It is necessary to develop efficient methods to produce renewable fuels from lignocellulosic biomass. One of the main challenges to the industrialization of lignocellulose conversion processes is the large amount of cellulase enzymes used for the hydrolysis of cellulose. One method for decreasing the amount of enzyme used is to recycle the enzymes. In this study, the recycle of enzymes associated with the insoluble solid fraction after the enzymatic hydrolysis of cellulose was investigated for pretreated corn stover under a variety of recycling conditions.It was found that a significant amount of cellulase activity could be recovered by recycling the insoluble biomass fraction, and the enzyme dosage could be decreased by 30% to achieve the same glucose yields under the most favorable conditions. Enzyme productivity (g glucose produced/g enzyme applied) increased between 30 and 50% by the recycling, depending on the reaction conditions. While increasing the amount of solids recycled increased process performance, the methods applicability was limited by its positive correlation with increasing total solids concentrations, reaction volumes, and lignin content of the insoluble residue. However, increasing amounts of lignin rich residue during the recycle did not negatively impact glucose yields.To take advantage of this effect, the amount of solids recycled should be maximized, based on a given processes ability to deal with higher solids concentrations and volumes. Recycling of enzymes by recycling the insoluble solids fraction was thus shown to be an effective method to decrease enzyme usage, and research should be continued for its industrial application. Limited oil resources and the devastating effects of climate change from the burning of fossil fuels make it necessary to identify sustainable alternative sources of energy for the future . Many alRecent commercial cellulase preparations have been shown to be effective at hydrolyzing cellulose under industrially relevant conditions, however the high cost of enzymes remains a significant barrier to the economical production of ethanol from lignocellulosic biomass ,4. It isThe cellulase enzymes currently employed in the hydrolysis of lignocellulosic biomass readily bind to cellulose, and those enzymes which are active on the cellulose polymer, specifically cellobiohydro-lyases (EC 3.2.1.91) and endoglucanases (EC 3.2.1.4) remain adsorbed to the cellulose polymer during hydrolysis -14. BecaA significant amount of work has already been carried out investigating the recycle of cellulases ,14,17-21The objective of this study was to determine if, by recycling the insoluble solids fraction, a significant amount of enzyme activity could be reused, and therefore increase overall product yields or decrease the amount of required enzyme needed to reach a given level of conversion. It was also desired to determine which process variables, such as solids washing and fraction of solids recycled, had significant effects on process yields, and how the manipulation of these variables would impact the hydrolysis reaction conditions. In this study, the recycle of cellulase enzymes by recycling the insoluble solids residue present after hydrolysis was investigated and evaluated at conditions which were closer to industrial processing conditions than many previous studies. The efficacy of enzyme recycle by the proposed method was evaluated for a number of successive recycle scenarios while modifying a number of recycle conditions and measuring the changes in product formation. The data from these experiments were then used to develop a computational model to predict process parameters after a large number of recycles, thus giving an idea of steady state conditions. The influence of the lignin rich residue was also directly evaluated for its effect on enzyme hydrolysis.From examining the amount of glucose produced in the course of the reaction, it could be seen that significant amounts of glucose were produced from the fresh substrate when the insoluble solids were recycled Figure . GlucoseIn the first factorial experiment, the 72 hour glucose hydrolysis yield (recycle round 0) was 77% . Glucose yields after the first recycle round  for each individual hydrolysis condition ranged between 30 and 65%, and between 2 and 77% after the fourth recycle round  for the prediction of all responses, and actual versus predicted had r-squared values between 0.97 and 0.99. The increase in glucose yield for recycle round 2–4 obtained with recycling of 100% of the solid, washed residues, and enzyme supplementation (34 mg EP/g cellulose) might be a result of both increased enzyme levels due to high supplementation and recycle levels and the impact of the removal of glucose (product inhibitor) and putative inhibitors resulting from the pretreatment during the washing step. The results regarding washing of the substrate agree with data published by others. Washing has thus long been known to remove acid and any eventual inhibitory substances that inhibit cellulolytic enzymes from erma sp. . More reerma sp.  showed terma sp. .Total glucose yields ranged between 28 and 93% of total cellulose added during the experiment , and under conditions with the highest makeup enzyme loading and solids recycle glucose production increased with each subsequent recycle, from 0.74 g to 1.02 g. This observation suggests that a constant amount of glucose production from recycle to recycle were obtained under recycle conditions with makeup enzyme loadings of 34 mg EP/g cellulose, even if the calculated glucose yields decreased for each individual recycle round . Washing resulted in lower glucose concentrations in the hydrolysate, which is not desirable for industrial scenarios. Coupling the non-significant impact of washing on total glucose yields with expenses that would be incurred by including a washing step in an industrial process, it was decided that solids washing was not beneficial to the recycle process. Therefore, the investigation of washing as an alternative for improving recycle performance was not continued.The most significant factors affecting the performance of enzyme recycle was the amount of additional enzyme applied, and the fraction of solids recycled. The washing of the solids was determined to not have an overall significantly positive effect on recycle performance. Initial glucose concentrations varied depending on how much of the non-washed residue was recycled. At the beginning of the recycle experiment, initial glucose concentrations were ~5 g/L from the pretreated slurry, and in some cases reached 20 g/L in the beginning of the 4When the initial % TS concentration (w/w) was increased from 10% to 15%, the glucose yield achieved after the initial 72 hours decreased from 77% to 69% w/w . Solids concentrations can be a limiting factor in lignocellulosic processes, primarily due to difficulties in mixing, and it is therefore important to consider how any new recycle method would affect this variable [Based on the performance and gravimetric data from the recycle experiments, it was possible to construct a mathematical model to determine process parameters for an extended number of successive recycle rounds. Of specific interest was the effect of recycle on the TS content of the total reaction mass Figure , and thevariable  and thusThe lignin content of the insoluble substrate was shown to increase significantly with subsequent recycles in the model, increasing from a starting lignin content of 27% to between 39 and 53% of total insoluble solids . This significant increase in reaction mass, and with it reaction volume, implies that any recycle method would require significantly larger equipment for the hydrolysis, and thus increased capital and operating costs. The starting cellulose composition of the insoluble substrate was found to decrease with subsequent recycles, and trended inversely to the lignin content of the insoluble substrate. The cellulose content of the insoluble fraction decreased from 63% to between 44 and 23% by the 10th modeled recycle round, depending on the fraction of insoluble solids recycled and the enzyme dosage.Similar trends to those exhibited by total solids concentrations in Figure Based on trends suggested by the model that show an increase in lignin in the insoluble fraction, it was desirable to determine the direct effect of this phenomenon on hydrolysis performance. It was found that for low solids hydrolysis conditions, increasing the fraction of lignin in the insoluble solids fraction did not have a negative effect on glucose yields Figure . GlucoseThe recycle experiments demonstrated that a significant portion of the enzyme activity could be recycled with the insoluble solids fraction after each hydrolysis. Total enzyme productivity was increased for all of the recycle scenarios, showing that the enzymes were better utilized during the reaction. The insoluble solid recycle method also increased enzyme substrate contact time, as unreacted substrate was returned to the reaction. However, the amount of enzyme activity which was successfully recycled was significantly less than the total amount of enzyme which was initially added to the hydrolysis. This significant loss in overall enzyme activity may be due either to thermal deactivation and precipitation of the enzyme, increased nonspecific binding by fresh lignin, and/or loss of soluble enzyme in the liquor fraction. Specifically, a loss in β-glucosidase activity in the soluble fraction, which has been shown to be present in significant quantities during hydrolysis in the liquid phase , could uThe recycle of the insoluble solids caused large impacts on the physical and compositional parameters of the hydrolysis. Specifically, the recycle led to significantly increased total solids concentrations, total reaction masses, and to an increase of lignin in the solids composition. These increases limit the amount to which solids recycle can be applied in an industrial process, as a significant solids purge would need to be incorporated to achieve steady state and to maintain acceptable operating conditions. As the ability to recycle enzyme activity was related directly to the amount of solids which could be recycled, the ability to recycle the enzymes would be effectively limited by the need for this solids purge. Determining the optimal tradeoff between recycling enzyme activity and increased operating solids concentration is highly process dependent, and is beyond the scope of this investigation. The increase in solids concentration due to recycling could also lead to decreases in final glucose concentrations. If it is assumed that a plant operates at the highest possible solids concentration, the addition of recycling would either necessitate increasing the maximum operating solids concentration, which would require modifying process equipment, or leaving the solids concentration the same, which would lead to a decrease in starting cellulose content. However, the upper working limit of solids concentration in a plant may also be limited by enzyme inhibition and hydrolysate toxicity to the fermenting organism, so there may be room for adjustment in a specific process to incorporate solids recycle.Interestingly, the increase in lignin in the insoluble fractions did not negatively impact the hydrolysis performance. With respect to washing of the solids, we did observe a tendency for improved glucose yields and thus better enzyme productivity with washing of the solids being recycled Figure . These iEnzyme dosage could be decreased by 30% to achieve the same amount of cellulose hydrolysis in a steady state condition for the best conditions of the solids recycle experiments. This is a significant decrease in enzyme usage. It was also shown that solids recycle coupled with higher dosages of enzyme could improve yields beyond the baseline of no recycle level. It is worth noting though that the initial enzyme loadings for this study were set so that glucose yields would not approach theoretical maximum levels , so that the effects of enzyme recycle could be observed in both the positive and negative direction from the control no recycle condition. Thus specific recycle performance results may vary based on what the desired level of cellulose hydrolysis is for a given process. As well, these varying results may impact process economics to the extent that solids recycle may or may not be economically