Endpoints compared baseline to posttreatment evaluations for allergic rhinitis and ADHD scores. Serum nerve growth factor levels were measured using ELISA. For allergy endpoints, combination therapy produced results superior to individual therapy. For ADHD, similar scores were achieved for individual therapy; however, combination therapy resulted in improved scores. Nerve growth factor levels were downregulated following this trend. We conclude that ADHD and allergic rhinitis may have common mechanism and represent a comorbid condition that links the nervous system to the immune system. Further studies are needed.The association between ADHD and allergy remains controversial. Our previous findings suggest that nerve growth factor may link the nervous and immune systems. The primary objective of this study was to determine if a combination of cetirizine + methylphenidate is effective in children with comorbid ADHD and allergic rhinitis. We also examined the role of nerve growth factor in these comorbidities. Our randomized, double-blind, placebo-controlled, crossover study enrolled 38 children diagnosed with comorbid ADHD and allergy using cetirizine ( Allergic rhinitis affects up to 30% of all children. Some medications currently being used to treat this disorder, which significantly impacts learning, school performance, and attendance –3, may aAttention disorders are among the most common chronic childhood and adolescent behavioral problems . While tThe role the immune system plays in allergic inflammation has been carefully examined . PreviouKeeping in mind that ADHD is a complex, multifaceted illness and that it is critical that we understand the role allergic response plays in the etiology of the subset of children with both diseases, we devised our study to (1) promote an understanding of the synergistic effects of treatment with both antihistamines and stimulants, (2) provide insight into the pathophysiology of this illness, and (3) determine the role NGF may play in children with both ADHD and allergic rhinitis.Ours was a randomized, 3-treatment group, double-blind, placebo-controlled, crossover study of 38 children with allergic rhinitis and ADHD. Approved by the local IRB, it was conducted in Colorado over a 4-year period during the tree and grass allergy seasons. We chose this period of time in order to capture results during the allergy season over an extended period of time. Subject inclusion criteria included boys or girls aged 8 to 18 years with a diagnosis and history of seasonal allergic rhinitis to a prevalent allergen , which required pharmacologic treatment at the time of enrollment and for the previous 2 years  and a diagnosis of ADHD and treatment regimen with stimulant medication.After obtaining written informed consent from a parent, legal guardian, or subjects of legal age, participants were randomized and screened using the Multidimensional Assessment of Anxiety in Children (MASC) ; the Chin = 12); methylphenidate, 20 mg if <65 kg and 40 mg if ≥65 kg po qam for 2 weeks (n = 12); or cetirizine 10 mg po qam + methylphenidate, 20 mg if <65 kg and 40 mg if ≥65 kg po qam for 2 weeks (n = 12). All subjects crossed over to placebo for a period of 2 weeks during each treatment period.Qualified subjects were then enrolled into 1 of 2 order conditions and 1 of 3 treatment arms: cetirizine, 10 mg po qam for 2 weeks ; the Total Symptom Severity Complex (TSSC); and the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) , 24 for NGF levels in serum were measured using a 2-site immune-enzymatic assay (ELISA). NFG was detected in sandwich ELISAs according to the manufacturer's instructions . All assays were performed on F-bottom 96-well plates . Tertiary antibodies were conjugated to horseradish peroxidase. Wells were developed with tetramethylbenzidine and measured at 450 nm. Neurotrophin content was quantified against a standard curve.t-tests were used to evaluate differences between treatment and placebo. Differences in change scores across the 3 treatment groups were compared (MANOVA). Additional factors, including gender, age, methylphenidate dose, depression (CDI), and anxiety (MASC), were assessed to determine any influence they may have had on scoring changes.Baseline scores and demographics for each of the 3 treatment groups were compared using MANOVA tests, which are best suited to analyses involving several variables. Within each group, mean scores for outcome variables were calculated for active treatment and placebo interventions. Paired Thirty-eight individuals  completed the study. This represented the normal gender distribution seen in ADHD patients. Endpoints measured allergy and ADHD-related events.For seasonal allergic-related symptoms, the 2-drug combination proved to be superior to either drug alone in reducing the TSSC . Scores When compared to cetirizine, methylphenidate had a superior effect on general scores and showed greater reduction of general symptoms . The drug combination decreased general symptoms from 9.1 to 7.2.The same phenomena were observed in nasal and eye symptoms. For example, for nasal symptoms, methylphenidate reduced scores from 9.2 to 6.1 versus the combination of drugs (8.1 to 6.0). For eye symptoms, combination treatment reduced scores from 7.8 to 5.2, while methylphenidate alone demonstrated a 7.8 to 3.2 reduction.Both methylphenidate and cetirizine displayed the same positive effect on emotional scores, showing reductions from 6.2 to 3.2 and 4.1, respectively.Generally, when a slow reaction time occurs with elevated omission (missing) and commission  errors, there is evidence of inattention.The omission error rate increased when subjects received cetirizine and methylphenidate individually. However, the combination drug group elicited a significant decrease in the error rate compared with placebo.Cetirizine lowered the commission rate from 27 to 18 and methylphenidate reduced it from 17 to 15. No effect was noted in the combination group.Hit reaction time (HRT) is defined as the mean response time (in milliseconds) for all target responses over all 6 time blocks. High HRT scores reflect slow response times. The combination treatment regimen had the most significant effect on HRT scores.The CRS-R, in the hyperactivity and ADHD index scores, was reduced from 70% (placebo group) to 62% (methylphenidate/cetirizine group). In contrast, there was no improvement in scores when the drugs were administered individually.Regarding inattention, the combination group also displayed the most improvement, with a reduction from 69% to 59%; in the individual drug groups, the change was minor (70% to 68%). This trend continued with the oppositional scores: there was a reduction of 64% to 59% in the combination group, while the groups who received cetirizine or methylphenidate alone experienced only a 61% to 60% change, respectively.t-scores, reducing the totals from 78 to 72 and 48 to 43 points, respectively. When evaluating inattention and oppositional t-scores, we observed the same trend; in particular, methylphenidate and cetirizine produced almost identical results in improving ADHD endpoints. The drug combination produced results superior to those derived from using the drugs individually.Methylphenidate and cetirizine had almost identical effects on A large body of evidence shows that nerve growth factor (NGF) exerts biological activity on the immune system, thereby influencing allergic diseases and asthma –31. In oWhen NGF serum levels were measured in both the treatment and placebo phases of this study, a significant reduction was noted in the treatment group versus the placebo group. In the methylphenidate group, the reduction in serum NGF levels was 21 ± 5.1 ng/mL; in the cetirizine group, it was 19.5 ± 4.1 ng/mL. In the combined treatment, the greatest reduction was noted at 56.4 ± 8.9 ng/mL .Overall, for the majority of measures for allergic rhinitis, ADHD, and NGF analysis, the methylphenidate and cetirizine combination produced a greater impact than did either drug individually or placebo.A number of studies have suggested a link between allergies and ADHD –38. Two In this study, we demonstrated an improvement in ADHD scores by using drugs known to regulate allergic inflammation ; the benefit of stimulant medication on allergic inflammation ; and the synergistic effect of methylphenidate and cetirizine on both allergic and neurological symptoms.Based on these results, we suggest that there is some overlap in the mechanism of action of allergy and ADHD in patients with a comorbid diagnosis. Moreover, by using a synergistic approach, the individual effect of each drug on allergic or neurological endpoints is enhanced.This study also raised questions and concerns for which there are currently no obvious answers. For example, why did not we get the expected results in reduction of TSSC with antihistamines in the comorbid population? Why did stimulant drugs have the same beneficial effect as antihistamines in reducing TSSC scores? And lastly, why did the combination drugs have a superior effect?In regard to the first point, patients diagnosed with ADHD have an unfavorable perception of life and, thus, antihistamine therapy may not be sufficient to control their TSSC scores. Additionally, in patients with specific comorbid disease, different cetirizine dosages may be required to achieve full control of allergy symptoms.Regarding the second question, over the years we have observed that stimulants, specifically methylphenidate, have an antihistamine effect . This antihistaminic effect may explain some of the improvements in TSSC scores in the comorbid population.In response to the third question, antihistamines, specifically cetirizine, may have an anti-inflammatory effect , 40. ThiThe linkage between allergic and mental disorders may have a bidirectional mechanism: allergic triggers induce either a neuroimmune inflammation with a direct effect on the CNS or CNS stimuli  . As we hThe mechanisms by which NGF may be involved in allergic disease or in comorbid disease of allergy and ADHD are unknown, but a small number of theories have been postulated. One theory is that, upon mast activation and differentiation, NGF release is increased. The differentiation of human mast cell subtypes that could perpetuate human allergic reactions is dependent on NGF. NGF is increased in biologic fluids of allergy/immune-related diseases and has been evaluated as a TH2 cytokine with a modulator role in allergic inflammation and tissue remodeling. In patients with allergic bronchial asthma, for example, elevated levels of neurotrophins have been reported. In a time course study of bronchoalveolar lavage fluid, levels of NGF correlated with the inflammatory response. It was shown that NGF, specifically, enhances inflammation in allergic early-phase response .The role of NGF in allergic-related diseases is unclear . AnotherAs part of neuroimmune healing, we need an intact apoptosis process. NGF belongs to the super family of CD40, which plays a crucial role in this process. Any failure in NGF signaling or regulation may lead to an abnormal apoptosis process and, as a result, may cause persistent inflammation. In turn, this persistent inflammation may be the cause of neurological manifestation of ADHD.Our findings support the hypothesis that (1) atopy may, in some cases, contribute to the pathogenesis of ADHD; (2) NGF plays a role in the pathogenesis of comorbid diseases; and (3) neurological triggers  may trigger the comorbid condition.In this study, the role of NGF was demonstrated by the modulating effect of the antihistamines and stimulants on NGF levels in patients with the comorbid diseases. NGF suppression had a direct correlation to clinical improvement.In conclusion, our research clearly demonstrated that the combination of an antihistamine (cetirizine) and a stimulant (methylphenidate) produced superior results when treating children with comorbid allergic rhinitis and ADHD, enhancing the efficacy of treatment for both allergic and ADHD symptoms. Our findings also suggest that (1) in patients with comorbid disease the treatment approach should include antihistamines and (2) a synergistic effect may be achieved by using both drugs, thus making it possible to reduce the dosage of the stimulant. We also discovered that NGF may play an integral role in these processes. NGF measurements followed the trends of allergic symptoms and ADHD and could possibly be used as a marker for measuring the severity of either condition. Further studies in larger populations are needed.


