Attention-deficit/hyperactivity disorder (ADHD) is a common neuro-psychiatric problem, affecting 7-9% of children. Pharmacological interventions are widely used with behavioral treatments in ADHD. Still, the origin of ADHD is unclear, limiting pharmacological effectiveness and making adverse effects common. The use of complementary and alternative medicine (CAM) has increased, especially for developmental and behavioral disorders, such as ADHD. CAM is used by 60-65% of parents of children with ADHD to relieve ADHD-associated symptoms and to avoid the side effects of conventional medication. Acupuncture has been widely used to treat patients with ADHD, but the available evidence of its effectiveness is insufficient. Our aim was to evaluate the effectiveness and safety of acupuncture in patients  with ADHD (any subtype) compared to the waitlist control.This study is a waitlist controlled open trial. We used a computer generated randomization scheme. This randomised, controlled trial had two parallel arms . Each arm consisted of 40 participants. The acupuncture group received acupuncture treatment two times per week for a total of 12 sessions over 6 weeks. Post-treatment follow-up was performed 3 weeks later to complement the 12 acupuncture sessions. Participants in the waitlist group did not receive acupuncture treatments during the first six weeks but were only required to be assessed. After 6 weeks, the same treatments given to the acupuncture group were provided to the waitlist group. The primary outcome of this trial included differences in Korean version of ADHD-Rating Scale (K-ADHD-RS) before randomization, 3 weeks and 6 weeks after randomization, and 3 weeks after completing the treatment.Subjective measurements, like K-ADHD-RS, are commonly used in ADHD. Although these measurements have adequate reliability and validity, lack of objective assessment in ADHD may lead to some disputes, like parental placebo effects. More objective measurements, like Computerized Neurocognitive function Test (CNT) in this study, are needed in ADHD trials. Furthermore, this trial will provide evidence for the effectiveness of acupuncture as a treatment for ADHD.Clinical Research Information Service (CRiS) KCT0000019 Attention-deficit/hyperactivity disorder (ADHD) is a common problem, affecting 7-9% of children. The defining features of ADHD are inattention, hyperactivity, and impulsivity . There iThe widespread use of stimulant medications for ADHD, such as methylphenidate (MPD) and dex-amphetamine, is thought to enhance short-term behavioral, academic, and social functioning . HoweverThe use of CAM therapies has increased, especially for developmental and behavioral disorders such as ADHD ,13,16-18Acupuncture can change brain activity -35. A brThere are a large number of studies of the clinical efficacy of acupuncture in ADHD published globally, especially in China, but not all demonstrate a beneficial effect on ADHD ,23,24,36The present study aimed to evaluate the effectiveness of acupuncture in patients with ADHD (any subtype) compared to waitlist control and to evaluate the safety of acupuncture in patients with ADHD (any subtype).A 6-week, randomised, waitlist controlled trial of acupuncture for the treatment of ADHD in children/adolescents is being conducted at Kyung-Hee Oriental Medical center, Seoul, Korea. All screening appointments and study visits occur in the neuropsychiatry clinic for outpatients. This study was ethically approved by the Kyung-Hee Korean Medical Center Institutional Review Board, and was registered with the Clinical Research Information Service (CRiS) (KCT0000019) as a waitlist controlled, randomised clinical trial. This study had two parallel arms (acupuncture and waitlist group) with a 1:1 patient allocation ratio (40 participants per arm).The providers went through 6 years of regular Korean medical college education and each was licensed a Korean Medical Doctor (KMD) degree. All the KMDs have undergone acupuncture safety education. These practitioners were chosen on the basis of their expertise in the field, their certified status and agreement to abide by the study protocols. Every practitioner is an apprentice doctor of "Department of Neuropsychiatry, College of Korean medicine, Kyung-Hee University" during this trial period.Parents were initially screened by phone, and their children were included in the study if the inclusion criteria were met. The inclusion criteria includes being between 7-18 years of age, having a diagnosis of ADHD (any subtype) according to Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria and having an informed verbal and written consent from parents and participants. It did not matter whichever intervention  was used, if there were not any change of ADHD treatments/symptoms for the past 2 weeks. Exclusion criteria are a diagnosis of a developmental disorder, past history of epilepsy, the presence of another neurotic disorder, pregnancy, and any changes in medications during the course of the study. During waitlist period, a CGI-I score ≥6, is a cue for the participant to stop waiting and to drop-out.DSM-IV ADHD diagnostic criteria ,37 were The primary outcomes for the study were changes in ADHD symptoms from baseline to week 6 (or from week 6-12) as measured by the K-ADHD-RS . The K-AThe Clinical Global Impression (CGI) rating scale is also a commonly used measure of symptom severity, treatment response, and the efficacy of treatments in treatment studies of patients with mental disorders . The CliThe Korean version of Child Behavior Checklist (K-CBCL) was used at week 3 and 6 . CBCL has been proposed as a non-ideological measure to characterize comorbidity in individuals with ADHD ,43. The The Frankfurt Attention Inventory (FAIR)  measurin© Sample size calculations are performed to determine the number of participants needed to detect effect sizes similar to those that have been reported in recent ADHD medication trials . This sthttp://www.ebombit.com and happiend.tistory.com. Short, text-only advertisements were also placed on several ADHD parents' internet community sites for free. As part of the informed consent forms, the parents of the participants were advised that they were free to withdraw their child/children from the study at any stage without any consequences.Recruitment for the study commenced in July 2010 and the first participant was enrolled in July 2010. Participant recruitment is ongoing. Each participant is qualified and enrolled into the study separately, and has their own start date. The study end-point goal is December 2011. Paid advertisements were placed in free-newspapers with metropolitan-wide circulations. Paid advertising bills were also inserted between the pages of the morning newspaper. Websites advertisements were placed on several blogs for free, including Group A (acupuncture group) continued with their existing program and the acupuncture protocol was added to their regimen. Group W (waitlist group) continued with their existing program and the waitlist protocol was added to their regimen. The participants in group A attended a clinical facility for the first 6 weeks and received 12 treatments (two times per week) for approximately 20 minutes. During this first 6-week period, group W consisted of children who continued with their existing ADHD treatment regimen as prescribed by their pediatrician, clinical psychologist and/or medical doctor. Then, the participants in group W were scheduled for another 12 treatments over the next 6 weeks .Acupuncture originated in ancient East Asia approximately 2,500 years ago and is a key component of traditional Korean medicine or traditional Chinese medicine. Acupuncture techniques involve insertion of needles and the stimulation of the needles may involve manual, electrical, heat, laser or other forms of stimulation .http://www.dbneedle.com; Seoul, Korea) are used. This treatment is conducted two times per week for 6 weeks. There are no co-interventions without a life-style education for their parents. An education for parents is conducted during visits in weeks 3 and 6.For every treatment visit, participants are treated with 13 acupuncture points  . After the waiting endpoint, participants will similarly be given acupuncture treatment for 6 weeks without an additional life-style education for parents.One of the advantages of acupuncture is that the incidence of adverse effects is substantially lower than that of many drugs used for the same conditions . In a reThe trial protocol was reviewed by the Kyung-Hee Korean Medical Center Institutional Review Board. We prepared two types of consent forms, one for participants who are 7-13-years-of-age (explained in easier words) and another for those who are 14-18-years-of-age. For 7-13-year-old participants, a "comprehension check form" is used to confirm their full understanding. All children participants make their own decisions about participation in a clinical trial. All parents of the participants are issued with duplicate copies of the informed consent forms, with the original copies kept by the hospital. The informed consent form conveys the following information: names of the chief investigator and supervisors; the name of the hospital and the department conducting the research, a brief description of the control and treatment groups, the duration of the study, the questionnaires used, the Ethics approval, the right to withdraw their child at any time, and the fact that the results of the study will be disseminated via conferences and publications while maintaining the child's privacy.2 for categorical variables. Every analysis conducted using the SPSS software (SPSS 12.0KO for Windows©), and performed among two randomised  groups and their stratified  sub-groups. The primary analysis will compare outcomes for each primary and secondary outcome measure among the groups to estimate treatment effect with 95% confidence interval (CI). An intention-to-treat (ITT) analysis will be undertaken of the 3-week and 6-week (respectively 9-week and 12-week) data from the K-ADHD-RS, due to some participants who commence the study but do not complete.Tests of potential differences across study groups on demographic and clinical history variables were performed by means of analysis of covariance (ANCOVA) for continuous measures and Pearson χWe have a presented the design and the protocol for the randomised controlled trial of acupuncture for childhood ADHD. The participants of this study will have acupuncture added to their existing medical regimen  or no previous therapy at all, and will be monitored for changes in their outcomes  in the short-term (3 and 6 weeks) and during a 9 week follow-up. Completion of this trial will help provide the answer to the question "Does acupuncture have a role to play in the management of children with ADHD?" Results of this trial will be disseminated at the completion of the study.This is the first acupuncture trial protocol study in ADHD. Case studies of acupuncture effects for ADHD already exist, especially in China, but trial protocols are not precisely described. Our protocol will help to make better quality acupuncture studies for ADHD. Furthermore, we tried to gather objective measurements using CNT40. Subjective measurements, like K-ADHD-RS in this study, are commonly used in ADHD and have adequate reliability and validity. But lack of objective measurements in ADHD may lead to some disputes like parental placebo effects.In traditional Korean medical theories, the insufficiency of yin, results in an excess of yang. The imbalanced condition of the whole body leads to impaired