Children with attention-deficit/hyperactivity disorder (ADHD) are characterized by deficits in their executive functioning and motivation. In addition, these children are characterized by a decline in performance as time-on-task increases . However, it is unknown whether these time-on-task effects should be attributed to deficits in executive functioning or to deficits in motivation. Some studies in typically developing (TD) adults indicated that time-on-task effects should be interpreted as depletion of executive resources, but other studies suggested that they represent depletion of motivation. We, therefore, investigated, in children with and without ADHD, whether there were time-on-task effects on executive functions, such as inhibition and (in)attention, and whether these were best explained by depletion of executive resources or depletion of motivation. The stop-signal task (SST), which generates both indices of inhibition  and attention (reaction time variability and errors), was administered in 96 children . To differentiate between depletion of resources and depletion of motivation, the SST was administered twice. Half of the participants was reinforced during second task performance, potentially counteracting depletion of motivation. Multilevel analyses indicated that children with ADHD were more affected by time-on-task than controls on two measures of inattention, but not on inhibition. In the ADHD group, reinforcement only improved performance on one index of attention . The current findings suggest that time-on-task effects in children with ADHD occur specifically in the attentional domain, and seem to originate in both depletion of executive resources and depletion of motivation. Clinical implications for diagnostics, psycho-education, and intervention are discussed.The online version of this article (doi:10.1007/s00787-017-1006-y) contains supplementary material, which is available to authorized users. Children with attention-deficit/hyperactivity disorder (ADHD) are characterized by inattention, hyperactivity, and/or impulsivity, which lead to problems in multiple domains. For example, children with ADHD have more academic problems  and adveWith regard to the executive pathway, several meta-analyses indicate that children with ADHD are impaired on multiple executive functions (EF) –11. For With respect to the motivational pathway, many empirical studies as well as theoretical models suggest aberrant motivation in children with ADHD (see  for an oEF performance in children with ADHD is often more characterized by a stronger decrease in performance over time (time-on-task) as compared to TD controls . It has Dual pathway models of ADHD do not directly speak to the role of motivation on time-on-task effects. However, the effect of motivation on time-on-task effects is central in the literature on resource depletion in healthy adults. Some resource depletion theorists argue that self-control capacities, a concept highly related to EF , are limTo sum up, the current study combines dual pathway models of ADHD and resource depletion models of time-on-task effects in healthy adults, to assess the origin of time-on-task effects in children with ADHD. That is, we test whether children with ADHD are more affected by time-on-task effects than TD children. To investigate the nature of these time-on-task effects, depletion of resources and depletion of motivation were disentangled. Children with and without ADHD performed twice on the stop-signal task SST; , 31), wh, wh31]),First, we hypothesize degraded performance of children with ADHD as compared to TD children in the first task and in the second task without reinforcement (effects of group) –11. SecoADHD participants were recruited from an academic outpatient mental healthcare center and TD control participants were recruited from elementary schools. In the ADHD group, children were included when they were diagnosed with ADHD , according to the assessment by expert psychologists or psychiatrists from the academic outpatient mental healthcare center, following DSM-IV-TR criteria . There wWhen using stimulant medication, participants were instructed not to take their medication on the day of testing, to reach total washout . InformeResponse inhibition and, indirectly, attention were measured with the standard stop-signal task SST; , 31), wh, wh31]),The SST was administered twice , both administrations consisted of one practice block and four experimental blocks of 56 trials each. In this task, children have to press one out of two marked buttons on the keyboard, corresponding to green go signals appearing in the center of the screen, as fast and accurate as possible . In T1 [X] required a left response and [O] required a right response; these were replaced by [H] and [S], respectively, at T2 to prevent learning effects. A choice between two response keys is necessary to create time to process a potential stop signal. This presentation order was counterbalanced across participants . In 25% of the cases, the green go signal turned red, indicating that the response tendency had to be inhibited. To ensure that participants succeeded to inhibit their response in 50% of the cases, the time between the go signal and the stop signal was adaptive. That is, if stopping was successful, the interval between the go signal and the stop signal  of the following stop trial was increased by 50 ms, making it harder to inhibit. On the other hand, if the participant failed to stop, the stop-signal delay of the following stop trial was shortened by 50 ms, making inhibition easier. Accordingly, the stop-signal reaction time (SSRT) can be estimated. This reflects the estimated mean time required to inhibit responses to stop signals, implying that a short SSRT indicates good inhibitory capacities. SSRT was calculated according to the integration method and the race model . AssuminFurthermore, the SST provides an index of choice errors , omission errors on go trials , and reaction time (including its variance). More omission errors, slower mean RT, and higher RT variability  are associated with problems in the domain of attention . More spTo induce time-on-task effects, the SST was administered twice in succession. Before every block, children were instructed to respond as fast and accurate as possible to go trials and to withhold their response if the signal turned red . To avoid adoptation of a waiting strategy, participants were also told that it was not allowed to wait for the signal to become red. In the second task, participants were randomly assigned to either a reinforcing or a non-reinforcing condition. In the reinforcing condition, children were told that they could earn coins which could be used to “buy” a present at the end of the task if they had earned at least ten coins. Reinforcement was not aimed at any specific aspect of the SST, and children were instructed to respond as fast and accurate as possible. Although the present was emotionally appealing for the participants, the monetary value was about 0.50 euro. To motivate participants, the box with presents was already shown before the beginning of the second task. After each block, children were informed on the screen about the amount of earned coins. Feedback on the amount of earned coins was manipulated; the cumulative amount of coins shown after each block was, respectively, 2, 5, 7, and 9 or 10.A repeated measures design with one within-subjects factor  and two between-subjects factors  was used. Note, however, that the design is not fully crossed, as none of the participants was reinforced during the first task. A fully crossed design would have led to power difficulties, given the limited availability of participants. Therefore, the current data could not be analyzed with a regular repeated measures analysis, but were analyzed with a multilevel analysis with time as a first level variable and group and reinforcement as second level variables . Age wasFive dependent variables were derived from the SST see “” section15 participants were excluded from the analyses . Four of them were excluded due to procedural errors. In addition, 11 participants were excluded because of aberrant performance: one ADHD participant refused to continue with the second task; one ADHD participant made choice errors on more than 50% of the go trials (at T1), indicating difficulty in understanding the task; one ADHD participant had a very abnormal response pattern in which RT variability was larger than mean RT (at T2 without reinforcement); four participants were excluded, because SSRT was below 100 ms, indicating that SSRT estimation was not reliable for these participants ; four participants were excluded, because the standardized value of at least one of the outcome measures was more than three standard deviations from the average  = 3.21, p = 0.002). Therefore, age was added as covariate in all further analyses. Groups also differed in gender  = 13.8, p < 0.001). For extra analyses with gender added as covariate, see Appendix 2.After exclusion, the sample consisted of 96 participants . Differences between the ADHD group and the TD control group were significant with regard to age. The mean age was 11.2 (SD = 1.0) and 11.8 (SD = 0.68) years for ADHD and TD controls, respectively: In the ADHD group, 31 children were diagnosed with the combined type, 5 with the inattentive type, 2 with the hyperactive-impulsive type, and 4 children were diagnosed with ADHD not otherwise specified. With regard to comorbidity, 24 children had no comorbid diagnosis, 7 children had a comorbid learning disorder, 5 had a comorbid disruptive behavior disorder , 3 had a comorbid parent–child relational problem, 2 had a comorbid mood disorder, and 1 had a comorbid communication disorder.p > 0.05). ANCOVAs revealed only group differences at baseline for reaction time variability  and omission errors . No differences were found for SSRT , mean reaction time , and choice errors   for all outcome measures in which we controlled for age differences between groups. The assumption of parallel regression lines was not violated for all five outcome measures  = −5.04, p < 0.001] and made more omission errors . No differences between ADHD and TD controls at T2 were found for SSRT, mean reaction time, and choice errors.When comparing ADHD and TD control groups at T2 (without reinforcement), the multilevel analysis indicated that participants with ADHD had a larger reaction time variability  and more omission errors  on the second task without reinforcement, as compared to the first task. No differences between T2 and T1 in ADHD were found for SSRT mean reaction time and choice errors. Time-on-task effects were thus only found on indices of attention, but not on inhibition.Children with ADHD were characterized by increased reaction time variability . As shown above, in the ADHD group, reaction time variability increased on the second as compared to the first task. The positive t value for the interaction effect indicates that this effect was less pronounced in the TD group. Visual inspection of the effect  = 3.70, p < 0.001]. In children with ADHD, the amount of omission errors increased on the second as compared to the first task , whereas visual inspection suggests that the amount of omission errors in the TD control group even decreased  = −2.73, p = 0.008]. Reinforcement did not influence SSRT, mean reaction time, omission errors, and choice errors. This indicates that children with ADHD performed better when they were reinforced as compared to when they were not reinforced, but only with regard