Pennisetum glaucum (L.) R. Br.) is a staple food and a drought-tolerant cereal well adapted to Sub-Saharan Africa agro-ecosystems. An important diversity of pearl millet landraces has been widely conserved by farmers and therefore could help copping with climate changes and contribute to future food security. Hence, characterizing its genetic diversity and population structure can contribute to better assist breeding programs for a sustainable agricultural productivity enhancement. Toward this goal, a comprehensive panel of 404 accessions were used that correspond to 12 improved varieties, 306 early flowering and 86 late-flowering cultivated landraces from Senegal. Twelve highly polymorphic SSR markers were used to study diversity and population structure. Two genes, PgMADS11 and PgPHYC, were genotyped to assess their association to flowering phenotypic difference in landraces. Results indicate a large diversity and untapped potential of Senegalese pearl millet germplasm as well as a genetic differentiation between early- and late-flowering landraces. Further, a fine-scale genetic difference of PgPHYC and PgMADS11  and co-variation of their alleles with flowering time were found among landraces. These findings highlight new genetic insights of pearl millet useful to define heterotic populations for breeding, genomic association panel, or crosses for trait-specific mapping.Pearl millet ( Low agricultural productivity causes food insecurity and malnutrition in Sub-Saharan Africa (SSA). This is due to climate variability, increased growth and needs of worldwide population, water demand, intensive exploitation of natural resources and environmental degradation. Therefore, better uses of natural resources could help overcoming some of these constraints and greatly contribute to improving productivity.Pennisetum glaucum (L.) R. Br.) is a major staple food for many SSA and Asian countries. Pearl millet is highly allogamous and mainly a rainfed crop, covering a wide range of different ecological zones and production systems. However, yield is low and variable, rarely reaching 1000 kg/ha. This is mainly explained by the limited exploitation of genetic resources and availability of improved varieties, but also by low soil fertility, drought, heat and highly variable rainfall  rainfall regions. Cultivars, called Sanio, are a less photoperiod-sensitive type than Souna, with a long cycle between 120 and 150 days, and are adapted to high (900–1200 mm) rainfall regions. Nationwide, Souna type occupies nearly half the area sown to cereals (51%) while Sanio type, mainly cultivated in the South, represents about 15% of total millet production  and an indel variation in PgMADS11 gene were associated with flowering time variation, annual rainfall and spike length of pearl millet  and read with GenemapperTM software .Five seeds per accession were grown in the greenhouse 3–4 weeks according to sampling date. About 200 mg of leaf sample from one individual per accession were collected and DNA extraction was carried out using the previously described protocol . Twelve K-value were performed. The values for the number of clusters (K) were assessed according to D.ΔK) criterion and the log-likelihood (Ln P (D | K)) plot. Individuals were assigned to a cluster if their ancestry was higher than 70%, q ≥ 0.7.Genetic diversity, heterozygosities (expected and observed) and F-statistics were calculated using Genalex 6.5 . For genadegenet package  and the logarithmic (ln(dij)) spatial distance between individuals. This distance was calculated as the Euclidian distances using spatial coordinates. The regression slopes bd and bLd were jointly assessed. Standard errors for the kinship coefficients were estimated using a jackknife procedure over all loci. We tested the significance of the kinship coefficients and the regression slopes bd and bLd estimates by comparing the observed values to those obtained after 10,000 random permutations.For spatial analysis of genetic variability, a total of 367 geo-referenced accessions including 281 early- and 86 late-flowering landraces were used. Spatial principal component analysis (sPCA) was performed using the  package  with R s package  followin package  implemen package . Mean muPgPHYC (Acc numbers FN376885–FN377564) (PgMADS11 (Acc numbers FN552468–FN552522) (Polymorphisms in both genes were associated with flowering time variation . The panN377564)  and PgMAN552522)  to test PgPHYC, a polymorphism at the 5′ of the gene was assessed. A C/G SNP at that position is cleaved by PvuII restriction enzyme and therefore accessions scored as C/C, G/G and C/G according to their digestion pattern . Genotyping data revealed a total of 101 alleles with an average of 8.4 alleles per locus (Supplementary Table Table 1). Early flowering landraces presented the highest level of genetic diversity as measured by observed HObs = 0.481 or expected heterozygosity, HExp = 0.567. In contrast, improved varieties showed the lowest, with HObs = 0.391. For early flowering landraces, only one locus (PSMP2249) was found not to be at Hardy-Weinberg equilibrium (HWE). Two loci were not at HWE (PSMP2249 and PSMP2246) in late-flowering landraces. Groups showed low levels of inbreeding with FIS values of 0.160, 0.128, and 0.258 for early and late landraces and improved varieties, respectively. Furthermore, early-, late-flowering landraces and improved varieties present 22, 8 and 1 private alleles, respectively. Low FST differentiation was found between improved varieties and early flowering landraces (0.004), between early- and late-flowering landraces (0.052) and between late-flowering landraces and improved varieties (0.063).The germplasm collected through this study is the most comprehensive sampling to date of landraces from Senegal . The value of the Evanno criterion (ΔK) was the highest for K = 2 , but showed intermediate ancestries. For the 10 villages where both early- and late-flowering landraces were sampled, all accessions of similar phenotype were assigned to their respective cluster.Bayesian clustering analyses showed a clear structure between early- and late-flowering landraces . The two first principal components explained, respectively, 5.2 and 2.8% of the inertia. PSMP2247 and PSMP2202 showed the highest contribution to the PC1. Two alleles, PSMP2247-199 and PSMP2202-146, showed high frequencies in late-flowering landraces . However, removing these two loci did not affect PCA results. Finally, any genetic differentiation was found between improved and early accessions.Similar results were found with PCA showing a clear distinction between early- and late-flowering landraces . Global structures, i.e., large spatial scale, were significant  with the first principal component, showing a high autocorrelation (Morran’s I = 0.50). In contrast, local structures were not significant . The first axis of the sPCA identified two clusters. Considering spatial information, early flowering landraces from Southern Senegal showed a more admixed pattern than observed with STRUCTURE, while no differences were observed considering late-flowering landraces. Bayesian and multivariate approaches confirm genetic assignments for late-flowering landraces from Central Senegal.Spatial principal component analysis revealed a more cryptic genetic structure (bE = -2.41E-05) and late-flowering (bL = -9.89E-05) landraces . Similar results were found for logarithmic distances. This suggests no significant pattern of isolation-by-distance.The pattern of isolation by distance (IBD) for early- and late-flowering landraces was investigated. Low IBD slopes were obtained for early flowering . For PgMADS11, a significant difference in genotypes frequencies  was observed with early flowering landraces having higher frequency of the allele (363 bp fragment). A significant correlation between allele G from PgPHYC with latitude  was observed. However, significance disappeared when taking into consideration genetic clustering (q ≤ 0.7). For PgMADS11, data reveal a significant correlation with longitude  even when considering genetic clustering in the mode.Landraces were genotyped for both HExp: 0.516) of pearl millet germplasm of Senegal is reported. Previous studies have reported a higher (HExp: 0.69) (HExp = 0.49) genetic diversity in Niger pearl millet (FIS = 0.30) in Niger germplasm than in Senegal germplasm (FIS = 0.18). However, these results are consistent with data from others studies carried out on accessions across SSA regions and India   and a lol millet . These dnd India . Pearl mnd India . This hind India  as in Wend India . TogetheGenetic proximity between early flowering varieties and improved varieties highlight a history of breeding programs and agricultural practices. In Senegal, few breeding programs have been undertaken on pearl millet but all focused on reducing the flowering cycle and were “population” varieties whose parental seeds were collected from local landraces. In addition, farmers still grow improved varieties jointly with landraces in their field, increasing gene flow and thus genetic proximity.Bayesian results clearly help identifying genetic structure associated with early- and late-flowering landraces. This genetic structure was partly explained by the geographic distribution of landraces as shown through the sPCA analysis, making it difficult to entirely disentangle spatial and genetic structure. More contrast in admixture patterns might have been obtained with a higher number of SSR markers. However, this was compensated by our sampling effort and we were able to reveal a clear structure in Senegal landraces where other studies failed with a higher number of markers .At a local scale, more contrasted admixture patterns were observed. In Central Senegal, clear differentiation between early- and late-flowering landraces was found. In contrast, more admixed patterns were observed in the Southern Senegal. The results might be related to the agricultural practices of the farmers, such as spatial cropping and seed circulation .Our data indicated two distinct genetic clusters in Senegalese pearl millet germplasm. In addition, comparing early- and late-flowering landraces, we found a slight genetic differentiation between the two groups of 0.052, which is of the same magnitude (0.053) found in Niger . A singlPgPHYC. Correlation between allele frequencies and rainfall were also found with PgMADS11  among individuals and/or genotypes. Knowing that responses to photoperiod and rainfall were genetically associated with both genes, implication could be their use to detect/track climate adaptive changes to environment variations. For example, earliness of flowering and latitude correlation observed in early landraces support assumption that a direct effect of selection for that trait which is associated with climate variations such as photoperiod and rainfall. Both traits are key targets in selection for millet genotypes to be cultivated in rainfed areas.Analyses of allelic variation of PgPHYC and PgMADS11 were found among individuals. These findings give new insights into Senegalese pearl millet germplasm and are promising for developing new cultivars and heterotic groups that can be used to breed synthetic and hybrid varieties with higher degrees of heterozygosity in order to intensify yield production under harsh semiarids environments.The genetic diversity and population structure of Senegalese pearl millet landraces were assessed using a large panel of accessions and a limited number of SSRs markers. Results highlight a high genetic diversity and an untapped potential of the germplasm. However, two clusters were clearly distinguished as revealed by differentiation between early- and late-flowering landraces. Further, genetic difference and allelic co-variation in flowering genes NK, AF, DD, MG, YV, and AB designed the study. OD, AF, MG, MP, HT, BD, and OS collected samples. OD, MC, MP, and LZ performed DNA extraction, PCR and sequencing. AB, CB-S, and OD performed the genetic analyses. OD, AB, CB-S, DD, and NK drafted the manuscript. All authors contributed to the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Attention-deficit/hyperactivity disorder (ADHD) is pervasive among the pediatric population and new treatments with minimal adverse effects are necessary to be studied. The purpose of this article is to review current research studying mind–body therapies for treatment of children diagnosed with ADHD. Literature was reviewed pertaining to the effectiveness of movement-based therapies and mindfulness/meditation-based therapies for ADHD. Many positive effects of yoga, Tai Chi, physical activity, and meditation may significantly improve symptoms of ADHD among children.  