This study used eye tracking to explore attention allocation to human and dog faces in children and adolescents with autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), and typical development (TD). Significant differences were found among the three groups. TD participants looked longer at the eyes than ASD and ADHD ones, irrespective of the faces presented. In spite of this difference, groups were similar in that they looked more to the eyes than to the mouth areas of interest. The ADHD group gazed longer at the mouth region than the other groups. Furthermore, groups were also similar in that they looked more to the dog than to the human faces. The eye-tracking technology proved to be useful for behavioral investigation in different neurodevelopmental disorders. The study of behavioral and neurophysiological patterns related to visual attention is a promising research field to understand the modulation of attentional performance at different ages and in various neurodevelopmental and neuropsychiatric disorders , 2.Although difficulties in social interaction, empathy, facial expression, recognition, and emotional exchange are core symptoms of autism spectrum disorder (ASD), it has been reported that people with attention deficit/hyperactivity disorder (ADHD) may also have impairment in social cognition and mood regulation, which may lead to high levels of peer rejection –6. SociaThe current DSM-5  does notAttentional modulation occurs in ADHD at different levels, influencing selective attention guided both to external information and to endogenous processes, linked to executive control and emotional self-regulation . In thisThe present study aimed to analyze face scanning in two neurodevelopmental disorders. Using eye-tracking techniques, we compared how children and adolescents with ASD, ADHD, and typical development (TD) scanned faces. In contrast with previous studies which have been conducted with high-functioning ASD individuals In our study, we compared the scanning of human and dog faces by children and adolescents with ASD, ADHD, and typical development (TD). There are well-documented benefits of human–animal interactions for humans of different ages, with and without special mental health conditions with respect to: social attention, social behavior, interpersonal interactions, and mood; stress-related parameters, such as cortisol, heart rate, and blood pressure; self-reported fear and anxiety; and mental and physical health . There aPhoto prints used in a preliminary study, which yielded less gaze aversion to dog than to human faces among ASD children , were coOur intent was to increase the accuracy of our measurements with the use of eye-tracking technology, extending the investigation to samples of ADHD and typically developing children. The results of this type of research could help to obtain behavioral data useful to the understanding of the differential and shared neuropsychological endophenotype underlying the processing of social–emotional cues in ASD and ADHD conditions.N = 45) consisted of children and adolescents, 15 with typical development (TD) controls , 15 with ASD , and 15 with ADHD . There was a male predominance in both clinical groups in line with the known prevalence of these disorders. The participants were evaluated in a Children’s Interdisciplinary Neuropsychological Care Center in São Paulo, Brazil, by neuropsychologists, pediatric neurologists, and child psychiatrists using DSM-V criteria. The ADHD group was composed of individuals with IQs in the normal range (scores above 85 on WISC-IV), matched to the control TD group. None of ADHD children were taking psycho-stimulant medication at the time of assessment. The Child Behavior Checklist (CBCL) was used as a screen for psychiatric comorbidity in both controls and ADHD groups. The ASD group was composed of low-functioning individuals (IQ below 70) and with scores between 30 and 50 on the childhood autism rating scale – CARS , taken from the Karolinska Directed Emotional Faces set (KDEF)  and fromThe eye movements of the participants were recorded with an infrared-based eye-tracking system (Tobii TX 300), integrated with a 23″ TFT monitor (with screen resolution 1920 × 1080 pixel). This equipment used a 300-Hz tracking frequency to collect information about the location and duration of the participant’s gaze fixations on stimuli displayed on the monitor screen  of equal size were selected on each stimulus image to determine gaze location: eyes region and mouth region. Two measures were taken: the number of fixations in each AOI and the total fixation time. Fixations were defined as a gaze of at least 200 ms duration within a 50-pixel radius, as recommended by Tobii manualDescriptive statistics summarizing total fixation time as a function of group, type of stimulus, and AOI Table  show thap = 0.003) and a significant interaction effect between Group and AOI (p < 0.001)  Table .p = 0.003) and a marginally significant difference dog × female (p = 0.055). No difference was found between male and female images (p = 0.262).With respect to type of stimulus, it is notable that, regardless of other factors, participants spent more time gazing at AOIs of dog images in comparison to human images Table . PairwisHeatmaps of the most attended areas of animal and human faces illustrate both the similarities and the differences among TD, ASD, and ADHD individuals Figure .p = 0.001) and TD versus ADHD (p = 0.002). In addition, the ADHD group gazed longer at the mouth region than the other groups. Pairwise comparisons with sequential SIDAK correction indicated significant difference ADHD versus ASD (p = 0.025), and a trend toward significance between ADHD and TD (p = 0.075).The interaction effect represented in Figure In this study, we investigated attentional modulation according to face regions in samples of ADHD, ASD, and typically developing children, by means of eye-tracking procedures. Participants from the ADHD group had considerably higher intellectual and adaptive functioning in comparison to those from ASD group. Nevertheless, they did not differ on time or region of interest of eye tracking, independently of the kind of stimuli. Compared to typically developing controls, the children in the two clinical groups spent less time viewing the eye region than other regions of the face.This result seems to reinforce previous evidence that difficulties in processing social cues may be shared by both clinical conditions. For instance, using functional neuroimaging techniques, Christakou et al.  found a Our results may be summarized in three main findings. The first is that all children looked at dog’s images more than at humans. This apparent greater interest of all participants for dog images suggests a widespread influence of motivational traits in attentional drive in childhood, which can be linked to an evolutionary perspective. A special human interest for other animals can be observed from a very early age . “BiophiThe second concerns is that the differences in gaze according to face region. All children looked at eyes longer than at the mouth region, but the duration of fixation was lower in ASD and ADHD groups in comparison to TDs. There are several evidences that the processing of facial expressions in ASD children differ than the processing showed by normally developing children. Such differences can be explained by affective or preferences in visual analysis. For instance, an influence of affective valences in the processing of emotions in faces has been reported frequently in ASD children . A prefThe third main finding is that ADHD children focused on mouth regions more than the other two groups. A possible influence of affective valences in the processing of faces regions may be considered. For instance, Pelc et al.  observedOur findings concerning a possible motivational effect of the interaction with dogs may have clinical implications, for instance, in the planning of alternative behavioral strategies in rehabilitation settings for children with neurodevelopmental disabilities. Theoretical implications include a better understanding of the maturational changes underlying social skill deficits. Finally, we consider that the eye-tracking technology proved to be useful for behavioral investigation even in low-functioning ASD children, and in this way its use in a more natural or ecological assessment setting looks promising.Some factors may limit generalization of our findings. For instance, we did not include a high-functioning ASD sample for comparison. The most important seems to be the small size and the demographic and clinical heterogeneity of the samples. ADHD were older than ASD children. Participants from ADHD and ASD groups were considerably different in terms of intellectual and adaptive functioning. Nevertheless, they were similar in some aspects of AOI while visually scanning human and dog faces. Other studies will be needed to confirm these findings.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders thought to have both genetic and environmental causes. It has been hypothesized that exposure to elevated levels of prenatal testosterone is associated with elevated traits of ASD and ADHD. Assuming that testosterone levels from a dizygotic male twin fetus may lead to enhanced testosterone exposure of its co-twins, we aimed to test the prenatal testosterone hypothesis by comparing same-sex with opposite-sex dizygotic twins with respect to neurodevelopmental symptoms.Neuropsychiatric traits were assessed in a population-based twin cohort from the Child and Adolescent Twin Study in Sweden (CATSS). Parental interviews were conducted for 16,312 dizygotic twins, 9 and 12 years old, with the Autism—Tics, ADHD, and other Comorbidities inventory (A-TAC).Girls with a female co-twin had an increased risk of reaching the cut-off score for ADHD compared with girls with a male co-twin. Both boys and girls with a female co-twin displayed a larger number of traits related to attention deficit and repetitive and stereotyped behaviors than those with a male twin. In girls, this also extended to social interaction and the combined measures for ASD and ADHD, however, with small effect sizes.Our results are reverse to what would have been expected from the prenatal testosterone hypothesis but consistent with a previous study of ASD and ADHD traits in dizygotic twins. The seemingly protective effect for girls of having a twin brother may be an effect of parent report bias, but may also be an unexpected effect of sharing the intrauterine environment with a male co-twin. Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) are neurodevelopmental disorders that are more commonly diagnosed in males than in females. The heritability is high in both ASD  and ADHDSeveral possible explanations for the high male-to-female ratio in autism have been put forward. The sex-differential threshold liability model for ASD proposes that a greater genetic burden is required for females than for males to develop ASD, implicating the existence of a yet unidentified female protective effect –7. The eTestosterone passes the blood–brain barrier and binds to the androgen receptor in the brain in both males and females, and a permanent  impact of prenatal testosterone exposure on fetal neurodevelopment has been confirmed in animal studies . The higAssuming that having a male co-twin increases the prenatal exposure to testosterone, the prenatal androgenization theory of autism  would prThis study was conducted using data from CATSS, an ongoing, population-based longitudinal twin study targeting all twins born in Sweden since July 1, 1992, at 9 or 12 years of age. The CATSS has a response rate of 80 % with little influence of the presence of neurodevelopmental disorders on the response rate . Zygositα = 0.86) and excellent for the 19 AD/HD items (α = 0.90) [ADHD and autistic traits were assessed with the Autism—Tics, AD/HD, and other Comorbidities inventory (A-TAC) –41 which = 0.90) . The pre = 0.90) . Two cutU test to analyze differences in module scores between index twins with a co-twin brother and index twins with a co-twin sister. The chi-square test was used to compare proportions of above cut-off scores between groups. In all analyses, both twins were excluded if either twin had a missing module score (46 pairs (0.6 %) for ASD score and 65 pairs (0.8 %) for ADHD score). Quade’s rank analysis of covariance [p values for multiple comparisons was deemed necessary.We studied differences in neuropsychiatric traits, as measured by the A-TAC modules, in index twins with either a female or male co-twin. In the main analysis, possible differences in scores for the composite modules for ASD and AD/HD were analyzed. In sensitivity analyses, differences with respect to cut-off rates for these modules, as well as differences with respect to scores of individual ASD and AD/HD submodules, were assessed. The three remaining A-TAC single modules spanning at least 5 points or more in the cohort were also tested to serve as control variables. In same-sex pairs, the index twin was selected randomly, in opposite-sex pairs the twin of the analyzed sex was selected as index twin. Due to non-normality and heterogeneity of variances of the residual distributions, we used Mann–Whitney variance  was usedParticipants in the CATSS study are protected by informed consent process—they are informed of what is being collected and given the option to withdraw their consent and discontinue participation. The CATSS-9/12 study has ethical approval from the Karolinska Institute Ethical Review Board: Dnr 02-289 and 2010/507-31/1.r < 0.1). There was no significant interaction effect between co-twin sex and age on autistic traits or autistic traits. Neither was there any interaction between co-twin sex and ADHD traits on autistic traits nor between co-twin sex and autistic traits on ADHD traits.As could be expected, the score of the outcome variables were extremely skewed. A total of 48 % of the male twins and 58 % of the female twins scored 0 points on autistic traits Table . The femU = 3,664,254, p = 0.004, r = 0.04), concentration/attention , social interaction , and flexibility . In boys, twins with a female co-twin had higher rank scores on concentration /attention  and flexibility  than those with a male co-twin. No differences were found in the modules language, impulsiveness/activity, “emotion,” or “opposition.”To further explore the results above, the differences in rank scores were also tested in each of the A-TAC modules spanning at least 5 points in scores: all differences pointed to a higher rank sum in the index twins with a female co-twin. Among the girls, the index twins with a female co-twin had higher rank scores than those with a male co-twin in four modules: “perception”  = 11.1, p = 0.001, ϕ = 0.04, with odds ratio 1.27 (95 % CI = 1.10 to 1.47). Although the frequencies were consistently higher in the twins with a female co-twin also for the ASD cut-off scores, in both girls and boys, these differences did not reach statistical significance , and thThere are some limitations to the present study. One is that neuropsychiatric traits were only assessed by parental assessment and by means of layman interviews. However, A-TAC is thoroughly validated and the cut-offs reliably mirror current estimates of the prevalence of ADHD and ASD, respectively , in the There is a small but increased risk for dizygotic twins with a female co-twin of displaying a high degree of parent-reported ADHD traits when compared with those with a male co-twin, indicating a possible protective effect of having a twin brother. Having a female co-twin is also associated with slightly elevated autistic traits, especially in the domains concerning flexibility of thought and social interaction, thus adding an intriguing complication to the hypothesis that elevated prenatal testosterone levels causes an increased frequency of autistic traits.


The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations.Eighty-three children with ADHD  and 72 typically developing (TD) children , aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder.Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found.This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs. Attention-deficit/hyperactivity disorder (ADHD) is a childhood psychiatric disorder characterized by a persistent pattern of age-inappropriate inattention and/or hyperactivity-impulsivity . SeveralWhile dopamine and serotonin hypotheses dominate current scientific work into ADHD, candidate gene study results are conflicting and effect sizes are small . In addiThus far, five case-control studies have been published on AAA blood concentrations in individuals with ADHD –25. ThreThe hypothesis that AAA concentrations are related to ADHD symptoms is the basis for a number of depletion and supplementation studies. Depletion of dietary tryptophan was found to impair sustained attention in adults with ADHD , and to Another aspect that requires further research, is the association between AAAs and symptoms of childhood psychiatric disorders that are highly comorbid with ADHD. As pointed out, dopamine and serotonin abnormalities have also been associated with ODD, CD and ASD. Indeed, tryptophan depletion have been shown to induce aggressive behaviour , 37, andTo summarize, there is inconsistent evidence that AAAs, acting as precursors of dopamine and serotonin, contribute to the expression of ADHD symptoms. The mostly outdated studies on this topic performed thus far are hampered by methodological shortcomings. Therefore, our aim was to explore concentrations of tryptophan, phenylalanine and tyrosine in a well-phenotyped sample of children with ADHD as compared to a control sample consisting of typically developing (TD) children. We firstly hypothesized that children with ADHD would show decreased blood concentrations of tryptophan, tyrosine and phenylalanine compared to controls, and that below average AAA concentrations would increase the risk of being diagnosed with ADHD. Secondly, we hypothesized that blood AAA concentrations would be related to ADHD symptoms. Thirdly, we hypothesized that abnormal blood AAA concentrations would be related to a decreased protein ingestion or by an aberrant AAA catabolism as evidenced by increased urinary AAA concentrations. Finally, we studied the possible confounding effects of symptoms of ODD, CD and ASD on our findings.th percentile on at least one of the ADHD scales  of the Disruptive Behaviour Disorder Rating Scale  was no exclusion criterion, neither was treatment with stimulant medication. Children on stimulant medication  discontinued drug use 24 hours before testing, in order to allow complete washout ) ASD symptoms were assessed using the 65–item Social Responsiveness Scale SRS; , 47), co, co47]),rs ranging from .86 to .96) [To investigate blood concentrations of tryptophan, tyrosine and phenylalanine, a dried blood spot technique was used. Collecting blood spots is less invasive for children than taking venous blood samples and the dried blood spot technique is sufficiently robust and stable for diagnostic purposes –51. Bloo to .96) . A bloodDaily protein intake was assessed during three days, using a parent-reported nutritional diary. Standardized dietary records and instructions were provided. Parents were instructed to register all consumed foods and drinks in the dietary record and to express the consumed amounts as accurate as possible. The amount of protein intake (grams/day) was calculated based on a computerized version of the Dutch food composition database . The DutIn order to examine urinary AAA concentrations, participants collected all urine excreted within 18 consecutive hours (after-school hours) in a urine collection container. During urine collection, the container was stored in a refrigerator (<5°C). A 10ml sample was sent to a laboratory for analysis, where the sample was stored at -20°C. An HPLC technique with fluorescence detection was used for the analysis of tryptophan in urine . The conThis study received approval from the local medical ethical committee of the VU University Medical Center Amsterdam, the Netherlands (#NL39922.029.12), and has been performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments. Written informed consent was obtained of parents of all children, and of children ≥12 years, prior to participation. Children with ADHD were recruited from mental health outpatient clinics, through the parental association for children with behavioural problems, and through a university research website. The TD group was recruited from primary schools located throughout the country. Children on stimulant medication discontinued drug use one day prior to participation (day 0), to ensure complete washout, and during the assessment of blood, urine and food intake (day 1 to day 3). On day 1 the blood spot was collected in the early morning, to rule out the effects of diurnal variation of blood AAA concentrations. The same day, after school time, urine collection started and continued for the following 18 hours, until the child would return to school the next morning (day 2). In the early morning of day 1 parents received detailed instructions on how to fill out the dietary record and how to collect urine of their child. After the instruction, parents started recording their child’s dietary intake, which continued for the following three days (day 1 to day 3). Parents and teachers were invited to fill out the questionnaires on a secured website. All data were collected between February 2013 and July 2014. The ADHD and TD group were recruited simultaneously, to control for possible seasonal effects on food intake or AAA metabolism.All statistical analyses were performed using R, version 3.2.1. All variables were inspected on outliers and missing values for the ADHD and TD group separately. Winsorising was applied to outliers, these were replaced with a value one unit bigger  than the previous most extreme score in the distribution of the group . Missingth percentile (M-1 SD) of the normative sample were used as a threshold value to define below average AAA concentrations . Odds ratios were calculated with their 95% confidence interval and Fisher’s Exact Test was performed to examine the significance of the odds ratios.To test the first hypothesis, group differences in AAA blood spot concentrations were assessed using Analyses of Variances (ANOVAs) with group (ADHD or TD) as fixed factor. Effect sizes were calculated in terms of partial eta squared, and