SHR/NCrl rats had higher i PDthan WKY/Nico controls for impulsiveness and inattention. There was a significant upward trend for i PDover experimental segments within sessions for attention in SHR rats, but not in WKY. i PDfor hyperactivity was correlated with i PDfor impulsiveness and we therefore excluded observations associated with short IRTs (< 0.67s); dispersion in hyperactivity outside this interval was also significantly higher in SHR rats than in WKY rats. Some studies indicate the sharing of symptoms of hyperactivity and impulsiveness in SHR and ADHD-affected humans; high IIV in operant behavioral metrics suggests that the SHR may be useful in elucidating the genetic basis for IIV in humans.Attention-deficit/hyperactivity disorder (ADHD) is characterized by numerous behaviors including inattention, hyperactivity and impulsiveness. ADHD-affected individuals also have high intra-individual variability (IIV) in reaction time. The genetic control of IIV is not well understood. The single study of the genetics of this phenomenon in humans detected only marginal associations between genotypes at two candidate genes for ADHD and variability in response time. The Spontaneously Hypertensive Rat (SHR/NCrl) is an animal model of ADHD, expressing high activity, inattention and impulsive behavior during operant and task tests. The SHR might be useful for identifying genes for variability, but it is not known whether it also expresses high IIV, as is symptomatic of ADHD. We therefore conducted an investigation of IIV in the SHR. We used 16 SHR/NCrl rats and 15 Wistar-Kyoto (WKY/Nico) controls applying a reinforcement schedule used in the validation of the SHR as an animal model of ADHD. We represented IIV as the average absolute deviation of individual behavior within the five 18-min segments of each experimental session from the average behavioral trait value within that session ('individual phenotypic dispersion',  Attention-Deficit/Hyperactivity Disorder (ADHD) is a common, highly heritable  and costMany studies have shown that the Spontaneously Hypertensive Rat (SHR/NCrl) shows the full range of ADHD-like symptoms, including increased motor activity, impulsiveness (short inter-response time) and decreased attention -17. It awith ad libitum access to food and water before being placed in the experimental chamber for one hour for initial habituation. After the first habituation session, rats were deprived of water for 21 hours each day before each succeeding session. This is a moderate but sufficient motivational deprivation approved by the Norwegian Animal Research Authority (NARA), in accordance with Norwegian laws and regulations on live animal experimentation.We compared IIV in elements of operant behavior representing activity, attention and impulsiveness in 16 SHR  and 15 WKY rats  in a simultaneous visual discrimination task using sixteen Campden Instruments operant chambers  recorded behavior and scheduled reinforcers (water droplets). Reinforcers for correct responses were delivered on an unpredictable basis, at a mean of 180 s . An extinction schedule (unassociated with any cue light) was present on the wrong lever. Each 90-min session was divided into five 18-min segments. For each segment, total number of presses on correct and incorrect levers, total number of correct (with water present) and incorrect (no water present) openings of the door into the recessed cubicle, number of reinforcers delivered, and the time between consecutive correct lever presses  were recorded.We used the total number of lever presses to represent general activity (hyperactivity) and the number of responses with short IRTs (< 0.67 sec) to represent impulsiveness see ,23). Att. Att23])iPD) was calculated as the average of absolute differences between behavior in each segment within session and the average behavior for the entire session as i within segment j (from 1-5) and i PDwas strongly non-normal for all traits  was measured as the average absolute deviation from mean individual operant behavior by session for each trait. Individual phenotypic dispersion  over sessions [iPD, fitting effects for strain, consecutive session day (1-5) and their interaction (the 'among sessions' test), ii) by increasing segment (1-5) within session, with i PDaveraged for each six-minute segment across all sessions [Using repeated ANOVA on log-transformed sessions  for PDi,sessions  (the 'wii PDfor impulsiveness (p < 0.001), hyperactivity (p < 0.0001) and inattention (p < 0.0001) than WKY rats  or that there were differences in IIV over sessions by strain (model i) (p > 0.40). IIV changed with time within sessions (model ii): i PDfor hyperactivity was negatively correlated with the sequence of sessions over time in both strains . i PDfor attention was strongly affected by segment within sessions (p < 0.0001). i PDin the SHR increased with segment (β = 2.40 ± 0.055) but decreased significantly in the WKY (β = -1.61 ± 0.057).There was no evidence that IIV increased or decreased with sessions (days) ; WKY: Wistar-Kyoto rat (WKY/Nico)ADHD: Attention-Deficit Hyperactivity Disorder; ANOVA: Analysis of Variance; IIV: Intra-Individual Variability; IRT: Inter-Response Time; PDDr. Faraone has in the past year received consulting fees and served on Advisory Boards for Eli Lilly, Ortho-McNeil and Shire Development, and has received research support from Shire and the National Institutes of Health. In previous years, Dr. Faraone has received consulting fees or has been on Advisory Boards or has been a speaker for Shire, McNeil, Janssen, Novartis, Pfizer, Ortho-McNeil and Eli Lilly. In previous years he has received research support from Eli Lilly, Shire, Pfizer and the National Institutes of Health. TS has received consulting fees or research support or has been on Advisory Boards or has been a speaker for: Shire, Janssen, and Eli Lilly. Dr Perry has no competing interests.GP provided the theoretical basis for this work, carried out the statistical analysis and wrote the article. TS provided the experimental data and participated in writing and editing the manuscript. SF supervised editing and the medical basis of the written work and the analysis. All authors read and approved the final manuscript.


It is widely considered that exposure to maternal cigarette smoking in pregnancy has risk effects on offspring attention-deficit/hyperactivity disorder (ADHD). This view is supported by consistent observations of association. It is, however, impossible to be certain of adequate control for confounding factors with observational designs. We use a novel “natural experiment” design that separates prenatal environmental from alternative inherited effects.The design is based on offspring conceived with Assisted Reproductive Technologies recruited from 20 fertility clinics in the United Kingdom and United States who were: 1) genetically unrelated, and 2) related to the woman who underwent the pregnancy. If maternal smoking in pregnancy has true risk effects, association will be observed with ADHD regardless of whether mother and offspring are related or unrelated. Data were obtained from 815 families of children ages 4 years–11 years with parent questionnaires and antenatal records. Birth weight was used as a comparison outcome. The key outcome considered was child ADHD symptoms.p < .02) than in the unrelated pairs , suggesting inherited effects.Association between smoking in pregnancy and lower birth weight was found in unrelated and related mother-offspring pairs, consistent with a true risk effect. However, for ADHD symptoms, the magnitude of association was significantly higher in the related pairs (β = .102, Our findings highlight the need to test causal hypotheses with genetically sensitive designs. Inherited confounds are not necessarily removed by statistical controls. The previously observed association between maternal smoking in pregnancy and ADHD might represent an inherited effect. It has generally come to be accepted that exposure to maternal smoking in pregnancy has a causal role in offspring attention-deficit/hyperactivity disorder (ADHD). It is biologically plausible, because it is known that smoking has an effect on physiological processes that might create risks relevant to the origins of ADHD, a childhood-onset neurodevelopmental disorder . ConfideA particular concern is that the relationship between maternal smoking in pregnancy and offspring ADHD arises from unmeasured confounds, including inherited ones. Fetal exposure to prenatal risk factors, especially those linked to offspring mental health, is not random . Public The research protocol was approved by the Wales Multi-Centre Research Ethics Committee. The sample  consisteFamilies of school-aged children were invited to participate. Children's ages ranged from 4 years to 11 years . The sample included 416 boys and 397 girls (2 had missing data), 626 singletons and 187 individuals who were the first born of multiple births . Ninety-six percent of mothers and 95% of fathers were of European origin. Further description on the sample is available . OverallPostal questionnaires were completed by 800 mothers and 552 fathers. Mothers from the United Kingdom were also asked for consent to examine their antenatal records for the index child, and 616 agreed (77%).Children's ADHD symptoms during the past 3 months were assessed with the 14-item DuPaul ADHD scale, rated on a 4-point scale . The summed score for each of the items provides total ADHD scores . BecauseMothers also reported on this “comparison” outcome. For birth weight, there was excellent agreement between their retrospective reports and antenatal records , and thuSmoking in pregnancy was assessed by a maternally rated questionnaire  that hasAlcohol use in pregnancy (yes/no) was assessed by maternal questionnaire alone, because we found this information was not reliably recorded in antenatal records . One hunr = .959, p = .001). Premature birth  was defined as <37 weeks gestation for singletons and <34 weeks for multiple births.Mothers reported in which week of pregnancy the child was born. The correlation between maternal report and information from antenatal records approached unity (Ninety mothers reported they currently smoked (11.6%). Fathers were also asked whether they smoked during the mother's pregnancy .Current annual family income was also assessed by maternal questionnaire. The mean income band was £30–40,000, range <£10,000 to >£60,000.n = 777) ranged from 0 to 34, mean score 8.4 (SD = 5.9). Father ADHD scores (n = 529) ranged from 0 to 45, mean score of 8.3 (SD = 6.3).Each parent was also asked to report on his or her own current ADHD symptoms during the past 3 months with the 18-item Barkley Adult ADHD assessment , rated op value indicates the statistical significance of that association. The difference in the magnitude of association between smoking in pregnancy and ADHD in the related and unrelated pairs was tested by undertaking multiple regression analysis with the whole sample and including a product term. Here the independent variables were maternal smoking in pregnancy and the product term (smoking × genetic relatedness). The dependent variable was ADHD scores.Association between maternal smoking in pregnancy and offspring ADHD scores in the related mother–child pairs and the unrelated mother–child pairs was examined with ordinary least squares regression analysis, where β is the standardized regression coefficient (a measure of the magnitude of association) and the Results are also presented for the comparison outcome measure of birth weight where, in contrast to offspring ADHD, it is known that maternal smoking in pregnancy has prenatal risk effects . BecauseSignificant association in unrelated mother–child pairs must be due to environmental pathways.Association in the genetically related pairs and greater magnitude of association between prenatal factors and outcome in related than in unrelated pairs is attributable to inherited pathways.Where there was evidence for association, we tested whether this was attributable to measured child, parent, and family factors, and repeated analyses including covariates with multiple regression analyses. We selected variables that are associated with ADHD symptoms or that could be associated with ADHD or maternal smoking in pregnancy on the basis of previous literature . Age, geAs a final test of the design, we tested for association: 1) between current maternal smoking and offspring ADHD scores, and 2) between paternal smoking in pregnancy and offspring ADHD for which we know there are no biological explanations of causal effects. For the analyses on paternal smoking, we examined offspring who were genetically related to father and unrelated to father .Comparisons of the families where mothers are genetically related and unrelated are shown in p < .01; unrelated pairs: β = −.11, p < .01; no significant differences in magnitude between the groups, p > .1, adjusting for maternal education, maternal