DIFFERENTIATING ATTENTION-DEFICIT/HYPERACTIVITY DISORDER INATTENTIVE ANDCOMBINED TYPES: A 1H-MAGNETIC RESONANCE SPECTROSCOPY STUDY OFFRONTO-STRIATO-THALAMIC REGIONSPedro Eugênio Mazzucchi Santana Ferreira, André Palmini,João Rubião Hoefel, Maurício Annès, PauloBelmonte de AbreuPontifícia Universidade Católica do Rio Grande do Sul. Departamento dePsiquiatria da Faculdade de Medicina da PUCRS e do Programa de Residência doHospital São Lucas da PUCRS.Few previous investigations have assessed neurobiological substrates fordifferentiating Attention-Deficit/Hyperactivity Disorder (ADHD) types throughthe use of modern neuroimaging techniques.We assessed the neurometabolic profile in frontal-striatal-thalamic right andleft regions through 1H-magnetic resonance spectroscopy (1H-MRS) in three groupsof subjects (age range: 15-24 years’ old): ADHD inattentive type ,ADHD combined type  and non-ADHD controls (n 12). Compounds thatcan be visualized with 1H-MRS include N-acetyl-aspartate (NAA),glutamate/glutamine/γ-aminobutyric acid (Glx),creatinine/phosphocreatine(Cr), and choline compounds (Cho).Major differences were detected in metabolic ratios in subjects with ADHD-Ccompared with those with ADHD-I and controls, even after adjustments forcomorbidity. Subjects with ADHD-C showed a lower mI/Cr ratio in the rightventromedial prefrontal cortex (VMPFC) than controls (p 0.004), higher Cho/Crratio in the left pulvinar  than the ADHD-I group (p 0.02),and higher Glx/Cr ratio in left putamen nucleus than both individuals withADHD-I and controls . No differences were detected between subjectswith ADHD-I and non-ADHD controls. NAA/Cr ratio differed between patients andcontrols in the left VMPFC only when all ADHD subjects were grouped together(p=0.03).Our findings corroborate previous results suggesting a different neurobiologicalprofile between the two main ADHD subtypes, and suggest that ADHD-C isassociated with an energetic deficit in frontal-striatal-thalamic regions. Thereare two main possibilities to explain our findings in patients with ADHD-C. Oneis related to interference with neuronal energy-producing mechanisms and theother with neurotransmitter imbalance. Both are probably inter-related within aneurochemical-energetic framework. This neuronal metabolic profile is in linewith the ADHD theory of ‘energetic deficit’ in frontal-striatal-thalamicstructures. Mioinositol, glutamate/glutamine (Glx) and choline are all relatedto the energetic neuronal cycle. Furthermore, the reduced mI/Cr in the rightVMPFC and increased Cho/Cr in the left pulvinar found in the group with ADHD-Cmay influence secondary messenger systems bearing upon cyclic-AMP production.The evidence presented here suggests that 1H-MRS of metabolic ratios of mI, Cho,and Glx related to creatinine may differentiate groups of patients with ADHD-Cand ADHD-I, without differentiating the inattentive subtype from normalcontrols. An intriguing explanation for these findings is that thesedifferential metabolic profiles may, at least in part, reveal a greaterreduction in the energetic metabolism of frontal-striatal-thalamic structures inthe combined subtype of ADHD.IMPAIRED OCCUPATIONAL AND SOCIAL FUNCTIONING IN SCHIZOPHRENIA LINKED TODECREASED DORSOLATERAL PREFRONTAL METABOLISM: A PROTON MAGNETIC RESONANCESPECTROSCOPIC IMAGING STUDYEloísa Elena Silveira Ferreira, Paulo Belmonte-de-Abreu,André PalminiUniversidade Católica do Rio Grande do Sul. Unidade Psiquiatra do HospitalSão Lucas da PUCRS.Reduced frontal N-acetylaspartate (NAA) has been repeatedly found in dorsolateralprefrontal cortex (DLPFC) of chronic schizophrenia and suggests neuronal loss ordisfunction. These neuroimaging studies revealed a positive association withreduced NAA and cognitive deficit and severity. Unfortunately, few studies havefocused on the association of brain metabolism and impairment in social andoccupational functioning.To assess the association among DLPFC metabolism by proton magnetic resonancespectroscopic imaging (1H-MRS), with occupational and social handicaps inschizophrenics.25 subjects with DSM-IV schizophrenia and 12 healthy controls were assessed by1H-MRS and by selected Scales of Functional Outcomes , ,cognitive deficit (WCST - Wisconsin Card Sorting Test) and symptom severity. Differences among means and medians ofmeasures of patients and controls were assessed by Student’s t test and the MannWhitney test, respectively, confirmed by Covariance Analysis (Ancova), inGeneral Linear Models with SPSS 10.0 software using age, sex, education, age ofonset and illness severity as covariates.There was a significant difference in metabolism among schizophrenics andcontrols regarding several parameters. Schizophrenics displayed lower RightDLPFC metabolism in NAA/Cr ratios . In the Right DLPFC amongschizophrenics, NAA/Co ratio (p=0.009) was associated to occupational and socialhandicap in EAFSO, and NAA/Co ratios (p=0.005) in GAF, and NAA/Cr ratios(p=0.050) were negatively associated to symptom severity (BPRS). On the DLPFC,NAA/Co ratios were negatively associated (p=0.050) to WCST number of completedcategories.The study provides fresh evidence about prefrontal metabolism in schizophrenia.The new finding is that lower Right DLPFC metabolism is associated to loweroccupational and social functioning in schizophrenia. The additional evidencesare (i) lower NAA metabolism (NAA/Cr and NAA/Co ratios) in schizophrenicscompared to normal controls, (ii) lower NAA metabolism and functional handicap cognitive deficit (measured by WCST) and (iv)negative association among DLPFC NAA and symptom severity (measured by BPRS).The confirmation of frontal metabolic deficits in schizophrenics compared tonormal controls, providing further insight about physiopathology of the illness.This study of metabolic deficits in schizophrenia, if confirmed by additionalstudies in high risk populations, will strengthen the understanding of neuronaldysfunction and/or neuronal loss, probably preceding schizophrenia onset.Increased brain dysfunction after illness onset would result in decreased copingability for daily life demands and worse occupational outcomes inschizophrenia.PREVALENCE OF PSYCHIATRIC COMORBIDITIES IN PATIENTS WITH TEMPORAL LOBEEPILEPSYJosé Augusto Bragatti, Juliana Bohn Assmann, Vivian Fontana,Clarice Rigotti, Maria Paz Hidalgo, Renata Gomes Londero, Gisele Gus Manfro,Sandra Leistner-Segal, Carolina Machado Torres, Marino MuxfeldtBianchinUniversidade Federal do Rio Grande do Sul.Psychiatric disorders are common in epileptic patients. However, the prevalence ofpsychiatric comorbidities might be different depending on the group of patientsstudied and tools used to evaluate neuropsychiatric disorders. Although some studieshave evaluated psychiatric comorbidities in epileptic patients, well-controlledstudies, using representative patient groups with valid and standardized diagnosticinstruments, are still lacking. The objective of this study was to evaluate theprevalence of major psychiatric comorbidities in a series of patients of ourpopulation with diagnosis of temporal lobe epilepsy (TLE), using a validatedstructured clinical interview.We analyzed 57 patients with TLE, diagnosed according to the 1989 InternationalLeague Against Epilepsy (ILAE) Classification of Epilepsies and Epileptic Syndromes,using clinical, electroencephalographic, and neuroimaging criteria. All patientswere submitted to neuropsychiatric evaluation using the SCID , divided into four major categories: mooddisorders, anxiety disorders, psychotic disorders, and drugs and alcohol abuse.Variables studied were age, age of epilepsy onset, duration of epilepsy, gender,family history for epilepsy, seizure frequency, seizure control and psychiatricdiagnostics.There were 21 (36.8%) men and 36 (63.2%) women, with a mean age of 41.8 years, andmean epilepsy duration of 26.1 years. Thirty four patients (59.6%) had majorpsychiatric comorbidities. Mood disorders, the most commonly occurring, wereobserved in 22 patients . Anxiety disorders were the second most frequentdisorder, observed in seven patients . Three patients had psychotic disorders, and another threepatients presented drugs or alcohol abuse . There were no differences among SCID-positiveand SCID-negative patients regarding age, age of epilepsy onset, time of epilepsyduration, gender, family history for epilepsy, seizure frequency, and seizurecontrol.Our results (psychiatric disorder in 59.6% of patients with TLE) are in line withliterature. Most authors have reported psychiatric problems in 19 to 80% ofepileptic patients. This