This paper applies machine learning techniques to propose an objective video-based method for assessing the degree of canine ADHD-like behavior in veterinary consultation room. The method is evaluated using clinical data of dog patients in a veterinary clinic, as well as in a focus group of experts.Canine ADHD-like behavior is a behavioral problem that often compromises dogs’ well-being, as well as the quality of life of their owners; early diagnosis and clinical intervention are often critical for successful treatment, which usually involves medication and/or behavioral modification. Diagnosis mainly relies on owner reports and some assessment scales, which are subject to subjectivity. This study is the first to propose an objective method for automated assessment of ADHD-like behavior based on video taken in a consultation room. We trained a machine learning classifier to differentiate between dogs clinically treated in the context of ADHD-like behavior and health control group with 81% accuracy; we then used its output to score the degree of exhibited ADHD-like behavior. In a preliminary evaluation in clinical context, in 8 out of 11 patients receiving medical treatment to treat excessive ADHD-like behavior, H-score was reduced. We further discuss the potential applications of the provided artifacts in clinical settings, based on feedback on H-score received from a focus group of four behavior experts. According to the American Psychiatric Association, Attention-Deficit/Hyperactivity Disorder (ADHD) is defined as persistent symptoms of inattention and/or hyperactivity-impulsivity which interfere with development and/or functioning. Recent surveys estimate the prevalence of ADHD among children within 1–12% . Such subjective measures are associated with the risk of informant biases  and ofteCanis familiaris) [In veterinary medicine, ADHD-like behaviors have been extensively described in domestic dogs (iliaris) ,12,13. Tiliaris) , hyperkiiliaris) , hypermoiliaris) , hyperreiliaris) , impulsiiliaris) , or hypeiliaris) . This diiliaris) ,20,21, iiliaris) ,23 or eviliaris) .Objective methods for assessment of ADHD-like behaviors in dogs have, to the best of our knowledge, not yet been explored.Assessment ADHD-like canine behavior in dogs is much less explored as compared to human ADHD assessment. There are several questionnaires measuring general canine behavior and temperament traits, indirectly addressing inattention and/or hyperactivity-impulsivity through some of their components, such as the Canine Behavioral Assessment and Research Questionnaire (C-BARQ) , the MonBoth the genetic and behavioral correlates of inattention and/or hyperactivity-impulsivity have been recently shown to have similarity in humans and dogs. For instance, low levels and poor regulation of serotonin and dopamine are associated with the disruptive and/or violent behaviors exhibited in ADHD in both humans  and dogsPromoting objective measures for the assessment of behavior in general, and of behavioral disorders in particular, is an important challenge for the assessment and diagnosis of both human and canine behavioral disorders.In the context of human ADHD assessment, objective measures that have been considered can take the form of neuropsychological tests, where the tested person is asked to perform some tests. A similar paradigm has been applied to dogs using touchscreens, supporting them as a model of the association between behavioral disinhibition and ADHD-like behaviors/symptoms . HoweverThe goal of this research is to explore objective measures that can be used for the assessment of canine ADHD-like behavior. Our starting point is looking at video recording of the dog’s behavior in the consultation room. One reason is this setup is cheap and feasible to install in any clinic. However, even more importantly, as canine ADHD-like behavior has been reported to be expressed as impulsive and inattentive ,19,24,35RQ1How can we objectively differentiate between dogs with ADHD-like behavior , and normal controls?RQ2How can we objectively assess the degree of dogs’ ADHD-like behavior ?RQ3How can such artifacts inform the design of automatic support for experts’ decision making in clinical contexts?We specifically address the following research questions:Before conducting the study, we captured explicit consent of the dog owners to participate in the study. The procedure was designed with, and approved by, two behavioral veterinarians, in line with published guidelines for the treatment of animals in behavioral research and teaching . RecordiFor automatically tracking the dog movement, we used the Blyzer system, which is described in further details in Exploration Trial: free exploration of the room: when entering the consultation room, dog was discharged off leash and left to freely explore the room.Dog–Robot Interaction Trial: 20 min into the consultation, the dog was presented a moving dog-like robot, and was left to freely interact with it.To address our research questions, we collected video data during behavioral consultations in two veterinary clinics at the ‘Veterinar Toran’ Hospital in Tel Aviv and Petach Tikva, Israel. The participating dogs were of two types: normal controls, who arrived to the clinic for standard checkup and/or vaccination procedures, and dogs with excessive ADHD-like behavior who received medical treatment due to this problem. These dogs were recorded in two situations:The dogs treated for ADHD-like behavior were recorded at two points in time: in their first visit, and follow-up visit after receiving medical treatment. The control group dogs were only recorded once. The process of data collection is presented in p > 0.05).) were 260 × 160 (Petach Tikva) and 340 × 220 cm (Tel Aviv), where video was captured by a web camera (Logitech HD Pro Webcam C920) fixed on the ceiling  and Petah Tikva (N = 10) clinic. A two-tailed Mann–Whitney U test found no significant difference for any of the variables  for treating excessive ADHD-like behavior.Participants 1–19 formed the H-group, according to the following inclusion criteria:Participants 20–38 formed the C-group, which included dogs with no reported health issues, visiting the hospital for annual checkup or vaccination. During their consultation, the behavioral vet ruled out any behavioral-related disorder and other comorbidities.here  and here (dog–robot interaction)) was started . The dog was allowed to freely move around the room while the veterinarian interviews the owner(s), also filling out information on his computer. The veterinary doctor and the owner(s) were always placed in the same location (fixed chairs in the room), except for the moment at which the robot was introduced in the middle of the room. An owner with his dog is shown in As mentioned above, the participants had two trials: (i) exploration and (ii) interaction with toy robot. For the first part, owner and dog entered the room simultaneously, the owner took place in the designated chair, the vet sat by his desk. The owner(s) took their place at a predefined spot in the room. They were requested not to interact or make eye contact with the dog during the experiment, regardless of what the dog was doing. Video recording (Recording samples can be found The second part had the following structure (A similar protocol was used in an earlier work ). The doAutomatic tracking. The automatic tracking module of Blyzer was run on the videos. The tracking method  used the following elements  percentage of frames where dog is present is at least 70% of the frames, and (ii) dog and robot are identified with average certainty threshold above 70%. In features, in our context they are related to the dog’s movement trajectory, and its interaction with robot. Thus, we needed to add to the library the implementation of features which are relevant for our problem and domain.In Blyzer architecture see , the feaA feature in machine learning (ML) is an individual measurable property of what is being observed . Many diExpert interviews. For elicitation of possible features from experts, we held in-depth semistructured interviews with four behavioral specialists.  in dog behavior.) During interviews, we first asked them to characterize (i) free movement of a dog with excessive ADHD-like behavior, and (ii) interaction of such dog with a toy robot, as opposed to a dog with no such problem. Animal movement metrics. The description of animal movement paths is also a cornerstone of movement ecology [tortuosity, or how much tortuous and twisted a path is. We hypothesized tortuosity can be related to the experts’ highlighting ‘erratic movement’ and ‘turning around’  filter-based methods, which select subset of features based on their correlation with the target feature, and (ii) wrapper-based methods, which search for well-performing subset of features [features ,46,47. WWe experimented with several well-known classification algorithms: stochastic gradient descent, random forest, k-nearest neighbors, gaussian process, gaussian naive bayes, multinomial naive bayes, bernoulli naive bayes, complement naive bayes, and support vector machines . Each ofTP), False Positive (FP), False Negative (FN), and True Negative (TN). TP and FP refer as correct/incorrect positive prediction (that the dog is hyperactive), while FN and TN refer to correct/incorrect negative prediction (that the dog is in control group).We used leave-one-out cross-validation, which is a standard method for evaluating the performance of classification algorithms . We furtP, or specificity) and Recall  are defined as follows:Precision  and noise .To provide the H-score which would assess the level of ADHD-like behavior, we decided to look at class probabilities offered by the different models.To evaluate the H-score and the whole approach of objective assessment in a clinical context, we conducted a semistructured Focus Group Discussion (FGD)  to exploAs the quality of FGD data relies heavily on the selection of appropriate participants and targeted questions , with onParticipants were welcomed by the moderator, and the purpose of the FGD was explained.Participants were asked to discuss (i) the use of ML for objective behavior assessment, and (ii) the use of ML for assessment of ADHD-like behavior within their professional practice.Next, we showed:here) and