have a series of advantages, such as better biocompatibility, stretchability, transparency, wearability, and capability of continuous detection. We shall discuss below that the flexible force sensors can be divided into resistivity sensors, capacitive sensors, and piezoelectric sensors.A resistive sensor is a sensor that converts the change in resistance of sensitive materials caused by an external stimulus into an electrical signal output. The active materials of flexible resistive force sensors are generally elastomer composites formed by incorporating conductive fillers, such as graphene , 6, carb−1 in the range of 0–2 kPa. The graphene/paper-based pressure sensor demonstrated great potential in monitoring wrist pulse, breathing, speaking, and motion states. In addition, Yang et al. [The utilization of substrates with microstructure surface offers an effective way to fabricate highly sensitive piezoresistive force sensors. As shown in Fig. g et al.  preparedEmbedding conductive materials with porous structure into elastomer matrix to construct two- or three-dimensional conductive networks is another approach to achieve high sensitivity in resistive force sensors , 19, 24.0 is the vacuum permittivity, εr is the relative permittivity of the dielectric, A is the effective overlap area of the two conductive plates, and d is the spacing between the two conductive plates. The electrodes of flexile capacitive force sensors usually use CNTs [Capacitive sensors can response indicating changes in the external forces through changes in capacitance. A capacitor generally consists of a dielectric layer sandwiched by two conductive plates. The formula used to calculate the capacitance is use CNTs , Ag nanouse CNTs , 3, and use CNTs . Low modThe sensing ability of capacitive sensors can be significantly enhanced by microstructuring electrodes or dielectric layers , 2, 28. −1) in the low-pressure regime < 8 kPa as well as fast response time (< 10 ms). These superior capabilities demonstrated that such a device is promising in high-fidelity measurements of wrist pulse wave.To improve the sensitivity, integrating with organic field-effect transistor (OFET) is also a widely studied project for capacitive sensors. In OFET devices, the source-drain current is directly dependent on the gate dielectric capacitance. Schwartz et al.  reportedCompared with resistive sensors, capacitive sensors generally have higher sensitivity and lower detection limits. However, their poor linearity response and susceptibility to parasitic capacitance and fringing capacitance can be challenges in practical applications.Piezoelectric effect refers to the phenomenon that the mechanical stimuli deforms some anisotropic crystalline materials and causes the polarization of internal dipoles, leading to potential differences existing between the two opposing surfaces of the crystals. Due to the unique characteristics of piezoelectric materials, piezoelectric sensors with rapid response time are capable to measure high-frequency dynamic signals efficiently and are quite promising for self-powered devices.3 nanocomposite [3 nanowires (PTNWs)/graphene heterostructure. In this device, the polarization charges induced by the strain in PTNWs acted as charged impurities in graphene and affect its carrier mobility. The working mechanism is that the polarization charges in PTNWs increased the scatterings of carriers in graphene thus resulting in decreased carrier mobility. Based on the aforementioned mechanism, as shown in Fig. Piezoelectric materials commonly used in flexible sensors include P(VDF-TrFE) , 32, ZnOomposite ) can exhomposite  employedomposite  reportedTemperature detection is an important part of sensing devices. Body temperature can reflect people’s physical condition to a large content. The body-core temperature of healthy people is relatively constant, generally contained between 36.2~37.2 °C. It is independent on the environment, while the shell temperature can be affected by both physical conditions and ambient temperature. Abnormal changes in body temperature usually indicate poor health. For example, an increased body-temperature is the symptom of fever or infection, while a degraded body temperature probably signifies anemia. For real-time detection of temperature in E-skin devices, many types of flexible temperature sensors have been developed.Detecting temperature through changes in the resistance of sensitive materials is the most commonly used method for temperature measurement in skin-like electronics devices. Temperature coefficient of resistance (TCR) is an important indicator of the sensitivity of resistive temperature sensors. It is defined as the relative variation of resistance when the temperature changes by 1 °C. Various resistive temperature sensors have been reported using pure metal elements  –42, metaMetals have been used for temperature detection for a long time due to their temperature sensitivity. The detection mechanism can be explained by the fact that the rise in temperature enhances the thermal vibration of the lattice, resulting in intensified scattering of the electron wave, thus increasing the resistivity. Traditional metal-based temperature sensors provide limited stretchability or bendability. Structure engineering, such as wrinkle buckling, in-line horseshoe-like structure, and rigid-island design , 41, 46,OD) can thus be suppressed as long as they match between the two branches.Above-mentioned works have effectively improved the flexibility of metal-based temperature sensors, but the structure engineering methods used in those devices limited the stretchability to 25–30%. To further break the tensile limit of flexible temperature sensors, the use of inherently stretchable materials is required. Harada and co-workers , 9 introIt is worth mentioning that such TFT structure device has been proven by other researchers to significantly improve the sensitivity of temperature sensors. Trung et al.  fabricat3, LiNbO3) and polymer ) [3 nanoparticles as well as piezo- and thermoresistive organic semiconductor channel(pentacene). The fabricated devices can extract effects from the target