Recent GWAS allow us to calculate polygenic risk scores for ADHD. At the imaging level, resting-state fMRI analyses have given us valuable insights into changes in connectivity patterns in ADHD patients. However, no study has yet attempted to combine these two different levels of investigation. For this endeavor, we used a dopaminergic challenge fMRI study (L-DOPA) in healthy participants who were genotyped for their ADHD, MDD, schizophrenia, and body height polygenic risk score (PRS) and compared results with a study comparing ADHD patients and healthy controls. Our objective was to evaluate how L-DOPA-induced changes of reward-system-related FC are dependent on the individual polygenic risk score. FMRI imaging was used to evaluate resting-state functional connectivity (FC) of targeted subcortical structures in 27 ADHD patients and matched controls. In a second study, we evaluated the effect of ADHD and non-ADHD PRS in a L-DOPA-based pharmaco-fMRI-challenge in 34 healthy volunteers. The functional connectivity between the putamen and parietal lobe was decreased in ADHD patients. In healthy volunteers, the FC between putamen and parietal lobe was lower in ADHD high genetic risk participants. This direction of connectivity was reversed during L-DOPA challenge. Further findings are described for other dopaminergic subcortical structures. The FC between the putamen and the attention network showed the most consistent change in patients as well as in high-risk participants. Our results suggest that FC of the dorsal attention network is altered in adult ADHD as well as in healthy controls with higher genetic risk. Attention-deficit hyperactivity/disorder (ADHD) is a neurodevelopmental disorder characterized by the onset of developmentally inappropriate levels of impaired inattention, hyperactivity, and impulsivity during childhood. ADHD is one of the most common mental disorders, with a worldwide prevalence estimate of 3–6% and a heritability estimate of more than 75% . ADHD isADHD treatment is based on multilevel intervention ranging from social, psychological to pharmacological approaches. Stimulant treatment in both children, as well as adults, demonstrates very high effect sizes . PharmacThe main neuroanatomical hubs of the reward system are the dopaminergic nuclei of the midbrain , which send their efferent axons to the whole brain, but especially to the basal ganglia. There, dopamine has an inhibitory function within this circuitry . Not only do hypodopaminergic states lead to motor symptoms like Parkinson’s disease but also to inhibition, anhedonia, and depression mediated via the ventral striatum . Restingn = 247 ADHD cases) study in refs. [Studies looking at resting-state functional connectivity (RSFC) with fMRI resting-state concentrated mainly on children, e.g., . This stin refs. , 13 repoin refs. ) the autin refs. . In thisn = 27 adult ADHD patients versus n = 27 controls to replicate previous L-DOPA-dependent RSFC in ADHD patients  demonstrated a topographical link between the cortex and striatum . The undInclusion criteria were age (18–50 years). Participants were excluded in case of physical illness or a history of psychiatric disorder. Contraindication to magnetic resonance imaging such as metallic objects in the body lead to exclusion. In the case of the ADHD patients, the diagnosis was confirmed in a specialized outpatient clinic of the university hospital Frankfurt, Goethe University. The diagnosis was based on the ICD-10 criteria and was done by a registered psychiatrist or a psychiatrist in training supervised by an experienced psychiatrist. A semi-structured interview was used as main diagnostic assessment: the diagnostic interview for adult ADHD (DIVA 2.0). This semi-structured interview assesses current and childhood ADHD core symptoms.n = 34 healthy volunteers of the pharmaco-fMRI study which were genotyped, and second, n = 54 participants of the ADHD versus healthy controls (HC) group. The university clinic’s ethics committee approved the study on August 24, 2016 (ID:256/16).Participants consisted of two samples, one sample with n = 27 participants. The mean age for the HC (23.77 a SD 3.04 a) and the ADHD group (24.03 a SD 3.38 a) was not significantly different (P = 0.76). Gender distribution was 16 male and 11 female participants for each group. The study was registered in the German study registry on November 11, 2016 under the ID: DRKS00011248.The participants of both groups were matched according to age and gender. The HC and the ADHD group consisted each of 45 healthy volunteers  were included, of whom 22 were male. The average body weight of the subjects included was 72.86 kg (SD: 12.91 kg) with an average height of 1.75 m (SD: 0.11 m). The approval to conduct the study was given by the local ethics commission  and is subject to the Declaration of Helsinki of the “World Medical Association: Ethical Principles for Medical Research Involving Human Subjects” and the “Guidelines for Good Clinical Practices (GCP)”). The study was registered in the German study registry on November 11, 2016 under the ID: DRKS00011209.The measurements were performed at the Brain Imaging Center (BIC) in Frankfurt am Main as a placebo-controlled, double-blind, 3-stage cross-over study. Participants received placebo, L-DOPA or amisulpride in a cross-over study design. In this paper, we report only on the L-DOPA and the placebo sessions because of ambiguous results and interpretation with amisulpride .Participants received a placebo or 125 mg levodopa ~75 min before the start of the resting-state measurement. The session with 200 mg mg amisulpride was not included in our analysis . Participants received each of the medications exactly once in a counterbalanced order.Genotype data were generated using the PsychChip array (15048346 B) with HumanCore, Human Exome, and custom psych content. Normalized intensity values were obtained using Illumina’s. GenomeStudio v2010.3 with the calling algorithm/genotyping module version 1.8.4. Individuals with a call rate >95% were included in the final sample.n = 34 out of 45) with available GWAS data using PRSice2 software (http://www.prsice.info/). The reference dataset for ADHD estimation of SNP-wise ADHD risk was based on a recent GWAS [r2 ≥ 0.1 (250-kb window) was used for clumping to remove SNPs in linkage disequilibrium. We controlled for population stratification by including four principal components as covariates for population stratification, regressed them out of the PRS and used the residual for the calculation of linear regression models.PRSs were computed for participants of the pharmaco-fMRI experiment with available blood samples  and an eight-channel head coil. A T1-weighted sequence (MPRAGE) with a duration of 4:28 minutes was measured and afterward a gradient echo sequence for the functional imaging data was performed, which lasted 8:01 minutes. The sequence information for the MPRAGE sequence are as follows: repetition time (TR) = 1900 ms, echo time (TE) = 3.04 ms, TI = 900 ms, flip angle = 9, FoV (field of view) = 256 × 256 mm, voxel size = 1 × 1 × 1 mm. And for the EPI sequence: repetition time (TR) = 1800 ms, echo time (TE) = 30 ms, flip angel = 90, FoV (field of view) = 192 × 192 mm, m, 28 layers with 4 mm, voxel size = 3 × 3 × 4 mm. Details were described in ref. . Foam paImages were realigned, slice-time corrected, spatially normalized to standard stereotactic space , resampled to 3-mm isotropic voxels, and smoothed with 8 mm full-width at half-maximum Gaussian kernel. A band-pass filtering was used in the frequency band frequency bands to 0.01–0.1 Hz to get rid of non-neural signals. Further noise correction was done by regressing out motion parameters and the 1st order derivative. Signal from the cerebrospinal fluid and white matter was regressed out with the aCompCor-strategy. For seed-voxel connectivity, we used the region-of-interest (ROI) masks from the high-resolution probabilistic in vivo atlas of human subcortical brain nuclei (CIT168)  to modeld = 0.7 for an alpha of 0.05 with a beta power of 0.8 for group comparison of n = 26 per group. For the pharmaco-fMRI study, we calculated a sample size needed for an effect of the pharmacological agent (d = 0.5) with 27 participants for a dependent test.A power analysis was done with GPower 3.1  to estimt test (in SPSS 25). For the analysis. FMRI group-level statistics were calculated in the CONN toolbox V1.7 [t test for each of the a priori-defined seed ROIs. For the analysis of the pharmaco-fMRI experiment, we calculated two types of group statistics. First, an estimation of the correlation between RSFC and PRS without pharmacological stimulation (only placebo session) by a linear regression with PRS was calculated and second, a between-session effect (L-DOPA versus placebo) was added to the model.A comparison of age among ADHD and HC group was done with an independent box V1.7 . For theFor all fMRI group statistics, we used a clusterwise p-FDR-correction, with a cluster defining threshold of <0.001.Table Table The putamen in ADHD patients showed a decrease in functional connectivity to a large cluster comprising parts of the precuneus and the superior parietal lobe. While not exclusively centered on the parietal lobe with some parts of the postcentral gyrus, we interpret the main part of the cluster as belonging to the dorsal attention network. In addition, the participants with a higher genetic risk were found to have lower FC to the angular gyrus, another major hub of the dorsal attention network. The FC between caudate and parts of the prefrontal cortex, namely orbitofrontal as well as inferior frontal gyrus showed an increase in FC for participants with higher genetic risk. The FC between the ventral striatum and other parts of the striatum increased for higher genetic risk and decreased for connection to the precuneus. Whole-brain seed-based FC from the ventral pallidum was not significant.Table The putamen demonstrates a pronounced reactivity to L-DOPA. In participants with a high genetic load, the connectivity between putamen, the superior parietal lobe, and the precuneus was increased by L-DOPA. This was not found for the caudate as a seed region. The nucleus accumbens demonstrated a wide loss in connectivity for a range of clusters from right Insula, occipital lobe, and frontal medial gyrus. These areas are part of the salience network and present with a decreased connectivity during L-DOPA-challenge in those patients with a higher genetic risk. The ventral pallidum demonstrated a decrease in FC to the precentral gyrus in those individuals with a higher genetic risk.P = 0.23), MDD (P = 0.29) nor body height (P = 0.29) showed significant correlation with putamen–precuneus connectivity during dopaminergic stimulation, suggesting that this effect is specific for the ADHD PRS.For evaluation of the PRS’ specificity, we extracted the functional connectivity for each participant from the putamen–precuneus connectivity during the L-DOPA challenge. We correlated this with the individual PRS for schizophrenia, MDD, and body height. Neither schizophrenia PRS , placebo genetic risk, and L-DOPA challenge genetic risk.A schematic overview of the result’s directionality is given in Fig. In ADHD patients, the caudate seed showed stronger connectivity to the prefrontal cortex than in healthy controls. Such hyperconnectivity was previously reported for ventral caudate connectivity to the PFC and is interpreted as neural equivalent of cognitive control over emotional circuits via connections with PFC, ACC, and amygdala. In contrast, dorsal caudate connectivity has been linked to cognitive control over networks dealing with initiation of action and directed movement . HoweverWhile previous studies have shown that the caudate is more tightly linked to fronto-executive circuitry, it is, therefore, plausible to expect more changes in FC from the seed putamen to the limbic system.In HC, the putamen showed more FC to the superior parietal lobe and the precuneus in comparison to ADHD cases. The superior parietal lobe is a major hub of the so-called dorsal attention network (DAN)  The connThe nucleus accumbens showed a significant increase of connectivity with a higher genetic ADHD risk to the putamen, pallidum and the precuneus. When probed by L-DOPA, this relation was inverted, pointing to a genetically mediated dopaminergic mechanism. Interestingly, this mechanism has no simple correspondence in our ADHD sample, where we could not detect significant NAcc-connectivity differences between HC and ADHD patients. Indeed, several studies in children and adolescents point to enhanced striatal connectivity in NAcc-related connectivity , 35. WhiThe ventral pallidum is of special interest, as a recent study demonstrated that the nucleus accumbens’ dopamine-D2-receptors increase motivation by decreasing inhibitory transmission to the ventral pallidum . This suThe punchline in our study is the dopaminergic challenge: when people with a higher genetic risk (high PRS) receive L-DOPA, increasing their dopamine levels, the functional connectivity increases as well during the dopaminergic challenge. This suggests that people with a genetic predisposition to ADHD have a connectivity fingerprint which (i) resembles ADHD in the DAN and (ii) which is strongly modulated by an acute dopaminergic challenge. This can be interpreted as the basis of psychopharmacological treatment. In participants with a higher genetic risk, L-DOPA leads to an increase in functional connectivity in the dorsal attention network but a decrease in the accumbens-related connectivity in the salience network. When interpreted with ADHD in mind, this demonstrates that dopamine is able to shift connectivity patterns from a “hot” subcortical salience network to a “cold” cortical attention network. Such a distinction between “hot” and “cold” circuitry has been proposed to underly ADHD-related network pathology .A recent meta-analysis of more than 700 patients with ADHD documented decreased connectivity between the FPN and the dorsal attention network, as well as the somatosensory network. The latter is comparable to our description of a VeP-network. Furthermore, this meta-analysis documented a hyperconnectivity between the FPN and the affective networks and/or the salience network. The latter corresponds in our approach to the connectivity of the nucleus accumbens as well as the DMN . AccordiWe tested whether the increased reacticity to the L-DOPA challenge was specific for the ADHD PRS by calculating the correlation between FC and a schizophrenia PRS, a MDD PRS and as non-psychiatric control a body height PRS. As these non-ADHD PRS were not significant, we conclude that the effect is a specific feature of the ADHD PRS.A limitation of our study is the small sample of our explorative genetic analysis in the pharmaco-fMRI study. However, previous power analyses were made for single SNPs or haplotypes, and it is not yet clear whether the sensitivity for polygenic risk scores is better. In addition, it is possible that a pharmacological challenge provides a strong lever in terms of effect size. However, implicit in such a logistically demanding strategy  are low sample sizes. While such an approach has its conceptual appeal, it should be replicated in other (larger) samples. As other pharmaco-FMRI studies are available , we urgeAnother limitation of our pharmaco-study is the lack of receptor specificity in L-DOPA. L-DOPA has some sedating effects and is not specific for D1- or D2 receptors. Future studies should investigate the effect of PRS scores on D1- versus D2-receptor signaling pathways, as these have been discussed as having opposing effects .While we discuss our findings in the context of ADHD and its genetically constraint dopaminergic functioning, we must underline an important missing aspect: ADHD is a developmental disorder and the dopaminergic system undergoes changes from childhood, adolescence to adulthood which were beyond the scope of our study. This is exemplified