presented their respective H-scores.An example of exploration trial of a normal dog and of a hyperactive dog (see the video here) and presented their respective H-scores.Two examples of exploration trials of a hyperactive dog before and after clinical treatment . The details of the comparison as well as the list of the prevalent features are presented in The H-score was taken as the class probability of the classification model. p < 0.00001).When comparing the H-scores of the first visit between C-group (N = 19) and H-group (N = 19), the C-group score was found to be significantly lower (median = 0.26) than that of the H-group (median = 0.96)  information from owner or the vet. However, the latter is also in some sense a limitation of the method in its ability to support diagnostic decision-making, as it may not take into account critical information which is not observed in the video.In this study, we introduced a novel method for assessing canine ADHD-like behavior using machine learning techniques. The method is completely We explored the potential of such approach to classify excessive indications of ADHD-like behavior, and to quantify its degree. We have found that the Random Forest classification algorithm reached the best performance . The most prevalent features were found to be total distance and average speed, reflecting the intuition of erratic movement around the room, expressed in expert interviews.We further explored the perceptions of behavioral veterinarians on the usefulness and feasibility of this approach in clinical settings using a focus group. The experts agreed on the potential of a tool offering objective measurement of symptoms of ADHD-like behavior in the context of their clinical practice, and also agreed that perhaps much better cannot be achieved, due to obvious lack of important information  in the short footage analyzed.Due to the exploratory nature of this research, we faced some major challenges, and had to make concrete decisions related to the design of this study, and its potential threats to validity, which we discuss below.Data collection in a consultation room of an animal hospital entails that the setting is not completely controlled. To mention just some aspects which may have affect on the dog’s behavior: scents and noises outside the consultation room, time of visit, and what the dog experienced prior to visit. To mitigate these threats, we made sure that the places where the vet and owner(s) sat were always fixed, using marking on the floor. We also excluded from the dataset consultations in which another veterinarian entered the room and interrupted the standard protocol, or the owner went out, leaving the dog alone in the room.which fragments to analyze were also crucial. After consulting with several behavioral experts, it was decided that the first three minutes of the visit are of crucial importance, as they introduce the dog into a novel environment, and its reaction at the first minutes is the most informative. Some participants of the focus group also remarked on including additional video footage, e.g., from the dog’s home as being potentially important. However, this poses challenges due to the non-uniform shooting angle and room size, as well as the complete inability to control the dog’s environment. Based on an earlier study [The use of Blyzer’s deep learning models for object detection made the processing of a whole consultation (approximately 40 min) infeasible in terms of processing times, and decisions er study  which usReflecting further on practical aspects of using the suggested approach in clinical settings, it is important to note that in addition to the high processing time needed to produce the tracking data (which can be addressed by using stronger machines), another problematic aspect with which we faced in our study was quality of data. This can be divided into two dimensions: (i) quality of detection when dog is in frame and (ii) quality of footage with the dog going out of frame too frequently. Item (i) can be addressed by improving the tracking models used by extending their training set to include more dogs of different sizes, colors, and breeds. Item (ii) was mainly by privacy considerations, as the owner needed to be left out of frame. This could be partially addressed by using more sophisticated interpolation techniques, predicting the dog’s movement even when it is not visible. However, it is clear that these considerations need to be taken into account when planning a tool that will provide real-time  H-score in a consultation room that would be integrated in the clinician’s workflow.Another limitation of this study is the rather limited number of dogs in our dataset. This is related to the fact that we decided to recruit participants who only exhibited pure ADHD-like symptoms without comorbidities. Re-examination of our results with a significantly larger dataset is a natural step for further research.A further direction for future research is considering other behavioral disorders than ADHD-like behavior, as well as ADHD mixed with further comorbidities such as anxiety, depression, etc. These may call for changes in the selected features, which need to be elicited in further interviewing experts concerning the specific way in which these conditions are reflected in the dog’s behavior and/or its interaction with humans or objects.objective tool which is much appreciated in behavior assessment which is usually based on subjective reports, or owner-filled questionnaires. An important aspect for future research is the role social cues play in eliciting hyperactive behavior. Extending our approach using protocols which integrate social cues  are an important direction for future research on objective assessment of ADHD-like behavior. Based on the focus group findings, the suggested approach seems promising in the context of clinical decision making of behavioral veterinarians, as well as for non-clinical behavior assessment of canine professionals, as it offers an


Arabidopsis seedlings, cotyledons and leaves. Liquid in the imaging chamber can be rapidly exchanged to introduce chemical treatments via microfluidic passive pumping. When used in conjunction with fluorescent biosensors, this system can facilitate live-cell imaging studies of signal transduction pathways triggered by different treatments. As a demonstration, we show how the HybriWell can be used to monitor flg22-induced calcium transients using the R-GECO1 calcium indicator in detached Arabidopsis leaves.One of the challenges of performing live-cell imaging in plants is establishing a system for securing the sample during imaging that allows for the rapid addition of treatments. Here we report how a commercially available device called a HybriWell™ can be repurposed to create an imaging chamber suitable for  Live-cell imaging refers to an experimental approach whereby living samples are observed via microscopy in order to study a biological process at the cellular and/or subcellular level. This approach stands in contrast to traditional microscopy in which non-living, fixed samples are analyzed. Live-cell imaging can be used to study cell biology, signal transduction, and a range of other biological phenomena. An important consideration for these experiments is that one needs to have a method available for mounting the sample that keeps it viable and in a stress-free condition throughout the imaging process. In addition, if one wishes to study how the sample responds to a chemical stimulus, the mounting method needs to allow for pulses of chemical treatments to be easily added and removed from the imaging chamber with minimal collateral stress.Most live-cell imaging studies involve the use of fluorescent probes and reporters in conjunction with epifluorescent or confocal microscopy. In the case of plant biology, a number of fluorescent sensors have been developed that allow one to measure the concentrations of glucose, inorganic phosphate, zinc, ATP, hydrogen peroxide, pH, and calcium in living plant tissue, and fluorescent reporters for the plant hormones auxin, gibberellic acid (GA), and abscisic acid (ABA) have also been described –12. A reArabidopsis root tissue has been previously described. This system, called the RootChip, is based on a custom-built microfluidic device that channels the growing primary root of an Arabidopsis seedling into a microfluidic channel fabricated on the surface of a microscope cover glass [Arabidopsis roots [An elegant method for performing live-cell imaging studies of er glass , 15, 16.Arabidopsis leaves for live-cell imaging that could be easily adopted by other labs with minimal effort. Here we describe how a commercially available device called a HybriWell™ , which is designed for performing microarray hybridization experiments, can be repurposed to serve as a live-cell imaging chamber for Arabidopsis leaves and seedlings.In the case of studies focused on leaf tissue, a variety of custom imaging chambers have been described that aim to hold the sample in place during microscopy while allowing chemical treatments to be perfused into the chamber –19. AlthPropidium iodide (PI) solution (1 mg/ml in water) was obtained from Sigma-Aldrich . For flg22 treatment, synthetic flg22 peptide (QRLSTG-SRINSAKDDAAGLQIA) was obtained from PhytoTechnology Laboratories , and the flg22 was dissolved in water to a concentration of 1 μM. HBW20 HybriWell devices were obtained from Grace Bio-labs (Cat. # 611102). 