large variation is probably attributable to the differentpatient groups investigated and the even greater variety of diagnostic methods. Dueto high prevalence of major psychiatric disorders found in our patients, we believethat centers with psychiatric service dedicated to the evaluation and treatment ofpsychiatric comorbidities might offer much better clinical care for epilepticpatients.PATTERNS OF SLEEP AND LEVELS OF STRESS IN HOSPITALIZED CHILDREN WHO PLAY OR NOTDURING HOSPITALIZATIONClarisse Potasz, Patrícia G. Ferraz, Luciane Bizari de Carvalho,Lucila F. do Prado, Gilmar F do PradoHospital Infantil Candido Fontoura. Faculdade Metropolitanas Unidas (FMU).Children are major users of health services but are seldom consulted as health-careconsumers. As they are in a state of constant physical and psychosocial development,their ability to understand and cope with different aspects of hospitalizationvaries with age and developmental stage. Hospitalization can cause stress andchildren may show immediate or longer-lasting behavioral and emotional problems.Stress may be considered an adaptive response that enables the organism to cope withthreatening stimuli. Stress reactions activate the Hypothalamic-Pituitary-Adrenal(HPA) axis leading to releases of glucocorticoids into the bloodstream. There is areciprocal interaction between the HPA axis hormone release and sleep, whereby whenhormonal levels vary, sleep may also vary. Therefore, changes in sleep may haveconsequences in the hormonal secretion pattern. Developmentally appropriate play isa useful strategy among other well-known resources that may be used in hospitalenvironments and is suitable for helping children cope with stressfulconditions.The objective of this study was to examine the effect of hospitalization in childrenregarding sleep parameters (SP) and stress, considering an intervention aimed tolower these levels of stress.We analyzed SP and urinary cortisol levels (UCL) of 57 children (31 boys) that played(PG) or not (NPG), hospitalized for respiratory diseases in a public pediatrichospital. SP were obtained through sleep logs and UCL were examined in 24-hour urinesamples. Children were randomly assigned to play or non-play wards, by doctorsresponsible for admission who were blind to the conducting of the study.There were no differences in baseline UCL considering the intervention play, gender,age range, social classification, children’s depression inventory scores andprevious experience with hospitalization. Cortisol levels differed significantly(P<0.001) in relation to the intervention play when gender and age range wereconsidered.In general, younger children slept more during hospitalization than the olderindividuals in line with their maturity phase. NPG slept significantly more than PGmainly during the day. This was probably due to the use of sleep as a refuge againststress. Boys in our sub groups slept more than girls and showed higher UCL. It iswell established that boys and girls show different abilities to cope with stress.PG slept more at night and presented higher rates of sleep efficiency showing thattheir sleep quality was better than NPG.In conclusion, our study showed through clinical results that hospitalized childrenmake good use of intervention intended to improve sleep quality and lower levels ofstress caused by the disease and the hospitalization process.PROMNESIC AND ANTIAMNESIC EFFECTS OF A STANDARDIZED EXTRACT FROM MARAPUAMA:ROLES OF ADRENERGIC, DOPAMINERGIC AND SEROTONERGIC RECEPTORS.Adriana Lourenço da Silva, Bárbara da Silva Martins,Juliana G. Ferreira, Domingos S. Nunes, ElaineElisabetskyUniversidade Federal do Rio Grande do Sul.Amazonian peoples use traditional remedies prepared with the roots of Ptychopetalumolacoides (PO), predominantly used by the elderly and those convalescents with CNSdisorders and/or those undergoing periods of high physical or mental stress. We hadpreviously shown that a standardized PO ethanol extract (POEE) facilitates long-termmemory (LTM) retrieval, and reverses memory deficits in ageing mice using theinhibitory avoidance task. In this study, we showed that memory amelioration wasconfirmed in aging (14 months) mice presenting memory deficits using the objectrecognition task. The effect is obtained with the extract given acutely (i.p. 100mg/kg or p.o. 800 mg/k). POEE  was also effective inreversing the acetylcholine antagonist scopolamine induced impairment in all threememory phases, and the memory consolidation deficit induced by the glutamateantagonist MK-801. Regarding memory phases, in this study we showed that POEEfacilitates short-term memory  acquisition, consolidationsand retrieval as well as long-term memory  retrieval whenadministered intraperitoneally (50 e 100 mg/kg) or orally (800 and 1000 mg/kg). Byusing specific antagonists we also verified that beta-adrenergic and D1 dopaminereceptors are required for the facilitatory effects of POEE on STM in all threememory phases, as well as for LTM retrieval. Moreover, POEE promnesic effects onshort-term  and long-term  memories areincreased by 5HT2A, but not 5HT1A, serotonin antagonists . These results are in agreement with previous data suggesting theinteraction of POEE with various neurotransmitter systems, and also in accordancewith the therapeutic properties alleged by traditional users of Marapuama basedhome-made remedies. Considering the results of this study, the anticholinesteraseand antioxidant properties previously identified for POEE and its traditional use,this study corroborates the significant potential of this species as a source fordrug development in the context of conditions associated with cognitive deficit,including ageing, and Alzheimer disease.NEUROLEPTIC DRUGS REVERT THE CONTEXTUAL FEAR CONDITIONING DEFICIT PRESENTED BYSPONTANEOUSLY HYPERTENSIVE RATS: A POTENTIAL ANIMAL MODEL OF EMOTIONAL CONTEXTPROCESSING IN SCHIZOPHRENIA?Mariana Bendlin Calzavara, Wladimir Agostini Medrano, Raquel Levin,Sonia Regina Kameda, Monica Levy Andersen, Sergio Tufik, Regina HelenaSilva, Roberto Frussa-Filho, Vanessa CosthekAbílioUniversidade Federal de São Paulo.The ability to identify emotionally salient information in the environment and forman appropriate and rapid behavioral response is critical to survival. Differentpsychiatric populations, including schizophrenic, bipolar disorder and attentiondeficit/hyperactivity disorder (ADHD) patients, present abnormalities in emotionprocessing.In this respect, impaired recognition of facial emotion has been demonstrated inschizophrenia, bipolar disorder and ADHD patients. A previous study showed thatspontaneously hypertensive rats (SHR), a putative animal model of ADHD, presentreduced contextual fear conditioning (CFC), the most common paradigm used to studythe biological basis of emotion. The aim of the present study was to characterizethe deficit in CFC presented by SHR. Adult male normotensive Wistar rats (NWR) andSHR were submitted to the CFC task.Sensitivity of the animals to shock, and CFC performance after repeated exposure tothe task or repeated training sessions were investigated. We also evaluated theeffects of increased foot shock intensity on the CFC. Pharmacologicalcharacterization consisted of the evaluation of the effects of the following drugsadministered previous to the acquisition of the CFC: pentylenetetrazole (anxiogenic)and chlordiazepoxide (anxiolytic); methylphenidate and amphetamine (used for ADHD);lithium, lamotrigine, carbamazepine and valproic acid (mood stabilizers);haloperidol, ziprasidone, risperidone, quetiapina, amisulpride, clozapine(neuroleptic drugs); metoclopramide and SCH23390 (dopamine antagonists withoutantipsychotic properties); and ketamine (a psychotomimmetic). The effects ofparadoxical sleep deprivation (which worsens psychotic symptoms) and performance ona latent inhibition protocol  were also verified.No differences in the sensitivity to the shock were observed. The repeated exposureto the CFC task, repeated training of this task and increased shock intensity didnot modify the deficit in CFC presented by SHR.Considering pharmacological treatments, only the neuroleptic drugs reversed thisdeficit. This deficit was potentiated by all pro-schizophrenia manipulations:amphetamine and ketamine administration, and paradoxical sleep deprivation. Finally,a deficit in latent inhibition was also presented by SHR. These findings suggestthat the deficit in CFC presented by SHR could represent a useful animal model tostudy abnormalities in emotional context processing related to schizophrenia.