sensing signals successfully while the flexible sensor is under multiple stimuli because the two chosen materials were able to respond to strain and temperature in a disproportionate manner simultaneously. This approach is able to distinguish the temperature effects from strain for flexible pyroelectric sensors.A variation of temperature will change the remnant polarization of pyroelectric materials thus generating opposite bound charges on both surfaces of the crystal. Materials that have been found to exhibit pyroelectricity include different ceramics ) –53. A loF-TrFE))  directlyF-TrFE))  developeIn order to understand all aspects of human health, various physiological biochemical sensors have been developed for analysis of vital biochemical signs, such as blood glucose , 57, 58 Continuous measurement of glucose is vital to maintain the health and quality of life of diabetics. Commercially available products for glucose detection are performed by invasive lancet approaches that requires sampling the patient’s blood, leading to pain to the patient. New electronics fabrication techniques on flexible substrates have been developed to enable noninvasive wearable glucose monitoring. Chen et al.  developeIntegrating multifunctional sensing components into one device is an important advance in wearable electronics. Future wearable electronics should enable to integrate the function of detecting multiple signals such as strain, pressure, temperature, humidity, gas , 62, 63,In order to develop highly integrated wearable system for applications in health monitoring, physical state assessment, and telemedicine, researchers have tried various manufacturing processes and device structures to combine different functions together. Self-powered modules working continuously without external power sources should be an integral part of future wearable electronics. In addition, for real-life application of wearable electronics in monitoring critical health information, a wireless digital system for processing and transmitting signals over long distances is necessary.−2 through harvesting biomechanical energy. Meanwhile, the TENG-based electronic skin can serve as a tactile sensor to sense pressure and achieved a sensitivity of 0.013 kPa−1. The development of self-powered, wearable platforms has opened up opportunities for many potential applications including soft robots, smart artificial e-skins, wearable electronics, etc. However, there are still limitations of flexible energy harvesting devices because the power generation of nanogenerators that have been reported so far cannot meet the needs of practical applications.To realize independent operation of wearable sensors, nanogenerators based on piezoelectric, pyroelectric, and triboelectric effects have been developed to incorporate into wearable systems –67. NanoThe integration of flexible sensors with information processing system is the next frontier for wearable electronics. Current research on flexible electronics mainly focused on the fabrication and optimization of sensing elements, while the research on flexible electronic circuits for information processing is relatively limited. The delivery and processing of human health information collected by the sensor still needs to be done by a computer. Wireless transmission of sensor data that has been reported so far is principally realized by combining a flexible sensor with a rigid silicon-based digital circuit technology. Pang et al.  built a Wearable electronic devices should be able to clearly identify the deformations caused by pulse, muscle movements, and external contact. While most of the flexible force sensors that have been reported so far cannot accurately identify the source and direction of external forces.In terms of temperature sensors, it is still difficult to achieve high stretchability, sensitivity, and strain adaptability simultaneously. Improving the sensing performance and eliminating the influence of the elastic deformation of the sensor on temperature detection remain important research topics.The detection accuracy of flexible physiological biochemical sensors is insufficient compared to traditional medical devices. Besides, most of the valuable physiological health information needs to be extracted from internal secretions. More biophilic implantable materials should be taken into consideration for the development of biochemical sensors to extract information from blood and muscles.Multifunctional sensors should be able to simultaneously detect pressure, stress, temperature, and other different signals such as humidity and gas atmosphere and avoid crosstalk between them. The realization of multifunctional sensors requires further development of new materials, nanotechnology, and device structure design.Processing the data in situ and transmitting them in real time are also essential parts of future wearable electronics. It is quite challenging to integrate multiple functional modules into a complete wearable system so that it can fully meet the requirements of practical applications.In past several years, the rapid development of wearable electronics attracts extensive attention. Researchers have made many fruitful attempts and achieved good results in developing wearable electronics with high sensitivity, flexibility, and stability. This review analyzed recent research strategy and advancements in wearable electronics for human health detection from the aspects of force sensors, temperature sensors, physiological biochemical sensors, multi-functional sensor, and other functional modules applied in flexible electronics. The successful fabrication of flexible sensing devices with high sensitivity, low-cost, portability, and long-term stability indicates that flexible and wearable electronics will definitely become the mainstream in the field of medical care in the future. However, there are certain challenges remaining for practical applications of current wearable sensors in real life.