Periclimenes yucatanicus forms symbioses with sea anemones that may serve as cleaning stations for reef fishes. The status of this species as a cleaner is ambiguous: only a single in situ cleaning interaction has been reported, and in the only test of its efficacy as a cleaner, it did not effectively reduce parasite loads from surgeonfish. It has subsequently been hypothesized by other authors to be a cleaner mimic. We conduct a comparative investigation of cleaning behaviour between P. yucatanicus and the ecologically similar, closely related, dedicated cleaner shrimp Ancylomenes pedersoni in Curacao, Netherlands Antilles. We provide the first detailed field observations on cleaning behaviour for P. yucatanicus and test multiple behavioural expectations surrounding mimicry in cleaning symbioses. We found that P. yucatanicus regularly signals its availability to clean, client fishes visit regularly and the shrimp does engage in true symbiotic cleaning interactions, but these are brief and our video reflects a species that appears hesitant to engage posing clients. In comparison to A. pedersoni, P. yucatanicus stations had significantly fewer total visits and cleans, and 50% of all cleaning interactions at P. yucatanicus stations were shorter than 10 s in total duration. Our behavioural observations confirm that P. yucatanicus is a true cleaner shrimp; we reject the hypothesis of mimicry. However, investigation is needed to confirm whether this species is a dedicated or facultative cleaner. We hypothesize that P. yucatanicus has a specialized ecological role as a cleaner species, compared to A. pedersoni.Cleaner shrimps are ecologically important members of coral reef communities, but for many species, cleaner status , clientele and ecological role remain unverified or described. On Caribbean coral reefs, the spotted ‘cleaner’ shrimp  Howe [et al. ,3,11,12.et al. [Periclimenes  has over 175 described species, all of which have been referred to as cleaner shrimps [Ancylomenes [et al. [Periclimenes (P. yucatanicus) has actually been observed engaging in a cleaning interaction [P. yucatanicus as a true symbiotic cleaner shrimp is weak [Periclimenes are dedicated or facultative cleaners.A total of 208 fish species and 51 shrimp species are classified as cleaners . Cleaneret al. ). Furtheet al. . The gen shrimps . Howeverylomenes , Vaughan [et al.  note thaeraction . Interes is weak , and it  is weak ,16, poss is weak . Thus, tin situ cleaning to conduct the first field-based assessment of the cleaning behaviour and clientele of the spotted cleaner shrimp P. yucatanicus in Curacao, Netherlands Antilles. Additionally, we test a series of behavioural expectations  surrounding mimicry in cleaning symbioses for P. yucatanicus to determine if previous speculation  surr surrin sni e.g. ,24)..in situ P. yucatanicus is a true cleaner is limited to a single in situ observation by Spotte et al. [P. yucatanicus, and in this mesocosm experiment [et al. [A. pedersoni, and the signalling behaviour, visitation rate and interaction lengths across a number of client species are well characterized [P. yucatanicus, despite both shrimp being sea anemone symbionts on Caribbean coral reefs, having similar patterns of host use , co-, co-P. yse  and the fangtooth blenny . To datic; e.g. ,23,38,39ic; e.g. ,22. No m2.2.1.in situ client visitation rate and clean length and provide observations of cleaner signalling.Accurately delineating the status of a species as a cleaner can be challenging. Standardized methods revolve around in-depth field observations to assess the frequency at which a prospective cleaner species is visited  , the lenP. yucatanicus and A. pedersoni were conducted over 10 days between 24 May and 2 June 2015 on the same fringing reef adjacent to the Caribbean Marine Biological (CARMABI) Research Institute in Curacao, Netherlands Antilles . The CARMABI house reef is approximately 50 m from shore; the reef crest is shallow (4–6 m) and quickly slopes to depths greater than 25 m. No major ecological data were quantified, but observationally the CARMABI reef is characterized by low scleractinian coral cover  and large, crustacean-hosting sea anemones are common. Both P. yucatanicus and A. pedersoni were common at our study site when we conducted the trials and were readily discernible from one another through in-life colour patterns; elsewhere, P. yucatanicus is typically less abundant than A. pedersoni [Comparative behavioural observations for both edersoni . As on o2; after Huebner et al. [P. yucatanicus (n = 30) and A. pedersoni (n = 15) over an approximately 80 × 20 m area of reef (approx. 1600 m2). All anemones used in this study were on reef crest and shallow fore reef habitats between 4 and 8 m depth. While we would have ideally controlled for anemone host, that was not feasible given the patterns of host use at this site. All P. yucatanicus hosted with their preferred host, the giant Caribbean anemone Condylactis gigantea [A. pedersoni stations were found in association with the corkscrew anemone Bartholomea annulata (one A. pedersoni was hosted by C. gigantea). While intraspecific group sizes generally do vary [P. yucatanicus stations at our study site hosted only one shrimp. Shrimp group sizes for A. pedersoni stations varied between one and six shrimp, but only three of these hosted more than a single shrimp.Before conducting behavioural observations, we measured (tentacle crown surface area (TCSA), in cmr et al. ), mappedgigantea , while a do vary ,32,36, aet al. [n = 23 cleaning stations for P. yucatanicus and n = 12 stations for A. pedersoni. Cameras were mounted to lead dive weights and placed approximately 1 m from each anemone station. An even representation of video was recorded continuously at each station  for the duration of battery life (approx. 100–200 min), with only one station recording less than 100 min of video. The duration of each recording did not significantly correlate with client visitation at either P. yucatanicus  or A. pedersoni  cleaning stations. Cameras were typically deployed at 8.00, but we did not control for time of day because Titus et al. [A. pedersoni. We did not video anemones lacking cleaner shrimp to control for whether anemone species differentially attract client fishes.Each day, we deployed GoPro Hero3 video cameras at individual stations we had not previously recorded video from and exited the water following Titus et al. ,30, to rs et al.  showed t−1), with a visit defined as a pause, or pose, directly in front of the cleaning station that lasted at least 2–3 s regardless of whether a cleaning bout immediately followed [−1) and the length of the interaction (s), with a clean being defined as physical contact between the shrimp and posing client reef fish [et al. [Videos were downloaded and cleaning interactions analysed after Huebner & Chadwick ,29. We qfollowed ,46. (ii)eef fish ,28,29. .  [et al. .