Cannabidiol is a component of herbal cannabis, studied for a number of potential pharmaceutical indications, more recently, its potential anti-psychotic effects with an extremely favorable side effect profile. Cannabidiol content of cannabis may also attenuate the psychotic and cognitive effects associated with cannabis use. Early psychosis is associated with alterations in the endocannabinoid system and is marked by limited engagement in treatment, reluctance to use traditional antipsychotics, sensitivity to medication side effects and heavy cannabis use. Cannabidiol may thus represent a more acceptable and tolerable antipsychotic medication in this phase of illness with a novel mechanism of action.Data will be presented from an ongoing double blind, placebo controlled, within subject, crossover study examining the effects of Cannabidiol (800mg/day) versus placebo in individuals within the first 7 years of their psychotic illness. Subjects participate in two treatment periods, each four weeks long separated by at least 2 weeks of washout.Data will be presented on the effects of Cannabidiol on psychotic symptoms , cognitive deficits (MATRICS battery), electrophysiological biomarkers of information processing (Resting EEG and ERPs relevant to psychosis and cannabinoids), metabolic parameters and general functioning.Cannabidiol is a novel drug that has shown potential efficacy in the treatment of psychotic symptoms. Early psychosis is a critical treatment period during which treatment engagement and adherence is critical and duration of untreated psychosis is associated with long term negative consequences. Cannabidiol may thus represent a more acceptable and tolerable medication to target this vulnerable population.


Knowledge of gestational age (GA) is critical for guiding neonatal care and quantifying regional burdens of preterm birth. In settings where access to ultrasound dating is limited, postnatal estimates are frequently used despite the issues of accuracy associated with postnatal approaches. Newborn metabolic profiles are known to vary by severity of preterm birth. Recent work by our group and others has highlighted the accuracy of postnatal GA estimation algorithms derived from routinely collected newborn screening profiles. This protocol outlines the validation of a GA model originally developed in a North American cohort among international newborn cohorts.Our primary objective is to use blood spot samples collected from infants born in Zambia and Bangladesh to evaluate our algorithm’s capacity to correctly classify GA within 1, 2, 3 and 4 weeks. Secondary objectives are to 1) determine the algorithm's accuracy in small-for-gestational-age and large-for-gestational-age infants, 2) determine its ability to correctly discriminate GA of newborns across dichotomous thresholds of preterm birth  and 3) compare the relative performance of algorithms derived from newborn screening panels including all available analytes and those restricted to analyte subsets. The study population will consist of infants born to mothers already enrolled in one of two preterm birth cohorts in Lusaka, Zambia, and Matlab, Bangladesh. Dried blood spot samples will be collected and sent for analysis in Ontario, Canada, for model validation.This study will determine the validity of a GA estimation algorithm across ethnically diverse infant populations and assess population specific variations in newborn metabolic profiles. Knowledge of gestational age is critical for guiding neonatal care and quantifying regional burdens of preterm birth. Novel methods of postnatal gestational age estimation are actively being sought.We and others have demonstrated that postnatal algorithms developed from newborn metabolic profiles provide gestational age estimates, accurate to within 1–2 weeks.Currently published gestational age algorithms have been validated in North American cohorts only.This protocol details an international validation study of a postnatal gestational age algorithm using data collected from newborns born in Zambia and Bangladesh.Knowledge of gestational age at the time of birth is important for distinguishing the preterm from the small-for-gestational age (SGA) infant, whose medical needs and expectations for achieving significant development milestones may be different. Reliable gestational age estimates are also useful for quantifying population burdens of preterm birth, which can facilitate appropriate allocation of resources to hospital centres and regions of greatest need. In many low-income and middle-income countries, maternal access to prenatal care, in particular to ultrasound dating services, is limited and imprecise measures, such as last menstrual period, fundal height, or examination of the newborn are relied on for gestational age estimation.In 2013, our research group identified significant variations in newborn screening analyte levels, including amino acid and endocrine markers, based on gestational age.Our work suggests potential value in using dried blood spot-derived analytes for the postnatal assessment of gestational age. This approach may be particularly useful in low-resource settings where reliable estimates of gestational age at the time of birth are difficult to obtain. Postnatal estimates may be useful both in guiding the course of care and for population surveillance of the burden of preterm birth. Before this goal may be realised, however, our previously published gestational age prediction model must be validated in other infant populations. This study aims to evaluate the performance of our reference model on newborn screening profiles taken from infants born in low-resource settings for whom prenatal dating ultrasound scans are available. Additionally, although newborn heel-prick samples are the standard used by newborn screening programs, cord blood may be more easily collected without discomfort to the infant and stress to the parents. We will therefore also evaluate model performance in data derived from cord blood samples.Our primary objective is to use dried blood spot samples collected from Southeast African (Zambian) and South Asian (Bangladeshi) newborns to evaluate the algorithm’s capacity to correctly classify gestational age within 1, 2, 3 and 4 weeks and also within categories of preterm birth.Our secondary aims are to: 1)determine the accuracy of the reference algorithm in small-for-gestational-age and large-for-gestational-age newborns; 2) determine the ability of the gestational age estimation algorithm to correctly discriminate across dichotomous thresholds of preterm birth ; and 3) compare the relative performance of algorithms derived from the full newborn screening panel and those restricted to a subset of newborn screening analytes.This project is led by the Ottawa Hospital Research Institute (OHRI) and Newborn Screening Ontario (NSO), located at the Children’s Hospital of Eastern Ontario (CHEO) with oversight of research by the CHEO Research Institute (CHEO-RI), in partnership with the Global Alliance to Prevent Prematurity and Stillbirth (GAPPS), International Centre for Diarrhoeal Disease Research, Bangladesh  and the University of North Carolina, Chapel Hill (UNC-CH) with the University Teaching Hospital (UTH) of Lusaka, Zambia. Funding is provided by the Bill & Melinda Gates Foundation.This is a non-interventional international validation study to assess the performance of a gestational age estimation model originally developed in a North American population using sex, birth weight and newborn screening values. This protocol outlines the collection, transport and analysis of samples from newborns whose mothers were enrolled into preterm birth cohorts in Lusaka, Zambia and Matlab, Bangladesh. Data handling and reporting procedures are also detailed.All procedures will be conducted in accordance with local standards of care. This study has been approved by the research ethics boards and institutional review boards of all participating institutes. Research agreements, including but not limited to material and data sharing agreements, will be developed in accordance with the preferred standards of the participating host institutions.The study population will consist of newborns whose mothers are already enrolled in one of two participating GAPPS-supported birth cohorts: (1) Preterm and Stillbirth Study in Matlab, Bangladesh , a prospective cohort study designed to assess biologic, environmental and social determinants of adverse pregnancy outcomes and (2) Preventing Preterm Birth in Zambia , a prospective cohort study and biorepository designed to characterise the factors associated with preterm delivery and outcomes of prematurity in Zambia. Sample size requirements for this study are addressed in online 10.1136/bmjgh-2017-000365.supp1All participants will provide written informed consent to participate in the study. Enrolment and participation in either the PreSSMat or ZAPPS Study preterm birth cohorts will not be affected by a woman’s choice to participate or not participate in the current protocol. Written consents have been translated into Bangla for participants in Bangladesh and into Bemba and Nyanja for participants in Zambia.Criteria for enrolment into the proposed study will be those already outlined for the established preterm birth cohorts. For ZAPPS, pregnant women will be enrolled if: ≥18 years old and residing within Lusaka, Zambia; gestational age ≤20 weeks with gestation confirmed by ultrasound; singleton or twin pregnancy with confirmed fetal heart tones; and willing to allow their newborns to participate in the study. For PreSSMat, pregnant women will be enrolled if: >15 years of age and <20 weeks gestation with gestational age confirmed by ultrasound; singleton or twin pregnancy with confirmed fetal heart tones, residing within Matlab, Bangladesh; and willing to participate in all antenatal, delivery and postpartum study milestones. All newborns born into the two cohorts will be