Skin and soft tissue infections (SSTIs) in hospital and community settings impose a substantial socio-economic burden. Therapeutic uncertainty due to the availability of a wide range of antibiotics and the need for empirical treatment decisions complicate SSTI clinical management. Completion of numerous pairwise meta-analyses to account for this variability in antibiotics is impractical, and many head-to-head comparisons of potential interest are likely not available. In comparing multiple antibiotics simultaneously, this network meta-analysis aims to identify the antibiotic(s) with the greatest value in the treatment of SSTIs, in terms of patient-important outcomes such as efficacy and safety.Staphylococcus aureus (MRSA)-associated infection are planned.We will conduct a systematic review to identify randomized controlled trials of persons with suspected or confirmed SSTI assigned to orally or parenterally administered antibiotic therapy that report results on at least one outcome of interest. We will search MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL), along with trial registries. Our primary outcome of interest is clinical success at the test-of-cure visit. Secondary outcomes may include (1) early clinical success (2–3 days after the therapy starts), (2) mortality, (3) adverse events, (4) treatment duration, and (5) length of hospital stay. Independent reviewers will complete screening of titles, abstracts, and full texts, data extraction, risk of bias assessment (using the Cochrane Risk of Bias tool), and evaluation of the certainty of evidence (using the GRADE approach) in duplicate. We will complete pairwise and network meta-analyses within the Bayesian framework when possible using a random effects model. We will stratify SSTIs by severity into uncomplicated and complicated SSTIs when possible. Subgroup analyses by age, infection type, comorbidity, and suspected or confirmed methicillin-resistant This study has several strengths compared to previous reviews: inclusion of a wider range of infection types, antibiotics, and outcomes; a comprehensive search strategy; a priori subgroup analyses; application of GRADE; and improved interpretability of findings through visual presentation of results. We hope our findings will inform future research, health care professionals, and policy makers resulting in improved evidence-based clinical management of SSTIs.CRD42018085607PROSPERO The online version of this article (10.1186/s13643-018-0804-8) contains supplementary material, which is available to authorized users. Staphylococcus aureus and beta hemolytic streptococci, are the most common [Staphylococcus aureus-related SSTI hospitalizations in the United States (US) significantly increased from 2001 to 2009  and was associated with an increase in national annual cost (from 3.36 to 4.22 billion dollars) [Staphylococcus aureus (MRSA) from 24 to 37% between 1994 and 2007 [Skin and soft tissue infections (SSTIs) can differ in clinical presentation, microbial etiology, and severity. They can range from uncomplicated cases, such as cellulitis lacking systemic signs of infection, to more severe cases, such as diabetic foot infection involving the soft tissue in a vascular compromised host –6. SSTIst common . The numt common –9. The idollars) . The Canand 2007 . SSTIs aAntibiotic therapy and severity stratification decisions for SSTIs are often based on clinical impression, before confirmatory laboratory testing, involving bacterial identification and antibiotic susceptibility testing, can be completed. Empirical treatment may curb clinical resolution, but is often a necessary intervention to prevent severe outcomes, such as comorbidity and death , 10. TheThe Infectious Disease Society of America (IDSA) published guidelines for the treatment of SSTIs in 2014. These recommendations were based on evidence from randomized controlled trials (RCTs) and well-conducted observational studies, which an expert panel reviewed and evaluated . With thIn network meta-analyses (NMAs), treatment options are compared directly  and indirectly (antibiotics not previously studied in head-to-head comparisons) through a common comparator between studies. Although NMAs are methodologically advanced, their clinical utility surpasses that of traditional meta-analyses that are limited to head-to-head comparisons. In comparing multiple antibiotics simultaneously by NMA, the antibiotic(s) with the greatest value in the treatment of SSTIs, in terms of patient-important outcomes such as efficacy and safety, can be identified .We are aware of four related NMAs that have been conducted in the last decade; however, they were limited in the antibiotics and infection types studied, generalizability and methodological rigor –21. To thttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85607) [This protocol was written according to the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) statement  , 23. We D=85607) .metaRegister to identify ongoing trials. We will examine references of included RCTs and other pertinent publications to reduce the risk of failing to include a relevant RCT. We will rerun each of the database searches before submission of the final manuscript to capture any newly published RCTs.We will customize literature search strategies to each database with the help of a research librarian, incorporating database-specific controlled vocabularies and text words. We will search MEDLINE  of persons with suspected or confirmed SSTI treated with orally  or parenterally  administered antibiotic (mono- or combination) therapy that report results on at least one outcome of interest (see outcomes section below). Outcomes of interest are based on those recommended by the US Food and Drug Administration (FDA) and those commonly reported in RCTs of antibiotics for SSTI treatment . FurtherOur primary outcome of interest is clinical success broadly defined as an improvement in signs and symptoms associated with SSTI at the test-of-cure (TOC) visit or closest clinical assessment to approximately 7–14 days after therapy completion. Secondary outcomes we are interested in are (1) early clinical success broadly defined as an improvement in signs and symptoms associated with SSTI at approximately 2–3 days after start of therapy, (2) mortality  assessed approximately 28 days after