−1, clean rate h−1, flinch rate min−1 and total time spent cleaning) were analysed using non-parametric Mann–Whitney U-tests in SPSS v.23 [Our data did not conform to a normal distribution. Comparative cleaning behaviours  and visual protective mimicry  are the two most plausible types of mimicry in a cleaner–mimic system. Other types of protective mimicry, such as Batesian, and Müllerian mimicry or reproductive mimicry seem less plausible because true cleaner shrimps are unlikely to be venomous or unpalatable models, or to directly use the cleaner–client relationship to enhance reproduction. Given these assumptions, we established the following expectations for how behavioural interactions between mimetic and client species should proceed under both aggressive and protective mimicry scenarios, recognizing that these may be overly simplified and not mutually exclusive alternatives. (i) Aggressive mimicry, defined here as a species with increased foraging success due to mimetic coloration. Aggressive mimics cheat posing clients and remove live tissue instead of ectoparasites [To test the hypothesis that arasites –20. Intearasites . Under tOne caveat to our behavioural expectations of an aggressive mimic is that if client fishes do not rapidly terminate the cleaning interaction following an immediate cheating event, and instead continue to pose and allow repeated cheating events, it may not be possible to distinguish between periodic cheating from a true cleaner species versus cheating from a cleaner mimic through behavioural observations alone. Under this scenario, additional types of data  would be needed.3.Periclimenes yucatanicus was slightly more abundant at our study site (1 shrimp/53 m2) than A. pedersoni (1 shrimp/62 m2), and their host anemone C. gigantea was significantly larger  than the primary anemone host of A. pedersoni, B. annulata . In total, we recorded 83 h of video at P. yucatanicus (52.48 h) and A. pedersoni (30.98 h) cleaning stations. We observed more than 300 visits and 80 cleans at both types of cleaner stations (−1) and cleaning rate (h−1) were significantly greater at stations hosting A. pedersoni , but there was a significant positive correlation between anemone host size and visitation rate to A. pedersoni cleaning stations . Additionally, we recovered a significant positive correlation between cleaner group size and visitation rate in A. pedersoni . Cleaning interactions were recorded at fewer than half (7/23) of the stations containing P. yucatanicus and at all but one (11/12) station hosting A. pedersoni . Interaction (clean) length and cumulative time (s) spent cleaning were also significantly greater at stations hosting A. pedersoni . Of the 19 total cleans observed at stations hosting P. yucatanicus, 50% were shorter than 10 s in total duration.stations . VisitatP. yucatanicus and A. pedersoni were observed cheating client reef fishes. We observed cheating in 16 of 19 interactions at P. yucatanicus stations and 49 of 66 interactions at A. pedersoni stations. At both types of cleaning stations where cleans were observed (n = 7 for P. yucatanicus and n = 11 for A. pedersoni), there was no significant difference in cheating frequency per cleaning interaction , or in the frequency of cheating per minute during cleaning interactions . At P. yucatanicus stations, 7 of 16 flinches occurred in the last 5 s of the interaction, suggesting that the cheating may have terminated the cleaning interaction. At A. pedersoni stations, only 9 of 49 flinches occurred during the last 5 s of the interaction. The proportion of flinches that appeared to terminate cleans at P. yucatanicus stations was not significantly greater than at A. pedersoni stations, but only marginally so .Both P. yucatanicus and A. pedersoni stations were similar , this species engages in true symbiotic cleaning interactions with reef fishes. Our video observations demonstrate that P. yucatanicus wave their long white antennae, signalling to client reef fishes that they are available to clean . This behavioural signal is the same signal used by A. pedersoni, is akin to other overt signalling behaviours that true cleaner shrimp use to engage client reef fish , one to dusk . It is uat night ,56. To dedersoni .A. pedersoni and cleaner gobies in the Caribbean [A. pedersoni and P. yucatanicus. Nine families of fish had members who visited both cleaner species at our study site in Curacao, in contrast to more than 20 families whose members have been documented visiting A. pedersoni stations throughout its range [P. yucatanicus stations, cleaning rates observed in A. pedersoni largely mirror those recovered in Honduras [A. pedersoni appears to be independent of region, reef site and local reef fish diversity, giving us confidence that our video data set accurately captures the scope of the usage of cleaner shrimp stations in Curacao. A follow-up study in a higher diversity setting would illuminate whether any client families specialize on specific shrimp species, but to date no client families have been documented as cleaner-shrimp specialists. If P. yucatanicus service the same community of reef fishes as A. pedersoni and cleaner gobies, as our data suggest they may, understanding how these (apparently) ecologically redundant cleaner species co-occur, compete for clients, and partition resources will be an important avenue for future research. One possibility is that different cleaners specialize on different parasites. Gobies clean more actively during dawn and show reduced cleaning activity as gnathiid isopod abundance naturally decreases throughout the day [A. pedersoni cleans regularly from dawn to dusk, which may suggest this species targets parasites that are more permanently attached (e.g. flatworms) [P. yucatanicus, as well as all co-occurring cleaner species, to determine whether specialization allows for overlapping clientele, or whether there are sufficient resources (i.e. parasite loads) to allow for such redundancy in service provisioning.Previous work has shown considerable overlap in clientele between aribbean . We demots range ,28–30. AHonduras  and US V the day ,54,57,58atworms) . More syA. pedersoni hosted by B. annulata, but because C. gigantea is the same size or larger than B. annulata, host size is not a general explanation for the differences in visitation or cleaning rate between shrimp species. Whether host species identity impacts cleaning activity is unclear and difficult to parse in our data because of the non-random association we see between host anemone and shrimp. However, fish may use sea anemones as visual cues to locate A. pedersoni shrimp, so anemone size may matter on some reefs [B. annulata which has thinner and more transparent tentacles than C. gigantea, and would explain why we observed a significant increase in fish cleaning rate with body size in B. annulata but not C. gigantea.While there is similarity in client diversity, the differences in visitation and cleaning rates between both species are striking. While some of these differences could be attributed to differences in host use, host size is not an appropriate explanation here. Anemone size has a positive effect on cleaning activity for me reefs . This maP. yucatanicus stations that result in cleaning bouts between shrimp and reef fish, we find no compelling evidence that P. yucatanicus is a cleaner mimic. The regularity of visitation to P. yucatanicus stations is much greater than we would expect given the species’ apparent apprehension to clean . In a typical cleaner system, high-quality service provisioning by the cleaner results in repeat visits by the client . Our findings are consistent with previous studies of cleaner gobies (e.g. [A. pedersoni [Because we find regular client visitations to nt (e.g. ). Howevees (e.g. ) and preedersoni  that theP. yucatanicus appears to be a true cleaner shrimp, the effectiveness of this species as a cleaner and its ecological role (dedicated or facultative cleaner) remains in question. Less than 15% of all client visits resulted in an actual cleaning interaction, and the brevity of these cleans (A. pedersoni on the same reef, probably resulted in minimal parasite removal. These observations and the findings by McCammon et al. [P. yucatanicus did not significantly reduce monogenean parasite loads on surgeonfish in a semi-natural setting paint a clearer picture of the ecological importance of P. yucatanicus. Additional study will be necessary to discern whether P. yucatanicus specializes on different ectoparasites than A. pedersoni or whether it varies in its cleaning activities across day or season, but we are sceptical that this species plays a role in ecosystem health that equals that of A. pedersoni.In conclusion, while e cleans , in compn et al.  that P.