45 × 50 mm microscope cover glasses 0.16–0.19 mm thick were obtained from Fisher Scientific .Arabidopsis thaliana seedlings were grown on 1% agar (w/v) plates containing containing 0.5 × Murashige and Skoog (MS) basal salt mixture under constant light at a light intensity of 115–130 μmol/m 2 sec at 20–23°C with the plates in a vertical orientation. A transgenic line expressing the intensiometric calcium indicator R-GECO1 was a kind gift from Melanie Krebs, and is described as line #7–8 from Keinath et al. [h et al. . ExperimArabidopsis cotyledon in a HybriWell, a 45 × 50 mm microscope cover glass was laid on a lab bench. A 5-μl drop of sterile ultrapure water was then placed in the center of the cover glass using a micropipette. Next, a cotyledon was removed from a 4- to 6-day-old seedling growing on a 0.5 × MS plate by snipping the petiole with small scissors. The cotyledon was grasped by the petiole using forceps and gently placed on the water drop with the abaxial surface facing up. Since the cotyledon typically floats on the surface of the water drop, a micropipette was then used to transfer water from below the cotyledon onto the top surface in order to fully wet the cotyledon on both its abaxial and adaxial surfaces. Excess water was then removed using the micropipette, being careful not to damage the cotyledon. The adhesive backing on the HybriWell was then exposed by peeling off the protective covering and forceps were used to gently lower the HybriWell down onto the cover-glass, positioning it such that the cotyledon is in the center of the HybriWell chamber. The back of the forceps is then used to gently press the adhesive portion of the HybriWell down onto the cover glass to fully seal the chamber, taking care not to press down on the top of the chamber. To fill the chamber with water, 300 μl of sterile ultrapure water was rapidly dispensed into one of the ports of the HybriWell such that water shoots out the second port during the filling process. This approach is necessary in order to minimize the chance of trapping an air bubble in the chamber. If an air bubble is trapped in the chamber, then an additional 300 μl of sterile ultrapure water can be flushed through the HybriWell to remove the bubble. Finally, a 200 μl drop of sterile ultrapure water was placed on top of one of the ports of the HybriWell to prevent evaporation of the 30 μl of water within the chamber. The HybriWell mounted to the cover glass was then placed inside a 100 × 15 mm round plastic Petri dish and covered to maintain sterility and humidity.To mount an The same process described above was used to mount intact seedlings, but in that case the seedlings were transferred to the drop of water on the cover glass by gently lifting them off the growth plate with a sterile plastic 200-μl pipette tip. For mounting true leaves, a single leaf was collected from a plant growing in soil by snipping the petiole with scissors and grasping the detached leaf by the petiole using forceps. The same process described above for cotyledons was then used to mount the true leaf samples in the HybriWell.2 sec.Samples were mounted as described above and then incubated in the HybriWell for 6–8 h prior to imaging. During this time the samples were maintained under constant light at 20–23°C at a light intensity of 115–130 μmol/m For the experiments using PI and green fluorescent protein (GFP), images were collected by confocal microscopy using a Zeiss  LSM 710 with 10x and 20x objectives. PI fluorescence was imaged by laser excitation at 594 nm with emission collected between 600 and 643 nm. GFP fluorescence was imaged by laser excitation at 488 nm with emission collected between 500 and 541 nm. 3-μm optical sections were collected as a Z-stack covering a total distance of 63 μm. Images were analyzed using Fiji software.For experiments using R-GECO1, images were collected by confocal microscopy using a Zeiss LSM 780 with a 20x objective. Samples were placed on the microscope and allowed to equilibrate for 30 min prior to imaging. R-GECO1 fluorescence was imaged by laser excitation at 561 nm with emission collected between 579 and 651 nm and an optical slice thickness of 2 μm. Single images were collected every 5 secs for the duration of the experiment. Images were analyzing using Fiji software, and the Fire lookup table was used to false-color the image to reflect fluorescent signal intensity.Arabidopsis Col-0 seeds were surface-sterilized and stratified on a 0.5 × MS plate at 4°C for 2 days. The plate was then placed vertically under constant light at 20–23°C for 3 days. Six seedlings were then mounted in sterile water in HybriWells, one seedling per HybriWell. Another six seedlings were transferred to a new 0.5 × MS plate. The HybriWells were incubated horizontally in covered Petri dishes under constant light at 20–23°C. The 0.5 × MS plates were incubated in a vertical orientation. Images of the seedlings were captured at 0- and 6-h time points using an Epson Perfection V700 Photo Scanner at 4800 dpi resolution . Root length was determined using Fiji software and growth rate was calculated.The HybriWell is a disposable plastic device that was originally designed to create low-volume chambers on microscope slides for use in microarray hybridization experiments. HybriWells are available in a variety of sizes and shapes, but the one that we selected for our experiments is a square patch of plastic 25 by 25 mm in size with a 20-mm diameter circular chamber in the center . After pArabidopsis samples, one first places the sample in a 5-μl drop of water on a glass cover glass. Next, a HybriWell with the adhesive exposed is carefully laid over the top of the sample using forceps  versus 0.44 mm/h ± 0.03 mm/h (n = 6) for the control samples. This difference was not statistically significant .Arabidopsis sample is mounted in a HybriWell for imaging, it is sandwiched between the top of the HybriWell and the glass cover. If the HybriWell is to be used for live-cell imaging experiments, it is important that a chemical treatment introduced into the HybriWell is able to rapidly reach the surface of the tissue that is being imaged. We therefore needed to determine if liquid added to a HybriWell through the inlet port efficiently flows through the space between the cotyledon and the glass cover. If the sample were too tightly pressed down upon the cover glass, it might prevent the added treatment from contacting the epidermis.The experiments using red food coloring described above demonstrated that the liquid within the HybriWell chamber can be efficiently exchanged. When an Arabidopsis seedlings used for this experiment expressed GFP throughout the cotyledon, which allowed us to visualize the cotyledon epidermis. An image collected 1 min after PI addition showed strong red fluorescence highlighting the cell walls of a substantial portion of the cotyledon epidermis, and the area of the epidermis stained by PI increased at the 3- and 5-min time points  was added to the HybriWell through the inlet port. PI is a red fluorescent dye that has been previously shown to stain plant cell walls. In addition, the e points . The imaIn these experiments we routinely observed that the red fluorescent signal in the central portion of the cotyledon was substantially lower than that observed in the outer regions . These oArabidopsis roots. For this experiment we mounted intact 3-day-old Arabidopsis seedlings in the HybriWell using the same technique described above for cotyledons. 1 min after adding 50 μl of 300-μM PI to the HybriWell we observed strong PI staining of the entire root (We next wanted to determine if the HybriWell could be used to image ire root . The fluArabidopsis [Arabidopsis leaves expressing R-GECO1 [Fluorescent biosensors that report the concentration or activity of signal transduction molecules are valuable tools for live-cell imaging studies. For example, R-GECO1 is an intensiometric calcium indicator in which the intensity of red fluorescence is proportional to free calcium concentration ,17,21. Ibidopsis ,23. We mBecause calcium signaling is known to be sensitive to mechanical stimulation, we also performed a control experiment where pure water was added to the HybriWell, rather than flg22 . We did Arabidopsis leaves and seedlings. We have observed that samples can be maintained in the HybriWell chambers for at least 6 h with no apparent negative effects on growth, indicating that this system is suitable for relatively long-term time-course experiments. Because HybriWell devices are low cost and commercially available, it should be straightforward for laboratories interested in performing live-cell imaging of Arabidopsis to adopt them for use in their experimental systems.Taken together, our results demonstrate that the HybriWell device is able to function as a microfluidic chamber for performing live-cell imaging studies of Supplementary


Roughly 25% of the prison population are known to meet the criteria for attention-deficit/hyperactivity disorder (ADHD), a five-fold increase on the general population. Medium secure psychiatric services receive a high percentage of referrals from the prison service. ADHD has primary symptoms of inattention, hyperactivity and impulsivity. Untreated ADHD could clearly have a detrimental impact on the effectiveness of therapeutic interventions, as well as increasing incidents of violence, aggression and other transgressive behaviours.There are two aims: To screen the medium secure services population at the Spinney Hospital, Atherton, UK for ADHD, using a validated screening tool. This would generate candidates for further structured clinical assessment for ADHD; To implement ADHD screening as a feature of the Admission Care Plan within medium secure services at the Spinney.The study population is the medium secure service at The Spinney Hospital, Atherton. At the time of study this was 52 male service users.The team members have evaluated several screening tools. The tool eventually chosen was the B-BAARS, which is a simple 6-question tool that is validated for use in adults. The tool takes around 1 minute to complete. All 52 service users were screened between 20/01/2021 and 30/01/2021.1 of the 52 service users had a current diagnosis of ADHD and was being treated with medication. 3 of the 52 service users had childhood diagnoses of ADHD that had lapsed in adulthood and who were untreated. Of the remaining 51 service users without a current diagnosis of ADHD, 9 were positive on screening as worthy of further assessment (17.65%). Assessments of the 9 service users positive in screening will be completed by medical and psychology disciplines.There appears to be clear merit for routine screening for ADHD within medium secure psychiatric services, given the service user population and the results described above. As a result of this survey, within The Spinney Hospital the B-BAARS will be incorporated into the Admission Care Plan of all new admissions to medium secure services as a Quality Improvement Intervention. Over time this will be re-audited and there will be assessment of any impact on incidents and positive engagement with activities.