interpreted as small (> .01), medium (>.06) or large (>.14) . In addiTo test the second hypothesis, Pearson product-moment correlation coefficients investigated the relationship between blood spot AAA concentrations and both parent and teacher rated symptoms of ADHD. The magnitude of correlation coefficients was interpreted as small (>.10), medium (>.30) or large (>.50) . Data ofp = .004), potential determinants of AAA abnormalities in blood spots , and symptoms of comorbid psychiatric disorders . Bonferroni adjusted results are reported.To test the third hypothesis, correlation analyses between blood spot AAA concentrations and protein ingestion and urinary AAA concentrations were performed in the whole sample. We also examined whether there were group differences in protein ingestion and urinary AAA concentrations using ANOVAs with group (ADHD or TD) as fixed factor. Lastly, correlational analyses evaluated whether blood spot AAA concentrations were related to parent- and teacher-reported symptoms of comorbid psychiatric disorders . If symptoms of ODD, CD or ASD were found related to the AAA concentrations, previous analyses were rerun with these symptoms entered as covariates. To correct for multiple testing, the alpha level of the correlation analyses was adjusted according to the Bonferroni procedure per outcome domain; ADHD symptoms . A below average (<16th percentile) blood spot concentration of phenylalanine increased the risk of being diagnosed with ADHD by 2.2, although this effect just escaped conventional levels of significance . A below average blood spot concentration of tryptophan  or tyrosine  did not increase the risk of being diagnosed with ADHD.No significant group differences were observed for blood spot concentrations of tryptophan, tyrosine, or phenylalanine, see rs < .24 and ps>.004). Furthermore, blood spot concentrations of tryptophan, tyrosine or phenylalanine were not significantly related to protein intake or urinary AAA concentrations . There were no differences between the ADHD and TD group with regard to protein intake or to urinary concentrations of tryptophan, tyrosine, or phenylalanine, see In the combined group of children with ADHD and TD children, AAA blood spot concentrations were not significantly related to ratings of ADHD symptoms  and therefore none of the previous analyses were repeated adjusting for the effects of symptoms of ODD, CD or ASD. Since the ADHD group consisted of considerably more males than the TD group, the groups analyses were rerun with gender as a covariate. These analyses did not alter the results.No significant associations between AAAs and symptoms of comorbid psychiatric disorders were found  children with ADHD. For instance, it might be that only children with severe deficiencies in executive functioning have decreased phenylalanine concentrations, as an altered dopamine functioning in the prefrontal cortex and the striatum is thought to impair executive functions, including sustained attention and interference control in ADHD , 67. Des


Attention Deficit Hyperactivity Disorder (ADHD) is a frequent neurodevelopmental disorder that increases accidental risk. Recent studies show that some patients with ADHD can also suffer from excessive daytime sleepiness but there are no data assessing the role of sleepiness in road safety in patients with ADHD. We conducted an epidemiological study to explore sleep complaints, inattention and driving risks among automobile drivers.From August to September 2014, 491186 regular highway users were invited to participate in an Internet survey on driving habits. 36140 drivers answered a questionnaire exploring driving risks, sleep complaints, sleepiness at the wheel, ADHD symptoms  and distraction at the wheel. 1.7% of all drivers reported inattention-related driving accidents and 0.3% sleep-related driving accidents in the previous year. 1543 drivers (4.3%) reported ADHD symptoms and were more likely to report accidents than drivers without ADHD symptoms . 14.2% of drivers with ADHD symptoms reported severe excessive daytime sleepiness  versus 3.2% of drivers without ADHD symptoms and 20.5% reported severe sleepiness at the wheel versus 7.3%. Drivers with ADHD symptoms reported significantly more sleep-related  and inattention-related  near misses than drivers without ADHD symptoms. The fraction of near-misses attributable to severe sleepiness at the wheel was 4.24% for drivers without ADHD symptoms versus 10,35% for drivers with ADHD symptoms.Our study shows that drivers with ADHD symptoms have more accidents and a higher level of sleepiness at the wheel than drivers without ADHD symptoms. Drivers with ADHD symptoms report more sleep-related and inattention-related near misses, thus confirming the clinical importance of exploring both attentional deficits and sleepiness at the wheel in these drivers. Road safety campaigns should be improved to better inform drivers of these accidental risks. According to the Diagnostic and Statistical Manual of Mental Disorders, 5 , ADHD i  on a new Internet epidemiological survey of a large sample of highway users. The main objective of this study was to explore the links between ADHD symptoms, sleepiness and accidental risk in a population of regular French highway users.With the assistance of the French highway association , we gained access to a database of registered drivers who used a computerized pay system to avoid long queues at highway toll booths.The Fondation AFSA conducts regular surveys via the Internet to improve their knowledge and understanding of drivers’ needs and behavior. An email newsletter was sent to AFSA highway Internet subscribers describing the main scientific objectives of the study. A link to the study questionnaire to be completed was inserted in the newsletter.For the survey, we used a methodology similar to that published by Powell et al. (2007)  and our From August to September 2014, 491186 subscribers of the 4 major highway networks covering Metropolitan France received a newsletter inviting them to participate in an internet survey on driving habits and driving risks. 36154 subjects answered the questionnaire. 14 questionnaires were eliminated because there contained aberrant responses. The analyses were conducted on a sample of 36140 drivers. The database was anonymous in accordance with the recommendations of the “Commissions Nationale Informatique et Libertés” which ensures the ethical usage of data collected for scientific purposes.Our team prepared a specific Internet questionnaire for the purpose of the study. It took a mean of 15 min to be completed. Volunteers had to respond to the following:Questions concerning socio-demographical characteristics .The Epworth Sleepiness Scale (ESS ) to explThe ASRS-1.1  to explore ADHD symptoms . Six of The Hospital Anxiety and Depression Scale (HADS) to explore anxiety and depression symptoms. The HADS is a fourteen-item scale in which seven of the items relate to anxiety and seven relate to depression. Scores for each subscale (anxiety and depression) range from 0 to 21 with scores categorized as follows: normal 0–7, mild 8–10, moderate 11–14, and severe 15–21 .Questions concerning sleep disorders (obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), insomnia, narcolepsy ⁄ hypersomnia) and sleep hygiene. Patients had to respond by “yes” or “no” if they suffered from a sleep disorder, and if “yes”, they had to respond from which sleep disorder by selecting in a list of sleep disorders (obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), insomnia, narcolepsy ⁄ hypersomnia).Questions concerning driving habits .Questions concerning accidental risks. Near-miss driving accidents were defined as an event that had not caused any harm and therefore had limited immediate impact (e.g. inappropriate line-crossing). Driving accidents were defined as an event that had caused material damage or physical injury. Two types of accidents and near-miss driving accidents were distinguished: related to sleepiness and related to inattention .Data were expressed as a proportion or as mean and standard deviation. We defined two groups of drivers: drivers without ADHD symptoms  and drivers with ADHD symptoms (Part-A ASRS subscore ≥ 4).First, univariate analyses with chi-squared tests on categorical variables and t-tests on continuous variables were conducted to compare the characteristics of the sample in terms of ADHD symptoms (absence or presence). Socio-demographical and clinical variables and driving habits were compared between the two groups.Then, multivariate analyses with logistic regression were conducted to control for potential confounding effects on the relationship between ADHD symptoms (absence or presence) and: i) behavioral sleepiness variables (severe excessive daytime sleepiness on the ESS and severe sleepiness at the wheel), ii) accident variables . Socio-demographical, driving and clinical variables that were significantly different between the two groups were included in the models. The clinical variables that were included in the multivariate analysis were: pathological sleepiness (Epworth ≥ 16), sleep disorders, pathological anxiety, pathological depression and drug consumption. Statistical test of the regression analyses permitted to estimate adjusted odd ratio (OR) and its 95% confident interval were presented to show the association.Finally, attributable fractions of severe sleepiness at the wheel needing to stop at least once per month for near-misses were estimated from the adjusted OR estimates and the prevalence of exposure in drivers with ADHD symptoms and drivers without ADHD symptoms .P-values were considered significant when p<0.05. The data were analyzed using the SPSS software package, version 20.0.36140 divers participated in the study. The mean age of the drivers was 55.2 years (±13.1) and 70.6% were male, 80.4% were married and 60.4% were currently employed, 4.8% were nocturnal or shift workers, and 17.8% were professional drivers. The mean score on the ESS was 7.8 (±4), the prevalence of severe excessive daytime sleepiness in the population was 3.7% (ESS>15), the prevalence of pathological anxiety was 6.2% (HADS anxiety > 10), the prevalence of pathological depression was 1.8% (HADS depression > 10), the prevalence of more than 3 glasses of alcohol per day was 6.9%, and the prevalence of a declared sleep disorder was 13.5%. The prevalence of ADHD symptoms was 4.3% (1543).Nearly half of the sample (46.1%) declared they experienced at least one episode of severe sleepiness at the wheel (i.e. requiring to stop driving), less than once a month and nearly 8% of the sample declared severe sleepiness at the wheel at least once a month. 40% of the drivers declared using their phone to call, 12.2% to write or read text messages while driving, and 41% using a GPS while driving.31.1% of the drivers reported at least one near-miss accident during the previous year, 23% of the drivers reported inattention-related near-miss accidents and 10.1% sleep-related near-miss accidents. 