eligible for inclusion in the current study. There will be no other explicit inclusion or exclusion criteria.Consent details already in place for each of the established birth cohorts include provision of information pertaining to the objectives, procedures, risks and benefits to participation. Participants will be made aware that participation is voluntary and that those choosing not to participate will continue to receive antenatal care and treatment according to local clinical standards. Participants will be assured that all reasonable measures will be taken to protect the information of themselves and their newborn. Participants will also consent to storage and future use of their samples for related preterm birth research under authorisation of presiding institutional committees.Participants will additionally be informed of the risks and benefits of heel-prick blood collection. Participants will be told that heel-prick collection may cause temporary discomfort to their newborn and that through their participation there is a possibility that their child may be identified to be at risk of one or more diseases. Participants will be informed that such incidental findings will be communicated to the study investigators, and recommendations will be made to confirm diagnoses and guide treatment of their infant if necessary. At the time of consent, participants will be informed of their right to request the full details of the screening results for their newborns.Dried blood spot samples will be collected according to standard operating procedures that will be provided to all collection sites. A procedure manual will similarly be distributed to all collection sites detailing the scope of work for all participating institutions, as well as procedures for reporting and management of incidental findings. A summary of the proposed workflow described herein is provided in Umbilical cord blood or blood from a large placental vein on the chorionic surface will be collected within 30 min of delivery of the placenta into an uncoated, sterile syringe. Drops of blood from the syringe will be applied to designated Whatman 903 filter paper. No more than 400 µL of cord blood will be required for the proposed study.To facilitate newborn screening analysis, newborn heel-prick samples will be taken 24–72 hours after birth or prior to discharge if the newborn is released from hospital within 24 hours of delivery. In brief, the newborn’s heel will be warmed at the skin-puncture site to promote increased blood flow. The puncture site will be disinfected and air-dried. A sterile lancet or heel incision device will be used to puncture the lateral aspect of the plantar surface of the newborn's heel. Following heel puncture, the first small drop of blood formed will be cleaned away and the formation of a second large drop of blood will be encouraged by intermittently applying gentle pressure to the newborn’s lower leg and heel. The Whatman 903 filter card will be applied gently against the blood drop and a sufficient quantity of blood allowed to soak through and completely fill a preprinted circle on the filter card. Each preprinted circle on the filter card will be filled by subsequently formed drops of blood. No more than 400 µL of blood will be required for heel-prick sample collection in the proposed study. Following sample collection, the newborn’s foot will be elevated above the body and a sterile gauze pad or cotton swab pressed against the puncture site until the bleeding stops.Labels with unique cohort-specific de-identified participant IDs and bar codes will be affixed to each filter card at the time of collection. Samples will be air-dried for 3–4 hours following which they will be transported to a designated secure study location  and stored in a climate-controlled setting prior to shipping. Clinical and demographic information essential for sample analysis will also be captured. Samples will be shipped from collection sites to NSO in Ottawa, Canada, every 7 days via preferred courier services. Appropriate shipping standards will be recommended to the collection sites to minimise risk of compromising sample integrity during the shipping process. A manifest including the sample information summarised in On receipt at NSO, the sample manifest will be cross-referenced against the physical sample cards. Any discrepancies will be resolved through follow-up with the collection site. Secondary accession numbers will be applied for use by internal NSO systems.NSO will refer to organisation and international standards to guide quality management of samples.Unsatisfactory specimens will not be used for study analysis. Specimens may be deemed unsatisfactory for several reasons. Parameters considered by NSO when determining sample quality and project specific actions for analysis are provided in Data loggers will be included in each shipment of specimens for assessment of temperature and humidity conditions. Should it be suspected that environmental conditions are affecting sample integrity, temperature and humidity control mechanisms within sample containers will be considered.NSO will generate reports summarising the quality of samples received on a per-shipment basis. These Quality Reports will be sent electronically to the collection site and used to address issues of sample collection, handling and storage prior to shipment. The Quality Report will summarise the Batch ID for the batch of samples received, temperature and humidity data gathered during the transportation period by data loggers, specimen details and the quality of the samples, as outlined above in Standard practice at NSO is to screen each sample for metabolites indicative of risk for 29 conditions.CFTR mutation analyses, TBX1 and purine profile assays, will be executed as per standard NSO practice provided sufficient sample is available from the original blood spot card.Full-panel analyses as per standard NSO practice will be executed on samples when possible . Any changes to standard practice of the full-panel analyses will be communicated via electronic bulletins to OHRI and the collection sites. Second-tier analysis of samples, including repeat confirmatory testing, Determination of ‘screen positive’ or ‘screen negative’ results will be based on comparison of analyte values against reference ranges set by NSO. Given that alert and screening logic are subject to change, active, complete newborn screening logic will be available to all participating institutions on request.There are two possible outcomes of newborn screening:If a newborn infant is screen negative, he or she has a low risk of having any of the diseases included on the screening panel.If the newborn infant is screen positive, this does not mean that the infant has a disease. However, it does mean that the infant is suspected to be at high risk of having a disease. Screen positive cases will be considered ‘incidental findings’ to the study.As with all screening tests, false-positive and false-negative results may occur with newborn screening. False-positive results may increase parental anxiety, while false-negative results may give a misleading sense of reassurance. If a newborn infant displays any unfavourable symptoms, the investigators will recommend to each collection site that the child should be investigated regardless of the results of the newborn screen.Although the conditions tested as part of the NSO screening panel are extremely rare, it is possible that, in analysing dried blood-spot samples, an infant will be identified to be at high risk of one of the screened conditions. Such risk poses clinical and ethical considerations of gathering newborn screening data for research purposes.not being undertaken as a newborn screening initiative and is designed explicitly a non-interventional study. Thus, when considering the management of incidental study findings, it was determined that real-time screening should only be provided for conditions that may be feasibly treated at the collection sites. The following factors were considered when surveying conditions warranting real-time reporting of screen positive cases.While this study involves newborn screening, this study is The diagnoses of some newborn screening conditions are affected by the timing of sample collection. Newborn screening samples are ideally collected 24–72 hours after delivery to avoid misdiagnosis as a result of natural postpartum fluctuations in metabolite levels. In this study, it is expected that many mothers will be discharged within 24 hours of birth. Environmental conditions such as heat/humidity may also impact newborn screening results.Ultimately, repeat and more complex confirmatory testing will be required for newborn infants with a screen positive result. Confirmatory testing may require urine analysis, sweat tests, gene sequencing and/or enzyme quantification, the materials and/or expertise for which may be neither available nor affordable to participant families. Conditions for which high positive predictive values could be set or those for which feasible confirmatory tests were available were preferred for real-time reporting.The complexity of intervention required to treat identified newborn conditions is an important consideration. Conditions for which standard treatments were simple, inexpensive and effective were preferred for real-time reporting.Based on the above listed considerations, three high-priority conditions were identified for which real-time reporting of newborn screening results should be provided to the collection sites: congenital hypothyroidism, haemoglobinopathies and medium-chain acyl-CoA dehydrogenase deficiency. In the event that analysis of dried blood-spot samples identifies a newborn infant as screen positive or high risk for any of these three conditions, NSO will circulate individual Alert Reports to the collection sites. In the circulation of Alert Reports, it will be recommended that positive screening results