beneficial. The enzyme recycle could be coupled with other methods for improving hydrolysis performance  which might enhance recycle performance. The solids recycle method was shown to be an effective way to decrease enzyme usage, however its specific application in a continuous industrial process has yet to be proved, and may vary greatly depending on the process applied. Enzyme recycle can be effective in decreasing enzyme usage, however its overall benefit to a specific process must be tested at a larger scale.It was possible to effectively recycle a significant amount of the enzymes in Cellic CTec2 by recycling the insoluble solid fraction after enzymatic hydrolysis of pretreated corn stover. Enzyme usage was decreased 30% while maintaining glucose yields when a majority of the insoluble material was recycled. Similar trends in the recyclability of the enzyme were seen at two total solids concentrations, suggesting that this process could be replicated at even higher total solids operating conditions. As well, specific enzyme productivity increased for all recycle scenarios.This represents a significant improvement in process performance and a significant reduction in the enzyme requirement for lignocellulose hydrolysis. However, by recycling the insoluble fraction, total solids concentrations, reaction masses, and the amount of lignin in the reaction increased significantly, and may therefore temper improved process performance and economics. This balance will be highly dependent on a specific industrial process and operating costs. Elevated levels of lignin residue were not found to negatively affect enzyme performance. Enzyme recycle remains a viable method for decreasing enzyme requirements and operating costs for renewable fuel production, and its industrial application should be further investigated.Dilute acid pretreated corn stover (PCS) used as the model substrate in this study, and was kindly provided by the National Renewable Energy Laboratory . The corn stover was pretreated using a dilute sulfuric acid pretreatment method in a continuous pilot scale pretreatment reactor . Two batEnzymatic hydrolysis was carried out using Cellic CTec2, a commercial enzyme preparation kindly provided by Novozymes . Enzyme was loaded on a mass of enzyme product (EP) per gram of glucan (cellulose) in the substrate basis.Enzymatic hydrolysis was carried out except where noted with an initial total reaction mass of 20 g, and an initial biomass concentration of between 10-15% TS (w/w) on a dry weight basis. Samples were prepared by adding deionized water , sodium citrate buffer , and sodium hydroxide for pH adjustment (4 N) to the correct amount of biomass substrate, loaded on a dry weight basis. Initial pH was between 5.1 and 5.3 for all samples. Three stainless steel 4 mm ball bearings were added to each sample to facilitate mixing during the reaction. All reactions were carried out at 50°C (+/− 0.5°C) for 72 hours in a rotisserie style incubator  rotating end over end at approximately 30 rpm. The reactions were carried out in batch mode for each recycle round.Enzyme recycle was carried out by recycling the insoluble solid residue present at the end of each hydrolysis period. For each recycle round the insoluble solids residue from the previous batch hydrolysis was mixed thoroughly with 20 g of fresh substrate slurry as the original initial % TS for the experiment. The recycle followed one of two similar methods, based on whether or not the solids were washed between recycles . The amount of makeup enzyme added was varied between 0 and 34 mg EP/g fresh cellulose added with the new slurry added in each recycle round. The categorical variable was the washing of the solids. Additional enzyme was applied only on the basis of the amount of new cellulose added, and not on the cellulose in the recycled insoluble solids. This experiment was carried out on batch 1 PCS with an initial 10% TS. A total of 4 recycle rounds were carried out, for a total reaction time of 360 hours. The initial enzyme loading at the start of the experiment for all conditions was 51.4 mg EP/g cellulose. The experiment was carried out in one batch with duplicate experiments, with the center point of the experimental design repeated 6 times. The data were statistically analyzed using least squares fit modeling and surface response fit to determine the significance and effects of each factor. Experiments were designed and analyzed using SAS JMP software . Significance was defined as probability value  below 0.05 for type I errors.The initial substrate solids concentration was increased to 15% TS for the second round of statistical experiments. The experiment was designed as a response surface central composite design to determine the impact of fraction of insoluble solids recycled, varied from 70-96%, and additional enzyme loading, which varied between 23–46 mg EP/g fresh cellulose. 3 recycle rounds were carried out for this experiment, for a total reaction time of 288 hours. The initial enzyme loading for all conditions was 51.4 mg EP/g cellulose. The center point was repeated 6 times and the rest of the experimental conditions were carried out in duplicate experiments.Lignin rich hydrolysis residue was produced by hydrolyzing batch 1 PCS with 51.4 mg EP/g cellulose for 144 hrs at 10% TS. This resulted in a residual insoluble solids material that consisted of 95% lignin and 5% residual cellulose. The material was thoroughly washed before addition. The lignin material contained residual enzyme activity, and it was applied both before and after a deactivation step . A volume of 800 μl of batch 2 PCS at 6.25% TS in citrate buffer (50 mM) was added to 2.5 ml reaction tubes. The lignin residue was added in varying amounts to the substrate . Enzyme loading was 34 mg EP/g cellulose based on the cellulose in the substrate. The tubes were placed in a tabletop shaker  temperature controlled at 50°C and mixed at 1300 rpm. Glucose concentrations were measured after 72 hours. Experiments were carried out in duplicate.The protein concentrations in the enzyme preparation were measured using the bicinchoninic acid (BCA) analysis assay method which has been described previously  . A BCA aSugar concentrations were measured using High Performance Liquid Chromatography (HPLC). The HPLC used was a Waters HPLC 2695 with a Biorad-H 87+ column . The eluent was 5 mM sulfuric acid with a flow rate of 0.5 ml/min. Percent solids (%TS) measurements were made using an 105 °C oven  method according to standard procedures developed at NREL .Yglucose, , and this concentration was subtracted from the final concentration of glucose  to avoid double counting (equation 1, Table Glucose yields, Total glucose yield was calculated based on total added cellulose during the course of the whole experiment and the mass of glucose produced over that same period. This reflected the glucose yield for the entire experiment, and controlled for varying levels of solids recycle and glucose removal during the recycles.Penztot, as it is referred to here, was calculated as a classic biocatalytic productivity term from the sum of all glucose produced during the course of the entire experiment divided by the total mass of enzyme protein product added during the experiment, with units of g glucose/ mg enzyme protein and calculated as shown in equation 2, Table The enzyme efficiency or productivity, A mathematical model was developed to predict reaction parameters under different recycle scenarios for extended recycle rounds beyond the limit of the experiments. The model was a mass balancing of the recycle experiments, and relied on batch kinetics and stepwise computation of forecast results. Experimental results from the recycle experiments were extrapolated to predict the composition of the substrate, the total solids concentration, and total reaction mass. This was done using calculations based on a mass and component balance of the system. It was assumed that the final glucose yields and sugar concentrations remained constant from the final experimental hydrolysis, that the efficiency of the solid liquid separation step remained constant, and that the input mass and%TS of the fresh substrate was constant throughout additional recycle rounds. The recycle scenario was modeled as a series of batch reactions with solids recycle taking place at the end of an unspecified reaction time. Calculations for the computation of selected forecast data are given in the Additional file BCA: Bicinchoninic acid; PCS: Pretreated corn stover; %TS: Percent total solids; EP: Enzyme product; NREL: National Renewable Energy Laboratory; RCF: Relative centrifugal force.Drs. Johan Börjesson and Lars S. Pedersen are employed at Novozymes A/S, a company that sells enzymes for lignocellulose processing. The authors declare that they have no competing interests.NW and JB conceived the study. NW designed experiments, carried out the laboratory work, and wrote the manuscript. JB provided supervision and research direction of the experimental work, as well as editing the manuscript. LSP provided project supervision, helped with statistical design and analysis, and edited the manuscript. AM provided academic supervision and edited the manuscript. All authors contributed intellectually via scientific discussions during the work and have read and approved the final manuscript.Process flow diagram for the recycle procedure for insoluble solids recycle.Click here for file


Attention-deficit hyperactivity disorder (ADHD) is considered to be one of the main risk factors for the onset and persistence of substance use disorders (SUD). Based on the work of – for instance – Joseph Biederman, Timothy Edwin Wilens or Stephen Faraone it has been well established that adults with ADHD abuse psychoactive substances more often, for a longer period of time and at an earlier age, and they show a faster transition from alcohol abuse to illicit substance abuse compared to those without ADHD. Therefore, early detection and treatment of attentional problems, hyperactivity and impulsivity (as distinct components of this disorder) is important in both the prediction and prevention of SUD onset. It is also crucial to broaden social cognition about ADHD as this disorder may have a severe impact not only on substance abuse but also on self-esteem, academic achievement, potential criminal activities or interpersonal relationships as well.Key Issues in Mental Health. The authors are ADHD-experts from the USA and Germany representing various scientific fields, such as psychiatry, psychology, neurology and genetics.The editors, Wolfgang Retz and Rachel G. Klein aimed to provide an overview of the most relevant aspects of ADHD – epidemiology, neurobiology, psychopathology, longitudinal course, comorbidity and social impairment – across lifespan, following the best traditions of Paul H. Wender and David A. Tomb present ADHD’s etiology, treatment options and symptomatology in Chapter 1, including childhood and adulthood characteristics of the disorder as well as highlighting core symptoms that ease differential diagnosis. Authors also provide a brief overview of the history of the ADHD Concept. The part where authors introduce case histories as well as the Appendix of several ADHD rating scales will surely be well-appreciated given their potential benefit in both clinical and scientific work.Christine Margarete Freitag and Wolfgang Retz delineate genetic background of ADHD in Chapters 2 and 3. Readers learn about the heritability of ADHD subtypes, the comorbidity of this disorder – Oppositional Defiant Disorder, Conduct Disorder, Major Depressive Disorder and Generalized Anxiety Disorder as most frequently occurring comorbid disorders –, sex differences based on the results of longitudinal twin, family and adoption studies. Molecular genetics of ADHD is presented through the findings of association studies . The role of the dopamine transporter and receptor genes – which play a significant role in the development of SUD too – as well as the dopamine-catalyzing enzymes, noradrenergic genes and serotonergic genes is highlighted by the authors.In Chapter 4, neurophysiology of ADHD is described by Christina G. Baehne and Andreas J. Fallgatter. Current methods of electrophysiological measures – such as EEG and quantitative EEG (qEEG) – are illustrated. Elevated theta power and reduced alpha and/or beta power in ADHD children or lower