Ma’aljobon (a kind of whey protein) that is derived from milk during cheese producing process is a popular dietary traditional product supposed to provide immune modulation and prevent neuropsychiatric disorder. We aimed to evaluate the efficacy of ma’aljobon in management of Attention-deficit/hyperactivity disorder (ADHD).Attention deficit hyperactivity disorder (ADHD) is a common, chronic, neurodevelopmental disorder that manifests in childhood with symptoms of hyperactivity, inattention, and impulsivity. Khorshid Hospital of Isfahan, Iran, were randomly assigned in the intervention group ) or control group (SCT only) for a period of 8 weeks. Scores of the Strengths and Difficulties Questionnaire (SDQ) and Conners’ Continuous Performance Test (CPT) were set as the outcome measures.In this open-label randomized, double arm, and controlled clinical trial, sixty four patients with ADHD who referred to out-patient child and adolescent clinic of  Parent reported hyperactivity scale of SDQ showed a significant decrease in the intervention group compared to the control group (P=0.04). However, no significant between groups differences were observed in other scales of parent-reported SDQ. Also, according to the results of CPT, there was a significant improvement in the intervention group regarding attention and focus score (P=0.01). Ma’aljobon might be considered as a complementary remedy for improving hyperactivity, attention and focus of children with ADHD. However, further researches with larger sample size and longer duration should be done for achieving more reliable results. Ma’aljobon is a kind of whey protein that is traditionally used in Persian medicine for different diseases [ma’aljobon in management of ADHD.Attention deficit hyperactivity disorder (ADHD) is a common, chronic, neurodevelopmental disorder that manifests in childhood with symptoms of hyperactivity, inattention, and impulsivity . It affediseases . Whey thdiseases -15 and pdiseases -19. The diseases ,20,21. Adiseases . Anotherdiseases . Howeverma’aljobon powder in management of children with ADHD.In this open-label randomized, controlled clinical trial, we investigated the safety and efficacy of  This study was carried out in the outpatient child and adolescent clinic of Khorshid Hospital of Isfahan, Iran from October 2016 to May 2017. The inclusion criteria in this study were school children (both of boys and girls) aged 6 to 13 years with a confirmed clinical diagnosis of ADHD . Informed consent form was signed by parents to enroll their child in the study. The exclusion criteria were having any significant physical impairment, history of a pervasive developmental disorder, schizophrenia, bipolar disorder, severe depressive episode, epilepsy or heart disease, and intelligence quotient (IQ) below 80.ma’aljobon powder (as a complementary intervention) for two months   as the intervention group, or receive no intervention as the control group. Consumption of less than 70% of ma’aljobon powder during the trial was considered as noncompliance. It should be noted that children in both groups continued their previous standard conventional ADHD medications. Additionally, there was no co-intervention .At first, the children were visited by a pediatrician and cases of ADHD were diagnosed. All eligible children with ADHD were divided into two parallel groups. Patients were randomly assigned to receive either The subscales scores of the Strengths and Difficulties Questionnaire (SDQ) and Conners’ Continuous Performance Test (CPT) were set as the primary outcome measures. SDQ is a multi-informant  behavioral screening questionnaire for children and adolescents aged 2- 17 years old. It measures emotional symptoms, conduct problems, hyperactivity, peer problems, and prosocial behavior. It should be noted that SDQ was designed by Robert Goodman and has now been translated into several languages, including Persian. Reliability and validity of the Persian version of SDQ are reported in previous studies . AdditioAccording to previous similar studies ,27 and b Before selecting the sample by questioning the parents and reviewing the children’s medical records, we made sure that there was no sensitivity to dairy products. All of the parents were requested to inform the research team of any side effects, including gastrointestinal problems , headache and allergic reactions. Also, the children were visited every month by a pediatrician.Khorshid Hospital of Isfahan, Iran. Sixty four eligible patients were randomized in two parallel groups. A non-stratified block randomization list  was created by an epidemiologist using Number Cruncher Statistical System. Then, the eligible children were assigned into two arms by the researcher according to the randomized list.Convenience sampling was done for all participants who referred to out-patient child and adolescent clinic of  This clinical trial is in compliance with the Declaration of Helsinki (1989 revision). It was reviewed, accepted, and monitored by the Ethics Committee of Yazd Shahid Sadoughi University of Medical Sciences (identification number: 17/1/296633/p). Moreover, the trial was registered by Iranian Registry of Clinical Trials with the following code: IRCT20180303038930N1. Informed consent form was signed by the parents to enroll their child in the study. In addition, verbal consent was obtained from the participating children. Data analysis was done using Statistical Package for the Social Sciences software, version 15 . The mean and standard deviation of the dependent variables were reported separately for each group. The Mann–Whitney U test was used for statistical comparison of data before and after the intervention. The Wilcoxon test was used to find out the changes in the outcomes between the two groups of the trial. P-values more than 0.05 were considered insignificant. From October 2016 to May 2017, seventy six children and adolescents were assessed for eligibility. Sixty-four eligible participants were randomized into two groups (32 members), . During the study, 8 patients in the intervention group and 11 in the control group were excluded due to lack of willingness to continue cooperation.  The mean age of the children in the trial was 9.39 (±1.99) and 9.37±2.37) years in the intervention and control groups, respectively. No significant difference was shown between the two groups of the study (P=0.922). Among the children, 19 boys and 2 girls were in the control group and 18 boys and 6 girls were in the intervention group. No significant differences were observed in sex distribution among the two groups of the trial (P=0.168). All variables were compared with baseline scores and there was no significant difference between the study groups at baseline P>0.05,  and 2..37 years As shown in ma’aljobon exacerbated the itching of the neck, and, in another case, whey protein exacerbated enuresis.No significant side effects were observed with whey protein. In one case, ma’aljobon in management of ADHD was investigated and the results showed that the children’ hyperactivity (according to the parent’s report) was significantly improved after the study in the intervention group in comparison to the control group. Also, whey consumption resulted in a significant improvement in the attention and focus score after 2 months. To the best of our knowledge, this is the first study that examined the efficacy of ma’aljobon as a kind of whey protein in management of children with ADHD. In recent decades, many studies have been done on the biological and therapeutic effects of whey protein. This diary product has been studied in different clinical trials on a wide variety of diseases such as cancer, AIDS, hepatitis, cardiovascular diseases, and osteoporosis [et al. demonstrated that whey protein could improve cognitive and coping ability in severe stress cases [In this open-label randomized double arm controlled clinical trial, the effect of oporosis ,28-34. Coporosis ,36. Accoss cases . For a more comprehensive understanding of the results, we should consider the limitations of our study. The small number of participants was the main limitation of this study. Considering the trend of the changes in the outcome measures of the study, if we had a larger sample size, we would possibly reach more reliable results. Lack of a placebo group was another limitation of this study which caused it to be designed as an open-label model and its own biases. In addition, it would have been beneficial for increasing the reliability of the results to add some other questionnaires to assess both symptoms and functional impairment of children with ADHD. This should be added as a suggestion for future research. Using only a fixed dose of whey protein and the short period of follow-up were the other limitations. Also, recording daily diet, parents’ level of education, and the socioeconomic status of the families and their number of children should be kept in mind for future research. They may affect the intervention’s outcome as possible confounding factors. Although two months is the standard time for evaluating ADHD treatment, longer follow-up of patients may have different results about the effectiveness of whey protein in the treatment of ADHD. Due to the chronic nature of the ADHD and the need for long-term treatment for patients, a long time intervention is required.ma’aljobon might be considered as a complementary therapy for improving hyperactivity, attention and focus of children with ADHD. However, it seems that it has no effect on the emotional symptoms, conduct problems, peer problems, and prosocial behavior. Hence, conducting studies in a longer period of time with larger trial sample size and removing our limitations are required for making more consistent opinions on whey protein use in ADHD.Results of this trial showed that  This study was a part of a PhD thesis by Dr. Zeinab Mostajeran. The authors thank the research vice chancellery of Yazd University of Medical Sciences for funding supports. The authors also thank Dr N. Shokrpour for the linguistic editing of this manuscript. None declared.