be communicated to patient families and that the newborn receive the appropriate follow-up for confirmatory testing and necessary medical interventions.Quarterly Reports summarising study progress will be generated by NSO and shared with the collection site and OHRI. Quarterly Reports will summarise the total number of samples received, sample transport data , newborn characteristic data  and the number and distribution of samples excluded from analysis based on ‘unsatisfactory’ quality. The Quarterly Report will also include a summary of all screening results of samples received to date.Study samples will be stored in Ottawa, Ontario until study closure, upon which a bulk shipment return of study samples to the collection site via preferred courier services will be accommodated. On return, samples will be stored within designated biorepositories where they will be housed for future investigations into the pathophysiological process of preterm parturition. Recommended storage conditions for dried blood-spot samples are −80°C.At study closure neonatal, maternal and birth data provided by the collection site  and birth weight. Continuous analyte and birth weight values will be modelled using restricted cubic splines. Fetal  and adult (A) haemoglobin levels will be modelled as (F+F1)/(A+F+F1) as previously described.Swartz Bayesian Criterion to guide the selection of covariates retained in the final model. Models will be internally validated using bootstrap validation methods to address overfitting.Forward stepwise variable selection will be applied using the We will also develop logistic regression models to distinguish between dichotomous categories of preterm birth  as we have done previously.c-statistic (area under receiver operator curve) and positive predictive value will be evaluated overall and among newborn infant subgroups  to investigate whether model calculations varied in quality across these subgroups.Model performance in terms of root-mean-square error, absolute prediction within ±1 week, This protocol details our approach to the collection and shipment of newborn blood spot samples from international preterm birth cohorts to Ottawa, Canada, for metabolic profiling using newborn screening approaches. We have addressed herein quality management of samples and our analytical approach. The data gathered for this study will be used to validate a postnatal gestational age estimation algorithm originally developed using newborn samples derived from a Canadian cohort.The strength of our approach includes leveraging the existing framework of large preterm birth cohorts operating in two ethnically distinct populations and our collaboration with NSO, a successful provincial newborn screening programme in Ottawa, Canada, that will lend greatly to the timely and accurate analysis of samples. We acknowledge that successful execution of the study will be dependent on the collection of a satisfactory number of newborn samples from each of the Zambian and Bangladeshi cohorts. A number of prospective participants may be unfamiliar with newborn screening procedures and thus uncomfortable with newborn heel-prick collection. Anticipating that some mothers may choose to decline participation on the basis of the newborn heel prick, participation will be open to those newborns from whom only single, unpaired cord blood or heel-prick samples may be collected. Validation of the metabolic postnatal gestational age estimation model using cord blood profiles will prove equally important to the aims of our study as we seek to optimise the practical utility of our approach. In the event that we find that a single global algorithm is not suitable for all newborn populations, we will tailor our approach to develop region-specific models to enhance gestational age estimation based on specific newborn populations.As discussed previously, novel methods are warranted to guide both local healthcare interventions and accurate population health estimates for low-resource regions of the world. In addition to providing insight into metabolic variations of newborn infant populations of varying ethnic background, gestational age and condition , we anticipate that validation of our approach will be of benefit to the search for new reliable methods for estimating gestational age at the time of birth.This study was approved by the Ottawa Health Science Network Research Ethics Board at the OHRI (20160219-01H) and the Research Ethics Board of the Children’s Hospital of Eastern Ontario Research Institute (16/20E). The protocol was also approved by Ethics Review Committee at the icddr,b (PR-16039), in Matlab, Bangladesh, and the University of Zambia’s Biomedical Research Ethics Committee (016-04-14) in Lusaka, Zambia.


Skeletal muscle displays considerable biochemical complexity, physiological plasticity, and cellular heterogeneity  studies show that EMG amplitude is significantly greater with high- vs. low-load RT thereby suggesting that higher loads are needed to fully stimulate the highest threshold motor units associated with type IIx fibers (Schoenfeld et al., Only a few studies have investigated this topic thus far Table . JacksonOnly one study was performed in older adults. Taaffe et al.  sought tOf crucial importance is that in both of the studies mentioned above, the RT program in the low-load groups was not performed to momentary muscular failure, indicating unequal training stimuli between high and low-load conditions. Employing a low-load RT program and not performing repetitions to momentary muscular failure may hinder muscular adaptation (Burd et al., Campos et al.  were theInterestingly, some studies report that low-load RT induces a greater hypertrophic response in type I muscle fibers. Vinogradova et al.  comparedUsing a within-subject design, Mitchell et al.  randomlyA common limitation in all of the studies above is the use of untrained participants. It has been shown that individuals with higher RT experience a blunted protein synthetic response post-resistance exercise, suggesting a possible ceiling effect of muscle gain (Damas et al., As with most RT research, the vast majority of studies that investigated this topic were of relatively short duration; it is not clear whether potential differences in fiber type hypertrophy specific to a given loading scheme may widen or narrow over time. Finally, all of the included studies assessed fiber growth in the vastus lateralis muscle. As previously highlighted, the vastus lateralis muscle is the most common muscle of choice for biopsies because of its mixed fiber type composition, accessibility, and trainability (Staron et al., The examination of fiber type changes via muscle biopsy has some inherent limitations. First, the biopsy technique involves extracting a small amount of tissue from a given muscle, which may not necessarily reflect fiber type-specific changes at the whole muscle level. Moreover, variations exist in the distribution of fiber types from superficial to deep and proximal to distal (Blomstrand and Ekblom, When low-load RT is not carried out to muscular failure, high-load training appears to provide a superior hypertrophic stimulus and thus greater growth of all muscle fibers. While some evidence indicates that low-load RT, when carried out to muscle failure, may induce a greater hypertrophic response in type I muscle fibers compared to high-load RT and that high-load RT may induce preferential growth of type II muscle fibers, the body of literature remains somewhat equivocal on the topic. In summary, there currently is not enough evidence to make a firm conclusion regarding changes that occur at the muscle fiber level with different loading schemes.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


That said, many methods were developed to assess masticatory performance. Consequently, systematic review of the literature would be of great value when it comes to identifying various methods for objectively assessing clinical masticatory performance and for evaluating these methods.Chewing and masticatory function constitutes one of the most important oral health factors that affect quality of life, especially in older individuals. Little consensus currently exists regarding ways to objectively assess clinical masticatory performance  identify methods to objectively assess clinical masticatory performance and (ii) evaluate psychometric properties  of the identified methods. A systematic literature search is required to do so in these sources: MEDLINE (Ovid), Embase (embase.com), Web of Science Core Collection (Thomson Reuters), Cochrane (Wiley), and Cinahl (Ebsco).Inclusion criteria: studies in scientific, full-text articles; development articles; validation articles; studies of the general adult population, ages ≥18. Exclusion criteria: topics and article types that cover interview methods and self-reported questionnaires; methods/instruments that measure subjective masticatory performance; qualitative studies and case studies; opinion and editorial pieces; animal studies; studies of humans with severe oral health complications.This systematic review will result in a comprehensive assessment of various methods designed to objectively measure clinical masticatory performance. This systematic review will rate these methods, assess their reliability and validity, and identify one or more methods that can be recommended for use in clinical and scientific environments. From what is currently known, no systematic evaluation of various methods for objectively assessing clinical masticatory performance has been published.CRD42016037700PROSPERO The online version of this article (doi:10.1186/s13643-016-0403-5) contains supplementary material, which is available to authorized users. An increasing number of older individuals retain dentition throughout life. Many have gone through oral rehabilitation with various dental constructions—often with the purpose of securing relevant chewing and masticatory