height, child gender, multiple birth, and maternal age at birth of child and excluding very preterm births [<31 weeks]).In this sample, as previously described , we findp < .02) with a mean ADHD score of 13.1  for those exposed and 10.0  for those unexposed to smoking in pregnancy. Statistically controlling for the effects of alcohol use during pregnancy did not alter the results . Smoking in pregnancy was not related to maternally rated offspring ADHD scores in the unrelated pairs . The mean ADHD score was 9.8  for those exposed to maternal smoking in pregnancy and was 11.7  for those unexposed. Testing for differences in the magnitude of association in the unrelated and related groups showed evidence of significant differences between the groups , suggesting significant inherited effects.Smoking in pregnancy was—in keeping with observational study findings —significantly associated with offspring ADHD symptoms in the related mother–child pairs  as well as between paternal smoking in pregnancy and offspring ADHD . There was no association in the unrelated pairs for current maternal smoking  and when paternal smoking in pregnancy was examined in unrelated fathers only .Finally we examined, as the predictor variables: 1) current maternal smoking, and 2) paternal smoking in pregnancy. In the genetically related pairs, there was evidence of association between current maternal smoking and offspring ADHD  have consistently shown that exposure to smoking in pregnancy is associated with ADHD . Many stFirst, in contrast to studies of birth weight, animal studies on cigarette and nicotine exposure in utero have not consistently demonstrated motor and cognitive changes similar to ADHD . Second,How important are natural experimental designs such as ours when much larger observational studies are available? Epidemiological studies suggest that measured confounders do not account for the link between smoking in pregnancy and offspring ADHD , and in Interestingly mother's current smoking and the father's smoking in pregnancy were also associated with offspring ADHD in the maternally related and paternally related groups, respectively, and the degree of association for current smoking and paternal smoking in pregnancy was similar to that for maternal smoking in pregnancy. These observations also further indicate that this maternal  behavior is indexing inherited liability for ADHD. If paternal smoking was important in terms of effects through passive smoking effects on the fetus, we would have expected to also observe association in the paternally unrelated sperm donation and embryo donation groups but not the related surrogacy group, because surrogates do not live with father; but we do not observe this (results available from first author).In terms of potential clinical implications, our findings together with those from other studies suggest that it is important for mothers to quit smoking in pregnancy and that smoking cessation could result in increased offspring birth weight but that this intervention might not be a useful public health intervention for reducing ADHD symptoms.As with all research designs, there are limitations. First, although with this sample size we were able to detect association between maternal smoking in pregnancy and birth weight in the unrelated group, we cannot rule out that association was not detected for ADHD, given the small number of smokers in our sample and in the unrelated group in particular. As a result, our power to detect significant prenatal environmental influences was low, and future replications are needed. Thus, we cannot be certain that there are no prenatal effects, only that there is significant evidence of inherited effects. Notwithstanding this observation, our findings, at the very least, suggest that a proportion of the association between smoking in pregnancy and ADHD observed in previous studies can be attributed to inherited factors. Second, we did not examine ADHD diagnoses; however, all the research to date suggests etiologic continuity between normal variation in ADHD symptoms and extreme scores . Third, Unsurprisingly, the rate of maternal smoking in this sample was lower than currently reported UK rates. It is likely therefore that the mothers who smoked in our sample are the most highly dependent on nicotine, which could potentially increase the shared genetic liability with ADHD. However, the magnitude of association between maternal smoking in pregnancy and ADHD in the related group is similar to that reported in general population samples . AnotherOur findings highlight the need to test causal hypotheses with genetically sensitive designs . Results


Current research suggests that attention-deficit/hyperactivity disorder (ADHD) is associated with larger behavioral sensitivity to reinforcement contingencies. However, most studies have focused thus far on the enhancing effects of tangible rewards such as money, neglecting that social-emotional stimuli may also impact task performance in ADHD patients.To determine whether non-social (monetary) and social  rewards differentially improve response inhibition accuracy in children and adolescents with ADHD, we applied an incentive go/no-go task with reward contingencies for successful inhibition and compared ADHD subjects with typically developing individuals.Both social and monetary contingencies improved inhibition accuracy in all participants. However, individuals with ADHD displayed a particularly higher profit from social reward than healthy controls, suggesting that cognitive control in ADHD patients can be specifically improved by social reinforcement. By contrast, self-rated motivation associated with task performance was significantly lower in ADHD patients.Our findings provide evidence for hyperresponsiveness to social rewards in ADHD patients, which is accompanied by limited self-awareness. These data suggest that social reward procedures may be particularly useful in behavioral interventions in children with ADHD. Recent models suggest that the core symptoms of attention-deficit/hyperactivity disorder (ADHD), namely inattention, hyperactivity and impulsivity, could result from dysfunction of two neurodevelopmental pathways: the executive and motivational pathways . While tHowever, the majority of studies have mainly focused on the effects of tangible rewards such as money, tokens or food incentives, and specifically how tangible reinforcement is able to improve cognitive control performance in subjects with ADHD . For insFocusing on the effects of non-social or tangible rewards on cognitive control  neglects how emotionally loaded, social stimuli may affect cognitive control performance in patients with ADHD. Recently, we demonstrated that not only money, but also social incentives such as smiles and friendly faces act as effective reinforcers in a go/no-go task, boosting response inhibition accuracy in developing boys between 8 to 12 years of age . MonetarThus, the aim of our study was to directly compare the effects of social  and non-social (monetary) rewards on cognitive control processes in subjects with ADHD. Testing how different reinforcers can effectively modulate cognitive control will improve future therapeutic intervention in affected patients.We chose a task in which cognitive control abilities, such as response inhibition, were specifically modulated by different reward contingencies . For thiIt has to be noted that the terms 'reward' and 'reinforcement' are used interchangeably throughout the paper . We forA total of 16 boys with ADHD and 16 healthy male controls participated in the study with both groups ranging in age from 8 to 13 years . Only participants with an IQ = 85 (based on the WISC-III) were included in this study.Children in the ADHD group met DSM-IV criteria for ADHD  and wereSeven participants with ADHD were coded as inattentive-only subtype, and nine children satisfied criteria for the combined subtype . Exclusion criteria included any potentially confounding diagnoses such as obsessive-compulsive disorder, psychosis, mania, major depression, substance abuse, pervasive developmental disorders or developmental disorders. None of the ADHD participants used any medication other than stimulants, which were discontinued at least 48 hours prior to testing.Informed consents were obtained from all participants and their parents. This study was approved by the Ethics Committee of the University Hospital, Aachen.ps > 0.1). However, children and adolescents with ADHD were rated as having significantly higher inattention, externalizing and internalizing scores as assessed with the CBCL, and stronger ADHD symptom severity in the FBB-HKS .Demographic data and descriptive statistics for task performance of the two groups are summarized in Table In our incentive go/no-go task . In the first experimental block, all children underwent the same non-reward baseline condition where meaningless feedback (represented by uninformative mosaic pictures) was given for both successful and failed response inhibitions. In the second experimental go/no-go block, children from both groups were reinforced for successful inhibitions with social or monetary rewards presented block-wise. One reward block consisted of six rewards of the same type. Altogether 5 blocks of social  and 5 blocks of non-social rewards  were presented in a pseudorandom order. Happy and exuberant facial expressions served as positive social reinforcers, while neutral facial expressions were shown after false alarms .Correct inhibitions in non-social trials were positively reinforced with money, symbolized by different colored wallets each filled with a 50 Eurocent coin; empty wallets were shown after false alarms. Each child in the two groups won additional three Euros, irrespective of his performance, although he was informed that a better performance in the money condition would result in a higher amount of money paid after the experimental session.Participants were reminded at the beginning of each experimental block to react quickly while maintaining a high level of accuracy.We did not incorporate response cost manipulations in our go/no-go task , since we primarily focused on motivational effects of rewarding stimuli and not on punishment or punishment avoidance.To ensure that all children understood the task instructions, experimental blocks were preceded by 20 practice trials with opportunities to repeat trials, if needed.After each block, children were required to complete a subjective rating questionnaire to assess self-reported motivation, insight into performance, and aspects of task manipulations.Following each experimental block, children were interviewed with a rating questionnaire. The questionnaire was developed to assess self-reports on subjective experiences associated with performing different experimental manipulations. A 5-point Likert-type scale (ranging from 0 to 4) was applied. The children were asked (1) how much they were motivated doing the task prior to the start of the experimental procedure, (2) how motivating and (3) how difficult they found the task, (4) how satisfied they were with their performance, and (5) how rewarding they found the different feedback stimuli.2p). Since omission errors were very infrequent (below 3%), they were not included in the analysis.Dependent measures of the incentive go/no-go task – false alarm rates (FA rates), reaction times for hits (RT for hits), and reaction times for false alarms  – were analyzed using a multivariate ANOVA model with group as the between-subjects factor , and reward type as a within-subjects repeated factor , followed by univariate ANOVAs. As age and IQ did not differ significantly between the groups and were not correlated with the dependent measures, these variables were not included as covariates in analysis of performance data. The alpha level was set at 0.05. In addition, effect sizes were calculated using partial eta square .ADHD = 2, MdnControls = 3; Mann-Whitney U = 89.5, ns).Subjects in both the ADHD and control groups started the experimental procedure equally motivated according to self-ratings  or in their satisfaction with task performance . However, children with ADHD rated the baseline condition as less motivating than healthy controls .After the non-reward baseline condition, self-ratings revealed that both groups did not differ in their ratings of task difficulty . However, self-rated motivation was significantly lower in children with ADHD compared with healthy controls under reward conditions .No differences between groups were detected for satisfaction with task performance  or subjectively perceived task difficulty .ADHD1 = 2, MdnADHD2 = 3; Z = -3.3, p < 0.001; MdnControls1 = 2, MdnControls2 = 4; Z = -3.5, p < 0.001). We found no significant group differences either in the baseline or reward conditions. Note that we did not assess reward value ratings separately for social and monetary rewards.When children rated the reward value of the