For the first time, chimpanzees have been observed using tools to clean the corpse of a deceased group member. A female chimpanzee sat down at the dead body of a young male, selected a firm stem of grass, and started to intently remove debris from his teeth. This report contributes novel behaviour to the chimpanzee’s ethogram, and highlights how crucial information for reconstructing the evolutionary origins of human mortuary practices may be missed by refraining from developing adequate observation techniques to capture non-human animals’ death responses. Social tool use is virtually absent in the animal kingdom. Apart from an early report by McGrew & Tutin1sensuNoel, a wild-born female chimpanzee living at the Chimfunshi Wildlife Orphanage Trust in Zambia, attended the dead body of Thomas, a nine-year-old male whom she adopted sensu when hisNoel approached Thomas’ body, sat down close to his head, turned her upper body sideways to select a hard piece of grass, put the grass in her mouth, and opened Thomas’ mouth with both of her hands. Then she wrapped her fingers around Thomas’ chin and jaw, and used her thumbs to explore his teeth. After 3 sec, she took the grass out of her mouth with her right hand, while maintaining focused grip on Thomas’ mouth with her left hand, and started to meticulously poke the grass in the same dental area as where her thumbs had been. During this time, Noel kept her face within 10 cm of Thomas’ face, never deflecting her gaze from his mouth. After 26 sec of teeth cleaning with the grass, Noel brought the grass to her mouth and inspected the grass orally, seemingly tasting debris removed from Thomas’ mouth. Soon thereafter, Noel engaged in cleaning Thomas’ teeth with the same piece of grass a second time , tasting the debris once more see  and 2.We consider the cleaning of a corpse’s teeth by Noel noteworthy for several reasons. First and foremost, to date, this behaviour has never been reported in chimpanzees or any other non-human animal species. The records of social tool use in animals are limited to McGrew & Tutin’s11Anecdotal evidence needs to be treated cautiously18The responses of group members to finding the dead body of Thomas were recorded with two video cameras from the moment that Thomas’ body was discovered until the caretakers requested for the recording to end so that they could make an attempt to climb the fence and retrieve the body from the enclosure. The recording comprised 20 min of uninterrupted filming and was previously used to investigate the group’s responses to the dead body in terms of proximity and individual differences based on association history with the deceasedHow to cite this article: van Leeuwen, E. J. C. et al. Tool use for corpse cleaning in chimpanzees. Sci. Rep.7, 44091; doi: 10.1038/srep44091 (2017).Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


The main aim of this study was to estimate the costs associated with diagnostic assessment and 1-year therapy in children and adolescents enrolled in 18 ADHD reference centres. Data concerning 1887 children and adolescents from the mandatory ADHD registry database during the 2012–2014 period were analysed. The overall diagnostic and treatment costs per patient amounts to €574 and €830, respectively. The ADHD centre, the school as sender, and the time to diagnosis constitute cost drivers. Non-pharmacological therapy resulted as being more expensive for patients concomitantly treated with drugs (€929) compared to those treated with psychological interventions alone . This study gives the first and reliable estimate of the costs associated with both diagnosis and treatment of ADHD in Italy. Although costs associated with mental disorders are difficult to estimate, continuing efforts are need to define costs and resources to guarantee appropriate care, also for ADHD.The online version of this article (doi:10.1186/s13033-017-0140-8) contains supplementary material, which is available to authorized users. The costs of psychiatric disorders have been scantly investigated, particularly with regard to those that affect children and adolescents , 2. MethAttention deficit hyperactivity disorder (ADHD) is a neurobiological disorder  characteDespite a pooled worldwide ADHD prevalence in children and adolescents of 5.3%, there is wide variability between and within countries . Such vaThe impairments of ADHD are multi-faceted and occur in multiple settings, as costs associated with ADHD impact multiple societal costs within and outside the healthcare sector , 24. StuOverall, in addition to the human suffering they cause, psychiatric disorders are among the most expensive of all health problems in adults , 28, eveIn June 2011 an official ADHD regional registry was activated in the Lombardy Region, designed as a disease oriented registry collecting information on all subjects who access ADHD centres for a suspected ADHD diagnosis –41, as pIn such a context, the objective of this study was to estimate the costs, from the National Health Service (NHS) perspective, associated with diagnostic assessment and 1-year therapy in children and adolescents aged 5–17 years enrolled in any of the 18 ADHD reference centres of the Lombardy Region between January 2012 and December 2014 for suspected ADHD.This study was designed as a review of patient medical records identified from the Regional ADHD Registry database, to estimate the costs of the diagnostic assessment and 1-year therapy for subjects with a suspected ADHD diagnosis. The research was approved by the Institutional Review Board of the IRCCS—Istituto di Ricerche Farmacologiche “Mario Negri” Milan, Italy. Written informed consent was obtained for all patients to put information in the registry database and analyze them anonymously.This study is part of a specific project supported by the Regional Health Ministry and aimed to ensure appropriate ADHD management for every child and adolescent once the disorder is suspected and reported, and includes commonly acknowledged diagnostic and therapeutic procedures as well as educational initiatives for health care workers (child psychiatrists and psychologists) of the Lombardy Region’s health care system. The project’s participants are all the 18 ADHD centres of the Lombardy Region, the most economically important and populated Italian region with 1.690.127 citizens under 18 years old, and with an average income earned per person equal to € 24.005 in the study period. The ADHD centres, accredited by regional health authorities, are the hubs specialised in ADHD (Tier 3) of the Child and Adolescent Neuropsychiatric Services (CANPS) network and provide diagnosis and treatment care free, or at a nominal charge, working mainly on an outpatient basis and in close connection with educational and social services. ADHD centres are also responsible for the prescription of pharmacological therapies and their monitoring over time. Moreover, ADHD centres are responsible for inputting data into the official ADHD registry and for providing parent, teacher, and child training treatments –41.Anonymized, updated data of the official ADHD registry of the Lombardy Region (as of 31 August 2015) were available, with 3163 subjects enrolled in the June 2011–August 2015 period. The study population includes children and adolescents from January 2012 to December 2014 who had both a first outpatient visit at one of the 18 ADHD centres for a suspected ADHD diagnosis in the same period and had a complete diagnostic evaluation and treatment prescription at the time of data extraction. Our goal was to identify only children who had never been evaluated and treated before for ADHD. We further required that all of the study children with a confirmed ADHD diagnosis were received a care continuity at the ADHD centre within a 1-year period.The guideline for all clinicians at the ADHD centres is to use the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition  criteriaOnce a patient receives a diagnosis of ADHD and a treatment prescription, the registry is designed to provide differently structured types of follow-up visits at periodic intervals: at 3 and 6 months after the diagnosis, and every 6 months afterward for all patients; while for those given methylphenidate at 1 week and 1 month after the diagnosis also (after only 1 month if they received atomoxetine or other psychotropic drugs). Moreover, patients that receive a methylphenidate prescription need to perform a visit called “dose-test” which is carried out in day hospital regimen before starting the drug treatment.Diagnostic pathway: all services supplied to patients with a suspected ADHD diagnosis, whether or not confirmed, by an agreed and shared child and adolescent neuropsychiatrists’ and psychologists’ assessment. In addition, the working days elapsed from the request a diagnosis of ADHD were calculated. In line with the regional health service perspective, only direct healthcare costs were estimated. Unit costs related to diagnostic tests were derived from tariffs reimbursed by the Lombardy Region in 2014. Detailed information is presented in Additional file Non-pharmacological therapies: Prescribed by physicians specialised in child and adolescent neuropsychiatry working in one of the 18 ADHD centres and provided by other therapists for example psychologists, also working within the ADHD centre. The direct health cost of non-pharmacological therapies was assessed by multiplying the estimated number of annual visits per patient by the unit costs derived from tariffs reimbursed by the Lombardy Region in 2014. Detailed information is presented in Additional file Pharmacological treatments: Prescribed by medical doctors specialised in child and adolescent neuropsychiatry working in one of the 18 ADHD centres (only prescriptions filled by patients). Drug utilization data were also derived from the Regional ADHD registry , 40. DetComplete data of all eligible patients were extracted. Besides anamnestic and clinical information regarding age, gender, diagnosis and comorbidity, detailed information was available on a patient medical records basis for the following cost domains:Data on the total annual consumption of ADHD medications that require a therapeutic plan prescription form were evaluated over 1 year after the date of the diagnosis. The trends in total consumption of ADHD drugs were also analysed based on changing patterns of the drugs’ prescription practices, dosages, and formulations.The unit costs of prescribed drugs were assessed based on: (a) price to public of medicines fully reimbursed by the Italian NHS and supplied through retail pharmacies (class A); or (b) sum of ex-factory price and 10.2% distribution margin of fully reimbursed drugs under direct distribution. Patient co-payment was not considered as it impacted a minority (<10%) of patients under drug treatment. The cost per milligram was calculated on the basis of the prescribed formulation  by selecting the generic, when marketed. Annual drug consumption was estimated for each patient by multiplying the daily dosage prescribed at each visit by the number days until the following visit.Laboratory tests,—including blood count, blood sugar, haemoglobin, ferritin, albumin, bilirubin, transaminases, gamma-glutamyl transpeptidase, erythrocyte sedimentation rate, thyroid hormones, uric acid, BUN, creatinine, urine—and EKG were carried out in day hospital (DH) setting only in patients undergoing pharmacological treatments, according to the Italian guidelines . Hence, 2 , Wilcoxon–Mann–Whitney , and Kruskal–Wallis (treatment and diagnosis related costs) tests were used to compare categorical variables. A multivariate logistic regression analysis with stepwise selection was carried out to assess the socio-demographic (baseline personnel and familiar data) and clinical, service models’ characteristics . Moreover, a multivariate linear regression analysis was performed to assess the drivers of diagnostic costs and time to diagnosis.All data were analysed with SAS Version 9.2, . Descriptive statistics were computed for the entire study population and for subgroups. As costs of diagnostic pathways , time to diagnosis, and treatment costs were not normally distributed, median and inter quartile ranges were analysed. The Student’s t test was used to compare continuous variables , while χData concerning 1887 children and adolescents who accessed 1 of the 18 ADHD centres for the first time during the 2011–2015 period and. completed the diagnostic evaluation at the time of data extraction  inter-centre variability was related to the completion rate of the recommended set of assessments  and the senders, with median time-to-diagnosis markedly reduced when the patient was referred by CANPS (91 days) or increased if referred by GPs (162 days), or by other specialist neuropsychiatrists practicing in agreement with the NHS . However, the time to diagnosis was slightly greater for patients receiving all the recommended tests (122 working days) compared to those who did not complete the assessment .Assuming that the time to diagnosis could be considered as a measure of efficiency by the regional health service , Fig. Non-pharmacological interventions: 1092 patients (86%), of whom 903 received a non-pharmacological intervention only (71%) and 189 (15%) combined with drugs;Drug treatments: 199 patients (16%), of whom 10 (1%) received drug treatment alone and 189 (90%) combined with non-pharmacological treatments.The following annual treatment costs were assessed for patients with an ADHD