Attention-deficit/hyperactivity disorder (ADHD) is a widespread chronic disorder affecting children’s well-being and success in life. The historical understanding of ADHD has changed over the years . ADHD waA landmark theory about the primary dysfunction of ADHD was developed by Russel Barkley called the Hybrid Neuropsychological Model of Executive (Self-Regulatory) Function . This thADHD has been correlated with many different genetic and environmental influences. It has been identified that genetic factors, environment, brain structure, neural pathways, and neurotransmitter levels influence ADHD and its symptoms ,5,6. In-complex trait disorder meaning that it is affected by many susceptibility genes. Each gene affects the risk of developing the disorder on a small scale (p. 51) . ADHD presents with a complex etiology and has multiple treatment options. Stimulant medication is the most often used medication for the disorder in younger children, and more recently, non-stimulant medications are used for children and adolescent populations. Other treatments include behavior modification, which includes therapy from clinicians, family or parent training and therapy, and school-based interventions in the classroom .A recent study of 152 children with ADHD revealed that initial treatment behavior modification was less costly than initial treatment with a low dose of stimulant medication. This experimental study found that, on average, children who underwent successful behavior modification training had a cost of $392 versus $1448 for pharmacological treatment over a 10-month school year . In addiBehavioral interventions and pharmaceutical regimens have been shown to be effective at reducing ADHD symptoms significantly, especially when used in combination . It deseIntegrative medicine offers an alternative or addition to pharmacological or cognitive-behavioral therapies for treatment of ADHD. There are limited well-designed studies of integrative therapies, making it difficult to generalize results. Current therapies to improve ADHD symptoms identified through evidence-based medicine include diet, nutrient supplementation, gut health, environmental health, and neurofeedback .Mind–body therapy includes but is not limited to mindfulness, biofeedback, deep breathing, guided imagery, progressive relaxation, hypnotherapy, and yoga . A reasoOne field of mind–body medicine is the practice of yoga. Yoga is an ancient physical practice, derived from Sanskrit word “yuj” meaning “to yoke,” and refers to uniting the body, mind and spirit. Yoga teaches individuals to master certain poses and breathing techniques which may promote self-control, attention, awareness and adaptive skills. Yoga has been used as a form of exercise and meditation. It has been currently studied as therapy for the treatment of stress, chronic pain, asthma, irritable bowel syndrome, and ADHD .Yoga has various components to unite the body, mind and spirit. It is comprised of the asanas , pranayamas (breathing techniques), and dharana/dhyana (meditation practices) . The goaOne study by Hariprasad et al. investigated the effects of yoga as a complementary therapy for children with ADHD who were admitted in a child psychiatry unit . The samSahaja yoga practice as family therapy may have a positive effect on ADHD symptoms and could possibly reduce dosage of medication in some cases. Another study investigated effects of Sahaja yoga meditation as a family treatment for children with ADHD . There wYoga may also help increase time on task for students with ADHD in the educational setting. One study investigated the effect of a yoga practice intervention on children’s time on task in school . The parThere are few experimental studies exploring the effects yoga on attention mechanisms. One study investigated how 20 yoga sessions for boys with ADHD would help attention versus a control of cooperative game activities . The expn = 24) and control (n = 25). The two groups were matched, so there were no significant differences in extraneous variables. They measured children at baseline and after intervention on the Visual Pursuit Test and Determination Test. These types of measurements may limit the application of this study because these two tests have not been used among ADHD populations. However, the Visual Pursuit Test is used in psychological diagnostics for selective and sustained attention and was used because attention deficits are symptoms of ADHD. Additionally, the Determination Test assesses for reaction speed, attention deficits, and reactive stress tolerance in the presence of external sensory stimuli. Findings revealed that the group who underwent yoga intervention had significantly better reaction time and response accuracy at the two measurements [In reference to the theory of executive dysfunction being the hallmark of ADHD, yoga practice must be evaluated in regards of its effect on these functions. Chou and Huang found that an eight-week yoga program significantly improved sustained attention and discrimination function in children with ADHD compared with a control group . The resurements . Another recent study investigated yoga and physical activity on measures of executive functioning . They exTai Chi is an ancient Chinese martial art consisting of slow movements coordinated with balancing body weight and breathing deeply. There may be potential benefit for improving ADHD symptoms of anxiety and hyperactivity with regular Tai Chi practice. A sample of 13 adolescents with ADHD was studied to find the effect of a five-week Tai Chi intervention on symptoms according to the Conners’ Scale rated by teachers. The participants were rated at baseline, at the end of the five weeks and two weeks after intervention. During the five weeks, participants completed two 30-minute sessions per week. It was found that the adolescents exhibited significantly decreased anxiety, decreased daydreaming, decreased inappropriate emotions, decreased hyperactivity, and increased conduct after the Tai Chi intervention. The scores persisted to be significantly affected even at the two-week post-intervention post-test . ResearcIn human studies, physical activity and fitness has shown to affect brain structure and increase brain activity that is associated with conflict and attentional control. Though ADHD is a disorder with a complex etiology, there are a few factors contributing to the likelihood of ADHD that may be affected by physical activity. Exercise has also been shown to improve dopamine function, known to be dysregulated in ADHD . Brain dp < 0.05) [A recent meta-analysis demonstrated that physical activity increases executive function and cognitive functioning with an effect size of 0.535 . In anot < 0.05) . Martial < 0.05) . The imp < 0.05) . While t < 0.05) . Mindfulness and meditation have been found to “change brain activation patterns, contribute to enhanced mood, reduce anxiety, improve stress management, reduce pain and enhance immune function”  (p. 510)The effect of an eight-week mindfulness training program for adults and adolescents with ADHD was considered . The groThis study by Crescentini et al. examined the effects of mindfulness training on 16 healthy primary school children ages seven to eight years old. The training consisted of three sessions per week for eight weeks . A pre-tThe effects of meditation on attention were studied by Jha et al. . Two expt-tests with significant effects at p < 0.10 in a two-tailed t-test. At eight weeks, it was found that the adolescents had improvements in attention problems, executive functioning and performance on the computerized attention test [p < 0.10. Further study should explore effects on mindfulness, perhaps with the same measurements but with larger sample sizes and interpreted with more strict significance scoring.Another study by Van de Weijer-Bergsma et al. incorporated parents and tutors into the mindfulness intervention . Ten adoion test . The sigStudies show that meditative practice causes measurable changes within brain-wave activity. One experiment by Lagopoulos et al. investigated the effects of nondirective meditation on theta and alpha activity in the brain as recorded by EEG . EighteeAn important factor to consider in the discussion of mindfulness or meditation for ADHD treatment is the type of meditation being used. Certain forms of mindfulness lead participants to greater awareness or attention on breathing or emotions, while others encourage free, relaxed mental states of “inattention.” For example, one form of meditation, known as Yoga Nidra, is characterized by leading participants to “lose executive control” and has been shown to cause decreased blood flow to areas of the brain that regulate executive functions . This stPotential benefits and mechanism of action of mind–body therapies have been evidenced through research and continue to be explored. Compared to pharmacological treatment, mind–body therapies have little to no unwanted side effects. There is little cost compared to clinical therapy since the only cost is for training or sessions that are typically conducted in groups. Activities such as yoga or Tai Chi can be practiced at home or school. Families and teachers can access videos online or purchase videos from reliable sources as resources to guide the therapy. Mindfulness and meditation can be done anywhere and at any time. Furthermore, mindfulness is a learned skill. It is counterintuitive that meditation has positive effects on ADHD symptoms because theta to beta ratios are typically increased in ADHD, and meditation further increases theta wave activity . MeditatMind–body training for parents has an added benefit to children’s ADHD symptoms. Parents who practice mindfulness with parenting techniques report better outcomes in ADHD symptoms of their children . It is pLimitations of current research are primarily due to small sample sizes and lack of control groups. More research needs to be done with larger sample sizes and more controlled settings. Many of the studies reviewed also gathered data from subjective self-report or parent/teacher surveys. More objective data should be measured alongside subjective data in future research.