feedback stimuli, both groups perceived the feedback after successful inhibitions as more rewarding in the reward block than in the baseline condition (Mdn2p = 0.11) was observed between groups. Group characteristics and task performance for the two groups are summarized in Table Under the non-reward baseline condition, no significant differences in FA rates, RT for hits and RT for false alarms  < 1, ns, ηp < 0.001, η2p = 0.89, and a significant Group × Reward interaction effect, F  = 2.81, p = 0.031, η2p = 0.40, while the main effect for Group, F  = 1.15, ns, η2p = 0.11, was found to be non-significant. This suggests that task performance in all children changed under conditions of reinforcement, but that rewards differentially affected performance in the two groups. Univariate ANOVAs showed that significant reward effects were only related to FA rates, F  = 65.41, p < 0.001, η2p = 0.69, and RT for hits, F  = 4.22, p = 0.019, η2p = 0.12, but not to RT for false alarms. The significant Group × Reward interaction effects were related to all three dependent measures .The 2 × 3 (Group × Reward) repeated measures MANOVA with FA rates, RT for hits and RT for false alarms as dependent measures revealed a significant main effect for Reward, F  = 33.46, p = 0.019, η2p = 0.17) but not monetary rewards, suggesting that response inhibition accuracy can be improved more by social incentives in children with ADHD compared to healthy controls.As shown in Figure p = 0.01, η2p = 0.19; RT for false alarms: p = 0.007, η2p = 0.22), but not to the social reward condition. Children with ADHD responded significantly slower (RT for hits) and less impulsively  under monetary reinforcement, whereas control subjects responded generally faster when money was at stake  emerged between ADHD subtypes. Furthermore, no significant subtype by reward interaction effects with regard to differential benefit from social and non-social reward could be found.Under the non-reward baseline condition, no significant differences in FA rates, RT for hits and RT for false alarms  = 1.1, ns, ηps > 0.1), suggesting that children did not slow down reaction times for go signals to improve inhibition accuracy.Possible speed-accuracy trade-off effects were inspected by calculating correlations between FA rates and RT for hits within each group for the three experimental conditions tested. All correlation coefficients were found to be non-significant (ps > 0.3).We also did not find significant associations between FA rates and RT for false alarms within each group for the three experimental conditions tested (ps > 0.05), suggesting that differential improvements in inhibition accuracy between the baseline and incentive conditions cannot simply be explained by changes in performance strategies between the two groups. As illustrated in Figure x = 0 and above y = 0), who obviously changed their response behaviors by slowing down reaction times to improve inhibition accuracy in the social as well as in the monetary reward condition (control group: n = 2 (12.5%); ADHD group: n = 7 (43.8%)).With respect to changes in performance strategies between the baseline and both reward conditions, we also controlled for associations between ΔRT (RT differences between baseline and reward conditions) and the individual change index for false alarm rates  within This study is the first to compare the effects of tangible and non-tangible reinforcers on cognitive control accuracy in ADHD subjects. For this purpose, we employed an incentive go/no-go task to explore the extent to which social  and non-social (monetary) rewards differentially impact response inhibition in children and adolescents with ADHD compared to healthy controls. As expected, we found that both social and monetary contingencies improved cognitive control performance  with best task performance during the monetary reward condition in all participants, confirming earlier findings ,16. HoweOur data partially replicate earlier findings that ADHD is associated with greater behavioral sensitivity to reinforcement contingencies ,8,10,17.Alternatively, but not mutually exclusively, it is also plausible that children with ADHD seek more social approval since they are frequently exposed to social disapproval by parents, siblings, and peers during interpersonal interactions and particularly in achievement situations . A lack Contrary to our prediction, we did not find a larger effect of monetary reinforcement on inhibition accuracy improvement in ADHD subjects compared to healthy controls. We could only detect that money differentially influenced reaction times in both groups, with slower RTs in ADHD children and faster RTs in healthy controls under financial reinforcement. The unexpected finding that money did not ameliorate response inhibition more in subjects with ADHD than in controls was similar to other studies that applied incentive go/no-go tasks ,25. NeveFurthermore, the discrepancy between lower self-rated motivation and higher sensitivity to social response contingencies in the ADHD group suggests poor insight into realistic task monitoring, supporting other findings of limited self-awareness abilities in this patient group .In contrast to previous studies that proposed deficient inhibitory mechanisms associated with frontostriatal brain abnormalities in ADHD patients ,28, we dhyporesponsiveness in the mesolimbic dopaminergic brain circuit  may be responsible for behavioral hyperresponsiveness to incentives, mirrored in impulsive seeking of immediate reinforcers as a compensation strategy. Although these imaging studies exclusively employed monetary incentives, the findings may also hold for social incentives. Future studies would benefit from brain imaging techniques  to increase our understanding of the neural basis of hypersensitivity to social incentives and its relation to behavioral symptoms in subjects with ADHD.Additionally, we did not investigate the underlying neurobiological mechanisms of reward responsiveness in ADHD subjects. Recent imaging data ,34 suggeHigher responsivity to social reinforcers, such as positive facial expressions, in ADHD children is particularly noteworthy since various studies have reported emotion recognition and/or theory-of-mind deficits in affected children ,36. HoweOur study has some limitations that should to be considered. First of all, as mentioned by Johansen and colleagues , given tOne main shortcoming of this study previously mentioned relates to our sample group and size, which consisted solely of 32 young boys. Our conclusions are thus limited and in need of replication with a larger, more diverse sample group.Although no clear subtype differences concerning reward responsiveness were previously reported for ADHD (see ), and weMoreover, we did not include a clinical comparison group, which limits the specificity of the present findings. Future studies could benefit from the use of both non-social and social incentives to explore how different types of response contingencies work in different psychiatric disorders. For instance, application of the incentive go/no-go task on children with autism spectrum disorder will help to obtain deeper insights into the nature of a hypothesized hyporesponsivity to social reinforcement in this patient group .It should be also noted that in our task design uninformative mosaic pictures were given for both successful and failed response inhibitions in the baseline condition, whereas in both reward conditions informative response contingencies were provided. Thus, it could be possible that the mere fact of having a feedback about task performance in the reward conditions compared to the non-reward baseline might have contributed to the higher reward value ratings of both reinforcement types in the subjective self-reports. However, most importantly, it is unlikely that this possible bias accounts for the impact of reward on task performance: Both social and non-social reinforcers served as performance feedback, but influenced response behavior differently.In sum, this is the first study that investigated the extent to which social  and non-social (monetary) rewards differentially impact cognitive control in subjects with ADHD. Concerning response inhibition improvement, external social reinforcement was more beneficial for the ADHD group than for controls. We extend earlier findings and interpret this result as a hyperresponsiveness to social rewards in ADHD subjects ,18. SuchThe authors declare that they have no competing interests.GK designed and coordinated the study, collected and analyzed data and drafted the manuscript. BHD participated in the supervision of the project and commented on the written drafts of the manuscript including interpretation of the results. KK supervised the project, participated in the statistical analysis, corrected the drafted manuscript and contributed to the interpretation of the results. All authors read and approved the final manuscript.


Tandem olefin metathesis sequences are known to be versatile for the generation of natural product scaffolds and have also been used for ring opening of strained carbo- and heterocycles. In this paper we demonstrate the potential of these reactions for the desymmetrization of 7-azabicycloalkenes.We have established efficient protocols for the desymmetrization of different 7-azabicycloalkenes by intra- and intermolecular tandem metathesis sequences with ruthenium based catalysts.Desymmetrization of 7-azabicycloalkenes by olefin metathesis is an efficient process for the preparation of common natural product scaffolds such as pyrrolidines, indolizidines and isoindoles. Azabicyclo [x.y.0]alkane scaffolds are ubiquitous structural elements in pharmaceutically important peptide mimetics –3 and seIn this context, ring closing metathesis (RCM) and tandem metatheses –13 have N-acylated with an unsaturated carboxylic acid and submitted to a ring closing metathesis (RCM).The application of RCM to the synthesis of azabicycloalkane scaffolds was first described by Grubbs for the N-acylated 2-azabicycloalkenes 4 as precursors for azabicyclo [X.3.0]alkanes like 6  and the following aromatization to 9 was the reason for the low catalytic efficiency of this conversion and tested this hypothesis with the conversion of the corresponding pentenoyl derivative 10 under RORCM conditions. As outline in 11 in good yield, verifying our previous assumptions.We assumed that the structure of the starting material 8 and 10 give relatively unstable products. In consequence, products can only be isolated as pyridones 9, derived from spontaneous aromatization or have to be hydrogenated to their saturated analogues 11.As a general trend, it turned out that benzannelated azabicycloalkene derivatives like 8 and 10 is not observed with other 7-azabicycloalkenes like 13 and 16 as depicted in 12,[13 and 16 were generated after deprotection under standard acylation conditions in good yields. Treatment of these bis-olefins with Grubbs catalyst 1 gave the expected bicyclic compounds 14 and 17 in good yield along with some byproducts 15 and 18, respectively. These byproducts are often observed, if the generated exocyclic double bond in the RORCM product is susceptible to olefin cross metathesis with the small amount of styrene that is derived from the precatalyst 1. These types of products are favored, if additional olefins are added as CM partners. With addition of 3 equivalents styrene (condition A in 15 becomes the main product.This unique reactivity of benzannelated metathesis precursors like ed in 12,–66 RORCM7 and 12. A sequence of ring opening and cross metathesis is extremely efficient for desymmetrization of 7 and 12 as depicted in 19 and the disubstituted pyrrolidine 20. In these cases, catalyst loadings can be low and yields are excellent.Having established suitable protocols for conversions of 7-azabicycloalkenes to racemic products, we tried next to develop stereoselective variants and started our studies again with Boc-protected 7-azabicycloalkenes 21 yet.Unfortunately the ROCM of 7-azabicycloalkenes appeared to be quite sensitive with respect to the olefin cross metathesis partner  and we h10 with the known chiral ruthenium catalyst 3.[11 in good yield (A more successful attempt to introduce selectivity, was the enantioselective catalytic desymmetrization of bis-olefin talyst 3. This reaod yield . HoweverIn this paper we have described efficient tandem metathesis protocols for the desymmetrization of 7-azabicycloalkenes. Desymmetrization is accomplished by intramolecular RORCM or intermolecular ROCM sequences to give a range of common natural product scaffolds such as pyrrolidines, indolizidines and isoindoles. The protocols use readily available starting materials, are simple and give densely functionalized metathesis products ready for further manipulations.File 1Experimental. Experimental procedures for the synthesis of all compounds described, and characterization data for the synthesized compounds.