mental symptoms like attention deficit, hyperactivity and impulsivity. Thirteen acupuncture points have been chosen in this context. The acupuncture points located on the head region takes a main role for controlling the spirit. Qi of five viscera and six bowels belong to the head region. For balance of the whole mind and body, acupuncture points in the head region are essential. Baihui (GV20), Sishencong (EX-HN1) are representative points for the head region. Quchi (LI11) takes a role in the elimination of excessive yang and Sanyinjiao (SP6) supplements insufficient yin. It yields a better mental balance. Hegu (LI4), Taichong (LR3) assists in harmonious circulating qi and blood.One limitation of this study involves the waitlist for the controlled group. Many researchers commonly prefer placebo controlled designs to the waitlist ones in randomised control trials. Placebo effects of acupuncture were actively studied in many articles and sham acupuncture is a representative method for an acupuncture placebo tool. But there is a lack of consensus on the most valid approach to establishing an acupuncture placebo. So, important aspects of the placebo acupuncture control need to be considered. "Inert" is the main topic in placebo acupuncture control. Placebo acupuncture strategies mainly consist of superficial  insertion, non-acupuncture insertion points insertion, and sham acupuncture. But each approach has some defects. First, a superficial  insertion is not a real placebo method because it induces peripheral sensory stimulation. It does not seem possible to insert acupuncture needles without any sensory stimulation ,65. In fNot separating assessor from randomization is an additional limitation. Every measurement was assessed by the person who conducted the screening phase, so as not to be blinded from randomization. Although we tried to maintain an objective standpoint, we could not exclude observer bias, which all researchers brought to their work and which helped to determine their method of research and their observations. To minimize this bias, we involved objective ADHD measurement tools, like CNT40 and FAIR.Finally, a paper case record form (CRF) was used in this study. These days, electronic case record form (e-CRF) system, like the Clinical Data Interchange Standards Consortium (CDISC) e-CRF, is become preferred because of its improved quality and efficiency in trial study. In July 2010, the Korea CDISC Coordination Committee (K3C) started making standard e-CRF forms, but we used paper CRF instead, due to insufficient e-CRF infrastructure. Paper CRF may lead to data loss and input errors. The Kyung-Hee Korean Medical Center Institutional Review Board strictly supervised data storage and management. We also reexamined the inputted data.Subjective measurements, like K-ADHD-RS, are commonly used in ADHD, and have the best evidence. Although these measurements have adequate reliability and validity, lack of objective assessment in ADHD may lead to some disputes, like parental placebo effects. More objective measurements, like the presently used CNT40, have to be validated in ADHD trials. Furthermore, as an evidence-based treatment in ADHD, acupuncture has little evidences compared with conventional pharmacological or psychosocial treatment. This study will give some evidence for the effectiveness of acupuncture as an add-on treatment in treating children with ADHD.ADHD: Attention Deficit Hyperactivity Disorder; CAM: Complementary and Alternative Medicine; DMPFC: Dorsomedial Prefrontal Cortex; FDG-PET/CT: Fluorodeoxyglucose Positron Emission Tomography combined Computed Tomography; K-ADHD-RS: Korean version of ADHD-Rating Scale; CRiS: Clinical Research Information Service; MPD: methylphenidate; KMD: Korean Medical Doctor; CGI: Clinical Global Impression rating scales; CGI-S: Clinical Global Impression severity scale; CGI-I: Clinical Global Impression improvement scale; K-CBCL: Korean version of Child Behavior Checklist; FAIR: The Frankfurt Attention Inventory; MV: marker value; PV: performance value; QV: quality value; CV: continuity value; CNT: Computerized Neurocognitive function Test; CPT: Continuous Performance Test; CPM: Colored Progressive Matrices; SPM: Standard Progressive Matrices; K-CPRS: Korean version of Conners' parent Rating scale; K-IOWA: Korean version of IOWA-Conners Rating scale; group A: acupuncture group; group W: waitlist group; SD: Standard Deviation; GV: Governor Vessel; EX-HN: Extra Points of Head and Neck; LI: Large Intestine Meridian; SP: Spleen Meridian; LR: Liver Meridian; B-cun: proportional bone cun; WHO: World Health Organization; CI: confidence interval; ITT: Intention-To-Treat; CRF: Case Record Form; e-CRF: Electronic Case Record Form; CDISC: Clinical Data Interchange Standards Consortium; K3C: Korea CDISC Coordination.The authors declare that they have no competing interests.SHC conceived the research project. SHC, SSH designed the study. SSH designed and tailored the protocol for the ADHD cohort. All authors contributed to the writing of the manuscript. All authors read and approved the final manuscript.


Low birth weight (LBW) is one of the leading causes of adverse perinatal outcomes and is closely related to neonatal disease and death. The incidence of LBW has been increasing. The aim of this study was to investigate the current incidence rate and factors affecting low birth weight infants and perinatal outcomes of full-term low birth weight infants in mainland China.This paper describes a retrospective analysis of children born in 39 hospitals of different types in 14 different provinces, municipalities, and autonomous regions in seven districts within China throughout 2011. The data were first collected in hardcopy format and then entered into computer network databases. Data covering a total of 112,441 cases were collected. Cases were excluded if data were incomplete and in the case of miscarriage before 24 weeks of gestation, multiple pregnancies, or induction of labor due to fetal malformation, intrauterine death, and other reasons, leaving a total of 101,163 cases. SPSS 18.0 and SAS 9.2 statistical packages were used to analyze the collected data.According to this research, the incidence of LBW in mainland China was 6.1%, which is higher than the 5.87% reported in 2000, and it varied across different areas. The incidence of LBW was significantly higher in tertiary care hospitals than in secondary care hospitals. LBW was found to be associated with maternal age of less than 20 years, low level of maternal education, previous histories of adverse pregnancies, and with pregnancy comorbidities and complications, such as hypertensive disorders during pregnancy, anemia, oligohydramnios, premature rupture of membranes, and gestational diabetes. The rates of stillbirths, severe neonatal asphyxia, and deaths among full-term LBW infants were 2.42%, 0.83%, and 3.49%, respectively. The rates of stillbirths and neonatal deaths among full-term LBW infants born by caesarean section were 0.5% and 1.0%, respectively, which was lower than vaginal delivery.The incidence of LBW has increased in China. LBW is a leading cause of adverse pregnancy outcomes. Health care during pregnancy and management of high-risk factors for LBW may reduce the incidence of LWB and the death rate of LBW infants. LBW refers to birth weights below 2500 grams. It is one of the major causes of adverse perinatal outcomes and death. A study has shown that neonatal death among infants weighing 1500–2500 grams is 20 times higher than among infants of normal weight . The incThe current report was performed in mainland China. It is a multi-centered, large sample cross-sectional study. The present paper discribes a retrospective analysis that was performed on 112,441 babies delivered in 2011 and their mothers. Clinical data were obtained from 14 provinces, municipalities and autonomous regions within China , covering 39 hospitals of different levels. The hospitals included 12 tertiary care general hospitals, 7 tertiary care specialty hospitals, 8 secondary care general hospitals, and 12 secondary care specialty hospitals : Neonates with birth weights lower than 2500 grams .Preterm birth (PTB): Delivery after at least 28 weeks (≥196 days) gestation but no more than 37 weeks (≤258 days) gestation [Gestational diabetes mellitus (GDM): GDM refers to various degrees of abnormal glucose tolerance occurring or found for the first time during pregnancy. Blood glucose threshold values for fasting OGTT and at 1 h, 2 h, were 5.1, 10.0, 8.5 mmol/L , respectively. If any measurement reached or exceeded these threshold values, the patient was diagnosed with GDM [Data were analyzed using SPSS 18.0 and SAS 9.2 statistical analysis software packages. For qualitative data, the chi-square test was performed; for quantitative data ANOVA was performed; for correlation analysis, multivariate unconditional logistics regression analysis was performed. P < 0.05 was considered statistically significant.In total, 101,163 deliveries ≥24 weeks of gestation were included in the present study. Of these, there were 6135 cases of LBW, resulting in an incidence rate of 6.1%. Out of all cases of LBW, there were 1863 births ≥37 weeks, and the incidence of full-term LBW was 2.0% (1863/93874). Based on gestational age, PTB LBW accounted for 69.6% of all LBW cases, and full-term LBW accounted for 30.4%.The incidence of LBW was highest in Southwestern China (9.4%) and lowest in central China (2.5%). The LBW incidences in all other regions were 5.1-9.0%. There was a significant difference in the incidence of LBW in different regions (P < 0.001). The incidences of LBW in Southwestern China and northeastern China were significantly higher than in other regions. The incidence rates in Beijing and Shanghai, which are large, thriving cities, were 4.9% and 4.2%, respectively. The incidence of LBW in Xinjiang, which is a remote and highly rural region, was 12.9%.Among the 101,163 pregnant women, the incidence of LBW in infants delivered in teriary care hospitals was 7.1% (5523/77338), and the incidence of LBW in infants delivered in secondary care hospitals was 2.6% (612/23825). The incidence of LBW in teriary care hospitals was significantly higher than in secondary care hospitals (P < 0.001).Unconditional logistics regression analysis was performed on possible factors related to LBW occurrence, including maternal age, maternal height, pre-pregnancy weight, body mass index (BMI), pregnancy weight gain, parity, previous history of miscarriage, history of fetal death and stillbirth, drinking, smoking, education level, gestational hypertensive disorders, gestational diabetes, premature rupture of membranes, abnormal amniotic fluid volume, anemia, pregnancy with uterine leiomyomas, heart disease during pregnancy, and other factors. Prescreening using univariate logistics regression analysis followed by unconditional binary logistic regression analysis showed that maternal age ≤20 years, low educational level, history of one or more spontaneous abortions, history of one or more stillbirths, pregnancy-induced hypertension, anemia, premature rupture of membranes, oligohydramnios, preterm birth, and BMI <18.5 were risk factors. In cases of GDM, weight gain was a protective factor  and preterm (<37 weeks), to control for the effects of PTB on pregnancy outcome. Delivery methods used in full-term LBW infants and in full-term infants with normal birth weight were compared. Full-term LBW infants were more likely to have been delivered by caesarian section (61.1%) than full-term infants with normal birth weight (52.9%). The difference