therapy completion, (3) adverse events, (4) treatment duration, and (5) length of hospital stay.We will pilot test a standardized form based on a priori inclusion and exclusion criteria and adapt it for each stage of screening: titles and abstracts, followed by full-text screening. Two independent reviewers will conduct screening after completion of calibration exercises. Disagreements will be resolved between the review pair, with the help of a third reviewer and correspondence with the potentially eligible study’s corresponding author when necessary. We will record reasons for exclusion of full texts and generate a PRIMSA flow diagram .We will pilot test and use a standardized Microsoft Excel form to extract data regarding study characteristics, participant demographics, antibiotic treatment, co-intervention(s) during treatment if any, analysis population for which a given outcome was ascertained , and outcomes of interest previously described. Reviewers will complete data extraction independently in pairs after performing calibration exercises. Disagreements will be resolved between the review pair and with the help of a third reviewer when necessary. We will contact corresponding authors of eligible RCTs for which data is missing or needs clarification. We will estimate mean and standard deviation (SD) for a continuous outcome from the median, range, and the size of the study sample when not available to be extracted .Independent reviewers will judge risk of bias in individual RCTs in duplicate according to the following domains outlined in the Cochrane risk of bias tool for RCTs: selection bias , performance bias , detection bias , attrition bias (incomplete outcome data), reporting bias (selective outcome reporting assessed by comparing outcomes reported in the protocol to those reported in the completed RCT whenever possible) and other sources of bias (e.g. for-profit funding). For a given domain, RCTs judged as definitely or probably being free of a given risk of bias will be considered low risk of bias, whereas RCTs judged as probably or definitely biased will be considered high risk of bias to reduce reporting of unclear bias assessments . The revWe will assess publication bias visually by judging asymmetry in the funnel plot and statistically provided at least 10 trials are included using the Egger test , 30.We will synthesize direct evidence using traditional head-to-head meta-analyses when possible. Given the variety of antibiotic therapies available, we anticipate that not all will have been studied in head-to-head trials. Insufficient or total lack of direct evidence for possible antibiotic comparisons will warrant inclusion of indirect evidence to better approximate the value of an antibiotic regimen. Indirect evidence may also complement direct evidence when available and improve precision of an observed summary effect estimate. Therefore, direct, indirect, and a combination of direct and indirect evidence will inform each summary effect estimate reported whenever possible , 32. SumWe will conduct NMAs provided the following assumptions are met. The transitivity (similarity) assumption gauges the appropriateness of combining evidence from individual trials of different treatments with a common comparator to enable analysis of indirect evidence. We will judge transitivity by comparing important clinical and methodological characteristics. The distribution of potential effect modifiers and the common comparator  should be similar between trials; otherwise, in the presence of large dissimilarity, NMA may be invalid , 37. TheWe will base NMAs on non-informative priors, for which the reference group may be the antibiotic most frequently trialed or placebo if there is wide spread in antibiotics trialed to facilitate interpretation. We will inspect model convergence using the Markov Chain Monte-Carlo simulation technique. The analysis will be run in three parallel chains, allowing for 20,000 burn-in simulations, followed by 100,000 simulations, which will be used to generate the outputs. We will also assess model convergence with the Gelman-Rubin diagnostic test and examination of Monte-Carlo errors –43.2) of infection. Organism-specific factors may include antibiotic resistance of SSTI-causing bacteria (suspected or confirmed MRSA or other drug-resistant organisms) [We will base investigation of methodological and clinical heterogeneity on a priori subgroups when appropriate. We still stratify SSTIs into the following groups based on severity: (1) uncomplicated SSTI (uSSTI) loosely defined as the presence of a skin lesion with local inflammation  and 2) complicated SSTI (cSSTI) loosely defined as the presence of a skin lesion with local inflammation complicated by at least one of the following host-, anatomic site-, or organism-specific factors. Host-specific factors may include the need for surgical intervention and hospitalization, systemic symptoms , comorbidities , or any of the following signs or symptoms: bullae, hemorrhage, out-of-proportion pain, rapid progression, crepitus, and anesthesia. Anatomic site-specific factors may include depth (involvement of deeper skin structures: fascia or muscle), location (significant head or hand involvement), and size (> 9% of body surface area or > 75 cm complicaganisms) , 44–46. 