Small, non-significant, benefits of NFPP over TAU were seen for parent-rated SNAP-IV, ADHD combined symptoms . NFPP significantly reduced parent-rated conduct problems compared to TAU across scales . No significant benefits of IY over TAU were seen for parent-rated SNAP, ADHD symptoms  or parent-rated conduct problems (p > 0.05). The cost per family of providing NFPP in the trial was significantly lower than IY (£1591 versus £2103). Although, there were no differences between NFPP and IY with regards clinical effectiveness, individually delivered NFPP cost less. However, this difference may be reduced when implemented in routine clinical practice. Clinical decisions should take into account parental preferences between delivery approaches.The objective of this study is to compare the efficacy and cost of specialised individually delivered parent training (PT) for preschool children with attention-deficit/hyperactivity disorder (ADHD) against generic group-based PT and treatment as usual (TAU). This is a multi-centre three-arm, parallel group randomised controlled trial conducted in National Health Service Trusts. The participants included in this study were preschool children (33–54 months) fulfilling ADHD research diagnostic criteria. New Forest Parenting Programme (NFPP)—12-week individual, home-delivered ADHD PT programme; Incredible Years (IY)—12-week group-based, PT programme initially designed for children with behaviour problems were the interventions. Primary outcome—Parent ratings of child’s ADHD symptoms . Secondary outcomes—teacher ratings (SNAP-IV) and direct observations of ADHD symptoms and parent/teacher ratings of conduct problems. NFPP, IY and TAU outcomes were measured at baseline (T1) and post treatment (T2). NFPP and IY outcomes only were measured 6 months post treatment (T3). Researchers, but not therapists or parents, were blind to treatment allocation. Analysis employed mixed effect regression models (multiple imputations). Intervention and other costs were estimated using standardized approaches. NFPP and IY did not differ on parent-rated SNAP-IV, ADHD combined symptoms [mean difference − 0.009 95% CI ,  Preschool attention-deficit/hyperactivity disorder (ADHD) impacts daily functioning  and predTo achieve this, here we present the Comparison of Preschool Parenting Interventions (COPPI) trial, the first randomised controlled trial (RCT) directly comparing the efficacy and cost-effectiveness of a PT programme delivered on a one-to-one basis—the New Forest Parenting Programme (NFPP)  and a grNFPP was selected for the trial, as it is the only widely available individually delivered programme developed as a PT intervention specifically for preschool children with ADHD. It is delivered at home on a one-to-one basis and tailored to the parent. It has four main therapeutic elements: (i) Psycho-education about ADHD; (ii) ADHD-tailored strategies to promote proactive parenting/better communication; learning to wait, and cueing the child into a change of task; (iii) play-based enhancement of the parent–child relations and; (iv) attention training through structured games and teachable moments –12. RCTsDuring the design of the study when considering which group-based PT comparator to use, we initially considered adapting the NFPP for use with groups to allow a direct comparison of group and one-to-one approaches of the same PT approach. However, as this would require a whole programme of research and development, before the current trial could be initiated, we decided on a more pragmatic approach—to contrast NFPP with a group-based approach that already had an established evidence base and was recommended by NICE . We chosOur research questions were: Is NFPP superior to IY and treatment as usual (TAU) in terms of reduction of parent-rated ADHD symptoms (our primary outcome)? Do any observed effects generalise to teacher-rated and directly observed ADHD symptoms and extend to parent/teacher-rated conduct problems (secondary outcomes)? What are the costs and cost-effectiveness of each type of treatment?A multi-centre three-arm, parallel randomised controlled trial comparing NFPP with both IY and TAU, for preschool children with a research diagnosis of ADHD.Participants were enlisted (February 2012 to January 2014) at three UK sites: (i) University of Southampton [with Solent NHS Trust (Southampton and Portsmouth Cities)]; (ii) North Staffordshire Combined Health Care NHS Trust; (iii) University of Nottingham . Ethical approval from the NHS Research Ethics Committee and site-specific approvals from the contributing sites were received. After being given a study description, parents provided informed consent. Participants were recruited and randomised in five (Nottingham and North Staffs) or six (Southampton) tranches in a way that allowed one or more IY groups to run at each site. Our aim was for our sample to be as representative of the entire preschool ADHD population as possible and therefore children, including those with co-occurring problems or living in difficult circumstances, were recruited from a wide range of sources. Sources included health visitors, Sure Start professionals, speech therapists, paediatric and child psychiatry clinics and adult mental health services. Posters, radio advertisements and social media were also employed. Children were included if: (i) they were between 2 years 9 months and 4 years 6 months old; (ii) had a parent/caregiver aged 18 years or over; (iii) screened positive for ADHD symptoms (score≥ 20) on the Werry-Weiss-Peters Activity Rating Scale (WWP) . To furtwww.tenalea.com] system [3 (NFPP): 3 (IY): 1 (TAU) ratio] to ensure power for the comparison of the two treatment arms. Stratification was by site and tranche. Parents and therapists were not blinded to treatment allocation. However, to protect blinding for all other members of the team including statisticians and researchers collecting and coding direct observations, only site PIs and designated administrative staff liaised with the trials unit and participants, with regard to allocation. Families were informed of the need to maintain blindness. This meant that researchers who collected outcome measures at T2 and T3 (see below) were, as far as possible, blind to treatment allocation. Teachers were also potentially blind to allocation. The coding of the observation data (which was videoed) was done by a researcher who had not met the family and was unaware of the group allocation. Inter-centre reliability of observation data was high.After all baseline (T1) measures were completed, participants were block randomised into study arms by the Southampton Clinical Trials Unit using the TENALEA . For all secondary outcomes, differences between NFPP and IY were small and not statistically significant  participants of the primary outcome. Small benefits of NFPP over TAU were seen for parent-rated ADHD SNAP-IV scores —effects just short of conventional levels of significance (p = 0.053). The effects on DOA also approached significance . One NFPP-related adverse event was reported—an accidental minor head injury.TAU T2 primary outcome data were missing for p = 0.121; Table p = 0.782; Table p = 0.785; Table p = 0.061; Table IY was not superior to TAU in terms of parent-rated ADHD  with a group-based package (IY) as recommended on grounds of lower cost by NICE. We had two principal findings. First, NFPP was no more or less efficacious for preschool ADHD than IY. The apparent lack of superiority of NFPP over IY went against our expectations, as NFPP was designed specifically for the treatment of preschool ADHD while the IY version used was not. Second, NFPP was less costly to deliver than IY—even after taking into account differences in the initial supervision costs. Like NICE, we predicted that many components of the costs of group and individual PT would be similar but that these costs would be spread more thinly in IY. In hindsight, some of the cost differences observed in favour of NFPP might have been expected especially given the high premium placed on training and supervision by IY, and particularly when running a trial with naive therapists. To what extent do these trial-based cost estimates represent the real world? A recent IY study found that similarly high costs during a trial phase fell dramatically when rolled out in everyday care  as once Whilst NFPP did show some benefits relative to TAU, especially for conduct problems, the effects on ADHD were lower than seen in prior NFPP trials , 11, 12.COPPI had considerable strengths relative to previous trials as the first RCT comparing group and individual PT for ADHD and, by some considerable margin, the largest ADHD PT trial to be conducted so far. These included a comparison with TAU and the use of teacher ratings and objective measures of change to examine issues of outcome blinding and generalisation. However, there were limitations. First, treatment attrition, particularly for the IY arm, was greater than planned for in the power calculation. Various strategies were employed to motivate families to remain in the trial including reimbursement of costs to parents for their time in completing questionnaires. This took the form of £5 gift vouchers for each set of complete data collected at baseline, T1 and T2. This was introduced roughly half way through the trial. Gift vouchers were handled by the researchers that collected the outcome data. However, it is possible that the challenging nature of the sample, as discussed above, could have contributed to the higher than expected levels of drop out. Importantly there was no evidence for selective drop out and so we were able to utilise a mixed effect regression model and multiple imputation to include information from all participants. Second, some elements of the IY implementation in COPPI may not have been optimised. Groups varied in terms of numbers of participants. IY developers recommend 12 individuals per group but most trials have started with eight—although numbers can drop during the treatment. The number of IY groups with less than 8 members at the time of recruitment was 13 out of 19—with a range 5–12 of participants per group and a modal value of 6/7. Furthermore, the twenty per cent of families that did not attend any sessions received no treatment. This high rate of IY “no shows” could be explained by: (i) parents failing to make the time/date of sessions (despite confirming their availability prior to randomisation); (ii) parents’ initial preference for individual over group approaches and/or (iii) difficulties in planning and organising their lives. Third, while overall IY content fidelity was acceptable for two sites (over 70%), data were not collected from one site. We do not know the full reason for this but it seems like it was due to a simple oversight. Staff changes made checking the return of ratings difficult. However, all therapists had attended supervision and their tapes had been discussed in supervision. Fourth, response rate for teachers was lower than that for parents. Fifth, there was a degree of turnover of staff in both programmes necessitating extra training and leading to increased costs. This was compounded by the late start of the trial in two centres and the need to run four additional tranches due to low recruitment . FinallyCOPPI was designed to address the appropriateness of NICE guidance recommending group-based PT for ADHD in young children. The finding that NFPP may be less costly than IY supports a revision of NICE’s recommendations in favour of group rather than individual services. Arguably, both individually delivered and group-based PT should be made available to families of children with preschool ADHD . An optiWe examined recent systematic reviews and meta-analyses of parenting training for ADHD (last published in 2014) and conducted a search using ISI Web of Knowledge and MEDLINE in August 2016 to identify recent RCTs. Search terms included—“parent training”, “Attention-Deficit Hyperactivity Disorder”, “ADHD”, “preschool”. Meta- analyses highlight the value of PT for pre-schoolers with ADHD—specifically improving parenting and reducing parent reported ADHD and conduct problem symptoms. No prior RCT has included a cost-effectiveness analysis of PT specifically for use in preschool ADHD populations. No prior study has compared the efficacy and cost-effectiveness of individually delivered and group-based parent training approaches.This is the largest RCT of parent training as a treatment for preschool children with ADHD, the first to incorporate a cost analysis and the first to compare an individually delivered (NFPP) and a group-based (IY) approach. NFPP and IY did not differ from one another in terms of their effects on ADHD or conduct problems although, against expectation, in the trial context NFPP was less costly. Furthermore, attendance was higher in NFPP families.The rate of attrition was higher than expected. The ability to check for fidelity of the delivery of IY in one of the centres was not possible. Aspects of IY delivery may not have been optimised. The cost estimates in the context of the trial may not reflect costs in routine care.PT plays an important role in the treatment of preschool ADHD. Given it established that NFPP was equally effective to IY but likely to be cheaper, the current trial did not support the NICE recommendation in favour of group-based over individually delivered parent training for the treatment of preschool ADHD.