by findings looking at U-shaped effects of striatal connectivity of resting-state-fMRI from childhood to adulthood . It mighA main advantage in comparison to large-scale studies combining genetics, brain imaging and clinical data, is that our analysis does not rest on purely correlational measures but is based on causal experimental challenge of the dopaminergic system. A drawback of such an approach with its requirements on regulatory and organizational aspects, is its small sample size, which might nevertheless be countered by a larger effect size. Large-scale studies should try to replicate our dopamine- and PRS-specific results in the future.How does dopamine mediate changes in connectivity? It is plausible that the PRS capture to some degree reactivity of the dopaminergic system: first, a recent study demonstrated an enrichment of dopaminergic gene ontologies in ADHD patients , and secThird, previous neurophysiological experiments point to the modulation of glutamatergic neurotransmission by dopamine , 45. ThiIn sum, our study replicated previous findings revealing a disturbed dorsal attention network in ADHD and in healthy participants dependent on the individual genetic ADHD risk. The DAN was sensitive to a dopaminergic challenge, and this was dependent on the individual genetic risk. Further striatal connectivity networks demonstrated a dependence of their reactivity to the dopaminergic challenge on the genetic risk, especially in accumbens-occipital FC. This indicates that the switch between a “hot” and a ”cold” network in ADHD  is media


Bartonella species. In the Americas, they were described as harboring Bartonella species; however, they were mostly characterized to the genotypic level. We describe here Bartonella isolates obtained from blood samples of one rodent  and two bat species  from Mexico. We sequenced and described the genomic features of three Bartonella strains and performed phylogenomic and pangenome analyses to decipher their phylogenetic relationships. The mouse-associated genome was closely related to Bartonella vinsonii. The two bat-associated genomes clustered into a single distinct clade in between lineages 3 and 4, suggesting to be an ancestor of the rodent-associated Bartonella clade (lineage 4). These three genomes showed <95% OrthoANI values compared to any other Bartonella genome, and therefore should be considered as novel species. In addition, our analyses suggest that the B. vinsonii complex should be revised, and all B. vinsonii subspecies need to be renamed and considered as full species. The phylogenomic clustering of the bat-associated Bartonella strains and their virulence factor profile (lack of the Vbh/TraG conjugation system remains of the T4SS) suggest that it should be considered as a new lineage clade (L5) within the Bartonella genus.Rodents and bats are the most diverse mammal group that host  Bartonella species are Gram-negative, facultative intracellular bacteria, transmitted by arthropods, infecting mammalian erythrocytes and endothelial cells [Bartonella species is reported in rodents and bats [Bartonella pathogens [Bartonella genus [al cells . Currental cells ,3. As thand bats ,5,6, rodathogens . Moreovela genus .Bartonella DNA in samples of rodents and bats in the Americas [Bartonella species detected or isolated in mammal hosts, especially in the Americas has not been fully described and has yet to be investigated and elucidated [Bartonella genomes acquired from Mexican rodents and bats. We analyzed their phylogenomic relationships and genome divergence among all known Bartonella species.Several studies described the presence of Americas ,13,14,15Peromyscus yucatanicus). Strains A05 and F02 were isolated from the blood of a common vampire (Desmodus rotundus) and a Parnell mustached bat (Pteronotus parnellii), respectively. The blood samples from these three strains were cultured on chocolate agar plates using 200 µL blood and M199 growth media with 5% amphotericin B. Suspected Bartonella colonies were re-plated and the DNA was extracted and submitted to conventional PCR to confirm that they belong to the Bartonella genus. Target genes of Bartonella from these samples are available in GenBank . After confirmation as Bartonella, the three samples were subjected to WGS.Blood samples were obtained from three different sites in Mexico in previous studies ,15. A ro260/280 and A260/230 > 1.5) with an average insert size of 350 bp according to the KAPA HyperPlus Kit protocol as described previously [The genomic DNA extraction was performed following growth on chocolate agar. Isolates were selected and the gDNA was extracted after lysis using Qiagen DNeasy blood and tissue kits . Each saeviously ,17,18,19eviously ,21.Bartonella using the software Orthologous Average Nucleotide Identity Tool (OAT v.0.93.1) [The whole genome sequences were trimmed, quality filtered, and quality assured using TrimGalore (v.0.5.0) . The tri.0.93.1) ,32. Deli.0.93.1)  and Ciuf.0.93.1) , conside.0.93.1) .Bartonella lineages were classified according to their virulence factors  following Wagner and Dehio [Bartonella genomes were retrieved from the NCBI database and analyzed by Geneious program v.7 . All the cassettes of virulence factor genes found in their genomes were evaluated and indicated on a phylogenetic tree.The nd Dehio . The seqBartonella genus was determined by the same genome sequences used in other analyses, including the Brucella abortus as an outgroup. The quality of genome sequences, contamination, completeness, and gene markers of lineage was performed using the CheckM [The pangenome of the e CheckM . The Proe CheckM . Core gee CheckM . To evale CheckM . A neighe CheckM . The “roe CheckM . Gene pre CheckM .Bartonella isolates were sequenced and their genome features are described in Bartonella strains A05 and F02 from bats of the species D. rotundus and P. parnellii, respectively. The topology of these two strains appears as a single branch of lineage 4 located between lineages 3 and 4 suggesting that it is an ancestor clade of the rodent-associated Bartonella  and 81 soft core genes (95–99%) was observed for 60 genomes. The known lineages (1–4) were recovered from the 1668 genes (15–95%). The unique genes were the most representative of the genus with 37,655 genes. Strain 220B contains more genes shared with the B. vinsonii complex and with the rodent-associated Bartonella clade. The two bat-associated strains, A05 and F02, do not share the same cassettes of shell genes shared with other lineages. The pangenome analyses show that the Bartonella species are significantly different among each other  and according to Goris et al. [Bartonella genome analysis and their OrthoANI values (cut-off less than <95%), they should be considered as three novel species of the genus Bartonella. However, to fully describe and name these bacteria as new species according to the International Code of Nomenclature of Prokaryotes (ICNP), the characterization of several phenotypic, biological, and biochemical aspects of the bacteria must be carried out in addition to the isolation and WGS [The genus enotypes ,44. In ts et al. , the Bar and WGS .Bartonella genotypes from the Yucatan dear mouse (P. yucatanicus) based on target genes and named strain 220B as Bartonella vinsonii subsp. yucatanensis; however, according to our analysis, its OrthoANI values of 90–91% indicate that it is a distinct species within the B. vinsonii complex. Our results support recent findings described by Amaral et al. [B. vinsonii complex needs to be revised, as the subspecies already described and named in this complex have OrthoANI values less than 95% between them  in different niches of mammalian host cells [Bartonella genus , the ruminant-associated Bartonella spp. [Bartonella strain isolated from D. rotundus which was not associated with L2, and belongs probably to a new lineage, distant from those described in previous studies.Two bat-associated complete genomes were annotated herein and indicated that they are