2 test for heterogeneity at alpha = 0.10. Furthermore, an I2 value of > 50% will indicate the presence of substantial heterogeneity [We will set the criterion for statistical significance for the Chiogeneity . We willWe expect some included RCTs to differ in their intervention and outcome definitions, especially regarding antibiotic dosing, breadth of adverse events captured, and timing of clinical assessments. We will be pragmatic in including these trials, but will perform sensitivity analyses to test the robustness of our results when trials whose differences are concerning are excluded. We will compare summary effect estimates from network comparisons of individual antibiotics and of antibiotic classes since we expect increased power to test differences in outcomes in network comparisons of antibiotic classes. We will conduct additional sensitivity analyses to test the robustness of our results to RCTs at high risk of bias.We will provide a narrative description of the connectedness of the antibiotic network, along with a network plot to visually assess its features, such as diversity of antibiotic treatments, frequency of antibiotic comparisons, and overall availability of evidence. The size of the nodes and width of the edges will be proportional to the amount of information they bear. The larger nodes and wider edges will contribute more to the NMA . We willWe will present network effect estimates and corresponding 95% CrIs in league tables and/or in forest plots against a standardized comparator. We will present the probabilities that a given treatment is the first, second, third, etcetera, best among all treatments for each outcome with cumulative probability rankograms , 49. We We will assess certainty in NMA effect estimates in duplicate following calibration exercises for direct and indirect evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach . We willThe high prevalence of SSTIs in community and hospital settings imposes a substantial socio-economic burden, which is exacerbated by their inappropriate clinical management , 14, 15.Previous NMAs have had several weaknesses, which limit our confidence in their results and their implications for the clinical management of SSTIs. They were restrictive in their searches (by antibiotics and infection types), had limited generalizability, and were poorly conducted  –21. The Limitations to the proposed NMA may include variability in included RCT methods , considerable unexplained heterogeneity, uncertainty in effect estimates , and unbalanced or underpowered networks. This review hopes to mediate some of these potential challenges through its comprehensiveness, a priori specified exploration of heterogeneity and sensitivity analyses, whenever possible.With the wide range of antibiotics available for the treatment of SSTIs, we hope findings from this study will identify the antibiotic(s) with the most value in terms of patient-important outcomes to better inform health care professionals and policy makers resulting in improved evidence-based clinical management. Currently understudied antibiotic comparisons may be identified by evaluation of the network to guide future research and RCTs.Additional file 1:Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) Checklist. (DOCX 32 kb)Additional file 2:Medline Search Strategy. (DOC 37 kb)


Focal dystonia is a movement disorder characterized by involuntary muscle contractions that determine abnormal postures. The traditional hypothesis that the pathophysiology of focal dystonia entails a single structural dysfunction  has recently come under scrutiny. The proposed network disorder model implies that focal dystonias arise from aberrant communication between various brain areas. Based on findings from animal studies, the role of the cerebellum has attracted increased interest in the last few years. Moreover, it has been increasingly reported that focal dystonias also include nonmotor disturbances, including sensory processing abnormalities, which have begun to attract attention. Current evidence from neurophysiological and neuroimaging investigations suggests that cerebellar involvement in the network and mechanisms underlying sensory abnormalities may have a role in determining the clinical heterogeneity of focal dystonias. It is often initiated or worsened by voluntary action and is associated with an overflow of muscle activity5. In adulthood, the lower limb has rarely been observed as a site of dystonia6.Idiopathic adult-onset dystonia, the most common form of dystonia, has variable clinical expression, though it often has a focal onset such as blepharospasm (BSP), oromandibular dystonia, cervical dystonia (CD), laryngeal dystonia, or arm dystonia3. Adult-onset dystonia has a limited tendency to spread to adjacent body regions5, which likely depends on the site and age of dystonia onset and on genetic factors8. Focal dystonias may be associated with rest/postural tremor in the head or upper limbs10.The demographic and clinical characteristics of adult-onset focal dystonias are now well established. Dystonias in the craniocervical area are more common in women, whereas occupational limb cramps are more common in men11, mild disturbances in executive functions12, and sensory symptoms13. In patients with BSP, sensory symptoms may include a burning, gritty sensation in the eye, dry eye, and photophobia, which may develop months or years before BSP onset. In patients with CD, dystonic movements are often associated with neck pain that contributes significantly to patient disability and a low quality of life. The overall burden of nonmotor symptoms may vary in different patients with focal dystonia14. All types of focal dystonia can be specifically relieved by sensory tricks, which are self-acquired maneuvers that transiently improve focal dystonia in a consistent proportion of patients16.In addition to motor signs, patients with adult-onset dystonia may also have a spectrum of nonmotor symptoms, including psychiatric manifestations et al.17 suggested that the basal ganglia play an important pathophysiological role in adult-onset focal dystonia. Indeed, early lesional studies showed that structural lesions in the basal ganglia determine dystonia  in contralateral body parts20. Since basal ganglia determine motor command in goal-directed motor learning (i.e. facilitate the desired motor output and concomitantly inhibit unnecessary motor output), basal ganglia dysfunction may conceivably determine abnormal motor command. Moreover, it was also observed that oscillatory activity of the globus pallidus internus (GPi) at a frequency of <12 Hz contributes to dystonic motor symptoms23 and that deep brain stimulation (DBS) of the GPi improved dystonia26.In an early paper, Marsden29, abnormal plasticity mechanisms in the cortical motor areas, and abnormal sensory integration34. Likewise, magnetic resonance imaging (MRI) studies showed gray matter volume differences in several cortical/subcortical regions in patients with