was statistically significant (P < 0.001). Of all full-term LBW infants, 41.1% were delivered by emergency cesarean sections. In contrast, only 31.1% of full-term infants with normal birth weight required emergency cesarean sections (P < 0.001).We compared pregnancy outcomes, including complications during childbirth and outcomes of neonatal infants, and full-term LBW infants delivered by different methods. Delivery methods included cesarean section, vaginal birth, assisted vaginal delivery, and assisted breech birth. Because of the small number of cases of assisted vaginal delivery and breech birth, comparisons were only made between cesarean section and normal vaginal delivery. There were significantly fewer stillbirths and neonatal deaths among those who underwent a cesarean section than those who underwent vaginal birth Tables  and 3.Analysis of prognosis of full-term LBW infants and infants with normal birth weight showed the occurrence of stillbirth, severe neonatal asphyxia, and neonatal death to be 2.42%, 0.83%, and 3.49%, respectively, among full-term LBW infants and 0.14%, 0.11%, and 0.14%, respectively, among full-term infants with normal birth weight. Differences between the two groups were found to be statistically significant (P < 0.001). Full-term LBW and adverse outcome of perinatal infants were significantly correlated.According to guidelines published by the World Health Organization (WHO), any neonate with a birth weight below 2500 grams is considered to have LBW. LBW and PTM are leading causes of adverse perinatal outcomes and are closely related to neonatal diseases and deaths. In addition, when LBW infants enter adulthood, they are substantially more likely to suffer from hypertension, diabetes, and other metabolic diseases than individuals of normal birth weight; therefore, increasing the burden on their families and the community ,11. BecaThe total incidence of LBW in the present study increased slightly from 5.87% in 2000, but was substantially lower than that reported in India and Brazil (14.7%) . It was In China, hospitals are managed on a class system based on the level of medical care provided and on personnel and equipment. In the present study, analysis of the incidence of LBW in hospitals of different classes revealed rather large differences. In tertiary care hospitals, that have medical equipment that is relatively up-to-date with health care that is of relatively good quality, the incidence of LBW was found to be relatively high, accounting for 90% of all cases of LBW. In secondary care hospitals, the incidence of LBW incidence was lower than in tertiary care hospitals. This suggests that differences in medical equipment and levels of hospitals in different classes may be relevant. The majority of PTB infants with LBW are transferred to teriary care hospitals where the quality of medical treatment is relatively high, and some women with high-risk pregnancies or pregnancy complications are also transferred to teriary care hospitals.LBW is caused by two leading factors in China, PTB and intrauterine growth restriction. In developed countries, it is caused mainly by PTB; however, in developing countries the main cause is intrauterine growth restriction . In 2000LBW is caused by both direct factors such as pregnancy complications and by indirect factors such as socio-economic development. The factors that contribute to LBW differ across different countries and across different regions within certain countries. Previous studies have reported that maternal age, level of education, race, occupation, family financial status, height, weight, smoking, drinking, health care during pregnancy, history of disease, pregnancy comorbidity, complications, and other factors are all related to LBW ,14. The Pregnancy outcomes of full-term LBW, and PTB and LBW are two major causes of adverse perinatal outcomes, and PTB is the major cause of perinatal deaths. Each year approximately 3 million neonates die of PTB worldwide . When prRegarding the prognosis of LBW, with the development of perinatology, the survival rate of LBW infants has substantially increased. However, some adverse outcomes are still relatively common, especially long-term complications such as cerebral palsy, delayed neurodevelopment, and visial and hearing impairments. These all have adverse effects on adults and their offspring. For these reasons, LBW merits considerable attention. To reduce the incidence of LBW, increases in nutrient intake before conception, proper pregnancy education, and good health care during pregnancy should be fostered, and high-risk factors for LBW should be avoided. This may allow LBW to be prevented or at least diagnosed early and treated properly. In addition, comprehensive assessment of the mother and child situation should be made to allow the selection of a proper delivery method, thus improving the prognosis of LBW neonates.The incidence of LBW in mainland China is currently higher than that reported in 2000. It is lower in economically developed cities and higher in remote, underdeveloped regions. The incidence of LBW is closely correlated with the maternal level of education, age, past history of adverse pregnancies, and pregnancy comorbidities and complications. The prognosis of full-term LBW infants is significantly poorer than that of full-term infants with normal birth weights. Therefore, the incidence of LBW is an important measure of social development, and maternal and child health care. Prevention and treatment of LBW infants are key issues in the fields of eugenics and perinatology. To improve survival and quality of life in developing countries it is crucial to reduce the incidence of LBW.The authors declare that they have no competing interests.YC performed the statistical analysis and prepared the manuscript. WYZ participated in the design and coordination of the study and revised the manuscript. YR and LYZ carried out the data collection. GHL and XW were partially involved in analyzing the data. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2393/13/242/prepubThe additional file is questionnaire of this paper. The questionnaire was designed by obstetric and statistical experts, it included pregnant basic information, history of abnormal pregnancy, pregnancy complications and comorbidities, intrapartum and postpartum, and neonates information.Click here for file


Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that starts in childhood and frequently persists in adults. In a comparison of adults with ADHD and a matched control sample, we previously showed that abnormal inhibitory processing is typically preceded or accompanied by other processing deficits in adult ADHD. We now compare these data further to additional data from first-degree relatives (fathers) of children with ADHD to identify whether this pattern of abnormal processing shares familial influences with ADHD in adults.Using a family design, we compared 20 fathers of children with the combined subtype of ADHD with 21 adults with ADHD combined subtype and 20 controls in event-related potential indices of preparatory states and subsequent response inhibition processing as elicited by a cued continuous performance task.Fathers of children with ADHD exhibited significantly weaker orienting attention to cues and inhibitory processing than the controls but not the ADHD sample.These findings provide evidence for the familial association of attentional orienting and response inhibition processes with ADHD in adults and indicate a familial and neurobiological link between ADHD in children and adults. Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder that persists into adulthood in around 65% of cases and is associated with high levels of clinical, psychosocial and economic burden ,2. ADHD Key requirements for intermediate phenotypes include association with the disorder, indicated by case-control differences, and presence in unaffected first-degree relatives of affected individuals with levels significantly higher than in the general population ,15. A liThe most established finding in the ERP literature on ADHD is that both children and adults consistently display deficits in motor preparation and attentional processes, which precede additional deficits in inhibitory processes -27. In aThe striking similarity of our previous findings on the cue P3, the no-go P3 and the CNV in adults with ADHD  to those21 male adults with ADHD, 20 fathers of children with ADHD and 20 male healthy control adults participated in this study on the basis of informed consent. The joint South London and Maudsley and the Institute of Psychiatry NHS Research Ethics Committee approved the study (086/05). The age range was 18 to 56 years. A one-way ANOVA indicated a significant main effect of group on age . All of the fathers who participated in the current study had a biological child with a DSM-IV combined subtype ADHD diagnosis following a research diagnostic interview . None ofSelf-report data were collected on current and retrospective ADHD symptoms, using the Barkley Adult ADHD rating scales  for all Fathers did not differ from controls in either current or retrospective symptoms whereas ADHD cases differed significantly from both fathers and controls in current and retrospective symptoms Table .Prior to the EEG assessment, participants' IQ was assessed using four subtests of the Wechsler Adult Intelligence Scale (WAIS-II): block design, vocabulary, picture completion and similarities . The IQ The task was a cued CPT with flankers ,32,36. TPerformance measures in the cued CPT flanker task included target reaction time , within-subject variability in reaction times (SD-RT), and the coefficient of reaction time variability , number of hits (target Xs detected between 200 and 1500 ms after stimulus onset), and number of false alarms (responses to letters other than target X). MRT and SD-RT were calculated across correctly answered target trials. Errors were broken down into subcategories .The ERPs were recorded with a sample rate of 500 Hz and cut-off frequencies of 0.1-30 Hz via Nihon Kohden Ag/AgCl cup electrodes (impedances kept below 5 kOhm) fixed to the scalp with electrolyte gel at electrode positions, which included the 19 standard electrodes of the 10-20 system system plus Oz, Fpz and FCz (recording reference) using a Neuroscan recording system. Vertical and horizontal electrooculograms (EOGs) were simultaneously recorded from electrodes above and below the left eye and at the outer canthi. The EEG data were analysed using Brainvision Analyzer (Version 1.05) and, after down-sampling to 256 Hz, were corrected for horizontal and vertical (blinks) eye movements using the Gratton and Coles method . Trials Two ADHD participants were excluded from the ERP analyses due to excessive movements. ERP amplitudes were restricted to leads and time windows for which effects were expected to be largest, based on previous studies  see Fig.no-go-P3 was calculated as the largest peak between 200 and 500 ms at Cz during "no-go" trials (random letters following a cue XOX). The cue-P3 was calculated as the largest peak between 200 and 500 ms at Pz during the presentation of cue (XOX) stimuli. The go-P3 was calculated as the largest peak between 200 and 500 ms at Pz during "go" trials (target OXOs preceded by a cue XOX). The CNV was calculated as the area at Cz between 1300 and 1650 ms during the presentation of cue (XOX) stimuli. The go N2 component was calculated as the largest peak between 150-300 ms at Fz during "go" trials. The no-go N2 component was calculated as the largest peak between 150-300 ms at Fz