ADHD) is a common neurodevelopmental disorder starting in childhood that may persist into adulthood. It can be managed through carefully monitored medication and nonpharmacological interventions. Access to care for children at risk of ADHD varies both within and between countries. A systematic literature review was conducted to investigate the research evidence related to factors which influence children accessing services for ADHD.Attention‐Deficit/Hyperactivity Disorder  by a minimum of two independent reviewers. Due to the heterogeneity in the study designs, a narrative approach was used to present the findings.Studies investigating access to care for children at risk of Twenty‐seven papers met the inclusion criteria; these were grouped into four main themes, with some papers being included in more than one. These were wider determinants (10 papers); identification of need (9 papers); entry and continuity of care (13 papers) and interventions to improve access (4 papers). Barriers and facilitators to access were found to operate at the individual, organisational and societal level. Limited evidence of effective interventions to improve access was identified.ADHD and the lack of evidence‐based interventions designed to address these issues, thereby indicating areas for service development and further evaluative research.This review explored the multilayered obstacles in the pathway to care for children at risk of  Attention‐Deficit Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder beginning in childhood and often persisting into adulthood  and the American Academy of Pediatrics both advocate a comprehensive approach to treating ADHD, including multidisciplinary assessment, support for parents and medication for children in moderate or severe cases , an approach to reviewing which can accommodate the different spheres of influence operating at multiple levels is required. We chose to adopt a broadly social‐ecological perspective ; PsycINFO; ISI Web of Science; The Cochrane Library ; OpenSIGLE, System for Information on Grey Literature in Europe (http://opensigle.inist.fr); International Political Science Abstracts (http://iab.sagepub.com/); NHS EED, National Health Services Economic Evaluation Database, CRD (http://www.crd.york.ac.uk/crdweb/ and TRIP database (http://www.tripdatabase.com/). Search terms were developed using keywords for ‘health service barriers’ and ‘ADD/ADHD’ as the relevant terms. The list of search terms is provided in the online supplementary Appendix S1. The initial search was not restricted by language or publication status. In addition, to find information on studies in progress and unpublished or grey literature, the following databases were also searched: World Bank Documents & Reports (http://www-wds.worldbank.org/); OECD (Organization for Economic Co‐operation and Development) Publications & Documents (www.oecd.org); APA PsycNET (http://psycnet.apa.org/); UK Clinical Research Network Database (http://public.ukcrn.org.uk/search/); National Research Register Projects Database ; Health Development Agency (http://www.hda-online.org.uk/); National Primary Care Research and Development Centre (www.npcrdc.man.ac.uk); Children's Society (http://www.the-childrens-society.org.uk/) and relevant American organisations such as the Centre for Disease Control and Prevention. The reference lists of included studies were also scanned to check for further relevant publications.The following databases were searched from inception to the end of April 2012: MEDLINE (PubMed); EMBASE  in influencing the help‐seeking process. Studies within the Entry and Continuity theme focused on clinical predictors of service utilisation and the role of professionals as gatekeepers to appropriate specialist services. In addition to using the Gulliford et al. (Interventions to Improve Access).It has already been noted that ‘access to care’ is a diffuse concept and is open to multiple interpretations. Drawing on the social‐ecological view of research implementation and the model developed by Gulliford et al.  to illusd et al.  categoriThe wide heterogeneity in study design meant that a meta‐analysis of the results was not possible and therefore the findings from the review are presented as a narrative under each theme heading. Although this approach has been taken, where they have been reported and add to the interpretation and synthesis of the papers, odds ratios and confidence intervals are also presented.Wider determinants are those barriers and facilitators to accessing care which relate to societal or macrolevel influences. Ten papers were identified within this theme with nine coming from the United States  and ethnic minority status  and contain a higher proportion of healthcare professionals (p < .001) , affirmative (p < .001) and instrumental (p < .0001) support.Possible explanations for these differences were explored by Bussing, Zima, Gary, Mason, et al. , BussingIn a subsequent paper, Bussing et al.  exploredTwo studies in the United States focused specifically on the influence of ethnicity on parental perceptions of symptoms of ADHD. In a vignette study, Gidwani et al.  investigThe Bussing, Zima, Perwien, et al. , BussingAdult recognition that a child has difficulties and identification of a need for services are fundamental steps for children to be able to access appropriate care. Seven studies discussed elements related to the identification of need and, of these, three were from the United States  or ADHD . By contrast, conceptualisation as ‘attentional difficulties' reduced the teacher's likelihood of making a referral by 13% . Accordingly, parents with a child with ADHD symptoms perceived the behaviour of the child as having less impact on his/her life than the other group of parents (p = .001). Maniadaki et al.  and teachers (p < .01) reported that it would be more beneficial to boys than girls. They suggested that this belief system influenced parents' and teachers' decision‐making, and mediated the relationship between gender and service seeking , parents (n = 161), healthcare professionals (n = 138) and adolescents (n = 148) were explored in relation to the reasons individuals gave for wanting to engage with services for ADHD. Parents and healthcare professionals were more willing to engage than adolescents (beta estimates of 0.55 and 0.44 respectively). Other factors that increased willingness to engage with services included feeling knowledgeable about the treatment options  available and a consideration that the treatment  was both acceptable and helpful (Bussing et al., Bussing et al.  expandedIn contrast to the methodology of the above studies which focused on individual factors and initial access, Chen et al.  suggesteOnly four papers, two UK‐based (Sayal, Hornsey, Warren, MacDiarmid, & Taylor, Sayal, Hornsey, et al.  delivereThe impact of school‐based screening and educational interventions on longer term outcomes including specialist service use was investigated by Sayal, Owen, et al. . SchoolsWilliams et al.  also evaWolraich et al.  investigIn this systematic review, the majority of the 27 included papers focused on the characterisation of existing barriers and facilitators within the pathway to care and unmet need within the population, with only four studies investigating interventions aimed at improving access to care for children at risk of ADHD. This review has been informed by both a social‐ecological view of research implementation and the Gulliford et al.  conceptuTo attempt to mitigate this, we have presented the review process as transparently as possible so that our decision‐making is clear, and practitioners and policy‐makers are able to make their own judgments about the transferability of the findings to their clinical areas. As outlined in the Methods section, we did not conduct an estimation of methodological rigour as would be expected in more traditional systematic reviews and this may be considered to be a limitation of the review process. Instead, we have focused on the ability of the identified studies to answer the review questions, a precedent set by Alborz et al. . We haveAlthough the majority of the included studies have come from the United States, the review has taken an international perspective with studies from Australia, Greece, Taiwan and the United Kingdom. The differential rates of recognition and diagnosis of ADHD between countries as well as variations in healthcare systems may have influenced the barriers and facilitators identified in the review. These societal and system factors can make comparisons across different countries challenging. It may also mean that some of the research findings are specific to the communities in which the original studies were conducted and caution may need to be applied when implementing them in different contexts. Despite the international focus of the literature review, a limitation is that it only reports on studies published in English. It is acknowledged that this approach may have missed key texts.This literature review has utilised a social‐ecological view of implementation and the Gulliford et al.  frameworAs well as individual‐level factors, organisational settings as both a place for identification and intervention were considered within the review. Schools, in particular, were investigated in three of the four included intervention studies (Sayal, Hornsey, et al., Although this review has focused on ADHD, individual and organisational barriers and facilitators to care have been identified for a range of paediatric conditions. These include asthma (Lakhanpaul et al., In summary, this literature review has identified barriers and facilitators to accessing care at multiple levels of influence and how they appear to affect the complex process of diagnosis and treatment for children with ADHD symptoms. Clinicians working with children and adolescents will benefit from an increased awareness of these barriers, to inform any attempts to improve equity in access to care. The studies included in this review suggest that clinicians should evaluate their patients in context, taking into account their age, gender, ethnicity, socioeconomic status, social networks that influence them and their views on possible stigma associated with a diagnosis of ADHD.The review has also highlighted large gaps in the evidence base, particularly in relation to interventions to improve access. Only a few trials, based in widely differing systems of healthcare, have been conducted and none of these has been replicated, so the little evidence which does exist is not generalisable.This dearth of research into how best to overcome the numerous barriers to treatment of ADHD is problematic for policy‐makers seeking to improve outcomes for children across the board (Department of Health, Timely and effective treatment of ADHD could afford long‐term savings (Lucas et al., For children at risk of ADHD, there are barriers and facilitators to the receipt of assessment and eventual treatment; these operate at a societal, organisational and individual level.There are inequalities in the access to care for ADHD: boys, younger children, White children, urban residents and children from higher SES are more likely to access services. This bias may be partially mediated by the influence of the child's gender on parent conceptualisation of the problem and variations in help‐seeking behaviour which are associated with ethnicity.There is a need to enhance the knowledge about ADHD in teachers, primary care clinicians and parents with special focus on awareness that ADHD might have a predominantly inattentive presentation and that treatment for ADHD is as effective in girls as in boys.Adolescents with ADHD may be aware of stigma and public perceptions in relation to ADHD. As this impacts on their engagement with services, age‐appropriate psycho‐educational initiatives delivered in nonstigmatising settings need to be developed.Interventions to improve the access of children at risk of ADHD to appropriate care have targeted the knowledge of professionals or aimed to enhance the communication between key adults; the effectiveness of those interventions was limited and their long‐term benefit has not been evaluated.There is a need for clinical guidelines to be appropriately implemented.Appendix S1. Literature review search terms.Appendix S2. Excluded studies table.Click here for additional data file.