new species with high divergence across the cies see . The twolineages . The L4 rnivores . The twolagellum ; howeverlagellum , these gplasmids . Most ofke genes . This tyst cells . The Bepla genus . Bats foy et al. , with eih Guiana ,55. The es virus . Due to es virus . In addies virus . From th America ,58,59,60Bartonella species showed high variability of unique genes compared with shared and core genes. The pangenome analysis indicated that the strains described herein should be considered as new species. Additionally, the genetic distance cut-off  and core genes similarity (%) should be established for Bartonella, as previously conducted for Hungatella hathewayi, a necessary step toward evaluating the intrageneric diversity [According to the pangenome analysis that was carried out in this study, the iversity .Bartonella species described herein that need further characterization in order to be fully named according to the ICNP. Based on phylogenomic clustering and virulence factors, the bat-associated Bartonella species, presented in this study, suggest the possibility of a new fifth lineage in the genus. Additionally, the analysis of OrthoANI values carried out herein suggests that there is a need to revise the B. vinsonii complex.A deeper understanding of the evolutionary diversification observed in this genus is made possible by the characterization and description of additional genomes in rodents and bats. Our study using genomic approach shows that in Mexico, there are at least three novel


Attention-deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders in childhood and is caused by both genetic and environmental factors. As genetic factors are nonmodifiable, environmental factors have attracted increasing attention.To investigate the relationships between urinary chlorpyrifos (CPF) levels, blood micronutrient levels, and ADHD prevalence in children living in rural areas of China.Diagnostic and Statistical Manual of Mental Disorders, 4th Edition. Descriptive statistics and univariate analysis were conducted using SPSS 21.0, and path analysis was conducted using Mplus 8.0.This cross-sectional study collected data on CPF exposure (according to urinary levels), blood micronutrient levels, and ADHD prevalence in children aged 1–6 years in rural China. The CPF levels were determined by mass spectrometry. Blood levels of micronutrients, including zinc, iron, calcium, copper, magnesium, and vitamin D, were measured by professional detection kits. ADHD was diagnosed according to the P < 0.05), with a direct effect of 0.197 (P < 0.05) and an indirect effect of −0.031 (P < 0.05) via vitamin D. The mediating effect of urinary CPF levels on ADHD risk via vitamin D was 18.67%.Of the 738 children who met the eligibility criteria, 673 children  were included in the final analysis. Baseline questionnaires and urine samples were collected from all 673 subjects. A total of 672 children provided blood samples for micronutrient testing, and 651 completed the ADHD assessment. Approximately one-fifth of children  had detectable levels of CPF in their urine, and 6.9% (45/651) were diagnosed with ADHD. Path analysis showed that the total effect of CPF exposure on ADHD risk was 0.166 (Higher levels of CPF exposure are associated with higher risk of ADHD. Additionally, increasing vitamin D levels may have a beneficial effect on the relationship between CPF exposure and ADHD risk. Our findings highlight the importance of modifying environmental factors to reduce ADHD risk and provide insight into future ADHD interventions. Attention-deficit/hyperactivity disorder (ADHD) is a neurological disorder characterized by persistent difficulty in regulating attention and affects 3.4 to 7.1% of school-aged children . EmpiricChlorpyrifos (CPF) is one of the most widely used organophosphorus pesticides and an important environmental pollutant. Due to its persistence and bioaccumulation in the environment, exposure to CPF is unavoidable. Recently, the neurotoxicity of CPF has attracted increasing attention. The classic manifestation of CPF-induced damage to the nervous system is cholinergic syndrome, which is caused by acute poisoning and is characterized by the inhibition of cholinesterase activity. Chronic exposure to low-level CPF may have long-term adverse effects on the structure and function of the nervous system, increasing the risk of neurodegenerative diseases and neurodevelopmental disorders . Most prNutrition and diet are also important environmental factors that influence the risk of ADHD . RecentlTo address the above two research gaps, this study aimed to investigate the relationships among urinary CPF levels, blood micronutrient levels, and ADHD risk in children aged 1–6 years. Based on the findings of previous studies, we made the following hypotheses: (1) exposure to CPF is a risk factor for ADHD; (2) micronutrients are protective factors against ADHD; and (3) micronutrients mediate the relationship between CPF exposure and ADHD risk.Medical Statistics textbook, we determined that the minimum sample size required in each of the three areas was 200 children. We administered questionnaires, assessments of urinary CPF levels, blood micronutrient assessments, and ADHD diagnosis to all eligible children.Using cluster sampling, we selected Xinhua County in Hunan Province, Sansui County in Guizhou Province, and Gong’an County in Hubei Province to represent mountain, hill, and plains regions, respectively. In each of the three counties, three villages were randomly selected. All children aged 1–6 years in these villages were observed, except for those with the following conditions: (1) abnormal birth history, such as premature birth, multiple pregnancy, or birth asphyxia; (2) a history of head trauma; or (3) a history of serious diseases, such as genetic metabolic diseases, congenital abnormalities, feeding difficulties, severe malnutrition, recurrent respiratory diseases, or severe abnormalities of liver or kidney function. Based on the sample size recommendation for path analysis  and the Prior to the field test, we verbally explained the purpose and process of the study to the parents of all children and emphasized the confidentiality of the data. The parents of all included children provided written informed consent. This study was strictly conducted according to international guidelines for the protection of human subjects and was approved by the Ethics Committee of the Third Xiangya Hospital of Central South University in Hunan, China. The ethics review number is 2014S162.The urine samples were collected and analyzed as follows: 20–30 ml of morning urine was collected using disposable sterile urine cups; this sample was further divided into 5-ml polypropylene bottles. Each sample was numbered and recorded. All urine specimens were sent to the laboratory within 24 h of collection and stored at −80 °C until analysis.