Attention Deficit Hyperactivity Disorder (ADHD) is associated with deficits in different functional domains. It remains unclear if deficits in different domains are equally strong in early childhood, and which deficits are specific to ADHD. Here, we describe functional domains in preschoolers and assess deficits in children with ADHD problems, by comparing them to preschoolers with other mental health problems or who develop typically.The ADHD Study assessed 1195 ca. 3.5 years old preschoolers through a semi-structured parent interview, parent questionnaires, and with neuropsychological tests. We determined functional domains by applying factor analytic methods to a broad set of questionnaire- and test-scales. Using resulting factor scores, we employed a Bayesian hierarchical regression to estimate functional deficits in children with ADHD.We found that preschoolers’ functioning could be described along the seven relatively independent dimensions activity level and regulation, executive function, cognition, language, emotion regulation, introversion, and sociability. Compared to typically developing preschoolers, those with ADHD had deficits in all domains except introversion and sociability. Only deficits in activity level regulation and executive functions were larger than 0.5 standardised mean deviations and larger than deficits of children with other mental health problems.Preschoolers with ADHD have deficits in multiple functional domains, but only impairments in activity level and regulation and executive functions are specific for ADHD and large enough to be clinically significant. Research on functioning in these domains will be important for understanding the development of ADHD, and for improving treatment and prevention approaches.The online version contains supplementary material available at 10.1186/s12888-021-03638-9. Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, impulsivity, and hyperactivity , which iThe terms function and functioning are broadly used when  describing characteristics of patients with psychiatric disorders. However, their definition can vary depending on the context. The current Diagnostic and Statistical Manual of Mental Disorders (DSM-5 ) prescriMotivated by overlapping characteristics of patients with different DSM diagnoses, and by the limited success of identifying clear and distinct  causes and mechanisms underlying distinct DSM diagnostic groups, functional domains have also been proposed to play an important role to further the understanding of mental disorders. The Research Domain Criteria framework  was proHence, we propose to use results from a broad range of instruments, including neuropsychological and performance tasks and parent-questionnaires about cognitive functioning and temperament  to identify functional domains. We chose this range of measures, because both performance-based and temperamental traits can contribute to mental health problems , 16. MorThe ADHD Study, a sub-study of the Norwegian Mother and Child Birth Cohort Study , documeHence, the aim of this article is to describe functional domains in preschoolers, and to explore how functional profiles of preschoolers with ADHD problems differ from profiles of children with other mental health problems and typically developing controls. Because the instruments used in examining ADHD are oriented towards key symptoms and impairments and because RDoC domains are highly relevant for ADHD, we hypothesize that the broad set of measures collected in the ADHD study is organized in domains similar to those described in the RDoC approach. We further hypothesize that preschoolers with ADHD have the greatest impairments in domains that are related to core ADHD symptoms.The Norwegian Mother and Child Cohort Study (MoBa) is an ongoing prospective population-based cohort study of Norwegian-speaking women that is conducted by the Norwegian Institute of Public Health . The curThe study used the semi-structured clinical parent-interview “Preschool Age Psychiatric Assessment”  to asseThe ADHD Study employed a number of instruments used for diagnosis of ADHD or to assess psycho-social functions that are generally thought to be associated with ADHD. To investigate functioning, we used only parent questionnaires and tests developed to assess psycho-social functions.inhibit, shift, emotional control, working memory and plan and organize. From the language section of the Child Development Inventory  assry CDI, , 33) we  we inhibry  is a tere EAS, , 36) use useinhibinhibition, visual attention, visuospatial processing and language. The Norwegian version of the Boston Naming Test  as an indicator of nonverbal working memory, the Object series, Pattern analysis/Matrices tests (OS/PAM) as an indicator of nonverbal IQ and the Comprehension/Vocabulary test (CM) as an indicator for verbal IQ. Finally, the ADHD study used a version of the Cookie Delay Task (CDT) to assess delay aversion. Because the ADHD Study was planned before the proposal of RDoC, the questionnaires and tests used in ADHD Study do not cover all RDoC domains equally well. In particular, the instruments employed do not allow a reliable characterization of the positive valence system. See the supplementary information for further details about the instruments and assignment of instruments to RDoC domains.The ADHD Study used a sub-set of the NEuroPSYchological Assessment Battery tests NEPSY, , 38), in, in38]),st  assess st  or anxiety  problems with impairment, if they fulfilled DSM IV symptom and impairment criteria. They were classified as having problems without impairment, if they fulfilled only symptom criteria. We also used clinicians’ global evaluation of the presence and impairing nature of language problems. Preschoolers who had multiple but only one impairing problem, were classified based on this problem. Children with multiple impairing problems were classified into the first of the following problem-groups for which they fulfilled diagnostic criteria: 1. ADHD, 2. behaviour, 3. anxiety, and 4. language problems. Problems-groups are ordered such that those with typically more co-morbid disorders and impairments are ranked higher. Children without a mental health problem were categorized as typically developing.  models  for eachThis step used test- and trait-scores calculated in the previous step. An initial analysis used a confirmatory factor analysis to examine if a theory-based assignment of scales to RDoC domains fitted the data well . For the data driven identification of functional domains we estimated exploratory structural equation models (ESEM). Lastly, we used CFA to explore if the model structure of the best ESEM factor model could be simplified by setting weak cross loadings to zero. Factor scores from the final model capture individual functioning in the different domains and were basis for further analyses.We employed a Bayesian hierarchical linear regression model to examine associations of mental health problems and functioning in all domains simultaneously, while also taking into account that associations might vary across gender and groups with different problems and degrees of impairment. By estimating the model in a Bayesian framework with weakly informative priors, one can reliably estimate variation in effect sizes between groups, and automatically control the multiple comparison problem . ConsistParents of 40% of at risk for ADHD and 25% of control children consented to participate. Altogether 1195 children participated in the assessment, of which 1184 children had less than 50% of missing data on tests and scales of interest. Of these participants, 219 fullfiled DSM IV ADHD symptom criteria (168 with and 51 without impairment) Table Initial CFAs, for which sub-scales were on theoretical grounds assigned to RDoC domains, did not describe the data sufficiently well , executive functions , cognition , language (LA), emotion regulation , introversion  and sociability . The average of the unsigned factor correlations was 0.15. Following factor correlations were larger than 0.30: r = 0.39, r = 0.32, r = 0.32 (c.f. Table Table P(SMD < −0.5) = 1). In comparison, functioning levels of preschoolers with ADHD in the domains CO, LA and ER was only around −0.50 SMD below typically developing controls (P(SMD < −0.5) = 0.56). Functioning in the domains SO and IN did not differ substantially from typically developing controls  = 0). Preschoolers with ADHD with and without impairment had similar functioning patterns. However, with exception of the domains CO and SO, those with impairment had around 0.30 SMD larger deficits than those without. We found overall small gender differences. Only in SO did boys with ADHD show somewhat weaker deficits than girls.Across all domains, functioning of preschoolers with ADHD was -0.42 standardised mean differences (SMD) below the functioning of typically developing preschoolers. The average SMDs for preschoolers with ADHD with and without impairment were -0.55 and -0.30, respectively. Preschoolers with language problems had functioning deficits similar to preschoolers with ADHD, whereas children with behaviour or anxiety problems had milder deficits , activity level and regulation (AL), cognition (CO), language (LA), introversion (IN), emotion regulation (ER) and sociability (SO). Compared to typically developing children, functional deficits of preschoolers with ADHD were especially pronounced in AL and EF, less pronounced in CO, LA, and ER, and absent in SO and IN. Compared to children with anxiety, behaviour or language problems, children with ADHD had similar or weaker deficits in all domains except AL and EF, where they had substantially greater impairments. Therefore, only EF and AL impairments appear specific to children with ADHD problems.A likely reason for divergences between our and the RDoC domains is that the set of instruments used influences which domains a study recovers. The use of many instruments to assess language and cognition likely contributed to our identification of two domains in this area, whereas the sparse assessment of reward processing likely impeded us from identifying such a domain or even specific concepts within reward processing like reinforcement learning of delay aversion. In sum, while the domains we identified are broadly consistent with the RDoC domains, we cannot make a confident statement in favour of or against RDoC domains, because the study was not designed to test the RDoC domains.Similar to earlier investigation, we observed only small correlations between assessments of the same construct with parent-questionnaires and tests. Toplak, West and Stanovich  hypothesAs expected, we found the largest deficits of children with ADHD in the domains of activity level and regulation and executive functions. The prominence of EF and AL impairments is consistent with a dual pathways view of the development of ADHD, which suggests that ADHD can be caused by earlier functional deficits . While tWhile the broadness of functions investigated in the ADHD Study and the large sample size set this study apart, some aspects of the study suggest caution when generalizing results to the broader population. The sample composition, which is characterized by self-selection into the study based on high parental education, high parental ratings of preschool ADHD symptoms, and absence of children with ASD , does nThe current study is of exploratory nature and reports only cross-sectional associations between different functional domains. Nevertheless, the presented results suggest that because impairments in AL and EF are much stronger and central than other deficits, first choice treatment of preschoolers with ADHD from populations similar to the study sample should focus on these areas, because other functional deficits will typically be less severe. Future research on cross-lagged associations between functioning in different domains (c.f ) is needIn sum, the current study identified functional domains similar to, but not identical with the RDoC framework. Preschoolers with ADHD have deficits in most functional domains, but only deficits in activity level and regulation and executive functions were clinically significant (SMD > 0.5) and more expressed in preschoolers with ADHD compared to those with other problems. Future longitudinal research on the development of functioning in domains over time will be important to investigate a causal role of early functional deficits in the development of ADHD, and for the further development of effective early interventions for ADHD.Additional file 1.