Bartonella spp. and Rickettsia spp. have been reported in bats sampled in Europe, Africa, Asia, North, Central and South America. However, there are few reports on the Bartonella and Rickettsia bacteria infecting Hippoboscoidea flies and mites. While Spinturnicidae mites are ectoparasites found only in bats, those belonging to the family Macronyssidae comprise mites that also parasitize other mammal species. This study investigates the occurrence and assesses the phylogenetic positioning of Bartonella spp. and Rickettsia spp. found in Streblidae flies and Spinturnicidae and Macronyssidae mites collected from bats captured in Brazil. From May 2011 to April 2012 and September 2013 to December 2014, 400 Streblidae flies, 100 Macronyssidaes, and 100 Spinturnicidae mites were collected from bats captured in two sites in northeastern Nova Iguaçu, Rio de Janeiro, southeastern Brazil. Forty (19.8%) out of 202 Streblidae flies were positive for Bartonella spp. in qPCR assays based on the nuoG gene. Among the flies positive for the bacterium, six (18%) were Paratrichobius longicrus, seven (29%) Strebla guajiro, two (40%) Aspidoptera phyllostomatis, five (11%) Aspidoptera falcata, one (10%) Trichobius anducei, one (25%) Megistopoda aranea, and 18 (32%) Trichobius joblingi, and collected from bats of the following species: Artibeus lituratus, Carollia perspicillata, Artibeus planirostris, Sturnira lilium, and Artibeus obscurus. Six sequences were obtained for Bartonella . The phylogenetic analysis based on gltA (750pb) gene showed that the Bartonella sequences clustered with Bartonella genotypes detected in bats and ectoparasites previously sampled in Latin America, including Brazil. Only one sample (0.49%) of the species Trichobius joblingi collected from a specimen of Carollia perspicillata was positive for Rickettsia sp. in cPCR based on the gltA gene (401bp). This sequence was clustered with a ‘Candidatus Rickettsia andaenae" genotype detected in an Amblyomma parvum tick collected from a rodent in the southern region of Brazilian Pantanal. The sampled Macronyssidae and Spinturnicidae mites were negative for Bartonella spp. and Rickettsia spp. This study demonstrated the first occurrence of Bartonella spp. and Rickettsia spp. DNA in Streblidae flies collected from bats in Brazil.The family Streblidae comprises a monophyletic group of Hippoboscoidea, hematophagous dipterans that parasitize bats.  The order Chiroptera is the second largest group of mammals in the world, comprising approximately 20% of mammals and more than 1200 species present in all continents, except Antarctica -3', Master Mix 2x buffer  and ultra-pure sterilized water  q.s.p. 10 μL. The amplification conditions were 95°C for 3 minutes followed by 40 cycles at 95°C for 10 seconds and 52.8°C for 30 seconds [Bartonella henselae-nuoG gene fragment. The number of plasmid copies was determined by (Xg/μL DNA/ [plasmid length in bp x 660]) x 6.022 x1023 x plasmid copies/μL.A previously described quantitative PCR (qPCR) protocol based on uoG gene  was used seconds . PCR amp−1/slope). The standard curves generated by 10-fold dilutions were used to determine the amount of DNA that could be detected with 95% of sensitivity  collected from Artibeus lituratus and Periglischrus ojasti (n = 50) collected from Sturnira lilium) mites were all negative for both Bartonella spp. and Rickettsia spp.The 100 Macronyssidae (Bartonella nuoG sequence (GenBank accession number MG65471) was 93% identical to Bartonella sp. WD16.2 previously isolated from a deer sampled in Japan (GenBank accession number CP019781), the other GenBank accession number MG65472) was 84% identical to B. alsatica (GenBank accession number EF659935). Two Bartonella gltA sequences GenBank accession numbers MG551538) were 93–98% identical to Bartonella sp. detected in bats sampled in Costa Rica (KJ816665 and KJ816687). One Bartonella rpoB sequence (GenBank accession number MG65474) was 89% identical to Bartonella sp. Khabarovsk detected in Asian mammals (AB779537). Finally, one Bartonella ribC sequence (GenBank accession number MG65473) was 84% identical to B. washoensis (AB292599). The query coverage ranged from 96% to 100% in all BLAST analyses carried out for the Bartonella sequences , previously described in a tick sample of the species Amblyomma parvum, collected from a rodent found in the Pantanal Sul-Matogrossense, Brazil, with query coverage of 100% (The only detected  of 100% .Bartonella gltA gene formed two distinct clusters. The Bartonella sequence (GenBank accession number MG551538) detected in a Strebla guajiro specimen collected from Carollia perspicillata in Rio de Janeiro state was positioned alone in a branch but closely related to Bartonella genotypes previously detected in bats from South America, one genotype detected in a bat (Sturnira lillium) in Paraná state, Brazil (KY356753), and other genotypes detected in bats from Guatemala, Mexico, and Costa Rica, with 100% branch support. Additionally, such sequences were positioned in a larger clade related to Bartonella sequences detected in rodents sampled in Brazil and U.S.A., together with a Bartonella genotype detected in a Polygenis gwyni flea collected from a Sigmodon hispidus rodent in the U.S.A., with clade support value of 83% in BI analysis. In another cluster, the Bartonella sequence (GenBank accession number MG65470) obtained in a Strebla guajiro specimen collected from Carollia perspicillata sampled in Rio de Janeiro state was closely positioned to a genotype previously detected in a specimen of Trichobius sp. fly collected in the Dominican Republic (JX416249), together with genotypes detected in bats in Mexico (MF467776) and Costa Rica , with branch support value of 86% probability in BI analysis. In addition, a larger clade grouped a Bartonella genotype (KY356754) detected in a specimen of Glossophaga soricina sampled in Paraná, Brazil, and sequences previously detected in cervids and bovines, such as B. capreoli (AF293392), B. schoenbuchii (AJ278181) and B. chomelii (AY254308), with 55% clade support in the BI analysis  obtained from a M. aranea specimen collected from C. perspicillata sampled in Rio de Janeiro state was closely related to a genotype detected in a bat (S. lillium) previously sampled in Paraná state, southern Brazil, with 100% of branch support. These two sequences were positioned in the same cluster formed by Bartonella taylorii (AF165995) and Bartonella genotypes detected in rodents (AB290276) and in a bat (Myodes rufocanus) (AB779537) from Asia, with a branch support of 93% of probability BI analysis  obtained from a M. arenea specimen collected from C. perspicillata sampled in Rio de Janeiro state was positioned alone in a branch by BI analysis, but closely related (74% of branch support) to Bartonella tribocorum (AB292600), Bartonella elizabethae (AF548030), Bartonella grahamii (DQ334264), Bartonella fuyuanensis (KJ361648), and Bartonella rattimassiliensis (AY515137) (The Y515137) .Bartonella nuoG sequences  obtained from Strebla guajiro and Megistopoda aranea specimens collected from bats of the species Carollia perspicillata and Artibeus obscuros, respectively, in Rio de Janeiro state, were positioned in a single clade separated from the others described, with 92% clade support in BI analysis  compared to the 66.4% (91/137) in Nycteribiidae flies collected from bats in Ghana ; additionally, the detected Rickettsia genotype was shown to be closely related to 'Candidatus Rickettsia andenae' detected in a tick collected from a rodent in Brazil. In addition, further studies on the vector capacity of Streblidae dipterans in the transmission of Bartonella and Rickettsia among bats are needed, since 75% of emerging infectious diseases comprises zoonosis, and most of them are transmitted by arthropod vectors [Finally, it is highlighted that the  vectors . The incn Brazil 9; 96; adBartonella spp. genotypes found in Streblidae flies according to the criteria defining a cut-off point for the Bartonella species based on the sequence identity of five gene regions  and of 16S-23S Intergenic spacer (ITS) previously established by La Scola et al. [Bartonella species circulating in bat ectoparasites, but phylogenetically close to those found in bats, rodents and ruminants.Finally, the results of this study raise an interesting question about the phylogenetic relationship between the a et al. . The lowBartonella and Rickettsia DNA in Streblidae flies collected from bats in Brazil. Future studies to evaluate the role of Streblidae flies as vectors for bacterial zoonotic agents in bats are desirable.To the best of authors’ knowledge, the present work presents the first evidence of


Introduction: Attention-deficit/hyperactivity disorder (ADHD) is the most common childhood psychiatric disorder. This disorder is more prevalent in some chronic diseases.Objectives: To investigate ADHD in children with overactive bladder.Patients and Methods: A number of 92 children with overactive bladder and 92 healthy children without overactive bladder (age range of both groups 5 to 12 years old) were included in this study as case and control groups, respectively. Participants were selected from children who had referred to a pediatric clinic in Arak city, Iran. ADHD types  were diagnosed by Conner’s Parent Rating Scale and Diagnostic and Statistical Manual of Mental Disorders IV-TR (DSM-IV-TR) criteria. Data were analyzed by chi-square and t tests.Results: In both groups, 51 children (27.7%) had ADHD. The prevalence of ADHD in the case group  was significantly higher than the control group  (P = 0.021). Inattentive ADHD was observed in 22 participants (23.9%) of the case group and nine participants of the control group (9.7%) (P = 0.047). Despite this significant difference, three (3.2%) and four (4.3%) children were affected by hyperactive-impulsive ADHD (P = 0.73), and eight (8.6%) and five (5.4%) children were affected by mixed ADHD (P = 0.42) in the case and control groups, respectively.Conclusion: ADHD bladder is significantly more common in children with overactive bladder than healthy children. The observed correlation between ADHD and overactive bladder makes psychological counseling mandatory in children with overactive bladder. Attention-deficit/hyperactivity disorder (ADHD) is more prevalent in some chronic diseases. Aside from the relationship between nocturnal enuresis and ADHD, there may be an association between overactive bladder and ADHD. Hence, this study investigated the prevalence of ADHD in children with overactive bladder.Attention deficit /hyperactivity