5.7% reported at least one driving accident in the previous year. 1.7% of the drivers reported inattention-related driving accidents (n = 598) and 0.3% (n = 125) sleep-related driving accidents.The population was divided into two groups: drivers without ADHD symptoms and drivers with ADHD symptoms. Results and p-values of univariate analyses are shown in Drivers with ADHD symptoms were more female , younger, less married (11.3% vs 12.2% p < .001), more shift workers , more professional drivers  and drove more than 25000 km per year . They reported more severe sleepiness at the wheel , more frequently using their phone to call , writing or reading text messages  during driving and using a GPS  than drivers without ADHD symptoms. Drivers with ADHD symptoms exhibited significantly more excessive sleepiness (ESS>15) than those without ADHD symptoms . They also declared more psychostimulant consumption (1% vs 0.1%) and more pathological anxiety (30.8% vs 5.1% p < .001), depression (9.7% vs 1.4% p < .001) and sleep disorders (25.8% vs 12.9% p < .001).14.2% of drivers with ADHD symptoms reported severe excessive daytime sleepiness at the ESS (>15) versus 3.2% of drivers without ADHD symptoms (p < .0001). The multivariate analysis with logistic regression found that the difference remained significant after taking into account confounding factors  . The mulDrivers with ADHD symptoms declared significantly more sleepiness-  and inattention-related  near misses than drivers without ADHD symptoms. The attributable fraction to severe sleepiness at the wheel for near-misses was 10.35% [7.1–12.8] for drivers with ADHD symptoms vs 4.24% [3.9–4.5] for drivers without ADHD symptoms.9.3% of drivers with ADHD symptoms reported at least one driving accident in previous year versus 5.5% of drivers without ADHD symptoms (p < .0001) . The mulThis study is the first to demonstrate the higher prevalence of sleepiness at the wheel in drivers reporting ADHD symptoms than in those without ADHD symptoms. Drivers reporting ADHD symptoms also presented higher scores on the Epworth Sleepiness scale compared to those without ADHD symptoms. One possible explanation is that this population reports a higher percentage of nocturnal sleep disorders . Another explanation, as demonstrated in one of our previous publications, is that ADHD patients suffer from objective pathological sleepiness independently of nocturnal sleep disorders . This goADHD patients are known to exhibit an increased risk of driving accidents owing to lack of attention and subsequent cognitive impairment . ADHD sySleepiness is a well-known cause of accidents owing to behavioral reasons (i.e. sleep deprivation) , 43 and This study has several limitations. First, because we used an internet survey we got a much lower rate of response than can be obtained when direct telephone interviews are performed. Since the aim of the study was not to establish prevalence data but rather an association between symptoms and driving risk, we believe that this method of selection does not affect the validity of our results. Second, the groups were defined on the basis of ADHD symptoms and not on an ADHD diagnosis based on the DSM criteria and a clinical interview. However, ADHD symptoms were frequently 4.3%) observed in an active population (i.e. drivers), which is in line with the estimated ADHD prevalence of 2.9% in France .3% obser, 38. IndDespite these limitations, the present study confirms the clinical importance of exploring both attentional deficits and sleepiness in subjects who complain of ADHD symptoms, in particular regarding the risk of driving accidents. When they receive an ADHD diagnosis, patients should be made aware of the risk that their propensity for distractive behavior and sleepiness may have on their driving. The present study also confirms the neurophysiological interest of studying the link between alertness and cognition in ADHD in line with the model that involves a deficit in alertness in the pathophysiology of ADHD –68. Aler


Attention-deficit/hyperactivity disorder (ADHD) is a recognized serious mental disorder that often persists into adulthood. The symptoms and impairments associated with ADHD often cause significant mental suffering in affected individuals. ADHD has been associated with abnormal neuronal activity in various neuronal circuits, such as the dorsofrontostriatal, orbitofrontostriatal, and frontocerebellar circuits. Psychopharmacological treatment with methylphenidate hydrochloride is recommended as the first-line treatment for ADHD. It is assumed that medication ameliorates ADHD symptoms by improving the functioning of the brain areas affected in the condition. However, side effects, contraindications, or non-response can limit the effectiveness of a psychopharmacological treatment for ADHD. It is therefore necessary to develop non-pharmacological interventions that target neuronal mechanisms associated with the condition in the same way as pharmacological treatment. We think that mindfulness meditation employed as a neuropsychotherapeutic intervention could help patients with ADHD to regulate impaired brain functioning and thereby reduce ADHD symptoms. In this paper, we highlight the mechanisms of such mindfulness meditation, and thus provide a rationale for further research and treatment development from a neuropsychotherapeutic perspective. We conclude that mindfulness meditation employed as a neuropsychotherapeutic intervention in therapy is a promising treatment approach in ADHD. Attention deficit/hyperactivity disorder (ADHD) is a serious mental disorder characterized by three core symptoms: inattention, impulsivity, and hyperactivity. In up to 60% of cases, ADHD symptoms persist into adulthood . It has It is assumed that the disorder relies strongly on impairments to neurobiological function , 6. IndiAdults with ADHD often suffer from comorbid disorders  and negative psychosocial consequences . TherefoPsychopharmacological treatment with methylphenidate hydrochloride is recommended as the first-line treatment for ADHD core symptoms . MethylpHowever, while psychopharmacological treatment with methylphenidate has undoubted positive effects on ADHD symptoms, it also has significant limitations. About 20–50% of adult ADHD patients are non-responders . Also, aGiven the limitations of treatment with methylphenidate, it is worth considering alternative treatment approaches that target both the underlying neurobiological mechanisms and the psychosocial difficulties of patients with ADHD. From our point of view, this is best achieved by administering treatment from a neuropsychotherapeutic perspective. Such an approach incorporates neurobehavioral interventions to enhance the functioning of brain regions affected in ADHD and specific cognitive behavioral interventions. In mindfulness-based cognitive therapy (MBCT), conventional cognitive behavioral interventions are combined with mindfulness meditation, which can be understood as a form of mental training . MindfulThis paper aims to illustrate our concept of a neuropsychotherapeutic approach for ADHD in adulthood.A search for trials on treatment, mindfulness, neuropsychotherapy, and psychotherapy in adult ADHD was conducted in the following bibliographic databases: PubMed, Embase, Medline, and Central . The following terms were used: (ADHD OR (attention deficit) OR (attention deficit) OR hyperactivity*) AND  AND (adult). Studies were selected and included according to their relevance for the subject.The concept of neuropsychotherapy represents the link between neuropsychology and psychotherapy. A neuropsychotherapeutic approach brings a neuroscientific perspective to therapeutic issues and aims to target underlying brain mechanisms that could be an obstacle to recovery in traditional therapy , 22.We define “neuropsychotherapy” as an approach that integrates cognitive behavioral therapy with neurobehavioral treatment. Neurobehavioral treatment refers to behavioral interventions that deliberately target neuronal mechanisms associated with psychiatric disorders, in the same way as pharmacological or surgical treatments .via concrete, intensive, and repetitive stimulation , which causes impairments in executive functioning , includiA meta-analysis of neuroimaging studies of ADHD in adulthood revealed ADHD-related hypoactivation located in the frontoparietal network, which includes the lateral frontal pole, anterior cingulate cortex (ACC), dorsolateral prefrontal cortex (dlPFC), anterior PFC (aPFC), lateral cerebellum, anterior insula, and the caudate and inferior parietal lobe , 29. TheThe functioning of the dorsal and ventral attentional networks, which are central parts of the attentional regulatory system, also seems to be impaired in ADHD , 32. TheFurthermore, impairments in the visual network have been proposed . This neThere is also evidence that the motor network  may be affected in ADHD .Attention deficit/hyperactivity disorder has also been conceptualized as a disorder of dysfunctional DMN activity. The DMN includes the medial prefrontal cortex (mPFC), ACC, and posterior cingulate cortex (PCC) . It has Given these neurobiological functional impairments in ADHD, it seems rational to employ principles of neuroscience in treatment, which we discuss next.A promising approach to improve the outcome of therapy in ADHD involves the neuropsychotherapeutic administration of meditation practice in MBCT. MBCT combines methods of cognitive behavioral therapy with mindfulness meditation. The treatment aims to provide the patient with an explanation for his symptoms, as well as information about ADHD. Behavioral interventions are designed to develop planning skills such as time management or problem solving. With cognitive methods, patients learn to identify and modify problematic thinking patterns . BesidesIt has been proposed that mindfulness meditation can help reduce mind wandering and distractibility in ADHD by improving the functioning of the DMN. For example, experienced meditators show reduced activation of the DMN during meditation and stronger functional connectivity of brain regions implicated in cognitive control and self-monitoring .A further possible beneficial effect of mindfulness meditation in ADHD is that it teaches patients not to act out but rather to observe emotional states as temporary and passing events, thereby helping patients to improve their regulation of emotion. Emotion regulation refers to strategies that help to exert influence on the occurrence, experience, and expression of emotions , 42. EveThe neurobiological mechanism of mindfulness meditation is currently not fully understood. It has been hypothesized that mindfulness meditation changes brain structure and function by myelinogenesis, synaptogenesis, dendritic branching, or adult neurogenesis . FurtherBesides these findings from neuroimaging studies, treatment studies have provided promising preliminary support for the feasibility and acceptability of mindfulness meditation in the treatment of ADHD. Recent studies indicate that mindfulness meditation training has ameliorating effects on ADHD symptoms and improves executive functioning, as well as emotion regulation (ISRCTN12722296 in preparation) , 50. FurGiven this evidence, we conclude that engagement in mindfulness meditation is associated with functional changes in brain areas suggested to be impaired in adults with ADHD. In addition, patients readily accept mindfulness meditation. Thus, mindfulness meditation appears to be a promising