An inter-war analysis of the British and Australian departments charged with compensating disabled First World War veterans and the British ex-service migrant in inter-war Australia illustrates how nation-states have failed to unify welfare and disability rehabilitation. Contemporary welfare states continue to codify and establish categories of prioritisation regarding communities with disabilities for public finance administered by national government departments. This binational case study identifies reoccurring type one and type two error problems: policy can deny legitimate claims for state assistance while also validating and financing potentially illegitimate claims. This underlines the factors that dictate which error type is ruled to be the least significant and the impact the resulting model has on individual claimants. This study reinforces the thesis of David Gerber who stresses the ahistorical centrality of ‘biopolitics’ or the relationship between societal and political perceptions of a conflict on state policy, in the treatment of veteran communities. No research has been published on the disabled British Army veteran of the First World War who resided outside of the British Isles despite the burgeoning literature on the treatment and experiences of disabled ex-servicemen of the British Army.There is, in contrast, a comprehensive historiography dedicated to British migrants residing overseas.This article provides the first analysis of the disabled British ex-service migrant. Australia is chosen as a case study as it was the most popular overseas destination within the British Empire receiving 16,514 of 37,199 ex-servicemen who settled abroad via the British Government’s Overseas Settlement initiative.This article examines the British ex-service migrant whose rehabilitation remained defined by the British Ministry of Pensions but who shared Australian facilities and society with Australian veterans under the remit of the Repatriation Commission. This triangulation highlights and explains the policy differences between the two countries and the subsequent impact on veteran communities and national expenditures. This cross-national framework seeks to highlight the immense historical benefit to the study of veterans through a migratory lens as the existing historiography remains largely constricted to individual nation states.Before the First World War, both Britain and Australia provided charity relief funds to returning veterans of colonial conflicts with limited state liability to assist those disabled by war service.Influenced by Britain’s establishment of the Ministry, Australia followed suit with the founding of its Repatriation Commission in 1917.The Australian Repatriation Commission also shared the British Ministry of Pensions’ emphasis on the importance of employment in the rehabilitation of disabled veterans, and of incorporating societal initiatives in the latter.In addition to catering for its domestic veteran populations, British and Australian migrants were also rehabilitated and compensated. While the welfare authorities of the migrant’s new host society administered payment and treatment, only their country of origin could approve of new pension awards. The Ministry had a special branch, located at departmental headquarters in London, dedicated to ‘overseas’ cases. The exception here was Canada. Due to the large concentration of around 11,500 pensioners in Canada and the USA, an individual Ministry representative and office was established in Ottawa. The Ministry appeared satisfied with its transnational remit writing: ‘Every effort has been made to ensure that a pensioner abroad has available to him all the medical skill and care of the country in which he is resident’.after their arrival in Australia.In 1918, Australian Prime Minister Billy Hughes welcomed the participation of British Army veterans in Australian settlements, proclaiming it as a ‘unique opportunity of securing the right type of immigrant’ from British ex-servicemen ‘in the prime of life, who would make most desirable settlers on soil’.Bureaucracy and enquiries regarding suitability were reduced for self-funders. The number of British ex-servicemen who migrated via this method is unknown although Australian officials estimated that the majority of British migrants were self-funders who were not properly vetted before arrival.complete jurisdiction over the British ex-service migrant to the Repatriation.The surge of supposedly unfit ex-servicemen migrating to the Dominions, who subsequently became an alleged burden on Australian society, was cited as a key reason to relieve Australian state officials of this increased liability.Hore recognised that Repatriation officials believed the Ministry’s rules to be ‘excessively restrictive’.There was an increased potency of ex-service lobbyists and in the political capital associated with veteran issues in Australia.Differences between the British and Australian schemes became further magnified with the UK’s implementation of the ‘Geddes’ Axe’, which enforced a host of tax increases and economic cutbacks across the UK public sector from 1921 onwards.This reduction in Ministry liability and state intervention was seemingly aided by the lessening in societal concern for the disabled First World War veteran as the British population became desensitised to their plight in a time of widespread austerity and employment scarcity.The Australian department saw things differently citing the differences in ‘basic principles governing the provision’ of the Australian and British systems:It might be said that the Australian ex-soldier is offered every facility to establish his claim for the necessary facility to establish his claim for the necessary treatment, whereas the British man has to prove his right to treatment and is not helped to the same extent by the Ministry.These contrasting standards of principle, in the opinion of one Repatriation official, explained why the relative cost of pensioners receiving treatment in Australia was much higher than the UK.Such simplistic and moralistic conclusions are complicated, however, by considering the resulting impact that Australian welfare legislation had on national expenditure. The Commission and its Chairman, for example, accepted that it was impossible for its associated medico-pensions official to decipher whether a fresh disability claim made years after discharge was war-induced.outside of medical institutions.Between 1925 and 1926, following an audit of administration carried out on behalf of the Ministry in North America, G. F. Gilbert, a senior official in the Ministry’s accounting department in London, visited India, imperial territories in British Africa, Australia and New Zealand.As an auditor, Gilbert’s primary function was to emphasise Ministry instructions and conditions to Repatriation officials. In total, the annual outlay paid for by the Ministry amounted to £255,000.Gilbert would also recognise the comparative liberality of the Commission. When discussing Repatriation medico-pensions officials examining veterans suffering from tuberculosis, he wrote that they largely attributed their condition to war service with little concern if it was induced by active service: “The Committee certainly give the benefit of the doubt to the applicant. In fact, I do not think it would be unjust to them to say they generally spend some time looking for the ‘shadow of doubt”. Gilbert referenced further legislative differences between Ministry and Repatriation policy, including the aforementioned lack of time limits and final awards.This liberality was born of the spontaneous sympathy and generous impulses of the Australian people, but I am afraid that it is now kept alive and fostered by the exigencies of politics. The political element apparently enters far more into pension matters in Australia than in Great Britain.Further distinctive political infrastructure in Australia improved the ex-serviceman’s position. While there was a Federal Parliament for the whole of Australia, each state had its own Parliament. This increased regionalism and democratisation gave ex-service bodies more political leverage:Every member of the Parliament deemed it his duty to obtain as much as possible for his constituents, irrespective of whether they were entitled to it or not. There is no doubt, also, that the Associations of ex-servicemen are able to exert far more pressure in the Commonwealth than in Great Britain.Gilbert interacted with a small number of Imperial Pensioners receiving in-patient treatment at Repatriation facilities. They declared their contentedness and comfort in the facilities provided. Included within Repatriation medical infrastructure, for example, were sanatoriums and mental hospitals reserved for tubercular and insane ex-servicemen, respectively. Such segregation of insane ex-servicemen supposedly spared them from the stigma of hereditary and degenerative mental illness.Australian treatment did not always surpass comparative treatment available in Britain. The British Legion, medico-military staff and contemporary historians have assessed that the British metal leg limb was superior regarding durability and flexibility in comparison to the wooden limb favoured in Australia.The crucial role of the family and philanthropic lobbyist also needs to be highlighted. Even when Australian in-patient facilities were superior to what was otherwise available in Britain, British ex-service migrants did not always benefit from these because of the absence of a family member or an ex-service association submitting a claim to the Ministry on their behalf. Some British ex-service migrants were treated in highly stigmatised and overcrowded public asylums overseas as pauper lunatics, with no recognition of their former war service.In contrast to the Ministry’s extensive reduction of exclusive medical facilities, funding for veteran medical facilities continued in Australia into the late 1930s, including extensive renovation in comforts and medical equipment throughout the country and the establishment of modernised out-patient facilities.The British Treasury and Ministry, in contrast, rejected identical lobbying on behalf of what the British termed as the ‘prematurely-aged ex-serviceman’ due to its 7-year time limit on claims. Despite the British Legion persistently agitating for the removal of the time limit, which included a deputation with the Minister of Pensions F. O. Roberts in June 1927, and associated medical conferences and articles, new claims were very rarely accepted in the late 1920s and 1930s.Evidence has always, therefore, been essential … in the reliance of this evidence, the Ministry have been able to resist the occasional demand that a definite presumption of war should be embodied in Warrant or legislation.Tellingly, the