during "no-go" trials.The ERP latency data were analysed using analyses of variance (ANOVA). The significance of age as a covariate was tested on the ERP data using regression-based analysis and excluded from further analysis if non-significant . FamiliaFamilial analyses on the performance measures were conducted using analyses of variance (ANOVA), with bonferroni analyses of post-hoc effects. As IQ did not differ between groups, we did not include it in analyses. As age significantly differed between the fathers and the other two groups, we initially included age as a covariate in familial analyses; we only report it where significant, as it was dropped from analyses otherwise. We adopted a significance level of p < 0.05 (two-tailed) throughout the analyses and, additionally, report trends (p ≤ .09).Effect sizes (Cohen's d) for the ERP amplitudes were calculated using the difference in the means, divided by the pooled standard deviation of the raw data.Age was not significant as a covariate for any of the cognitive performance measures [all p > 0.51]. Fathers of children with ADHD were intermediate to ADHD participants and controls in all RT measures Table  and mainAge was not significant as a covariate for any of the ERP measures [all p > 0.35]. The groups differed significantly in the latency of the cue-P3  with the ADHD group activating the preparatory process earlier than the control group (p = 0.02) but not the fathers (p = 0.21). No differences emerged in latency between the fathers and controls (p = 1.00) Tables  and 5. AA significant main effect of group emerged for the amplitude of the cue P3  (Figure  = 12.91,A comparison of 20 fathers of children with DSM-IV combined type ADHD, with 21 adult males with DSM-IV combined type as children and meeting criteria for ADHD as adults, and 20 healthy controls, indicates shared familial influences on ADHD in adults and attentional and inhibitory processes, as indexed by the cue P3 and no-go P3 respectively. Fathers of children with ADHD were significantly different from controls but were similar to a clinical sample of adults with ADHD in these two measures. Both genetic and shared environmental influences can contribute to the observed familiality of these measures. However, due to the relatively limited evidence for shared environmental influences on ADHD ,43 and tDespite a strong association between ADHD, in both children and adults, and response preparation, as indexed by the CNV ,25,28,32In terms of task performance, adults with ADHD were slower with more variable RTs than controls . FathersWe also observed that the level of ADHD symptoms reported in the parents of children with ADHD was not significantly increased compared to the control group. Although this might seem surprising given the high familial risks for ADHD there are three potential reasons to explain this observation in our sample. First, the sample size is relatively small and may be underpowered to show a familial effect; secondly, although we did not control for unaffected status among the fathers who were invited to take part in this study, parents with high levels of ADHD symptoms may be less likely to participate in this kind of study; and finally, because self-rated ADHD symptoms in adults are known to show only small to moderate familial/genetic effects in twin studies . The ERPIn contrast, the significant familial effects for the cue P3 and no-go P3 show how sensitive these measures are to the underlying genetic risk for ADHD in adults compared to either the behavioural measures or cognitive performance measures. This suggests that the processes indexed by the cognitive-electrophysiological measures may be particularly important for our understanding of neurobiological processes that underlie risk for ADHD, but replication of these findings is required. Further work is therefore required to understand more about the aetiology of these sensitive markers of genetic risk and their relationship to the development of ADHD. A possible avenue for future research is the use of these measures in classification and discriminant analyses to identify if they are sensitive to genetic vulnerability for ADHD.To test the generalisation of the findings reported here to more typical clinical samples, future studies could include individuals with common psychiatric comorbidities associated with ADHD, compare and contrast ADHD with the major co-morbid conditions and include a wider range of IQs. Another potential limitation in this study was the poor match for age between the fathers of children with ADHD and the ADHD case and control groups. The data do not, however, indicate an effect of age on any of the cognitive or electrophysiological variables used in this study. Further, if the cognitive processes associated with ADHD improve with age, reflecting the general tendency for reduced ADHD symptoms in adults as compared to children, we would expect any bias due to the age differences in the sample to lead to an overall reduction in father-control differences.In conclusion, we obtained evidence for shared familial influences on ADHD in adults and attentional and inhibitory processes indexed by sensitive cognitive-electrophysiological measures. These processes may be particularly useful in studies that aim to further our understanding of the mechanisms that mediate genetic influences on hyperactive-impulsive and attentive behaviours. Further research should aim to clarify whether these represent pleiotropic effects of genes or whether these are intermediate phenotypes that mediate effects between genes and the developmental processes that underlie the onset and course of ADHD throughout the lifespan. Understanding the aetiological influences and interactions of the various processes involved may elucidate predictive indices for clinical outcomes in ADHD that can be used to target interventions and develop novel prevention and treatment strategies.The authors declare that they have no competing interests.GM carried out the EEG assessments, performed the data analysis and drafted the manuscript. BA, TB, DB and AR provided training and supervision in EEG analysis. PA and JK conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.


A randomized and controlled clinical study was performed to evaluate the use of neurofeedback (NF) to treat attention-deficit/hyperactivity disorder (ADHD) in children and adolescents.The ADHD population was selected from an outpatient clinic for Child and Adolescent Mental Health in Norway. Ninety-one of the 275 children and adolescents ranging in age from 6 to 18 years (10.5 years) participated in 30 sessions of an intensive NF program. The reinforcement contingency was based on the subjects’ production of cortical beta1 activity (15–18 Hz). The ADHD participants were randomized into three groups, with 30 in the NF group, 31 controls in a group that was given methylphenidate, and 30 in a group that received NF and methylphenidate. ADHD core symptoms were reported by parents using the parent form of the Clinician’s Manual for Assessment by Russell A. Barkley.Ninety-one children and adolescents were effectively randomized by age, sex, intelligence and distribution of ADHD core symptoms. The parents reported significant effects of the treatments, but no significant differences between the treatment groups were observed.NF was as effective as methylphenidate at treating the attentional and hyperactivity symptoms of ADHD, based on parental reports.Current Controlled Trials NCT01252446 Attention-deficit/hyperactivity disorder (ADHD) is a developmental mental disorder characterized by persistent symptoms of inattention or inattention in combination with hyperactivity and impulsivity. Its prevalence may be up to one in four ,2. The sMany clinical trials have found that neurofeedback (NF) effectively treats the symptoms of ADHD ,13. The NF has been discussed as being an effective ADHD treatment when given alone or in combination with medications . One stuNF is a learning process in which the brain is rewarded for positive changes in its activity . The resDifferent approaches regarding NF treatment have been developed for ADHD ,12,21. TThe lack of large and controlled studies may have limited the use of NF treatments in the clinic -27. ManyIn addition, several non-randomized studies found a large effect size (ES) for attention and a medium ES for hyperactivity , but a rUse of sham feedback (placebo) for evaluating the efficacy of NF in the ADHD population was declared unethical by the University of California, San Diego ,33. ThisThe present study was a controlled and randomized clinical study that included children and adolescents with ADHD, who were followed at a Child and Adolescent Mental Health Clinic in Norway. The aim of the study was to evaluate the effects of NF on the core symptoms of ADHD, including attention and hyperactivity.Over a period of 3 years (2007-9), 628 children and adolescents aged six through 18 years were referred for the treatment of ADHD to the Child and Adolescent Mental Health Clinic, Haugesund Hospital, Rogaland County in Norway. Of these, 285 (45 %) met the criteria for ADHD according to the International Classification of Disease (ICD-10)  has been described in detail in earlier papers ,35. Chil. The children were evaluated using the Wechsler Intelligence Scale for Children (WISC-IV) [All children with ADHD met the following criteria to be included in the study: 1) symptomatology consistent with ICD10 criteria for the diagnosis of ADHD; 2) age 6–18 years; 3) cognitive function above IQ 70WISC-IV) ,37.The children with ADHD were randomly placed into three groups: 1) the NF group received NF; 2) the NF + MED group received NF and methylphenidate (MPH); and 3) the MED group received MPH  and Theta suppression (4–7 Hz) were assessed. The treatment site used was in the central area and unipolar electrodes was placed on the Cz, whereas the ground electrode was placed on the earlobe .NF was conducted three times a week with 30 treatments for each child and adolescent. Each treatment lasted 40 minutes and was separated into pre and post 5-minute baseline periods  and 30 minutes of NF (beta/theta training). Theta activity was defined as 4–7 Hz, alpha activity as 8–12 Hz, SMR activity as 13–15 Hz, beta activity as 16–20 Hz, and electromyography (EMG) activity as 80–150 Hz activity . The eveSubjects in the MED and NF/MED group were administered methylphenidate (MPH) twice per day at the recommended dose 1 mg per kg with the final medication doses from 20 to 60 mg daily doses.1, T2). The baseline evaluation T1 was completed prior to the treatment. The effects of the treatments were evaluated as a change in ADHD core symptoms from T1 to T2. All children underwent post-treatment evaluations approximately 1 week after the NF had been completed (T2).Two core symptoms of ADHD were evaluated. Attention and hyperactivity were evaluated using the Clinician’s Manual for the Assessment of Disruptive Behavior Disorders – Rating Scale for Parents, from Russell A. Barkley . The manThe Regional Ethics Committee on Medical Research approved the project protocol used in this study, and written consent was obtained from all subjects and their parents.