The frontoparietal network is known to be related to hyperactive and impulsive behaviors. Intelligence quotient (IQ) is an important factor in ADHD, and we predicted IQ scores using the results of our connectivity analysis. IQ was predicted using degree centrality values of networks with significant interaction effects of age and symptom. Actual and predicted IQ scores demonstrated significant correlation values, with an error of about 10%. Our study might provide imaging biomarkers for future ADHD and intelligence studies.Attention deficit hyperactivity disorder (ADHD) is a pervasive neuropsychological disorder that affects both children and adolescents. Child and adolescent ADHD patients exhibit different behavioral symptoms such as hyperactivity and impulsivity, but not much connectivity research exists to help explain these differences. We analyzed openly accessible resting-state functional magnetic resonance imaging (rs-fMRI) data on 112 patients , and 28 adolescent NC). We used group independent component analysis (ICA) and weighted degree values to identify interaction effects of age (child and adolescent) and symptom (ADHD and NC) in brain networks. The frontoparietal network showed significant interaction effects ( Attention deficit hyperactivity disorder (ADHD) is a common neurobehavioral disorder that affects both children and adolescents . ADHD paMany neuroimaging techniques were adopted to explore age related ADHD brain alterations . BresnahMany neuroimaging studies regarding ADHD have adopted magnetic resonance imaging (MRI) and EEG techniques . MRI is Intelligence quotient (IQ) tests were designed to assess intelligence, and they are commonly administered using the Wechsler Abbreviated Scale of Intelligence (WASI) . Full-scChild and adolescent ADHD patients exhibit different behavioral symptoms, particularly hyperactivity and impulsivity . The behn = 77) and a NC group (n = 84). Each group was further divided into child and adolescent groups. Patients under 10 years of age were considered children, and those between 10 and 19 years of age were considered adolescents (n = 28) in each group. We assigned the same number of samples in each group to reduce bias. Finally, 28 child ADHD, adolescent ADHD, child NC, and adolescent NC subjects were considered for the study. We repeated the random removal process three more times and obtained three additional sets of four comparison groups. All four sets of data were analyzed to check the reproducibility of this study. Results of one representative set were reported in the main text and those of the remaining three sets were reported in the Supplementary Material. Our main objective of the study is to identify group differences between child and adolescent ADHD patients. Age matched NC group was necessary so that we could remove effects of the normal aging. If age related difference existed in both NC and ADHD groups, we would not treat it as relevant to aging in ADHD. We considered age related difference relevant only if it existed in ADHD group and not in NC group. Comparison of sex ratio, ADHD scores, and ADHD subtype ratio did not yield significant differences (p > 0.05) between the child and adolescent ADHD groups (Table 1). There were more boys than girls in ADHD group and it is a natural condition as boys make up larger portion of ADHD patients than girls (p > 0.05) between the child and adolescent NC groups (Table 1). Detailed participant information is given in Table 1. IQ was measured using the WASI  of Sungkyunkwan University with written informed consent from all subjects. All subjects gave written informed consent in accordance with the local IRB guidelines. We obtained T1-weighted structure data and resting-state fMRI (rs-fMRI) functional data from the New York University Child Study Center involved in the ADHD-200 database . The ADHlescents . The ADHan girls . Comparithe WASI , and scothe WASI .T1-weighted structure data were preprocessed using the AFNI software , and skuAll subjects’ preprocessed functional data were temporally concatenated and fed into the FSL MELODIC software . The gro, where rij represents the edge value between the nodes i and j .Connectivity information was assessed with a graph structure using nodes and edges . We adop i and j . The β v i and j . The corWe adopted degree centrality that is a simple and sensitive local connectivity measure . It is dr- and p-value statistics. P-values were corrected using the Holm-Bonferroni method  values and percent-error. The prediction procedures were performed using MATLAB .A simple linear model used in the correlation analysis was used to predict IQ scores using each brain network. The prediction procedure was performed with a leave-one-out cross validation approach. One subject was used as the test set, and the remaining 55 subjects were used as the training set. A linear equation was generated from the training set and was applied to predict the IQ scores of the test set. The linear model was built from 55 subjects and the model was applied to predict the IQ score of the remaining test case. The remaining test case already has IQ scores available and thus we could compare predicted IQ and actual IQ. The process was repeated 56 times each time choosing a different test case. We computed 56 predicted IQ scores and they were compared with actual IQ scores. The percent error was calculated by dividing the absolute error between actual and predicted IQ scores by actual IQ scores. The mean percent error was reported. The significance of prediction was quantified with p < 0.05) interaction effects were regarded as significant networks affected by both age and symptom. The quality of correlation between degree centrality values of each brain network and IQ scores was quantified using r- and p-value statistics. We applied the Holm-Bonferroni method to obtain corrected p-values .Interaction effects of age and symptom were assessed using two-way ANOVA approach . Brain np-values . The quaFigure 1). Generated ICs were compared with known RSNs, and 11 functionally interpretable ICs remained (Table 2)  . RSNs 1,F = 7.6047, p = 0.0068] interaction effects (Table 3). The identified IC covered bilateral superior, middle, and inferior frontal gyri, inferior parietal gyrus, and angular gyrus.We adopted two-way ANOVA approach to identify brain networks that show significant interaction effects of age and symptom. One IC involved in the frontoparietal network (IC 5 and RSN 9) demonstrated significant [Table 4. IC 5 (RSN 9) demonstrated significant correlation with FSIQ, VIQ and PIQ  . Correlation between degree values of identified ICs and IQ scores of three additional analysis sets were reported in Supplementary Table Degree values of the identified IC were correlated with IQ scores and reported in r- and p-values, and RMS and percent-error between actual and predicted IQ scores were computed (Table 5). The actual and predicted FSIQ using degree values of IC 5 yielded significant results (r = 0.2857 and p = 0.0023) with an RMS error of 12.99 and a percent error of 9.81% . The actual and predicted VIQ using degree values of IC 5 yielded significant results (r = 0.2495 and p = 0.0080) with an RMS error of 13.30 and a percent error of 9.52% . The actual and predicted PIQ using degree values of IC 5 yielded significant results  with an RMS error of 13.38 and a percent error of 10.59% . IQ prediction results of three additional analysis sets were reported in Supplementary Table Degree values of the identified IC were used to predict IQ scores in a leave-one-subject-out fashion. Degree values of the identified IC were used as regressors in a regression framework. Quality of prediction was assessed with The cingulo-fronto-parietal (CFP) network is highly related to ADHD symptoms, as it regulates attention, working memory, executive control, and response inhibitory control . Many ADTable 1; Supplementary Table p < 0.05) interaction effects of age and symptom in the frontoparietal network and the visual network showed significant interaction effects only in the third additional set (Supplementary Table p < 0.05) correlated with degree values of the frontoparietal network in the first additional set. Only PIQ showed significant (p < 0.05) correlation in the second additional set, and VIQ and PIQ showed significant (p < 0.05) correlation in the third additional set. FSIQ and VIQ in the second additional set and FSIQ in the third additional set did not show significant (p > 0.05) correlation but the p-values were close to 0.05 . These results imply that those IQ scores were not significantly correlated at 0.05 level but still moderately correlated  to degree values of the frontoparietal network. The IQ prediction results were reported in Supplementary Table We randomly removed a few patients to have matched number of subjects in four comparison groups. We repeated the random removal process three more times and obtained three additional sets of four comparison groups. All four sets of data were analyzed to check the reproducibility of our findings. Demographic data were similar between the main data set and the additional data sets  and the degree values of the frontoparietal network demonstrated high correlation with IQ scores (average r = 0.31). Furthermore, actual and predicted IQ scores yielded significant results, with an approximate error of 10%. Our study suggests a possible statistical link among behavioral symptom differences  between child and adolescent ADHD patients and brain networks, and our study might provide potential imaging biomarkers for future ADHD and intelligence studies.We identified brain networks that showed significant interaction effects of age (child and adolescent) and symptom (ADHD and NC) using group ICA and weighted degree values. The frontoparietal network showed significant interaction effects (B-yP and HP wrote the manuscript and JH and S-HL aided the experiments. HP is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.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.