μm filter, and GC‒MS analysis was performed.Before the gas chromatography–mass spectrometry (GC‒MS) analysis, acetonitrile was added to the urine samples, and they were vortexed for approximately five minutes. NaCl was then added, and the mixture was vortexed for approximately one minute. The supernatant was pipetted into a rotary steaming flask, evaporated until nearly dry, and then diluted to a volume of 1 ml with ethyl acetate. This solution was transferred to an Eppendorf (EP) tube with 50 mg of primary secondary amine (PSA), vortexed for 30 s, and centrifuged at 8,000 r/min for four minutes. Finally, the supernatant was passed through a 0.22-Measurements of the CPF levels were performed as described elsewhere using GC‒MS analysis (Agilent GC7890A-5975). Laboratory quality control parameters for CPF levels were verified with reference to NY/T 788-2004 Pesticide Residue Test guidelines, which is the agricultural industry standard in China.We collected venous whole blood samples from children in the morning after an overnight fast; these samples were refrigerated, transported, and stored until analysis. Measurements of micronutrients were conducted within 48 h after collection.Vitamin D measurements were carried out using an enzyme-linked immunosorbent assay (ELISA). Monoclonal antibodies were used to detect 25-OH-D in whole blood samples with kits provided by the Oumeng Company (Germany). Calcium, iron, zinc, copper, and magnesium levels were all determined by atomic absorption spectrometry using Beijing Bohui Company's innovative photoelectric technology BH7100S. A total of 40 μl of whole blood was added to the instrument, and the samples were atomized by flame combustion, producing numerous ground-state free atoms that absorbed the characteristic spectrum of the measured elements emitted through a hollow cathode lamp. The levels of vitamin D (25-OH-D), calcium, iron, zinc, copper, and magnesium were treated as continuous variables. The blood level of lead was treated as a categorical variable (>10 µg/dl or ≤ 10 µg/dl), according to the levels of blood lead toxicity proposed by the Chinese Centers for Disease Control and Prevention (CDC). Laboratory quality control parameters for micronutrient assessment were conducted between laboratories in China every year and acquired the certificare from the national center for clinical laboratories.The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV) was used to evaluate ADHD in children aged 1–6 years. The evaluation consists of two parts, including nine symptoms of attention deficits and nine symptoms of hyperactive/impulsive behavior. An individual is diagnosed with ADHD if they exhibit six or more of the nine symptoms in one of the two dimensions and if these symptoms persist for at least six months. The ADHD outcome (with or without an ADHD diagnosis) was treated as a categorical variable.We used questionnaires to collect demographic characteristics and medical information from the children, such as age, sex, date of birth, primary caregiver and their educational level, annual family income per capita, maternal age at pregnancy, weight at birth, and breastfeeding history. The questionnaire consisted of a one-on-one survey with the children's primary caregivers. The investigators were uniformly trained before administering the survey.P < 0.05) identified in the univariate and correlation analyses and demographic characteristics related to ADHD risk  were included in the next step of the path analysis (χ2 goodness-of-fit statistic (χ2/degrees of freedom [df]), comparative fit index (CFI), Tucker and Lewis's index of fit (TLI), and root mean square error of approximation (RMSEA). A model was considered to exhibit acceptable fit if it met the following criteria: χ2/df <5, RMSEA <0.08, TLI >0.90, and CFI >0.90.All data analyses were conducted using SPSS version 21.0 for Windows  and Mplus 8.0 . The mean (standard deviation [SD]) or the median (25th and 75th percentiles [P25 and P75]) were used to describe the distribution of continuous variables based on the normality of their distribution; n (%) were used to describe categorical variables. Nonparametric tests, t tests, nonparametric tests, or chi-square tests were used for univariate analysis. Pearson or Spearman correlation analyses were then conducted to examine the correlation among all study variables. Prior to the path analysis, we used logistic regression analysis to examine whether there were significant interactions between micronutrients  and CPF levels. As shown in analysis , 25. TheOf the 738 children who met the eligibility criteria, 673 (91.2%) were included in the final analysis. Baseline questionnaire data and urine samples were collected from these 673 subjects. A total of 672 children provided blood samples for micronutrient testing, and 651 completed the ADHD assessment . The meaThe distributions of lead levels and descriptive statistics of each variable, including levels of zinc, iron, calcium, copper, magnesium, and 25-(OH)-D, are shown in Approximately one-fifth of children  had detectable levels of CPF in their urine. The number of positive samples and their corresponding CPF concentrations are shown in a histogram .In total, 45 children were categorized as having ADHD, a positive rate of 6.9% (45/651). As shown in P < 0.05; see The correlation results showed that vitamin D levels and age in months were positively correlated with CPF exposure, that annual family income per capita and vitamin D levels were positively correlated with ADHD risk, and that primary caregiver education was positively correlated with vitamin D levels (P < 0.05) as well as an indirect effect via vitamin D levels . The mediating effect of urinary CPF levels on ADHD risk via vitamin D was 18.67%.The path model showed good fit, as shown by the normed chi-square value of 2.37, RMSEA of 0.048, TLI of 0.901, and CFI of 0.984. As shown in In the present study, we investigated the relationships among urinary CPF levels, blood micronutrient levels, and ADHD risk in rural Chinese children aged 1–6 years. Consistent with our hypotheses, we found that (1) CPF exposure was a risk factor for ADHD; (2) higher levels of vitamin D may reduce the risk of ADHD; and (3) vitamin D levels mediated the relationship between CPF exposure and ADHD risk.This cross-sectional study investigated CPF levels in children's urine and found that 21.4% of children had detectable CPF levels. In 2016, a cross-sectional study of 140 children living near a banana plantation in Talamanca, Costa Rica reported that 40.7% (57/140) of children had urine samples positive for the CPF metabolite 3,5,6-trichloro-2-pyridinol (TCPy) . In addiThe ADHD assessment revealed that 6.9% of children in rural China had ADHD in our study, a rate similar to that in previous studies of children in mainland China (6.3%) . Our stuin situ, upregulating the synthesis of nitric oxide synthase by glutathione; nitric oxide synthase has neuroprotective and neuromodulatory functions , which are more direct and consequential for verifying the impact of environmental factors. Univariate and multivariate analyses revealed that vitamin D levels have a protective effect against the risk of ADHD, a finding consistent with the results of previous studies. Accumulated data suggest that decreased levels of vitamin D may also be a significant risk factor for ADHD –38 and tunctions –44. Addiunctions . Furtherunctions –48. TherFurthermore, path analysis showed that CPF exposure was significantly correlated with vitamin D levels. The interaction between CPF and Vitamin D was studied in lab experimental setting. Krzysztof et al. reported that CPF can interfere with vitamin D3 metabolism in skin cells by altering the expression of the vitamin D3 receptor and enzymes such as CYP27A1, CYP27B1, and CYP24A1 , 50. As This study has several limitations. First, our study was based on cross-sectional data. Further research using a longitudinal design is needed to confirm the causal relationship between CPF exposure and ADHD risk. Second, there may be self-report bias regarding ADHD. Future research should consider using different forms of data collection to verify whether such measurement bias exists. The third limitation of our study is the possibility of residual confounding, which can not be fully eliminated in an observational study. For example, in this study we did not include children's allergy history and eating behaviors, which may result in biases in our analyses. These variables should be taken into consideration in future studies , 52. FinIn conclusion, we investigated the relationships between CPF exposure, ADHD risk, and micronutrient levels in rural Chinese children aged 1–6 years. We found that exposure to CPF was a risk factor for ADHD in children and that higher levels of vitamin D protected against ADHD. Supplemental vitamin D for children may thus help protect against ADHD risk in children exposed to CPF. Our findings provide insights for future ADHD interventions that involve modifying environmental risk factors, such as reducing CPF exposure and increasing vitamin D intake, to reduce ADHD risk.