During the last decade, pharmaceutical spending for patients with attention-deficit-hyperactivity disorder (ADHD) has been escalating internationally.First, to estimate future trends of ADHD-related drug expenditures from the perspectives of the statutory health insurance  in Germany and the National Health Service (NHS) in England, respectively, for children and adolescents age 6 to 18 years. Second, to evaluate the budgetary impact on individual prescribers (child and adolescent psychiatrists and pediatricians treating patients with ADHD) in Germany.A model was developed to predict plausible scenarios of future pharmaceutical expenditures for treatment of ADHD. Model inputs were derived from demographic and epidemiological data, a literature review of past spending trends, and an analysis of new pharmaceutical products in development for ADHD. Only products in clinical development phase III or later were considered. Uncertainty was addressed by way of scenario analysis. For each jurisdiction, five scenarios used different assumptions of future diagnosis prevalence, treatment prevalence, rates of adoption and unit costs of novel drugs, and treatment intensity.Annual ADHD pharmacotherapy expenditures for children and adolescents will further increase and may exceed €310 m  in 2012 . During this period, overall drug spending by individual physicians may increase 2.3- to 9.5-fold, resulting from the multiplicative effects of four variables: increased number of diagnosed cases, growing acceptance and intensity of pharmacotherapy, and higher unit costs of novel medications.Even for an extreme low case scenario, a more than six-fold increase of pharmaceutical spending for children and adolescents is predicted over the decade from 2002 to 2012, from the perspectives of both the NHS in England and the GKV in Germany. This budgetary impact projection represents a partial analysis only because other expenditures are likely to rise as well, for instance those associated with physician services, including diagnosis and psychosocial treatment. Further to this, by definition budgetary impact analyses have little to nothing to say about clinical appropriateness and about value of money.Providers of care for children and adolescents with ADHD should anticipate serious challenges related to the cost-effectiveness of interventions. In the United States, identification of attention-deficit/hyperactivity disorder (ADHD) among children and adolescents showed the greatest increase of all categories of psychosocial problems , and theMeanwhile, the growth of pediatric psychotropic prescriptions has become an international phenomenon . For stiMuch of the debate triggered by this trend has focused on medical aspects, such as concerns about potential overuse of psychostimulants ,22 and aBeyond clinical implications, in an era of limited available resources, the economic dimension associated with increased health care utilization can no longer be ignored. In economic terms, the opportunity cost of medical interventions will be approximated by their budgetary impact – in particular, if a payers' perspective is adopted. Indeed, budgetary impact analyses are requested by a growing number of health care policy makers as an input into the decision-making process about health care resource allocation . In pracnew products  and €51.6 million in 2004 ,43. AparIn England spending for ADHD-related pharmacotherapy, including modafinil and atomoxetine, increased from 1998 (₤3.1 million) to 2005 (₤24.4 million) by +695% Figure , again eThe high rate of adoption of new products with once-a-day administration schedules reflects the well-known problems associated with administration of a mid-day dose (during school) in children and adolescents with ADHD ,46. ObviA forecasting model was developed to project the likely pharmaceutical expenditures for children and adolescents (age 6–18 years) with a diagnosis of ADHD in England and Germany through 2012, specifying assumptions and assumed relationships between variables in a transparent manner. Model outcomes were used to estimate the impact on drug spending by individual German physicians involved in care for ADHD patients, after validation of the model by replicating historic data (from 1998 to 2005). Key uncertainties were addressed using scenario analysis, combining objective information with specific assumptions about future events .The model was restricted to pharmaceutical spending. It combined, in a hierarchical structure, (1) epidemiological information  with assumptions on 2) recognition rates , (3) rate of patients receiving drug therapy , (4) availability and adoption of new products, incorporating information on therapeutic profiles, (5) diffusion and market shares for alternative preparations, by category and by product, including generic substitution, (6) treatment intensity (expressed as average number of days times defined daily doses), (7) acquisition cost per defined daily dose for each product, from the perspectives of the NHS (England) or the GKV (Germany), respectively. For validation of the model, available data on the variables above were used to compare model outcomes with the historic evolution of drug spending in England and Germany. Extensions of the model were used to estimate the impact of the projections on drug budgets of individual pediatricians and specialists in child and adolescent psychiatry participating in care for patients with ADHD in Germany. Details on data sources and assumptions are provided in Table  recognitThe market for ADHD treatment has attracted pharmaceutical companies to invest heavily in new product development. Results of literature searches and the database analysis  are summR in the United States, April 2006) of methylphenidate with duration of action of 12 hours . At present, in the absence of head-to-head trials against established oral formulations, the main advantage of this product seems to be convenience-related [A number of further pharmaceutical preparations and variants of methylphenidate are in phase III of clinical development in Europe, some of which have already received marketing authorization in the United States. These include a transdermal system  in the US in May 2005, also as an extended-release formulation [R will become available in Europe without a price premium over branded immediate-release  or modified-release methylphenidate , respectively. Given its investment in FocalinR, it has been considered unlikely that Novartis would launch RitalinR LA (a long-acting preparation of methylphenidate available in the United States and some other markets) in England and Germany.Dexmethylphenidate, the chirally pure active isomer of methylphenidate, has been licensed as Focalinmulation ,52. As tmulation ,53, it hR) and duration of action of 12 hours [R". For modeling it was assumed that the product will be introduced to the English and German markets in 2008 and (except for the "Extremely Low Case" scenario) overtake modified-release methylphenidate products in terms of prescriptions by 2012. Obviously, this rests on the assumption that clinical advantages of NRP104  will be confirmed.At the time of writing, few scientific data were in the public domain about lisdexamphetamine mesylate (NRP104), a new chemical entity that is an inactive prodrug of amphetamine believed to have a reduced potential for abuse and overdose compared to other ADHD drugs. The reason is that the amphetamine is conjugated to a specific amino acid and is activated only when metabolized in the gastrointestinal tract. Shire filed the product with the Food and Drug Administration (FDA) in December 2005 for the treatment of ADHD in children aged 6 to 12. Phase III study results presented at the Annual Meeting of the American Psychiatric Association in Toronto, May 2006, indicated similar efficacy and tolerability compared to mixed amphetamine salts  woulR, AdderallR XR, by Shire) but have been licensed neither in England nor in Germany. It is believed that these products will not become available in Europe. Further compounds in phase II clinical development for ADHD include selective GABA-B receptor antagonists  and ampakine molecules (by Cortex). These projects have been excluded from the present study in light of their inherent uncertainty; statistically, attrition rates of compounds in clinical phase II are as high as 62% [Finally, mixed amphetamine salts are marketed successfully in the U.S. . Besides a base case for projection through 2012 Figure , four adWhile all scenarios will be described briefly below, Tables The base case scenario, which is believed to reflect the most probable course of future events, implies an increase of drug spending for children and adolescents with ADHD for year 2012 by a factor of 12 (GKV in Germany) or 10 (NHS in England) over 2002. Assuming an annual growth rate of 5% for drug expenditures between 2005 and 2012 (except for ADHD in children and adolescents), then the projected ADHD treatment costs  would make up 3.8% of NHS spending for CNS drugs in 2012, compared to just 0.77% in 2002. For the German GKV , the corresponding figures would be 12.9% of total spending for psychotropic drugs in 2012, compared to 1.8% in 2002. This increase is driven by the multiplicative effects of increasing awareness and recognition of ADHD, growing rates of pharmacotherapy, somewhat increased intensity (dose and duration) of treatment, and the shift to novel, more expensive products LisDEX – lisdexamphetamine, a prodrug of amphetamine in phase III clinical developmentMAS – mixed amphetamine saltsMOD – modafinilMPH – methylphenidateMR – modified release (formulation)MR08 – modified release formulation with duration of action of approximately 8 hoursMR12 – modified release formulation with duration of action of approximately 12 hoursNHS – National Health Service (England)SHI – statutory health insurance in Germany (see GKV)TDS – transdermal system