P3 amplitudes as part of event-related potentials are well-studied neurophysiological characteristics of the disorder.Marc Schenider, Michael Rösler and Wolfgang Retz introduce the findings of brain imaging studies in Chapter 5. Brain region-specific results – the role of the frontal, temporal, parietal and occipital lobes and more specific areas, including basal ganglia or corpus callosum – and ADHD-related brain functioning – the subcortical location of arousal and alerting networks as an example – are also described here.Rolf-Dieter Stieglitz in Chapter 6 introduces diagnostic criteria and prevalence rates of ADHD showing some overlap in content with Chapter 1. In addition to this, however, the multimodal assessment and the diagnostic process which are presented here with several practical recommendations make this chapter more than helpful for clinicians and psychologists. For instance, Figure 1, that presents the diagnostic process with diagnostic aids such as when to use screening instruments, structured interviews or rating scales during this process, is a truly useful guideline for clinicians.A full chapter is dedicated to the comorbidity of ADHD with other disorders and was written by Rachel G. Klein and Salvatore Mannuzza (Chapter 7). Here the volume is slightly repetitive again, even if SUD is firstly mentioned by Klein and Mannuzza as a typical comorbid disorder of ADHD. Methodological and diagnostic difficulties are also addressed in this chapter.The correlation between ADHD and criminality is exposited in an intriguing chapter by Michael Rösler. Functional impairments that lead to criminal activities and dysfunctions in the everyday life of ADHD patients – e.g. earlier onset of sexual activities, lack of parenting skills or high risk of accidents – are described. Several figures and tables make this chapter easier to follow, while individual and social issues related to ADHD are superbly outlined.Alexandra Philipsen, Harald Richter, Swantje Matthies and Bernd Hesslinger present psychotherapeutic possibilities in Chapter 9. In the psychological treatment of ADHD cognitive behavioral therapy (CBT) is well-known, authors, however, introduce many more, less familiar therapeutic approaches, such as disorder-oriented group and individual programs. The goals of these approaches are demonstrated by describing the Freiburg Treatment Program. This program aims to enhance patients’ problem-solving skills and affect regulation using mindfulness techniques, behavior analysis, impulse control tasks, involving partners and family members as well.Attention-deficit hyperactivity disorder (ADHD) in adults is a plainly recommended reading which can also be used as a handy guideline for psychotherapy and pharmacotherapy as well.In the final chapter, Götz-Erik Trott lists available psychopharmacological treatment options, starting with a brief historical overview of the therapeutical use of benzedrine and methylphenidate. Trott emphasizes that stimulant medications are still the first-line treatment options for the pharmacotherapy of ADHD, although the use of anti-depressants and alpha-adrenergic agents is also a significant part of pharmacological treatment. For adult ADHD patients the use of atomoxetine as a non-stimulant medication is found to be one of the best pharmacotherapeutical options. The volume is a complex and up-to-date summary of the many aspects of ADHD. Its focuse on adulthood (as opposed to childhood) is favorable given that ADHD was handled and considered as a childhood disorder for many years, therefore individual and social impairments of ADHD in adulthood had been largely neglected. The main strength of this book lies in its capability to provide useful information not only for the experts of this field but also for lay individuals who are either directly or indirectly impacted by ADHD in their lives, or seek answers to their questions related to this disorder.


Studies throughout Northern Europe, the United States and Australia have found an association between childhood attention deficit hyperactivity disorder (ADHD) and family socioeconomic disadvantage. We report further evidence for the association and review potential causal pathways that might explain the link.N = 19,519) was used to model the association of ADHD with socioeconomic disadvantage and assess evidence for several potential explanatory pathways. The case definition of ADHD was a parent-report of whether ADHD had been identified by a medical doctor or health professional when children were 7 years old.Secondary analysis of a UK birth cohort (the Millennium Cohort Study, ADHD was associated with a range of indicators of social and economic disadvantage including poverty, housing tenure, maternal education, income, lone parenthood and younger motherhood. There was no evidence to suggest childhood ADHD was a causal factor of socioeconomic disadvantage: income did not decrease for parents of children with ADHD compared to controls over the 7-year study period. No clinical bias towards labelling ADHD in low SES groups was detected. There was evidence to suggest that parent attachment/family conflict mediated the relationship between ADHD and SES.Although genetic and neurological determinants may be the primary predictors of difficulties with activity level and attention, aetiology appears to be influenced by socioeconomic situation. Childhood attention deficit hyperactivity disorder (ADHD) has been reported to be more prevalent among socioeconomically disadvantaged groups in many regions of the developed world. Studies from the United States , the UniADHD is diagnosed when a child demonstrates inattentive, hyperactive and impulsive behaviours in multiple settings which cause functional impairment :Does low SES mean that mothers are more likely to smoke in pregnancy, leading to greater rates of ADHD?Does low SES affect parenting adversely, increasing the odds of a child having ADHD?Finally, two risk factors consistently implicated in the literature were tested for mediating effects. These were smoking in pregnancy  and lack of parent attachment/family conflict . The questions raised were These exposures were intended to be illustrative examples of plausibility of mediation by differential exposure to risk factors as a pathway from socioeconomic disadvantage to ADHD.n = 318) as a proxy for other disorders  because being diagnosed with alternative problems could confound the relationship between ADHD and SES (as symptoms of other disorders often co-occur with hyperactivity and some are linked to SES). Children who were twin or triplet siblings were also omitted as the study was underpowered to examine within-family variance. At sweep 4, the mean age was 7.2 years . The included sample size in this study who had reported on their child's ADHD status was 13305.The MCS has followed 19,519 UK children, born between 2000 and 2002, via surveys and direct cognitive testing, carried out by trained interviewers face-to-face in family homes. Information was gathered from the first MCS survey when children were 9 months old, and three, five and 7 years of age: four sweeps of data collection. Informed parental consent was obtained at each stage of the study; the MCS ethical review gives details . Sample Details of fieldwork, coding and questionnaires for MCS measures used are documented at length by n = 187). This measure has been used to estimate the prevalence of ADHD  had attention deficit hyperactivity disorder (ADHD)?Parent-reports of ADHD diagnosis by a medical doctor or health professional were taken as ADHD case definition  and used to generate ‘Conflict’ and ‘Closeness’ scores. The ‘closeness’ score was reversed and scores were combined to create a family conflict/distant parent score. Approximately 98% of respondents were mothers.Records of whether mothers smoked during pregnancy were taken when children were aged 9 months old. Pregnant mothers were classified as smokers or non-smokers. Missing data were not analysed. The Child–Parent Relationship Scale (CPRS) adapted from the Student–Teacher Relationship Scale  was usedThe Strengths and Difficulties Questionnaire (SDQ) is a behavioural screening questionnaire for children aged 4–16  that incFirst, the association between the outcome of ADHD diagnosis and a range of indicators of socioeconomic disadvantage, including maternal education level, poverty, income, lone parenthood, family size, birth weight, being a younger mother, and index of SES was established using logistic regression. Standardised weights accounted for attrition and disproportionate sampling in MCS. The odds ratios (OR) from the analyses indicate the increase in odds of being identified with ADHD corresponding to an incremental increase in each predictor.n = 8193). Further sensitivity analysis utilised propensity score matching to define a control group who had comparable socioeconomic disadvantages to families with a child with ADHD when their children were 9 months old. Nearest neighbour matching was used to define controls, with income at 9 months, child's sex, mother's highest qualification, and lone parenthood as conditioning variables. Study children in control families had neither diagnosis of ADHD, nor statement of SEN by age 7. Linear regression was again used to compare the increase in family income between cases and controls over the 7-year study period. In addition, change in the number of single parent families was plotted for children with ADHD over time.The reverse causality hypothesis . This was to establish whether the association between clinical ADHD diagnosis and socioeconomic disadvantage existed independently of levels of parent–teacher reported symptoms, i.e. a clinical labelling bias.To test for labelling effects, the association between the outcome of ADHD diagnosis and measures of SES was again modelled using logistic regression, but adjusting for the effects of parent/teacher-reported hyperactivity-inattention symptoms and their impact , and £10.99 for the rest of the sample . As FigureChange in income over time for families with and without a study child with ADHD was plotted Figure. OverallAfter propensity score matching, change in income with time was also not significantly different between the two groups. Control families' initial average weekly income was £244 as opposed to £249 for families with a child with ADHD. Over the 7-year study period, income increased by £11.63 per year  for controls. Families with a child with ADHD child did slightly better, as noted above, although confidence intervals overlapped substantially.According to the reverse causality hypothesis, a child with ADHD might put additional strain on family resources leading to increase in marital breakup. ADHD is rarely identified before age 3; hyperactive and inattentive behaviours are highly prevalent, and considered ‘normal’ in many toddlers, not just those who go on to a diagnosis of ADHD . We therLogistic regression reported in Tablep < 0.001; even after adjustment for measures of socioeconomic disadvantage OR = 1.09, 95% CI (1.05–1.21), p < 0.001.Both smoking during pregnancy and family conflict/distant parenting were independently associated with all the measures of SES. Where more conflict and less closeness was reported between parent and child, families were more likely to experience social or economic disadvantage. Distant parenting/family conflict was also associated with having a child with ADHD, OR = 1.11, 95% CI (1.08–1.13), p < 001. Smoking in pregnancy was still independently associated with ADHD after adjusting for salient measures of SES, although its effect was weaker, OR = 1.53, 95% CI (1.03–2.29) p = 0.036.In MCS, 5239 mothers reduced their tobacco use during pregnancy with 2327 mothers giving up smoking, and 1664 continuing to smoke: these were more likely to be from low SES backgrounds. Mothers were more likely to have a child with ADHD if they smoked during pregnancy: OR = 2.26, 95% CI (1.54–3.31) Figureper se  and its behavioural symptoms have often been associated with socioeconomic disadvantage.In a 2008 sample representative of the United Kingdom, ADHD was associated with a range of indicators of social and economic disadvantage.The study provided no evidence to suggest childhood ADHD was a causal factor of socioeconomic disadvantage and no evidence of labelling bias.Parent attachment/family conflict apparently mediated the relationship between ADHD and SES.