The olefin metathesis reaction has found numerous applications in organic synthesis. This is due to a number of advantages, such as the tolerance of most functional groups and sterically demanding olefins. This article reviews recent advances in the application of the metathesis reaction, particularly the metathetic cyclization of dienes and enynes, in synthesis protocols leading to (hetero)aromatic compounds. Transition-Metal-Mediated Aromatic Ring Construction was published with a chapter by Yoshida on olefin metathesis ..14].Of the many types of olefin metathesis, the most useful in organic synthesis are the cross-metathesis of olefins (CM) and the metathetic cyclization of dienes (RCM) .The mechanism of olefin metathesis also allows for transformations involving triple bonds, i.e., ene-yne cross-metathesis (EYCM) and enyne ring-closing metathesis (RCEM) (Metathetic transformations of the triple bond can lead to a mixture of regio- and stereoisomers . Fortuna3)(CF3)2}2M=CH] (Mo-1)  (Mo-1) . AlthougOlefin metathesis has gained a number of applications in advanced organic synthesis, chemical biology, medicinal chemistry, the synthesis of simple molecules, and the total synthesis of natural products ,2,3,4.Olefin metathesis, especially ring-closing metathesis (RCM), has been extensively used in the synthesis of heteroaromatic compounds of divergent types. It has been exploited efficiently as a key step for the preparation of the pyrroles, furans, pyridines, imidazoles, and related systems. All of these compounds are largely important as structural units in natural products and are used as synthons in further transformations. In this section, different approaches to the synthesis of heteroaromatic compounds using olefin metathesis as a key step are reviewed. The syntheses of heteroaromatics involving olefin metathesis as one of the key steps has been summarized in several reviews ,25,26,27This section presents various strategies for the synthesis of heteroaromatic compounds by using olefin metathesis as a key step. Knowledge on the synthesis of heteroaromatic compounds involving olefin metathesis as one of the key steps has been summarized in several review papers ,25,26,27Since pyrrole and furan synthons are commonly present in many pharmaceuticals and biologically active molecules, the efficient synthesis of these compounds continues to be of interest to organic chemists. In 2015, Castagnolo and co-workers described an elegant methodology that represents the first example of one-pot synthesis of substituted pyrroles via enyne cross-metathesis (CM) cyclization reaction, using propargylamines and ethyl vinyl ether as reagents. The described CM/cyclization protocol is performed in the presence of Ru-2, is microwave-assisted, and offers a convenient approach to the synthetically challenging 1,2,3-substituted pyrroles  28]..28].H)-ones . Th. ThN-sula]quinoline derivatives as novel near-infrared absorption dyes [a]quinoline derivatives from substituted N-allyl-N-benzylanilines  giving the intermediates nearly quantitative yields. Unfortunately, the electronic effects of substituents on the aromatic ring were responsible for the low substrate reactivity during the 1,3-dipolar cycloaddition step. It was observed that substrates bearing an electron-withdrawing group in the aromatic ring afforded higher yields in the 1,3-dipolar cycloaddition, thus giving the target molecules overall yields ranging from 22 to 55%.In order to understand a structure and absorption−wavelength relationships, the authors performed calculations by using a time-dependent density functional theory (TD-DFT).Whiting and Carboni showed a different approach to the synthesis of pyrroles . In the Second step involved a nitroso-Diels–Alder reaction between a series of previously obtained dienyl boronic esters and nitrosoarenes with the formation of a heteroaromatic ring .The authors developed a new and efficient route to a series of cyclic 1,3-dienyl boronic esters via diene or enyne metathesis that were further transformed with good yields to fused pyrroles, using a one-pot nitroso-Diels−Alder/ring contraction sequence.The unprecedented cascade procedure based on the Grubbs-catalyzed ring-closing metathesis of diallyl ethers, followed by laccase/TEMPO-catalyzed aromatization, was successfully developed by Castagnolo  39]. Th. Th39]. 3C-symmetric star-shaped phenyl and triazine central cores bearing oxepine and benzofuran ring systems  and investigated an alternative method of double-bond migration, using potassium tert-butoxide (KOt-Bu) in THF. Isomerization products were obtained as a mixture of isomers in 89–94% yields. The final step in the construction of the heteroaromatic ring involved an RCM step, providing the corresponding benzofurans, with a yield of 84–85%. Using the proposed procedure, a wide range of products differing in the substituents on the 6-membered ring was obtained. In addition, naturally occurring benzofurans, such as 7-methoxywutaifuranate, were also synthesized with good yields (80%), using the described protocol  and its derivatives based on a ring-closing metathesis reaction of pyridinium azadienes in the presence of the second-generation Grubbs catalyst (Ru-2) or Hoveyda–Grubbs catalyst (Ru-3) (a]isoquinolinium) cation by RCM   44]. Th. Tha]pyrn by RCM . The proα-aminonitrile in a two-step approach. At first Strecker reaction starting from benzaldehyde, allylamine, and potassium cyanide was performed to afford 2--2-phenylacetonitrile. Then deprotonation with the use of KHMDS, followed by alkylation with allyl bromide, was applied to give corresponding diallyl-substituted α-aminonitrile. Finally, the RCM of unprotected allylic amine and subsequent spontaneous dehydrocyanation and oxidation were employed as the key steps of the developed sequence . Finally, dihydropyridoindoles were effectively transformed into aromatic derivatives via a DDQ-mediated oxidative aromatization protocol aromatic compounds uses a metathesis step in a sequence of reactions involving the formation of a carbo- or heterocyclic ring and its subsequent aromatization. The sequence using the diene RCM step is shown in RCM enynes (RCEM) and ene-yne cross-metathesis  are usedRecently, Dash overviewed applications of RCM for the synthesis of carbazoles and indole-fused heterocycles .A new method for the synthesis of carbazoles via ring-closing metathesis of 2,2-diallyl-3-oxindoles, followed by ring-rearrangement aromatization of the resulting spirocyclic indoles, was proposed by Dash and co-workers  51]. Th. Th51]. N-substituted isatins   a, starti analog) b 52]..b]benzofRCM proceeded efficiently in the presence of a second-generation Grubbs catalyst under mild conditions and was followed by dehydration step performed in the presence of pyridine hydrochloride .The benzofuran core was obtained by dehydrogenative aromatization of diene ring, using 2,3-dicyano-5,6-dichlorobenzoquinone (DDQ) .Tokuyama and co-workers reported the catalytic activity of ruthenium alkylidene complexes in the aerobic catalytic dehydrogenation of nitrogen-containing heterocycles with dioxygen as an oxidant . The reaThe usefulness of the Tokuyama procedure was demonstrated by its application to the synthesis of the natural antibiotic pyocyanin.Most of synthetic effort in the synthesis of simple hetero- and carboarenes via metathesis was performed during the huge development of olefin metathesis applications in organic synthesis and is described in previous reviews ,8,10. CuLobo and co-workers reported a procedure for obtaining terephthalates, which includes the use of the CM, Diels–Alder cycloaddition and dehydrogenative aromatization sequence  54]. Th. Th54]. The highest activity of the cross-metathesis step was achieved in the presence of modified Hoveyda–Grubbs catalyst Ru-6 .Ward described a procedure of the generation of monosubstituted aromatic rings that uses a ring-closing metathesis and spontaneous 1,2-elimination sequence  55]. Th. Th55]. The sequence ene-yne cross-metathesis, Diels−Alder cycloaddition, and aromatization were applied to synthesize a series of biaryls, starting from alkynes . In the o-terphenyls can be synthesized from easily accessible substituted benzils. The proposed synthetic