neurobehavioral intervention, with several potential pathways to improving neuropsychological functioning in patients with ADHD.There is emerging evidence that mindfulness meditation ameliorates ADHD symptoms and may cause neuroplastic changes in brain regions impaired in ADHD. However, the study of the neurobiological mechanisms of mindfulness meditation and its beneficial effects in ADHD is still in its infancy. This allows only speculative statements about possible future treatment directions. The following limitations have to be considered, along with recommendations arising out of them.Research is needed that uses larger sample sizes, active control conditions, and longitudinal, randomized research designs , 51.To our knowledge, no neuroimaging study has investigated the effects of mindfulness meditation on the adult ADHD brain. Future research should aim to expand understanding of the neurobiological effects of mindfulness meditation in ADHD and to connect neuroscientific findings with behavioral data.Furthermore, it has been suggested that ADHD is a heterogeneous condition, which probably includes different diagnostic subtypes , possiblM = 11 h, SD = 7 h) compared to low engagement in mindfulness  is associated with improved working memory control and improved positive affect , which could contribute to improved treatment outcomes.Attention-deficit/hyperactivity disorder, in adulthood is a serious mental condition with a strong neurobiological component that causes a wide range of impairments in affected individuals. Psychopharmacological medication is the first-line treatment for ADHD. However, not all patients respond well to it, and others have a preference for non-psychopharmacological treatment. Healthy psychological functioning in ADHD seems to rely greatly on the well-coordinated functioning of neuronal networks. There is promising preliminary evidence that mindfulness meditation employed as a neurobehavioral intervention in therapy can help ADHD patients to regulate impaired brain functioning and thereby improve self-regulation of attention and emotion control.KB: literature research and writing, AL: literature research and writing, AP: literature research and writing, supervision.AP (MD) declares that she has served on advisory boards, given lectures, performed phase three studies, or received travel grants within the last 3 years from Eli Lilly and Co., Lundbeck, MEDICE Arzneimittel Pütter GmbH and Co. KG, Novartis, Servier, and Shire; and has authored books and articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, Karger, and Springer. KB declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. AL (MD) declares that she received travel grants within the last year from MEDICE Arzneimittel Pütter GmbH and Co. KG.


Attention deficit hyperactivity disorder (ADHD) is a highly prevalent neurodevelopmental disorder characterized by a definite behavioral pattern that might lead to performance problems in the social, educational, or work environments. In the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, the symptoms of ADHD were restricted to those associated with cognitive (attention deficit) and behavioral (hyperactivity/impulsivity) deficits, while deficient emotional self-regulation, a relevant source of morbidity, was left out. The etiology of it is complex, as its exact causes have not yet been fully elucidated. ADHD seems to arise from a combination of various genetic and environmental factors that alter the developing brain, resulting in structural and functional abnormalities. The aim of this paper was to review epigenetics and ADHD focused on how multidimensional mechanisms influence the behavioral phenotype. Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by a definite behavioral pattern that might impair the affected individuals’ performance in the social, educational, or work environments. According to epidemiological studies, ADHD affects approximately 3–6% of schoolchildren worldwide and continues into adolescence and adulthood in most cases 50–80%) –4. This 0–80% –4.According to Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V), the symptoms of ADHD manifest as inappropriate levels of inattention, hyperactivity, and impulsivity, including behaviors, such as inability to pay attention to details, difficulty organizing tasks, and activities, and restlessness or inability to remain sitting in appropriate situations . There iNeuroimaging studies indicate that ADHD is a result of abnormal anatomical functioning and connectivity throughout fronto-striatal, fronto-temporal, fronto-parietal, and/or fronto-striato-parieto-cerebellar circuitry. In addition to circuitry, specific structures and areas of the brain have also received attention and include, among others, the prefrontal cortex, anterior cingulate cortex, caudate, globus pallidus, parietal regions, temporal regions, corpus callosum, splenium, cerebellar vermis, and cerebellum . NeuropsIn recent years, studies suggested that executive dysfunction is the main deficit in ADHD . The EFst-score >180 but <210 on the attention, aggression, and anxiety/depression subscales of the CBCL. Approximately 44% of the children with ADHD exhibited a positive CBCL-DESR profile versus 2% of the children without ADHD  . DESR inout ADHD . Those sout ADHD . From thThe etiology of ADHD has been the subject of several studies. Although the number of such studies is large, the exact causes of ADHD have not yet been fully elucidated. ADHD seems to result from a combination of genetic and environmental factors that alter the developing brain, resulting in structural and functional abnormalities .Several genetic linkage and association studies have been conducted in recent years to identify candidate genes related to ADHD . A recenDespite the small number of truly significant findings involving genes, it is known that genetic factors strongly influence ADHD . This phThe main targets of such research are the genes that encode components of the dopaminergic, noradrenergic, and serotonergic systems –42. DopaThere is emerging evidence that GABAergic and glutamatergic system play important roles in the pathophysiology of ADHD. Children with ADHD appear to have more than twice the level of glutamate, which is an excitatory neurotransmitter for neuronal cells, and low level of gamma-aminobutyric acid (GABA), which acts as an inhibitory molecule to inhibit stimulated neuronal cells . GeneticSome evidence points to an association between the synaptosomal-associated protein 25 (SNAP-25) gene and ADHD. SNAP-25 is one the proteins of the presynaptic plasma membrane and is highly and specifically expressed in neurons, being crucial for the fusion of synaptic vesicles and neurotransmitter release. A study showed that rats with mutations in that gene exhibited marked hyperactivity and other behaviors consistent with ADHD phenotype . SubsequThe environmental factors that are epidemiologically associated with ADHD include psychosocial adversities, maternal mental disorders, violence, stress, smoking, and drinking alcohol in the prenatal period and childhood. A longitudinal study conducted in Brazil by Pires and colleagues sought to correlate the family environment and pregnancy with ADHD diagnosis in children and the symptoms described by various informants (mothers and teachers). These authors found that family dysfunction, lack of social support for mothers, adverse life events, and disagreements in the course of pregnancy were associated with mother-reported ADHD . ADHD isExposure to tobacco smoke in the prenatal period and/or childhood might be highly detrimental to the child’s neurodevelopment because it induces changes that alter the cell dynamics, triggering a cascade of neurotoxic risk factors that negatively affect sensory processing . UnhealtSome evidence suggests that prenatal exposure to alcohol also causes pathological changes that increase the risk for ADHD, mainly resulting from the effect of alcohol on the modulation of the expression of the catecholamine transport system. Kim and colleagues found that prenatal exposure to ethanol in physiologically significant concentrations induced hyperactive, inattentive, and impulsive behavioral phenotypes in rats and their offspring associated with increased DAT protein expression and reduced methyl CpG-binding protein 2 (MeCP2) expression in the prefrontal cortex and striatum .It is believed that the actions of the environmental factors associated with ADHD are mediated by epigenetic mechanisms . AccordiThe term “epigenetics” derives from the Greek prefix “epi” and literally means, “above or beyond genetics.” As a whole, this term refers to any potentially inheritable change that might alter the expression of a gene without any direct modification of the nucleotide sequence in the DNA. It includes transient and modifiable cell alterations, as well as stable mechanisms responsible for the phenotypic identity of a given cell type –77. At tn = 182) aged 5–10 years old. The results suggest that differences in DNA methylation are apparent in early childhood, even between genetically identical individuals, and that individual differences in methylation are not stable over time. That longitudinal study indicated that environmental influences behave as relevant factors in the production of individual differences in DNA methylation in the genome  allows for the identification of the methylation pattern that underlies clinical phenotypic variations. Wide association of the epigenome and changes in the methylation profile might be used in the investigation of patients exhibiting symptoms regarding deficits in self-regulation and behavioral disorders, such as ADHD. The ability to screen the genome for high-resolution opens a new perspective for neurophysiological diagnosis, contributes to elucidation of the roles that epigenetic mechanisms play in the susceptibility to various emotional clinical phenotypes and might contribute to the formulation of positive behavioral interventions targeting individuals with ADHD, in addition to grounding appropriate treatments.