to RT variability.Children with ADHD who were vs. were not reinforced were characterized by lower RT variability , whereas children with ADHD and comorbid disorder(s) had higher SSRTs than controls .Potential explanations might relate to participant characteristics. For example, only a subgroup of children with ADHD is characterized by inhibitory deficits –56. FurtF 1,6 = 1.4, Relatedly, Daugherty and colleagues  explain However, increased RT variability in children with ADHD as compared to TD control children was apparent both at baseline and on the second administration without reinforcement. This concurs with a large body of literature, arguing that increased RT variability is a typical and robust finding in ADHD . RT variability and omission errors have been linked to problems with sustained attention and attentional lapses , 42, 58.With respect to the third hypothesis, the effect of reinforcement in ADHD was partly as expected: reinforced children with ADHD had a smaller RT variability as compared to children with ADHD who were not reinforced in the second task, which might indicate that reinforcement prevented attentional lapses. This finding is in line with a recent meta-analytic review that found small improvements in RT variability as a result of external reinforcement .However, no effect of reinforcement was found on all other outcome indices. This implies that, among all outcome variables, RT variability might be particularly sensitive to the effects of reinforcement. Furthermore, discordant to expectations, reinforcement effects did not differ between groups for all indices, implying that children with ADHD did not profit more from reinforcement than their typically developing peers. This contradicts several studies, reporting that children with ADHD profited more from reinforcement . In terms of depletion theories, reinforcement prevented a time-on-task effect on RT variability, implying that the time-on-task effect in the non-reinforced condition could be, at least partly, explained by a depletion of motivation. On the other hand, reinforcement did not affect the time-on-task effect on omission errors, implying that this time-on-task effect could be driven by a depletion of executive resources. Finally, no time-on-task effects were found on other indices, among which inhibition. This implies that, compared to lower level attentional capacities, higher order executive functions, such as inhibition, seem to be less susceptible to the effects of depletion of executive resources and depletion of motivation.t (91.24) = −2.02, p < 0.05]. Therefore, this additional analysis partly supports our conclusion that problems (in this case attention lapses) originating in a depletion of motivation can be counteracted with reinforcement.In the current study, slower mean RTs and higher RT variability  were interpreted as potential indicators of attention lapses. However, as attention lapses produce a skew in RT distributions, an ex-Gaussian model might be more appropriate, in which a third parameter (τ) indexes this skew specifically  . Conceivably, these excluded participants had most pronounced symptoms, and effects were larger if data from these children were taken into account (see Appendix 3 for results without excluding any of the participants). These testing difficulties demonstrate an obvious limitation of the depletion paradigm, in which multiple monotonous tasks are administered in succession, in samples with ADHD. This is in line with a recent meta-analytic review, which described an increase in core ADHD symptomatology  in highly cognitive demanding situations as compared to situations with low cognitive demands . Therefok = 24, n = 937). Hence, inhibitory problems in the control group seem unlikely.Second, it would have been more optimal to diagnose ADHD participants by means of a semi-structured clinical interview, as the currently used clinical diagnoses might be more lenient and potentially included some children with ‘subclinical’ ADHD. Relatedly, clinical diagnoses might be subject to biases . HoweverThird, the absence of reinforcement effects is interpreted as evidence in favor of executive over motivational depletion. However, self-evidently, another explanation for the absence of those effects could be that statistical power was not high enough. Therefore, these results should be interpreted with caution.Fourth, the validity of the SSRT as a pure index of response inhibition is subject to debate. This SSRT deficit might reflect general attentional or cognitive processes that go beyond purely inhibitory processes , 49. HowThe current study has several implications, for future research as well as for clinical practice. EF was assessed under depleting circumstances, which matches most children’s daily school routine, in which they have to use their EFs over prolonged periods of time. This is not to say that we advocate the SST as an ecologically valid EF instrument, as laboratory EF tasks do not correlate well with real life measures  and the Our results showed that attentional problems in ADHD became more apparent in the second task. Moreover, the relatively large drop-out in our study potentially indicates that core psychiatric symptoms might come to light easier after a certain amount of time. Hence, we recommend future research to further investigate the diagnostic value of this paradigm in clinical samples.With regard to treatment of ADHD, psycho-education to children with ADHD and their parents and teachers should emphasize the tendency for problems to increase after prolonged exertion. If children recognize depletion, they can be taught to adjust their behavior accordingly, for example, by taking a short break or switch to less demanding tasks. Furthermore, we suggest therapists to keep their sessions short and offer short breaks, to prevent attentional lapses. If time-on-task effects occur, for example, during school work, this can be partly counteracted with reinforcement.The current approach was adopted to distinguish between depletion of executive resources and depletion of motivation. However, recent studies show that children with ADHD show heterogeneous patterns of deficits, some having especially deficits in executive functioning, whereas in others, mainly, motivational aberrations are observed , 72, 73.In sum, children with ADHD are more affected time-on-task effects than TD controls, as shown on measures of inattention (RT variability and omission errors), but not inhibition. These time-on-task effects seem to originate in a depletion of executive resources as well as a depletion of motivation. Offering external reinforcement is a promising way to compensate for depletion of motivation and, consequently, to prevent attention lapses in children with ADHD. The depletion paradigm offers both a new perspective on diagnostic assessment of ADHD and provides further clues for optimizing treatment of children with ADHD.Supplementary material 1 (DOCX 19 kb)Supplementary material 2 (DOCX 22 kb)Supplementary material 3 (DOCX 21 kb)Below is the link to the electronic supplementary material.


MAOA and MAOB genes in the etiology of ADHD. Due to high heritability rate of ADHD, we tested familial transmission of MAOA and MAOB variants to ADHD probands in 190 nuclear families having ADHD probands from Indo-Caucasoid ethnicity.Attention deficit hyperactivity disorder (ADHD) is an etiologically complex childhood onset neurobehavioral disorder characterized by age-inappropriate inattention, hyperactivity, and impulsivity. Symptom severity varies widely and boys are diagnosed more frequently than girls. ADHD probands were reported to have abnormal transmissions of dopamine, serotonin, and/or noradrenaline. Monoamine oxidase A (MAOA) and B (MAOB), mitochondrial outer membrane bound two isoenzymes, mediate degradation of these neurotransmitters and thus regulating their circulating levels. Case-control analyses in different populations, including Indians, suggested involvement of Subjects were recruited following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV). Appropriate scales were used for measuring the behavioral traits in probands. Genotyping was performed through PCR-based amplification of target sites followed by DNA-sequencing and/or gel-electrophoresis. Data obtained were analyzed by family based statistical methods.MAOA and rs4824562, rs56220155, rs2283728, rs2283727, rs3027441, rs6324, rs3027440 from MAOB). Statistically significant maternal transmission of alleles to male probands was observed for MAOA rs5905809 ‘G’ (p = 0.04), rs5906957 ‘A’ (p = 0.04), rs6323 ‘G’ (p = 0.0001) and MAOB rs56220155 ‘A’ (p = 0.002), rs2283728 ‘C’ (p = 0.0008), rs2283727 ‘C’ (p = 0.0008), rs3027441 ‘T’ (p = 0.003), rs6324 ‘C’ (p = 0.003), rs3027440 ‘T’ (p = 0.0002). Significantly preferential maternal transmissions of different haplotype combinations to male probands were also noticed (p < 0.05), while female probands did not reveal such transmission bias. Behavioral traits of male probands exhibited significant association with gene variants. Age of the mother at pregnancy also revealed association with risk variants of male probands.Out of 58 variants present in the analyzed sites only 15 were found to be polymorphic  contains supplementary material, which is available to authorized users. Attention deficit hyperactivity disorder (ADHD) is an etiologically complex neurobehavioral disorder, diagnosed mostly during early childhood . The disBeing a multi-factorial disorder with almost 76% heritability , 12, ADHTwo flavin containing isoenzymes, monoamine oxidase A (MAOA) and B (MAOB), help in the deamination of biogenic amines from both endogenous and exogenous sources , 24. BotMAOA gene showed association with aggressive phenotypes across species [MAOA gene, encoding for the MAOA enzyme, a prime candidate for ADHD [In men of a Dutch family, MAOA deficiency showed association with aggressive behavior  and dele species –31. MAOA species  and a po species , making for ADHD , 34, 35.MAOB polymorphisms [MAOB was also postulated to regulate impulsivity, attention and vulnerability to ADHD through metabolism of dopamine, although to a lesser extent as compared to MAOA , 32. Cororphisms . Howeverorphisms .MAOA knockout mice showed increased levels of serotonin, norepinephrine and dopamine in the brain [MAOB knockout mice [MAOA or MAOB single knockout mice [Proportional analysis in patients revealed that the absence of MAOA leads to greater change in neurotransmitter metabolism than absence of MAOB . While Mhe brain , only leout mice . MAOA anout mice  and incrout mice .MAOA and MAOB genes, located on the X chromosome [MAOA and MAOB gene variants were studied and the data obtained were neither consistent nor conclusive [MAO gene variants revealed association of a number of variants with ADHD [MAOA and MAOB [In this backdrop of information, both romosome , were coromosome , 44–46. nclusive , 44–47. ith ADHD , 49. DueA total of 190 ADHD probands  and their biological parents, of Indo-Caucasoid ethnicity from the eastern India, were recruited from the out-patient department of Manovikas Kendra Rehabilitation and Research Institute for the Handicapped, Kolkata, India. Diagnosis was performed by child psychiatrist and clinical psychologist following the Diagnostic and Statistical Manual of Mental Disorders-4th edition (DSM-IV) criteria . 