pathway involves RCM for the synthesis of a tricyclic skeleton and subsequent aromatization step. It enables the synthesis of symmetrical and unsymmetrical o-terphenyls containing both electron-rich and electron-deficient groups  was observed. For maximum aromatization efficiency, the crude cycloaddition product was immediately treated with trimethylamine and silica gel. The method yielded a library of sugar–oxasteroid–quinone hybrids.a]anthracenes and related compounds [De Koning and co-workers proposed novel methods for the assembly of benz[ompounds . Their sExamples of structures of antibiotics from the angucycline group are shown in d]azepines starting from Wang resin-immobilized allylglycine was reported by Soural [The solid-phase synthesis of numerous polycyclic tetrahydroisoquinolines and tetrahydro-benzo[y Soural . SubsequRecently, Sparr and co-workers reported on the great potential of metathesis in the atroposelective formation of arenes . The autIn the presence of commercially available molybdenum catalysts , enantioIn order to optimize the yield and enantioselectivity, tests were carried out in the presence of a series of catalysts obtained in situ by reacting a dipyrrolyl molybdenum precursor with binaphthol ligands differing in stereoelectronic properties .It was shown that the most enantioselective catalyst was the binaphthyl complex containing pentafluorophenyl substituents. Under optimized conditions, a variety of conformationally dynamic triene substrates were efficiently and enantioselectively converted into binaphthyl atropisomers .Finally, Tanaka and co-workers discussed the possibility of using RCM for the in vivo synthesis of cytostatic agents . Thus, cThe promising results show new possibilities for the use of artificial metalloenzymes and metathesis cyclization in pro-drug therapy.para-phenylene) macrocycle were reported by Merner and co-workers [syn diastereomer.Cycloparaphenylenes have gained the interest of many research groups in the hope that these systems can be used for the bottom-up chemical synthesis of carbon nanotubes ,64. A se-workers ,66,67,68p-terphenylophane to m-terphenylophane, which was observed for the arene-bridged macrocycle  aromatization through aerobic oxidation eliminates the need for strong oxidants, which can expand the reaction scope and/or improve the yields achieved. A fascinating idea is to use RCM for the synthesis of atropisomers, using metathetic cyclization of conformationally dynamic trienes. The development of the method may open up a new area of application of metathetic cyclization in the asymmetric synthesis of aromatic compounds. Exciting reports have been made on the syntheses of macrocyclic aromatic strips with high ring strain. The efficient synthesis of linear ladder polymers with a stiff coplanar structure has been achieved using the strong thermodynamic driving force of aromatization. Due to the stiffened structure, such polymers exhibit improved physicochemical properties compared to non-ladder analogues. Finally, the possibility of using metathesis/aromatization sequences in the synthesis of prodrugs is described. This opens up a new and poorly explored area of research.The survey clearly shows that the field of research will continue to develop in the coming years. In particular, material and medicinal chemistry, in the broadest sense, remain an important and underexplored area of research.


Attention deficit hyperactivity disorder (ADHD) has a growing incidence and prevalence in the United States and throughout the world, much of which is contributed to increased awareness of the condition and solidified diagnostic criteria. Substance use disorder (SUD) similarly has seen a sharp increase, particularly with the rising cases of opioid abuse. Management of ADHD is done primarily with pharmacologic therapy, often stimulants and with psychosocial interventions  for adjunctive management. Management of SUD involves cessation and treatment based on the underlying drug of abuse. Many clinicians are uncomfortable treating ADHD in patients with SUD based on concerns the intervention may lead to an adverse event, including drug relapse, and the development of other psychiatric comorbidities. Concerns also arise about stimulants acting as a gateway drug in adolescents leading to the onset of SUD.Thus, in this narrative review, we aim to shed light on ADHD in relation to SUD and to provide clinical insight based on the current scientific literature on the topic. ADHD causes lesions in subcortical structures in the basal ganglia and limbic system. Treatment of ADHD with stimulants has been shown to normalize malformed neuroanatomical variations and lead to improved long-term outcomes compared to non-treatment of ADHD. Based on current scientific literature, it is recommended to treat ADHD with guideline-directed pharmacologic agents including stimulants along with non-pharmacologic interventions primarily exercise. There may be some improvement in reducing risky behavior, such as substance abuse, and may even help prevent the development of SUD. EpidemiologyAttention deficit hyperactivity disorder (ADHD) is diagnosed in patients who show patterns of persistent impulsivity, hyperactivity, and inattention. The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) is the leading resource for physicians to classify symptoms and in creating the diagnostic criteria for ADHD. Some of these symptoms include careless mistakes in schoolwork, inability to hold a conversation, distractibility, and losing items for daily tasks . ADHD remains a diagnosis in adolescents less than 17 years of age however, the diagnosis in adults is made based on refined criteria [The prevalence of ADHD has increased substantially. Globally, 2%-7% of people have been diagnosed . Data frAdolescent substance abuse is considered to be the number one public health threat in the United States by multiple public health organizations. Adolescents diagnosed with substance use disorder (SUD) often have comorbid psychiatric conditions including depression, anxiety, and ADHD. Management of SUD involves removal of the offending agent and avoidance of medications known to increase addictive behaviors, which are often used in the management of ADHD . Co-manaPathophysiology of ADHDA proposed pathophysiologic mechanism for ADHD is secondary to catecholamine imbalance of dopamine (DA) and norepinephrine (NE). The prefrontal cortex (PFC) is integral for executive functions such as working memory and attention regulation . The PFCADHD managementPharmacologic management for ADHD is categorized into two categories: stimulants and non-stimulants. The mechanism of action for stimulants includes a synaptic blockade of the reuptake of catecholamines such as dopamine (DA) and norepinephrine (NE) and the direct release of catecholamines into the synaptic cleft leading to increased neurotransmission. Examples of such stimulants include amphetamine/dextroamphetamine and methylphenidate. Non-stimulants function as NE reuptake inhibitors or as alpha 2 agonists. Atomoxetine, viloxazine, guanfacine, and clonidine are categorized as non-stimulants. Atomoxetine and viloxazine are NE reuptake inhibitors. Guanfacine and clonidine are alpha 2 agonists . Non-pharmacologic treatment modalities are available for ADHD as alternatives to pharmacotherapy but there is limited evidence to suggest substantial efficacy. Examples of holistic modalities include, but are not limited to, physical exercise, changes in diet, various supplements , mindfulness, and biofeedback techniques. Unlike FDA-approved pharmaceutical products, most alternative treatments for ADHD have not been studied in randomized controlled trials. Digital health interventions such as wearables and smartphone apps may also hold potential as non-pharmacologic interventions . EvidencSUD managementManagement of SUD in adolescents requires close communication between the individual, physician, and family. Psychosocial interventions continue to be the main-stay management of SUD. These interventions are mediated through family-oriented therapy and cognitive behavioral therapy. Many of these interventions hope to uncover underlying triggers and social pressures that promote young