diagnosis (n = 753):The remaining 174 patients (14%) were not included because they were still being monitored (watchful-waiting) at the time of data extraction. Detailed information is presented in Additional file.The median total treatment cost per patient, including laboratory and instrumental assessment needed to begin the drug therapy, was €830.00 , followed by atomoxetine (10.1%). Median drug cost for 1 year was €97.60, of which €65.36 covered by stimulant treatment and €32.34 by non-stimulant treatment. Inter-centre variability , 99 (30%), and 222 (67%) were classified as severe, moderate and mild, respectively. No action was required for 208 adverse events, while, for the remaining events, patients recovered upon drug discontinuation  or dose changing . No patient was treated or hospitalised due to adverse events so no adjunctive cost estimation was needed.This study presents the first, and most comprehensive, estimate to date of the costs, from the NHS perspective, associated with both the diagnostic assessment and a 12-month therapy in children and adolescents with ADHD in Italy. The overall diagnostic and treatment costs per patient amounts to €574 and €830, respectively . In our opinion, this is a reliable and representative estimate of ADHD health costs in Italy. Indeed, in our country, the management of ADHD patients was provided mainly by a network of specialized hubs on ADHD (Tier 3)—the Regional ADHD centres—who are responsible for following the most appropriate diagnostic procedures and treatment prescriptions according to the Italian guidelines , 43. ThiThese costs are consistent, in some cases, and not, in others, with those previously suggested in other countries , 50–56. Our cost analysis is relevant from the perspective of the Italian NHS not only for ADHD . Indeed,Istituto Superiore di Sanità, ISS) [Interestingly, when community CANPS (Tier 2) was the sender, time to diagnosis markedly decreased (1 month), with a relative increase (7%) over the total cost. As such, the recommended pathway of care by the Italian National Institute of Health   when a cThere is public concern that the more rapid efficacy, in symptomatic terms, of pharmacological therapy, combined with its lower cost compared to non-pharmacological interventions, could favour an increased use of drugs alone for the ADHD management . As prevMoreover, it has also become apparent from our analysis that the cost of the non-pharmacological therapies is higher whether these are combined with drug treatment. This finding is probably related to the fact that patients requiring a combined treatment more often present greater severity in terms of both symptomatology and functional impairment. We can thus expect that, for these patients, not only is a more intensive (in terms of frequency) psychoeducational approach needed, but there is also a need that this approach be carried out in several different settings in the children’s life .Finally, the ADHD project of the Lombardy Region ensured that the diagnostic and therapeutic protocol followed by the ADHD centres, on which the cost analysis was based, was strictly monitored by the official registry, that it has been established according to the main recommendations of the national guidelines and that it is representative of the real clinical practice of an entire region. Indeed, the compliance to the shared diagnostic and therapeutic evaluation, according to the project guidelines, estimated by the analysis of data recorded by all 18 ADHD centers is very high and homogeneous in the Regional context . We can’t expect similar conclusions assuming to analyze ADHD health care differences and similarities between the Italian regions: various socioeconomic and service organization characteristics, i.e., may be explain a part of these differences and highlighting an important and broader issue, but not specific to the ADHD management. Limited literature data available from the Italian context are not enough to reach useful comparisons and comments about regional differences among ADHD management.However, the Regional ADHD Registry, as the main tool to monitor the ADHD project, was designed as a disease-oriented registry collecting information not only on ADHD patients treated with pharmacological therapy  but also on all patients who access ADHD centers for a diagnosis of suspected ADHD.These reasons strengthen the potential use of our findings as a proxy model to estimate the cost of the implementation of the guidelines in clinical practice for the development of similar projects in other Italian regions or for other mental health disorders.A few study limitations should be mentioned. First, our estimate was based on tariffs reimbursed by the Regional Health Service that does reflect the direct medical costs and not all costs of care provided. Furthermore, the estimates did not include other perspectives considered in cost studies, such as societal and caregiver perspectives. Subjects with mental health problems, including ADHD patients, require support from several dimensions in life, not only from the healthcare system, i.e. social care, housing, and employment , 60. SerThis study gives a reliable indication of the economic effect of both diagnosis and treatment of ADHD in Italy from the NHS perspective. There is clearly a need, however, for a comprehensive picture of the total health and societal costs of ADHD. There also is an urgent need for studies on cost-effectiveness of interventions and for consequent support arrangements for specialised ADHD services that address the needs of patients and their families so as geographically equitable and efficient as to the best evidence care management.The costs associated with mental disorders are difficult to estimate, but continuing efforts to do so increase available evidence as well as the understanding of the struggles of the individuals and families who need appropriate and adequate care.


Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in childhood. A wide variety of treatments have been used for the management of ADHD. We aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents.We performed a systematic review with network meta-analyses. Randomised controlled trials (≥ 3 weeks follow-up) were identified from published and unpublished sources through searches in PubMed and the Cochrane Library . Interventions of interest were pharmacological , psychological  and complementary and alternative medicine . The primary outcomes were efficacy (treatment response) and acceptability . Secondary outcomes included discontinuation due to adverse events (tolerability), as well as serious adverse events and specific adverse events. Random-effects Bayesian network meta-analyses were conducted to obtain estimates as odds ratios (ORs) with 95% credibility intervals. We analysed interventions by class and individually. 190 randomised trials (52 different interventions grouped in 32 therapeutic classes) that enrolled 26114 participants with ADHD were included in complex networks. At the class level, behavioural therapy , stimulants, and non-stimulant seemed significantly more efficacious than placebo. Behavioural therapy in combination with stimulants seemed superior to stimulants or non-stimulants. Stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants. Behavioural therapy, stimulants and their combination showed the best profile of acceptability. Stimulants and non-stimulants seemed well tolerated. Among medications, methylphenidate, amphetamine, atomoxetine, guanfacine and clonidine seemed significantly more efficacious than placebo. Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. Methylphenidate and clonidine seemed better accepted than placebo and atomoxetine. Most of the efficacious pharmacological treatments were associated with harms , but an increased risk of serious adverse events was not observed. There is lack of evidence for cognitive training, neurofeedback, antidepressants, antipsychotics, dietary therapy, fatty acids, and other complementary and alternative medicine. Overall findings were limited by the clinical and methodological heterogeneity, small sample sizes of trials, short-term follow-up, and the absence of high-quality evidence; consequently, results should be interpreted with caution.Clinical differences may exist between the pharmacological and non-pharmacological treatment used for the management of ADHD. Uncertainties about therapies and the balance between benefits, costs and potential harms should be considered before starting treatment. There is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents. PROSPERO, number CRD42014015008. Attention deficit hyperactivity disorder (ADHD) is one of the most commonly diagnosed psychiatric disorders in children and adolescents. Recent estimates suggest that ADHD affects about 3–7% of young people worldwide –2, produIn recent years, the management of ADHD has become increasingly complex as new therapies are introduced in clinical practice. The comparative efficacy and safety of pharmacological and non-pharmacological treatments are largely unknown, mainly because of the paucity of head-to-head trials. A wide variety of interventions have been used for the treatment of ADHD, including pharmacological and psychological interventions, herbal and homeopathic remedies, and dietary management. Despite the extensive body of research into the epidemiology and pathophysiology of ADHD, less emphasis has been placed on methodologically sound comparative research questions evaluating and comparing different ADHD treatment options. For example, which ADHD treatment modality works best in children and adolescents, psychological interventions, pharmacological therapy or both? Among broad groups of treatment interventions, is there any particular treatment which is clinically superior (or inferior) to others? Is there a unique role of complementary and alternative medicine used in the treatment of children and adolescents with ADHD? Although the evidence is not strong, pharmacological treatment using stimulant medication is generally recommended for school-age children and adolescents with ADHD, along with implementation of psychological interventions based on behavioural approaches –11. VeryKnowledge gaps in the current evidence base present opportunities for the application of novel evidence synthesis methods to complex networks of trials and interventions, as well as rigorous comparative evaluations of multiple treatments for ADHD. Relatively new methods have been developed to analyse such complex trial data, including network meta-analysis, which helps to integrate and synthesise diverse results to determine the relative merits of multiple treatments. Network meta-analysis has been recommended as a next generation tool for evidence synthesis when a heterogeneous set of treatments and trials is included in the same review –24. NetwAccordingly, we aimed to compare the efficacy and safety of pharmacological, psychological and complementary and alternative medicine interventions for the treatment of ADHD in children and adolescents. We used network meta-analyses comparing multiple interventions to integrate direct and indirect evidence into unified networks of all available randomised trials.This systematic review was conducted and reported in accordance with the reporting guidance provided in the PRISMA statement extension for systematic reviews incorporating network meta-analysis  S1 Chec. We deveWe included randomised controlled trials which: (1) had at least three weeks follow-up  as this is the minimum length of treatment chosen in trials designed to measure dose responses or efficacy; (2) compared pharmacological or non-pharmacological interventions against each other or against placebo/control in the treatment of children and adolescents (under 18 years of age) with a diagnosis of ADHD . All ADHD subtypes  were considered for inclusion. We included trials that enrolled patients with comorbid conditions . Eligible interventions were pharmacological, psychological, complementary and alternative medicine, and combined interventions. Pharmacological interventions were not required to be licensed for ADHD. Control conditions were placebo or no treatment, waitlist , and usual care or control  ; Non-stimulants ; Antipsychotics ; Other unlicensed drugs .Psychological interventions. A diverse range of psychological therapies is available for the treatment of ADHD in children and adolescents. Psychological interventions were: Behavioural therapy: an intervention directed at changing behaviours (increasing desired behaviours and decreasing undesired behaviours), based on social learning principles and other cognitive theories. These include classical contingency management, behaviour therapy (mainly through mediators such as parents or teachers) and cognitive behaviour therapy . These treatments are usually offered in several sessions over time, either through training the parents (teachers) or the child or both. Cognitive training: working memory training incorporating adaptive schedules that are hypothesized to strengthen ADHD-deficient neuropsychological processes. We retained studies including training interventions that aim to directly train a cognitive function, or working memory, or attention . Neurofeedback using the visualization of brain activity to teach children to increase attention and impulse control. Neurofeedback is commonly based on electroencephalography; sensors are placed on the scalp to measure