function that has been shown to be one of the most important oral health factors associated with the quality of life in older individuals –3.performance refers to someone’s objective ability to mix or comminute food bolus) [Many clinical assessment methods were developed to assess masticatory performance, for example, color-changing chewing gums, sieving comminuted food or artificial food, optical scanning of masticated particles, or measuring release of dye when chewing food . Currentd bolus) . For praThe most common approach to evaluating masticatory performance has been to sieve comminuted food and determine the degree of food breakdown –9. Food Another common masticatory performance assessment method involves mixing ability tests. One study indicated that a mixing ability test discriminates better  than comminution tests . In anotWhile comminution and mixing tests are common methods when quantifying masticatory performance, others were also developed. Some studies used color-changing chewing gums , 18; herWhile most of these tests were used in laboratory studies, no established method for evaluating a patient’s objective masticatory performance is available within clinical practice, and the clinician must rely on masticatory performance assessments via oral status appraisals, existing dentition, or patients’ subjective experiences. The Eichner index, which is used to classify occluding contacts, was validated as a method in relation to masticatory performance .masticatory function was used for objective and subjective measurements [masticatory performance, because this term relates more to the objective aspects of mastication [The term urements . In thistication , and it tication –22.Monitor masticatory performance objectively before treatmentAssess whether treatment is indicatedRestore masticatory performanceEvaluate objective masticatory performance after treatmentOur scoping reviews identified two reviews that were published in this field. Oliveira et al. presented a review of various methods used for evaluation of masticatory performance in patients with conventional complete dentures . Fifty-t– Identify methods for objectively assessing clinical masticatory performance– Evaluate psychometric properties  of the identified methodsPrimary objectives are to:– Compare measurement properties of the identified methods– Identify any types of reported adverse events in development or validation of methods in the selected studiesSecondary objectives are to:The Preferred Reporting Items of Systematic Reviews and Meta-Analyses Protocol (PRISMA-P) guidelines are to be used for documenting review results . AdditioStudies will be included in this systematic review if they are reported in scientific, full-text articles. Study designs must describe development of methods that objectively assess clinical masticatory performance in adult individuals (development article) or evaluate measurement properties of methods that objectively assess clinical masticatory performance in adult individuals .Time frame for completing assessments such as before, during, or after dental proceduresSettings in which assessments were conductedThere will be no restrictions regarding type of:This systematic review will include studies of the general adult population, ages ≥18These topics and article types will be excluded from this systematic review: interview methods and self-reported questionnaires; methods/instruments that subjectively measure masticatory performance; qualitative studies and case studies; opinion and editorial pieces; animal studies; and studies of humans with severe oral health complications, for example, oral cancer, malocclusions, and trauma .If a study is unavailable in full-text, then the abstract will be excluded.In this systematic review, clinical masticatory performance is considered a method that assesses an individual’s ability to mix or comminute food/artificial food bolus.Methods for objectively assessing clinical masticatory performance Measurement properties described in the identified methods Adverse events that occurred during method development or validationOutcomes from this systematic review will be lists/tables/descriptions of:Scientific articles published in English only will be selected for this systematic review. A list of possible relevant titles in other languages will be provided in an appendix.These databases will be searched from their inception up to January 2017: MEDLINE (Ovid), Embase (embase.com), Web of Science Core Collection (Thomson Reuters), Cochrane (Wiley), and Cinahl (Ebsco). To complete our searches in the databases, the Google Scholar search engine will be used to search potential databases such as university databases and conference proceedings, among others, for articles. If only abstracts are identified, then authors will be contacted to obtain full-text articles.The reference lists of included articles or relevant reviews identified in the search will be manually screened. Experts and investigators in the field will be contacted to obtain information on ongoing or unidentified studies.The overall search strategy was developed with librarians at Karolinska Institute’s university library. The staff at this library has extensive expertise and experience in developing search strategies for systematic reviews. Library staff will also conduct the literature search.Search strategies will be developed for each database, with appropriate terms from controlled vocabulary . Main terms will be mastication, bite force, chewing gum, and deglutition—combined with different terms for measurement properties. Along with the terms from MeSH and Emtree, a broad range of current free-text terms will be used. The free-text terms will, if appropriate, be truncated and/or combined with proximity operators.A further search will be done with the names of the methods found in the original search. These names will be combined with AND—with the requirements for the target population and measurement properties.Additional file All citations will be imported into the EndNote (version X7.5) reference program. The library staff will save the electronic searches, and summaries of the searches will be printed to capture results of the searches for the protocol records.The EndNote reference manager software will be used during the study selection. After the initial search, obvious duplicates will be removed using the reference manager software. One reviewer will perform this procedure. Two independent reviewers will assess remaining titles and abstracts eligibility. If a title or abstract is not enough to determine eligibility, then the full-text article will be obtained.Full-text articles will be obtained from the remaining eligible abstracts. Two reviewers will independently judge each article for eligibility. If the information in the full-text article is not enough to determine eligibility, then authors will be contacted to obtain missing information. Discussions between the two reviewers will resolve any disagreement. If agreement is not reached, then a third reviewer will decide whether the article will be included. The reasons for excluding an article will be documented. Two team members will independently screen the references lists of the all included articles for any additional relevant studies.All review team members will receive training in using EndNote and the data extraction forms before procedures in each phase  during the systematic review. Training sessions will be organized for calibrating assessments among members. Regular team meetings will be held to discuss issues—to adhere to criteria in each phase. Several abstracts and articles will be pilot tested to ensure agreement and clarify decisions among reviewers.Two reviewers will implement data extraction for the included articles by using standardized data extraction forms developed for this study , country of study, study purpose(s), study design, study sample, description of method to objectively assess clinical masticatory performance, and adverse events.consensus-based standards for the selection of the health measurement instruments (COSMIN) group will be used to assess the measurement properties of the different methods [The predefined quality criteria for rating the measurement properties of instruments and methods recommended by the  methods . The pre methods .The criteria relate to these measurement properties and aspects of measurement properties: reliability , validity , and responsiveness. Also, under consideration will be whether development of any methods included in the systematic review was based on an a priori conceptual framework/model. Two independent reviewers will assess the measurement properties for each method. If consensus is not reached, a third reviewer will decide the outcome.COSMIN Checklist will be used to evaluate the methodological quality of the included studies [The  studies . This asCOSMIN Checklist: ratings of the rigor of the reliability, validity, responsiveness, and interpretability with related measurement properties and aspects of measurement properties. Additional file COSMIN Checklist consists of 5 to 18 items that cover methodological standards. In addition, each item can be scored on a four-point scale . Taking the lowest rating for each item in one box, an overall score is obtained for each measurement properties separately [Four domains are distinguished in the parately .COSMIN Checklist. This process will generate a separate rating for each of the measurement properties, where estimated in each study. Second, the estimated measurement properties of the methods will be assessed against the established criteria of measurement properties  will be contacted and a version or information in English will be requested.Two of the authors have earlier experience in reading and searching for eligible articles for systematic reviews, and all authors will be trained in this work—with the library staff—before the systematic review starts.