Bartonella quintana endocarditis affecting a prosthetic valve in a person with no known risk factors for this infection. Bartonella should be considered as a cause of endocarditis in any clinical setting.We describe the first case of  Bartonella have been described as a cause of endocarditis in humans: Bartonella quintana, B. henselae, B. elizabethae, and B. vinsonii subsp. berkhoffii. Although infection with the latter two species has been reported only as single cases, endocarditis caused by B. quintana and B. henselae has been increasingly recognized in recent years. Most cases in which B. quintana has been implicated as the infecting species  have had known risk factors such as homelessness, alcoholism, or human HIV infection , prosthetic heart sounds, an ejection systolic murmur, and an early diastolic murmur consistent with aortic regurgitation. Respiratory examination was unremarkable, and splenomegaly (1-cm enlargement) was detected in the abdomen. Residual left hemiparesis and hemianopia, resulting from her previous cerebrovascular accidents, were present.Urinalysis showed proteinuria and hematuria; urinary protein excretion was measured at 2.54 g/L. The patient was anemic, with a hemoglobin of 7.2 g/dL with normal leukocyte and platelet counts. The serum creatinine was elevated at 168 μmol/L, and serum globulins were increased with low serum albumin (27 g/dL). The C-reactive protein was elevated at 66 g/dL. Six blood cultures were sterile, and an HIV antibody test result was negative. A transthoracic echocardiogram was unremarkable, but a transesophageal study showed two 1.5-cm vegetations attached to the prosthetic aortic valve, with moderate paravalvular regurgitation. A diagnosis of culture-negative endocarditis was made, antibiotic treatment with vancomycin and gentamicin was commenced, and the patient was referred for surgical assessment.Despite antibiotic therapy, fever, progressive renal impairment (serum creatinine 300 μmol/L), and leukopenia developed. In view of the valvular pathology, the aortic valve prosthesis was replaced with a homograft root into which the coronary arteries were reimplanted. Microbiologic examination of the excised valve showed no organisms on Gram stain and no bacteriologic growth. There was insufficient material for histologic examination.Chlamydia serology was found to be positive, with Chlamydia trachomatis and C. pneumoniae immunoglobulin (Ig) G titers >512 by microimmunofluorescence . Bartonella serology was positive by immunofluorescence, with IgG titers >8,192 for both B. henselae and B. quintana and a positive IgM for both species (titer >80). Genomic DNA was extracted from the vegetation removed at surgery by using the QIAamp Tissue Kit . Two pairs of oligonucleotide primers were used to amplify overlapping fragments of the 16S ribosomal DNA (rDNA) gene. The first primer pair amplified a 296-bp segment of the Bartonella gene, as described B. quintana sequences deposited in GenBank . In contrast, the sequence had nine nucleotide differences (98.8% similarity) from that of B. henselae, the next closest match, establishing B. quintana as the infecting species in this case.During screening for rarer causes of endocarditis, Bartonella IgG and IgM antibodies. Initial postoperative therapy with teicoplanin and ceftriaxone (given for 1 week) was changed to ciprofloxacin for a total of 1 month. Oral clarithromycin was then given for another month. Six weeks after surgery, the patient was afebrile, the valve was functioning satisfactorily, and splenomegaly had resolved. Both the C-reactive protein and serum creatinine had returned to normal.A serum sample drawn in October 1999 was retrospectively tested and also found to be positive for B. quintana endocarditis affecting a prosthetic valve; after surgical and medical therapy the outcome was favorable. The first descriptions of human disease caused by B. quintana emerged during World War I (1914-1918), when approximately 1 million cases of trench fever occurred B. quintana infection, although direct evidence for this is lacking. Valve replacement has been the rule in the few reported cases of Bartonella endocarditis. This surgical intervention may reflect either a poor clinical response to medical therapy or the fact that diagnostic delay, as in our case, may lead to valve destruction to a degree that necessitates valve replacement.This case report documents the first description to our knowledge of B. quintana were present. B. quintana native-valve endocarditis in persons without recognized risk factors appears rare Bartonella infection. Thus, as with any emerging disease, the clinical and epidemiologic features of contemporary B. quintana infection remain to be fully described. Using a large bank of control sera, Raoult et al. Bartonella IgG titer >1,600 has a positive predictive value for endocarditis of 0.884. Detection of high-titer Bartonella antibodies will therefore be a powerful diagnostic tool in cases of suspected endocarditis; such results could have established the diagnosis 8 months earlier for our patient.An interesting aspect of our case is that none of the previously known risk factors for infection with Bartonella was estimated to cause 3% of all cases of endocarditis Bartonella endocarditis in countries such as the United States or the United Kingdom is unknown. Of 66 sera taken from cases of culture-negative endocarditis and sent to the Public Health Laboratory Service in London, United Kingdom, 18% were positive for Bartonella antibodies Bartonella endocarditis Bartonella infection. We recommend that in the diagnostic work-up of patients with suspected endocarditis, Bartonella infection should be sought by serologic testing at an early stage, regardless of the presence or absence of recognized risk factors.In the recent study from Canada and France,


This paper presents a review on recent progress in quantitative structure-property relationship (QSPR) studies of surfactants and applications of various molecular descriptors. QSPR studies on critical micelle concentration (cmc) and surface tension (γ) of surfactants are introduced. Studies on charge distribution in ionic surfactants by quantum chemical calculations and its effects on the structures and properties of the colloids of surfactants are also reviewed. The trends of QSPR studies on cloud point (for nonionic surfactants), biodegradation potential and some other properties of surfactants are evaluated. Therefore, they are soluble in both organic solvents and water. Due to their unique amphiphilic structures, surfactants have been widely used in traditional industries . FurtherOn the other hand, close attention has been given to the impact on the environment, especially on soils and waters, caused by the use of large quantities of surfactants . It is eConsequently, studies on quantitative structure-property relationships (QSPRs) of surfactants and understanding of the effects of molecular structures on their functions and properties are becoming increasingly important ,16. In t2.et al. ..45].ab initio 6-31G basis set, electrostatic potential surface was calculated for dodecyl carboxylate and decyl sulfate and proved that there is a partial negative charge on the alkyl chain of these surfactants . Th. Th45]. factants , α-CH2 w2 is different from those around the other methylene groups and this may lead to its association with water molecules. Huibers et al. have quantified charges on these groups and shown that a relatively high amount of charge is located on the α-CH2 and thus have supported the idea that the α-CH2 belongs to the polar head group [2 and that of the charge on polar head can be the same or opposite. These results showed that existence of local charge on the tail of the alkyl chain of surfactants provide a need to reconsider the properties for micelle cores. Normally, for treatment of micelle formation and solubilization, ‘water drop’ model has been employed without consideration of repulsive interaction between the alkyl chains [2 and terminal methyl group, has an important effect on their properties. Polar head charge and charge on α-CH2 have varying effects on cmc of different surfactants. Inequality of local charges on the alkyl chains can rationalize polarity of micelles and effects of polar head charge on molecular self-assembly.NMR data from Zhao and Fung  also indad group . In addil chains ,50. Obviet al. [Furthermore, using the Huckel molecular orbital theory, Jacobs and Anacker have computed charges on hydrophilic group for decyl pyridinium chloride , findinget al.  have stui.e., to model the solvation environment is a fairly complex process, since this kind of models needs to reflect the characteristics of flowing media with a certain dielectric strength. Consequently, further studies on model establishment theory and calculation capability are needed in order to predict such a complex system as surfactant micelles.In the meantime, it should be realized that the above calculations are based on gaseous-phase models. Although no environmental effects are considered in the calculations and only pure charge distribution is provided, this can be used to compare different surfactants. To consider the environment’s perturbation on charge distribution, 3.2.To study interactions between molecules, some researchers have used solvent-accessible molecular surface area as a descriptor. There have been some reports on descriptors for molecular surface area, atomic charges and charge scaling factors and their applications –56. StanThe geometric model for CPSA descriptor is to utilize overlapping of hard spheres defined by the van de Waals radii of atoms. The calculation for this descriptor was performed with a UNIX system (Sun4/1102) and ADAPT software. Solvent-accessible area calculation adopted SAVOL algorithm developed by Pearlman . Atomic 4.f) calculated by quantum mechanics, total energy of a molecule (ET), molecular mass (Ws) and dipole moment (D) etc to regress vs. minimum surface tension at cmc (γ0) and established several types of related models. Among them, the best model is [Surfactants can to some extent balance interfacial unsaturated force fields to reduce surface tension. Different structures of surfactants and the resulted difference in intermolecular interactions can be understood at different levels. The Wang group has focused on parameters of molecular structure of surfactants , used asmodel is :(9)γ00 contains 30 diverse structures of nonionic surfactants and molecular descriptors ΔHf, ET and D are obtained from calculations using MNDO-MOPAC 7.0. Through energy and electronic parameters, this model set up indirect QSAR between surface tension and electron motion.Their chosen data set of γet al. have also established quantitative models for 20 anionic surfactants with different structures concerning their surface tension reduction effect expressed as surface pressure (II) at different temperatures (t) and different counter ion concentrations (c) [f), dipole moment (D) and Kier & Hall zeroeth-order index (KH0) for hydrophobic moiety. The model containing five descriptors is as follows [Wang ions (c) . This ef follows :(10)Ical values calculated with this model is highly related to the observed values, and the regression equation is as follows:The IIcmcet al. [etc. against these descriptors, and established surface tension prediction models. 