74.74% Peripheral blood of the study participants was collected by a trained phlebotomist and used for genomic DNA preparation following the standard protocol . The tarMAO genes are located on the X-chromosome. For the same reason, family-based analysis on male ADHD probands was carried out considering only the maternal transmission. Paternal transmission was considered for female ADHD probands only. Haplotype-based haplotype relative risk (HHRR) analysis [MAO genes are X-linked, for female probands the parental genotype data and for male probands only the maternal genotype data were used for comparative analysis.Genotypic counts of only the female subjects  were used for analyzing the Hardy-Weinberg equilibrium , since tanalysis  was perfanalysis  to identanalysis . Pair-wianalysis , consideN = 166). DSM-IV score for ODD trait and PACS for conduct problems of ADHD probands were also obtained. CPRS-R ‘T scores’ ranged between 38 to 90 while DSM-IV scores and PACS scores ranged between 0 to 36 and 0 to 90 respectively. Behavioral traits/scores of ADHD probands were utilized for genetic association analysis. Male probands were divided into two sub-groups based on the presence/absence of the derived allele of each variant. Allelic association with behavioral scores was analyzed using Student’s t-test [N = 109) were considered under ‘early onset’, while those with detectable symptoms after 7 years (N = 57) were classified under the ‘late onset’. Association of alleles with age-of-onset of ADHD in the male probands was calculated using the chi-square test [N = 71) were compared to that of male probands born to mothers at >26 years (N = 81) of age using the chi-square test [Based on the CPRS-R, respective ‘T scores’ for oppositional behavior, cognitive problems / inattention, hyperactivity, and ADHD index were obtained for ADHD probands  were found to be polymorphic. All the studied polymorphic variants followed the Hardy-Weinberg equilibrium in the female subjects, i.e. female ADHD probands and mother of the ADHD probands , rs5906957 ‘A’ (p = 0.04) and rs6323 ‘G’ (p = 0.0001) alleles and MAOB rs56220155 ‘A’ (p = 0.002), rs2283728 ‘C’ (p = 0.0008), rs2283727 ‘C’ (p = 0.0008), rs3027441 ‘T’ (p = 0.003), rs6324 ‘C’ (p = 0.003) and rs3027440 ‘T’ (p = 0.0002) alleles to the male probands  (Table p = 0.002) intra-genetic haplotypes of MAOA were rs5906883-rs6323 ‘C-G’, rs5905809-rs6323 ‘G-G’, and rs5906957-rs6323 ‘A-G’ (Table p = 1.66E-05) intra-genetic haplotypes of MAOB were rs3027440-rs2283727 ‘T-C’ and rs3027440-rs2283728 ‘T-C’  were rs6323-rs2283727 ‘G-C’ and rs6323-rs2283728 ‘G-C’ (Table p ≤ 0.05) of several haplotypes were also noticed . CPRS-R ‘T scores’ obtained were 62.81 ± 1.23 for oppositional behavior, 72.38 ± 0.79 for cognitive problems / inattention, 74.50 ± 0.99 for hyperactivity, and 71.74 ± 0.68 for ADHD index. DSM-IV scores for ODD trait was 15.05 ± 0.85 and PACS scores for conduct problems was 16.77 ± 1.19. Male ADHD probands having rs6323 ‘MAOA 30 bp-uVNTR 3-repeat (3R), rs6323 ‘G’, and rs1137070 ‘T’ variants in the male ADHD probands  haplotype was observed [MAOA variant was reported by family based study [MAOA polymorphisms were reported to be transmitted to only the male probands having hyperactive/impulsive subtype [Several investigators have tried to find out whether nclusive –47, 68. ociation . In Euroto do so . In the observed . In Cauced study . In the ed study . In the  subtype .MAOA variants with the disorder [MAOA variants [MAOA and MAOB with ADHD could be due to ethnic variations in the frequency of risk variants in the population.On the contrary, in Caucasian ADHD subjects from the United Kingdom, family based association studies found no significant association of disorder , 71. A lvariants . This reN = 73) revealed preferential maternal transmission of the 30 bp-uVNTR ‘3R’ allele to the male probands [N = 126) revealed biased transmission of ‘3R-T’ haplotype (30 bp-uVNTR-rs6323) with high relative risk (8.06e + 007) indicating significant risk of association with ADHD [3R-T’ haplotype to the male probands [MAOA and MAOB genes. Out of the 58 variants, only 15 were polymorphic in this population. Statistical analysis was conducted on ADHD subjects (N = 190) stratified based on gender since MAO genes are located on the X-chromosome and dosage is different in the male probands as compared to the females. Significantly preferential maternal transmissions were observed for MAOA  and MAOB  variants in the male probands. Maternal transmissions to the male probands were also biased for several haplotypes. The 30 bp-uVNTR ‘3R’ allele, as part of haplotypes with other variants, showed transmission bias in the male probands. This observation provided further support to our earlier notion that the ‘30 bp-uVNTR 3R allele’ could be a risk factor for ADHD and is maternally transmitted to the male probands. This bias may, at least partly, be responsible for the male preponderance of the disorder. Further, preferential transmission of MAOA and MAOB variants from the mother to the male probands could be responsible for the higher heritability of the disorder, at least in this population. In the female ADHD probands, no such bias in parental transmissions was observed. However, the number of female probands was limited in the present investigation. Further investigation, involving large cohort of subjects from different ethnicity, would help us to elucidate the actual role of MAO in the etiology of ADHD.Our earlier investigation on limited number of Indo-Caucasoid ADHD probands  and three MAOA variants, 30 bp-uVNTR ‘3R’, rs6323 ‘G’, and rs1137070 ‘T’ in the male ADHD probands. Out of these three variants, rs6323 also exhibited transmission bias, association with behavioral problems, formed part of haplotypes and was in strong LD with various variants. On the basis of this observation, it may be concluded that these MAOA variants, with higher occurrence in probands born to younger mothers, may be contributing to the pathophysiology of ADHD.This first ever investigation on association between maternal age and The major limitation of the present study was the sample size and hence, further in depth analysis on a large cohort of samples belonging to different ethnic groups would help in validation of the present observation.MAOA and MAOB gene variants could be considered as risk factors for ADHD in the Indo-Caucasoid population from eastern India. Our study also revealed association of gene variants with behavioral problems often detected in ADHD subjects and thus could be useful for therapeutic intervention of these subjects. Probands with 30 bp-uVNTR ‘3R’ allele may not show improvement in behavioral attributes after treatment with MAOA-inhibitor, since they already possess a compensated amount of the enzyme [It may be inferred from the data obtained that both e enzyme .Additional file 1:MAO polymorphic variants in female subjects. (PDF 29 kb)The Hardy-Weinberg equilibrium test performed in female subjects. Description: The table summarizes the genotypic distributions and Hardy-Weinberg equilibrium test performed for Additional file 2:MAO alleles in female ADHD probands. (PDF 19 kb)Parental allelic transmission in female ADHD probands. Description: The table summarizes the parental allelic transmission of Additional file 3:MAO haplotypes to male ADHD probands. (PDF 37 kb)Maternal haplotypic transmission to male ADHD probands (only significant data presented). Description: The table summarizes the maternal haplotypic transmission of Additional file 4:MAO haplotypes not-transmitted to male ADHD probands. (PDF 35 kb)Maternal haplotypes not-transmitted to male ADHD probands (only significant data presented). Description: The table summarizes the maternal Additional file 5:MAO haplotypes to female ADHD probands. (PDF 101 kb)Parental haplotypic transmission to female ADHD probands. Description: The table summarizes the parental haplotypic transmission of Additional file 6:MAO polymorphic variants . Description: The table summarizes the D’ and r2 values for pair-wise LD analysis in male probands, mothers of male probands, female probands and parents of female probands. (PDF 67 kb)Pair-wise Linkage Disequilibrium (LD) pattern of Additional file 7:MAO alleles. (PDF 23 kb)Analysis of allelic association with CPRS-R ‘T scores’ for oppositional behavior and PACS scores for conduct problems in male ADHD probands. Description: The table summarizes statistical comparisons between the mean scores and Additional file 8:MAO alleles. (PDF 25 kb)Analysis of allelic association with the status of age-of-onset of ADHD in the male probands. Description: The table summarizes statistical comparison of the early and/or late onset of disorder with


The need to extract oil from wells where it is embedded on the surfaces of rocks has led to the development of new and improved enhanced oil recovery techniques. One of those is the injection of surfactants with water vapor, which promotes desorption of oil that can then be extracted using pumps, as the surfactants encapsulate the oil in foams. However, the mechanisms that lead to the optimal desorption of oil and the best type of surfactants to carry out desorption are not well known yet, which warrants the need to carry out basic research on this topic. In this work, we report non equilibrium dissipative particle dynamics simulations of model surfactants and oil molecules adsorbed on surfaces, with the purpose of studying the efficiency of the surfactants to desorb hydrocarbon chains, that are found adsorbed over flat surfaces. The model surfactants studied correspond to nonionic and cationic surfactants, and the hydrocarbon desorption is studied as a function of surfactant concentration under increasing Poiseuille flow. We obtain various hydrocarbon desorption isotherms for every model of surfactant proposed, under flow. Nonionic surfactants are found to be the most effective to desorb oil and the mechanisms that lead to this phenomenon are presented and discussed. The energy demand will be met by a global energy mix that is undergoing a transition from the current dominance of fossil fuels to a more balanced distribution of energy sources2. This challenge becomes an opportunity for technologies such as secondary and enhanced oil recovery (EOR) that can mitigate the balance between supply and demand1. EOR techniques can significantly extend global oil reserves once oil prices are high enough to make these techniques economically attractive3. Physically, the essence of the EOR methods lies in the reduction of interfacial tension between oil, surface and water thereby making it easy for oil to coalesce and flow out of the reservoir to production wells4. This is achieved using surfactants. The search for new and efficient models of surfactant molecules is challenging. For instance, Iglauer et al., proposed new surfactant classes for EOR using coreflood tests on Berea sandstones5; they documented how diverse theoretical and experimental studies can be used to propose new formulations of surfactants. Recent developments in surfactant EOR have greatly reduced the surfactant concentration required for effective oil recovery. Bera et al., reported that the adsorption of surfactants on rock surfaces can be reduced or altered by fixing the solution’s pH for nonionic and ionic surfactants, which is an prominent issue regarding the economic feasibility for surfactant flooding6. Surfactant manufacturing is now delivering more advanced and safer EOR products at a lower cost than ever before. Early research on surfactants used in EOR focused on the injection of microemulsions into reservoirs. Microemulsions are also potential candidates in EOR, especially due to the ultra-low interfacial tension values attained between the contacting