Analgosedation is a fundamental part of traumatic brain injury (TBI) treatment guidelines, encompassing both first and second tier supportive strategies. Worldwide analgosedation practices continue to be heterogeneous due to the low level of evidence in treatment guidelines (level III) and the choice of analgosedative drugs is made by the treating clinician. Current practice is thus empirical and may result in unfavourable (often hemodynamic) side effects. This article presents an overview of current analgosedation practices in the paediatric intensive care unit (PICU) and addresses pitfalls both in the short and long term. We discuss innovative (pre-)clinical research that can provide the framework for initiatives to improve our pharmacological understanding of analgesic and sedative drugs used in paediatric severe TBI and ultimately facilitate steps towards evidence-based and precision pharmacotherapy in this vulnerable patient group. The main goal of (paediatric) TBI treatment is the provision of supportive care to guarantee adequate cerebral perfusion to meet cerebral metabolic demands and limit secondary brain injury , 2. ApprA literature search was performed using search strategies with MeSH terms and synonyms of ‘brain injury’, ‘analgesia’, ‘sedation’ and ‘children’ with the search databases Embase, Ovid, Cochrane Central, Web of Science and Google Scholar. A total of 1160 potential references were found that were reviewed by the primary author for relevance based on the aim to provide a pharmacological overview of paediatric severe TBI analgosedation practice and principles. Additional references were added by cross-reference check. It must be emphasized that the 2012 international guidelines for paediatric TBI management remain the mainstay of treatment recommendations . This arThe application of analgesia and sedation in the stabilisation and (supportive) treatment of paediatric severe TBI occurs in various settings from the scene of the accident, emergency department, perioperatively and after admission and stay in the paediatric intensive care unit (PICU). The primary aim for administering analgosedation is to lower cerebral metabolic demand which can be increased by anxiety, stress and pain induced by the primary trauma and further exacerbated by noxious stimuli such as (invasive) procedures and invasive ventilation , 12–14. Most PICUs adopt a TBI protocol based on international guidelines, consensus and local variations in practice. The provision of sedation and analgesia is subdivided in so-called first and second tier therapies in a step-up approach to control ICP and maintain adequate cerebral perfusion pressure (CPP) , 15. AdhAnalgesic compounds described in the literature for paediatric severe TBI are opioids , Acetaminophen and Metamizole , 17–20. Most commonly, a combination of an analgesic and sedative drug is prescribed as a continuous infusion with a step-up approach in dosing based on clinical effect . The sedative effect of most analgesic compounds during dose escalation is often an added benefit in ICP control . AdditioAt this point, it needs to be noted that ‘efficacy’ of analgosedation is often titrated solely on the effect of ICP- and CPP-control and clinical signs of agitation. However, there is increased awareness that there are additional factors which need to be considered to develop a holistic picture of risk factors for secondary injury that could serve as pharmacodynamic (PD) markers in analgosedation studies. Multimodal neuromonitoring seems especially important when defining clinical parameters of therapeutic efficacy. PD markers of effective drug therapy could include cerebral oxygenation (PbtO2), cerebral metabolic state  and brain activity as monitored by continuous electroencephalogram (EEG) . FurtherThe potential negative effects of commonly used analgosedative drugs can be subdivided into short- and long-term pitfalls. Short-term pitfalls mostly refer to undesirable hemodynamic side effects, i.e. a decrease in mean arterial blood pressure (MAP) resulting in a decrease in cerebral perfusion pressure (CPP), which can further exacerbate secondary brain injury. Potential pitfalls based on specific drug or patient characteristics are summarized in the following paragraph. A more extensive overview of side effects is provided in Tables Continuous infusion of Propofol is associated with Propofol infusion syndrome (PRIS), which is characterized by the onset of metabolic acidosis, rhabdomyolysis, acute renal failure, cardiac dysthythmias and hyperlipidemia , 38. AltN-methyl-D-aspartate (NMDA) receptor agonists (such as Ketamine) led to less spreading depolarizations, but Midazolam increased the amount of spreading depolarization clusters. These findings need to be investigated further but provide an interesting angle into pitfalls and possibilities of these drugs [Spreading depolarizations present a potential threat to functional neurons, resulting in necrosis or degeneration and possibly poor outcome after brain injury. Analgosedation acts by influencing neuronal homeostasis and has been investigated for preventing or propagating spreading depolarizations. One study found that se drugs . Finallyse drugs .Long-term pitfalls have been described in the context of (major) withdrawal symptoms and delirium, which obscure adequate neurological evaluation. This suggests not only the need for dose escalation in the acute phase of patient stabilisation but also the development of guidelines to optimally taper analgosedation afterwards . ValidatPharmacogenetics can be considered part of patient-specific pitfalls. Important examples are so-called ABCB1 polymorphisms, which encode for P-glycoprotein transporter that is responsible for morphine efflux over the blood-brain barrier. This can result in different cerebral morphine concentrations and associated (prolonged) effect. The latter has mostly been investigated in the context of prolonged respiratory depression after opioid administration during elective procedures , 55.Finally, there are concerns about the potential neurotoxic apoptotic effects of certain drugs, especially in the developing brain. Animal studies have demonstrated mechanisms by which analgosedative agents of different classes  trigger upregulation of apoptotic cerebral cascades , receptors or blocking of voltage gated sodium channels). This results in inactivation of cell survival signalling proteins and activation of inflammatory cytokines . FurtherTo date, current approaches have not been able to conclusively yield the desired answers, i.e. which drugs are safe and effective to prescribe in (paediatric) TBI? The high failure rate in CNS drug development and research can in part be attributed to the fact that ‘golden standard’ approaches, such as randomized controlled trials (RCTs) and comparative effectiveness designs, fail to take into account the heterogeneity of the disease process and drug- and patient-specific characteristics. In particular, the unique functionality of the blood-brain and blood-cerebrospinal (CSF) barrier, and therewith drug transport into and out of the brain, are not elucidated. Thus, drug target site concentration  are unknown. Information on the target site concentrations is fundamental in understanding drug action. Therefore, assessing target site pharmacokinetics is the primary step before attempting to study the resulting pharmacodynamics , 11, 59.Bottlenecks in pharmacological research, especially in children, are ethical concerns about performing invasive studies of compounds with unproven benefit in minors, and difficulty obtaining adequate sample size to provide definitive answers. Another obstacle in paediatric drug research is the limited number and volume of blood or cerebral fluid samples which can be obtained per patient due to smaller circulating volumes. This is where ‘bench-meets-bedside’ research can be of value. Animal-based PBPK models can be translated to humans and thereby serve as templates of what happens to a drug in the body under various clinical conditions. After translation of the animal PBPK model to humans, full drug concentration PK profiles in human brain can be predicted. The PBPK human model can be validated by comparing predicted drug concentration values to a number of observed drug concentrations in the human CNS . Especially for paediatric PK analysis, obtaining individual plasma PK is crucial to predict a drug concentration time profile in the CNS due to the various developmental differences that have an impact on PK profiles. Collecting sufficient human samples can be challenging, but ‘sparse sampling population-based PK (PPK) analysis’ is an innovative statistical technique that can be used to solve this challenge. Practically, this model requires only a limited number of samples per patient. The samples of various patients are then used as a single ‘population’  providing enough data points to compile drug-specific pharmacokinetic time profiles under different clinical conditions and developmental differences. In other words, the combination of PBPK and PPK modelling allows prediction of drug concentrations at various target sites  at different dosing regimens for each paediatric patient. It has been enlightening that drug plasma concentrations do not represent cerebral drug concentrations, highlighting the unique properties of the blood-brain and blood-cerebrospinal fluid barrier , 59–61.Although focus must shift ‘back to basics’ with regard to improved pharmacological understanding of frequently used analgesics and sedatives, this does not mean observations from the clinical field should be dismissed. For example, comparative effectiveness research could provide direction as to which drug compounds warrant further PK-PD research. Finally, pharmacology is dynamic, complicated and an indispensable part of clinical practice. It is imperative we understand basic principles but also cooperate with experts in the field to optimize our treatment. In this respect, a clinical pharmacologist or hospital pharmacist can be of great value to point out significant drug interactions and provide alternative options as well as dose adjustments based on clinical status. It is becoming increasingly clear that a multifactorial, complex disease like (paediatric) severe TBI warrants a multidisciplinary approach, also as regards pharmacology.Practice is heterogeneous and leads to serious concerns about efficacy and safety. Pitfalls, besides the well-known side effects of frequently used drugs, include paediatric-specific concerns in terms of potential neurotoxicity in the developing brain and age-specific differences in drug distribution and metabolism. Possibilities to enhance our pharmacological understanding include the implementation of animal-based pharmacokinetic models that enable prediction of drug concentrations at target sites. This combined with multimodal neuromonitoring can link cerebral drug concentrations to drug effect and ultimately lead to more evidence-based analgosedation therapies in (paediatric) TBI.Analgosedation is a crucial part of severe (paediatric) TBI management but evidence-based guidelines are not available leaving the choice of analgesic and sedative drugs to the treating physician.