disorder (ADHD) is the most common psychiatric disorder of childhood. According to the fourth edition of Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria, it has three types: inattentive, hyperactive-impulsive, and mixed .ADHD affects 3% to 5% of all children in the United States . The cauAs the evidence suggests, in addition to the aforementioned disorders, voiding dysfunction and bowel habit disorders can also be associated with ADHD in children -13. In tChildren with an overactive bladder typically exhibit urinary frequency, urgency, and urge incontinence . The blaAlthough the etiology is poorly understood, disturbances in nerves, detrusor smooth muscle and urothelium are all thought to lead to overactive bladder. Overactive bladder is more likely to occur in association with certain risk factors  and a number of other medical conditions such as depression and anxiety . Some auAside from the relationship between nocturnal enuresis and ADHD ,18-20, tThis case-control study was conducted on 184 five to twelve years old children (95 [51.63%] boys and 97 [52.71%] girls) who were referred to a pediatric clinic in Arak city, Iran. They were investigated in two groups based on the inclusion/exclusion criteria; 92 children with overactive bladder as the case group and 92 healthy children without overactive bladder as the control group.Overactive bladder is a type of voiding dysfunction in children. In children with voiding dysfunction signs, kidney and urinary tract ultrasound with or without voiding cystourethrogram is recommended in order to diagnose the type of voiding dysfunction and examine neurogenic bladder and anatomical abnormalities of the bladder . Thus, iOveractive bladder was defined as the presence of urinary frequency, urgency, and urge incontinence in medical history and the presence of dilation of the urethra with distal urethral narrowing and contraction of the bladder neck in voiding cystourethrogram ,16.Clinical interviews were carried out with the children and their parents to study the inclusion/exclusion criteria. The inclusion criteria were; 1) Being five to twelve years old; 2) Having overactive bladder according to its diagnostic criteria. The exclusion criteria were; 1) Having a history of considerable psychiatric disorders, mental retardation or nervous system disorders, 2) Having congenital and chromosomal abnormalities, 3) Having a history of considerable or chronic medical disorders such as seizure, asthma, diabetes, immune deficiency and malignancy, 4) Having a history of sleep apnea or other sleeping disorders which can cause ADHD-like symptoms, 5) Having a strong family history (first-degree relatives) of major psychiatric disorders. All participants and their parents signed an informed consent before participating in this study.Mental retardation was defined as the intelligence quotient of 70 or less . The heaADHD was diagnosed according to DSM-IV criteria and the 48-item Conner›s Parent Rating Scale (CPRS-48). Based on DSM-IV criteria, ADHD has three types: inattentive, hyperactive-impulsive, and mixed ,7,21,22.CPRS was standardized by Conners and colleagues in 1999. It has two versions; 93-item and 48-item. In this research, the 48-item version has been used. This version of Conner’s questionnaire evaluates five factors of conduct, psychosomatic-impulsivity, hyperactivity, anxiety and learning problems scored from 0 (never) to 3 (very high). The score of each article is converted into t scores with the average of 50 and standard deviation of 10. If the t scores are two standard deviations higher than the average, the individual has a problem .After CPRS-48 was completed by the parents and different types of ADHD were identified in the children, they were referred to an expert psychiatrist as the project administrator for the confirmation of ADHD diagnosis by clinical interview based on DSM-IV diagnostic criteria ,7,21,22.The research followed the tenets of the Declaration of Helsinki; informed consent was obtained; and the research was approved by the ethical committee of Arak University of Medical Sciences.t test. Categorical data were expressed as number (percentage) and compared with chi-square test. P values less than 0.05 were considered significant.The collected data were analyzed with statistical package for the social sciences (SPSS) software version 18.0 . Descriptive statistics were used for frequency determination. Numerical data were expressed as mean±standard deviation (SD) and compared with In this nine-month study (from December 2013 to September 2014), 124 children with overactive bladder were examined for having the inclusion and not having the exclusion criteria. Among them, 32 (24.2%) children were excluded and were replaced with other qualified participants. In order to find replacements, 36 other patients with overactive bladder were evaluated. Among the 32 excluded children, 24 (75%), 6 (18.7%) and 2 (6.2%) children were excluded due to their parents’ dissatisfaction to complete of CPRS-48 questionnaire, having a history of mental retardation and having a history of considerable psychiatric disorders (anxiety disorders), respectively. For the control group, 92 out of 108 investigated children were selected. The rest were excluded because of not completing the questionnaires.P=0.017), maternal education (P=0.001), household incomes (P=0004) and type of delivery (P=0 .001) were significantly different in both groups. The average age of children with inattentive, hyperactive-impulsive and mixed ADHD were 8.8±1.81, 8.37±1.59 and 8.2±1.23 years old, respectively, which were not significant (P>0.05). Of the 184 participating children in both groups, 51 (27.7%) children had ADHD, among whom 31 (60.7%), 7 (13.7%) and 13 (25.4%) children were affected by inattentive, hyperactive-impulsive, and mixed types, respectively.The mean age and birth weight of all children were 8.12 ±1.69 years old and 2866.10±617.77 g, respectively. The mother’s age at birth was 25.32±5.64 years old . Mother’P = 0.021). Although the frequency of inattentive ADHD in both groups (22 (23.9%) in the case group versus 9 (9.7%) in the control group; P=0.047) was significant, the difference of hyperactive-impulsive (3 (3.2%) versus 4 (4.3%); P=0.73) and mixed ADHD  was not significant in the two groups (P=0.001), gestational age (P=0.001), marital status of the parents (P=0.001) and type of delivery (P=0.001) and ADHD types (ADHD with 33 cases (35.9%) in the overactive bladder group was significantly higher than the control group with 18 cases (19.6%) . In a retrospective review of patients with ADHD, urinary incontinence and nocturnal enuresis, Crimmins and colleagues (P<0.01). Treatment noncompliance was found in 48% of the ADHD patients compared to 14% of control group (P<0.01).To the authors’ knowledge, no study has been conducted on the relationship between ADHD and overactive bladder in children. However, different studies have been conducted on ADHD and other voiding dysfunctions in children. In 2003 Duel and colleagues  studied lleagues  showed tP<0.001) (In 2009 Elia and colleagues  investigP<0.001) . AccordiP<0.001)  reportedP<0.001)  reportedIn this study, CPRS was the diagnostic tool for ADHD, and this diagnosis was confirmed in the next stage by DSM-IV-TR criteria. According to the evidence, this questionnaire and its different versions have good reliability and validity for the diagnosis of ADHD in children -35. The According to earlier studies, ADHD onset is higher in boys than girls ,36,37. HIn some studies, the prevalence of ADHD in the general population of children in Iran was different from the overall frequency of ADHD types in healthy children of our study (19.6%). In the studies by Hebrani and colleagues  and Abdea) the significant relationship between ADHD and voiding dysfunction  (b) the significant association between nocturnal enuresis and overactive bladder (c) the negative impact of ADHD on treatment response in children with nocturnal enuresis (Considering (nuresis) ,18,27-30 bladder , and (c)enuresis , the relAlthough a significant association was found between ADHD and overactive bladder in our study, in clinical situation the relationship between these two disorders cannot be easily proved based on this result. Furthermore, we could not notice the comorbidity of ADHD cases because most of them were inattentive, not hyperactive-impulsive. Therefore, a patient with overactive bladder should be assessed with a psychological questionnaire or at least some questions be asked to reveal ADHD.ADHD is significantly more common in children with overactive bladder than healthy children. The observed correlation between ADHD and overactive bladder makes psychological counseling mandatory in children with overactive bladder. Since geographical differences seem to be effective in the prevalence of ADHD and no epidemiological study has been done on the prevalence of ADHD in the central part of Iran, further studies are needed. Also, further studies on the relationship between ADHD and overactive bladder are recommended for clinical application of such findings. Since assessing the severity of overactive bladder and its relationship with ADHD in children can be effective in showing the relationship between ADHD and overactive bladder, it is recommended to be considered in future studies.Among the limitations of our study, we may indicate lack of cooperation of some parents to fill in ADHD questionnaire and the psychiatric examination of the child performed by the psychiatrist. Although this criterion led to excluding some eligible children, we attempted to remove such limitation by encouraging the parents for possible usefulness of the study and help them fill in the questionnaire. In addition, lack of assessment the severity of overactive bladder and its relationship with ADHD, was another limitation of our study. Therefore, future studies with consideration of more clinical factors are recommended.PY; participated in the design of the study, performed the data collection, performed the statistical analysis and served as the lead author of the manuscript. MS; participated in the design of the study, statistical analysis and in finalizing the manuscript. MR; participated in the design of the study and statistical analysis. BS; wrote some parts of the draft. All authors read and approved the final manuscript.The authors declare no conflict of interest.Ethical issues  have been completely observed by the authors.This study was financially supported by Arak University of Medical Sciences (Grant # 878).