We previously hypothesized that poor task-directed sensory information processing should be indexed by increased weighting of right hemisphere (RH) biased attention and visuo-perceptual brain functions during task operations and have demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies. However, in our recent distributed effects model of ADHD, we surmised that this phenotype is not ADHD specific, but rather more broadly reflective of any circumstance that disrupts the induction and maintenance of an emergent task-directed neural architecture. Under this view, increased weighting of RH-biased attention and visuo-perceptual brain functions is expected to generally index neurocognitive sets that are not optimized for task-directed thought and action, and when durable expressed, liability for ADHD.The current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD was associated with common ADHD characteristics and comorbidities .Barring one exception (non-right handedness), we found that it was. Rightward parietal asymmetry (RPA) was associated with carrying the DRD4-7R risk allele, being male, having mood disorder, and having anxiety disorder. However, differences in the specific expression of RPA were observed, which are discussed in relation to possible unique mechanisms underlying ADHD liability in different ADHD RFs.Rightward parietal asymmetry appears to be a durable feature of ADHD liability, as predicted by the Distributed Effects Perspective Model of ADHD. Moreover, variability in the expression of this phenotype may shed light on different sources of ADHD liability. We recently presented a distributed effects perspective (DEP) model of ADHD that addresses specific challenges associated with the elucidation and treatment of dimensionally defined psychiatric disorders  . The modRight hemisphere (RH) specialization is well established for top–down task-directed attention functions, such as vigilance, sustained, and selective attention –7. It isThe current line of research began with the precept that complex task-directed actions heavily rely on the first of these . We conceptualized this as “task-specialized” sensory information processing, and considered it to reflect variable mixtures of selective, sustained, and/or vigilance related functions depending on the nature of a given task. We hypothesized that ADHD involves a specific deficit for, and/or reduced expression of this task-specialized manner of sensory processing, with a proportional increased expression of non-task-specialized forms (items 2–4 above). We posited that this circumstance should result in mixed expression of: (a) unneeded scrutiny of visual details, (b) increased attentional shifting to off-task content, and/or (c) task-inappropriate orientation toward sensory-immersive processing. The net effect being an increased attentional effort and exposure to visual sensory content beyond what is strictly required to perform task operations. We conceptualized this as “visual sensory overflow” (in relation to task objectives), and predicted that it would be indexed by a relative increased weighting of visuo-perceptual versus verbal-categorical processing during task challenges.We have performed and published three behavioral laterality –19, two Although not yet widely understood, the above findings are well aligned with extant ADHD literature. Abnormal information processing in ADHD is now well established , 29, witWith complex executive function (EF) tasks the literature is more variable, showing diffuse effects mainly consistent with variable weaknesses across multiple brain systems –58. NeveFinally, increased RH relative to LH contribution may be consistent with common ADHD characteristics, such as: increased leftward motor preference , 70, whiIn sum, abnormal information processing is now well established in ADHD. Our work, in association with the above literature, strongly suggests that this abnormality is linked to an atypical increased weighting of RH visuo-perceptual versus LH verbal-categorical processing.The distributed effects perspective (DEP) model of ADHD asserts that task-directed brain functioning, including task-specialized sensory information processing, is facilitated by the induction and maintenance of an emergent neural architecture (neurocognitive network or brain state) that optimizes multiple distributed systems toward task-directed thought and action . The modThe DEP model suggests that ADHD symptom sequelae manifest from TD-APS system impairment, no matter the cause, and that ADHD heterogeneity reflects the diversity of ways in which any such complex distributed system may come to be compromised. Under this view, common ADHD characteristics and/or comorbidities are predicted to reflect common factors that imperil TD-APS system functioning . Furthermore, “pure ADHD” is conceived to reflect incidences where TD-APS system impairment is both life-disruptive and linked to subclinical causal impairments to its constituent elements. If such impairments are clinically manifest , an alternative primary and/or comorbid diagnosis is expected .An additional important assertion of the model is that variable causal deficits to the TD-APS system are expected to produce “convergent deficit effects” that reflect the system being less able to achieve its primary computational goals. Specifically, TD-APS system impairment, no matter the cause, is expected to result in: (1) a reduced capacity to orchestrate task directives , indexed by poor working memory and EF-control; (2) a reduced capacity to assert top–down task-directed control over sensory information processing , indexed by increased weighting of RH-biased visuo-perceptual versus left hemisphere (LH) biased verbal-categorical processing; and (3) a general loss of TD-APS system stability , indexed by greater performance variability.Each of these deficit effects has been established in ADHD .The current study tests the assertion that previously identified RH-biased sensory information processing in ADHD is reflective of the DEP model’s proposed external-convergent deficit effect. If true, this characteristic (RH-biased processing) should be directly linked to common ADHD characteristics and comorbidities . To test this hypothesis, we used a large previously collected sample of ADHD children to examine the impact of: (1) being male , (2) carAs a secondary objective, we also performed exploratory analyses to test whether individual ADHD RFs might be associated with different underlying causal impairments to the proposed TD-APS system. We reasoned that if ADHD RFs are associated with unique causal deficits to this system (distributed deficit effects), rightward parietal EEG asymmetry (the convergent outcome) should exhibit different patterns of association to metrics that tax TD-APS system constituent elements. For example, if the primary mechanism underlying TD-APS system weakness among males is reduced verbal ability relative to females, then male-related increases in rightward parietal EEG asymmetry should exhibit an association to verbal metrics. To explore this idea, for each ADHD RF, we examined the pattern of association between rightward parietal EEG asymmetry and a battery of temperament and cognitive metrics. We also conceptualized that different “points of deficit origination” across TD-APS brain-system constituent elements could result in variant expression of RH-biased brain function, as indexed by variability in the frequency, location, and testing-condition of rightward parietal EEG asymmetry in ADHD RFs.The sample consisted of 274 children from an earlier ADHD family genetics study , 95. SubIdentification of subjects with comorbid mood was based on a definite diagnosis of at least one current mood disorder as assessed by direct interview using the Schedule for Affective Disorders and Schizophrenia-Lifetime Version (SADS-LAR). Identification of subjects with comorbid anxiety required definite diagnosis of at least two current anxiety symptoms as assessed by direct interview using SADS-LAR.A DRD4 7R group was identified based on subjects possessing at least one copy of the seven-repeat allele (ref). Blood samples were collected from subjects, and DNA was isolated using the Puregene Kit following the manufacturer’s recommendations . DRD4 polymorphisms (48-bp VNTR and 120-bp repeat) were genotyped according to standard procedures and have been reported elsewhere . Since tHandedness was assessed with a shortened version of the Edinburgh Handedness Inventory . This scUsing a score of less than two standard deviations below the mean on any or our standardized measures of reading, phonologic, or spelling ability produced a small sample n = 16) comprised of variable linguistic weaknesses. Hence, we chose to not include reading disability as an ADHD associated RF in this study. There were no significant differences in linguistic ability based on RF status, as assessed by measures of reading, spelling, phonological, and vocabulary skill . During the visit, each family member underwent a clinical, cognitive, and EEG testing battery, with the order of delivery of each component determined by logistical considerations. However, during EEG testing the Conners’ CPT  was deliEEG recording was carried out using 40 silver chloride electrodes using the International 10/20 locations and was referenced to an average of singles recorded separately at each ear lobe. Eye movements were monitored by electrodes placed on the outer canthus of each eye for horizontal movements and by electrodes above the eye for vertical eye movements. EEG recording consisted of 2 baseline conditions lasting 5 min each [eyes open (EO) and eyes closed (EC)] and a cognitive activation condition lasting 15 min (Conners CPT-II) .2) from 1 to 21 Hz was exported in 1 Hz bins . Technicians involved in the EEG recording and processing were blind to ADHD diagnostic status.Continuous EEG data were subjected to automatic artifact detection via MANSCAN software  designed to identify dead and bad channels, vertical and horizontal eye movements, saturation, muscle and movement artifact, and line frequency noise. Subsequent to this automated procedure an experienced EEG technician then visually inspected all data and identified any residual contaminants. Next, continuous EEG was broken into 1-s epochs and artifact-containing epochs were removed on a channel specific basis. Remaining artifact free epochs were then Fast Fourier Transformed (FFT) using MANSCAN EEG software, which uses a Welch’s Periodogram approach . We specFor the current study, we evaluated the EEG frequency bands that were previously associated with abnormal EEG asymmetry in ADHD , 44, 67.Commonly used measures are listed in Table Social functioning characteristics were assessed using the mother’s report on the Social Problem scale of the child behavior checklist (CBCL) , as wellThe CPT requires subjects to monitor a central fixation on a computer screen while single capital letters are sequentially and centrally presented during six continuous blocks of 20 trials with either 1, 2, or 4 s inter-stimulus intervals (ISIs) (two blocks for each ISI). The order of ISI-block presentation is randomized within subjects. The task requires subjects to press the space bar using their dominant hand with every letter presentation except for the letter “X.” The “X” occurs on 10% of the trials within a given ISI block. Behavioral performance was assessed using the following standard measures : (1) comIn this spatial delay response task (SDRT) , subjectThis task requires subjects to detect an emotional tone