Ministry cited that the Repatriation Commission ‘have to their disadvantage, in the absence of precisely this evidence, been driven to adopt’.Repatriation concessions had their detractors in both Britain and Australia. Writing to the Auditor General of the Melbourne state government, Gilbert wrote in 1934: ‘I certainly share your views that there is too much economic waste and extravagance in the commonwealth’.As you say, the members of the Commonwealth parliament seem to be more keen on catching votes than on conserving the resources of the country, and the government certainly gives way to them much more readily than our government does.Historians who have analysed the efforts of the Repatriation Commission also suggest that the department may have underestimated the potential for abuse its liberal infrastructure allowed.These contrasting welfare models had significant economic repercussions. While the financial outlay of the Ministry had been reduced by almost 51 per cent between 1921 and 1930, Repatriation costs increased by 25 per cent during the same period.The Ministry’s second inspection of Australia, lasting for 8 months between 1935 and 1936, was undertaken by W. F. N. Smith.Smith heard repeated criticisms of the treatment of British migrants throughout his tour by Commission officials, charity workers and British migrants alike. Smith reasoned ‘the Imperial in Australia, without effective local representation from the Ministry, felt himself to be neglected by his own government and treated with a lack of sympathy and inadequate knowledge by the country of his adoption’.Migrant ex-servicemen in Australia were further hampered by their isolation. Empathetic judgements appear increasingly unlikely if claims were based only on paperwork as opposed to personal testimony.Great War Pensions (1924) booklet to provide clear and concise information regarding Ministry policy.Even with valid claims, the distance from Ministry officials in London caused substantial delay in communication and gaining approval. A period of 12 months was the average for an official decision on a claimant’s response.after their arrival in Australia.A council of ex-service charity workers in Melbourne held that most of the dissatisfied applicants amongst the British ex-service migrant population were those who had sought assistance only when their health had broken down Disability and relief claims were, for example, evident amongst struggling British migrants who attempted to settle in the mining districts of New South Wales.British settlers shared the fate of Australian ex-servicemen whose health was detrimentally affected by working on failing land settlements.Writing to the House of Commons in Britain, one newly formed association of British ex-service settlers in Victoria pleaded for British governmental assistance. Describing the settlement schemes as ‘a hollow sham’, many British ex-servicemen were claimed to be ‘in a state of dire poverty and want … Settlers soon abandoned holdings to avoid starvation, while departments looked on and did nothing’. Both the Secretary of State for Dominion Affairs and the Commonwealth Treasurer proved unwilling to intervene on behalf of the British migrant responding that any complaints were to be addressed to the relevant Australian authorities.The dire and isolated position which many ex-service migrants found themselves is highlighted by the deaths of ex-servicemen who died in destitute circumstances and were buried in pauper graves. Unless the migrant’s death was related to a pensionable ailment, the Ministry proved unwilling to cover funeral and burial expenses, sparing the deceased veteran this shame.Previous research has described the Australian inter-war infrastructure as being ‘truly exceptional’ in its treatment of its ex-servicemen, even benefiting those who had not suffered considerably due to their war service and those affluent enough to be financially secure without additional government entitlements. This ‘welfare apartheid’ would ensure sporadic resentment aimed at ex-servicemen from the non-veteran communities.Smith conceded the administration of rehabilitation by the Ministry in Australia was not as ‘all embracing’ as that which the Commission afforded its ex-service population.It seems only natural that more complaints proportionally will be received from British pensioners residing in Australia, than those resident in the UK, as the British pensioner will come in contact nearly everywhere with the Australian war pensioner, who receives a more liberal deal so far as pension matters are concerned.Smith further advanced that the relative liberalism of the Repatriation Commission would inevitably give rise to discontent amongst British settlers:It is not easy in such an atmosphere to discuss freely the hard facts which must on occasion override sentiment. All these factors, and others of similar nature in the Australian scheme, inevitably tend to create dissatisfaction with the administration of a system which, by the test of time, has proved adequately to meet conditions in the UK.Australia’s distinct socio-political circumstances continued to influence the increasing divergence in national welfare policy. As Smith attested:Ex-service questions [were] always a live issue in Australia … political considerations provide an active part in pensions policy, and in Parliament by constant representation in the press and on wireless programmes, the public is continuously reminded of the demands or aspirations of the ‘diggers’.Claims for welfare or medical treatment were hampered by Ministry regulations, which stressed continuity of medical evidence directly related to war service in association with its 7-year time limit.In Brisbane, RSSILA officials held the lesser pensions provided to tubercular Imperial Pensioners were unjust and miserly.The plight of the British ex-service migrant in Australia was also reflected in their social standing. Not only was the King’s National Roll not extended to Australia, but also British ex-service migrants suffered as a result of a lack of inclusion and protection within Australian Federal law, which decreed that government positions must be filled by certain quotas of Australian ex-servicemen.If any promises were made, they had been made to men of the AIF who went away on service. This preference was now constituted as one of the methods of Repatriation. If anybody was responsible for the repatriation of British ex-servicemen that was the British government not Australia. If the government of Australia agreed to the extension of the principle of preference to Ex-Imperial Service Men, there would probably by an influx of them into Australia right away, and Australia’s own men would be out of work.Smith similarly noted a ‘definite antipathy on the part of the Australian public to providing for Imperial ex-servicemen … the general attitude was that if the disability were connected with the war, the responsibility should be that of the Imperial Government’.The Ministry’s policy and procedure were thus judged to be inadequate amongst ex-service bodies in Australia.both the World Wars.By the summer of 1939, just months before the outbreak of a second global conflict, the Commission was still describing the ‘considerable numbers’ of fresh claims from AIF veterans.The Ministry wrote in 1934 that no government department had been criticised more across British society.Contemporary welfare states continue to establish categories of prioritisation for public finance administered by national government departments. This binational case study identifies reoccurring type one and type two error problems in the administration of disability-induced welfare: policy can deny legitimate claims for state assistance while also validating and financing potentially illegitimate claims. Previous historians of rehabilitative departments have cited that pensions and treatment became a battleground in which a ‘protracted civil war was fought’ between veterans, families and charities versus state apparatus.improved their legal and political rights. With regards to the British ex-service migrants who shared Australia with AIF veterans, and to borrow from the lexicon of the First World War, they were positioned in a ‘no man’s land’. Ultimately, the British ex-service migrant did not benefit from British societal assistance integral to the Ministry’s rehabilitation of disabled veterans. To magnify their discontent, those residing in Australia shared a country offering more generous and liberal compensation packages to its disabled veterans, where AIF-veteran rights were ring-fenced by a sympathetic public who not only protected but also


There is mixed evidence on the association between headache and attention-deficit/hyperactivity disorder (ADHD), as well as headache and ADHD medications. This systematic review and meta-analysis investigated the co-occurrence of headache in children with ADHD, and the effects of ADHD medications on headache. Embase, Medline and PsycInfo were searched for population-based and clinical studies comparing the prevalence of headache in ADHD and controls through January 26, 2021. In addition, we updated the search of a previous systematic review and network meta-analysis of double-blind randomized controlled trials (RCTs) on ADHD medications on June 16, 2020. Trials of amphetamines, atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with a placebo arm and reporting data on headache as an adverse event, were included. Thirteen epidemiological studies and 58 clinical trials were eligible for inclusion. In epidemiological studies, a significant association between headache and ADHD was found , which remained significant when limited to studies reporting ORs adjusted for possible confounders. The pooled prevalence of headaches in children with ADHD was 26.6%. In RCTs, three ADHD medications were associated with increased headache during treatment periods, compared to placebo: atomoxetine , guanfacine , and methylphenidate . The summarized evidence suggests that headache is common in children with ADHD, both as part of the clinical presentation as such and as a side effect of some standard medications. Monitoring and clinical management strategies of headache in ADHD, in general, and during pharmacological treatment are recommended. Headache in childhood is common and disabling. The estimated prevalence during 1 month to lifetime is 58.4%; migraine affects 7.7%  is a neurodevelopmental condition characterized by impairing inattention, hyperactivity and impulsivity, with a worldwide prevalence of 5–7% in children and adolescents  vary across studies. Therefore, pooled results from a meta-analysis could provide a more robust and precise point estimate with a higher statistical power than the information derived from individual