activity, and measurements displayed using video displays or sound. By learning to control their brain activity based on behavioural principles of operant conditioning, it is hypothesized that ADHD patients will learn to regulate the associated attentional states and processes.Complementary and alternative medicine interventions. Complementary and alternative medicine is a group of diverse medical and health care systems, practices and products that are not presently considered to be part of conventional medicine. A diverse range of interventions are being used for the treatment of ADHD in children and adolescents: Dietary therapy, such as restricted elimination diet or ‘few foods approach’  and artificial food colour elimination from child’s diet ; Polyunsaturated fatty acids (PUFA e.g. omega-3 and omega-6 fatty acids); Vitamins ; Minerals ; Amino acids . Herbal therapy ; Homeopathic treatment and any other supplementary interventions; Mind- and body-based interventions .Control comparators. Eligible control conditions were: Placebo , waiting list , and control .The pre-specified primary outcomes were treatment response and all-cause treatment discontinuation rates, chosen because they are among the most clinically meaningful and consistently reported estimates of treatment efficacy and acceptability in mental health research ,31. We dwww.clinicaltrials.gov) and manufacturer clinical trial registers , regulatory agencies websites , and review of references of relevant papers, health technology assessment reports and clinical practice guidelines. We contacted authors for missing outcome data or unclear information. Furthermore, we contacted the European Medicines Agency for unpublished data through its recent transparency policy [We used a staged approach to study identification, beginning with a systematic search of relevant trials included in systematic reviews available in PubMed/MEDLINE , the Cochrane Database of Systematic Reviews  and/or existing meta-analyses of which we were aware  of studies, two reviewers were responsible for independent data extraction on general characteristics  and outcome data. The Cochrane Risk of Bias tool  that conWe analysed interventions by class  and individually . In general, treatments with similar mechanisms of action were classified in classes in which treatment effects were considered to be similar. Our primary class-level analyses classified therapeutic class interventions used in monotherapy and/or combination as separate treatment nodes irrespective of their doses: controls , psychological interventions , pharmacological interventions  and complementary and alternative medicine interventions . For the primary outcomes, we expressed comparative effects of therapeutic class interventions using placebo as the reference comparator. Additionally, we also expressed individual effects of commonly prescribed pharmacological interventions  using me2 index [Whenever possible we used results from intention-to-treat analyses in which the original random participant assignment was maintained in the data analyses. For each outcome, we presented graphically the geometry of the treatment network of all comparisons . Using a2 index  and the 2 index . Small s2 index ,50. Cons2 index  for netwSensitivity analyses were conducted to explore the impact of potentially important effect modifiers on findings from network meta-analysis. These included separate analyses that involved exclusion of the following: studies at overall high risk of bias, studies where both the assessor and the patient (or caregiver) were unmasked , and small studies (with less than 100 participants). Other pre-planned analyses were the extension of the primary unadjusted network meta-analysis model to include covariates in meta-regression models  that conAll Bayesian network meta-analyses were conducted using WinBUGS 1.4.3 , while pairwise meta-analyses and network diagrams were generated using Stata 13 .The systematic search identified 5,606 citations (from 116 systematic reviews and updated searches), of which 804 were examined in full-text review and 540 were excluded. Accordingly, we included 190 studies (described in 264 publications). A PRISMA flowchart documenting the process of study selection is shown in The mean duration of follow-up of included studies was 12 weeks (range 3–96) and the mean sample size was 137 (range 9–1323), with 91 trials (47.9%) having at least 100 participants and 7 trials (3.8%) having more than 400. Studies assessed 52 interventions or control conditions, which were grouped in 32 therapeutic classes . Most studies (86%) included two groups; while smaller totals included three groups (11%) or more (3%). Most studies were conducted in North America and Western Europe (75%). At baseline, the mean and median age was 10 years (range 3–16) and the mean percentage of male participants was 77%. Fifty-three trials excluded children and adolescents with a comorbidity. Oppositional defiant disorder was the most common comorbidity (mean 44% of participants at baseline among studies reporting data), followed by conduct disorder (21%). In terms of methodological quality , 100 triFigs Summaries from all network meta-analyses are provided below for each outcome.Treatment response (efficacy) was reported in 8,916 of 19,398 patients from a total of 113 trials evaluating 26 classes of interventions or control conditions. Low quality evidence suggests that behavioural therapy alone, stimulant monotherapy, and non-stimulant monotherapy seemed significantly more efficacious than placebo . AntidepThe acceptability outcome  was observed in a total of 4,822 of 22,961 patients from a total of 171 trials evaluating 32 classes of interventions or control conditions. Low to very low quality evidence suggests that behavioural therapy alone and stimulant monotherapy showed the best profile of acceptability, leading to significantly reduced chance of discontinuation compared to placebo . Non-stiCognitive training, neurofeedback, antipsychotics and complementary and alternative medicine  did not have greater effect on the primary outcomes of efficacy and acceptability compared with placebo; the effects of these interventions were not significant or were very imprecise .Results from network meta-analyses performed at the agent level for commonly prescribed medications are presented in Estimated effects for the secondary outcomes of tolerability (discontinuations due to adverse events), serious adverse events and specific adverse events are presented in Discontinuations due to adverse events were reported in 740 of 18,863 patients from a total of 105 trials. Very low quality evidence suggests that stimulants, non-stimulants and the combination of stimulants and non-stimulants were each well tolerated compared to placebo .Stimulants , non-stimulants , combinations of stimulants and non-stimulants , antidepressants  and other unlicensed drugs  produced anorexia ; whereas stimulants , non-stimulants  and other unlicensed drugs  led to weight loss .Stimulants led to unspecified sleep disturbances , whereas regimens containing either stimulants , non-stimulants  or both , and other unlicensed drugs  caused insomnia .Treatment estimates for serious adverse events  and anxiety  were non-significant or were highly imprecise. Given the limited number of trials reporting data on syncope, this outcome was not evaluated in the network meta-analyses.In terms of cardiovascular events, a limited number of trials reported similar outcome definitions on vital signs for different pharmacological interventions. For example, some studies reported the following: an increase in blood pressure ; a decrease in blood pressure ; an increase in heart rate ; a decrease in heart rate ; palpitations ; and QT prolongation . Given this wide variability of reporting of cardiovascular events, network meta-analysis for these specific events was considered not feasible.The full details of the additional analyses including sensitivity analyses, subgroup analyses, model fit evaluations and small study effect bias assessments are reported in the report ADHD is one of the most commonly diagnosed and treated psychiatric disorders in childhood. In many Western countries, the prescribing rates have increased dramatically, with wide variations in medical practice –56 that Our main findings have potential implications for informing evidence-based treatment selection, but also establishing recommendations in clinical practice guidelines as well as the future design of new studies. Some treatments for the management of ADHD differed in both clinical and statistical aspects. In terms of response, behavioural therapy , stimulants and non-stimulants seemed significantly more efficacious than placebo; stimulants seemed superior to behavioural therapy, cognitive training and non-stimulants; and behavioural therapy in combination with stimulants seemed superior to monotherapy with stimulants or non-stimulants. Among single drug agents, methylphenidate, amphetamine, atomoxetine, guanfacine, clonidine and modafinil seemed significantly more efficacious than placebo (even though less clear confidence with clonidine and modafinil). Methylphenidate and amphetamine seemed more efficacious than atomoxetine and guanfacine. In terms of acceptability, behavioural therapy and stimulants (and their combination), showed the best profile of acceptability leading to significantly fewer discontinuations that did placebo. Methylphenidate and clonidine seemed superior to placebo, whereas methylphenidate and clonidine seemed better accepted than atomoxetine (even though limited evidence for clonidine). Most of the efficacious pharmacological treatments  were associated with anorexia, weight loss and insomnia.One of the most important clinical implications is that behavioural therapy, particularly given by parents and with active child and teacher involvement, is the only non-pharmacological intervention that was found to be associated with statistically significant benefits in our analyses. Cognitive training, neurofeedback, dietary therapy (such as restricted elimination diet), polyunsaturated fatty acids, amino acids, minerals, herbal therapy, homeopathy, and physical activity cannot be recommended as evidence-based interventions for global functioning and core ADHD symptoms until better evidence of their comparative efficacy is reported in well-designed and conducted clinical trials. However, a healthy, balanced diet and regular exercise should be emphasised for all children and adolescents, including those with ADHD . StimulaOur systematic review suggests that treatment effects are larger when behavioural therapy is combined with stimulants . The clinical decision to combine these interventions should be driven by the symptoms presented, the needs of the children and their family and the availability of healthcare services. The value of combined treatment for ADHD is recognized as an area of interest because it might lead to potential beneficial effects in different domains . CombiniThere are multiple and diverse clinical practice guidelines worldwide for the management of ADHD ,40,78–80Along with broad recognition that data from some clinical trials and treatment comparisons were sparse, and that more and higher-quality data could improve estimations and recommendations, aspects of the general approach of previous systematic reviews and meta-analyses –17,81–83There are some limitations to be noted regarding our study. We used established methods –34 to leAlthough we adopted reproducible definitions, the heterogeneous reporting of events in studies posed a major challenge. None of the trials examined and reported all the outcomes of interest. The overall quality of the network meta-analyses evidence ranged from low to very low as assessed by the GRADE approach  see . In factThere is still room for improvement in the design, conduct and reporting of trials in the field. The clinical research agenda of ADHD is incomplete and needs better designed and reported randomised trials to assess the benefits and harms of the multiple interventions available for the management of ADHD in the young people. In this respect, ADHD complex pathogenesis implicates multiple factors of a diverse nature that should be considered in clinical research –8. A perIn conclusion, although the quality of evidence is not strong, clinical differences may exist between the pharmacological and non-pharmacological treatments commonly used for the management of ADHD. Behavioural therapy and pharmacological treatment may improve the symptoms of ADHD and global functioning in the short-term. Our findings can help clinicians, healthcare providers, parents, and caregivers make informed decisions regarding treatment selection for the management of ADHD. An open and honest discussion with parents and older children about uncertainties of available treatments and the balance between benefits, costs, and potential harms should be established before starting treatment. In addition, there is an urgent need for high-quality randomised trials of the multiple treatments for ADHD in children and adolescents.S1 Checklist(DOCX)Click here for additional data file.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S4 Text(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S7 Table(DOCX)Click here for additional data file.S8 Table(DOCX)Click here for additional data file.S9 Table(DOCX)Click here for additional data file.S10 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.