χ2 test) were used to investigate the baseline data. The treatment effects were investigated using a general linear model (GLM) for repeated measures, which was implemented for each of the subscales . The model included the raw scores at both time points as dependent variables and the treatment groups as factors. We fitted both an unadjusted model and a model adjusted for sex and age. Even if the adjusted model may be more complete and more reliable, it was reasonable to examine the unadjusted model because of the small sample size and concomitant lack of power in the adjusted model. In the GLM, we estimated both within-subjects contrasts to test treatment-induced changes in the ratings and between-groups effects to test for differences between the treatments. Significant differences were further examined using post-hoc tests. Additionally, we estimated the standardized ES δRM for each treatment change [Basic descriptive methods , exact t change .1-T2) because we wanted an improvement associated with a positive number.Note that we used a negative definition of the treatment changes , a Bonferroni corrections method would be too conservative. As such, we decided to set the significance level to 0.01, as a compromise between a Bonferroni correction and not accounting for multiple comparisons. In the GLM, we investigated only highly correlated variables, thereby reducing the number of comparisons. Therefore, we did not adjust the significance level. All computations were done using PASW 18.There were no significant differences in demographic factors or ADHD core symptoms between the treatment groups at baseline T1) . Additionally, we noted that the MED and NF + MED group had a confidence interval that included 0. The NF group had the largest ES δIn the present controlled and randomized clinical trial, NF treatment seemed to improve the core symptoms of ADHD, as assessed by parental reports. In addition, NF and MPH produced similar improvements.The strength of the present study was the effective randomization by age, sex, and intelligence, and the distribution of ADHD core symptoms (hyperactivity and attention). However, the number of subjects in each treatment group was somewhat low.NF improved attention and hyperactivity symptoms in children and adolescents with ADHD. This is in accordance to findings in other studies, including a study by Kaiser, Thomsen and Othmer that found significant improvements in ADHD symptoms with NF for more than three in four ADHD subjects ,44. We dHowever, regarding the improvement of the core symptoms of ADHD, nonspecific factors may contribute to the positive effects induced by NF ,16. MainEven if we did not find significant differences in the core symptoms of ADHD, we observed a lower ES for the combined treatment for all symptoms. Such a tendency would lie in contrast to previous studies, which found NF and MPH was associated with the best improvements in the core symptoms of ADHD .The results of the present study support the use of NF as an alternative treatment for ADHD, especially in the 20% of children with ADHD who do not respond to medications. In addition, findings from this study support previous suggestions that medications may be reduced when given in combination with other treatments for ADHD .NF produced a significant improvement in the core symptoms of ADHD, which was equivalent to the effects produced by MPH, based on parental reports. This supports the use of NF as an alternative therapy for children and adolescents with ADHD.1. NF improves the core symptoms of ADHD based on parental reports.1. NF and MPH produce equivalent improvements in the core symptoms of ADHD based on parental reports.ADHD = Attention-deficit/hyperactivity disorder; NF = Neurofeedback; MED = Medication.The authors declare no potential conflicts of interests with regard to the authorship or publication of this article.NSD and IBE made substantial contributions to the design, analysis, and interpretation of the data, and they were involved in drafting the manuscript and revising it critically. JA contributed to the statistical analyses and data interpretation. DG acquired the funding and contributed to the study design. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-244X/12/107/prepub


BRCA1 and BRCA2, which are linked to hereditary breast and ovarian cancer. Since that time, Myriad has been a forerunner in the field of personalized medicine through the use of effective commercialization strategies which have been emulated by other commercial biotechnology companies. Myriad’s strategies include patent acquisition and active enforcement, direct-to-consumer advertising, diversification, and trade secrets. These business models have raised substantial ethical controversy and criticism, often related to the company’s focus on market dominance and the potential conflict between private sector profitability and the promotion of public health. However, these strategies have enabled Myriad to survive the economic challenges that have affected the biotechnology sector and to become financially successful in the field of personalized medicine. Our critical assessment of the legal, economic and ethical aspects of Myriad’s practices over this period allows the identification of the company’s more effective business models. It also discusses of the consequences of implementing economically viable models without first carrying out broader reflection on the socio-cultural, ethical and political contexts in which they would apply.In 1996, the US-based biotechnology company Myriad Genetics began offering genetic diagnostic tests for mutations in the genes  Myriad offers genetic diagnostic tests for mutations in these genes, which allow physicians and genetic counsellors to better assess their patients’ risk of developing a hereditary cancer and tailor risk management strategies such as prophylactic therapy to that risk profile. Since this method allows treatment to be chosen based on an individual’s own genetic information, Myriad can be considered a good example of a company involved in the growing field of personalized medicine.Myriad Genetics is a biotechnology company based in Salt Lake City which holds patents on a number of cancer-linked human genes, including BRCA testing to become an uncommon commercial success story in the biotechnology industry. This paper presents a concise look back at the legal, commercial and ethical aspects of four business models that have been part of Myriad’s strategy for its BRCA diagnostics: the initial patenting phase to clear the market of competitors, the use of direct-to-consumer advertising to expand the market, diversification to other geographic regions and a combination of multiple genetic diagnostic tests, and the transition to a model based on trade secrecy in order to preserve an advantage in test accuracy after Myriad’s BRCA patents expire (see Table 1). By studying the long-term benefits and drawbacks of these strategies, a great deal can be learned about their implications within the developing field of personalized medicine.Myriad has come under intense scrutiny due to its choice of business models and role in setting a worldwide precedent for companies involved in genetic diagnostics. Yet despite its involvement in these controversies, Myriad has used its exclusive rights to provide 1.1BRCA1  mutation and approximately 1 in 500 people carries a BRCA2  mutation. These mutations account for about 15% of the extra risk seen in first-degree relatives of patients with breast cancer. Studies have found that BRCA1 mutations lead to a breast cancer risk of 40 to 87% and an ovarian cancer risk of about 16 to 68% by age 70, while BRCA2 mutations lead to a breast cancer risk of 40 to 84% and an ovarian cancer risk of 11 to 27% by that age [Approximately 1 in 800 people carries a BRCA1 and BRCA2 tests in order to draw attention to its services [® to physicians and clinicians, for the price of about $2,400 USD [® Large Rearrangement Test (BART), which costs approximately $700 USD and is ordered by about 65% of BRACAnalysis® purchasers [Myriad Genetics was formed in 1991 by a group of scientists from the University of Utah’s Centre for Genetic Epidemiology, who had been studying breast cancer susceptibility in a large database of Mormon family pedigrees. Their research was partly funded by the National Institutes of Health (NIH) and partly by private investors such as Eli Lilly and Company . Prior tservices . That mo,400 USD . Since 2® to gain a reputation for high-quality genetic tests so that it could build strong affiliations with health care providers, laboratories, and insurers, and eventually begin selling diagnostics for other genes as well [These diagnostics are widely seen as a significant breakthrough in personalized medicine, and many clinicians have expressed a preference for Myriad’s accuracy, price and turnaround time , 8. Myri as well .2. Although its legality has been challenged in many jurisdictions including the United States, the patenting of isolated genes and processes involving these genes  remains a established practice in most countries with strong biomedical research infrastructure [A patent grants its holder a set of exclusive rights over their invention from the date on which the claim is filed . Althougtructure , 10-12.BRCA1 on August 12, 1994 and for BRCA2 on April 29, 1996. These patents were granted on December 2, 1997 and November 17, 1998 respectively [BRCA sequences, as well as related techniques such as gene therapy and the ability to test anticancer drugs on cells and organisms genetically modified to have BRCA mutations [BRCA1 [Myriad filed for its first United States patents on the coding sequences, amino acid sequences and associated primers for ectively , 14. Myrutations , 16. MyrBRCA tests in response to Myriad’s cease-and-desist letters; however, some continued to provide diagnostics under the guise of “research testing” for patients who could not afford Myriad’s prices [BRCA testing in the United States [Myriad began threatening to enforce its US patents in 1998, shortly after its broadest claims had been granted by the United States Patent and Trademark Office (USPTO) . All buts prices . By 1999s prices , 18. ThrThe commercial success of Myriad’s patent enforcement strategy in the United States is demonstrated by the fact that other privately-owned companies continued to follow in its footsteps even after this model had become criticized by some researchers, academics and patient groups in other countries. For example, Athena Diagnostics  notably used aggressive patent enforcement to maintain its monopoly on testing for Alzheimer’s disease predisposition, and PGx Health  has done the same for long-QT syndrome , 17, 20.BRCA1 and BRCA2 patents outside of the United States until several years later; for example, its principal Canadian patents were granted on October 10, 2000 and April 3, 2001, respectively [BRCA1 and BRCA2 tests had to be done either through Myriad or Myriad’s local licensee MDS [However, Myriad’s business model met with substantial resistance in other jurisdictions, even those in which the company was granted patents similar in scope to its US ones . Myriad ectively , 22. Ovensee MDS , 12, 23.nsee MDS , 11.