of voice or to identify a word during dichotic presentations of four words  spoken in four different emotional tones  by a male speaker. Stimuli for the “word” and “emotion” tasks are identical and only the instructions to the subject change between conditions. Because dichotic presentations suppress ipsilateral auditory channels, the stimuli in each ear project to the opposite hemisphere via fibers that cross at the superior olive and inferior colliculus , 109. ThWe first present analyses to characterize ADHD RF groups with respect to clinical, temperament, and cognitive characteristic. Next, analyses aimed at testing the DEP model of ADHD are presented and discussed in two parts. Part 1 addresses our primary aim of examining whether RH bias is a general feature of ADHD RFs. Part 2 addresses our secondary/exploratory aim of examining whether ADHD RFs show different patterns of association between RH bias and temperament and/or cognitive characteristics. Section specific discussions are presented for Parts 1 and 2, followed by a general discussion. A summary of all study findings is provided in the supplement .Non-independence in our data (sibling pairs) is distributed across the levels of our grouping variables, making it somewhat ambiguous with respect to increasing our decreasing our ability to detect RF group differences. For instance, with regard to the “being male” RF, siblings are just as likely to be the same or different genders. If different, non-independence hurts our capacity to detect a gender difference – if the same, it helps. Moreover, because our emphasis was to uncover conceptually meaningful patterns, rather than individual effects, our interpretation of results is conceptually insulated against type 1 error. Nevertheless, steps were taken to reduce this risk (described below).In primary analyses of rightward parietal asymmetry (RPA) in ADHD RFs (Part 1), the multivariate multilevel modeling approach limited the number of tests and accounted for non-independence (by modeling family membership). Analyses to characterize our samples, and secondary/exploratory analyses (Part 2), utilized large batteries of cognitive and temperament metrics (41 measures – see Table Univariate ANOVA (SPSS v21) was used to examine each ADHD RF with respect to: ADHD symptoms, temperament, and cognitive abilities. For these analyses, a clinical, temperament, or cognitive measure of interest was entered as the dependent variable, an ADHD RF of interest was entered as the grouping variable, with age plus the remaining ADHD RFs entered as covariates in order to assess the unique impact of the ADHD RF being tested.DRD4 7R carriers exhibited fewer inattentive symptoms. Male, mood, and anxiety RFs were associated with greater hyperactivity. Non-right handedness had no effect on symptoms  examination of parietal EEG asymmetry, (2) examination of RPA association to ADHD symptoms, and (3) examination of dichotic listening behavioral performance.We tested whether individual ADHD RFs were associated with increased rightward parietal EEG asymmetry (RPA) using multilevel models (software: R 2.15.2). The first level was the EEG asymmetry measure . The second level was the parietal area. The third level was the family. To limit the number of tests we first examined whether there were overall effects of parietal EEG asymmetry , then significant effects were further decomposed by looking at pairwise comparisons of individual parietal asymmetry indices.ADHD RFs were shown to impact overall parietal EEG asymmetry. Effects were broadly expressed for DRD4 7R carriers and males, but specific for mood, anxiety, and non-right handedness Table .Assessment of location-specific asymmetry indices showed that 38 of 39 significant findings exhibited RPA. RPA was broadly expressed in DRD4 7R carriers and males, but specifically expressed in mood and anxiety groups. RPA appeared strongest at the P8-7 LI. Although both DRD4 7R carriers and males showed broad RPA expression, the DRD4 7R group showed asymmetry effects mainly in alpha at the TP8-7 and P8-7 indices, while males showed asymmetry effects mainly in beta  across all three parietal locations. Mood only showed RPA effects during EC in beta2, while anxiety only showed RPA during active visual processing  in beta1. Individuals who were not strongly right-handed did not show RPA (Table Linear regression (SPSS v21) was used to examine whether RF groups interacted with individual parietal EEG asymmetry indices to predict ADHD symptoms, while controlling for age and other RF groups. Here, a symptom metric was entered as the outcome variable, then age and the “not to be examined” RF groups were entered as predictors, followed by the RF group being examined, the parietal asymmetry index being examined, and their interaction term.Mood had no effects. All other RFs showed associations between parietal EEG asymmetry and ADHD symptoms, with anxiety showing the strongest and most numerous effects with unique weighting toward the alpha band. The findings generally demonstrated that RPA was associated with increased symptoms, except for two instances. DRD4-7R carriers showed a link between RPA and fewer inattentive symptoms, and two of eighteen significant effects for anxiety showed a link between RPA and reduced hyperactivity. In males and DRD4-7R carriers, RPA was associated with more hyperactivity. In non-right-handers, it was associated with more inattention. In anxiety, it was associated with more inattention and hyperactivity. In DRD4 7R carriers, males, and non-right handed individuals, a relationship between RPA and ADHD symptoms was mainly present for the P4-3 LI  Table .As a secondary behavioral validation of RH-biased processing among ADHD RFs, we examined whether ADHD RFs exhibited RH-biased signal detection during the dichotic listening paradigm, using the same univariate ANOVA procedure described in Part 1.Mood and non-right handedness showed no effects. All significant effects showed faster responses for RF groups. DRD4 7R carriers were faster for word processing in both ears, but the effect was stronger for left-ear (RH) trials. Moreover, they did not show the standard right-ear (LH) speed advantage for word stimuli, and instead showed a left-ear (RH) advantage. DRD4-7R carriers also showed a speed advantage for detecting right-ear emotion stimuli. This trial type is understood to depend on left-to-right hemisphere transfer of emotion stimuli due to strong RH specialization for these stimuli . Males sWe previously hypothesized that non-task-specialized sensory information processing should be indexed by increased weighting of RH-biased attention and visuo-perceptual brain functions during task operations, and demonstrated this phenotype in ADHD across multiple studies, using multiple methodologies . HoweveThe current study tested this view by examining whether previously identified rightward parietal EEG asymmetry in ADHD , 26, 27 We view the single outlying handedness result with caution. Due to sample constraints, we did not test left-handedness versus right handedness, but rather the effect of being “strongly” versus “not strongly” right-handed, with the latter group including weakly right-handed, ambidextrous, and left-handed individuals. Moreover, secondary analyses implicated RH-biased processing in the “not strongly right-handed” group. Hence, we think it is reasonable to refrain from interpreting these conflicting outcomes until a better test of pure left-handedness is performed.The otherwise clear pattern of RPA across the remaining ADHD RFs demonstrates, as predicted by the DEP model, a connection between RH-biased parietal brain function and liability for ADHD, and by inference, a general reduced capacity for task-directed thought and action. This outcome is well aligned with the established role of right-lateralized parietal brain function in attention and visual sensory information processing.Although much remains to be elucidated about parietal brain function, multiple lines of research indicate that it plays a key role in processing information in a spatial context , with a Continuing this pattern, the LH temporal-parietal junction (TPJ) shows specialization for verbal articulatory coding  , while tWe have previously demonstrated that ADHD is associated with abnormal increased rightward asymmetry across each of these parietal regions  –25, and The current study has now demonstrated that this same pattern of R > L parietal brain functions is an independent feature of multiple ADHD RFs. This ads strong support to the view that RPA may generally index: (1) brain function that is not optimized for task-directed thought and action and (2) when durably expressed, liability for ADHD.This secondary/exploratory analysis examined whether ADHD RFs exhibited different patterns of association between RPA and temperament and cognition metrics. It used the same linear regression approach described above, but with temperament and cognition metrics (rather than symptom measures) entered as outcome variables. This analysis helped us to explore whether different mechanisms  might underlie RH-biased brain function across different ADHD RFs. General results patterns and summary tables are provide here, with full results details available in the study supplement .RPA showed associations to temperament characteristics in each ADHD RF. Except for males, most RPA associations to temperament occurred in the alpha-frequency band. In males, these effects were mainly in beta. Males, mood, and anxiety showed strong associations between RPA and social functioning. RPA was linked to better social functioning in males, but worse social functioning in mood and anxiety. This effect was especially pronounced for mood sufferers . Two effects in DRD4-7R carriers and 12 in non-right handed individuals indicated RPA association to self-oriented, rather than socially oriented, characteristics. For DRD4-7R carriers greater RPA was linked to increased self-determination and reduced novelty seeking (positive outcomes). For non-right handed individuals, greater RPA was linked to increased novelty seeking and reduced persistence and self-determination (negative outcomes). The locations of temperament effects were generally mixed, except for males , and non-right-hander (mainly at the TP8-7). Finally, of 31 findings involving the CPT, all but three were linked to social functioning, suggesting that this task taps brain-function characteristics important for social operations . DRD4-7R, anxiety, and non-right handed RFs showed both positive and negative effects. A link between greater RPA and better SWM ability was evident for all groups . In DRD4-7R carriers, greater RPA was associated with better linguistic, but poorer attention ability. In males and mood sufferers, greater RPA was associated with better linguistic and attention ability. In anxiety sufferers, RPA was associated worse linguistic, WM, and EF ability. In non-right-handers, it was associated with worse WM and EF ability.Associations between RPA and cognitive abilities were most evident during active visual processing (CPT and EO conditions). Males showed abundant effects at the P4-3 LI. Mood only showed effects at the TP8-7 LI. Other RFs showed mixed associations to parietal LIs. In DRD4-7R carriers, RPA associations to cognition were mostly in the alpha frequencies. Anxiety showed mixed frequency effects. Males, mood, and non-right-handers showed the majority of effects in beta frequencies. Lastly, CPT measured sustained attention was almost exclusively tied to RPA at the TP8-7 LI, while CPT