During recent years, non-invasive brain stimulation, including transcranial electrical stimulation (tES) in general, and transcranial direct current stimulation (tDCS) in particular, have created new hopes for treatment of neurological and psychiatric diseases. Despite promising primary results in some brain disorders, a more widespread application of tES is hindered by the unsolved question of determining optimum stimulation protocols to receive meaningful therapeutic effects. tES has a large parameter space including various montages and stimulation parameters. Moreover, inter- and intra-individual differences in responding to stimulation protocols have to be taken into account. These factors contribute to the complexity of selecting potentially effective protocols for each disorder, different clusters of each disorder, and even each single patient. Expanding knowledge in different dimensions of basic and clinical neuroscience could help researchers and clinicians to select potentially effective protocols based on tES modulatory mechanisms for future clinical studies. In this article, we propose a heuristic spatiomechanistic framework which contains nine levels to address tES effects on brain functions. Three levels refer to the spatial resolution  and three levels of tES modulatory effects based on its mechanisms of action . At the group level, this framework could be helpful to enable an informed and systematic exploration of various possible protocols for targeting a brain disorder or its neuroscience-based clusters. Considering recent advances in exploration of neurodiversity at the individual level with different brain mapping technologies, the proposed framework might also be used in combination with personal data to design individualized protocols for tES in the context of precision medicine in the future. Transcranial electrical stimulation (tES), as a non-invasive brain stimulation technique, consists of delivering weak electrical currents ~1–2 mA) to the head for several minutes (~5–30 min) via scalp electrodes. The applied currents can be direct , alternating , or random noise , phase (for AC current), electrode size, shape, number, montage and also duration, number and interval of stimulation sessions . Distributed brain areas interact with each other and form large-scale networks . It has been suggested that complex brain functions emerge from these interactions , the physiological response of the brain to tES can be explained based on its “neurochemical” or “neuroelectrical” consequences, or its effects on “brain oscillations or waves”. In the following, we go forward step by step by explaining each of the nine levels in the proposed spatiomechanistic framework and reviewing some relevant evidence in the basic and clinical neuroscience fields.There is a micro-macro association between neurochemicals and various neural processes such as cortical plasticity. Different cognitive functions such as emotion, memory and even consciousness might be mediated by the complex interactions of many neurotransmitters. Various psychiatric disorders and neurodegenerative diseases have some roots in the dysfunction of neurotransmitter systems. Advancement of knowledge about brain neurochemistry may yield to better identification of the molecular basis of disorders and disease-specific biomarkers.tES can affect brain neurochemistry; i.e., it can modulate molecular, cellular and biochemical aspects of the nervous system and mechanisms of molecular signaling and communication. Thereby, it influences the function of neurons and neural processing. tDCS modifies the synaptic microenvironment and regulates different neurotransmitters by modulating glutamatergic and gamma-Aminobutyric acid (GABA)-ergic activity , e.g., increased myoinositol concentration only underneath the anodal electrode placed over the right M1  to measure changes of extracellular dopamine concentration in the putamen following rTMS of the motor cortex. They showed that rTMS of the left primary motor cortex leads to reduced [11C]raclopride binding potential in the left putamen which indicates focal dopamine release in this area  resulted in a significant decrease in glutamate and glutamine within the anterior cingulate, a trend towards decreased glutamate and glutamine in the thalamus, and a trend towards increased GABA in the anterior insula  enhanced BDNF serum levels. This suggests that tDCS might promote neuroplastic changes in pain pathways including modulation of pain-regulating neurotransmitter release. BDNF is widely distributed in the central nervous system, has been suggested to be a possible neuroplasticity marker, and could act as a molecular marker of global neuronal activity. Therefore, tDCS, with the ability of regulating BDNF and other neurotransmitters in the plasma, could be considered as a modulator of global neural activity  during performance of a picture naming task affects the frontal naming network and reduces the Blood-oxygen-level dependent (BOLD) signal in both inferior frontal sulcus, and left ventral premotor cortex. Results of dynamic causal modeling revealed different excitatory and inhibitory connections between the ventral premotor cortex and inferior frontal sulcus with anodal compared to sham stimulation. Interestingly, a linear positive correlation was revealed between reaction time of the naming and dynamic causal modeling-derived values for ventral premotor cortex to inferior frontal sulcus connection; i.e., participant-specific DC-induced performance changes were related to the strength of this link  after stroke. It is thought that in this condition the healthy hemisphere exerts too much inhibitory influence on the ipsilesional hemisphere. This unopposed inhibitory force might hinder the recovery process of the affected hemisphere  showed significantly modulated regional cerebral blood flow  in extensive cortical and subcortical areas including the left M1, right frontal pole, right primary sensorimotor cortex and posterior brain regions under both stimulation variants compared to sham  is crucial to explain how neurons and neural networks process information. Electrophysiological and neuroimaging techniques such as resting state-fMRI have been used to acquire data for the analysis of interconnections linking various brain regions. These datasets  combined with computational connectivity analysis methods have been employed to reveal tES-induced alternations of the architecture and connectivity of human brain functional networks at the large scale level. In a related study, anodal/cathodal stimulation of M1/contralateral frontopolar cortex resulted in an alteration within some cortico-subcortical functional networks; i.e., it created a connectivity-driven modulation of functional coupling between stimulated M1 and thalamus, and between striatum and the main components of the default mode network. Attenuation of connectivity between default mode network elements has been speculated to be associated with the activation of motor task-related cortico-subcortical functional networks  has been proposed as an important communication mechanism across different cortical regions. tACS has been successfully used to entrain oscillatory activity in the circumscribed cortical areas and exogenously boost the coupling between different cortical regions within a specific frequency band. In a study by Polanía et al. , in-phasModulation of brain rhythms by tES can have an effect on extensive regions of the brain. An example is the study by Ozen et al.  who applIn a study by Polanía et al. , EEG sigModeling approaches can be useful to interpret and predict EEG alternations induced by various stimulation configurations. In a modeling study, Merlet et al.  simulateComputational approaches for inferring brain connectivity and functional networks based on oscillatory activities reflected in EEG and magnetoencephalography (MEG) data fall into this category as well. Functional connectivity between regions can be estimated based on the coherence between recorded EEG signals from the two regions. A combined tDCS-EEG study by Notturno et al. , for exaAs mentioned previously, the nine levels of the framework are interdependent, and not isolated from each other. In principle, no intervention can claim to exclusively exert influence on only one level, rather effects are often present across multiple levels. The main target of every intervention, which is defined based on the pathophysiology of the disorder, is in most cases restricted to one level , however, there are usually alterations at other levels as well, which can be secondary. Pharmacological interventions, for instance, are designed primarily based on their neurochemical effects, but neurochemical changes are accompanied by alterations of neuroelectrical and oscillatory properties of the nervous system as well. For example, the main symptoms of Attention Deficit Hyperactivity Disorder (ADHD) have been suggested to arise from decreased dopamine concentration