® tests it performs in the United States [BRCA testing to uninsured women who meet certain medical and financial criteria through its financial assistance program [According to Myriad, insurance covers more than 90% of the cost of 90% of the BRACAnalysisd States . Myriad  program . But mos program . Many he program . The res program .Several additional concerns were raised by clinicians and researchers internationally. Although public health care administrators in 2001 had familiarity with kit-based genetic testing, they had not previously experienced business models in which the patent holder retained control of the testing process . They alBRCA genes, engaged in over 100 scientific collaborations, and claims not to have pursued any researchers other than those from the University of Pennsylvania’s Genetic Diagnostic Laboratory, which it believed to be using the test for commercial purposes [Myriad also made some opponents in the scientific community due to the somewhat erroneous impression among researchers and advocacy groups that Myriad would enforce its patents against academic researchers; in fact, it permitted all basic research on the purposes , 17, 26.purposes . ® tests [BRCA genes, this puts them in an ethical bind because they are not allowed to tell women who have contributed to the research about their personal results, even when they may be at high risk [Although it was stated in some interviews and a written memorandum of understanding with the National Cancer Institute (NCI) that Myriad had no interest in enforcing patents against non-commercial research, its position was poorly communicated to researchers , 26. Som® tests . Furtherigh risk . AlthougMyriad has generally chosen not to address these criticisms in academic literature. Its lack of transparency and its assertiveness in sending cease-and-desist letters may also have made it difficult to follow up on its initial positions and overcome these impressions . The neget al. searched newspaper articles in Canada, Australia, the UK and the United States for references to Myriad Genetics and its BRCA patents. Overall, 78% of the articles were predominantly negative, 16% were neutral, and only 6% were positive. Coverage in the United States was the least negative with respect to gene patenting, largely because many stories from Utah reported Myriad’s perspective on the controversy. However, only 56% of the newspaper articles contained multiple perspectives on the issue, indicating the one-sidedness of the discourse [Whatever the underlying causes of this widespread distrust among stakeholders, the resulting negative portrayal of Myriad in the mass media was likely detrimental to its international public image. In 2007, Caulfield iscourse . As a result of this public outcry, the biotechnology industry attempted to portray Myriad as an outlier rather than a representative of a commercially successful business model . Surpris® test  is not currently protected by patents. Myriad has announced plans to add the gene MYH (MutY homolog (E. coli)) to the test, for which it owns the worldwide composition-of-matter and method-of-use patents. This would allegedly allow it to offer a colon cancer diagnostic that is both more sensitive than the competition and protected by patents until 2022 [®, Colaris®, Colaris AP®, Melaris® and Panexia® tests into a single panel called myRisk Hereditary Cancer beginning in 2015. The new test will initially cover twenty-five genes associated with different types of cancer, including eight currently-proprietary ones BRCA1, BRCA2 and MYH [Myriad has also used patenting to reinforce its market dominance on other diagnostics. For example, its Colaristil 2022 . However and MYH .3BRCA testing but not for its other products like colon cancer diagnostics, which are also provided by other companies [One method which Myriad has employed to expand its market in the United States  is the use of direct-to-consumer advertising (DTCA) on a large scale . Indeed,ompanies .While drug advertising in the United States is regulated by the FDA, genetic tests are not subject to the same federal oversight , 30. Alt® referrals increased by over 240% during this period [® began in Boston, Hartford, Providence and New York in September 2007, and expanded to Florida and Texas that October. Gregory Critchfield, the former president of Myriad’s diagnostic laboratory subsidiary, stated that “the return on investment was sufficiently high that it was worthwhile to go to the next region to extend the benefits of testing to those individuals” [1).Myriad ran its pilot DTCA campaign in Denver and Atlanta from September 2002 to February 2003, targeting both women and physicians through television, radio and print media. One health care provider, Kaiser Permanente Colorado, found that BRACAnalysiss period . Myriad’viduals” . Myriad viduals”   began to seek testing unnecessarily [However, Myriad’s campaign also received criticism from clinicians, academics, the mainstream media, and public health agencies such as the Centers for Disease Control . It was  systems , 29. Indessarily . Accordiessarily , and it essarily . ® before a test can be ordered, as well as post-test counselling to determine a management plan [Myriad requires that patients receive counselling from their physicians on the benefits and limitations of BRAC Analysisent plan . Howeverent plan -31. Althent plan , 29, soment plan .42). Myriad’s ability not only to survive but to prosper equates to considerable commercial success in the biotechnology industry: although 8,791 start-ups have been spun out of US universities since the passage of the Bayh-Dole Act in 1980, only 3,927 (45%) were still active in the 2011 fiscal year, including 670 created that year [Despite this criticism, Myriad’s tests have continued to sell very well. Myriad stock prices have performed much better than that of most other personalized medicine companies, increasing by 415% from the end of 2003 to the end of 2008 . In facthat year .Myriad’s estimated revenue of $595 to $600 million USD for the fiscal year ending June 30, 2013 represents a growth of 20 to 21 percent over last year, and in fact it turned its first profit in October , 78. WhiBRCA testing has continued to become more valuable as the company increases its penetration into the large, untapped market of eligible customers [BRCA testing. Indeed, many of Myriad’s business models can be construed as attempts to retain control of a geographically and temporally limited market.According to Myriad executives, ustomers .Yet sincThe patents that gave Myriad the greatest advantages over its competitors begin expiring in 2014 and 2015, although executives have stated that the remaining patents out of the original 24 should provide enough protection to ensure exclusivity until at least 2018, and Myriad’s supplemental BART test provides another layer of protection , 8, 40. ® make up about 74% of Myriad’s total revenue and BART testing represents another 11%, the company also offers other profitable cancer predisposition tests, such as the Colaris® test for colorectal and endometrial cancer, Panexia® for pancreatic cancer and Melaris® for melanoma [® in 2015 [® for prostate cancer aggressiveness and Melapath® for skin biopsy malignancy, as well as thirteen other neurology, dermatology, and autoimmune tests still in development [Although sales of BRACAnalysismelanoma , 6, 41.  in 2015 . Myriad elopment . Myriad elopment . BRCA1 and BRCA2 testing [BRCA1 patent was dismissed by the Federal Court [In order to increase its market overseas, Myriad has developed a distribution network for its tests in 61 countries . Recentl testing , 18, 42. testing . It has al Court . An appe® varies by payer, although it is frequently quoted as approximately $3,120 USD, not including the additional cost of a supplementary BART test [An additional challenge which Myriad may have to face within a few years is the rapidly decreasing price of whole-genome sequencing. The price of BRACAnalysisART test , 8, 26. ART test , 46. HenART test . HoweverART test .BRCA genes would constitute a violation of Myriad’s patents, although a recent paper in Nature Biotechnology presents a compelling argument that current forms of whole-genome sequencing do not produce the isolated sequences claimed by most gene patents [The utility of whole genome sequencing as an alternative to Myriad-style diagnostic tests could also depend on how DNA patents are interpreted and enforced . It is n patents , 46. A t patents .BRCA1 and BRCA2 genes both lack mutational hotspots, diagnostic analysis must cover their entire coding sequences, and thousands of different mutations in them have been identified [BRCA gene are found to have a VUS [Because the entified . Althougentified , 47-49. entified , 47-49. ve a VUS , 47-49. ve a VUS .®.Nevertheless, finding accurate and efficient methods to classify VUSs is becoming an important health issue, since their interpretation is necessary to guide genetic counsellors in identifying risk levels and choosing appropriate management strategies , 50, 51. BRCA test voluntarily provide Myriad with their family medical histories in order to aid in risk assessment, and the company obtains even more data through its policy of free testing for the family members of patients with newly-discovered VUSs [The American Journal of Human Genetics, Community Oncology, Cancer, Cancer Research and other journals, it did not include its analytic algorithms or sequence data. This choice ran counter to pre-existing recommendations by the National Academies, as well as the Uniform Requirements for Manuscripts Submitted to Biomedical Journals which would later be published by the International Committee of Medical Journal Editors [Most patients who use ared VUSs , 52. By red VUSs , 40. Alt Editors . Indeed, Editors , 40.Myriad’s policies make it extremely difficult for other geneticists to construct and update the algorithms necessary to accurately interpret the effects of genetic variants . This giThe European Society of Human Genetics (ESHG) issued a statement claiming that Myriad’s new strategy would give them an unfair advantage against European academic institutions and hinder the progress of personalized medicine . Some crYet Myriad has a number of advantages which will endure even if it are forced to drop its patents or accommodate new data access policies, including its efficient laboratory, pre-existing network of health professionals and payers, and trained sales force . Myriad 5BRCA tests have been critically analyzed by experts, adopted by other companies, and since become common practice in the biotechnology industry. As such, Myriad has served as an important indicator in assessing the pros and cons of emerging business models in personalized medicine.Since its formation, Myriad Genetics has been at the forefront of the movement towards personalized medicine and the resulting controversies associated with the commercialization of genetic diagnostic testing. Many of the strategies first employed by Myriad in the context of its BRCA patents, Myriad responded by diversifying its products, adopting the DTCA advertising approach and looking at the possibility of combining tests and applying new method-of-use patents to make its previously-unpatentable products proprietary. Myriad also decided to make an important shift towards a business model that has gotten increasing attention from private biotechnology companies in recent years: the keeping of genetic data and diagnostic results as trade secrets. This last strategy could have great appeal for private companies working in personalized medicine, especially in Europe, where robust intellectual property protection for databases is recognized by law [Myriad did not so much invent new commercialization models as demonstrate a remarkable capacity for adapting existing ones to ensure its survival. The company entered the personalized medicine field with a fairly traditional patenting and licensing strategy, albeit with restrictive licensing terms and proactive enforcement practices aimed at protecting its market dominance. As the effectiveness of this strategy was gradually weakened by political controversy, legal challenges and the natural expiration of the d by law . At a tiBRCA diagnostics, direct-to-consumer advertising is meant to build brand fidelity and data secrecy is meant