Attention deficit/hyperactivity disorder (ADHD) is a common neuropsychiatric disorder in children and adolescents worldwide, and children with ADHD have elevated risk of injuries. Our aim was to assess the risk of hospitalizations with injury diagnoses and their various subtypes in children and adolescents with newly diagnosed ADHD compared to those without ADHD, as well as to study sex effects on this risk in the setting of the German health care system.The German Pharmacoepidemiological Research Database, in which 20 million insured from four statutory health insurances in Germany are included, was used to set up a matched cohort study of 3- to 17-year-old children and adolescents with and without ADHD. We calculated age-specific incidence rates and used Cox regression to obtain hazard ratios (HRs) for hospitalizations with injury diagnoses. We used the injury mortality diagnosis matrix for classification of injuries.The matched cohort comprised a total of 75,300 children. The age-specific incidence rates for hospitalization with injury diagnosis for males with ADHD displayed a u-shaped form with highest incidences in the in the age groups 3–6 years  and 18–21 years . Girls with ADHD were less affected in younger age-groups, but the incidence rate for 18–21 year olds was similar to boys with ADHD . The adjusted HR for children with ADHD was 1.40 (95% CI 1.30–1.49) compared to non-affected children. With respect to nature of injury, ADHD was associated with hospitalization with injury diagnoses of the internal organs, open wounds, and contusions but not with other injuries. With respect to body regions, children with ADHD were more prone to hospitalizations with injuries of the abdomen, traumatic brain injuries, other head injuries, and system-wide injuries such as poisoning and intoxication. No significant associations were seen for the other body regions. Differences between sexes were only seen for system-wide injuries.Children and adolescents with ADHD are at an increased risk for hospitalizations with diagnoses of injuries compared to non-affected children. Despite differences in health-care systems, the risk increase is at a similar level in Germany as in other countries. Attention deficit/hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children worldwide. The core symptoms include inattention, hyperactivity, and impulsivity . The worStudies using claims data to assess the association between injuries and ADHD have mostly been conducted in the US and Canada using populations with different case assessments, sample sizes, age-ranges, and in different years. In total, they showed an elevated risk up to a factor of five for those injuries which require hospital treatment among children and adolescents with ADHD compared to individuals without ADHD –16. In aThe diagnostic methods used for ADHD vary between countries, but the difference can be even larger in their practical application in different health care systems, for example regarding the diagnostic threshold , 25. ThiSex differences in injury subtypes are known for children and especially for adolescents . Due to Taking advantage of a large cohort study of ADHD children and controls, addressing various research questions , 31–34, The German Pharmacoepidemiological Research Database (GePaRD), which comprises data of 20 million insured (one fourth of the population) from all over Germany, was used to select a matched cohort with children with ADHD diagnoses. The database is described elsewhere , 36. In According to German Social Insurance Code , no informed consent was needed from the insurants for this study. The use of the data for this study was approved by all four SHIs, the Federal Ministry of Health, and the Senate of the Federal State of Bremen. Since this study was based on routinely collected pseudonymized data, no ethical approval was needed. Within GePaRD exists a data protection concept, which protects the privacy rights of each insurant.Study entry for the children and adolescents was between 2005 and 2007. Eligible subjects had to reach an age between 3 and 17 years in their year of study entry, had to have a continuous insurance period of 1 year free of ADHD indicators like diagnoses or prescriptions for MPH or atomoxetine (ATX) directly before study entry, and had to have a continuous insurance period of at least one year subsequent to their study entry. Study participants were followed until the 31st December 2009 or their end of insurance, whichever came first. Among these, newly diagnosed ADHD-cases were identified by the following algorithm based on ICD-10-GM diagnoses and drug dispensations: children had to have received either one inpatient diagnosis F90.0 or F90.1, or at least two outpatient diagnoses F90.0, F90.1, or F90.9 (of which one had to be F90.0 or F90.1) within a period of 1 year, or a dispensation of methylphenidate  or ATX (ATC code: N06BA09) together with one outpatient diagnosis F90.0 or F90.1 within 1 year. The first date of the events considered for the case identification as the index date of the case.This cohort study used a matched design. We included identified ADHD-cases with an index date situated between 2005 and 2007. For each of them, a subject without ADHD was matched on sex, birth year, region of residence and insurance company and the potential follow up of the matched subject had to be at least as long as of the ADHD case. Study entry date for both of a matched pair was the index date of the ADHD case and consequently both had to fulfill the defined inclusion criteria at this date. Further, the follow-up of the matched subject was censored at the follow-up end of the corresponding ADHD case. Subjects with an ADHD case index date after 2007 were excluded before matching.For the ascertainment of injuries, we used the injury mortality diagnosis (IMD) matrix developed by Fingerhut and Warner  to standFor the descriptive analyses, the study population was stratified by sex, 3-year age classes , case status (ADHD yes/no), and nature of the injury or injured body region . SubsequIn the years 2005–2007, 37,650 children and adolescents 3–17 years old with a new ADHD diagnosis were identified and matched 1:1 to subjects without ADHD. Follow-up of the cohort until 2009 accumulated to a total of 254,985 person-years. During this time, we identified 3,995 inpatient treatments due to injuries. The age-specific incidence for hospitalizations with at least one injury diagnosis showed an almost u-shaped form among boys with ADHD, with highest incidences in the age-groups 3–6 and 18–21 years  for a hospitalization with injury diagnosis for children and adolescents with ADHD was 1.40 (95% CI 1.30–1.49) compared to those without ADHD. The results were similar for hospitalizations with injuries of internal organs, open wounds, and contusions, while other categories of injuries like fractures, other specified injuries (see IMD matrix), and unspecified injuries were not associated with an elevated risk in the presence of ADHD Figure . ConcernThe risk of hospitalizations with injury diagnoses among individuals with ADHD and without ADHD was not modified by sex, with the exception of system-wide injuries where the ADHD associated risk increase was less pronounced in boys compared to girls Figure .Taking advantage of a large matched cohort of children and adolescents with and without ADHD in German health insurance data, we studied the relative risk of hospitalizations with injury diagnoses associated with ADHD and how it depends on sex. We confirmed the higher risk of hospitalizations with injury diagnoses among children with newly diagnosed ADHD compared to sex- and age-matched controls without ADHD. We observed significantly elevated HRs for injuries of the abdomen, traumatic brain injury as well as for system-wide injuries among children with ADHD. Children or adolescents with ADHD also had a higher risk for hospitalizations with diagnoses of injuries of the internal organs, open wounds, and contusions compared to those non-affected. We showed no differences by sex with respect to ADHD for all studied subtypes of injuries apart from the hospitalizations with system-wide injuries where the risk increase related to ADHD was less pronounced in boys compared to girls.These findings are consistent with previous studies, in which children and adolescents with ADHD displayed a higher risk of injuries than healthy controls , 14, 21,The risk estimates of various injury patterns were elevated by a factor of two, except for system-wide injuries for which the HR was 3.5, indicating a particularly strongly increased risk. Among studies reporting the risk of poisoning, which is after intoxication the main type of system-wide injuries in children with ADHD, we only identified two reporting significantly elevated risk in children with ADHD compared to their non-affected controls , 43. TheWe also found a higher risk of system-wide injuries for girls with ADHD compared to boys with ADHD. This effect has not been reported in the past. Our findings are corroborated by the well-known fact that female adolescents are at a higher risk of self-related harm and intoxication than male adolescents –30. In lThe risk of hospitalization with injury diagnoses was generally higher for boys than for girls. This is consistent with studies in the general population . PotentiThe main strength of this study is the use of a large administrative database, which in several previous studies showed agreement with data representative for Germany , 45. TheHowever, the current study has also a number of limitations. As it is true for every study conducted with administrative data, information gathered in the database was not collected for research purposes. For example, the diagnostic criteria for ADHD were not standardized for the purpose of this study, but followed the routine diagnostic standard in the German health care system. In this study both, cases and controls, were assessed in the same database, and therefore affected on equal terms. Still, patients are more likely to be consistently recorded as ADHD cases in claims data if they have a more severe form of ADHD and/or receive treatment. Consequently, if preferentially persons with more severe forms of ADHD are included in our case group, this could inflate our estimates. On the other side, we did not account for any treatment of ADHD. Recent studies using case only designs indicate a risk reduction due to medication, particularly with respect to injuries being more specific for ADHD , 46, 47.We focused in our analysis on hospitalizations with injury diagnoses. The way the data is recorded does not allow determining beyond doubt that the injury was the cause for the hospitalization, but it is likely the case. Unfortunately, we were not able to study the injuries treated in outpatient and emergency room settings, because diagnoses are recorded only quarterly wise and can be continued if related visits take place. For example after hospitalization, injury diagnoses can be recorded in outpatient follow-up. In consequence, we were not able to establish injury events for the outpatient setting.Finally, we were not able to address influence of socioeconomic status since our data does not provide this information. As ADHD is associated with a low socioeconomic status  and a loIn summary, our results indicate that the risk of children and adolescents with ADHD for hospitalizations with injury diagnoses was substantially higher compared to their non-affected controls. We conducted an extensive analysis for various injury patterns concerning the affected body region and the nature of injury. In this context, we found that besides of system-wide injuries, there were no differences by sex. Parents and teachers of children with ADHD need to be advised of the higher risk of injuries. Moreover, attention should be paid to specific risks for girls with ADHD during adolescence.The study is based on routine data and therefore exempt from ethical review.CL, IL, TB, RM, and EG were involved in the acquisition and the design of the study. CL, IL, RM were involved in the statistical analyses. All authors gave substantial contribution to the interpretation of the data. All authors were involved in drafting the work or revising it critically for important intellectual content. All authors gave approval for the publication of this version.IL is working for a department that occasionally performs studies for pharmaceutical industries. EG, RM, and CL were at the time of study conduct employees of this department. The pharmaceutical companies include Bayer, Celgene, GlaxoSmithKline, Mundipharma, Novartis, Sanofi-Aventis, Sanofi Pasteur MSD, and STADA. EG has been a consultant to Bayer, Takeda, Nycomed, GlaxoSmithKline, Schwabe, Teva, Astellas, Consulting AstraZeneca, and Novartis. These activities are unrelated to the current topic of this study. TB served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Medice, Novartis, Oxford outcomes, Otsuka, PCM scientific, Shire, and Viforpharma. He received conference support or speaker’s fee by Medice, Novartis and Shire. He is/has been involved in clinical trials conducted by Shire & Viforpharma. He received royalities from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships.