different focal dystonias. However, owing to the wide array of connections between the basal ganglia and several brain areas, these changes were generally interpreted as consequences of a primary basal ganglia dysfunction.Earlier neurophysiological studies demonstrated reduced inhibition at the level of the primary motor cortex, brainstem, and spinal cord37. It has therefore been proposed that dystonia may not be due to a lesion or an abnormal function of only one structure, namely the basal ganglia, but rather may be due to dysfunctional mechanisms in other brain areas, either concomitantly with or secondary to altered basal ganglia influence, that contribute to the pathophysiology of the condition. This may be particularly true for CD. Animal models of reversible dystonia induced by means of muscimol inactivation have suggested a dysfunction of a circuit including mesencephalic reticular formation neurons, cerebellum, tectum, and the basal ganglia, known to play a fundamental role in control of eye, head, and coordinated eye and head movements44. The dysfunction, however, may not be primary in these regions but rather reflect an abnormal activity originating in other structures providing feedback to the network such as the cerebellum. In this vein of thought, the role of the cerebellum in the pathophysiology of focal dystonias has attracted great interest in the last decade46.The assertation that focal dystonia is exclusively the result of basal ganglia dysfunction has recently been challenged by the remarkable clinical heterogeneity of the motor and nonmotor manifestations characterizing the different forms of adult-onset focal dystonias, as well as by lesion studies demonstrating that secondary focal dystonia is related to structural lesions in various sites in the nervous system, such as the basal ganglia, thalamus, and cerebellumIn this paper, we provide a comprehensive overview of the new findings from recent neurophysiological and neuroimaging investigations regarding the pathophysiology of adult-onset dystonia and highlight the remaining knowledge gaps in the understanding of this condition.In recent years, neurophysiological investigations have largely focused on the pathophysiological mechanisms linking the hypothesized basal ganglia dysfunction to the activity of distant sites and the mechanisms underlying sensory abnormalities in focal dystonias, specifically altered temporal discrimination of sensory stimuli and pain .et al.47 demonstrated that chronic DBS reduces exaggerated alpha oscillations and alpha band interhemispheric coherence in the motor cortex, thus confirming that clinical improvement with GPi-DBS reflects DBS-induced direct suppression of abnormal oscillatory activity in the motor cortex48.Using scalp EEG recordings in dystonia patients implanted with DBS electrodes in the GPi and subthalamic nucleus, Miocinovicet al. recently recorded single unit neural responses and local field potentials from the GPi in CD patients undergoing DBS surgery. Firing rate and discharge pattern of the GPi were asymmetric in patients with torticollis. Neuronal asymmetry correlated with the degree of involuntary head turning. Sedovet al. concluded that asymmetric pallidal activity results in asymmetric feedback to the mesencephalic neural integrator causing dysfunction in the network integrating eye and head coordinated movement50.Sedov53. The observation that mutations inTHAP1 andKMT2B genes, highly expressed in the cerebellum, can induce generalized dystonia further supports the cerebellum’s role in the pathophysiology of dystonia55. In humans, cerebellar involvement in dystonia pathophysiology has recently been tested using eye blink classic conditioning (EBCC) and motor learning paradigms involving adaptation mechanisms. EBCC consists of a Pavlovian learning protocol integrated at the level of Purkinje cells and deep cerebellar nuclei. Some authors have shown that EBCC is impaired in patients with idiopathic focal hand dystonia and CD56. Conversely, adaptation learning, which tests the predictive ability to adjust motor execution after a perturbation, has been found to be normal in patients with CD58. The contrasting findings obtained by these two neurophysiological tests tentatively exclude a global cerebellar dysfunction in dystonic patients. Since patients with dystonia, specifically those with CD, often have concomitant tremor, some authors have investigated whether the presence of tremor may be the clinical feature reflecting cerebellar involvement. Hence, in studying CD patients with and without tremor, Antelmiet al.59 observed that patients with dystonic tremor showed a decreased number of conditioned responses in the EBCC paradigm as compared to healthy controls and dystonic patients without tremor. Similarly, when investigating anticipatory movement control during a bimanual task, Avanzinoet al.58 found that adaptation of anticipatory adjustment was altered in patients with CD and tremor but not in CD patients without tremor and healthy subjects. These observations therefore suggest that cerebellar dysfunction more likely determines tremor than dystonia. Nonetheless, since most neurophysiological investigations testing the cerebellar hypothesis were conducted in patients with CD, further investigations should also assess whether this conclusion also applies to other types of focal dystonia.Studies using animal models of dystonia, however, also showed that cerebellar output alters basal ganglia activity and determines dystonic postures60. In healthy subjects, the SEP amplitude obtained by stimulating two adjacent nerves simultaneously is smaller than that obtained by stimulating a single nerve due to inhibitory mechanisms65. In dystonic patients with upper limb involvement, some authors have reported impaired suppression of SEPs at the spinal, brainstem, and cortical levels after mixed stimulation of the median and ulnar nerves67, thus implying reduced inhibition at multiple levels of the sensory system. Supporting this hypothesis, several studies on patients with various forms of focal dystonia have reported increased temporal discrimination thresholds (STDTs), the