oil and water microphases that compose them7.Recovery is at the heart of oil production from underground reservoirs. If the average worldwide recovery factor from hydrocarbon reservoirs can be increased beyond current limits, it will alleviate a few issues related to global energy supply8. The concurrent removal of surfactant and oil remains unsolved because the existing filtration membranes still suffer from low surfactant removal rate and due to surfactant-induced fouling9. For instance, in the surfactant – based remedial technologies, the cationic surfactants are more likely to adsorb onto the surface of negatively charged soil particles and aquifer materials, which inevitably increased the consumption of surfactants. Therefore, more cases that use anionic surfactants, instead of cationic surfactants, for soil washing or aquifer flushing were reported10. Cationic surfactants are, in general, more expensive than anionic surfactants because of the high-pressure hydrogenation reaction required during their synthesis, yet they are often of great commercial importance, such as in corrosion inhibition11.For ionic surfactants, it is now widely accepted that there are significant changes in the free surfactant concentrations the total surfactant loading is increased above the critical micelle concentration. This is confirmed by experiments14, simulations17 and theory20. The magnitude of the decrease in free surfactant concentration for nonionic surfactants is significantly smaller than that for ionic surfactants and still somewhat controversial21. Depending on the nature of the hydrophilic group, synthetic surfactants are classified in four types. The hydrophilic group is usually a sulphate group, a sulfonate group, or a carboxilate group (for anionic surfactants), a quaternary ammonium group (for cationic surfactants), polyoxyethylene, sucrose, or polypeptide (for nonionic surfactants). The most common hydrophobic parts of the synthetic surfactants are paraffins, olefins, alkylbenzenes, alkylphenols, and alcohols22.Surfactants are commonly used in EOR processes for various purposes, including reduction of oil/water interfacial tension, wettability alteration, and foam generation23.Despite recent advances in the development of new and more effective surfactants to improve the EOR process, the essential interactions between oil and surfactant molecules and the desorption mechanisms taking place are not yet fully understood. In this sense, computer simulations allow one to access parts of the system in detail, and the emerging quantitative results yield a link to the data from experimental approaches. Simulation models for science and technology have been developed from the early days of computers and have become—with the increasing performance of computers—a standard tool in physics, chemistry, applied sciences and engineering25 under constant Poiseuille flow. DPD is a mesoscopic method that employs soft repulsive potentials, enabling the sampling of particle – based systems with time steps that can be up to three orders of magnitude larger than those used in conventional molecular dynamics26. DPD simulations of surfactants have been carried out by several groups to understand their structural and thermodynamic properties. Recent reviews28 report studies dealing with the use of DPD for the prediction of the spatial arrangement of amphiphilic molecules in a solvent. Jury et al.29 used DPD to simulate a dense solution of an amphiphilic species consisting of rigid surfactants in solution, finding a phase diagram that agreed with experimental data. Similarly, Nakamura30 obtained the same phase diagram as Jury et al.29 from his DPD simulation of amphiphilic molecules, and noted that the formation of the hexagonal phase takes longer to form than the lamellar phase. Nakamura and Tamura31 investigated the hydrophilicity dependence of the phase structure more qualitatively by varying the interaction potential between hydrophilic molecules and water molecules, using DPD simulations. The dependence of the excess pressure and surface tension for binary mixtures of monomeric liquids were investigated, as functions of surfactant concentration at the interface32. It has been observed in the DPD simulations of Li et al.33 on surfactant monolayers at the interface between oil and water that for decreasing the interfacial tension, it is better to have the same structure for the hydrophobic chains of surfactants and oil since the molecules at the interfacial layer could array compactly. Rekvig et al.34 examined the effects of size and structure of surfactants on reduction of interfacial tension and the influence of branching of the hydrophobic tail. Also, Rekvig et al.34 reported that branching has a positive effect on the efficiency of surfactants at the interface only if the head groups are sufficiently hydrophilic to prevent molecules from staggering. Amphiphilic monolayers on the interface between oil and water were simulated also by Rekvig et al.35 using DPD, confirming that the thickness of the layer affects the rigidity more than the density of the layer. They also found that mixtures of short and long surfactants are more flexible than medium length surfactants of the same average chain length. Using the DPD model, Dong et al.36 studied the orientation of sodium dodecyl sulfonate and sodium dodecylsulfate (SDS), and they found that strong hydrophilic head groups and the addition of salt results in the surfactants being stretched and ordered. Mesostructures and morphologies of mixed surfactant solutions containing cationic Gemini and anionic SDS surfactants were investigated by Wang et al.37, who found a variety of mesostructures by controlling the conservative term in the DPD algorithm, which were consistent with experiments. From the DPD simulations of Yang et al.38, different phase structures of an anionic surfactants mixed in water were observed, and the influence of concentration and temperature on the phase behavior of lamellar regions were studied. To explore the properties of polymer and surfactant systems, Yuan et al.39 selected two cationic surfactants and a polymer in their DPD simulations, and in subsequent work40, they carried out similar DPD simulations for the investigation of other surfactant–polymer mixtures.In this study, we undertake the challenge of the removal of hydrocarbons from surfaces through association with surfactants as a mechanism for EOR. Surfactant–polymer systems are investigated using dissipative particle dynamics (DPD) numerical simulations42. As shall be discussed in what follows, increasing the value of the external flow promotes desorption of the hydrocarbon (HC) at smaller surfactant concentration, which means that flow is an important variable that should be considered when studying EOR mechanisms. Following experimental and numerical reports48 we start by modeling oil as a mixture of mainly four hydrocarbons: butane, heptane, decane, and dodecane, with sixty molecules of each of those in the simulation box. Figure 4H10, C7H16, C10H22, C12H26, respectively, which constitute our HC model. On the other hand, the solvent is modeled as a fluid made up of monomeric DPD particles. The interactions of these monomers with themselves and with the rest of the particles depends on the number of water molecules a DPD solvent particle is thought to encapsulate, in our case this  is three water molecules, see Fig. Here we report extensive non–equilibrium DPD simulations of linear hydrocarbons (HC) adsorbed on flat surfaces as a model for oil embedded in rocks. To promote de desorption of the HC, a varying number of surfactant molecules dissolved in water is added to the system, as a mechanism for EOR. Two types of linear surfactants are used: a nonionic, and a cationic surfactant. In each case, five – bead and ten – bead surfactant chains are modeled. A crucial novel aspect of the work reported here is that all the particles within the fluid confined by the parallel, flat surfaces are subject to a constant, external force in the direction parallel to the plane of the surfaces, leading to stationary Poiseuille flowTo obtain desorption isotherms we start by fixing the number of HC molecules in the simulation cell; those molecules adsorb on the surfaces because they are dissolved in an aqueous solvent and they are subject to hydrophobic attraction for the walls. After all HC molecules have been adsorbed we add surfactants in increasing concentration to each simulation cell, until desorption of the HC molecules is observed. In Fig. 52 as well as in equilibrium simulations of complex fluids with polymers and surfactants53. Increasing the surfactant concentration leads eventually to the almost complete desorption of the HC chains . Each data point represents a simulation cell with a given surfactant concentration. Only long, nonionic surfactants were used to obtain this desorption isotherm, see the image on the right side in Fig. Following the procedure described above one can construct HC desorption curves, which are shown in Fig. s. At relatively low values of Cs there is virtually no HC desorption, and they form layers near the surfaces, as indicated by the maxima in Fig. s = 0.070) at z = 8 and z = 20. To trace further the desorption mechanism and reduce variables we focus in the rest of this work on systems that contain only heptane molecules, and study instead the influence of the surfactant chain length and its electrostatic nature (ionic vs. nonionic). Figure Figure surfactant, regardless of whether they belong to long or short surfactant chains. Since the volume of the simulation cells and the number of heptane molecules are the same in all simulations, all curves shown in Fig. 53, for ionic surfactants there appears also the electrostatic attraction between the charged groups in the surfactants and their counter ions. Additionally, there is electrostatic repulsion between the ionic surfactants that associate with the HC molecules, and this is turn leads to higher surfactant concentration before complete desorption of HC takes place, as shown in Fig. 54.Comparison of long and short surfactants is carried out at the same mass concentration, rather than at the same molar concentration. Therefore, the number of beads that make up surfactant molecules is the same at a given value of CThe density profiles of heptane molecules along the direction perpendicular to the surfaces shed light on the desorption mechanisms described previously, as they show how heptane molecules arrange themselves according to the composition of the fluid that surrounds them, as seen in Fig. Figure The snapshot on the left in Fig. 34. This means that there is no need to include bond angle an dihedral interactions46 at the relatively large coarse – graining degree in DPD we use in this work. To show this is the case we have performed additional simulations in which three – body interactions between neighboring bonds along the heptane chain were included . Figure Coarse – grained simulations such as those reported here group several atoms into a single particle whose size can be larger than the persistence length of the polymer chain, as is the case hereTo investigate the desorption mechanisms when ionic and nonionic interactions compete simultaneously we performed an additional series of simulations where the surfactants added to the system were a 50:50 mixture of long, ionic and nonionic surfactants under the same conditions as in the previous simulations. By carrying out simulations at increasing concentration of the mixture of surfactants, we calculated