and SWM tasks that required sustained attention and task-directed visual processing were predominantly linked to beta frequencies  that mobilizes RH resources in a specific task-specialized manner that facilitates fast  identification of task-relevant content. Any impairment to this system, no matter the cause, is expected to reduce this capacity, and produce an associated increased expression of RH attention and non-task-entrained visuo-perceptual processing. Variable deficits to this system are expected to underlie ADHD heterogeneity, and manifest variant forms of this shared characteristic. The model also postulates that variable primary deficits might be elucidated by examining the relationship between RH-biased processing and constituent system operations. We explored this possibility in our secondary analyses.As predicted, different ADHD RFs showed variant expressed forms of RPA, along with different patterns of association between RPA and clinical and cognitive metrics. This supports the view that RPA is tied to different mechanisms in different ADHD RFs. The current study design cannot resolve what these are; however, through consideration of our total study findings, we can begin to speculate about possible differences in this regard. The following discussion of this topic and associated findings is highly speculative, but is provided to help stimulate further conceptual and experimental analysis of this topic.The most obvious difference across ADHD RFs was that DRD4-7R and males exhibited RPA in multiple brain regions, frequencies, and conditions, whereas mood and anxiety showed very specific effects. One possible explanation is that genetically linked risk for ADHD  is tied to more generalized and stable brain-function characteristics, while more experience-linked conditions (mood and anxiety) involve more state and/or circumstance specific abnormal brain functioning. Regardless, this pattern indicates that categorically different forms of brain function may underlie RPA in more genetically versus experience weighted conditions.Within these domains, additional unique RPA characteristics were evident. The DRD4-7R group was predominantly associated with RPA in the alpha band , while being male was predominantly associated with RPA in the beta band (10/15 effects in beta). According to recent conceptualizations of these frequencies, this might indicate increased RH internal-processing control in DRD4-7R carriers –123, butBehavioral laterality outcomes appear to support this speculation. DRD4-7R carriers showed an atypical pattern of being faster for word targets in the right versus left hemisphere , 127. ThMood and anxiety also differed in their expression of RPA and behavioral laterality outcomes. In mood, RPA was only evident during the EC condition (with no active sensory engagement). In anxiety, it was only evident during the EO and CPT conditions (with active sensory engagement). Consistent with this, mood showed no behavioral laterality effects during the dichotic listening task that requires active sensory processing, while anxiety was associated with faster responses for the trial type (noted above) that requires left-to-right transfer of information . Hence, In order to generate more specific hypothesis about the nature of abnormal brain function across ADHD RFs, we will now consider individual RFs clinical characteristics, and patterns of RPA association to symptoms, temperament, and cognitive abilities. This analysis is again speculative, but is presented to help generate testable hypotheses for future analysis.Carrying the DRD4-7R allele was generally distinguished by having more positive outcomes, and RPA effects being mainly in the alpha band. It was associated with having fewer inattentive symptoms and an advantage for spatial working memory. RPA  was associated with fewer inattentive symptoms, positive temperament characteristics, and better ability for tasks amenable to visual strategies. Negative RPA associations were exclusive to the CPT, and indicated a link to impulsive and variable performance.The CPT requires verbal encoding and maintaining a task-directed set for a prolonged period . This perhaps makes the CPT less amenable to alternative RH strategies. Moreover, negative RPA-CPT performance associations only occurred for RPA in the TPJ . This may indicate a link between cognitive flexibility and poor CPT performance in this ADHD RF. Given this pattern, and indications of strong positive selection for the DRD4-7R allele , we specBeing male was generally distinguished by poorer verbal ability, and by RPA effects occurring mainly in the beta band. Males exhibited worse letter discrimination and coding ability. RPA (mainly in beta) was associated with greater hyperactivity, better social functioning, and better cognitive ability . As with the DRD4-7R carriers, we speculate that being male is linked to an evolved emphasis on RH-biased brain function that is less conducive to task-directed thought and behavior, albeit in a different manner.EEG beta has been linked to early-stage encoding of attentionally selected information  andWomen exhibit greater specialization for top–down object-oriented processing , while men emphasize bottom–up analysis of motion, fine detail, and high resolution spatial and temporal content . MHaving mood disorder was distinguished by greater inattention, poorer inhibition, RPA being exclusively expressed during the EC condition, and no RPA associations to symptoms, but abundant RPA associations to poor social functioning. For example, mood sufferers exhibited greater CPT commission errors . Poor inhibition is consistent with RH frontal pathology in mood disorders , 135. MoTaken together, we speculate that RH bias in mood sufferers, identified here and elsewhere , may reFurthermore, greater R > L TPJ activation was tied to better cognitive outcomes for the mood RF. It is interesting to consider that a more flexible cognitive set might help mood sufferers be more responsive to external social cues, and thereby make socially appropriate transitions into task-directed cognitive sets. If true, mood derived risk for ADHD should be moderated by factors that promote more flexible and/or externally oriented cognitive and attentional sets . Consistent with this, in our ADHD sample, comorbid mood was associated with low self-transcendence  .Having anxiety disorder was distinguished by being the most impaired RF, by RPA occurring only during sensory engagement, and by having the most numerous RPA associations to symptoms and poor cognition. The DRD4-7R group was associated with reduced general knowledge (information task), being male was associated with poorer verbal ability, and mood was associated with poor inhibition, having anxiety disorder was associated with each. It was also tied to greater hyperactivity, harm avoidance, and social problems. RPA showed the most numerous associations with symptoms, marginal association to poor social functioning, and mixed effects on cognition, but with the most numerous negative effects. Different from DRD4-7R carriers, anxiety sufferers showed a standard pattern of RPA association to positive outcomes for spatial tasks, and poor outcomes for standard verbal tasks and the CPT. Hence, rather than increased RH processing control, we speculate that anxiety imparts a more fight-or-flight like increase of bottom–up visuo-perceptual processing. If true, anxiety may produce a similar, albeit more severe, version of the ADHD liability that we suggest occurs in males .In considering the sum total of our findings, along with relevant literature, we speculate that RPA is tied to different causal mechanisms in different ADHD RFs. We suspect that DRD4-7R carriers may adhere to visual cognition strategies that bear liability for tasks that are not amenable to visual cognition strategies. Males and anxiety sufferers may bear an increased tendency toward bottom–up visual processing (automatic sensory responsivity) that makes the induction and maintenance of a task-directed neural architecture more difficult . We suspect that in males this is typically overcome, but nevertheless imparts risk for ADHD, while in anxiety sufferers, it more consistently underlies attention related pathology. Finally, we speculated that internal affective processing in mood sufferers might diminish entrainment to social cues needed to guide attention.The DEP model conceptualizes ADHD to be a set of clinical characteristics that manifest with any form of poor task-directed brain functioning . It asserts that R > L posterior brain function is a similarly manifest physiologic outcome. We tested this by examining whether R > L parietal EEG asymmetry was generally associated with common ADHD RFs, and found that it was. This suggests that ADHD liability is generally associated with increased weighting of RH visuo-perceptual versus LH verbal parietal brain functions, and highlights two possible mechanisms: (1) a TPJ state-setting effect and (2) an SPL/IPL applied attention effect. Moreover, we hypothesize that abnormal RH contribution in ADHD during task operations can be conceived to include: (1) reduced top–down task-directed control over visual processing (low RH), (2) a more diffuse/flexible attentional and cognitive set, associated with greater expression of non-task-specialized forms of visual processing (high RH), and (3) compensatory attentional effort (high RH).In secondary analyses, we explored whether RPA (a convergent feature of ADHD liability) might be tied to different causal mechanisms in different ADHD RFs. Different patterns of RPA and RPA association to symptoms, temperament, and cognition suggest that it is. We suspect that ADHD RFs disrupt the induction and/or maintenance of a task-optimized neural architecture , albeit in different manners. We also expect that multiple additional acute , developmental , genetic , and/or mechanistic  factors can produce this outcome. Under this view, ADHD symptoms are considered to reflect the convergent or shared outcome of poor task-directed brain functioning, no matter the cause, with the syndrome of ADHD reflecting such circumstances that get durably expressed and that are life disruptive.Viewed in this way, it is clear that the challenge of understanding and treating ADHD is, at its core, synonymous with the challenge of understanding complex task-directed thought and action, and the multitude of ways that ability might be compromised. It also highlights that identification of primary deficits may require a greater emphasis on longitudinal analysis of ADHD individuals and/or clinically meaningful subgroups. However, as demonstrated by current drug treatments, alleviation of ADHD symptoms may not require a complete knowledge of deficit causality.Given the diffuse anatomy of catecholomine systems, stimulants likely impart broad, rather than specific effects . One posIn sum, the current study and DEP model of ADHD have attempted to highlight, and begin to address, the challenges associated with trying to map sharply defined diagnostic categories onto underlying pathophysiology, as abnormal brain-function characteristics are often shared by multiple disorders. To this end, aberrant rightward asymmetry has been reported across multiple conditions that are linked to attention difficulties, and that are often comorbid with ADHD  , 140–147The 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.http://journal.frontiersin.org/article/10.3389/fpsyt.2015.00063The Supplementary Material for this article can be found online at Click here for additional data file.