Preterm birth has been associated with an increased risk for ADHD-like behavioural symptoms and cognitive impairments. However, direct comparisons across ADHD and preterm-born samples on neurophysiological measures are limited. The aim of this analysis was to test whether quantitative EEG (QEEG) measures identify differences or similarities in preterm-born adolescents, compared to term-born adolescents with and without ADHD, during resting-state and cognitive task conditions. We directly compared QEEG activity between 186 preterm-born adolescents, 69 term-born adolescents with ADHD and 135 term-born control adolescents during an eyes-open resting-state condition (EO), which previously discriminated between the adolescents with ADHD and controls, and during a cued continuous performance task (CPT-OX). Absolute delta power was the only frequency range to demonstrate a significant group-by-condition interaction. The preterm group, like the ADHD group, displayed significantly higher delta power during EO, compared to the control group. In line with these findings, parent-rated ADHD symptoms in the preterm group were significantly correlated with delta power during rest. While the preterm and control groups did not differ with regard to absolute delta power during CPT-OX, the ADHD group showed significantly higher absolute delta power compared to both groups. Our results provide evidence for overlapping excess in the absolute delta range in preterm-born adolescents and term-born adolescents with ADHD during rest. During CPT-OX, preterm-born adolescents resembled controls. Increased delta power during rest may be a potential general marker of brain trauma, pathology or neurotransmitter disturbances.The online version of this article (doi:10.1007/s00787-017-1010-2) contains supplementary material, which is available to authorized users. One individual was excluded because of IQ <70. Eight preterm-born individuals met diagnostic criteria for a research diagnosis of ADHD. Since here preterm birth is investigated as a potential risk factor for ADHD, preterm-born individuals who demonstrated high levels of ADHD symptoms were not excluded from the analysis .ADHD and control sibling pairs, who had taken part in our previous research , were inAt follow-up, six participants from the ADHD–sibling pair sample were excluded from the group analyses because of missing parent ratings of clinical impairment. Therefore, their current ADHD status could not be determined. Two additional participants from the ADHD–sibling pair sample were excluded because of drowsiness during the cognitive task. Two participants with childhood ADHD, who did not meet ADHD symptom criteria but met clinical levels of impairment at follow-up, were excluded to minimise heterogeneity in the ADHD sample. Six control participants were removed from the analyses for meeting DSM-IV ADHD criteria based on the parent-rated Barkley Informant Rating Scale . In addiThe final sample consisted of 186 preterm-born participants , 69 ADHD participants  and 135 controls .Participants completed the cognitive-EEG assessments, including an IQ test and clinical interviews, in a single 4.5 h session. Participants completed a 3-min eyes-open resting-state condition (EO) as well as a 3-min EC resting-state condition prior to performing on a cued CPT (CPT-OX) . QEEG dihttp://www.neurobs.com). EEG data were analysed using Brain Vision Analyzer 2.0 . Researchers were blind to group status during EEG pre-processing and analysis. Raw EEG recordings were down-sampled to 256 Hz, re-referenced to the average of all electrodes and digitally filtered using Butterworth band-pass filters . All trials were also visually inspected for electrical artefacts  or obvious movement, and sections of data containing artefacts were removed manually. Ocular artefacts, corresponding to blink-related and vertical and horizontal eye movements, were identified using the infomax independent component analysis (ICA) algorithm [The EEG was recorded from a 62-channel direct-current-coupled recording system (extended 10–20 montage), using a 500-Hz sampling-rate and impedances under 10 kΩ. FCz and AFz were the recording reference and the ground electrodes, respectively. The electro-oculograms were recorded from electrodes above and below the left eye and at the outer canthi. Participants were seated on a height-adjustable chair in a dimly lit video-monitored testing cubicle. Stimuli were presented on a computer monitor at a distance of approximately 120 cm, using the Presentation software package  within each frequency band was averaged across frontal , central  and parietal  regions from individual scalp electrodes to reduce the number of statistical comparisons , theta (3.5–7.5 Hz), alpha 7.5–12.5 Hz), beta 1 (12.5–18.5 Hz) and beta 2 (18.5–30 Hz) frequency band –14 diffe2.5 Hz, bd), which was calculated using the difference in the means divided by the pooled standard deviation, is also reported [d = 0.20 constitutes a small effect, d = 0.50 a medium effect and d = 0.80 a large effect.Data were analysed using random intercept models in Stata, to control for non-independence of the data, i.e. data coming from siblings of one family, in a repeated-measures design, using a ‘robust cluster’ command to estimate standard errors . Regressreported . Accordireported , d = 0.2z = −0.87, p = 0.382), beta 1 , beta 2 , theta  or delta  power  when IQ was included as a covariate. No significant main effects of group emerged for absolute alpha , beta 1 , beta 2 , or theta  power when IQ was included as a covariate.The random intercept model indicated no significant main effects of group for absolute alpha , theta  and delta  power. No significant main effects of condition were found for absolute alpha  and beta 1  power. Significant main effects of condition arose for absolute beta 2 , theta  and delta  power when IQ was included as a covariate. No significant main effects of condition were found for absolute alpha  and beta 1  power when IQ was included as a covariate.Significant main effects of condition arose for absolute beta 2 , beta 1 , beta 2  and theta  power. The random intercept model further indicated no significant main effects of site for absolute delta power . Significant main effects of site were found for alpha , beta 1 , beta 2  and theta  power when IQ was included as a covariate. The random intercept model further indicated no significant main effects of site for absolute delta power  when IQ was included as a covariate.Significant main effects of site were found for alpha  , beta 1 , beta 2  or theta  power. When IQ was included as a covariate, the random intercept model yielded a significant group-by-condition interaction for absolute delta power , but no significant group-by-condition interactions were found for absolute alpha , beta 1 , beta 2  or theta  power.The random intercept model yielded a significant group-by-condition interaction for absolute delta power (01) Fig. . No signz = 2.35, p = 0.019) and a significant group-by-condition-by-site interaction was found for absolute delta power . No other significant interactions were found. When IQ was included as a covariate, a significant group-by-site interaction was also found for absolute beta 1 power  and a significant group-by-condition-by-site interaction was found for absolute delta power . No other significant interactions were found when IQ was included as a covariate.A significant group-by-site interaction was found for absolute beta 1 power , with moderate effect size (d = 0.31), but not compared to the ADHD group . As previously reported [t = 4.56, p < 0.001), with moderate effect size (d = 0.32). During CPT-OX, the preterm and control groups did not differ significantly with regard to delta power. However, the ADHD group showed significantly higher delta power compared to both the control  and preterm  groups during CPT-OX, with moderate-to-large effect sizes . In the ADHD group, increased delta power during CPT-OX was significantly correlated with poorer cognitive performance in the CPT-OX, namely with increased MRT , RTV , number of OE  and number of CE . In the preterm group, delta power during CPT-OX was not significantly correlated with CPT-OX MRT , RTV , OE  or CE . In the control group, delta power during CPT-OX was not significantly correlated with CPT-OX performance timing on MRT  or RTV , but delta power increases showed a significant association with poorer CPT-OX performance on accuracy measures OE  and CE . When IQ was included as a covariate, the preterm group also demonstrated higher delta power during EO compared to the control group , with moderate effect size (d = 0.30), but not compared to the ADHD group . As previously reported [t = 1.44, p = 0.151), with small effect size (d = 0.19).Post‐hoc regression analyses revealed significantly higher delta power during EO in the preterm group compared to the control group , as well as a significant increase in delta power from EO to CPT-OX in the ADHD group . No significant change from EO to CPT-OX was found in the control group  , RTV , OE  or CE . Since no significant change from EO to CPT-OX was found in the control group, correlations between change in delta power and cognitive-performance measures were not run.Post‐hoc regression analyses further demonstrated a significant decrease in delta from EO to CPT-OX in the preterm group , but not CPT-OX . When IQ was included as a covariate, DIVA ADHD symptom scores in the preterm group were significantly positively correlated with delta power during EO , but not CPT-OX .DIVA ADHD symptom scores in the preterm group were significantly positively correlated with delta power during EO . Excluding females from the analyses did not alter the results either .In this study investigating the relationship of EEG indices of cortical activity in preterm-born adolescents, term-born adolescents with ADHD and term-born controls, the preterm group showed higher absolute delta power compared to controls during the resting-state condition, as observed in the ADHD group . No signIncreased delta power during resting state was observed in the preterm group, similar to the ADHD group , with boIn contrast, no significant differences in delta power arose between the preterm and control groups during CPT-OX, whereas the ADHD group demonstrated significantly higher delta power compared to the preterm group during CPT-OX. Concurrently, no significant correlation between parent-rated ADHD symptoms and delta power were found in the preterm group during CPT-OX. The association of increased CPT-OX delta power with poorer CPT-OX task performance, particularly in the ADHD group, suggests that delta power not only reflects impairment during the resting state in the preterm group, but also the impairment of the ADHD group during the attentional challenge during CPT-OX task performance, and thereby supports the finding of partly distinct profiles of impairment in these two groups. While delta power significantly decreased in preterm-born individuals from the rest condition to the task condition, the ADHD group showed an increase in delta power and no significant change in delta power from EO to CPT-OX was seen in the control group. The findings, therefore, suggest differences in brain function between preterm-born individuals and individuals with ADHD during CPT-OX, as well as differences in task-dependent modulation of absolute delta power. Pertinently, delta power has been suggested to play a role in the modulation of the default mode network (DMN) , which iMoreover, power in the delta band was significantly higher in the ADHD group compared to controls during both the resting-state  and the A few limitations should be considered along with the present results. First, we examined cortical activation for fixed frequency bands. While some researchers have advocated abandoning fixed frequency bands , the groOur results provide some of the first QEEG evidence for commonalities in oscillation patterns in the delta range during rest, but differences with regard to delta power during CPT-OX and rest-to-task transition effects, between preterm-born adolescents and term-born adolescents with ADHD. Overall, our results suggest that preterm birth may present a risk factor for both ADHD and additional impairments. This vulnerable population may, therefore, benefit from routine psychiatric screening to facilitate early psychological referral. As this is one of the first studies to directly compare preterm-born adolescents to term-born adolescents with ADHD and term-born controls on measures of cortical activation, these findings require replication in larger-scale studies. Future studies should build on these results by also investigating the relationship between preterm birth and ADHD and associated neurocognitive impairments at various developmental stages such as in very early childhood during the development of neural networks and in mid-childhood when ADHD is typically diagnosed.Supplementary material 1 (DOCX 16 kb)Supplementary material 2 (DOCX 25 kb)Supplementary material 3 (DOCX 21 kb)Below is the link to the electronic supplementary material.