the heptane desorption isotherm, and compared it with those obtained for the pure nonionic and pure ionic surfactant cases. The results can be found in Fig. Figure x – direction, in particular, Fext(x) = αf with αf = 0.0075 in reduced DPD units. In Fig. αf = 0.0075), and the green line (triangles) is the isotherm obtained at αf = 0.0150. Under equilibrium (zero flow) conditions, even the optimal surfactant concentration is incapable to desorb all HC molecules, but as soon as an external force is applied nonionic surfactants become a useful additive as a means of EOR. The onset of desorption in surfactant concentration is reduced when the external flow is increased, as the green line in Fig. Csurf = 0.04 in Figs x – component of the velocity of the particles in the fluid along the direction perpendicular to the surfaces. When the system is in equilibrium (no flow), the velocity profile along the pore is constant, see black dotted line in Fig. 55. The stronger the flow, the more parabolic the velocity profile becomes, in agreement with simulations performed by others, see56 and reference therein.Lastly, and considering that EOR is a procedure that is performed under flow, we study the influence of the strength of the external flow imposed on the fluid. All results presented so far correspond to a constant value of the external force that creates Poiseuille flow along the In conclusion, we have shown that the association of nonionic surfactants with heptane is a useful mechanism to promote the desorption of hydrocarbon molecules from surfaces where they are embedded, as occurs in many oil reservoirs, which works best when the fluid is subjected to constant external flow. Ionic surfactants were shown to be not as effective as nonionic ones in desorbing heptane, mainly because the electrostatic repulsion between the surfactants’ heads leads to larger concentrations being required to desorb the hydrocarbon molecules. Hence, desorption is promoted by the reduction of the interfacial tension between hydrocarbons and the surface driven by surfactants, and enhanced by the external flow.The DPD model was used to carry out numerical simulations in the canonical ensemble (constant density and temperature), with the global density set equal to three, as is usually done. The electrostatic interactions were included using Ewald sums with charge distributions centered within the DPD beads. The surfactant and hydrocarbon molecules were constructed as chains of beads joined with freely rotating harmonic springs, and in one case a three – body angle harmonic potential between bonds was also included. The surfaces confining the fluid were defined as effective short – range forces. All computational details, model parameters, components of every system and full details of the work can be found in the Supplementary information


The presence of attention-deficit/hyperactive disorder (ADHD) symptoms and impaired attention performance are commonly noted in individuals with autism spectrum disorder (ASD). However, little is known about attention performance in their unaffected siblings. This study aimed to investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits.We assessed the intention, hyperactivity-impulsivity, and oppositional symptoms, and attention profiles of 199 probands with a diagnosis of ASD , their unaffected siblings, and 196 typically developing controls (TD) by their parents’ reports on the ADHD-related symptoms and the Connors' Continuous Performance Test (CCPT), respectively.Compared to TD, unaffected siblings of ASD probands were more hyperactive/impulsive and oppositional, particularly unaffected siblings of AS probands. In CCPT, unaffected siblings of AS have intermediate levels of performance between probands with AS and TD on focused attention and sustained attention but were not statistically different from AS probands or TD in these attention profiles. In contrast, unaffected siblings of autism probands have significantly better CCPT performance when compared to autism probands but not to TD. In addition, stereotyped behaviors predicted ADHD-related traits in both sibling groups, but distinctive patterns of other correlates for ADHD-related traits were found between the two sibling groups.This work suggested that unaffected siblings of AS, but not autism, have more hyperactive/impulsive traits and a trend of pervasive attention deficits assessed by CCPT which might serve as potential endophenotypes for genetic studies in AS.NCT01582256ClinicalTrials.gov, The online version of this article (doi:10.1186/s13229-017-0153-9) contains supplementary material, which is available to authorized users. The heritability of ASD has been estimated higher than 90% , with siAttention deficits are commonly associated manifestations of ASD. Literature documents that 52–78% of individuals with ASD also meet the diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD) –15. OppoN-methyl-d-aspartate receptor subunit-encoding genes (GRIN2A and GRIN2B) confer an increased susceptibility to attentional impairment measured by CPT in ADHD patients  to medium (Cohen’s d > 0.5) , or even lower  (Table The differences between probands and TD showed large effect sizes (defined by Cohen’s Probands with ASD (autism and AS) performed poorer than unaffected siblings and TD on most CCPT indexes, while the attention profiles of the unaffected siblings were not different from those of TD except a longer RT in unaffected siblings than TD  and two indexes of cognitive impulsivity , without significant differences between unaffected siblings of autism probands and TD  and sustained attention (hit SE block change) Table ; unaffecR-square 0.428~0.559) than unaffected siblings of autism (R-square 0.094~0.187)  after Bonferroni correction, in line with an earlier study showing that unaffected siblings of autism probands may have more delinquent behaviors but not inattentive problems . Our finAs to CCPT performance, our results do not support attention deficits in unaffected siblings of autism probands but show a trend of mild but pervasive attention deficits in unaffected siblings of AS probands, whose performance was at the intermediate position between AS probands and TD without a substantial difference from AS probands. Hence, our findings imply that the compromised focused attention  and sustained attention (hit SE block change) assessed by CCPT might be potential endophenotypes for AS but not for autism. Our findings again reflect the differences between unaffected siblings of autism probands and unaffected siblings of AS probands regarding the patterns of attention deficits. Literature has documented attention characteristics in AS, including greater variability as assessed by the CPT  or Test Our findings of positive associations between stereotyped behaviors/interest and ADHD-related traits in unaffected siblings correspond to those found in probands with ASD , 66. SucExcept for stereotyped behaviors, unaffected siblings of autism probands and unaffected siblings of AS probands showed distinct correlates for their ADHD-related traits. First, the association between hyperactivity and impaired communication in unaffected siblings of AS probands was consistent with previous studies in ASD , 66 and SHANK3 variants between the subtypes of ASD [Our finding that unaffected siblings of AS probands performed in between probands with AS and TD on several aspects of attention assessed by CCPT implies that these traits may constitute a substantial endophenotype of AS, and could be considered as one of the surrogates in searching genetic etiology of AS. However, whether the observed CCPT deficits were inherent to ASD or only a reflection of co-occurring ADHD traits needs further clarification. In the subsidiary analysis, we found the CCPT deficits in the AS probands disappeared when attention problems were controlled while those in autism probands remained significant (data not shown), implying that co-occurring ADHD traits may contribute to the CCPT deficits in AS but not autism. Although the unaffected siblings did not show more inattentive symptoms, CCPT deficits underlying AS and ADHD might suggest their utility in searching for common genetic etiology underlying the overlapping neurodevelopmental conditions, like Rommelse et al.  proposeds of ASD .This study has four limitations. First, the probands and TD were male-predominant and age-limited whereas the siblings were equal in sex distribution. Because ASD population is male predominant, this problem cannot be avoided in any study design. Therefore, we adjusted sex and age in all statistical analyses. Second, we used parents’ reports to evaluate inattentive and hyperactive/impulsive symptoms but not the clinical diagnosis. Though, SNAP-IV is a valid instrument to measure ADHD and oppositional symptoms dimensionally; CBCL attention problem subscore was also collected to capture the behavior phenotype by checklist. Both measures consistently showed increased ADHD traits in the probands, with SNAP-IV more specifically reflected the hyperactive/impulsive trait in the siblings of AS probands. Third, this study design is unable to answer whether the CCPT deficits in ASD probands or siblings were specific to ASD or were associated with the comorbid ADHD. To address the specificity of CCPT deficits, future studies may consider comparing CCPT performance either among “ASD only,” “ASD comorbid with ADHD,” “ADHD only,” and “controls without ADHD and ASD;” or between unaffected siblings “with ADHD,” and “without ADHD.” Finally, IQ was not controlled in the group comparisons because the performance IQ of unaffected siblings was not statistically different from TD. However, lower IQ in the probands, which was particularly true in probands with autism, may cause the group comparisons confounded by IQ. Though, researchers have argued that controlling IQ may be over-adjustment and may not be necessary since the deviations on intelligence could be inherent to ASD psychopathology. To ensure that all the participants understand the task, participants who had full-scale IQ below 70 were excluded. Such restriction of the sample may limit the generalizability of our results to the whole ASD population. Nevertheless, several features of this study constitute its strengths. This study provides important evidence regarding the hyperactive/impulsive and oppositional traits in unaffected siblings of ASD probands, in a representative sample recruited from both clinical population and community. In addition, an objective, valid, and widely used instrument, CCPT, was used to assess and to compare a wide range of attention performance among the ASD probands, unaffected siblings, and TD groups, based on a newly proposed factor structure .In conclusion, based on a large-scale sib-pair sample, our findings provided evidence to support that compromised focused attention and sustained attention might serve as potential endophenotypes for genetic studies in AS. Attention performance on CCPT may be used in detecting genetic effects underlying complex cognitive functions mediated by a broad functional brain network. The unaffected siblings of probands with ASDs usually obtain less attention from the parents and clinicians than their probands. However, they may benefit from clinical assessment and management for co-occurring hyperactive/impulsive and oppositional traits, particularly for the siblings of AS probands.Additional file 1:Autistic symptoms of probands (autism and Asperger’s disorder), unaffected siblings and typically developing controls. This table presents five group comparison on Social Communication Questionnaire subscores and the subcores of Autism Diagnostic Interview-Revised for the probands. (PDF 174 kb)Additional file 2:Comparison of ADHD-related symptoms and CCPT performance between probands with autism spectrum disorders, unaffected siblings of ASD, and typically developing controls. This table presents the three group comparison of ADHD-related symptoms and CCPT performance between probands with autism spectrum disorders, unaffected siblings of ASD, and typically developing controls adjusting for sex and age. (PDF 162 kb)Additional file 3:Comparison of CCPT performance between probands with autism, unaffected siblings of autism probands, and typically developing controls. Comparison of CCPT performance between probands with autism, unaffected siblings of autism probands, and typically developing controls adjusting for sex and age. (PDF 103 kb)Additional file 4:Selected Conners’ Continuous Performance Test indexes showing that probands with Asperger’s disorder (AS) performed differently from typically developing youths (TD) and their unaffected siblings performed in the intermediate position. (a) Omission, Reaction time standard errors (RT SE), and Variability; (b) Reaction time; (c) Hit reaction time standard error (Hit SE) block change and Hit reaction time inter-stimulus (Hit RT ISI) change  (PDF 79 kb)