Attention-deficit/hyperactivity disorder (ADHD) is a debilitating mental health problem hampering the child’s development. The underlying causes include both genetic and environmental factors and may differ between individuals. The efficacy of diet treatments in ADHD was recently evaluated in three reviews, reporting divergent and confusing conclusions based on heterogeneous studies and subjects. To address this inconsistency we conducted a systematic review of meta-analyses of double-blind placebo-controlled trials evaluating the effect of diet interventions (elimination and supplementation) on ADHD.2 was calculated to assess heterogeneity if necessary and additional random effects subgroup meta-regression was conducted if substantial heterogeneity was present.Our literature search resulted in 14 meta-analyses, six of which confined to double-blind placebo-controlled trials applying homogeneous diet interventions, i.e. artificial food color (AFC) elimination, a few-foods diet (FFD) and poly-unsaturated fatty acid (PUFA) supplementation. Effect sizes (ES) and Confidence intervals (CI) of study outcomes were depicted in a forest plot. I2 = 11%) and 0.21  [parent ratings], 0.08  [teacher ratings] and 0.11  [observer ratings]. The FFD ESs were 0.80  [parent ratings] and 0.51  [other ratings], while the PUFA ESs were 0.17  [parent ratings], -0.05  [teacher ratings] and 0.16  [parent and teacher ratings]. Three meta-analyses (two FFD and one AFC) resulted in high I2 without presenting subgroup results. The FFD meta-analyses provided sufficient data to perform subgroup analyses on intervention type, resulting in a decrease of heterogeneity to 0% (diet design) and 37.8% .The AFC ESs were 0.44  to simplify the FFD approach in children with ADHD. Attention-deficit/hyperactivity disorder (ADHD) is a child psychiatric disorder with a worldwide prevalence estimate of 6%  and charThe current multimodal standard of ADHD therapy consists of pharmacological treatment and/or behavioral or psycho-social therapy , 16. PsyUnfortunately, the causal pathways of ADHD are largely unknown; ADHD is a complex disorder and multiple factors may contribute to its etiology . Apart fResearch into the effect of food on ADHD started forty years ago when pediatric allergist Benjamin Feingold hypothesized that both artificial food additives (colorings and flavors) and foods rich in salicylates  might bwas a meta-analysis. The differences between the three previously published reviews and this review are listed in The efficacy of diet treatments in ADHD was recently evaluated in three reviews –42. The This systematic review aims at determining the effect of diet interventions on the behavior of children with ADHD, based on published meta-analyses including double-blind placebo-controlled (DBPC) trials only and differentiating between types of interventions, thus addressing the above-mentioned limitations of previous reviews on ADHD and diet. To our knowledge this is the first review that exclusively focuses on meta-analyses of DBPC trials in children with ADHD, concomitantly segregating between the different types of diet intervention.No pre-specified protocol existed for this review. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed see . In Dece2—as measure of heterogeneity—was calculated if necessary and possible. Substantial heterogeneity  statistics reported in the identified meta-analyses. LMP and KF independently reviewed the meta-analyses, discussing discrepancies until consensus was reached. If different outcome measures were available, a measure was chosen that was most frequently used in the other meta-analyses in order to increase the homogeneity of results. If different ADHD symptom ratings were available, the total symptom score (i.e. inattention and hyperactivity/impulsivity) was included. If results were provided by different raters and reported for each rater separately, we included the ratings accordingly. Effect sizes (ES) and Confidence intervals (CI) of relevant study outcomes were depicted in a forest plot. An inventory was made of reported publication bias and of heterogeneity assessments. I75% high ) decreas75% high  and the 75% high , underli75% high . Consequgrouping , using tThe literature search, an overview of which is provided in The six eligible meta-analyses , 60, 61 2 = 11%) and 0.21  [parent ratings], 0.08  [teacher ratings] and 0.11  [observer ratings]. The FFD ESs were 0.80  [parent ratings] and 0.51  [other ratings], while the PUFA ESs were 0.17  [parent ratings], -0.05  [teacher ratings] and 0.16  [parent and teacher ratings]. The results are depicted in Two meta-analyses evaluating either AFC elimination  or PUFA 2 using the Q statistics or the raw data provided  repg et al.  did not g et al. , 50 are 2 = 61%, which is considerable. Subgroup analytic results were not provided; consequently we performed sub-analyses to assess the effect of subgrouping. However, we first performed a recalculation of this meta-analysis based on the data in the original papers to verify the results, since in one study included by Benton [The FFD meta-analysis by Benton , publishy Benton  mean andy Benton , while iy Benton  the numby Benton . Please Benton included the DBPC parent ratings resulting from four of five RCTs –73. The 2 = 72%) without providing subgroup-analyses. Preparatory to performing sub-analyses we executed a recalculation of this meta-analysis based on the data derived from the original papers , publispers see , since SContrary to Benton , includiIn the study by Egger et al. parent and psychologist ratings were provided . Sonuga-In the study by Schmidt et al., conducted in an inpatient population, teacher ratings and two observer ratings (ward and test observations) were provided . Sonuga-Sonuga-Barke et al.  presenteThe meta-analytic results of our recalculation are provided in In sum, both FFD meta-analyses , 50 provWe additionally evaluated the risk of bias. Commensurate to Sonuga-Barke et al.  we were The results of this systematic review, conducted to synthesize meta-analytic results of diet interventions in children with ADHD in order to determine the effectiveness of diet treatments on ADHD, show that the average ESs of AFC elimination and PUFA supplementation are too small to contribute significantly to ADHD treatment, while the FFD ESs are medium to large, possibly offering novel treatment opportunities. The differences in outcomes between diet types, the quality of the evidence provided in the subgroup meta-analyses, the differences in conclusions between our and previous reviews, and the importance of addressing CIs and heterogeneity is discussed below.The higher FFD ESs might also be the consequence of parental investments necessary to apply the intervention, specifically since the FFD is considered a strenuous intervention , 82, 83.The disparity in ESs might also be explained by the numbers of foods involved. According to Rucklidge & Kaplan it would be unlikely that one supplemented nutrient resolved all vulnerabilities present in a complex disorder like ADHD, thus explicating the small behavioral effects of supplement research that focuses on single nutrients . ComparaFinally, low ESs may be explained by suboptimal intervention conditions. Contrary to most DBPC medication studies, using optimal medication doses because suboptimal doses would result in biased and less optimal outcomes , in mostUnlike the conclusions of previous reviews on ADHD and diet –42, our In addition, the impact of statistical significance in medical research may also be deduced from the PUFA meta-analyses included in this review. The first study reported statistically non-significant results (ES = 0.17), concluding that “Overall, there is little evidence that PUFA supplementation provides any benefit for the symptoms of ADHD in children” . ConversThe confusion concerning statistical significance and clinical relevance in medical research is demonstrated in one of the recent reviews on diet and ADHD , statingSecond, the three recent reviews –42 did nWhen evaluating the clinical relevance of an intervention not only the average effect of an intervention, i.e. the ES, but also the range of the average treatment effect, i.e. the 95% CI, should be considered , taking 2 of 58.6% decreases to 0%  and 16.6%  when subgrouping diet types and raters. This reduction is comparable to the decrease of I2 following subgrouping in medication meta-analyses [Furthermore, in meta-analytic research heterogeneity testing is important to estimate the consistency of study outcomes. Specifically in meta-analyses combining different raters and interventions heterogeneity is to be expected ; a meanianalyses .However, despite a decrease of heterogeneity and the concurrent increase of consistency and reliability of the beneficial effect of a FFD on ADHD in groups of children, subgroup meta-analyses do not provide information of whether an intervention would be beneficial for an individual patient, neither do high ESs and small 95% CI’s, representing the average treatment effect only . For exaThe bias results concerning blinding and attrition, presented in Furthermore, Based on the results depicted in Figs This review has some limitations. First, we limited our search to PubMed and Web of Science, so we may have missed relevant meta-analyses, although we also searched reference lists of all 14 meta-analyses and of recent reviews on the topic. Second, our review was limited to meta-analytic reviews; other reviews were not included. Third, we only included published meta-analyses that focused on DBPC trials investigating the effect of diet on the behavior of children meeting the criteria for ADHD or the equivalent psychiatric standards relevant at the time the study was done. Fourth, it is conceivable that only parents interested in diet treatment will participate in a diet trial, thus limiting the results of this review to children whose parents are receptive to a dietary approach of ADHD.www.isrctn.com and www.ClinicalTrials.gov (search date April 2016) for registered and on-going PUFA, AFC and FFD trials in ADHD  we found 26 registered clinical PUFA trials, 7 of which on-going, illustrating that the interest in PUFA research is substantial. Further PUFA research might 1) address the limitations reported by Gillies et al. [Our systematic review, evaluating the results of all published meta-analyses including DBPC trials investigating the effect of diet interventions on ADHD, shows that the average ESs are -0.05 to 0.17 (PUFA), 0.08 to 0.44 (AFC) and 0.51 to 0.80 (FFD). First, the PUFA ESs are small to negligible, warranting the conclusion that as yet PUFA supplementation should not be advised as a treatment of ADHD, although it should be acknowledged that the individual effect of an intervention may be different from the average group effect. When searching s et al. , 2) incls et al.  and, in s et al. , 3) focus et al. .Second, the AFC ESs, though exceeding the PUFA ESs, are too small to contribute to ADHD treatment. Consequently, provision of additives lists that can be given to parents of children with ADHD  is not wThird, the FFD ESs are medium to large. Combined with the decrease of heterogeneity resulting from subgroup-analyses, these results would justify administration of this intervention in children with ADHD, in line with a previous implementation advice . Howevermay affect ADHD towards the question how food exerts its effect, and in which children. Establishing the biological basis of environmental influences on psychiatric disorders, including research into neuroendocrine mechanisms, is important to define ‘how environments get under the skin’ [When searching for registered and ongoing FFD trials we only found two RCTs, both already published , 82. In he skin’ . In the he skin’ . In facthe skin’ , 118 andhe skin’ , 120. Fuhe skin’ , differehe skin’  and the he skin’ , these f2 and of providing a complete picture of ratings cannot be underestimated in meta-analytic research.Several recommendations ensue from this review. First, we noted heterogeneities in nomenclature of diet and of blinding. Recommendations for unequivocal diet and blinding nomenclatures are given in Based on double-blind placebo-controlled evidence our systematic review shows that the effect sizes of AFC-free diets  and PUFA supplementation  warrant the conclusion that as yet these interventions should not be advised as general ADHD treatment. Conversely, the effect sizes of a few-foods diet are medium to large, justifying implementation of a diagnostic FFD in subgroups of children with ADHD, thus offering innovative treatment opportunities for ADHD. Further FFD research should focus on the mechanism of food in children with ADHD. Finding pathways may result in an easier diagnostic procedure to differentiate between diet responders and nonresponders, in an easier therapeutic approach in children responding to foods and in a personalized disease strategy. The findings of this review are in line with the position of the International Society for Nutritional Psychiatry Research, recently stating that there is ‘emerging and compelling evidence for nutrition as a crucial factor’ in mental disorders, and suggesting that ‘consideration of nutrition should be part of standard practice’ .S1 PRISMA Checklist(PDF)Click here for additional data file.S1 DataPart 1. Effect size calculations in the meta-analyses included in this review see . Part 2.(PDF)Click here for additional data file.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.S1 Fig, except for the teacher data provided by Schmidt et al., which are replaced by the test observation data. Forest plot of FFD effects and homogeneity statistics.(PDF)Click here for additional data file.S2 FigForest plot of FFD effects and homogeneity statistics.(PDF)Click here for additional data file.S1 Text(PDF)Click here for additional data file.S2 Text(PDF)Click here for additional data file.S3 Text(PDF)Click here for additional data file.