interval needed to discriminate two consecutively applied stimuli69. Recently, Antelmiet al.70 recorded the high-frequency potential oscillations (HFOs) related to SEPs in order to understand the mechanisms responsible for altered STDT in dystonia and found that patients with CD had a reduced area of the early component of HFOs and reduced paired SEP inhibition that correlated with increased STDT values. Since HFOs are generated by the activity of a population of 3b cortical inhibitory interneurons that receive thalamo-cortical inputs71, the authors concluded that impaired temporal discrimination in dystonia arises from defective inhibitory mechanisms in the primary somatosensory cortex.Earlier studies tested the sensory system in dystonic patients by assessing somatosensory-evoked potentials (SEPs), electrical potentials generated in sensory pathways at peripheral, spinal, subcortical, and cortical levels of the nervous system73. Though an earlier investigation74 showed, and a recent study confirmed65, that nociceptive pathways are normal, as tested by laser-evoked potentials in patients with CD, Tinazziet al.75 recently investigated whether pain arises from dysfunction of regulatory pathways of nociceptive transmission. To this aim, the authors applied a protocol, termed the conditioned pain modulation protocol, to test descending inhibitory control on nociceptive neurotransmission. This protocol consists of delivering a painful conditioning stimulus alongside another experimentally induced painful test stimulus. The ratio of the laser evoked N2/P2 potential amplitude during the application of the heterotopic noxious conditioning stimulation, as compared to baseline, reflects the physiological reduction of the perceived conditioned stimulus. The authors found that patients with CD have a reduced conditioned pain modulation response as compared to patients with BSP and healthy subjects and concluded that the endogenous inhibitory pain system is primarily defective in CD. Although this abnormality was present regardless of the presence of pain in these patients, it is likely that this alteration makes patients with CD more susceptible to developing pain. In addition, the evidence that this response is normal in patients with BSP implies that the two types of focal dystonia may differ in their pathophysiological mechanisms75.As regards pain, there is some evidence from quantitative sensory testing that the thermal detection threshold and pain sensitivity are abnormal in patients with dystonia79. Motor tasks such as hand movements, writing, playing instruments, and blinking are the most common tasks that have been used in dystonia. Sensory and motor task-related fMRI studies first showed an abnormal activation of the primary sensory and motor cortices, secondary motor cortex, basal ganglia, and the cerebellum that were consistent across different dystonia phenotypes88. Changes were detected while patients with dystonia performed tasks with and without dystonia induced by the movement itself and also when the tasks involved clinically unaffected body regions85. Altered sensory processing and abnormal somatotopic sensory organization in the basal ganglia and sensory cortex were also found, most consistently in the hand area of the primary somatosensory cortex82. Dysfunction was also detected during motor preparation and motor imagery83.The introduction of functional neuroimaging investigations has allowed investigators to view changes in the functional activity of various brain areas in dystonia . Changes89. In another study in CD patients performing a hand force task, symptom severity was associated with increased activity of the cerebellum and decreased functional activity of the somatosensory cortex90. Using a visuospatial task, Filipet al.91 found a reduced activation of the cerebellum associated with a reduced connectivity of the cerebellum with basal ganglia and the motor cortex, and a reduced activation of temporal, premotor, and parietal associative areas.In the last three years, task-related fMRI studies have aimed to test the involvement of the cerebellum in focal dystonia and to identify functional correlates of altered sensory processing. In patients with CD, isometric head rotation in the direction of dystonic head rotation was associated with an increased activation of the ipsilateral anterior cerebellum, whereas isometric head rotation in the opposite direction was associated with increased sensorimotor cortex activity92. In writer’s cramp, the sensory processing of stimulation sequences (transient finger pressure) before the execution of a motor task revealed widespread decreased activation of the sensorimotor network, suggesting defective sensory processing during motor planning in these patients93.As regards sensory processing, temporal discrimination deficits corresponded to disrupted superior collicular activity during looming stimuli in patients with CDIn conclusion, recent evidence with fMRI has shown that the cerebellum is involved in altered connectivity and has identified functional correlates of altered sensory processing. However, since dystonic symptoms often worsen or are triggered by motor task execution, a relevant issue with task-related fMRI findings is that they are unable to determine whether functional abnormalities are causes or consequences of dystonic motor disturbances. Similarly, the cerebellar involvement in the abnormal connectivity can be either primary or compensatory. Studies in unaffected carriers of dystonia-related mutations and unaffected relatives of dystonic patients may help clarify this important issue.99 in patients with BSP, Huanget al.100 observed alterations in multiple neural networks including the sensory–motor network , the right frontoparietal network , and the salience network . Abnormalities in regions of the default mode network and sensory integration network have been reported in patients with BSP101. Further confirmation of an abnormal functional connectivity between the right caudate and left striatum and right supplementary motor area correlating with BSP severity comes from the study by Niet al.102. In