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Some inter-country differences emerged, e.g., achieving the best degree of symptom control was more important to parents in some countries than others. In conclusion, the study showed that duration and degree of symptom control were the most important aspects of treatment for parents in all countries. The findings revealed cultural differences in the relative importance of attributes.The objective is to identify attributes of ADHD stimulant medications that influence treatment preferences of parents of children and adolescents with ADHD across six European countries, using a discrete choice experiment (DCE). Different attributes (and associated levels) of stimulant therapies were identified through literature review and clinician input. Attributes included duration and degree of symptom control after each dose, frequency of medication dosing, potential for treatment to be abused, the side effects of vomiting, loss of appetite, and sleep disturbance. Attributes and levels were combined using an orthogonal design to produce a number of discrete hypothetical treatments. Parents were recruited via patient panels in different countries and asked to complete a survey. DCE data were analyzed using conditional logit models to explore the impact of each attribute on participants’ choices. Six hundred individuals (220 parents of adolescents and 380 parents of children) participated. All attributes were significant predictors of choice (The online version of this article (doi:10.1007/s00787-013-0515-6) contains supplementary material, which is available to authorized users. Stimulant treatments for attention-deficit/hyperactivity disorder (ADHD) have been shown to provide effective relief of symptoms and improve functioning and health-related quality of life (QoL) for many patients –3. The tPatient/parent preferences between different stimulant therapies may be influenced by a range of factors. In addition to the characteristics described above, different treatments for ADHD can have different side-effect rates and profiles. Common adverse events include nausea, loss of appetite, and sleep problems , which aStandardized methods for eliciting an individual’s treatment preferences are widely used in healthcare research . Such mep < 0.01), with symptom control and side effects considered the most important treatment attributes. Conner et al. [Lloyd et al.  exploredr et al.  exploredr et al. –9, 14. Tr et al. , 10, andThe current study extends existing knowledge in two ways. First, it includes specific treatment attributes, such as substance abuse liability and specific side effects of stimulant medication that have not been systematically explored in preference research to date. Second, it provides the first cross-national comparison of patient preferences regarding ADHD treatments, comparing responses from participants in six European countries  where different approaches to ADHD management may result in different ADHD treatment patterns.A focused literature search was conducted with the specific goal of identifying important elements or attributes of ADHD stimulant medications to be included in the preference survey, including reviews of the published literature, the Food and Drug Administration (FDA)-approved package inserts/labels (US), and the Summary of Product Characteristics produced by the European Medicines Agency (EMA) for ADHD stimulant treatments. A targeted literature search was conducted in PubMed, EMBASE.com, and Google Scholar to identify articles published between 1997 and 2009 presenting evidence regarding the common side effects of treatment and information on the abuse of prescription medication in ADHD. Literature search terms included ‘treatment’ OR ‘quality of life’ OR ‘patient reported outcome’ OR ‘preference’ OR ‘clinical trial’ among other terms and ‘ADHD’ OR ‘inattention’ OR ‘hyperactivity’ OR ‘impulsivity’. The narrow scope and targeted nature of the search meant that only a limited number of highly relevant articles were retrieved. Of 12 articles initially identified, four were relevant for the present study –17.Potential attributes were generated from the literature review in consultation with an ADHD expert on the research team (ESB). The list was then shortened to the final study attributes based on further study team and expert review. The number of attributes was limited to seven in order to avoid an excessive number of preference item combinations, which would create an excessive burden on the participants. The attributes to be tested in the final list included: (a) duration of ADHD symptom control; (b) degree of ADHD symptom control; (c) potential for treatment abuse; (d) frequency of administration; (e) risk of vomiting; (f) risk of loss of appetite; and (g) risk of sleep disturbance.Each attribute was described using three levels considered to reflect a relevant and realistic range for that attribute by the study team .Table 1AThe attribute describing the potential for treatment abuse was only included in the survey for parents of adolescents (at least 13 years old). It was considered inappropriate and clinically irrelevant to ask parents of younger children about this.http://neilsloane.com/oadir/). Participants were presented with 18 pairs of hypothetical treatment choices differing systematically in terms of attributes and levels, and were asked to indicate whether they preferred treatment A or B in each choice set. Parents were also asked to categorize their child’s current treatment in terms of the attributes included in the survey, by stating which level best described their child’s current medication. All study-related documentation was translated into each target country’s local language using one forward- and one back-translation methodology in line with best practice [The DCE included a background questionnaire and a clinical history form. The seven attributes and three levels were combined using a published orthogonal array .N = 100 per country). These countries, covering Northern and Southern parts of Western Europe, were selected in order to sample broadly across differing national and cultural approaches to the diagnosis and management of ADHD. The study team aimed to recruit equally sized samples of parents of children and adolescents. The study employed a convenience sample recruited and screened by a specialist patient recruitment agency and were invited to complete the online questionnaire after giving online consent. The panel approached parents who had previously indicated that they had a child with ADHD and would be willing to take part in research. Parents reported the child’s diagnosis on his/her behalf. To minimize the possibility of recruiting non-ADHD patients in the sample, all participants completed an eligibility screener before completing the survey. This screener was designed with clinician input to help validate the sample recruitment. Further, the specialist patient recruitment agency runs continuous validation procedures to ensure the accuracy of their sample. Parents were excluded if the child or adolescent had been diagnosed with a significant psychiatric disorder (other than ADHD) that influenced the child or adolescent in a way that could not be distinguished from the impact of ADHD, including pervasive developmental disorder, Asperger’s syndrome, autism, depression, and/or conduct disorder; this determination was based on the self-report of parents. Participants received nominal compensation after completing the survey (approximately €2.50).Parents and/or primary carers of children (aged 6–12 years) or adolescents (aged 13–17 years) with ADHD were recruited in France, Germany, Italy, the Netherlands, Spain, and the UK  on the participants’ choices (dependent variable). Analyses were separated by country and as a total sample. The conditional logit model evaluated choice responses after conditioning them on the attributes of the other treatment alternatives available within the choice set. Hence, if, for example, ‘Treatment option A’ was preferred in the choice set #1, this preference was conditional on the attributes of ‘Treatment option B’. The coefficients obtained from the logit model provided an estimate of the (log) odds ratios (ORs) of preference for treatment attributes. In addition, interactions were explored to see whether there were any country-specific differences in the preferences of parents. In the conditional logit model, participants serve as their own controls. As a result, estimates cannot be confounded by omitted between-patient covariates, making the estimates less sensitive to model specification than those based on random intercept models . As therA total of 600 participants (220 parents of adolescents and 380 parents of children with ADHD) completed all study questionnaires. Demographics and background clinical data are presented by country  . For the child group, this preference was even stronger .p < 0.01). The impact of each of the three side effects on treatment preferences was similar for the two parent groups. A 1 % increase in the probability of any side effect reduced the likelihood of choosing a treatment by 30–50 %. Loss of appetite was considered the most important side effect to avoid  and sleep disturbance was considered the least important  by parents of both groups. Parents of adolescents reported a significant preference for a treatment with a reduced risk of substance abuse . Parents were 30 % less likely to choose a treatment associated with a 10 % increase in the risk of substance abuse. ‘Frequency of medication’ had a significant but relatively smaller impact on parents’ treatment choices. Treatments that required an additional administration per day reduced the likelihood that parents would choose that treatment by 11 % for adolescents  and by 14 % for children .A comparison of the child and adolescent groups showed that the attribute ‘duration of symptom control’ of ADHD was approximately equally important for both sets of parents. Parents preferred 12 h of symptom control to therapies with a shorter duration of action. Compared with a duration of symptom control of 4–6 h, both sets of parents were 1.6 times more likely to prefer a medication with a duration of symptom control of 12 h  across all levels compared with parents in Germany, the Netherlands, and the UK. ‘Duration of symptom control’ and ‘potential of substance abuse’ were equally important across all countries for parents of adolescents. Dutch and German parents were also more concerned than other parents in general about the experience of side effects such as vomiting  and loss of appetite . Dutch and French parents of adolescents were more concerned than UK parents about sleep disturbance associated with medication . For the ‘frequency of medication’ attribute, German parents stated a stronger preference (compared with UK parents) to avoid a treatment that needed to be taken more than once daily . In contrast, Spanish , Italian , and French  parents were less concerned than British parents about the number of times per day that their child required medication.Parents of children in Italy placed less value on the duration and degree of symptom control than British parents (this was consistent with the findings from the adolescent parents). Achieving the best level of symptom control was important for parents of children in Spain and the UK, with British parents placing most value on this attribute. Dutch and German parents of both groups were most concerned with side effects of medication . Dutch parents placed similar importance on the need to take more than one tablet per day as British parents . When comparing the two groups in Italy, parents of children were less concerned about the need to take more than one tablet per day than parents of adolescents . Spanish parents of children placed more value on the best level of symptom control, while the Germans were more concerned about loss of appetite as a side effect.This study is the first large-scale pan-European, cross-national comparison of parental preferences for all stimulant treatments for ADHD licensed within Europe. Our analysis considered a broader range of medication attributes than has been explored in previous studies, including the degree and duration of ADHD symptom control, treatment side effects, and perceived risks and concerns of abuse potential in shaping parental preference for selecting one ADHD medication versus another. Information