studies. Second, previous systematic reviews investigated the risk of ADHD in individuals with headaches, not vice versa  for headache in ADHD Thus, we conducted a systematic review and meta-analysis to examine two research questions (RQ): (1) Does the prevalence of headache differ between children with and without ADHD? (2) Is the use of common medications for ADHD associated with headaches in children?This systematic review was conducted in accordance with the PRISMA statement  with a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders (DSM)  or hyperkinetic disorder (HKD) in the International Classification of Diseases and Related Health Problems (ICD) , ascertained by either clinical assessment or validated instruments, or a positive answer to the question to parents: “Did a doctor/healthcare professional ever tell you that your child has ADHD?” The indicators for headache were either (1) A positive answer to the question to participants/parents: “Do you have (Have you ever had) headache/migraine?” “Does your child have (Has your child ever had) headache/migraine?”; or (2) a diagnosis of primary headache  recorded in medical files/registries, or made by clinicians in a research setting. OR was the principal summary measure when comparing headaches in children and adolescents with ADHD A systematic search was conducted with the assistance of two information specialists from the Karolinska Institutet University Library using the databases Embase, Medline and PsycInfo from their inception to January 26, 2021. This search was limited to studies published in English and in peer-reviewed journals. The complete search strategy is provided in eSearch strategy in the Supplement.Two reviewers independently screened the abstracts of the retrieved articles for eligibility, and then assessed the full text of potentially relevant publications. A manual search for additional studies was performed by screening reference lists of identified pertinent review articles. Disagreements between reviewers were resolved by consensus. When no consensus could be reached, a third reviewer acted as arbitrator. Data extraction was conducted using a standardized form by two independent reviewers. Extracted information included: study type, study settings, diagnostic tools for ADHD and headache, number and demographics characteristics of participants, and information for risk of bias assessment.The risk of bias was assessed independently by two reviewers using the Newcastle–Ottawa scale (NOS)   was calculated. Freeman–Tukey double arcsine transformations . The comparison group comprised of 2 464 878 participants, all recruited from the community.A total of 13 records were identified for inclusion in the review (eIncluded articles 1 in the Supplement). See study selection process in n = 12), as well as the results of subgroup analysis for the community studies with cross-sectional design. One small outlier study with an OR of 14.79  suggested higher rates of headache in ADHD than in non-ADHD controls (range of crude OR 0.90–3.37). Regarding the relationships between diagnostic assessments and ORs, three studies used clinical assessment for both ADHD and headache , we also conducted subgroup analysis for the studies with adjusted OR, the studies measuring migraine, and those measuring tension headache  = 1.98 (1.60–2.45)]. However, heterogeneity was still high among the studies measuring migraine , and no difference in the risk of tension headache was found between ADHD and controls. The pooled prevalence of overall headache in children with ADHD over a period of 1 year to lifetime is shown in eFigure 1 , with significant heterogeneity detected.headache . The synData on the risk of bias of each study are presented in eTable 1 in the Supplement. The most frequent sources of risk of bias were inadequate ascertainment of ADHD and headache, as well as the lack of non-response rate in both ADHD and non-ADHD groups. Regarding the comparability of cases and controls, most studies were cross-sectional studies without control groups matched for demographic characteristics. The heterogeneity across studies became non-significant in the adjusted subgroup analysis. This underscores the need for appropriate statistical methods to address the influence of possible confounders on the estimates. In addition, most studies did not include information on the treatment status of ADHD, which might influence the prevalence of headaches.t = − 1.79, p = 0.104). Nevertheless, some estimates lying on the top of the funnel plot but outside the triangular region suggest sample selection variance across studies , which could arise from the diversity of methods for identifying participants with ADHD.The results of Egger's test indicated no evidence of publication bias  were rated as overall low risk of bias regarding the outcome of headache, 16 trials (27.6%) with some concerns, and 1 trial (1.7%) as high risk of bias (eTable 2 in the Supplement).The majority of included trials (Except for bupropion and clonidine (one eligible study for each was identified by our search), the pooled OR on the risk of headache between treatment and control groups for five different ADHD medications are summarized in None of the included nine trials reported a significant difference in risk of headache between treatment and control arms . No evidence of heterogeneity was found in the meta-analysis, although the CI is wide compared to the synthesized results of other ADHD medications.p = 0.043), but did not survive in those with larger , and the association was also found in trials using forced titration (p = 0.041), but not in those using flexible/optimized dose , one trial reported a higher risk of headache in participants treated with atomoxetine, while others showed no difference between treatment and control groups. The synthesized results indicated a significant association between atomoxetine and headache in children with ADHD [pooled OR (95% CI): 1.29 (1.06 − 1.56)]. Two types of subgroup analyses were performed. The effects of dosage showed paradoxical findings, in which the association remained significant in trials with smaller dosage : 0.79 (0.33 − 1.93)].The only included trial investigated the efficacy and safety profiles of clonidine and methylphenidate among children with ADHD. There was no significant difference in the risk of headache between the group treated with clonidine and placebo [OR (95% CI): 1.73 (0.38 − 7.99)].None of the eight trials in the meta-analysis reported a difference in the risk of headache between treatment and placebo groups. However, the pooled estimates indicated that the odds of headache in the treatment group were 1.43 times higher than in the placebo group [pooled OR (95% CI): 1.43 (1.12 − 1.82)].n = 15, pooled OR (95% CI): 1.41 (1.12 − 1.78)]. When considering the duration of drug action, long-acting formation [the osmotic-release oral system (OROS) and extended release] was significantly associated with a higher risk of headache with the treatment of methylphenidate compared to controls : 1.33 (1.09 − 1.63)], and also in the subgroup analysis on trials using an oral formation with monotherapy design . However, the CI was wide due to the relatively small sample size.This is the first systematic review and meta-analysis on the association between headache and ADHD, and the effects of ADHD medications in childhood. Results indicate that in pediatric ADHD there is a doubled risk compared to those without ADHD to have a headache, with a pooled prevalence of 26.6%. Despite the heterogeneity across studies in the meta-analysis of crude data, the association survived when pooling ORs adjusted for possible confounders, including age, sex, and socioeconomic status (Bigal & Lipton, α2A adrenergic receptors (Bello, v. immediate-release formulation (Adler & Nierenberg, The effect size of the pooled estimate for atomoxetine was relatively small, and there was an effect of dosing strategy but not dose-related effects on headache. However, the finding may reflect a long-term tolerability profile of atomoxetine, in which headache is the most frequent treatment-emergent adverse event, reported by more than 50% of pediatric patients with 3–4 years treatment duration (Donnelly et al., s Bello, . Methylps Bello, , but hass Bello, . MoreoveMost trials included in this systematic review were underpowered to detect side effects. This makes it difficult to draw conclusions from single trials, especially since headache naturally co-occurs with ADHD. The majority of included trials did not report an increased risk of headache. Still, a significant risk was observed for several agents when looking at the totality of trials. This might explain why headache, despite being among the most common treatment-related adverse events of ADHD medication (Clavenna & Bonati, Headache phenotypes in pediatric ADHD have not been discussed in detail in the literature previously. Our results suggest an increased risk of migraine in children with ADHD, but not a risk of tension-type headache, in line with the findings from a previous meta-analysis (Salem et al., Several gaps in the literature were identified. For example, no eligible longitudinal studies aiming to disentangle the temporal relationship between the emerging of attention problems and headache symptoms were identified. In addition, only a limited number of studies recruited clinical samples of children with ADHD, which might experience headache profiles different from community samples. Further, most of the included epidemiological studies did not obtain the participants' history of pharmacological treatment. Finally, studies were not adjusted for other risk factors of headache, such as family history, medical conditions, and psychiatric comorbidity (Bellini et al., The results of this systematic review should be considered in the context of several limitations. First, the heterogeneity of outcomes across the included epidemiological studies diminishes the confidence of pooled ORs. This could partly reflect a bias of misclassification introduced by the inconsistent indicators used for identifying ADHD. Therefore, our confidence in the pooled proportion of headaches in ADHD children is restricted. Second, the majority of the included clinical trials did not detect treatment-related headaches in a standardized way, such as the Side Effects Rating Scale for stimulants (Barkley & Murphy, In conclusion, findings show that children and adolescents with ADHD are more likely to experience headaches than their peers. Clinicians should be aware that headache is a common comorbidity of pediatric ADHD, but also a frequent side effect of pharmacological treatments. To enable practitioners to provide better care for children with comorbid ADHD and headaches, clinical guidelines supported by empirical evidence are desirable.