This study intended to determine whether former and current ADHD symptomatology is associated with suicidal ideation in a non-clinical sample of 18 year old males. We performed a cross sectional descriptive study of 3280 men during the examination for military service. The investigation included a screening for substance abuse, past (WURS) and current (ADHD symptom checklist) ADHD symptomatology and an interview about suicidal ideations. We found a correlation of suicidal ideations with a history of ADHD symptomatology. ADHD symptoms were strongly consistent over time. These results indicate that a history of (diagnosed or undiagnosed) ADHD could be a predictor for suicidal ideations. Surveying a history of ADHD in primary care might help identify subjects at risk for suicidal tendencies. Attention Deficit-Hyperactivity Disorder (ADHD) is a chronic developmental psychiatric disorder affecting 3–12 % of all children and around 1–6 % of adults , 15, 49.Suicide is among the leading causes of death worldwide but the need for diagnosis and treatment of suicidal behavior is still unmet , 36. ComVery little is known about the interaction of ADHD symptoms and suicidal behavior in young adults. This group however has to be considered at special risk, as only about 15 % of young people with attention deficit hyperactivity disorder (ADHD) make a transition into an adult psychiatric treatment setting . Also, aThis investigation set out to examine the association of ADHD with suicidal ideation in a non-clinical sample of 18-year-old males. Additionally, we examined the added effect of comorbid substance use disorder on rates of suicidal ideation in individuals with ADHD.In Austria military service is mandatory for all 18-year-old males. Conscription of military servicemen is based on a preliminary psychological and medical examination of all males who turn 18 in the respectable year. This investigation includes blood and urine testing as well as a psychological examination in order to assess the subject’s fitness and capability to perform National Service. In order to obtain an unbiased and representative sample we chose 11 districts including urban and rural areas, agricultural and industrial regions, as well as lower and higher income areas.Data collection has been performed from January 2010 to December 2010 at two of a total of six recruitment centers for military service in Austria. One of these centers was located in the province of Tyrol, the other one in the province of Lower Austria. All male residents of the selected districts born in 1992, who were liable to enlistment to the Military Service were included in the study. Participation in the study was declined by 60 out of 3340 persons (22 (1.70 %) of 1297 young men from the districts in Tyrol and 38 (1.86 %) of 2043 subjects in Lower Austria). With a response rate of 98.20 %, a total 3280 subjects have thus been enrolled in the investigation. Data were collected in addition to the standard procedure performed by Military Service authorities. Our examination was performed anonymously after the examination for the Military Service, subjects were aware that no information they gave would be communicated to the examiner of the Armed Forces.Life time prevalence of ADHD was examined using the Wender Utah Rating Scale (WURS-K) , 50, an p < 0.001.The frequency of alcohol consumption was reported according to the question: “Do you drink alcohol?” (0) I do not drink, (1) less than once a week, (2) once a week, (3) several times a week, (4) every day. In addition, the CAGE questionnaire  was used to rate alcohol related behavior. The CAGE questionnaire  has goodSmoking was assessed with the question: “Do you smoke?” (“Yes” or “No”) followed by the Heavy Smoking Index (HSI), which consists of two questions: “How many cigarettes do you smoke per day?”  and “When do you smoke your first cigarette in the morning?” (“Within 5 minutes” “6–30 minutes” “31–60 minutes” and “After more than 60 minutes”). Both questions were scored between 0 and 3 and an HSI-sum score ranging between 0 and 6 was built. The HSI has been previously validated by plasma and saliva cotinine, as well as carbon monoxide levels .To assess experiences with illicit drugs, the subjects were asked, “Have you ever consumed one of the following drugs?” The response options for each substance  were: (0) never, (1) once, (2) several times (3) regularly. Based on these reports, a dummy variable “drug experience” was build, representing at least one drug experience during lifetime.Suicidal ideation was assessed by the question “Have you ever considered to commit suicide?” with the response options: (0) never, (1) at some earlier point in life, (2) last month, (3) last week. A positive answer (being any answer from 1 to 3) was considered as lifetime suicidal ideation in further analyses.To verify reports, GGT, MCV, ALT, AST, were determined in serum samples as were illicit drugs in urine samples Carbon monoxide (CO) levels in exhaled air were determined using a “smokerlyser” .Differences in characteristics between subjects with and without ADHD symptoms were assessed by T‑tests and Mann–Whitney-U tests for not normally distributed variables.P-values at the level of p < 0.05 were considered significant. Log-linear analysis was performed to determine a possible synergistic effect of ADHD and drug abuse on suicidal ideations. Data Analysis was conducted using IBM SPSS Statistics 21.0 software .Regression analyses  were used to investigate whether suicidal ideations were associated with prevalence of ADHD. p = < 0.001). Alcohol consumption at any rate was very common (91.4 %) with 19.3 % meeting the CAGE cut-off score of 2 or higher, indicating an alcohol problem. Regular smoking was reported by 43.9 %, life time use of cannabis was stated by 19 %. The prevalence of Cocaine abuse was 2.6 % that of benzodiazepine abuse was 2.1 %. Unspecific psychoactive substances have at least once been used by 1.8 % and opiates by 0.2 % of all participants. For details also see Table The sample included 3340 18-year-old males of which 3280 consented to participate in the investigation. Out of the total sample 2.7 % stated that they have been treated for ADHD and 1.5 % reported that they had at one point received pharmacological treatment for the condition. Concerning WURS, 10.1 % had a score above the cut-off of >36 indicating past ADHD symptoms. There was a strong association of former (WURS) and current (ADHD checklist) symptoms  and drug abuse (p < 0.001) significantly predicted suicidal ideations in the subjects investigated. Odds for suicidal behavior increased with the number of symptoms. The log-linear analysis determining the influence of both ADHD an drug abuse on suicidality produced a model with significant two-way-interactions between ADHD and suicidal ideas (χ² (1) = 60.54, p < 0.01), between ADHD and drug abuse (χ² (1) = 4.67, p = 0.03) and between drug abuse and suicidal ideas (χ² (1) = 20.37, p < 0.01), but no significant three-way-interaction (χ² (1) = 0.02, p = 0.89). Alcohol and Nicotine abuse did not have any significant influence on suicidality both in subjects with and without ADHD symptoms (Table Suicidal ideation at any time was found in 6.8 % of all subjects. Former ADHD symptoms (This study examined the association between ADHD symptoms and suicide ideation in 18-year-old males during their routing investigation for military service. In this sample we found a proportion of 6.8 % reporting lifetime suicidal ideations.An earlier investigation performed in high school students in the same country  and otheClinically relevant former ADHD symptoms were found in 10 %, which can be considered comparable to the percentage estimated for the general population . About oConcerning substance abuse, we were surprised not to find an association of smoking or alcohol consumption and suicidal ideation. Abuse of these substances has been identified as independent risk factors for the development of suicidal behavior , 52. WhiIt has recently been suggested that ADHD is associated with a small but definite increase in the risk of suicide , 35. MorIn consideration of possible reasons for the connection of ADHD and suicidal thoughts in young adults, the trait of impulsiveness  might beCurrently, a trend towards the revision of nosologic criteria and deconstruction of global assessments of ADHD into component subtypes can be observed  by elaboAlthough suicide prevention programs and research on factors contributing to suicidal behavior have been extensive for many decades, current research on suicide prevention in subjects suffering from ADHD is limited. The finding that young adults in the general population with a history of ADHD have an increased risk for suicide ideation has several implications. On the one hand prospective studies on the interaction of ADHD and suicidal behavior in order to better understand the relationship between ADHD and suicidal behavior in this age group are needed. On the other hand, preventive strategies focusing on young adults with a history of ADHD ought to be established.As always, the results of this study must be interpreted in the context of several limitations. Firstly, the sample consists of men only. Secondly, as subjects had to be fit enough to perform military service, men with severe mental or physical disorders were excluded, thus generating a possible bias towards the inclusion of subjects healthier than in the general population. Finally, the cross-sectional study design does not allow making conclusions about the temporal relationships between ADHD symptoms and suicidality.In terms of strengths our sample is highly representative including 6.8 % of all males born in Austria in 1992 all 18-year-old males of the respective areas fit enough to be enlisted for military service. Districts of investigation were carefully chosen in order to obtain an unbiased and representative sample. All subjects were rated by one single person, who was very experienced in all questionnaires applied. We have employed widely used questionnaire instruments with recognized reliability and validity. Reports on substance use were verified by examination of blood, urine and breath.