on the participants’ current medication was also collected, which allowed comparisons between the hypothetical treatment preferences and the current medication profile. The parent preference data were also examined at a country level. These analyses often indicated that preferences of parents in the Northern European countries  were similar and these preferences differed from those of parents in the Southern European countries .Parents rated symptom control as the most important treatment attribute, with both degree of control and its duration influential in determining preferences. These findings are consistent with previous work by our group and by Mühlbacher et al. , which iThere were some cross-national differences in relation to this second aspect of symptom control and the need/preference for multiple dosing of short-acting medications. Respondents in Southern European countries were less concerned about the need to take more than one tablet per day. It is possible that this reflects cross-European lifestyle differences. Where families take a longer break during the middle of the day for lunch, it may be more feasible to administer a second dose of treatment. Parents in Southern European countries, particularly outside of the big cities, may be more likely to take a longer break during the day than parents in the Northern European countries. A question for manufacturers, therefore, arises as to how new formulations and delivery mechanisms can extend the duration of symptom control without leading to an unacceptable increase in side effects like sleep disturbances. A similar question is also relevant to clinicians, in terms of how they can combine existing therapies to extend the duration of symptom control of the medication. Treatment choices are always based on a balance between the positive attributes of treatments and the negative aspects.Other attributes of treatment were significant drivers of parent choice. The current DCE method allowed evaluation of the extent to which parents are willing to trade the benefits of treatments against their risks. In general, despite symptom control being the most important determining factor when it comes to treatment preferences, parents were willing to accept some reduction in symptom control in order to avoid even a relatively small increase in side effects or risk of substance abuse. Both symptom control and side effects were independently significant predictors of choice; therefore, it is possible to estimate the marginal rates of substitution between these attributes. The data also demonstrate that parents would prefer a treatment with equal efficacy but no associated risk of abuse or side effects. Previous studies have reported similar findings, whereby efficacy was regarded as the most important attribute; however, side effects and dosing were also identified as key aspects of treatment , 14.‘PotSome other interesting differences emerged between the parents in the different countries in terms of their experience of ADHD and the care their children had received. There was evidence of a shorter length of time between the first appearance of symptoms to the diagnosis of ADHD in Southern European countries. At least in this dataset diagnoses were made at a younger age in these countries. Given the sampling approach taken, it is difficult to determine whether this difference is a real cultural effect or rather something specific to the particular samples recruited for this study. The analyses also identified some differences in prescribing patterns. The Northern European countries reported higher use of MPH, whereas the Southern European countries reported a more varied range of treatments, particularly amphetamine-based and non-stimulant products. This may reflect different patterns of medication availability and treatment patterns in the different European countries .There are some important limitations to this study that should be considered when interpreting the results. The sample was obtained through a specialist patient recruitment agency and, therefore, it was a self-selected group that may not have been completely representative of the European population. This could bias the findings and affect the results in different ways in different countries. In addition, parents/caregivers who participated in the study may have children/adolescents with more severe symptoms, which may partially explain why participants reported a higher use of baseline amphetamine in the sample than in the general ADHD population. The mean age at diagnosis was lower than expected in this study. This could partially be explained by the fact that diagnosis of ADHD was gathered from parents and not confirmed with patient medical records. Thus, the low age of diagnosis may be confounded by parental recall bias that cannot be confirmed with patient medical records.The fact that the survey was performed online may have precluded some people from taking part, i.e., participants with no internet access or who do not know how to use the internet. This may have biased the type of respondents, e.g., towards a younger or more educated population, although all efforts were made to recruit a sample representative of the population in terms of age and gender in each country. Practical constraints required the research team to limit the number of attributes that were included in the DCE in order to avoid an overly complex survey. Consequently, the choices that parents were asked to make may be a simplification of actual, real-life treatment choices. However, the survey was not designed to capture information on all aspects of ADHD treatment; rather, an assessment of key factors/attributes that is more meaningful to parents when they are faced with decisions to choose the most appropriate therapy among the stimulant class was wanted. In fact, this survey focused on the attributes of stimulant medications only and, therefore, there is the possibility that only benefits unique to this specific class of medications were captured. The attribute describing duration was expressed in terms of the number of hours per day of symptom control. The attribute did not specify at what time in the day the treatment would provide symptom control (e.g. morning or afternoon). This may be an important issue to examine in future studies.The findings of this study may provide insight to clinicians, regulatory bodies and decision makers regarding the key attributes that drive patient/parent preferences for the choice of ADHD treatments across countries. Importantly, it is acknowledged that poor patient/parent satisfaction with pharmacotherapy may lead to poor adherence to treatment, which could have a negative impact on clinical outcomes . FurtherThis study identified parent preferences for different aspects of ADHD treatment in six European countries. Duration and degree of symptom control were the most important aspects of treatment for parents in all countries; however, the findings revealed cultural differences in the relative importance of other attributes. The DCE data also reveal participants’ preferences for attributes in relation to administration, potential of treatment abuse, and tolerance of side effects. The DCE method allows clinicians and decision makers to identify the key aspects of treatment that are important to parents, which may lead to better tailoring of treatments and improved adherence, persistence, and patient/caregiver relevant outcomes.Supplementary material 1 (DOCX 70 kb)Below is the link to the electronic supplementary material.


All participants were between 8–25 years and groups did not differ in mean age or gender. Follow-up analyses were conducted to examine the role of antisocial behaviour (conduct problems) on FA and MD values in both groups. Comorbid ODD in ADHD was associated with lower FA in left frontotemporal WM, which appeared independent of ADHD symptoms. FA was negatively associated with antisocial behaviour in ADHD + ODD, but not in ADHD-only. Comorbid ODD is associated with WM abnormalities in individuals with ADHD, which appears to be independent of ADHD symptoms. Altered WM microstructure in comorbid ODD may play a role in inconsistencies in the current DTI literature in ADHD. Altered development of these tracts may contribute to social-emotional and cognitive problems in children with oppositional and antisocial behaviour.Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid disorders. ADHD has been associated with altered white matter (WM) microstructure, though the literature is inconsistent, which may be due to differences in the in- or exclusion of participants with comorbid ODD. WM abnormalities in ODD are still poorly understood, and it is unclear whether comorbid ODD in ADHD may have confounded the current ADHD literature. Diffusion Tensor Imaging (DTI) was used to compare fractional anisotropy (FA) and mean diffusivity (MD) between ADHD patients with ( Attention-deficit/hyperactivity disorder (ADHD) is one of the most frequently diagnosed childhood psychiatric disorders, characterised by symptoms of inattention and hyperactivity/impulsivity which lead to functional impairment in daily life . One of Neuroimaging studies have consistently implicated abnormalities in brain structure and functioning in ADHD , 4, inclGiven the high comorbidity of ODD in individuals with ADHD, it is possible that the inconsistencies in the ADHD DTI literature are—at least partly—due to differences between studies in the in- or exclusion of subjects with comorbid ODD. ODD is associated with widespread volumetric and functional brain abnormalities in regions including the frontal cortex, amygdala, and insula , 11. HowTaken together, ADHD is associated with altered WM microstructure throughout the brain. WM abnormalities in ODD are still poorly understood, but may be expected in partly similar regions. Importantly, most previous DTI studies in ADHD have either not described the in- or exclusion of ODD, or included participants with ODD but did not test or describe the possible confounding effects. Therefore, it is possible that ODD-related WM abnormalities may have influenced the current DTI literature in ADHD, and that some of the WM abnormalities that are currently being attributed to ADHD may be better explained by the presence of comorbid ODD. To explore WM abnormalities in ODD, and shed light on the possible confounding effect of ODD-related abnormalities in ADHD DTI research, we compared WM microstructure between ADHD patients with and without comorbid ODD. We hypothesized that comorbid ODD would be associated with additional, or partly different, WM abnormalities compared to our previously reported ADHD-related WM abnormalities . More spn = 42, including 7 participants with ODD + CD) and an “ADHD-only” group .Participants were part of the NeuroIMAGE cohort . InclusiOf note, group differences between ADHD and controls in the NeuroIMAGE cohort have been described in detail in a previous publication , in whicTo determine ADHD and ODD diagnoses, all participants were assessed with the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL) . Parentsr = 0.32, p < 0.001).The presence of antisocial behaviour (conduct problems) was assessed with the Observed Antisocial Behavior Questionnaire (OAB) . The OABFull