embouchure dystonia, changes in resting state connectivity were found in sensorimotor and auditory areas and in the cerebellum103. Abnormalities in both intraregional brain activities and interregional functional connectivity were also described in patients with CD104. Functional changes extensively involved both cortical and subcortical structures, and common alterations of the two measures were identified bilaterally in the postcentral gyrus as well as in the basal ganglia and thalamus. Overall, the above-cited findings with resting-state MRI have shown that in patients with focal dystonias altered connectivity in various brain networks is present independently from the execution of specific sensorimotor tasks, related or not to dystonia. Using both graph theoretical analysis108 and ICA, Battistellaet al.109 compared patients with task-specific (eight spasmodic dysphonia and seven writer’s cramp patients) and non-task-specific dystonia (nine CD and nine BSP patients) and found that every patient exhibited unusually expanded or minimized neural communities. In addition, patients with task-specific dystonia had substantial connectivity alterations in the primary sensorimotor and inferior cortices and abnormally formed hubs in the insula and superior temporal cortex, as compared to patients without task-specific dystonia109. Results from graft theory analysis, therefore, suggest a large-scale alteration of network architecture in focal dystonia, with distinguishing features between task-specific and non-task-specific dystonia.Using resting-state fMRI with independent component analysis (ICA)112 studies showed microstructural alterations in the fiber tracts connecting the brainstem nuclei, basal ganglia, thalamus, cerebellum, motor cortex, and sensory cortex, and in the white matter (WM) of limbic, occipital, and prefrontal cortices in different forms of focal dystonia114. In recent years, Bermanet al.115 used DTI in patients with BSP and CD to show that there are focal alterations in various brain structures that are specific to the two forms of focal dystonia . Consistent with the hypothesis that specific focal alterations may distinguish between focal dystonia phenotypes, Bianchiet al.116 observed that spasmodic dysphonia phenotypes may be distinguished on the basis of focal structural abnormalities in the areas of motor control of speech production and auditory–motor integration, whereas spasmodic dysphonia genotypes were associated with structural changes in higher-order extra-Sylvian regions and their connecting pathways. Similarly, differences in structural integrity have been reported by Kirkeet al.117 in patients with spasmodic dysphonia, both with and without tremor. Compared to patients with spasmodic dysphonia without tremor, patients with spasmodic dysphonia and tremor exhibited a greater extent of WM changes in the right posterior limb of the internal capsule at the junction of the corticospinal/corticopontine tracts and superior thalamic radiation103.Earlier diffusion tensor imaging (DTI)et al.37 used an MRI technique termed “lesion network mapping” from connectome data of a large cohort of healthy subjects to test whether lesions causing CD belong to a common brain network. However, the authors found that patients with CD had heterogeneous lesion sites  that all belonged to a single functionally connected brain network.Finally, CorpFor a long time, the pathophysiology of adult-onset focal dystonia has been thought to involve, uniquely, a basal ganglia disturbance. However, accumulating evidence in recent years now points to the anatomical and functional involvement of several brain regions. Recent findings have demonstrated an association between acquired focal dystonia and lesions in various brain regions, including the cortex, the basal ganglia, thalamus, brainstem, and cerebellum. Convincing evidence from both neurophysiological and neuroimaging investigations supports the hypothesis that the cerebellum intervenes in the pathophysiology of dystonia. However, although it is widely accepted that abnormal cerebellar output may determine tremor in dystonia, it is still unclear whether the cerebellum is the primary node where aberrant communication arises. Moreover, it is also unclear whether the cerebellum plays a substantial role in all forms of focal dystonia or only in CD.The neurophysiological reports of impaired sensory and motor inhibition at multiple levels of the central nervous system  may well reflect not only a direct basal ganglia disturbance but also disturbances in the activity of basal ganglia-thalamo-cortical and cerebello-thalamo-cortical projections. Pain in CD patients, likely due to impaired descending regulatory mechanisms of nociceptive transmission, implies an additional dysfunctional network in this form of focal dystonia. In summary, recent neurophysiological and neuroimaging studies demonstrate that focal dystonias involve disordered communication among several brain networks, in which basal ganglia and, possibly, the cerebellum act as entraining structures. Although different forms of focal dystonia all share alterations in neural structures belonging to the basal ganglia-thalamo-sensorimotor cortical network, specific clinical dystonic features may also emerge because of characteristic neural signatures in specific networks.Finally, increased attention is now directed towards the remarkable clinical heterogeneity of motor manifestations and the variable occurrence of sensory, psychiatric, and executive function disturbances. The heterogeneous clinical features together with the neurophysiological and neuroimaging advances support the trend towards “splitting” focal dystonias, insofar as, taken to the extreme, each focal dystonia is unique to each patient.BSP, blepharospasm; CD, cervical dystonia; DBS, deep brain stimulation; DTI, diffusion tensor imaging; EBCC, eye blink classic conditioning; GPi, globus pallidus internus; HFOs, high-frequency potential oscillations; ICA, independent component analysis; MRI, magnetic resonance imaging; SEPs, somatosensory-evoked potentials; STDT, increased temporal discrimination threshold; WM, white matter.