146 compounds were selected for the regressions, among which 74 compounds are from alkane type , 44 compounds from α-ester type (accounting for 30.1%), and 28 compounds from alcohol type (accounting for 19.2%) [2 = 0.983, s = 0.4 dyn/cm). After studying inter-correlations of these descriptors, these authors indicated that the topological descriptors are of a significant correlation to the molecular surface area, and intermolecular interaction increases with a rise in the molecular surface area. This will result in a relatively high surface tension, and thus molecular surface area is the most influential factor for surface tension.Stanton et al.  and Stanet al.  have focr 19.2%) . This mor 19.2%) , among w5.versus temperature behavior in water and therefore “cloud out” at some point as the temperature is raised. It is affected by salinity, being generally lower in more saline fluids. Cloud point is a critical factor in the performance of nonionic surfactants (such as those containing polyoxyethylene polymers as their hydrophilic moieties) in detergent formulations [The cloud point of a nonionic surfactant is the temperature where the mixture starts to phase separate and two phases appear, thus becoming cloudy. This behavior is characteristics of non-ionic surfactants containing polyoxyethylene chains, which exhibit reverse solubility ulations ,67. Noniulations ,69.et al. studied cloud point of 20 nonionic surfactants with alkyl zwitterions groups, obtaining QSAR models Cet al. developed another equation to predict cloud point for nonionic surfactants with their several structural, electronic, spatial and thermodynamic properties, and their best regression was [P is the octanol/water partition coefficient, A is the molecular area, Mr is the relative mass, and μ-y and μ-z were the molecular dipole.In 2003, Yuan sion was :(13)Tet al. developed the QSPR models to predict cloud points and study the cloud phenomena of nonionic surfactants in aqueous solution [K, and then to do linear regression in this space. SVM models performed better both in fitness and in prediction capacity. For the test set, they gave a predictive correlation coefficient of 0.9882, root mean squared error of 4.2727, and absolute average relative deviation of 9.5490, respectively. The proposed models can provide some insight into what structural features are related to the cloud points of compounds, i.e., the molecular size, structure, and isomerism of the hydrocarbon moiety and the degree of oxyethylation.In 2006, Ren solution . Four deMore recently, QSPR analysis has been directed to a series of pure nonionic surfactants containing linear alkyl, cyclic alkyl and alkyl phenyl ethoxylates . Modelin6.etc., on biodegradable activity [i.e., carbon-containing) matter is decomposed by the action of micro-organisms present in the environment. The evaluation of biodegradability of anthropogenic organic substances is an essential parameter for environmental risk assessment and required according to appropriate legislation.QSPR studies with respect to cmc, charge distribution and surface tension prediction of surfactants have received a high attention as described above. However biodegradation potential of surfactants should be another highly important issue as this decides their environmental impact. Concerning biodegradation of surfactants, the reported studies include effects of alkyl chain structure (straight and branched chains) and position of branching in the chain, activity –75. BiodBiodegradation with respect to surfactants is defined as primary biodegradation, ultimate biodegradation and ready aerobic biodegradability. Primary biodegradation means the structural change (transformation) of a surfactant by microorganisms resulting in the loss of its surface-active properties due to the degradation of the parent substance. Ultimate biodegradation means the level of biodegradation achieved when the surfactant is completely used by micro-organisms resulting in its breakdown to inorganic end-products such as carbon dioxide, water and mineral salts of any other elements present  and new microbial cellular constituents (biomass). Ready aerobic biodegradability is an arbitrary classification of surfactants which have passed certain specified screening tests for ultimate biodegradability; these tests are so stringent that it is assumed that such ,77.et al. developed a modified river water die-away test for controlling the biodegradability of anionic surfactants and non-ionic surfactants of detergent powders and investigated twelve powders. They found that anionic surfactants were much more easily biodegraded than non-ionic surfactants, and non-ionic surfactants were very different in terms of biodegradability [et al. have carried out a study to research the influence of several environmental factors on the biodegradation of a commercial anionic surfactant (LAS) in waters and sediments of Cadiz Bay (southwest Iberian Peninsula). They concluded that degradation is basically an aerobic process, and hence the introduction of air to the solution will favour it [et al. have conducted a study to interpret the differences in biodegradation of LAS and its coproducts from the electronic structure characteristics and to explore the mechanism of LAS biodegradation. In their research, electronic descriptors of LAS and its cocproducts, including orbital energy, dipole moment, charge distributions and local electronic characteristics of surfactant molecule were calculated by using semiempirical quantum chemical method at the PM3 level. They have explained why biodegradation of model compounds at first takes place in the terminal CH3 group, and they have given two reasonable explanation: (1) there is no transferred H atom in the S-O bond; (2) the degrees of S-O bonding are higher than those of the terminal C-H bonding in the model compounds [Siwiski dability . Sales eavour it . Li et aompounds .PFC surfactants can resist degradation by acids, bases, oxidants, reductants, photolytic processes, microbes and metabolic processes –84. Somei.e., 1-CF3– to 6-CF3–PFOS) were theoretically investigated by density functional theory (DFT) calculations with the B3LYP functional and a 6-31++G basis set [3–PFOS, 5-CF3–PFOS, and 6-CF3–PFOS isomers.Structural, electronic, and thermodynamic properties of linear perfluorooctane sulfonate (PFOS) and its trifluoromethyl-branched isomers . One multiple linear regression model 14 included 46 anionic surfactants belonging to four series of alkyl sulfates and alkyl sulfonates, with the optimal squared correlation coefficient (R2) being 1.000, and the other multiple linear regression model 15 involved 73 structures including polyoxyethylene, acetate, propionate and fluorinated anionic surfactants, with the optimal squared correlation coefficient being 0.993 [It is well known that surfactants are typically amphiphilic molecules that contain both hydrophilic and lipophilic groups. The hydrophile-lipophile balance (HLB) is one of the indicators representing the ratio of the hydrophilicity of a surfactant to its hydrophobicity. The value of HLB number is between 0–60 defining the affinity of a surfactant for water or oil. Chen ng 0.993 .(14)HIt is noteworthy that using these quantum mechanical descriptors can differentiate the differences between the HLB values of different isomers of the surfactants and overcome the difficulty encountered by Davies equation (HLB = ∑(hydrophilic group numbers) + ∑(hydrophobic group numbers)). Davies in the 1950s developed a system based on the analysis of group numbers. The “group number” characterizes the contribution of each specific functional group to the energy that would be required if a solvent molecule were changed from water to an organic solvent .et al. have established a QSPR model between molecular electronegativity—distance vector (MEDV) and HLB Values of anionic surfactants. Their model was examined by both internal and external validation on its stability, and the details were shown in Liu et al. established some QSPR models to predict solubility of nonionic solutes in anionic micelle, and their QSPR models were tested for an external prediction set of 11 compounds randomly chosen from 62 compounds. The squared regression coefficients of prediction for the multiple linear regression and partial least squares regression methods were 0.9679 and 0.9728 respectively [Ghasem ectively .et al. studied effects of surfactants on attachment of bacteria to cellulose acetate (CA) and aromatic polyamide (PA) reverse osmosis membrane [on, MaxQpos and Ka3 stand for the sum of absolute values of charges on nitrogen and oxygen atoms in a surfactant molecule, the largest charge on all atoms and the third-order Hall & Kier index, respectively. Sensitivity analysis of the variables above demonstrated that for CA membrane system, Ka3 and cmc were the most effective factors to determine surface active effects, while dipole moment and other descriptors had very limited effects. For PA membrane system, cmc was a strongest factor, and dipole moment and lgP had very limited effects.Campbell membrane . They anmembrane :(17)Cet al. performed a theoretical study on the formation of rod-shaped micelles from sphere-shaped micelles [c = 8–12), Rh value increased linearly approximately and was more dependent on temperature with the chain length. At high concentrations of NaCl, the growth of micelles depends strongly on temperature, and when concentration of a surfactant is higher than cmc, micelles would be transformed into a cylindrical shape from a spherical shape by bonding to each other [Structure of alkyl chain, especially the chain length, has a direct or indirect effect on properties of a surfactant. By using the methods of quasielastic light scattering spectroscopy, Biz and Occelli derived hydrodynamic radius of alkyl sulphate micelle (Rh) . On the micelles , derivinch other .et al. studied correlation of detergency of some nonionic surfactants with these physicochemical properties and established a QSPR model to predict cleaning effect (Y) [0 is constant; b1, b2 and b3 stand for contribution to cleaning effect from each respective variable; b11, b22 and b33 reveal whether in this effect, variable can give maximum/minimum values; b12, b13 and b23 stand for interaction of different variables. According to this model, detergency effect of surfactants is influenced mainly by (in order of importance): longest carbon chain in the hydrophobic part (redc); critical packing parameter where the branching of the hydrophobic part is taken into account (redcpp); hydrophilic-lipophilic balance (HLB); derivative of the cloud point curve (dCP); relationship between the longest carbon chain and the total amount of carbon in the hydrophobic part (redc/c) and amount of nonethoxylated fatty alcohol . It was also shown that detergency effect of nonionic surfactants was related to cmc, molecular weight, unit of ethyleneoxy in the hydrophilic part and the number of carbon atoms in the hydrophobic part. Washing temperature was affected by the number of different carbon chains present in the hydrophobe (chains), cloud point, etc. These all indicated that detergency effect of surfactants was affected by molecular structures.By changing surfactant concentration, washing temperature and washing time, Lindgren fect (Y) :(19)YWarszynski and Lunkenheimer analyzed experimental results on surface tension for dimethyloxy phosphine with 7–13 carbon atoms in alkyl chain and its homologues , indicatet al. investigated the interaction of CH3 (CH2)7OSO3− with 1 to 6 water molecules at the air-water interface with quantum mechanics [3(CH2)7OSO3− (H2O)n (n = 0–6) and calculate their molecular frequencies at the B3LYP/6–311+G* level. The results revealed that the hydration shell was formed in the form of H-bond between the hydrophilic