scale IQ was estimated by a two-subtest short form (Vocabulary and Block Design) of the Wechsler Intelligence Scale for Children-III (WISC-III) or Wechsler Adult Intelligence Scale III , to be used for exclusion of participants with IQ < 70. Additional information was collected to assess autism spectrum symptoms , comorbid internalizing disorders (using the K-SADS-PL sections for depression and anxiety disorders), history of ADHD medication use (yes or no), and socio-economic status.p = 0.46). The study was approved by the Dutch local medical ethics committees, and all participants signed informed consent (parents signed for participants under 12 years of age). Afterwards, participants received a reward of €50 and a copy of their MRI scan.The current study was part of a comprehensive assessment protocol , includib value of zero), followed by 60 volumes with non-collinear gradient directions .MRI scanning was carried out on either a 1.5 Tesla Sonata or a 1.5 Tesla Avanto MRI scanner , using the same Siemens 8-channel head coil. Whole-brain, high-resolution T1-weighted anatomical images were acquired in the sagittal plane . Eddy current-compensated diffusion-weighted SE-EPI images were collected during one acquisition consisting of five volumes without directional weighting , unwarping image distortions, and correction of motion-induced artefacts, using SPM8 (Wellcome Trust Centre for Neuroimaging) functionality and in-house developed methods. Tensor images were estimated, and FA and MD maps were derived for each participant, which were further processed using FSL’s Tract-Based Spatial Statistics (TBSS)  using stt test contrasts were set up to investigate main group differences (ADHD + ODD versus ADHD-only) on FA and MD. Second, additional contrasts were set up for group-by-age and group-by-ADHD symptom count interactions, to investigate whether group differences in FA or MD differed as a function of age or ADHD symptom count. Results were obtained using Threshold-Free Cluster Enhancement (TFCE), providing results at p < 0.05 using FWE correction for multiple testing. Anatomical labels of voxels that showed significant effects were identified using the built-in Harvard-Oxford and JHU atlases for WM tracts in FSLview. Given the group differences in IQ and autism spectrum symptoms . Voxelwise TBSS analyses were performed in FSL with the randomise tool, which is based on permutation testing. A General Linear Model (GLM) was built with diagnostic group as predictor (ADHD + ODD versus ADHD-only). Covariates were included for the number of ADHD symptoms (given the group difference in ADHD symptoms), age (given our broad age range and the strong association between age and WM microstructure) and scan site (to correct for possible site differences). First, n = 7).Subsequent follow-up analyses were conducted to further examine the nature of the significant group differences. All follow-up analyses were conducted in SPSS on mean FA or MD values from regions in which a significant group difference was found in the TBSS analysis. Linear Mixed Models (LMM) were used with a random intercept per family, to account for correlated data within families, and the same predictors and covariates were included as in the TBSS analysis . First, to check whether our results were applicable to all ages in our broad age range, we performed a median split on age and re-ran the LMM on both age groups separately. Second, to investigate whether lower FA in the ADHD + ODD group could be explained by higher rates of antisocial behaviour, the LMM was run with a dimensional measure of antisocial behaviour  and its interaction with diagnostic group as predictors. Last, to test whether participants with comorbid CD had confounded our main effect or the interaction with antisocial behaviour, both LMMs were re-run after excluding the participants with comorbid CD (p < 0.05). Results from these additional analyses show that group differences in FA were robust for subclinical autism spectrum symptoms and are present at all levels of cognitive functioning.The TBSS analysis revealed several clusters of decreased FA for ADHD + ODD compared to ADHD-only Fig. ; Table 2F1,152 = 6.658, p = 0.011), which was further examined by testing the association between antisocial behaviour and FA in each diagnostic group separately. Results revealed a significant negative association between antisocial behaviour and FA in the ADHD + ODD group  but not in ADHD-only . Excluding participants with comorbid CD (n = 7) did not change the significance of the main group effect or the interaction with antisocial behaviour. Additional follow-up analyses were conducted to examine whether the observed left-sided lateralization of TBSS findings was associated with language impairment in ODD. To this end, the LMM was re-run with the Vocabulary standardized score of the WISC-III/WAIS-III and its interaction with diagnostic group as predictors. Results revealed no effect of Vocabulary on FA  and no significant interaction with diagnostic group .Follow-up analyses were conducted in SPSS on mean FA values from the significant voxels of reduced FA in ADHD + ODD. First, we re-ran the LMM in two separate age groups, split at the median age (17.5 years). Results remained the same for both the younger and the older age group. Second, we examined the association between diagnostic group and antisocial behaviour as measured by the OAB Fig. . A signiThis is the first study investigating WM microstructure associated with comorbid ODD in ADHD. We aimed to shed light on WM microstructure in ODD as well as the possible confounding effect of ODD comorbidity on previous DTI findings for ADHD.Several regions of reduced FA were found in individuals with ADHD + ODD compared to those with ADHD alone, mainly located in frontotemporal WM tracts and subcortical regions of the basal ganglia in the left hemisphere. More specifically, reduced FA was located in the left corticospinal tract, inferior fronto-occipital fasciculus or uncinate fasciculus, forceps minor or genu of the corpus callosum, and internal capsule. No differences in MD were observed between the groups, and group differences in FA were not dependent on ADHD symptom count. These findings could indicate an additive or differential effect of ODD on ADHD-related WM pathology, in line with a previous study that showed a similar pattern of findings for adolescents with ODD/CD with and without comorbid ADHD . Of noteImportantly, current results show some striking similarities and differences with results from our previous study in a largely overlapping sample, in which we found reduced FA for ADHD compared to controls in widespread regions . QualitaOur findings are helpful in resolving the inconsistencies in the prior DTI literature for ADHD by showing that ADHD patients with and without ODD differ in WM microstructure in several tracts. It is possible that findings from previous studies, especially in (orbito)frontal WM regions, have been attributed to ADHD, while they may better be explained by comorbid ODD in the sample. Furthermore, individuals with comorbid ODD appear to have more severe WM abnormalities than individuals with ADHD alone in temporal and striatal regions, which may have led to differences in the strength of effects in previous studies that differ in their in- or exclusion strategies. Future studies should clearly test and describe the possible confounding effect of ODD comorbidity in their sample, and current findings should be kept in mind in interpreting previous literature in which ODD comorbidity was not described or excluded.in combination with high rates of antisocial behaviour. Comorbid ODD with low rates of antisocial behaviour, and antisocial behaviour without an ODD diagnosis, did not appear to be associated with lower FA. Importantly, our measure of antisocial behaviour largely overlapped with CD-like behaviours. Therefore, it is possible that our finding in fact signifies an interaction between ODD and  CD, and that WM pathology is strongest in individuals with both disorders combined. Although ODD and CD are highly correlated constructs, this result suggests that both disorders may interact on a neurobiological level, indicating that ODD and CD should be treated as separate constructs in future studies investigating WM microstructure. It is important to note that young children in our sample may still go on to develop ODD and/or CD in the future. Hence, it is difficult to know whether the currently defined subgroups will hold in the future, or whether children may shift from the ADHD-only to the Comorbid group in a few years’ time, and if so, whether group differences in WM microstructure will remain the same. It would be informative to replicate current results in a longitudinal sample following ODD and conduct symptoms, as well as WM microstructure, over time.Antisocial behaviour, or conduct problems, interacted with group status in such a way that WM abnormalities were mainly present in individuals with comorbid ODD Current findings fit well within theories of frontotemporal and frontostriatal brain dysfunction in individuals with ODD and/or CD –33. The Tracts of lower FA in comorbid ODD were lateralized to the left hemisphere, suggesting that findings may be related to a lateralized brain function such as handedness or language functioning. While handedness is unlikely to explain the lateralization of our results, given that our groups did not differ on handedness, our groups did differ on vocabulary skills, and language deficits have been suggested to play a role in disruptive behaviour disorders such as ODD . DTI stuOur current findings should be viewed in the light of some strengths and limitations. Strengths include our large sample size, 60-direction diffusion imaging, and the possibility to check for a wide variety of confounding factors, which was a caveat in many studies performed so far. The lack of a pure ODD group restricts the generalizability of findings to comorbid ODD in ADHD, but not to pure ODD (without ADHD). Nevertheless, ODD did not interact with ADHD symptom severity, which suggests that our findings for comorbid ODD appear to be largely independent of ADHD and may generalize to pure ODD. This is especially the case for findings in (orbito)frontal regions, which we did not find in our previous ADHD-control comparison . HoweverThe current study adds significantly to the scarce literature on WM microstructure in ODD and is the first to describe the effects of comorbid ODD in ADHD. Our results show that comorbid ODD in ADHD is associated with altered WM microstructure, compared to individuals with ADHD alone, suggesting more severe and partly different WM abnormalities in comorbid individuals. WM pathology was strongest in individuals with comorbid ODD in combination with high rates of antisocial behaviour (conduct problems) and was mainly located in frontotemporal and striatal regions. It is possible that altered development of these tracts during childhood may underlie problems with social-emotional decision making, reward processing and motivational control, and predispose to the development of oppositional and antisocial behaviour, although longitudinal studies are needed to investigate the causality of this association.