Cyanocitta stelleri) and territory characteristics influence genetic fidelity of socially monogamous pairs. We used seven highly polymorphic microsatellite markers to assign paternity to 79 offspring, and identified 12 (15.2%) as extra-pair young (EPY). Steller's jays with extra-pair young had significantly lower values of feather brightness and hue, indicating more ultraviolet-blue shifted coloration, and nested in closer proximity to the forest edge than Steller's jays with no detected EPY. Body size, crest height, asymmetry of ornamental crest stripes, as well as vegetative composition of territories and their proximity to supplemental feeders appeared to have little relationship to EPP. These results indicate that extra-pair parentage plays a role in the evolution of secondary sexual characteristics in both sexes, and suggest local density and availability of resources may influence Steller's jay mating dynamics.Genetic analysis of avian mating systems has revealed that more than 70% of monogamous species show incidence of offspring parentage that does not match the social partner. Extra-pair parentage (EPP) has been linked to a variety of factors, including size and symmetry of ornamental traits, coloration, resource availability, and local conspecific density. We examined how ornamental plumage traits of individual Steller's jays ( The resource-based nature of serial monogamy makes it the most prevalent mating strategy in avian species with finite resource availability The discrepancy in energy demands between the sexes generally allows males to copulate indiscriminately to increase their fitness, while females are restricted by the costs of reproduction and are thus more selective Several hypotheses attempt to explain the pervasiveness of EPC in socially monogamous birds. From the female's perspective, mixed paternity broods from EPCs may function to increase genetic diversity of a brood, thereby increasing the probability that at least some offspring will survive, which would be advantageous in dynamic and spatially heterogeneous environments Cyanocitta stelleri), a generalist corvid, exist in higher densities along forest edges Studies have linked paternity success to a variety of ornamental traits, including length and symmetry of crest Steller's jays are a long-lived species, forming long-term pairs that work together to raise young and defend year-round territories o59′N, 124o06′W). This population lives year-round on the fringe of second growth redwood (Sequoia sempervirens) forest. Steller's jays in this area utilize feeding stations modified with sliding doors that can be drawn closed to selectively capture individuals We examined a suburban population of individually marked Steller's jays that has been intensively monitored since 2005 in Arcata, California  to create 100 m radius buffers around previously identified nest locations (recorded in NAD83 UTM Zone 16N using a Garmin GPS). These territory sizes were chosen to reflect core use areas of similar size of those measured using radio telemetry with Steller's jays . To avoid pseudoreplication for pairs with multiple nest attempts in the same year (10% of cases), we found the centroid point among nests around which to place the territory region. We quantified habitat characteristics within these territories by digitizing polygons from BING base map imagery , available for use in ArcMap 10.0.n = 7), we used the most recently gathered habitat data for that pair, as territories did not differ substantially between years. Finally, we depicted the distribution of territories on a map to allow for visual interpretation.We measured percent cover within regions for the categories 1) conifers 2) hardwoods, 3) shrubs, 4) grass and dirt plots and 5) impervious surface (following Aphelocoma coerulescens): Apco2, Apco29, Apco30, Apco37, Apco40, Apco41 Aphelocoma ultramarina): MJG3 To prepare blood samples for analysis, we used a traditional phenol-chloroform method for DNA extraction with proteinase K digestion We assigned both maternal and paternal parentage to offspring using CERVUS 3.2 We included all adult birds that were possibly alive in a given birth year as parent candidates in the analysis; however, individuals hatched the prior year (second years) were included only if their presence was noted in the months preceding a given breeding season. We excluded all unobserved second year birds due to high dispersal rate of juveniles and to minimize the possibility of a non-present individual being assigned as a parent to a younger sibling. All individuals genotyped at fewer than five microsatellite loci were excluded from analysis.Within-pair young (WPY) were assigned when the most likely candidate parents given by CERVUS 3.2 for an offspring matched a known social pair. In a few instances, a known social pair was given as the second or third most likely parent pair. In all of these cases the Delta scores between top putative parents were small and no candidate set could be identified with 95% confidence, therefore we assumed that these offspring belonged to the known social pair. Possible EPPs were considered only when no known social pairs had positive LOD scores, and one or both candidate parents could be assigned with 95% confidence.We calculated the mean of repeated measurements for physical variables of individuals, including only those measured on adult birds prior to the end of the time frame of this study, for use in analysis. Because of the apparent monomorphism of Steller's jays, we analyzed both sexes together and treated extra-pair parentage as a binomial response variable . We separately examined the influence of physical traits and nesting habitat characteristics using logistic regression models that were pre-selected based on relevant hypotheses. Regression models for appearance and habitat were ranked separately according to Akiake's Information Criterion (AIC) and adjusted for small sample size (AICc). Relative strengths of top models were assessed using evidence ratios To reduce the number of tested parameters, we performed Principal Component Analyses (PCA) to create an index of body size using wing chord, gape and tarsus lengths s = −0.894, n = 39, P<0.001), therefore we only included the latter in the analysis in order to reduce the number of candidate models. Additionally, conifer cover and distance from edge were correlated , so we included only distance from edge as an analysis variable. Due to missing or incomplete data, 20 individuals were eliminated from the appearance analysis and 8 nesting pairs were eliminated from the territory analysis. We chose not to model average competitive models because of the explorative rather than predictive nature of this study In Steller's jay territories, overall vegetative cover  was correlated with the proportion of impervious surface , and the second with hue , monogamous Siberian jays (Perisoreous infaustus) and cooperative breeding Florida Scrub-jays, to as high as 40% of nestlings assigned to group members other than the cooperative partner (one of the highest rates reported) in the plural breeding Mexican jay Genetic parentage construction revealed moderate rates of EPP in an urban fringe population of Steller's jays in northern California (15% of 79 typed progeny). This is the first study to examine the fidelity of Steller's jays and subsequently report the occurrence of EPP in the species. Assessments of extra-pair behavior in other corvid species report a range of incidence from 0% occurrence for the colonial-nesting Jackdaw  than the feathers of individuals with no extra-pair success. Extra-pair parents were also less bright, which may allow a greater proportion of reflectance in the UV range, and signal more durable, higher quality feathers The good genes hypothesis posits that higher quality males will gain superior access to extra-pair copulation opportunities Steller's jays with EPY nested in closer proximity to the forest than those with WPY only , which cLimited knowledge of social partnerships and delineation of a sampling area in a contiguous population restricted parentage assignment in this population of Steller's jays. Neighboring or floater males that resided just outside our study area, such as in the un-sampled adjacent forest, likely sired extra-pair young of known nesting females. Similarly, failure to assign maternal or any parentage to an offspring is equally likely a consequence of this ‘open population’, as well as a result of not knowing all social partnerships. In some cases we were unable to assign any parentage to an offspring. Because of the inaccessibility of nests and their sensitivity to disturbance In summary, our results support the good genes hypothesis, highlighting the importance of UV coloration in sexual selection on males. Additionally, our results indicate concurrent plumage selection on females, which may be explained as a consequence of predictions from the ‘constrained female hypothesis’. Furthermore, this study suggests that local density may play a role in Steller's jay mating strategies, though more research is needed. Steller's jay affinity for urban/wildland interfaces, and their apparent ecological Figure S1Secondary feathers of an adult Steller's jay illuminated under florescent black light to show UV coloration.(TIFF)Click here for additional data file.Figure S2Feather brightness  subdivided by gender and detection of extra-pair parentage (EPP) in breeding Stellers jays.(TIFF)Click here for additional data file.Figure S3Comparison of feather hue of adult Steller's jays with and without extra-pair parentage (EPP).(TIFF)Click here for additional data file.Figure S4Comparison of nest distance from forest edge (m) of adult Steller's jays with and without extra-pair parentage (EPP).(TIFF)Click here for additional data file.File S1Dataset for appearance analysis.(CSV)Click here for additional data file.File S2Dataset for habitat analysis.(CSV)Click here for additional data file.