Attention-deficit/hyperactivity disorder (ADHD) in adulthood is a serious and frequent psychiatric disorder with the core symptoms inattention, impulsivity, and hyperactivity. The principal aim of this study was to investigate associations between brain morphology, i.e., cortical thickness and volumes of subcortical gray matter, and individual symptom severity in adult ADHD.Surface-based brain morphometry was performed in 35 women and 29 men with ADHD using FreeSurfer. Linear regressions were calculated between cortical thickness and the volumes of subcortical gray matter and the inattention, hyperactivity, and impulsivity subscales of the Conners Adult ADHD Rating Scales (CAARS). Two separate analyses were performed. For the first analysis, age was included as additional regressor. For the second analysis, both age and severity of depression were included as additional regressors. Study participants were recruited between June 2012 and January 2014.F = 26.27, p < 0.001, adjusted R2 = 0.4744]. No significant associations were found between cortical thickness and the scores on CAARS subscales in women. No significant associations were found between the volumes of subcortical gray matter and the scores on CAARS subscales, neither in men nor in women. These results remained stable when severity of depression was included as additional regressor, together with age.Linear regression identified an area in the left occipital cortex of men, covering parts of the middle occipital sulcus and gyrus, in which the score on the CAARS inattention subscale predicted increased mean cortical thickness [Increased cortical thickness in the left occipital cortex may represent a mechanism to compensate for dysfunctional attentional networks in male adult ADHD patients. Attention-deficit/hyperactivity disorder (ADHD) is a serious and frequent psychiatric disorder in children, adolescents and adults with the core symptoms inattention, impulsivity, and hyperactivity . SeveralIn numerous cross-sectional studies, MRI has been used to identify local and global differences in brain structure and function between individuals with ADHD and age-matched healthy participants , 4. In eAs the available studies on brain morphology in ADHD have pointed at gray matter reductions in several different areas, quantitative meta-analyses of voxel-based morphometry data have been performed to identify changes across a larger number of studies and patients. Based on seven original studies, the quantitative meta-analysis of Frodl et al. has found significantly smaller volumes of the right globus pallidus and right putamen in children and adolescents with ADHD compared to healthy individuals, but no cortical differences . In a moIn adult patients with ADHD, subcortical abnormalities were also detected, such as smaller volumes of the right  and leftBy contrast, a large study on 131 adult patients with ADHD and 95 age-matched healthy individuals did not find local changes in gray matter volume between groups . The quaTo summarize, the existing literature on morphological characteristics of pediatric and adult ADHD provides an inconsistent and in parts contradictory picture of the neuroanatomical basis of ADHD. The remarkable differences between morphometric studies of ADHD and the small number of commonalities are probably due to several factors. First, ADHD is a remarkably heterogeneous disorder. Individual patients have distinct combinations of ADHD symptoms and comorbidities, each at an individual level of severity. A small number of studies have taken this heterogeneity into account, reporting significant correlations between disease severity and cortical thickness  or the vThe objective of the present study was to investigate potential associations between the severity of the characteristic symptoms of adult ADHD—inattention, hyperactivity, and impulsivity—and (a) cortical thickness and (b) subcortical gray matter volumes for all patients and for men and women separately. We hypothesized that more severe ADHD symptoms will be associated with decreased cortical thickness and smaller subcortical gray matter volumes in regions involved in the control of the respective brain functions , 14.The data of 64 ADHD patients  were analyzed. The clinical characteristics of all participants are summarized in Table Participants were recruited from the specialized ADHD in adulthood outpatient clinic as well as from the inpatient units of the Department of Psychiatry and Psychotherapy, Medical Center—University of Freiburg, Germany. In addition, the study was announced on the website of the University Hospital, the local ADHD support group and on the website of the German ADHD advocacy organization.Inclusion criteria were as follows: age between 18 and 65 years, diagnosed with ADHD, free from ADHD medication or any psychotherapeutic treatment during study participation, and verbal IQ > 85. Exclusion criteria were as follows: previous therapy with methylphenidate (even during childhood), a comorbid diagnosis of schizophrenia, bipolar disorder type I, antisocial or borderline personality disorder, drug addiction, developmental disorders , acute suicidal ideations, auto-aggressive behavior and neurological disorders, as well as MRI-specific contraindications .The diagnosis of ADHD was established by expert psychiatrists according to DSM-IV criteria  and valiParticipants were evaluated for comorbidity using the German version of the Structured Clinical Interview for DSM-IV (SKID) . The GerT1-weighted anatomical images of the brain were acquired on a 3-T Siemens Magnetom Trio with a 12-channel head coil at the Freiburg Brain Imaging Center using a three-dimensional magnetization-prepared rapid acquisition gradient echo sequence with the following parameters: voxel size 1 mm × 1 mm × 1 mm, field of view = 256 mm, 256 × 256 matrix, 160 sagittal slices, slice thickness 1 mm, phase encoding direction anterior → posterior, repetition time (TR) = 2,200 ms, echo time (TE) = 4.11 ms, non-selective inversion recovery, inversion time (TI) = 1,000 ms, flip angle = 12°, no acceleration, and acquisition time 7:04 min.Cortical reconstruction and volumetric segmentation were performed with the FreeSurfer 5.3 image analysis suite on Mac OS X .3 Image The thickness maps are not restricted to the voxel resolution of the original data  and thus can detect submillimeter differences between groups. Measurements of cortical thickness using FreeSurfer have been validated against histological analysis  and manumris_preproc and mri_surf2surf commands). A linear model was used to calculate the effect of the scores on the CAARS inattention, hyperactivity, and impulsivity subscales on cortical thickness (using FreeSurfer’s mri_glmfit) for all participants and for women and men separately.For group analysis, the cortical thickness maps of all individual participants were resampled onto the fsaverage [Montreal Neurological Institute (MNI) 305] template and spatially smoothed at 10 mm full with at half maximum .Cluster-wise correction for multiple comparisons was performed by running a Monte Carlo simulation  and in women and men separately. Women had significantly higher scores on the inattention (p < 0.01) and impulsivity subscales (p < 0.01) than men. The most frequent comorbidities were depression and anxiety disorder. Comorbid depression was diagnosed in 23 of 35 women (65.7%) and in 14 of 29 men (48.3%). The BDI-II score was 19 or higher (indicating at least moderate depression) in 27 of 64 patients (42.2%).Table Education and employment status were similar in women and men with the majority of patients currently in an education program or regularly employed: 28 of 35 women (80%) and 27 of 29 men (93%). There was a significant difference in personal monthly income with more women in the lower income group. This difference has to be interpreted with caution because 11 patients (17.2%) chose not to answer this question.F = 26.27, p < 0.001, adjusted R2 = 0.4744, Figure x = −35.7, y = −85.2, and z = −1.4; corrected p = 0.01375). For visualization purposes, the pial surface was inflated in Figures Using linear regression, we found an area in the left occipital cortex of men, covering parts of the middle occipital gyrus and sulcus, in which higher scores on the CAARS inattention subscale predicted increased mean cortical thickness [F,27 = 26.F,27 = 26.For Figure Adding the BDI-II depression scores as additional regressor, together with age, to the regression models did not change the overall results. The left occipital area in men remained significant. Additional significant clusters did not emerge.p values were a positive relationship between the volume of the left pallidum and the CAARS inattention score and a negative relationship between the volume of the left hippocampus and the CAARS impulsivity score, both in women. After Bonferroni correction for multiple comparisons, these associations were not significant anymore (corrected p < 0.05/108 = 0.0004).Significant associations between subcortical gray matter volumes and CAARS scores were found in linear regression models with age as additional regressor . Among the associations with highest Again, adding the BDI-II depression scores as additional regressor, together with age, to the regression models did not change the overall results . After Bonferroni correction for multiple comparisons, no significant associations between CAARS scores and subcortical gray matter volume remained.Linear regression did not reveal a significant association between severity of depression, as represented by BDI-II scores, and cortical thickness in all patients. Similarly, no significant association was found between severity of depression and volumes of subcortical gray matter.No significant associations were found between CAARS scores and age using linear regression Figure . Moreoven = 64). Table Figure n = 64). After Bonferroni correction for multiple comparisons, the volumes of left and right putamen, left and right pallidum, left and right accumbens, and right caudate were significantly associated with age at a corrected p < 0.05/12 = 0.004. The volumes of left and right hippocampus as well as left and right amygdala were not associated with age, even at an uncorrected p < 0.05.Table Cortical thickness was not significantly different between men and women when using age and total intracranial volume as additional regressors, after cluster-wise correction for multiple comparisons.Moreover, the volumes of subcortical gray matter were not significantly different between men and women when using age and total intracranial volume as additional regressors, after Bonferroni correction.The present study performed surface-based morphometry in a group of 64 adult patients with ADHD, 35 women and 29 men, who have never been treated with methylphenidate. In men, but not in women, linear regression identified an area covering parts of the left middle occipital sulcus and gyrus, in which the individual score on the CAARS inattention subscale predicted increased cortical thickness: men suffering from more severe inattention had higher mean cortical thickness in this area Figure . No furtEven though frontostriatal networks have often been reported with respect to functional and structural abnormalities in ADHD, there is increasing evidence for structural and functional changes in occipital regions  with theWe therefore suggest that the left middle occipital gyrus represents an important node in attentional networks and speculate that increased cortical thickness in the left middle occipital gyrus in adult ADHD patients may represent a mechanism to compensate for dysfunctional attentional networks , most liOur understanding of anatomical and functional brain differences between male and female patients with ADHD is still in its infancy. Only a small number of studies have covered this topic so far, most of them with small sample sizes. At present, there is no well-founded explanation why cortical thickness in the left occipital cortex is associated with inattention in the men, but not in the women of our sample.In our sample of adult ADHD patients, no cortical or subcortical regions were identified in which higher scores on the CAARS subscale were associated with decreased cortical thickness or subcortical gray matter volume. Thus, we did not find support for our initial hypothesis, predicting cortical thinning in patients with more severe ADHD core symptoms. Our results provide additional evidence for the notion that morphometric alterations seen in children and adolescents with ADHD may diminish or even disappear during the transition into adulthood , 55.Recent studies have shown increased cortical thickness in patients with first-episode depression (but without ADHD), primarily in the frontal cortex and cingulate gyrus , 57. LarDepression is the most frequent comorbidity in adult ADHD , 63. AduIn another exploratory analysis of our cross-sectional sample, we found that age is associated with widespread cortical thinning and volume reduction of the basal ganglia Figure  and 3, sIn healthy adults, the morphology of female and male brains differs in various respects, mainly in areas related to the limbic and language systems . SpecifiIn boys with ADHD, gray matter volumes of the ventral anterior cingulate cortex were decreased compared to healthy boys and increased in girls with ADHD compared to healthy girls . In men,In our exploratory analysis, we did not find sex-related differences in brain morphometry. This analysis needs to be regarded as preliminary, because our patients were not recruited with the aim to compare brain structure between the sexes. In the recruitment process, there was no matching of male and female participants. As a result, women in our sample were significantly older and had significantly higher scores on the inattention and impulsivity subscales Table . Future Our investigation has several limitations. First, in morphometric research, in particular, in patient populations, sample size is of major concern. In the recent meta-analysis by Norman et al., 27 voxel-based morphometry studies were included with a mean ADHD sample size of 34 patients (minimum: 12 patients, maximum: 131 patients; see Table Second, with a mean age of 42 years in women and 38 years in men, our sample is older than the patient samples included in the meta-analysis by Norman et al. , 55.Third, we cannot compare our results to a control group of healthy individuals without ADHD. The randomized controlled trial, for which our structural brain images were acquired, contained a treatment arm and an active control arm, both of ADHD patients. Therefore, we did not recruit a healthy control group.Increased cortical thickness in the left occipital cortex may represent a mechanism to compensate for dysfunctional frontoparietal attentional networks in male adult ADHD patients. Future studies on ADHD brain structure and function should explore potential compensatory networks that might develop in adults with ADHD.All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of the Faculty of Medicine, University of Freiburg, Germany.AP conceptualized, designed and supervised the study. MK, EH, SM, and BF were involved in the design of the study and collected the data. PS analyzed the data, prepared the figures, and wrote the manuscript. All the authors interpreted the data, provided important feedback, and revised the manuscript.AP has served on advisory boards, given lectures, performed phase 5 studies, or received travel grants within the last 3 years from Eli Lilly and Co., Janssen-Cilag, Lundbeck, MEDICE Arzneimittel Pütter GmbH and Co. KG, Novartis, Servier, and Shire; and has authored books and articles on psychotherapy published by Elsevier, Hogrefe, Schattauer, Kohlhammer, Karger, Schattauer, Springer, and Oxford Press. HM received speaker’s compensation from LivaNova PLC. AL declares that she received travel grants within the last year from MEDICE Arzneimittel Pütter GmbH and Co. KG and has authored articles on psychotherapy published by Elsevier and Springer.