At present, there are no well-validated biomarkers for attention-deficit/hyperactivity disorder (ADHD). The present study used an infrared motion tracking system to monitor and record the movement intensity of children and to determine its diagnostic precision for ADHD and its possible associations with ratings of ADHD symptom severity.A Microsoft motion sensing camera recorded the movement of children during a modified Go/No-Go Task. Movement intensity measures extracted from these data included a composite measure of total movement intensity (TMI measure) and a movement intensity distribution (MID measure) measure across 15 frequency bands (FB measures). In phase 1 of the study, 30 children diagnosed with ADHD or at subthreshold for ADHD and 30 matched healthy controls were compared to determine if measures of movement intensity successfully distinguished children with ADHD from healthy control children. In phase 2, associations between measures of movement intensity and clinician-rated ADHD symptom severity  were examined in a subset of children with ADHD (n = 14) from the phase I sample.Both measures of movement intensity were able to distinguish children with ADHD from healthy controls. However, only the measures linked to the 15 pre-determined 1 Hz frequency bands were significantly correlated with both the CGI scores and ADHD-RS total scores.Preliminary findings suggest that measures of movement intensity, particularly measures linked to the 10–11 and 12–13 Hz frequency bands, have the potential to become valid biomarkers for ADHD.The online version of this article (doi:10.1186/s13034-016-0135-2) contains supplementary material, which is available to authorized users. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder, with an estimated prevalence rate of 5.3% worldwide . In the As a result, researchers have become increasingly interested in identifying objective assessment procedures for ADHD that are comparable to the “gold standard” and are more likely to put into practice by clinicians. One approach that has gained traction in recent years is the use of motor tracking systems during neuropsychological tasks of attention and response inhibition. Examples include the use of infrared motion tracking systems that record the vertical and horizontal position of reflectors while children complete a continuous performance task –13, or aparent ratings of ADHD symptom severity .After applying the FDR adjustment, 12 out of 15 frequency bands were correlated with the CGI-S scores and 10 out of 15 bands were correlated with the ADHD-RS total scores, 10 out of 15 bands were correlated with the ADHD-RS hyperactivity subscale and 7 out of 15 bands were correlated with the ADHD-RS inattentive subscale. The 10–11 and 12–13 Hz frequency bands had the strongest correlations with the ADHD-RS  and CGI-S scores  and a movement intensity distribution measure across 15 frequency bands (FB measures)] were able to distinguish children with ADHD from healthy controls. However, only the measures linked to the 15 pre-determined 1 Hz frequency bands were significantly correlated with both the CGI scores and ADHD-RS total scores. The 10–11 and 12–13 Hz frequency bands had the strongest correlations with these ADHD symptom severity measures. Both of these frequency bands were also significantly associated with the inattentive and hyperactive/impulsive subscales of the ADHD-RS. The following discussion considers potential implications for these findings, limitations of this study’s design, and future research directions.The first phase of this study examined the discriminating capabilities of our movement intensity measures with respect to children with ADHD and healthy control children. Our results aligned well with prior studies using other measures extracted from movement data, as children with ADHD performed less well and engaged in more movement than healthy control children when completing a neuropsychological task of attention and response inhibition while their body movements were recorded , 29. In might be an effective biomarker for children with ADHD at the individual level. More specifically, we are interested in determining whether measures of movement may contribute to a clinician’s ability to diagnose, evaluate, and monitor a disease, as well as track an individual’s response to treatment [It is also worth noting that the measure of movement intensity used in this study achieved a better classification accuracy than did a functional neuroimaging procedure using functional near-infrared spectroscopy (fNIRS) during the course of a Go/No-Go task . This sureatment , 23.clinician-rated measures of ADHD symptom severity were used, which are considered more objective than parent or teacher ratings. In contrast, the Go/No-Go performance measures failed to significantly correlate with any measures of ADHD symptom severity. These findings underscore the potential value of monitoring movement intensity associated with body movements, over and above neuropsychological tasks of attention and response inhibition, to objectively assess ADHD symptom severity over time and in response to treatment. However, our results need to be replicated by comparing the discriminating capabilities of the movement intensity measures to other neuropsychological tasks  before any firm conclusions can be made.The second phase of this study was aimed to further examine the usefulness of measures of movement intensity as potential biomarkers for ADHD by looking at associations between these movement intensity measures and ADHD symptom severity. As predicted, our measures of movement intensity were significantly correlated with overall ADHD symptom severity in addition to symptoms of hyperactivity/impulsivity and inattention whereas movement measures isolated to one location of the body are not . Indeed,Another novel approach used in this study concerns the potential value of movement intensity measures that are linked to specific frequency bands. Our preliminary data indicate that the 10–11 and 12–13 Hz frequency bands are particularly promising. One possible explanation for the strong correlations found between these specific frequency bands and clinician ratings of ADHD symptoms is that the high frequency signals, after Fourier transformation, reflect minor waves of movement intensity that are associated with small movements like fidgeting actions of the fingers or partial body discordant movements. Such a possibility highlights the sensitivity of this particular measure and its potential clinical utility.Another finding that deserves some attention is that the total movement intensity measure did not correlate with most measures of ADHD symptom severity. A possible explanation for this finding could be that the body movements associated with ADHD were only reflected in a portion of the frequency bands and the total movement intensity is the sum of all frequency bands. This also provides preliminary support that a frequency domain perspective may be a more refined approach to monitor ADHD-related body movements.ADHD is frequently comorbid with other neurodevelopmental and neuropsychiatric disorders including oppositional defiant disorder, conduct disorder, Tourette syndrome, depression, anxiety disorder, and learning disorders . Future In this study, we recruited participants with ADHD across all diagnostic presentations. However, we did not compare differences in movement intensity across presentations because of our limited sample size. Future research should consider determining whether or not our movement intensity measures are capable of differentiating children across ADHD presentations. Longitudinal studies are also needed to examine the test–retest reliability of these measurements as well as their ability to monitor symptom severity over time. Indeed, a key question concerns the sensitivity of this measure to detect clinical improvement following treatment. Assessing simultaneously measures of movement intensity and fNIRS in regions identified in the right prefrontal cortex during a Go/No-Go task, as was done in a previous study, might be another promising line of research .With respect to study limitations, we compared our movement intensity measures to a multi-method clinician-driven method of diagnostic classification, which is an approach commonly used in clinical trials , 18, 46;Locomotor activity and movement intensity are emerging as core constructs in our understanding of ADHD. In this study, movement intensity measures extracted from body movement data by an infrared motion-sensing camera during a Go/No-Go task was found to distinguish children with ADHD from typically developing children and to be highly correlated with clinician ratings of symptom severity. These results suggest that using infrared motion detecting systems to calculate measures of movement intensity has the potential to become a useful clinical tool that may have several advantages over traditional approaches. Specifically, these methods have the potential to be more time and cost efficient than the “gold standard” of ADHD assessment, thus enhancing the likelihood of clinicians making use of this objective indicator without relying on single informant measures that are subject to biases. These advantages highlight the importance of replication studies, as movement intensity measures extracted from body movements may prove to be a new behavioral biomarker of ADHD.