Exploratory factor analysis confirmed four AAQoL subscales. Internal consistency was acceptable . The AAQoL total score showed moderate convergent validity with CAARS-Inv:SV 18-item total ADHD symptom and clinical global impression-ADHD-severity (CGI-ADHD-S) scores; and strong convergent validity with Behavior Rating Inventory of Executive Function—Adult Version: Self-Report Global-Executive-Composite Index scores. Mean AAQoL total scores were significantly different among patients grouped by CGI-ADHD-S scores, suggesting good discriminant validity. The AAQoL total and subscale scores presented good responsiveness from baseline to 12 weeks. The AAQoL scale shows comparable validity in European and US adults with ADHD.The adult attention-deficit/hyperactivity disorder (ADHD) quality-of-life (AAQoL) scale was previously validated in adult patients in the USA; here, the AAQoL is validated in adult European patients. Data from a 12-week open-label acute treatment period with atomoxetine (80–100 mg/day) in adults with ADHD were used. Patients (≥18 to ≤50 years old) had a score ≥2 on ≥6 items on the inattentive or hyperactive core subscales of Conners’ Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV); a CAARS-Inv:SV 18-item total ADHD symptom score ≥20; and Conners’ Adult ADHD Rating Scale-Observer: Screening Version 6-item inattentive or hyperactive core subscale scores ≥2. Data were stratified based on patients’ geographic region (Europe vs USA). Scale validation psychometric properties results were very similar between European (The online version of this article (doi:10.1007/s12402-014-0160-z) contains supplementary material, which is available to authorized users. Effects of attention-deficit/hyperactivity disorder (ADHD) in adults go beyond symptoms of inattention, hyperactivity, and impulsivity that characterize the disorder . In 2006, the AAQoL was first validated in a retrospective cohort study conducted in the USA that included adult patients with ADHD (n = 989) treated with atomoxetine. Psychometric validation results showed the ability of the AAQoL to quantify the QoL consequences of ADHD  scale assesses QoL in adult patients with ADHD  versus placebo in adult outpatients with ADHD. Data were used from the open-label treatment phase of the study, during which all enrolled patients received treatment with atomoxetine  for 12 weeks. The study was conducted in 152 centers across 18 countries. For the current analyses, only data collected during the 12-week open-label treatment period in 50 centers in the US and in 82 centers in European countries were used. European countries included Austria, Belgium, Denmark, Finland, France, Germany, Italy, the Netherlands, Portugal, Spain, Sweden, Switzerland, and the UK. Data from additional non-European study centers located in Argentina, Canada, Mexico, and Russia were not included in the present analyses.Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision™ (DSM-IV-TR™) criteria and a score of ≥2 on at least 6 items of either the inattentive or hyperactive core subscales of the Conners’ Adult ADHD Rating Scale-Investigator Rated: Screening Version (CAARS-Inv:SV) with adult ADHD prompts, were enrolled. In addition, patients had a CAARS-Inv:SV total ADHD symptom score of ≥20, a score of ≥2 on at least 6 items of either the inattentive or hyperactive core subscales of conners’ adult attention-deficit/hyperactivity disorder rating scale-observer: screening version (CAARS-O:SV), and a score of ≥4 on the CGI-ADHD-S. Excluded were patients who met full DSM-IV-TR diagnostic criteria for any history of bipolar disorder, current major depression, a current anxiety disorder , or any history of a psychotic disorder (confirmed by the structured interview); patients with HAMD-17 or HAMA scores of ≥15; and patients with organic brain disease.Adults (≥18 to ≤50 years old) of either gender with a current and historical diagnosis of ADHD, as defined by In the current analyses, four different rating scales assessing disease severity were included—the AAQoL, the CAARS-Inv:SV total ADHD symptom scale, the CGI-ADHD-S scale, and the Behavior Rating Inventory of Executive Function—Adult Version: Self-Report (BRIEF-A) scale. All scales were translated using well-recognized scientific guidelines for translation of patient-reported outcome measures . It includes four domains : (1) Life Productivity (11 items), including “getting things done on time,” “completing projects or tasks,” “remembering important things,” and “balancing multiple projects;” (2) Psychological Health (6 items), including “feeling anxious,” “overwhelmed,” and “fatigued;” (3) Relationships (5 items), including “tension,” “annoyance,” and “frustration in relationships;” (4) Life Outlook (7 items), including “perceptions that energy is well spent,” “people enjoy spending time with you,” “you can successfully manage your life,” and “you are as productive as you would like to be.” Each item is rated by patients on a 5-point Likert scale ranging from “Not at all/Never” (1) to “Extremely/Very Often” (5). To derive overall and subscale scores, item scores are transformed to a 0–100-point scale. Then, the item scores are summed up and divided by item count to generate subscale and overall scores. If >1 item of a subscore was missing, the subscore was treated as missing. If >3 items for the overall score were missing, the overall score was treated as missing . A higher score indicates greater QoL , the Hyperactivity/Impulsivity subscale , and the ADHD Index   was used.Data from all European and US patients who enrolled in the 12-week open-label treatment phase were included in the analyses. Data were analyzed in three groups: European patient group, US patient group, as well as both groups combined. To analyze the data, statistical software SASAn exploratory factor analysis was used to examine the underlying constructs of the AAQoL in the European patient group and the US patient group. The number of factors (4) examined in the analysis was based upon the known number of AAQoL subscales, and a value of ≥0.30 was deemed to indicate successful factor loading Cronbach . PrincipThe degree to which each item of a rating scale co-varies is captured by measures of internal consistency. Internal consistency for the AAQoL total and subscale scores was assessed at baseline and week 12 by use of Cronbach’s alpha (α), a measure of the average correlation of items within a scale Cronbach . CronbacConvergent validity estimates the degree to which any two measures that assess the same or similar entities are related to each other , Cronbach’s α values were >0.70 at baseline and week 12, indicating acceptable internal consistency in European and US patients.Overall, very similar values for Cronbach’s α were observed for European and US patients. Internal consistency remained high and acceptable with Cronbach’s α > 0.70 when patients from European and US groups were combined, at both baseline and week 12 Table .Table 3IAs assessed with Pearson correlation coefficients, at 12 weeks, AAQoL total scores demonstrated moderate convergent validity with CAARS-Inv:SV total ADHD symptom and CGI-ADHD-S scores, in both European and US patient populations. Correlations between AAQoL total scores and BRIEF-A GEC Index scores were strong in both European and US patient populations .Overall, European and US patient populations showed very similar correlation values between AAQoL total scores and CAARS-Inv:SV total ADHD symptom scores, CGI-ADHD-S scores, and BRIEF-A GEC Index scores, indicating very similar convergent validity in European and US patient groups .In an exploratory analysis, Pearson correlation coefficients between AAQoL subscale scores and AAQoL total scores as well as CAARS-Inv:SV hyperactive/impulsive score, CAARS-Inv:SV inattentive score, CGI-ADHD-S score, BRIEF-A Metacognition Index score, BRIEF-A Behavioral Regulation Index score, and BRIEF-A GEC Index score at 12 weeks were assessed .All four AAQoL subscale scores had moderate-to-strong correlations with the AAQoL total score in European and US patients. Correlations with the CAARS-Inv:SV hyperactive/impulsive subscale score were weak for all AAQoL subscale scores in European and US patient groups. For the CAARS-Inv:SV inattentive subscale, correlations with AAQoL subscale scores were weak to moderate for European and US patient groups. All AAQoL subscale scores showed weak correlations with the CGI-ADHD-S score with the exception of the Life Productivity subscale, which demonstrated moderate correlation with the CGI-ADHD-S score in both European and US patients. The AAQoL Productivity subscale score was also moderately correlated with both the BRIEF-A Metacognition Index score and the BRIEF-A GEC Index score. For the remaining 3 AAQoL subscales, scores were low moderately correlated with the BRIEF-A Metacognition Index score and the BRIEF-A GEC Index score. Correlations between all AAQoL subscale scores and the BRIEF-A Behavioral Regulation Index score were low-moderate to moderate in European and US patient groups . Overall, correlations between AAQoL subscale scores and comparator scale scores were very similar in European and US patient groups.P ≤ 0.0001 for European and US patient groups) differences in mean AAQoL total scores at week 12 between patients with a CGI-ADHD-S score of 1 versus patients with CGI-ADHD-S scores of 2 through 5, indicating discriminant validity of the AAQoL  was very similar between European and US groups, with comparable mean AAQoL scores for patient groups with identical CGI-ADHD-S scores. Mean AAQoL total scores decreased with increasing CGI-ADHD-S scores in European and US patients, indicating lower QoL in patients with higher ADHD symptom severity. Furthermore, analyses revealed significant (P < 0.001) mean changes from baseline to week 12 in European and US patient groups, indicating good responsiveness.The AAQoL total and subscale scores showed significant  versus another subpopulation (US patients) in which the AAQoL had been previously validated. Overall, results of all measures for internal consistency, convergent and discriminant validity, and responsiveness were very similar between regions within our study, as well as between our study populations and a prior validation of the AAQoL , the previously published  does not capture the full impact of ADHD on QoL. Consequently, QoL assessment at baseline and during treatment is of much importance. Both DSM symptoms and QoL should be assessed to demonstrate improvement in patients with ADHD, as expressed in the European Medical Agency (EMA) guidelines for drug development in ADHD.Overall, the moderate correlation between the AAQOL and the CAARS-Inv:SV supports the idea that the 18-item total ADHD symptom score listed in the The interpretation of the results of the current study is limited by the open-label study design. Because this study was not designed for a priori investigation of psychometric properties of the AAQoL in a European population, the scales that were chosen as comparators for convergent and discriminant validity were not the standard scales that could be used for that purpose. However, psychometric findings in European and US patient populations in this study were overall very consistent. Together with the prior validation study of the AAQoL in a US population Below is the link to the electronic supplementary material.