This is one of the first studies to examine the structural brain anatomy and connectivity associated with an ADHD diagnosis and child as well as adult ADHD symptoms in young adults. It was hypothesized that an adult ADHD diagnosis and in particular childhood symptoms, are associated with widespread changes in the brain macro- and microstructure, which can be used to develop a morphometric biomarker for ADHD.Voxel-wise linear regression models were used to examine structural and diffusion-weighted MRI data in 72 participants (31 young adults with ADHD and 41 controls without ADHD) in relation to diagnosis and the number of self-reported child and adult symptoms.Findings revealed significant associations between ADHD diagnosis and widespread changes to the maturation of white matter fiber bundles and gray matter density in the brain, such as structural shape changes (incomplete maturation) of the middle and superior temporal gyrus, and fronto-basal portions of both frontal lobes. ADHD symptoms in childhood showed the strongest association with brain macro- and microstructural abnormalities. At the brain circuitry level, the superior longitudinal fasciculus (SLF) and cortico-limbic areas are dysfunctional in individuals with ADHD. The morphometric findings predicted an ADHD diagnosis correctly up to 83% of all cases.An adult ADHD diagnosis and in particular childhood symptoms are associated with widespread micro- and macrostructural changes. The SLF and cortico-limbic findings suggest complex audio-visual, motivational, and emotional dysfunctions associated with ADHD in young adults. The sensitivity of the morphometric findings in predicting an ADHD diagnosis was sufficient, which indicates that MRI-based assessments are a promising strategy for the development of a biomarker. Attention-Deficit/Hyperactivity Disorder (ADHD) is characterized by inattention, hyperactivity, and impulsivity. It is one of the most frequently diagnosed neurodevelopmental disorders with a prevalence rate of approximately 5% in children and 2.5% in adults . EstimatThe most frequently used approaches to measure brain structures are based on Magnetic Resonance Imaging (MRI). T1-weighted anatomical imaging is used to assess the brain macrostructure, such as the volume and structure of white matter  and grey matter , while diffusion-tensor imaging (DTI) is a more recent approach to specifically assess the brain microstructure. DTI provides information about the mobility of water molecules in white matter via the scalar parameters: fractional anisotropy (FA)–directionality of water diffusion perpendicular to white matter fibers ; radial A number of studies documented the macro- and microstructural pathophysiology associated with an ADHD diagnosis. Initial brain macrostructural studies revealed that children and adolescents with ADHD show smaller brain volumes in all regions . HoweverBesides these macrostructural indicators, it was suggested that ADHD primarily involves the fronto-striatal  as well It was suggested that changes in the striatum and its connections are associated with hyperactivity-impulsive symptoms in children with ADHD . HoweverIn children and adolescents, severity of ADHD symptoms was linked to decreased frontal and temporal grey matter, caudate and cerebellar volumes,  and decrThe purpose of the study was to close this gap in knowledge by analyzing structural and diffusion-weighted MRI data in relation to ADHD diagnosis and the number of self-reported childhood and adult symptoms in young adults. The aim of the study was threefold: 1. to examine macro- and microstructural correlates of an ADHD diagnosis in young adults with ADHD, 2. to study associations between brain structure and child as well as adult symptoms of ADHD, and 3. to assess if the morphometric correlates of ADHD can be used as a potential biomarker to predict an ADHD diagnosis. Based on previous research showing widespread changes in the brain macro- and microstructure, it was hypothesized that an adult ADHD diagnosis is associated with frontal, basal ganglia, anterior cingulate, temporal, and parietal regions in young adults with ADHD. In addition, it was hypothesized that correlations between brain structure and ADHD symptoms in childhood are more widespread and prominent  than ADHD symptoms in adulthood. Moreover, the morphometric findings may predict the ADHD diagnosis in more than 80% of cases, which would demonstrate that morphometric data have the potential to be used as a biomarker for the diagnosis of ADHD.2 = 4.73, p = 0.03), more ADHD symptoms  as well as subtype diagnoses , and currently used more stimulant medications .Seventy-two participants participated in the study of which 31 met the diagnostic criteria for ADHD according to DSM-IV , and 41 All participants were physically healthy and had no chronic illness such as heart disease, irregular heartbeat, hypertension, diabetes, skin allergies, or skin diseases. The study was approved by the Institutional Review Board of the University of California, Irvine and written consent was obtained from each participant between July 2009 and April 2014.Participants were asked to close their eyes and relax while in the MRI scanner. The duration of the scan was 20 minutes .2, one volume with isotropic gradients at b = 1000 s/mm2, and a reference volume without diffusion-weighting (b = 0 s/mm2).MRI data were acquired on a Philips Achieva 3T scanner, equipped with an 8-channel phased array coil. T1-weighted images were acquired using a Turbo Field-Echo (TFE) sequence with TR 11 ms, TE 3.7 ms, flip angle 18 degrees, 150 sagittal slices with a matrix of 240 x 240 voxels, corresponding to an isotropic resolution of 1.0 mm. Diffusion-weighted images were acquired using a diffusion-weighted spin-echo EPI sequence with TR 7.0 s, TE 80.0 ms, flip angle 90 degrees, 60 axial slices with a matrix of 116 x 112 voxels, corresponding to a resolution of 1.8 mm x 1.8 mm (in plane), 2 mm slice thickness. Thirty-two image volumes were acquired using different diffusion weighting gradient directions at b = 1000 s/mmhttp://sip.eng.uci.edu). All T1-weighted MR images were inspected for acquisition-related artifacts and signs of neurological diseases. Heads were aligned with the stereotaxic coordinate system [σ = 2, FWHM of 4.7 mm) and logit-transformed. From the deformation field obtained above, the determinant of the first partial derivative (the Jacobian) was computed. This value can be used to detect local shape changes . Data were smoothed using a Gaussian filter (FWHM of 4.7 mm), and log-transformed. Thus, maps were obtained for the GM (WM) concentration and Jacobian (JAC) for each subject in normalized space.Data analysis followed the general outline of voxel-based morphometry (VBM). The BRIAN software package was used to analyze the imaging data . To correct for subject motion, image volumes corresponding to all gradient directions were registered with the non-diffusion weighted reference image volume using affine registration and mutual information as an image similarity metric. Then, diffusion tensors were computed from the registered diffusion-weighted images using a nonlinear procedure including anisotropic noise filtering [The BRIAN software package was used to analyze the imaging data  were determined and assessed for significance (p < 0.05) based on the theory of excursion sets in Gaussian random fields [p-value threshold of p = 0.01 and a cluster-level (secondary) p-value threshold of p = 0.05 was used, which are standard settings for this approach. Average z-scores were computed over all voxels in a given cluster that passed the significance test. The center-of-mass, extent (in mm3), peak and average z-score were computed for each cluster, and addressed an anatomical label based on Talairach coordinates using the labeled map developed by Lancaster et al. [Structural MRI data (T1- weighting) and the diffusion-weighted MRI data were analyzed in relation to diagnosis (ADHD and Controls) and the number of self-reported childhood and adult symptoms. For each of the six image series above, voxel-wise linear regression models were computed, for diagnosis , childhood and adulthood symptoms, and gender, as well as age at time of examination as covariates. For the independent variable grey matter (white matter) concentration, computation was restricted to a mask with a corresponding probability m fields . This apr et al. , and areIn order to assess whether any combination of the subject-wise measures can be used to predict an ADHD diagnosis, we extracted voxel-wise measures from regions that significantly differed by the diagnostic label. For each subject and each analysis, continuous voxel-wise measures  in significantly different regions were collected and averaged, resulting in one score per subject and analysis. Logistic regression was used to find a single score that best predicted an ADHD diagnosis. To assess the combined predictive power of all scores, we performed a principal component analysis (PCA) to reduce the dimensionality of the data, and used a linear discriminant analysis (LDA) to develop a simple classifier in the reduced space.An ADHD diagnosis was associated with different grey (white) matter concentrations, and shape differences as computed from the Jacobian maps JAC, see  Maps. ThIn contrast to diagnosis, no association was found between brain macrostructure and ADHD symptoms. However, ADHD symptoms were associated with microstructural findings, which were more prominent  for the childhood total symptoms see  Maps, coOverall, a single measure of white matter concentration best predicted ADHD diagnosis (p = 6.18e-06). The receiver operating curve (ROC) analysis revealed that the “area under the curve” (AUC) was found at 0.917, which may be considered as a reasonably high discriminative power of this model. To assess the combined information of six measures , PCA was used to reduce the dimensionality to three measures, representing a cumulative variance of 97.5%. Subsequent LDA to develop a simpler classifier correctly predicted an ADHD diagnosis in 83.3% of all cases see . A repeaAn ADHD diagnosis in young adults was associated with decreased grey matter concentration, increased white matter concentration, and decreased shape in widespread areas involving frontal, temporal, striatal, parietal and limbic regions. These widespread macrostructural changes suggest that many of the brain areas associated with an ADHD diagnosis in childhood  continueOur findings revealed reduced gray matter concentrations in the right middle frontal gyrus, right inferior frontal gyrus, right superior temporal gyrus, right middle temporal gyrus, left caudate head, and left parahippocampal gyrus with corresponding white matter increases associated with an ADHD diagnosis in young adults. Thus, frontal, temporal, striatal, parietal, and limbic abnormalities associated with ADHD are not unique to children and adolescents but are also seen in young adults, revealing that the pathophysiology of the disorder seen