group of CH3(CH2)7OSO3− and 6 waters. The strength of H-bonds belongs to medium. Binding free energy revealed that the hydration shell was stable. The increase of the number of water molecules will cause increases of the total charge of hydrophilic group and S10-O9-C8 bond angle, but decreases of the alkyl chain length and the bond lengths of S10-O11, S10-O12 as well as S10-O13, respectively.Wang echanics . DFT (deθCH2) indicated that steadiness of solvation free energy as function of alkyl chain length made SDS, SdecS and SOS have similar solvation energy. An important conclusion was drawn from this that the solute existed in polar hydrophobic moiety of micelles, rather than in the nonpolar core part. In addition, an effect of solute functional group on its internal positioning and orientation was also discussed in this work.Based on linear solvation energy relationships (LSERs), Vitha and Carr studied fundamental chemical interactions responsible for solute retention in micellar electrokinetic capillary chromatography (MEKC) . The syset al. have obtained a quantitative structure-property relationship (QSPR) for 30 compounds belonging to six classes with their molecular forms as follows: CnH2n+1COOH, CnH2n+1OH, CnH2n+1NO2, CmH2m+1COCnH2n+1, n-CmH2m+2 and CnH2n+1 pyrrolidone [ΔHf is the heat of formation of molecule, tE is the total electronic energy, ELUMO and EHOMO are the energies of the lowest unoccupied molecular orbit and the highest occupied molecular orbit, KH0 is the Kier and Hall index of zero order of the hydrophobic fragment of compound and RNNO is the relative number of oxygen and nitrogen atoms of the hydrophilic segment. R2, F, s2, and n are the correlation coefficient, the F-test, the standard error, and the number of the regression model, respectively.For predicting the interaction parameters rolidone . By combet al. established two kinds of equations of the surface tension vs. the concentration for ideal binary mixtures of surfactants with Newton iterative method [2H25PO(CH3)2/C10H21PO(CH3)2, C12H25 (CH3)3NBr/C16H33 (CH3)3NBr in aqueous solutions (25 °C), C8F15O2NH4/C9F17O2NH4 in 0.1·mol·L−1 ammonium chloride solution (25 °C). Their research also suggested that the astringency velocity of the two kinds of iterative methods was very fast and the relative error of expression was below 1%. Wang et al. have defined synergisms in surface tension reduction efficiency and mixed micelle formation of binary surfactant mixtures in aqueous solution by appointing the ideal mixture system of surfactants as the standard of comparison, and they have deduced the conditions and the corresponding optimum point values of these two kinds of synergisms based on the regular solution theory and the ideal solution theory [It is known that when more than two surfactants with different molecular structures are mixed, their surface activities often can be increased intensively (synergism) . The inte method . Their an theory .8.In previous paragraphs, the progress in the QSPR studies on surfactants relating to cloud points, charge distribution, surface tension, degradation and other properties have been reviewed . In earlAt present, it has been understood that biological surfactants have some properties which synthetic surfactants do not have, especially in the aspects of biological degradation, safety and physiological activity. For surfactants or molecule with amphiphilic structure ,106, eff


Incidence rates for many cancers are lower in India than in Britain and it is therefore of interest to compare rates in British Indians to British whites, as well as to rates in India. We present estimates for Leicester, which has the largest population of Indian origin in Britain, and also has virtually complete, self-assigned, ethnicity data.We obtained data on all cancer registrations from 2001 to 2006 for Leicester with ethnicity data obtained by linkage to the Hospital Episode Statistics database. Age-standardised incidence rates were calculated for British Indians and British whites as well as incidence rate ratios, adjusted for age and income.Incidence rate ratios for British Indians compared with British whites were significantly less than 1.0 for all cancers combined (0.65) and for cancer of the breast (0.72), prostate (0.76), colon (0.46), lung (0.30), kidney (0.36), stomach (0.54), bladder (0.48) and oesophagus (0.64), but higher than 1.0 for liver cancer (1.95).These results are likely to be the most accurate estimate of cancer incidence in British Indians to date and confirm that cancer incidence in British Indians is lower than in British whites in Leicester, particularly for cancer of the breast, prostate, colon and lung (and other smoking-related cancers), but much higher than in India. There are wide variations in cancer incidence internationally and studies in migrant populations may help explain the relative contribution of genetic and environmental factors to these differences and aid our understanding of cancer aetiology . IncidenSuch comparisons have been of limited accuracy in the past due to the incomplete ethnicity data held by cancer registries. Since 1995, however, self-assigned ethnicity has been recorded in the Hospital Episode Statistics (HES) database (using the same classification as the census) and HES data can now be linked to cancer registration data thus providing more reliable information on ethnicity than was previously available . Deprivation was assessed using the income domain of the Index of Multiple Deprivation 2007 (IMD 2007) and coded according to national quintiles. The IMD 2007 contains seven domains of deprivation: income, employment, health deprivation and disability, education skills and training, barriers to housing and services, crime and living environment . We usedPopulation estimates for the local authority of Leicester were obtained from the 2001 census, stratified by sex, age, ethnicity and quintile of the income domain of the IMD 2007. Analyses were performed using STATA and the R statistical software packages.First, we estimated age-standardised rates of cancer per 100 000 person-years for British Indians and British whites using the 1960 Segi world population, with age at diagnosis of cancer being classified into the following five categories: <45, 45–54, 55–64, 65–74 and >75 years. We then used Poisson regression to estimate incidence rate ratios (comparing British Indians to British whites) adjusting for age and income.The majority of British Indians in Leicester are of Gujarati origin (about 80%) either having come directly from India or via East Africa . We wereThe study was approved by the Oxford Research Ethics Committee.In 2001 the population of the local authority of Leicester was 279 921 with 72 033 people (26%) identifying themselves as British Indian and 169 455 (61%) as British white . DemograIn total there were 6615 cases of cancer over the period 2001 to 2006 in Leicester. Data on ethnicity were available for 98% of these cases with 4609 (70%) British white and 742 (11%) British Indian, as shown in The numbers of cases of individual cancers for men and women and estimates of the age-standardised incidence rates for the most common cancers (at least one case per year) in British whites and British Indians are presented in n=149), prostate (n=63), lung (n=53), non-Hodgkin's lymphoma (n=41) and rectum (n=39) whereas the five most common in British whites were of the lung (n=723), breast (n=710), colon (n=367), prostate (n=423) and rectum (n=179).The five most common cancers in British Indians were of the breast , our results also suggest that overall cancer incidence in British Indians in Leicester is higher than in both Ahmedabad and Mumbai, mainly due to a higher incidence of breast, prostate, lung and colon cancer. Incidence rates for nearly all cancers in British Indians are closer to the rates in British whites than to Indians in India with breast, prostate, lung and colorectal cancer now also the most common cancers in British Indians. Breast cancer incidence in British Indians is still lower than in British whites but their rates would be expected to increase and approach those in British whites as they adopt the reproductive habits and lifestyle of British whites. Incidence rates in the UK are also increased by screening which of course is not present in India. The higher prostate cancer rates in British Indians compared with Indians in India may also reflect increased surveillance in the UK compared with India as well as the effects of changes in lifestyle. The lower lung cancer rates in British Indians compared with British whites are to be expected given the lower prevalence of smoking in British Indians 20–30 years ago, particularly among women . SimilarThe results for colon cancer are particular interesting as rates in British Indians are still much lower than in British whites, which is in contrast to the experience of other migrant groups (e.g. Japanese migrants to the USA) who were found to have similar rates of colon cancer to white Americans within one generation  have antThe results for colon cancer are also in contrast to those for rectal cancer for which incidence rates in British Indians were the same as in British whites. Rectal cancer also has a higher incidence than colon cancer in some parts of India, including Ahmedabad  as it undergoes its own rapid epidemiological transition. We also note that although the incidence of lung, breast and colon cancer is lower in British Indians than in British whites, rates of diabetes and ischaemic heart disease are higher, even though some of the risk factors are similar  . In contWe were unable to analyse Indians by their religion, which would have been useful as there are important differences in lifestyle and culture that could affect the incidence of some cancers (e.g. vegetarianism is much more common in Hindus than Muslims or Sikhs). We also did not have information on whether the British Indians were first or second generation, their age at migration or duration of residence. This would have enabled us to see if rates were higher in those who had been here longer or were born here (and are therefore more likely to be ‘acculturated’ and had greater ‘exposure’ to the UK environment). The comparison of rates between British Indians and India is also limited by the fact that the data from Ahmedabad cover an earlier time period (1993–1997) and there were problems with the quality of the data . There mOur study results are likely to be the most accurate estimate of cancer incidence in British Indians to date and confirm that cancer incidence in British Indians is lower than in British whites, particularly for cancer of the colon, breast, prostate, lung and other smoking-related cancers.We have also shown that cancer incidence in British Indians is much higher than for Indians in India  consistent with the hypothesis that it is changes in environmental factors that are mainly responsible for the changes in cancer incidence, although there may also be differences in genetic susceptibility.