to prevent other companies from practically testing for BRCA mutations. All three of these practices can help maintain Myriad’s exclusivity over a prolonged period of time, and some could even be seen as attempts to extend its bundle of exclusive rights beyond the twenty-year period of time designated by the patent system.It is worth noting that all three of the principal business models discussed in this paper  have raised ethical concerns relating to two particular areas: Myriad’s methods of securing dominance over the market, and the conflict between the corporate need for profitability and public health. Whereas the aim of patenting and enforcement is to prevent competing companies from offering commercial Meanwhile, much of the criticism directed towards Myriad can be attributed to concerns  that these strategies have enabled the company to set a standard of care that maximizes its revenue but results in health inefficiencies such as cost-ineffectiveness, lack of external quality control, public misinformation, potential overutilization, and patent abuse.Myriad’s opponents have shown singular persistence in denouncing the company’s business practices in scientific and public media. Critics have sometimes benefited  from the high profile taken by the debate and their personal stand against Myriad. Moreover, the intense media coverage led to a polarization of the respective positions. These two factors, as well as the unpopularity of gene patenting, could have contributed to the singling out of Myriad as the representative of biotechnology companies that patent and commercialize human genomic innovations. This, in turn, made it increasingly difficult for Myriad to effectively communicate its position on key ethical and social issues associated with its practices.The preceding comments should not be read as an attempt to set aside the substantial ethical issues raised by some of Myriad’s practices. Although personalized medicine entrepreneurs would do well to take inspiration from Myriad’s business acumen and adaptability, they must also consider the ethical and social pitfalls the company encountered and the associated costs. It is possible that these difficulties did not lie inherently with the different business models used by Myriad, but were instead created by the heavy handed approach sometimes used to implement and promote them. The fact that Myriad unintentionally managed to become the standard example of a biotechnology company embroiled in legal and ethical controversy has undoubtedly led other companies to pursue more cautious patent enforcement strategies while paying more attention to maintaining their public image . It must5.1®, and the potential ethical concerns associated with them, hold true for other examples of personalized medicine.Given the evident importance of Myriad in setting both positive and negative examples for the biotechnology industry, it is important to examine the extent to which the business models used for BRACAnalysis“Personalized medicine” is concerned with the customization of patients’ health care to their medical needs, particularly on the basis of their genetic information. In personalized medicine, genetic diagnostics are typically used to determine the viability of genotype-dependent treatments for patients who have already been diagnosed with a certain disease. Hence, this practice extends beyond mere diagnostic testing to the incorporation of personalized therapeutic measures based on the information uncovered this way. Therapeutic products released alongside genetic tests in this way are referred to as “companion drugs” , 56.® test differs from this norm in two major ways: it is targeted to people at high risk  rather than those who have already developed the disease; and it is not marketed alongside a companion drug. Although many women who are found to be at a high risk of breast cancer are prescribed the drug tamoxifen, this drug is not offered by Myriad and the prescription does not depend directly on the genomic information uncovered by BRACAnalysis®. Many women also choose to undergo prophylactic mastectomies rather than rely on medication, a catchall treatment which falls outside the scope of pharmacogenomics. However, Myriad has recently moved in the direction of the personalized medicine business model by partnering towards the development of a number of diagnostics for companion drugs, such as the HRD test mentioned in the previous section.Myriad’s BRACAnalysis® by Genentech alongside the HercepTest™ diagnostic by Dako) and imanitib mesylate (offered as Gleevec® or Glivec® by Novartis). A good comparison can be drawn between the HercepTest™ and BRACAnalysis®, since both products were developed by start-up companies at approximately the same time for the treatment of the same type of cancer, resulting in a greatly overlapping customer base [Two of the most established drugs used in personalized medicine are trastuzumab  protein, which occurs in approximately 20% to 30% of breast cancer cases and is associated with poorer prognosis , 59. FDAnd BRCA2 . Yet unl® and Gleevec® became very financially successful, both largely as a result of being offered at high prices. According to a recent paper comparing Myriad and Genentech, Myriad was one of the first companies to apply a “blockbuster” financial model to a diagnostic test at a time when the strategy of charging high prices for a patented product was mainly used to recoup the extremely high cost of developing pharmaceuticals [®: one year of treatment can cost $54,000 USD [® [®, Herceptin® was readily approved for funding in Canada due largely to patient enthusiasm over its therapeutic benefits [Herceptineuticals . Genente,000 USD . As a re0 USD [® . Yet unlbenefits . Hence, HER2 tests were difficult to analyze, despite the availability of additional training from their manufacturer [Yet as previously discussed, since Myriad was only offering a diagnostic test they were able to conduct their business without having to comply with the FDA’s regulations for drug development and advertising. Since the HercepTest™ is targeted to a specific subgroup of cancer patients rather than the general population, there was no real necessity for Genentech to conduct DTCA. However, it did conduct a significant information campaign to promote the HercepTest™ among physicians, which ended up raising many of the same concerns that Myriad encountered in their DTCA program: a 2005 study found that one fifth of European physicians surveyed felt that facturer . Apparen®, like Myriad’s earliest patents, expires in the European Union in 2014. Roche has also been focusing on diversification within the field of cancer drugs, including a number of new breast cancer medications [® patent approaching, Dako has been successful in having the HercepTest™ approved by the FDA for new companion drugs, including Genentech’s breast cancer medicines Perjeta® (pertuzumab) and Kadcycla™ (ado-trastuzumab emtansin) [The patent on Herceptinications . The Denications . With thmtansin) , 67. Thi® was approved by the FDA in 2001 as a treatment for chronic myeloid leukemia (CML). CML is characterized by a Philadelphia chromosome resulting from a reciprocal translocation between chromosomes 9 and 22, containing a chimeric gene called BCR-ABL. This gene produces a tyrosine kinase protein seen in 95% of CML patients, which is inhibited by Gleevec®. Hence, the presence of this translocation is used diagnostically as well as therapeutically to measure patients’ response to the drug. Gleevec® also inhibits another kinase called c-KIT, which has enabled its use for patients who are diagnosed with KIT-positive gastrointestinal stromal tumours [Novartis’ drug Gleevec tumours , 68, 69. tumours .®, like BRACAnalysis® and Herceptin®, has come under fire for being overly expensive. When introduced to South Korea in 2001 for the proposed price of 2,886,000 won per month (roughly $2200 USD and 30 times the tablets’ production cost), activist groups claimed that Novartis was trying to overcharge Koreans. Although it offered to pay a third of the outpatients’ costs through the Novartis Patient Fund, critics claimed that the company had based its pricing on the precedent of wealthier countries and had failed to take into account the fact that Korean patients are required to pay 30% of their total medical costs themselves [Gleevecemselves . Like My® so that South Korean companies would be able to produce the drug for lower prices [® and Herceptin®, the patents on Gleevec® begin to expire in 2014, meaning that Novartis has begun to advocate the use of its other leukemia drugs in order to maintain its dominance in that market [® have been mirrored in other personalized medicine products for cancer over a similar time frame. In 2002, civic groups filed a request to waive Novartis’ licence for Gleevecr prices . Althougt market . These eCYP2D6 and CYP2C19 genes, which may affect a patient’s metabolism of tamoxifen when that drug is used to treat breast cancer [Recent trends in the field of personalized medicine such as multiplex testing and drug repurposing have promised to facilitate the increased use of pharmacogenomics in health care. Multiplex testing allows clinicians to easily retrieve information about a large number of potential biomarkers; for example, Roche’s AmpliChip CYP450 Test uses approximately 240 unqiue probes to detect variants in the t cancer . MultiplDrug repurposing, which involves the introduction of pre-existing drugs for new clinical applications, is a cost-efficient way to improve the availability of treatments for the many disease subgroups uncovered through the use of genetic diagnostics. This has the potential to be a particularly useful technique in the context of health care, since personalized medicine often allows the use of drugs for patients with specific genotypes that would not be considered sufficiently effective to be approved for the general population . Given tBRCA genes is an enormous topic in its own right and beyond the scope of this paper, it is also worth mentioning that Myriad is poised to set yet another important precedent for the field of personalized medicine and for intellectual property law when the validity of its gene patents is decided by the Supreme Court of the United States. It is not likely that the results will greatly affect Myriad’s business plan, as those patents will be almost expired by the time they could be affirmed or overturned. Myriad’s choice to move toward a trade-secret based model, build brand recognition through direct-to-consumer advertising, and diversify into new products and jurisdictions may even be seen as preparations for the potential loss of patent-based exclusivity for genetic tests in the United States. In this sense, Myriad has done well in protecting itself from the potential fallout of a controversy it first engendered. It will be interesting to see if public and academic attention moves away from Myriad as BRACAnalysis® is discontinued and its business models continue to evolve with the development of personalized medicine.Although the ongoing legal struggle over Myriad’s patents on the In conclusion, a study of the business strategies of Myriad Genetics and their ethical implications provides important information about the evolving context of genetic testing in the biotechnology industry and personalized medicine in particular. By understanding the commercial and ethical successes and failures of this company, we can gain a better understanding of the social and economic forces that shape an increasingly important component of modern health care.


Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity.We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls.We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution  in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes.A reduced focal  motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology. As hyperactivity is one of the core symptoms of attention deficit hyperactivity disorder (ADHD), it is crucial to understand the role of the motor system in the disease. Structural magnetic resonance imaging (MRI) studies and recent functional imaging data indicate that a disturbance of motor function in the primary motor cortex might contribute to ADHD pathophysiology Indirectly, the top-down control of the motor system can be assessed when MRP are examined under specific conditions. An increased number of very slow responses in children with ADHD may reflect more frequent lapses of attention. Thus responses with long reaction times have been used to examine functional states in which the subjects are less concentrated than in trials with short reaction times Finally, the motor system is crucially influenced by dopamine. MRP could reflect an excellent neurophysiological marker to monitor the effects of stimulant medication in ADHD In order to characterize how ADHD, response speed (i.e. more or less concentrated states) and stimulant medication would differentially affect the neuronal activation related to triggering a movement (iMP) or its post-processing in short term motor memory (mPINV), we analysed lateralized MRP in a previously characterized sample of children with ADHD and matched controls Seventeen boys with attention deficit hyperactivity disorder according to the ICD-10 criteria for F90.0 (corresponding to the DSM IV combined type of ADHD) by an interdisciplinary team  and 20 age- and IQ-matched healthy control boys  were recruited (group means were matched). For the response-locked EEG analysis in the current paper, we had to exclude one ADHD patient due to an insufficient number of successful response trials (N<10). The remaining sample consisted of N = 16 patients . IQ was assessed by the German version of the Wechsler Intelligence Scale for Children (HAWIK III).Two reports about stimulus-locked data analysis in this sample have been published before The study was approved by the ethics committee of the Medical Faculty of the University of Würzburg, Germany. All subjects and their parents provided written informed consent according to the Declaration of Helsinki.Subjects performed a modified version of the continuous performance test (CPT-OX) EEG was recorded from 21 gold cup electrodes which were placed according to the international 10–20 system using a sampling rate of 256 Hz and a band pass filter of 0.3 to 70 Hz. The current analysis focused on movement-related potential components which are evoked in response to cued reactions (details are given below). These components have a shorter duration Only trials with correct responses within 1 second were included in the analysis. Data were segmented on response triggers from −2500 to 2000 ms. The first 200 ms of this epoch served as baseline. Taking into account that median reaction times were about 400–500 ms and that there was an interval of 1800 ms between the onset of the cue ‘O’ and the onset of the the target ‘X’, this baseline fell before the cue for nearly all responses in all subjects when fast reactions below the median were analyzed. We refrained from an even earlier baseline in order to avoid a contamination by preceding responses, though cues were preceded by distractors. We made sure that this baseline was not contaminated by lateralized responses to the cue or late MRP to the preceding trial. In Data were corrected for ocular artifacts using the algorithm according to Gratton and Coles . Artifacts were automatically rejected when the signal amplitude exceeded 150 µV due to the higher background EEG in children compared to adults. This procedure was controlled by visual inspection. The average reference was calculated offline.lateralization of iMP or mPINV was assessed) was calculated as the lateralized amplitude in the time window −70 to −20 ms before the response trigger by the formula (C3–C4)/2; the mPINV’ was calculated in the same way as the lateralized amplitude in the time window 500–800 ms after the response trigger, in accordance with previous reports Response locked lateralized MRP were assessed at C3 versus C4 Group differences in reaction times as well as effects of medication and learning were examined by Student’s t-tests.Group effects: iMP’ and mPINV’ amplitudes were examined in an ANOVA with the between subject factor GROUP  and the repeated measurement factor COMPONENT (iMP’ versus mPINV’). The factor component was introduced to test for differential group effects (interaction GROUP x COMPONENT) on pre- and post-movement potentials as these have been shown to differ in their maturational trajectories Effects of stimulant medication (10 mg MPH): iMP’ and mPINV’ amplitudes were examined in an ANCOVA with the repeated measurement factors COMPONENT (iMP’ versus mPINV’) and MEDICATION (on/off methylphenidate). Again, median reaction times (off medication) served as a covariate in an additional analysis. Reaction time off medication was used as covariate instead of the mean between reaction times on and off medication because theoretically, medication effects on reaction time could have masked relevant findings. However, results did not change when the mean value of median reaction times on/off medication was used as a covariate instead of median reaction times off medication (not shown).Finally, in order to assess the effects of response speed, a median split was performed into trials with slow and fast reaction times. An ANOVA with the between subject factor GROUP  as well as the repeated measurement factors COMPONENT (iMP’ versus mPINV’) and REACTION TIME (below versus above median reaction time) was calculated.Pearson correlation coefficients between median reaction times and iMP’ amplitudes were calculated. This was done separately for the two diagnostic groups because we obtained group differences for iMP’ amplitudes (see group effects above).Without medication, ADHD subjects had longer median reaction times compared to healthy control children . The difference was more pronounced for slow responses above  than fast responses below median reaction time . Median reaction time was reduced in ADHD subjects under methylphenidate compared to the run without medication .The time-course of potentials at central leads C3 versus C4  showed aThere was a main effect of COMPONENT as well as an interaction between diagnostic GROUP and COMPONENT in the ANOVA with these two factors see  when iMPControlling for REACTION TIME as a covariate, the factors diagnostic GROUP and COMPONENT still interacted  = 4.9; p = 0.03). Newman Keuls post hoc tests showed that iMP’ amplitude was reduced in children with ADHD .Stimulus locked waveforms are given for comparison in supplementary The ANOVA with the factors MEDICATION and COMPONENT did not yield any significant main effect or interaction . HoweverResponse speed affected the group differences in MRP amplitudes  = 4.4; p = 0.04). Group differences were present only for fast reaction times below the median (p = 0.045) but not for slow reaction times above the median  but a negative correlation in the ADHD group  exhibited a significantly reduced lateralization in children with ADHD compared to healthy controls, especially when reaction times were short. For the motor memory trace (mPINV’) this effect was not found, mPINV’ amplitude was even non-significantly higher (i.e. more negative) in trials with slow responses. Unlike control children, unmedicated children with ADHD showed significantly larger mPINV’ than iMP’ amplitudes. While in healthy controls shorter reaction times were associated with more negative iMP’ amplitudes, this pattern was reversed or at least absent in ADHD subjects. This finding appears plausible as several structural Short reaction times may be taken as indication of better concentration on the task. Movement kinetics themselves  have been found to be largely independent of lateralized MRP amplitudes Previous studies of lateralised ERP in ADHD support our findings and have shown a reduced contingent negative variation Methylphenidate tended to normalize prolonged response latencies in ADHD children like in previous studies Taken together, these findings indicate a qualitative difference in focal motor cortex activation in ADHD, which cannot be compensated for by medication or top-down control when only trials with short reaction times are taken into account. Previous studies have repeatedly shown a polarity reveral during childhood The identification of lateralized movement-related potentials with their characteristic time course We would like to emphasize, that ADHD is not a simple maturation delay, as findings about differences which persist into adulthood demonstrate. Some aspects of maturation seem to be delayed in ADHD and may contribute to (though not fully explain) ADHD pathology A limitation of our study is the small sample size and that data from a continuous performance test were re-analyzed. The fact that subjects had to be prepared to inhibit their responses in some trials may have influenced our results. Future studies should include a standardized characterization of clinical motor problems in the examined sample and employ a wider range of motor paradigms ranging from freely selected spontaneous movements to pre-programmed movement sequences.Response speed crucially modulates lateralized MRP amplitudes. Surprisingly, the most pronounced differences between ADHD and healthy control children were found in trials with fast reaction times, i.e. good concentration. The inverse association of response speed and iMP’ amplitude in the control and the ADHD group pointed towards a maturation delay in the motor system of ADHD children in our sample. Stimulant medication tended to normalize response speed, but did not normalize iMP’ amplitudes, giving further support to the hypothesis that the substitution of axodendritic by axosomatic synapses may be delayed in the motor cortex in ADHD children. This hypothesis warrants further investigation.Figure S1Stimulus-locked lateralized potentials ([C3−C4)/2). There was a negative peak in healthy control children with a latency of about 300 ms. Most likely, it corresponds to the response-locked iMP’ in fast responses (latency about 360 ms). In ADHD children, even taking into account their slightly longer reaction times, no corresponding peak could be found. Stimulus locked lateralized potentials should be interpreted with caution due to possible confounding effects of P300/late positive complex.(TIF)Click here for additional data file.Table S1Data before the calculation of lateralization (mean ± standard error).(DOC)Click here for additional data file.