in childhood carries on into young adulthood. In addition, the reduced grey matter concentrations in the left caudate head in young adults with ADHD suggest that the macrostructural abnormalities in the basal ganglia may normalize at a later stage in adults with ADHD , 10, 24.With regards to microstructural brain abnormalities, our findings corroborate an abnormal cortico-cortical connectivity that develops early and persists into young adulthood . More spThese DTI findings in young adults with an ADHD diagnosis are in agreement with recent data using whole-brain tractography , which rThe present findings also corroborated the hypothesis that brain microstructural abnormalities were more associated with child symptoms of ADHD compared to adult symptoms of ADHD. More specifically, dividing into childhood and adult symptoms, the strongest associations between symptoms and morphometric findings were determined by the combination of self-reported childhood symptoms and diffusion-weighted measurements, but less so for childhood symptoms and T1- weighted measures. Although less prominent, a similar pattern was found for the adult symptoms. However, microstructural differences were more strongly associated with childhood than adult symptoms, which may suggest that while microstructural findings are strongly linked to childhood symptoms, such association weakens with adult ADHD symptoms, which may be due to improved structural changes or coping skills.Intriguingly, childhood symptoms were associated with reduced FA and increased RD in the frontal lobe and putamen/external capsule, which suggests decreased myelination in the frontal–basal ganglia network. Adult symptoms, on the other hand, were associated with reduced FA as well as increased RD and AD in the in the left cingulum and right dentate nucleus, suggesting decreased myelination in these structures in young adults with ADHD. These findings, in part, corroborate previous results of white matter differences associated with symptoms severity , 26, 55.While reduced grey matter in the left caudate was associated with an ADHD diagnosis, reduced FA, as well as increased RD and MD in the left putamen, it was also correlated with child symptoms of ADHD, but not adult symptoms of ADHD. This suggests that disturbances in connections reaching the caudate may be associated with an ADHD diagnosis in young adulthood, whereas reduced FA in the putamen may be an index of symptom severity in childhood.At the brain circuitry level, the present findings may suggest that the superior longitudinal fasciculus (SLF) and the cortico-limbic associated circuitry are dysfunctional in individuals with ADHD see . The SLFThe cortico-limbic associated circuitry connects the amygdala with the thalamus and orbital frontal cortex. It is primarily responsible for emotional learning and behavioral regulation. The present findings involving the caudate head , parahipIntriguingly, MRI based data predicted the diagnosis of ADHD correctly in 83% of all the cases. Thus, further research towards defining a MRI-based biomarker is promising, which requires a larger and more diverse patient sample as well as an extended MRI protocol. Future studies could focus on the probability of certain areas and circuitries in predicting an ADHD diagnosis.The findings have to be interpreted with caution because childhood symptoms were assessed via self-report by young adults, which may be problematic due to memory bias or distortion. In addition, emerging evidence suggests that the ADHD inattentive and ADHD combined subtypes in children may be different disorders based on their unique WM microstructure , which wAn adult ADHD diagnosis and in particular child symptoms were associated with widespread micro- and macrostructural changes in the frontal, basal ganglia, anterior cingulate, temporal, and occipito-parietal regions in young adults with ADHD. The associations between brain structure and ADHD symptoms in childhood were more widespread and prominent  than ADHD symptoms in adulthood. In addition, the analysis of the diffusion-weighted measures yielded stronger results  than the measures derived from T1-weighted data. Thus, in relation to the diagnosis and symptom scores, changes in the microstructural properties of white matter fiber tracts appear to be stronger and more extensive than macrostructural differences. This highlights the importance of the microstructural architecture in the pathophysiology of ADHD.The overall morphometric findings predict the ADHD diagnosis in 83% of cases, which demonstrates sufficient sensitivity to aid in the clinical assessment and potential as a biomarker for ADHD in young adults. At the brain circuitry level, the involvement of the SLF and cortico-limbic areas may suggest complex audio-visual, motivational, and emotional dysfunctions associated with ADHD in young adults, which could be investigated in future studies. Investigating the SLF and cortico-limbic circuitries may be an interesting and novel research direction, which may lead to a better understanding of the underlying mechanisms of ADHD and the development of novel treatments that target audio-visual, motivational, and emotional dysfunctions.S1 Template(GZ)Click here for additional data file.S1 Map(GZ)Click here for additional data file.S2 Map(GZ)Click here for additional data file.S3 Map(GZ)Click here for additional data file.S4 Map(GZ)Click here for additional data file.S5 Map(GZ)Click here for additional data file.S6 Map(GZ)Click here for additional data file.S7 Map(GZ)Click here for additional data file.S8 Map(GZ)Click here for additional data file.S9 Map(GZ)Click here for additional data file.S10 Map(GZ)Click here for additional data file.S11 Map(GZ)Click here for additional data file.S12 Map(GZ)Click here for additional data file.S13 Map(GZ)Click here for additional data file.S14 Map(GZ)Click here for additional data file.S15 Map(GZ)Click here for additional data file.


Attention-deficit/hyperactivity disorder (ADHD) is among the most commonly diagnosed mental disorders in childhood and is associated with substantial deficits in executive functioning and lost academic and occupational attainment. This study evaluates symptoms of ADHD and their association with neurocognitive deficits in a cohort of rural Ugandan children who were born to HIV-infected mothers.We assessed ADHD symptoms and executive function (including memory and attention) in a non-clinical sample of children born to HIV-infected mothers in rural eastern Uganda. Analyses included assessments of the psychometric properties, factor structure, and convergent and discriminant validity of the ADHD measure ; and executive function deficits in children meeting symptom criteria for ADHD.s.d. 2.0)] were assessed for ADHD and executive function deficits. The ADHD measure showed good internal consistency (α = 0.85.) Confirmatory factor analysis showed an acceptable fit for the diagnostic and statistical manual of mental disorders (DSM-5) two-factor model. Subjects meeting DSM-5 symptom criteria for ADHD had worse parent-rated executive function on six out of seven subscales.232 children [54% female; mean age 7.8 years (Our results demonstrate structural validity of the ADHD measure with this population, strong associations between ADHD symptom severity and poorer executive function, and higher levels of executive function problems in perinatally HIV-exposed Ugandan children with ADHD. These findings suggest that ADHD may be an important neurocognitive disorder associated with executive function problems among children in sub-Saharan African settings where perinatal HIV exposure is common. Over 60% of children in sub-Saharan Africa (SSA) are estimated to be at high risk for failing to reach their potential in cognitive development, with subsequent effects on educational attainment and poverty  ADHD instrument measures a similar and coherent construct  due to previously reported risk factors of being born to HIV-infected mothers and living in a region with high rates of poverty where malaria is endemic. While we anticipated high rates of ADHD and executive function problems in this sample, an accurate estimate of prevalence of these problems was beyond the scope of the current study. Instead, the primary aim of this study was to address the broader question of whether ADHD symptoms were associated with important and expected impairments in cognitive function (i.e. executive function problems) among Ugandan children with et al. While behavioral rating scales are commonly used in the assessment of ADHD, there is little information available about the cross-cultural validity of such tools in SSA settings. To assess ADHD symptoms, we selected the ADHD-Rating Scale IV . Research permission was issued by the Ugandan National Council for Science and Technology.This study was conducted in a community  setting in rural eastern Uganda. Uganda is a low-income country in East Africa that is home to 37.6 million people  and child neurodevelopmental performance tests  before data collection started.Exclusion criteria for caregivers from the parent study included current suicidality or psychosis. Exclusion criteria for study children included: history of serious birth complications, severe malnutrition, bacterial meningitis, encephalitis, cerebral malaria, or other known brain injury or disorder requiring hospitalization.et al. et al. Baseline data were collected on demographics, clinical  characteristics, family characteristics, the Home Observation for Measurement of the Environment (HOME)  were the informants for the ADHD-RS-IV and BRIEF and the children completed the KABC-II and TOVA. Parent report measures (ADHD-RS-IV and BRIEF) were collected by reading the questionnaire items to the caregivers, word by word. In case of lack of understanding, the interviewer was instructed to repeat the item to the caregiver as many times as necessary. In very few cases, caregivers did not understand in spite of repeated attempts and clarification was used to put the item in context. The ADHD-RS-IV and BRIEF (preschool or standard versions) were administered for all children, whereas the TOVA and KABC-II were administered only to children aged >5. All measurements were made prior to initiation of the caregiver training intervention.et al. et al. et al. et al. ADHD symptoms were assessed using parent report on the ADHD-RS-IV, an 18-item scale that assesses the presence and severity of DSM-IV symptoms of ADHD, including a nine-item subscale for inattention and a nine-item subscale for hyperactivity/impulsivity .To assess executive functioning, we employed the BRIEF school-age version (ages 5–12) ; graphically representing the eigenvalues to visually analyze the relative importance of the factors, where a sharp drop in the plot signals that subsequent factors are ignorable (scree plot); and using parallel analysis to adjust for sample bias in the observed eigenvalues Dinno, . Exploraet al. The primary assessment of convergent validity was association between ADHD-RS-IV