Attention-deficit/hyperactivity disorder (ADHD) is a complex condition that interferes with development and/or functioning. Our objective is to investigate the potential association between ADHD and inflammation.We conducted a systematic review of human studies measuring inflammatory markers in ADHD. The studies were identified by searching PUBMED, MEDLINE, EMBASE, PSYCHINFO, COCHRANE, and SCOPUS databases for peer-reviewed journals published until September 2016. We included cytokine gene expression and protein measured. Fourteen papers met the inclusion criteria.Seven studies evaluated the association of cytokine gene polymorphisms in ADHD, and six studies measured cytokines levels in blood. One study analyzed the presence of cytokines in cerebrospinal fluid in patients with ADHD. Altogether, these studies indicate a possible role of inflammation in ADHD pathogenesis, despite the significant heterogeneity and contradictory results.Evidence points to the association of ADHD with inflammatory processes, but more studies are warranted. Attention-deficit/hyperactivity disorder (ADHD) is a mental condition characterized by a persistent pattern of inattention and/or hyperactivity-impulsivity. ADHD symptoms must start before the age of 12 and be observed in more than one setting. ADHD can occur in 5% of children and 2.5% of adults, and is associated with significant impairment of social, academic, and occupational functioning across the lifespan  of this condition. Due to the potential importance of the aforementioned association, we conducted a systematic review on the role of inflammation in ADHD. We will divide this review in genetic factors, and peripheral protein levels.A systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. A literature search was conducted in PUBMED, MEDLINE, EMBASE, PSYCHINFO, COCHRANE, and SCOPUS databases using the keywords “ADHD OR attention deficit hyperactive disorder” AND cytokine OR interferon OR interleukin OR inflammation. The following limits were applied: published from 1946 to September 2016, humans, original articles, and English, Portuguese, and Spanish languages. Studies evaluating cytokine gene expression, protein production, or genetic polymorphisms were also included, provided they also met the previously mentioned inclusion criteria. Two independent reviewers conducted the search. The articles and their relevant reference citations were additionally reviewed.in vitro studies, irrelevant/unrelated studies, or duplicated studies. A total of 14 articles satisfied the inclusion and exclusion criteria and a summary of these studies is shown in Table Literature search identified 76 articles in PubMed, 52 articles in Medline, 112 articles in EMBASE, 13 articles in PsycInfo, 80 articles in Scopus, and no articles in Cochrane. Manual review of all these references resulted in exclusion of those articles which were review articles, ADHD is a highly heritable disorder and numerous molecular-genetic studies have been performed. The participation of genetic factors (heritability) in ADHD is high, around 70–78% . Our lit2 = 4.07, P = 0.04) and decreased transmission of the 2-repeat allele  in children with ADHD. The IL-1Ra 4-repeat allele was associated with a significantly increased risk for ADHD , whereas the IL-1Ra 2-repeat allele was associated with a significantly decreased risk for ADHD . However, a larger study involving 178 ADHD families could not replicate this finding and did not show significant association between the IL-1Ra polymorphism with ADHD  gene in 77 nuclear ADHD families (86 children with ADHD and their parents) . They reP) for assessment of attention, respectively  genes in 119 children with ADHD and 153 healthy controls . A statiectively . IL-6 AAively  (P = 0.002)  and found that two SNPs at the IL-16 gene were associated with inattentive ADHD subtype . They also reported that SNPs at the genes Interleukin-16 (IL-16) and S100B moderated the association between birthweight percentile range and hyperactive-impulsive symptom severity in children with ADHD  and child ADHD   .Six studies reported measurements of peripheral cytokines in patients with ADHD , 18–20. In 2010, Oades et al. reported the serum measurements of IL-1β, IL-2, IL-6, TNF-α, interferon-gamma (IFN-γ), IL-10, IL-13, and IL-16 in 21 children with ADHD who were treatment-naïve (mean age: 8.9 ± 1.4 years)  and continuous performance task measures . The authors reported statistically significant correlations between cytokines levels and ADHD symptoms . IncreasOades et al. also conducted a very original study assessing the relationship between outcomes of inflammatory markers in children and adolescents with ADHD, and pregnancy/perinatal features . IncreasIn another study involving 103 children (age range 6–12 years) with ADHD, a significant reduction was observed in the levels of C-reactive protein and IL-6 after 8 weeks of supplementation therapy with omega-3 fatty acids. The decrease in cytokine levels was correlated with significant improvement in the Conners’ Abbreviated Questionnaires scores .O’Shea et al. measured 25 inflammation-related serum proteins on postnatal days 1, 7, and 14 in 600 premature infants, born before 28 weeks of gestation . The invA more recent study provided further supports that the cytokine mediated inflammation is likely to be an important pathogenic factor in ADHD . Donfrann = 42)  in patients with ADHD (n = 42) . It was n = 42) . This stThe current systematic review relied on data from 14 manuscripts and shows variable results regarding the association between inflammation and ADHD. Seven studies evaluated the possible association of cytokine gene polymorphisms in ADHD, six studies measured cytokines levels in blood and one study analyzed cytokines in CSF of patients with ADHD. Despite their significant heterogeneity, these studies indicate a possible role for inflammation in ADHD pathogenesis. It is worth mentioning that the heterogeneity of the molecules assessed in these different studies prevented us to perform meta-analyses.Among the studies that evaluate immune-related genes, the results point to an association between increased risk for ADHD and enhanced/impaired inflammatory response. However, different genes were investigated, and the issue of results replication in psychiatric genetics was also noticed here. Segman et al. found that IL-1Ra 4-repeat allele was associated with a significantly increased risk for ADHD . This reThe results on peripheral cytokines levels were also complex, but overall they suggest a low-grade inflammation in patients with ADHD. Interestingly, Oades et al. reported lower levels of IFN-γ and IL-13 in medicated patients with ADHD  when comHigh levels of pro-inflammatory cytokines can influence synaptic plasticity and neurogenesis . AccordiThere are several limitations in the literature addressing the role of inflammation in ADHD, including heterogeneous and small samples, lack of standardization of the biomarkers assessed, preventing comparisons among the studies. Even when the same molecule (IL-1Ra) was investigated by different studies, the results were not concordant. Accordingly, there is still much work to be done. Future studies must evaluate greater samples, including patients in different stages and across the spectrum of severity of the illness, and follow them prospectively with a representative panel of immune/inflammatory markers. This approach may determine a subgroup of patients in which inflammatory mechanisms play a meaningful pathophysiological role and, therefore, is more susceptible to immune-based strategies. In this context, an intriguing report needs to be replicated, i.e., high frequency of anti-Yo antibodies, an autoantibody known to impair cerebellar function . RegardiIn conclusion, over the past years, it has become recognized that inflammation may represent a common pathophysiological mechanism of major psychiatric disorders. Evidence also points to the association of ADHD with inflammatory processes. A better characterization of the involvement of inflammatory mechanisms in ADHD is warranted, and may reveal important aspects of the pathogenesis and psychopathology of ADHD, with the potential to effectively advance its treatment.DA and GC contributed to perform the search, data collection, screening, and drafting the article. GZ helped writing the manuscript and CZ contributed writing and reviewing the manuscript. AT participated in the study design and the review of the manuscript. All authors have read and approved this final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.