primarily in the PFC  data, but can also include other personal biomedical information across many layers, from molecular levels to behavior. These can incorporate clinical, behavioral, physiological and environmental parameters such as polymorphisms, anatomy, age, health history, lifestyle and diet. Tools employed in precision medicine can include molecular diagnostics, imaging, software/analytics, and methods for using large datasets. Many of these data types and tools can be relevant when thinking about the development of precision medicine in tES applications. Specifically, cutting edge and emerging brain mapping technologies, including state-of-the-art neuroimaging and electrophysiological devices, can provide valuable information about temporal, spatial, and other aspects of neural states, and might offer approaches towards the discovery of clinically valuable diagnostic, prognostic and therapy-outcome-predictive biomarkers. Therefore, in this section, we focus on the potential applications of brain mapping technologies for tES individualization.The proposed framework, inspired from new advances in neuroscientific knowledge about tES action mechanisms, could offer a systematic strategy to explore the tES protocol space, make a more informed selection of protocols, and propose new ideas about designing participant-tailored protocols. Protocol individualization has the potential benefit of improving response and avoiding waste of time according to patient treatment with ineffective therapies. In this section, we describe how the proposed framework can provide a rationale to produce hypotheses about physiologically-based optimized/tailored stimulation protocols in three stages: (1) tailoring based on the group-level data of a brain disorder; (2) tailoring based on various clusters of patients with a brain disorder; and 3) tailoring based on individual-level data. In the previous sections, we have focused on the first two stages. In this section, we review them and introduce the third stage. The whole procedure is summarized in Figure  tailorinThis article aims to support researchers in different scenarios of clinical trial design. This includes proof of concept studies to evaluate the efficacy of tES for the treatment of a brain disorder, but also studies aimed to enhance stimulation outcomes compared to previous tES studies targeting the same disorder. In either case, one of the key steps in experimental design is to select an appropriate stimulation protocol. The proposed framework in this article recommends to look for answers to the two following main questions based on the available empirical evidence:Is tES going to be used to affect brain neurochemistry, its neuroelectrical aspects, or its rhythms?What is the spatial extent of the target that is intended for modulation? A specific region, a small network, or a large network in the brain?To answer these questions, the knowledge base about the target disorder is essential. The following aspects might be especially relevant: “Is there any specific brain region involved in this disorder?”; “Is this region directly accessible for transcranial local stimulation or should it be accessed indirectly by modulating a cortical node within a network?”; “Does this disorder change some neurochemicals in the brain? If yes, how large is the spatial extension? Are these alterations limited to a specific region, involve a small network or even the whole brain?”; “Is there some reduction or increase of the activity in a region, small network or large scale network?”; “Does evidence demonstrate the presence of pathological neural oscillations? If so, do they occur within a brain region or a network?” To date, most clinical studies have addressed only one or two of these questions. However, to advance clinical translation of tES, future studies need to address most/all of these questions in a comprehensive manner using multiple approaches and analyses.Gathering this information will result in identification of one of the nine levels of the framework as the “most relevant” one (which obviously will not be exclusive). The next step would be to identify a potentially effective protocol by examining the current knowledge base of brain stimulation and specifically tES studies with special attention to various employed protocols and underlying action mechanisms, and to identify a potentially effective protocol. In a recently published article, tDCS montages have been categorized in a framework of four groups. This framework can provide useful insights for montage selection at this stage  tDCS  causes locally reduced GABA neuronal activity  to counteract this pathological dysbalance.- Suggested Protocol• Neuroelectrical/Large-scale Networks- Neuroscience Evidence:▪“Resting-state fMRI and modularity network analysis show impaired interactions between the salience network, default-mode network, and executive control network in disorder X. The salience network pathologically allocates attentional resources towards internal stimuli, which leads to abnormally enhanced activity of the default-mode network and decreased activity of the executive control network”.- Stimulation Evidence:▪“tDCS-fMRI studies have revealed the ability of tDCS to reconfigurate large-scale brain network activity; specifically bilateral tDCS over dorsolateral PFC regions  decreased activity of the default-mode network  to scale down the activity of the default-mode network and increase the activity of the executive control network in the disorder X.- Suggested Protocol: Some hypothetical examples for the neuroelectrical level of the proposed spatiomechanistic framework are provided in this section.• Oscillatory/Local▪Neuroscience Evidence: On one hand, deficient response inhibition is considered to be the primary deficit and the major characteristic of disorder X; on the other hand evidence suggests an association between behavioral inhibition and theta band activity in the right inferior frontal gyrus. Furthermore, some of the available pharmacological treatments for disorder X have been shown to decrease the absolute and relative power of theta band in the right inferior frontal gyrus.▪Stimulation Evidence: In a population of healthy participants, anodal tDCS over the right inferior frontal gyrus coupled with cathodal tDCS over the left orbitofrontal cortex (1.5 mA for 15 min) induced a selective reduction in the power of theta band in the right inferior frontal gyrus area  might be beneficial for regulating theta band activity and improving behavioral inhibition deficits in patients with disorder X.• Oscillatory/Small-scale Networks▪Neuroscience Evidence: Evidence shows pathological beta oscillations in the deep region A in patients with disorder X associated with specific clinical symptoms.▪Stimulation Evidence: Both pharmacological and deep brain stimulation treatment for disorder X diminish beta-band activity in region A. This suppression is associated with improvement of related clinical symptoms. Beta activity of region A has been shown to be negatively correlated with alpha activity in cortical region B. Anodal tDCS has been able to enhance alpha activity in region B. Moreover, excitatory rTMS over cortical region B has been shown to reduce beta-band activity in region A in these patients.▪Suggested Protocol:Application of anodal tDCS over the cortical region B to modulate beta oscillations in the deep region A.• Oscillatory/Large-scale Networks▪Neuroscience Evidence: A lack of resting state low frequency alpha activation in the default-mode network has been shown in a group of awake, relaxed patients with disorder X. This aberrant default-mode network activity has been associated with cognitive impairments in these patients.