total symptom score and the BRIEF ‘inhibit’ scale , suggesting plausibility of a two-factor model of ADHD. Measures of comparative fit suggested that the two-factor model was superior to the one-factor model  (p < 0.001 level after adjusting for child age and sex (which were both associated with executive function deficits). Higher total ADHD symptom scores were also associated with worse performance-based measures of executive function on the TOVA (p = 0.01–0.04), but not with the TOVA ADHD Index (p = 0.92) (p = 0.14) (p = 0.15)Greater total ADHD symptom scores were strongly associated with higher levels of parent reported executive function problems on the BRIEF (e Index) . All ass = 0.92) . Total A = 0.14) . Total Az-score for height, MUAC), having a non- parent caregiver, both parents unemployed, total HOME score, and harsh parenting (an index of five items from the HOME related to harsh/punitive parenting practices). There were no significant associations between either opportunistic infection prophylaxis and ADHD (p = 0.44) or HAART and ADHD (p = 0.68). Of note, we were unable to assess odds ratios for history of malaria or preterm birth, since all children meeting ADHD symptom criteria had been exposed to malaria and none of the ADHD cases were born preterm.Multilevel mixed-effects logistic regression analysis did not reveal significant associations between ADHD and any of the individual or family-level risk factors assessed. Factors evaluated included: sex, age, HIV proxy variables (i.e. on HAART or on opportunistic infection prophylaxis), anthropometric measures (n = 27), and (2) continuous ADHD symptom scores as the dependent regression variable. In the first analysis, there were no individual or family level risk factors. In the second analysis, age, MUAC, and height z-score were significantly associated with ADHD symptom scores, whereas sex and HIV proxy variables remained non-significant. In adjusted regression models , only age remained significantly associated with ADHD symptom scores.To further investigate ADHD risk factors in this novel study setting, we conducted two additional sensitivity analyses  using: (1) an alternate categorical definition with subjects scoring in the upper 10th percentile on the ADHD-RS-IV classified as ‘cases’  on all indices and scales of the BRIEF  (results not shown). There were no significant differences in performance tests of executive function between children who met symptom criteria for ADHD and those who did not. These findings remained consistent in a sensitivity analysis defining children in the upper 10th percentile of ADHD-RS-IV scores as ‘cases’.Children meeting symptom criteria for ADHD had significantly higher mean problem scores in all domains of executive functioning as measured by the BRIEF see . In addiet al. Our study demonstrated strong associations between ADHD symptom severity on the ADHD-RS-IV and greater executive function problems in Ugandan HIV-affected children. Children meeting symptom criteria for ADHD were significantly more likely to exhibit deficit-level impairments in all measured domains of executive function on parent-reported measures. Overall, the findings of this study are comparable with studies in the USA and elsewhere demonstrating significant executive dysfunction in children with ADHD  that precluded an accurate calculation of malaria or HIV status as risk factors for ADHD. Likewise, we were unable to assess risk due to perinatal HIV exposure since all included children were exposed.et al. Several strengths of our study should also be noted and include the availability of in-depth neuropsychological test results performed by trained researchers and the use of a community-based  sample. This study also incorporated a rigorous evaluation of the construct validity of a widely used DSM-IV-TR-based scale [ADHD-Rating Scale-IV  (Klasen & Crombag,


Attention deficit hyperactivity disorder (ADHD) involves characteristic electroencephalographic (EEG) activity. We developed a single-channel EEG marker for attention: the Brain Engagement Index (BEI’). In this study, we evaluated the use of BEI’ for distinguishing between ADHD patients and controls, and for monitoring the effect of pharmacological treatment on ADHD patients. The BEI’ values of 20 ADHD patients and 10 controls were measured using a 1-min auditory oddball paradigm and a continuous performance test (CPT) task. We showed that CPT BEI’ is trait-specific and separates controls from ADHD patients. At the same time, oddball BEI’ is state-specific and identifies differences in attention level within the two groups of ADHD participants and controls. The oddball BEI’ also associates with response to treatment, after distinguishing between treatment effect and learning/time effect. The combined use of this marker with common computerized tests holds promise for research and clinical use in ADHD. Further work is required to confirm the results of the present study. To date, the diagnosis of Attention deficit hyperactivity disorder (ADHD) has been based on clinical evaluation and questionnaires. Although objective computerized tests of attention, such as continuous performance test (CPT), are used at times in clinical practice, their specificity and sensitivity, such as the CPT, has not justified recommending its use in practice guidelines. Due to the subjective nature of ADHD diagnosis, it seems important to develop biomarkers that reflect pathological understanding and are practical for use  activity , a marker for sustained attention ), and 10 age-matched controls ) were included in the study. Participants were recruited by advertisements in relevant ADHD and student Internet forums. Candidates underwent a psychiatric evaluation, using a semi-structured interview based on DSM5 criteria, at the Shalvata Mental Health Center, in Hod Hasharon, Israel, to establish the clinical diagnosis of ADHD. Exclusion criteria included: (i) diagnosis of any active psychiatric disorder or diagnosis of bipolar disease, psychotic disease, or major neurological disorder; (ii) recent history of substance or alcohol abuse; (iii) major cognitive impairments; and (iv) significant hearing impairment. The control group underwent a similar evaluation, and a diagnosis or a history of a diagnosis of ADHD was added to the above-mentioned exclusion criteria. All participants signed an informed consent form. The study was approved by the local ethics committee of Shalvata Mental Health Center . Each participant was presented with the study procedure and was only included in the study after signing an informed consent.All participants completed the Adult ADHD Self-Report Scale . MOXO reports four indices for each block, and for the entire test: attention, timing, impulsiveness and hyperactivity , with one frontal electrode (~Fpz) and one reference electrode on the earlobe, using a sampling rate of 512 Hz. In previous works, we noted that our template marker could be extracted from any sagittal or para-sagittal electrode in the central and frontal regions, if the reference is peri-auricular . ADHD participants who used regular pharmacological treatment  were instructed to use the same treatment during the study. Participants who did not use a regular treatment were prescribed by the study psychiatrist a standard pharmacological treatment. We verified that no treatment was taken on the study day, before starting the sampling.After completing the informed consent process and filling out the questionnaires, each candidate underwent a full clinical evaluation by an experienced psychiatrist, including a semi-structured portion, to verify  that participant meet DSM 5 criteria for ADHD  is graded in each block on a scale ranging 0–100. We averaged the four indices for the first and last blocks, generating a block grade for these two basic blocks, without distracting stimuli. For ADHD participants, we computed the within-session difference, which is the difference in between the first and last blocks in the first MOXO session, which do not involve distractors. We also computed the difference between the first basic block index of the second MOXO session  and the best basic block index in the first MOXO session: the between-sessions difference. We allocated ADHD participants to the treatment effect group if the between-sessions difference was greater than the within-session difference; and we allocated ADHD participants to the time/learning effect group if the within-session difference was greater than the between-sessions difference.BEI is a standard computation we use for analyzing the EEG data obtained from the first minute of the stimulus-related sample. The computation is based on template matching . In the MOXO test  ≈ 0.51; p ≈ 0.48).As expected based on previous studies, both the ASRS Figure  and the t Figure , more ADt Figure , and thep < 0.001). For the auditory oddball, the BEI’ did not differentiate between the two groups  ≈ 12.22; p ≈ 0.002).The oddball BEI’ was associated significantly with performance on the MOXO CPT for both ADHD patients and controls Figure , as oppoOne of the complexities in evaluating treatment effect in cognitive testing has to do with the time/practice effect; therefore, we divided the ADHD participants into three main groups: participants for whom the change occurred mainly between the sessions and could be ascribed to treatment effect; participants for whom the change occurred mainly within the first session and could be ascribed to the time/learning effect; and participants for whom no significant change (change ≤ 5%) occurred . The MOXO BEI’ did not show such discriminative value (n.s.). Note that a decrease in BEI’ means higher attention.An increase in oddball BEI’ was specific to those who had no change in the CPT or those whose change was related to time/learning, whereas a decrease in oddball BEI’ was specific to patients with CPT improvement between sessions Figure . Thus, tIn the present study we conducted a preliminary evaluation of the usability of a new marker for attention in ADHD: the BEI’. The marker is practical and easy to use. The present study supports its possible use in clinical and research work with ADHD.Addition of the BEI’ measurement during the performance of a cognitive task (MOXO CPT in the present study) can help identify ADHD patients. ADHD patients and controls differed in the BEI’ of the pre-treatment MOXO: average BEI’ was lower in the ADHD group. This may be unexpected, because the BEI’  is expected to be lower when there is better recruitment of attention. But other electrophysiological analyses of task-related samples also reported higher attention-related indices in the ADHD group . UN, GE and SM recruited the patients and performed clinical evaluations.The research was funded by BrainMARC Ltd., the developer of the BEI . GS is co-founder and chief scientist of BrainMARC Ltd. YB served as principal investigator in the study, which was conducted at his clinical center. The other 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.