Attention-Deficit/Hyperactivity Disorder (ADHD) is a prevalent, complex disorder which is characterized by symptoms of inattention, hyperactivity, and impulsivity. Convergent evidence from neurobiological studies of ADHD identifies dysfunction in fronto-striatal-cerebellar circuitry as the source of behavioural deficits. Recent studies have shown that regions governing basic sensory processing, such as the somatosensory cortex, show abnormalities in those with ADHD suggesting that these processes may also be compromised.We used event-related magnetoencephalography (MEG) to examine patterns of cortical rhythms in the primary (SI) and secondary (SII) somatosensory cortices in response to median nerve stimulation, in 9 adults with ADHD and 10 healthy controls. Stimuli were brief (0.2 ms) non-painful electrical pulses presented to the median nerve in two counterbalanced conditions: unpredictable and predictable stimulus presentation. We measured changes in strength, synchronicity, and frequency of cortical rhythms.Healthy comparison group showed strong event-related desynchrony and synchrony in SI and SII. By contrast, those with ADHD showed significantly weaker event-related desynchrony and event-related synchrony in the alpha (8–12 Hz) and beta (15–30 Hz) bands, respectively. This was most striking during random presentation of median nerve stimulation. Adults with ADHD showed significantly shorter duration of beta rebound in both SI and SII except for when the onset of the stimulus event could be predicted. In this case, the rhythmicity of SI (but not SII) in the ADHD group did not differ from that of controls.Our findings suggest that somatosensory processing is altered in individuals with ADHD. MEG constitutes a promising approach to profiling patterns of neural activity during the processing of sensory input  and facilitating our understanding of how basic sensory processing may underlie and/or be influenced by more complex neural networks involved in higher order processing. Attention-Deficit/Hyperactivity Disorder (ADHD) is an impairing neurodevelopmental disorder that remains inadequately understood. Along with the observable behavioral symptoms of inattention and hyperactivity/impulsivity, there is robust evidence of structural, functional, and neurochemical brain differences in ADHD -3 particforms of impairment but also of multiple sources of impairment. Emerging evidence not only shows abnormalities in neural regions governing higher order function but also in regions governing basic function such as somatosensory cortex .SAM analysis indicated that for individuals in both the comparison and ADHD groups, the control period showed little or no somatosensory activation with average peak values being approximately 5% of active period values . In the control group, the early ERS in SI was a broad-frequency increase in power occurring approximately 20 to 200 ms post-stimulus. This immediate response was followed by a broad-frequency ERD; a transitory suppression of source power below baseline that occurred from 200 to 400 ms post-stimulus. Following the suppression, the final phase of activity demonstrated a rebound of ERS specific to the beta band that began approximately 400 ms after median nerve stimulation and lasted for about 1200 ms  plots clearly demonstrated that there were three distinct phases of rhythmic changes in the somatosensory cortex. These occurred in both primary and secondary cortices  in both controls and those with ADHD; (i) early-ERS (approximately 20 to 200 ms post-stimulus); (ii) ERD (approximately 200 to 400 ms post-stimulus); and (iii) late-ERS, known as s Figure . Our finIn the ADHD group the early SI ERS, occurring approximately 20 to 200 ms post-stimulus, was characterized by strong early ERS in the lower bandwidths  and high beta band (25+ Hz), with more moderate activity in the midrange (10 to 22 Hz) compared to baseline. ERD occurred across the spectrum of frequencies from 200 to 400 ms post-stimulus while beta rebound ERS commenced at approximately 400 ms but continued for only 600 ms which was considerably shorter in duration than controls Figure .Group comparisons revealed that adults with ADHD showed substantially less power between 10 and 15 Hz during the early ERS, compared to the control group and substantially less power during beta rebound Figure . The grop > 0.05]. Permutation analysis revealed that the grand averaged time-frequency responses for controls did not differ statistically between the random and predicted stimulus conditions  = 0.198, p > 0.05] or from the control predicted temporal onset . Interestingly, permutation analyses of the ADHD TFRs suggested a a slight within-group difference between conditions from 1200 to 1500 ms in the 17 to 25 Hz range  = 0.79, In the control group, the TFR analysis of the early SI ERS revealed intense activity from 5 Hz to 50+ Hz followed by ERD and a strong beta rebound ERS Figure . NotablyThe TFR analysis of the ADHD group showed a strong early ERS in the lower bandwidths  and high beta band (25 to 40 Hz), but little power in the midrange (10 to 22 Hz) followed by ERD and a rebound ERS composed of strong activation during the first half of the rebound period and reduced activation in the latter half Figure . AdditioEven though we observed some general group differences in power of the early ERS, ERD, and beta rebound ERS in the Predicted condition Group comparisons between controls and those with ADHD Figure  there weSAM analyses showed prominent activation of secondary somatosensory cortices (SII) within the parietal operculum. Bilateral SII activation was observed with contralateral and ipsilateral activity profiles being very similar. For brevity, only contralateral SII information, the recipient of contralateral SI information, is reported.p > 0.05].The control and ADHD groups both showed consistent, robust peak activity in SII Figure . For conThe grand-averaged TFR In the control group showed strong early ERS in the trial followed by strong ERD and beta rebound ERS activity similar to that observed in SI. The early ERS and the ERD was characterized by robust activity from 5 to 20 Hz, with the strongest activity oscillating around 7 Hz while frequencies 15 to 30 Hz contributed to the ensuing rebound Figure . By contGroup comparisons revealed that overall, SII responding of adults with ADHD showed markedly less source power than that of controls Figure . These gp > 0.05]. Grand averaged time-frequency responses did not statistically vary between the two conditions they experienced  = 0.651, p > 0.05] Grand averaged time-frequency responses did not statistically vary between the two conditions the ADHD group experienced except for the period of ERD in which the SII response showed significantly more desynchrony in the alpha band (between 8 and 10 Hz) in the predicted condition than in the random one  did not statistically vary between random and predicted conditions [t(9) = -0.318, In the control group, SII exhibited strong early ERS from 5 Hz to 25 Hz followed by ERD and beta rebound ERS, consistent with the control Random SII response. Similar to the SI Predicted response and contrary to the SII Random response, the SII Predicted control response showed mu ERD followed by a rebound ERS late in the trial Figure .In the ADHD group, the SII predicted response showed modest early ERS composed mostly of alpha and some beta oscillations followed by corresponding ERD and a small beta rebound ERS. Minor activation around 10 Hz from 1000 ms to 1600 ms suggests a faint mu rebound effect Figure .Group comparisons revealed that, as in SII Random, the overall responding of adults with ADHD was considerably less than the controls Figure . The perThere were no group differences in their detection of stimulus patterns during median nerve stimulation: where no participants detecting a pattern during the random condition and all participants reported detecting a pattern during the predicted stimulus condition.This study used MEG with median nerve stimulation to determine whether somatosensory processing was altered in adult ADHD. We measured frequency specific changes in evoked spatiotemporal patterns of neural activation in response to non-painful electrical stimuli in adults with and without ADHD. Major findings included a marked reduction in the duration of beta rebound in the ADHD group compared to controls in both SI and SII. Beta rebound is a post-stimulus beta phenomenon which commences approximately 400 – 600 ms after median nerve stimulation. Additionally, the ADHD group showed a substantial decrease in SII alpha and beta power during ERD  and ERS .or predictably presented, the ADHD group showed substantive power decreases in SII alpha and beta ERD and SII beta rebound ERS relative to controls as well as a significantly shorter SII beta rebound. From SI, somatosensory information is thought to project to SII, where stimulus information is integrated and contextualized [When the stimuli were randomly presented, the ADHD group showed reduced SI ERS power during the immediate N20m response and a significantly shorter SI beta rebound than the controls. This suggests that incoming somatosensory information is less well-characterized at a basic neural level in those with ADHD. Irrespective of whether stimuli were randomly tualized ,63. WithTo our knowledge this is the first demonstration of reduced duration of somatosensory evoked beta rebound in a clinical population. Little is known regarding the functional significance of the beta rebound response. Historically, beta rebound was thought to be an epiphenomenon that originated in the motor cortex in response to volitional movement . More reFurther evidence supports the notion that beta rebound plays a significant role in cortical inhibition of neural regions unrelated to current task performance . For insTo our knowledge, this is the first application of MEG to investigate changes in somatosensory alpha or beta power in individuals with ADHD. Here we demonstrate that adults with ADHD showed less changes in source power in the alpha and beta bands overall in response to a somatosensory stimulus. Correspondingly, reduced alpha and beta powers have consistently been associated with ADHD EEG profiles (review: ). IntrigOur findings support the notion that cortical oscillations are altered during somatosensory processing in those with ADHD. It is possible that impaired somatosensory processing may impede sensorimotor development, as has been found in a substantial proportion of children with ADHD -74. Our Our study is limited by the fact that we were unable to investigate effects of gender, comorbidity, or treatment history as the sample of adults with ADHD used in this study was small and heterogeneous, with variation in age, comorbidity, and/or medication . Additionally, right hemisphere SI activity was not investigated as median nerve stimulation was only delivered to the dominant arm. In spite of these limitations, several findings reach statistical significance, emphasizing the powerful nature of the differences in somatosensory processing between the two groups. Future studies will investigate the effects of gender, comorbidity, and medication, as well as the activity of the right SI in response to a contralateral stimulus. Future steps to examine the cortical activity in regions that are in communication with the somatosensory cortex are necessary goals to further elucidate differences in basic processing in individuals with ADHD.In summary, this study revealed several novel observations regarding somatosensory activity in an ADHD population. It is the first to profile somatosensory ERS and ERD in ADHD and the first to show that beta rebound is not a uniform phenomenon but one that can be modified in the presence of a psychiatric disorder. Profiling impaired cortical rhythms in response to basic sensory processing in ADHD will provide a more in depth understanding of the breadth of deficits in individuals with ADHD and aid in reconstructing the conceptualization and clinical understanding of ADHD.The author(s) declare that they have no competing interests.CD developed the design of the study, carried out MEG recordings (subject testing), statistical analyses, and drafted the manuscript. WG participated in the design of the study, contributed to the interpretation of the results. DC participated in the design of the study and contributed to the development of the source analysis methods and interpretation of the results. FW carried out MEG recordings, statistical analyses, and computer programming. FXC contributed to the interpretation of the results. RT participated in the overall conceptualization and supervision of project, including the design and interpretation of the results, All authors read, contributed to, and approved the final manuscript.Example of a control subject's SAM peak locations and values during control  and active  states in somatosensory cortexClick here for fileExample of an ADHD subject's SAM peak locations and values during control (SAM = 1.3) and active  states in somatosensory cortexClick here for fileControl SI Frequency and Power Dynamics During Predicted versus Random Presentation of a Somatosensory Stimulus (A). Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for control subjects during Predicted presentation of a stimulus. The plot was baselined using the average spectral energy observed in the pre-stimulus period (-100 – 0 ms). (B) Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for control subjects during Random presentation of a stimulus. (C) Mean TFR differences between conditions. (D) Statistically significant values remaining once condition differences were thresholded to p </= 0.05.Click here for fileADHD SI Frequency and Power Dynamics During Predicted versus Random Presentation of a Somatosensory Stimulus (A). Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for subjects with ADHD during Predicted presentation of a stimulus. The plot was baselined using the average spectral energy observed in the pre-stimulus period (-100 – 0 ms). (B) Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for subjects with ADHD during Random presentation of a stimulus. (C) Mean TFR differences between conditions. (D) Statistically significant values remaining once condition differences were thresholded to p </= 0.05.Click here for fileControl SII Frequency and Power Dynamics During Predicted versus Random Presentation of a Somatosensory Stimulus (A). Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for control subjects during Predicted presentation of a stimulus. The plot was baselined using the average spectral energy observed in the pre-stimulus period (-100 – 0 ms). (B) Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for control subjects during Random presentation of a stimulus. (C) Mean TFR differences between conditions. (D) Statistically significant values remaining once condition differences were thresholded to p </= 0.05.Click here for fileADHD SII Frequency and Power Dynamics During Predicted versus Random Presentation of a Somatosensory Stimulus (A). Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for subjects with ADHD during Predicted presentation of a stimulus. The plot was baselined using the average spectral energy observed in the pre-stimulus period (-100 – 0 ms). (B) Grand Mean TFR of the individual, virtual channel, spatially-filtered single trials for subjects with ADHD during Random presentation of a stimulus. (C) Mean TFR differences between conditions. (D) Statistically significant values remaining once condition differences were thresholded to p </= 0.05.Click here for file