Attention-deficit/hyperactivity (ADHD) symptoms have been associated with the decision to become self-employed. Although these symptoms are generally regarded as disadvantageous, there may also be a bright side. To our knowledge, however, there has been no systematic, epidemiological evidence to support this claim. This paper examines the association between ADHD symptoms and self-employment in a population-based sample from the STAGE cohort of the Swedish Twin Registry (N = 7208). For replication, we used a sample of Dutch students who participated in the Global University Entrepreneurial Spirit Students’ Survey . In the Swedish sample, we found a positive association with self-employment for both general ADHD symptoms  and hyperactivity symptoms , whereas no association was found for attention-deficit symptoms . The positive association between hyperactivity and self-employment was replicated in the Dutch student sample . Our results show that certain aspects of ADHD, in particular hyperactivity, can have a bright side, as they are positively associated with self-employment. Prominent entrepreneurs have publicly credited their attention-deficit hyperactivity (ADHD) symptoms as a driver of their decision to become self-employed –3. ExampADHD is a neurodevelopmental disorder characterised by attention-deficit and hyperactivity –7. The oAlthough prior research has mainly focused on the negative consequences of ADHD for individual performance in formal education and wage employment –19, receIn the popular press, it has been suggested that individuals with ADHD symptoms are able to break through organisational inertia due to their ability to envision and create new ‘realities’ and (successfully) start their own ventures –4. AllegThe present study was designed to examine the association between self-reported ADHD symptoms and self-employment in a population-based sample of 7208 individuals from the STAGE cohort of the Swedish Twin Registry of the Karolinska Institute. The findings were replicated in a sample of 13,119 students participating in the Global University Entrepreneurial Spirit Students’ Survey (GUESSS) 2011 in the Netherlands. Given the discussions in the (popular) literature and the circumstantial scholarly evidence, we expected a positive association between ADHD symptoms and the decision to become self-employed , 29. We We used the STAGE (Swedish Twin Studies on Adults: Genes and Environment) cohort from the Karolinska Institute in Stockholm, Sweden, as the discovery sample. The STAGE cohort is part of the population-representative Swedish Twin Registry (STR), which was established in the 1950s to study the effects of smoking and drinking on cancer and cardiovascular diseases . At presAll twins born between 1959 and 1985  received an invitation letter with information about the project in May and June 2005. The response rate was 59.6 % . The entire questionnaire contained approximately 1300 questions, of which the respondents answered 800–900 questions on average . DropoutParticipants answered two questions about their involvement in self-employment: whether they were self-employed full-time (yes/no) and whether they were self-employed part-time (yes/no). We constructed one measure of self-employment (yes/no), which was coded 1 if the participant was self-employed part-time or full-time and 0 if (s)he was not self-employed. In the STAGE cohort, 14,039 out of 25,364 participants (≈55 %) provided their self-employed status (yes/no). A total of 2096 participants (≈14 %) were self-employed, of whom 1270 (≈9 %) were self-employed full-time and 826 (5 %) were self-employed part-time. Three participants answered ‘yes’ to both the part-time and full-time self-employment question and were excluded from the analysis. Furthermore, we randomly dropped one twin from each pair because their similarity would violate the assumption of independent observations, resulting in a final sample of 7208 participants . Of these respondents, a total of 897 (≈12 %) were self-employed, of whom 515 (≈7 %) were self-employed full-time and 382 (≈5 %) were self-employed part-time, which was similar to the total sample distribution.ADHD symptoms were assessed using the Adult ADHD Self-Report Scale ASRS-v1.1), which consists of 18 items reflecting the DSM-IV-TR criteria . Attenti.1, whichThe symptom scores were added to create a scale of ADHD symptoms and two sub-scales of attention-deficit and hyperactivity . Values In the STAGE cohort, we included the following demographic variables: age, gender, and whether the participant attended university  as an initial test to control for additional effects.We attempted to replicate the analysis linking ADHD symptoms to self-employment in a student sample from the Global University Entrepreneurial Spirit Students’ Survey (GUESSS)The response rate for the GUESSS study was 7.6 % for educational institutions that systematically recruited participants , leadingIn the GUESSS study, self-employment was measured as a dichotomous variable indicating whether students were self-employed in their own founded firm during their studies. ADHD symptoms were measured using the six-item Adult ADHD Self-Report Scale v1.1 (ASRS v1.1) screener, developed by Kessler et al. , 40, whip values at 5, 1, and 0.1 % levels, respectively) using asterisks .To examine the association between ADHD symptoms and self-employment, we estimated binary logistic regressions. First, in the STAGE cohort, we examined the association between the sum score on the DSM-IV diagnostic criteria items for all ADHD symptoms (18 items), attention-deficit and hyperactivity symptoms (each 9 items), and self-employment (part-time/full-time). Second, we replicated this analysis using data from the GUESSS study. Specifically, we estimated the associations between the sum score on the ASRS-6 v1.1 screener items for all ADHD symptoms (6 items), attention-deficit symptoms (4 items), hyperactivity symptoms (2 items), and self-employment. We report the effect sizes in terms of odds ratios (OR) and the associated 95 % confidence intervals (95 % CI). In the tables, we denote statistical significance  ADHD symptoms and self-employment in the STAGE cohort that could not be replicated  in the GUESSS study. Furthermore, the association between attention-deficit symptoms and self-employment was significantly negative in the GUESSS study and insignificant in the STAGE cohort. Finally, the association between hyperactivity symptoms and self-employment was significantly positive in both the STAGE cohort and the GUESSS study.We performed a series of sensitivity analyses using both the STAGE and GUESSS data. First, we reran the logistic regressions using the entire STAGE database, including pairs of twins instead of randomly dropping one twin, and clustered the standard error at the family level to account for the joint characteristics of twins. In the larger sample of approximately 11,000 respondents, the association between ADHD symptoms and self-employment remained intact . Furthermore, the results of the sub-scales remained stable: attention-deficit was not significantly associated with self-employment , and hyperactivity was positively associated with self-employment .3Second, to compare the results of the GUESSS study with those of the STAGE cohort, we examined the associations between ADHD symptoms and self-employment in the STAGE cohort using the 6 items from the ASRS-6 v1.1 screener instead of the 18 item ASRS-v1.1 score. In line with the GUESSS findings, we found no evidence of a significant association between general ADHD symptoms and self-employment . However, we did not find support for a significant (negative) association between self-employment and attention-deficit symptoms . We did find a positive association between hyperactivity symptoms and self-employment , which is in agreement with the analyses.4Third, we examined the association between ADHD symptoms and self-employment using a stricter definition of ADHD that was closer to an actual psychiatric diagnosis . In the Fourth, we re-estimated the logistic regressions including additional control variables. Specifically, because unemployment is an important push factor for self-employment  and becaOverall, the association between ADHD symptoms and self-employment remained intact but became insignificant when more controls were added. In the STAGE data, this was the case when considering whether someone was mainly wage employed in the past 3 years. This is not surprising given the fact that approximately 60 % of the respondents were currently wage employed and had mainly been working in wage jobs in the past 3 years. In the GUESSS data, the association between ADHD symptoms and self-employment appeared sensitive to the inclusion of career motives , which may be related to the importance of the person-occupation fit for individuals with ADHD symptoms .Finally, using the STAGE data, we tested for linkages between ADHD symptoms and other occupations. The findings showed no association with wage employment , suggesting that a regular wage job may not be as suitable as self-employment for people with high levels of ADHD symptoms. Together with our finding that ADHD symptoms are positively associated with unemployment , we are unable to reject a potential push effect by which people with ADHD symptoms become self-employed because of a lack of (suitable) alternative occupations.The present study moved beyond the clinical view of ADHD as a pathological disorder and used the symptoms of ADHD across the entire measurement spectrum to examine a potentially positive aspect: the association of ADHD with the involvement in self-employment. Hence, the aim of this study was not to diagnose individuals with ADHD and then examine the viability of self-employment as a career option. Instead, we investigated whether individuals who exhibit higher levels of ADHD symptoms–but who do not necessarily screen positive for ADHD in a clinical sense–are positively associated with self-employment. In line with previous research, special attention was paid to whether this association involved general ADHD symptoms or the separate attention-deficit and hyperactivity symptom dimensions , 49–51.The present research is part of a series of investigations on the relation between ADHD and entrepreneurship. In Verheul et al. , the intTwo independent samples were used for the present analysis: Swedish adults (STAGE cohort) and Dutch students (GUESSS study). In the Swedish sample, we found a positive association of both general ADHD symptoms and hyperactivity symptoms with self-employment, whereas this association could not be found for attention-deficit symptoms. The positive association between hyperactivity symptoms and self-employment was replicated in the Dutch sample. The effects remained intact in a series of sensitivity analyses.ADHD is typically characterised by high energy levels that are expressed as severe and persistent attention-deficit and hyperactivity and that are driven by behavioural ‘disinhibition’ or a lack of restraint , 41, 54.The present study has implications for further research. Our results may be an initial step towards establishing a link between ADHD symptoms and career choices, such as self-employment, or other manifestations of entrepreneurship. The outcomes of this study may help to ‘destigmatise’ ADHD as a disorder, particularly given the positive associations with self-employment in view of its contribution to socio-economic life. Given the high occurrence of moderate psychiatric symptoms, it is plausible (from a Darwinian perspective) that psychiatric symptoms not only confer risks but can also be beneficial for the individual. For the field of psychopathology, it is important to study the potential benefits of demonstrating a high level of ADHD symptoms , 59, 60 Although the present study only investigates one single outcome, self-employment as a possibly positive aspect of ADHD symptoms, it highlights some promising avenues for future research. First, the current data do not enable us to examine the association between ADHD symptoms and the performance of self-employed individuals. The question that arises is whether self-employed individuals who score higher on ADHD symptoms also have better-performing ventures . Second,To conclude, our results indicate that the positive association between ADHD symptoms and the decision to become self-employed primarily hinges on the hyperactivity symptoms of ADHD, whereas the overall association between ADHD symptoms and self-employment is only significant in one of our two samples. For future research, it is important to understand how ADHD symptoms are associated with more specific self-employment and entrepreneurship behaviours, such as the level of risks taken or performance in self-employment or as a business owner. This research may enhance our understanding of the positive effects of ADHD symptoms or even ‘destigmatise’ ADHD as a disorder that always deserves treatment.