▪Stimulation Evidence: Low frequency rTMS over one of the main nodes of the default-mode network (right or left angular gyrus) increases resting-state alpha power density in the neural regions involved in this network  of the default-mode network with an extracephalic return electrode  to increase the power of respective alpha rhythm.Tailoring based on the Various Subtypes (Clusters) of a Brain Disorder). Obtained information from efforts for delineating subtypes of different disorders such as auditory hallucinations . Considerable inter- and intra-individual variability in response to tES currently limits tES translation from research to clinical practice. Multiple mechanisms contribute to this inter-individual variability, including genetics, gender, age, head anatomy, hormone levels and time of day of intervention. Just focusing on stimulation dosage, studies have reported dose-dependent significant differences of tES after-effects. In 2015, for instance, Chew et al. . Furthermore, physiologically validated modeling approaches can provide pivotal complementary help in tailoring stimulation parameters to overcome interindividual variability. We pointed out two categories of models employed in tES studies: (1) biophysical models of the head and electrodes; and (2) network/neuronal models.Biophysical models can be used to individually calculate/predict current density distributions and adapt the stimulation parameters according to the structural and functional features of individual subjects. These models can help to: (1) tailor electrode montage and stimulation protocols to affect the brain regions of interest; (2) normalize stimulation parameters based on individual variations ; (3) customize stimulation parameters for potentially vulnerable populations ; (4) design novel electrode shapes and electrode montages ; (5) assess and quantify current distribution and densities when using novel electrode shapes and/or montages; (6) consider compliance with safety guidelines; and (7) interpret patient-specific results. These computational models have the potential to act as a starting point to help in designing safe and effective electrotherapies, specifically for disorders in which brain structure changes are relevant  tailoring based on the group-level data of a brain disorder; (2) various clusters of patients with a brain disorder; and (3) individual-level data. Various challenges must be addressed to bring the ambitious goal of providing precision tES therapy for patients in routine clinical settings to fruition. To begin with, high-quality characterizing information must be obtained consistently in the diagnostic setting. Also, dependent on the availability of relevant knowledge bases, it is crucial to take action based on the obtained data. Different questions persist regarding the extent of required data, the cost-effectiveness of various paradigms, and how rapidly various data can be delivered for treatment individualization. Further longitudinal studies are necessary to determine whether and how these neurophysiological and neuroimaging data might act as biomarkers for fingerprinting of the respective brain disorders.Beyond treatment selection, the proposed framework can also help to generate ideas about treatment effect monitoring. Regular monitoring of response to therapy is crucial to be sure about the efficiency of treatment, absence of adverse effects and to facilitate treatment completion. Depending on the selected level of the respective framework, it can help to define appropriate human brain mapping methods and parameters of interest for assessment of the response and to decide how and where to monitor tES treatment effects in a mechanistic way and address different responses to determine treatment fidelity.Closed loop tES, i.e., online adjustment of stimulation parameters according to “intra subject” dynamic brain states, might be the final step on this road and is currently under development. One example is to adaptively change tACS frequency based on frequency information derived from EEG recordings (Boyle and Frohlich, FY, MAN and HE made substantial contributions to the conception of the work, as well as drafting and revising it critically for important intellectual content and final approval of the version to be published; agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved; came up with the idea and wrote the article.MAN is in the Advisory Board of Neuroelectrics. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Although human iPSC-derived neuronal models are increasingly regarded as a useful tool in cell biology, there are a number of limitations, including the relatively early, fetal stage of differentiated cells and the mainly two dimensional, simple nature of the in vitro system. Furthermore, clonal variation is a well-described phenomenon in iPSC lines. In order to account for this, robust baseline data from multiple control lines is necessary to determine whether a particular gene defect leads to a specific cellular phenotype. Over the last few years patient-derived neural cells have proven very useful in addressing several mechanistic questions related to central nervous system diseases, including early-onset neurological disorders of childhood. Many studies report the clinical utility of human-derived neural cells for testing known drugs with repurposing potential, novel compounds and gene therapies, which then can be translated to clinical reality. iPSCs derived neural cells, therefore provide great promise and potential to gain insight into, and treat early-onset neurological disorders.The study of neurological disorders often presents with significant challenges due to the inaccessibility of human neuronal cells for further investigation. Advances in cellular reprogramming techniques, have however provided a new source of human cells for laboratory-based research. Patient-derived induced pluripotent stem cells (iPSCs) can now be robustly differentiated into specific neural subtypes, including dopaminergic, inhibitory GABAergic, motorneurons and cortical neurons. These neurons can then be utilized for  Over the last decade, significant advances such as whole exome and genome sequencing have facilitated genetic screening of patients, resulting in an ever-increasing number of inherited human diseases. Despite this genetic revolution, the molecular mechanisms downstream of a specific gene mutation or genetic variant remain yet to be fully elucidated for the majority of diseases. Future research priorities must therefore lie in studying such disorders in more depth, to not only understand the disease, but also to develop novel therapies for clinical translation.in vitro tool for studying human disease. However, human tissue is often either unavailable or simply not accessible. This is clearly exemplified by neurological disorders, where accessing the brain and neuronal tissue for cell culture and future study is near impossible. Since the first human embryonic stem cells (ESCs) were isolated in 1998  have been successfully derived from PSCs and several protocols for PSCs differentiation into a broad variety of mature neurons and glial cell subtypes have been published -derived neurons as an rs Table , althougDifferentiation of iPSCs into neural cells is based on recapitulating embryonic development and relies on the use of specific factors that can promote or inhibit specific signaling pathways. All methods published so far can guarantee high purity of NSCs, but it is more challenging to obtain decent percentages of specific subtypes of desired mature neural cells. To date, it is possible to derive a wide variety of neuronal cell types from PSCs, including forebrain neuronal neurons  are lost during this re-set to an embryonic stage  structures resembling whole organs  improved mitochondrial functionality, thereby rescuing motor neuron degeneration in vitro.The development of new drugs to treat human disorders is a challenging field. Indeed, many drugs tested in animal models have failed in human clinical trials due to lack of efficacy or intolerability  patient-derived iPSCs have been utilized to test the effect of IGF1 and gentamicin These and other studies Table , have maFMR1, which leads to the absence of FMR protein. Both studies used patient derived iPSCs and differentiated them either in NSCs or neural precursors. In the first study 5000 compounds (both novel and approved drugs) were tested  disorder is caused by loss-of-function mutations in The combination of genetic engineering techniques and the promise of human PSCs differentiated cells as a donor source for cell replacement therapies, could in the future lead to the generation of patient-derived “corrected” cells that could potentially be used in autologous transplantation to replace affected disease cells. Such use of patient derived, genetically corrected neural cells may also potentially overcome immune-mediated responses that might be triggered by using allogenic neural cells. Overall, even though such approaches are extremely promising and although PSCs are already used in clinical trials (Kimbrel and Lanza, Patient derived iPSCs represent a unique and increasingly utilized tool for the study of human genetic neurological diseases of childhood. iPSCs are an extraordinary model that can facilitate new insight into the molecular basis of disease and aid the development of new therapies, especially for pharmacoresistant diseases where human tissue is inaccessible for research purposes. Like all other laboratory models, human iPSCs have some limitations, namely that the model can be time consuming and costly to establish, shows clonal variability and genetic background can influence phenotype. Despite this, the ever-growing number of studies using human iPSCs to both model genetic disease and discover new therapies, render them an extremely promising tool, capturing the attention of researchers worldwide.SB: conceptional design and writing of the manuscript. MAK: conceptional design and writing of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling Editor declared a shared affiliation, though no other collaboration, with the authors SB, MAK and states that the process nevertheless met the standards of a fair and objective review.