The use of ADHD drugs among adults is controversial and has until recently not been approved for use in adults in most countries. The aim was to investigate use of ADHD drugs (stimulants and atomoxetine) among the entire adult population in the Nordic countries.We conducted a multinational population-based prescription register study based on the entire adult population in the five Nordic countries . All users of ADHD drugs aged 18–64 years during 2008–2012 were included, which for 2012 comprised 76,896 drug users among 15.8 million adult inhabitants.Annual prevalence of drug use increased during the study period for both genders and all age groups. The overall prevalence increased from 2.4 to 5.3 per 1000 men and 1.8 to 4.4 per 1000 women. Incidence also increased, but to a lesser extent in the last part of the study period. Methylphenidate was used by 88 % of drug users. Treatment was discontinued within the first year by 21 % of new drug users. Among all users of ADHD drugs, 53 % of men and 64 % of women concurrently used other psychotropic drugs, most frequently antidepressants and hypnotics. Psychotropic co-medication increased with age and was more pronounced among women than men.Use of ADHD drug among adults more than doubled over a 5-year period, and a majority were concurrently treated with other psychotropics. Adults constitute a substantial proportion of persons treated with ADHD drugs. Thus, evidence for long-term efficacy and safety in adults is urgently needed.The online version of this article (doi:10.1007/s00228-016-2125-y) contains supplementary material, which is available to authorized users. The diagnosis of attention-deficit hyperactivity disorder (ADHD) among adults is controversial –4. NeverThis population-based study examines the use of ADHD drugs among adults aged 18–64 years in ambulatory care in all five Nordic countries , comprising in total 15.8 million inhabitants in this age range. Data on prescription drugs dispensed from pharmacies were retrieved from the nationwide prescription registers in each country . Data onThe number of inhabitants in each country by gender and age group was retrieved from national population registers  in Finland and the bureau of statistics in the other countries). In 2012, the number of inhabitants aged 18–64 years was as follows: 3.4 million in Denmark, 3.3 million in Finland, 199,000 in Iceland, 3.1 million in Norway and 5.8 million in Sweden .Medical products in the Nordic countries are classified according to the Anatomical Therapeutic Chemical (ATC) classification system . For thePrescription data from each country were uploaded to a server at Statistics Denmark and analysed by a common programme in Stata version 13. Drug utilization was measured during 2008–2012, whereas data from 2006 to 2007 were used in specific analyses as a run-in period to define new users of ADHD drugs. Results are presented by gender and age attained at the start of the year by four age groups , combined for all Nordic countries (main results) and by country .Prevalence: Annual prevalence proportion (per 1000) of ADHD drug use was defined as the number of individuals who filled at least one prescription in one calendar year divided by the gender- and age-specific population of the same year.Incidence: Annual incidence (per 1000) of ADHD drug use was defined as the number of individuals who filled at least one prescription in one calendar year, and with no prescription fills during the previous 2 years (730 days), divided by the gender- and age-specific population of the same year.Type of ADHD drug used at treatment initiation: The type of ADHD drugs received at treatment initiation (i.e. first prescription fill) was assessed among new users during 2008–2012. New users were defined as individuals that had not previously filled any prescription for ADHD drugs (going back to 2006).Early discontinuation and switch in drug treatment: Among new users of ADHD drugs (defined as above), early discontinuation of treatment was defined as filling no more than two prescriptions for ADHD drugs during the first year (365 days) after initiating treatment. Prescriptions filled on the same date were counted as on prescription. Early switch in treatment was assumed if an individual who initiated treatment with methylphenidate filled a subsequent prescription for atomoxetine during the first year, or vice versa. In this analysis, users initiating treatment in 2012 were disregarded to ensure 1 year of prescription data follow-up.Co-medication with other psychotropic drugs: Use of other types of psychotropic drugs was examined among prevalent users of ADHD drugs. For all individuals who filled a prescription for an ADHD drug in one calendar year, the proportion (%) that filled prescriptions for other psychotropic drugs concurrently [urrently  with an ADHD drug use was examined using the following definitions.Personal identity numbers were encrypted. In accordance with laws and regulations, no ethical approval is needed for use of the Danish, Finnish and Norwegian prescription register data. The study was approved by the Icelandic Bioethics Committee (VSNb2013010018/03.07) and the Icelandic Data Protection Authority (2013010062TS/--), and in Sweden, it was approved by the the Karolinska Institutet regional ethics committee.n = 42,450), 4.4 per 1000 women  and 4.9 per 1000 in total  filling a prescription for ADHD drugs.The source population was the Nordic population aged 18–64 years. In 2012, this comprised 15,828,232 inhabitants, with 5.3 per 1000 men  to extended release (ER) methylphenidate formulations; 64 vs 73 % of users received ER formulations in 2008 and 2012, respectively, while IR formulations decreased from 41 to 34 % in the same period. The proportion using atomoxetine remained stable at 12–14 %, while less than 5 % used amphetamine and dexamphetamine.The annual incidence of ADHD drug use increased modestly among all age groups and both genders during the study period, and mainly in 2008–2010 Fig. . The chaMethylphenidate was the preferred drug at treatment initiation throughout the study period; 88 % of new users during 2008–2012 received methylphenidate on the first prescription fill, 11 % received atomoxetine, whereas amphetamine and dexamphetamine were rarely used Fig. . In totaAmong 62,144 new users of ADHD drugs during 2008–2011, 13 % filled only the initial prescription and 9 % filled only one more prescription, while 79 % filled 3 or more prescriptions of any ADHD drug during the first year of treatment. When restricting to users who initiated treatment on methylphenidate, 21 % filled only one or two prescriptions of any ADHD drug during the first year (discontinuation), while 8 % received atomoxetine within the first year (switching). Among users who initiated treatment on atomoxetine, 25 % filled only one or two prescriptions while 32 % received methylphenidate within the first year.Co-medication with other psychotropic drugs was common among ADHD drug users in all age groups and both genders Table . DependiThis multinational study provides a detailed overview of ADHD drug utilization among the entire adult population of the five Nordic countries. Use of ADHD drugs more than doubled during the 5-year study period, with 5.3 per 1000 men and 4.4 per 1000 women filling a prescription in the last year of the study. One in five patients discontinued ADHD drug use within the first year of treatment initiation. Co-medication with other psychotropics among users of ADHD drugs was common.This study utilises data from high-quality prescription registers with mandatory reporting that cover the entire population of the Nordic countries . Our resLicencing of ADHD drugs for use also in adults may partly explain the substantial increase in use observed in the present study. Methylphenidate has been extensively used in the treatment of ADHD in children and adolescents , 30–32. Guidelines that also focus on the management of adult ADHD have only recently been published in all Nordic countries but Finland, stating that methylphenidate is first-line treatment while atomoxetine is second-line treatment –19. Our The present study reveals a markedly increased prevalence of ADHD drug use during 2008–2012. However, the prevalences reported in the present study  are substantially lower than what has been observed in the USA (12 per 1000 aged 20 years or older in 2005) , and higThe prevalence of ADHD drug use increased substantially during the study period and was 4.9 per 1000 in 2012. Nevertheless, it is lower than the reported prevalence of the ADHD diagnosis, ranging from 10 to 80 per 1000 . Our resOur results indicate that 21 % of persons who initiated treatment had discontinued all ADHD drugs within the first year. Other studies have revealed higher levels of discontinuation in adults –40. ContStudies of epidemiological and clinical populations of adults with ADHD have revealed that comorbid psychiatric illnesses are very common, in particular depression and substance use disorders , 9, 15. The present study did not reveal to what extent persons receiving pharmacological treatment with ADHD drugs also had a diagnosis for ADHD or other psychiatric illnesses, or vice versa. There is generally less evidence on the efficacy and safety for ADHD drugs in adults than in children, which is of concern given the substantially higher rates of comorbid psychiatric and somatic disorders in the adult population. For instance, ADHD drugs have been linked to a moderate increase in heart rate and blood pressure although evidence does not point to increased rate of serious cardiovascular events –45. The The present study revealed that the use of ADHD drug among adults more than doubled over a 5-year period, and a majority were concurrently treated with other psychotropics. Because of these recent developments in ADHD drug use patterns, adults now constitute about half of the persons using ADHD drugs in the Nordic countries. Thus, evidence for long-term treatment efficacy and safety in adults is urgently needed.ESM 1(PDF 556 kb)