individuals towards substance abuse. And by addressing these concerns, cessation of usage can be achieved . Supportive management is indicated and has shown some efficacy in being useful. Other interventions include mindfulness-based meditation and exercise; however, further research is needed in this field to assess long-term abstinence. Pharmacologic-based intervention for SUD is substance-specific. For example, managing nicotine abuse is best done with nicotine replacement therapy. Alcohol abuse with naltrexone or acamprosate, and opioid abuse through buprenorphine and methadone. Selective serotonin reuptake inhibitors (SSRIs) are also used in SUD with comorbid psychiatric conditions . Cases oWith the rising cases of ADHD and the increasing prevalence of SUD, co-managing these two conditions continues to be an area of difficulty amongst some clinicians. We aim to give insight into evidence-based practices that have shown adequate co-management of both conditions and to shed light on the relationship between ADHD management and substance abuse disorder.We completed a literature search using PubMed/MedLine/PubMed Central with broad search terms related to ADHD and SUD. Further search terms included epidemiology, screening, pathophysiology, pharmacologic and non-pharmacologic interventions. No specific inclusion and exclusion criteria were utilized. Articles included original research, meta-analyses, and mixed systematic and meta-analyses. The review was completed with adherence to the Scale for the Assessment of Narrative Review Articles (SANRA) guidelines.Comorbidity of ADHD and SUDThe development of neuropsychiatric conditions like ADHD has long been considered a diagnosis of adolescents and may be correlated with childhood adversity. Similarly, SUD presenting in the adolescent years has had some correlation with adverse events in childhood. However, more research is needed on this hypothesis ,18. One Screening for ADHDScreening for ADHD in both childhood and adulthood is done using clinical algorithms and is one weapon in a clinician’s arsenal to tackle ADHD. One such algorithm that can be used in the screening for ADHD is the World Health Organization’s Adult ADHD Self-Report Scale (ASRS). The ASRS bases its criteria for screening on the Diagnostic and Statistical Manual (DSM-V) and is the most common algorithm used in the diagnosis of ADHD. A recent study pooling patients from both the United Kingdom and the United States showed overdiagnosis of ADHD based on the ASRS criteria. The study revealed an approximate 7-10 times over-prediction in the diagnosis of ADHD. Thus, the authors of this study point toward using accurate clinical assessments and controlling for other psychiatric conditions which may show increased impulsivity . Patients who screened positive for ADHD using the ASRS criteria were also found to have an increased prevalence of comorbid psychogenic non-epileptic seizures (PNES) compared to epileptic seizures in the epilepsy monitoring unit (EMU) . This pr(SUD) is a major public health threat in adolescents throughout the world. Screening for substance abuse in adolescents is imperative for the physician in improving morbidity and mortality in young people. Multiple screening tools have been used for this purpose. Commonly used screening tools include CRAFFT and DAST questionnaires. The utilization of these questionnaires aims to recognize substance abuse more readily with the hope of earlier intervention. The Screening, Brief Intervention, and Referral to Treatment (SBIRT) strategy was developed in the United States to tackle the immense public health threat that SUD poses . Recent Specific pharmacologic treatment strategies for ADHDTreatment recommendations for ADHD in children differ based on age group . Current guidelines do not recommend diagnosing ADHD below the age of four. Symptoms typically develop during school-age ages 6-12). Diagnostic workup initially should include evaluation for both psychiatric stressors and medical conditions. These acute stressors commonly affecting children at this age include tense interpersonal relationships between siblings and marriage difficulties between parents. The diagnosis of ADHD in adolescents greater than the age of 12 is less common, therefore physicians should be vigilant when screening for these acute stressors including school bullying and depression . First-l2. DiagnoAs clinicians, it is essential to consider the efficacy of various medications available for ADHD, including methylphenidate, amphetamines, and non-stimulants. Methylphenidate is most efficacious with reduced hyperactivity, impulsivity, and inattention in dosages around 0.3 to 0.6 mg/kg. It is available as a tablet, chewable tablet, or liquid. After six months, a discontinuation trial is recommended to reassess the severity of symptoms. Amphetamines are classified as single salt dextroamphetamine or amphetamine sulfate or as a mixed dextroamphetamine-amphetamine salt. It is available in tablets and oral solutions. Another amphetamine is lisdexamfetamine, a prodrug of dextroamphetamine. Formularies for lisdexamfetamine include immediate and sustained release  .Although highly efficacious for many patients, methylphenidate and amphetamines bear notable side effects. Common side effects are poor growth during childhood, weight loss in childhood, loss of appetite, sleep deficits, psychomotor irritability, and emotional disturbances. Mixed dextroamphetamine-amphetamine salts are associated with less weight loss but an increased likelihood of irritability when compared with methylphenidate. Less common side effects include, but are not limited to, increased heart rate, increased blood pressure, headache, dizziness, gastrointestinal discomfort, priapism, and peripheral vasculopathy. Preschool-aged children are at an increased risk of experiencing side effects than school-aged children. Contraindications to stimulant use in children and adolescents with ADHD may be considered when analyzing the risk of such stimulants. Contraindications include, but are not limited to, history of drug abuse, symptomatic cardiovascular disease, hypertension, hyperthyroidism, anxiety, motor tics or Tourette syndrome, glaucoma, and concurrent use or use within two weeks of monoamine oxidase inhibitors ,27.Alpha-2-adrenergic agonists, clonidine and guanfacine, are commonly used non-stimulant treatment options for ADHD. These medications are therapeutic for children with ADHD who need an adjunct to stimulant therapy or after stimulants and/or atomoxetine have failed. Clonidine can be prescribed in an extended-release form for children and adolescents aged six to 17 years . AdjunctGuanfacine may also be prescribed for adolescents aged six to 17 years as primary or adjunctive therapy to stimulants for ADHD. Guanfacine has fewer side effects and a longer half-life than clonidine. Both extended release and immediate release are available. However, guanfacine is still likely to produce a rebound increase in blood pressure once discontinued and should be tapered. Four randomized, double-blind studies have shown that extended-release guanfacine is efficacious and well-tolerated compared to placebo when treating ADHD in children and adolescents, including those with the comorbid oppositional defiant disorder (ODD) -32. CombNon-pharmacologic treatment options for ADHD and SUDNon-pharmacologic interventions proposed for the management of ADHD include mindfulness-based stress management, exercise, and meditation amongst others. Pharmacologic management of ADHD remains the long-term management option given its proven benefits, however, using non-pharmacologic interventions can be used for adjunctive management ,14. One Long-term outcomes of untreated ADHDADHD remains an underrated and under-treated condition. ADHD, when left untreated, has been shown to cause increased risky behavior, motor vehicle accidents, frequent breakups, and substance abuse . It can Relationship between pharmacologic management of ADHD and SUDThere is significant discussion about whether or not treating patients  with ADHD can lead to substance abuse later in life. This concern arises because methylphenidate, the most common medical treatment for patients with ADHD, has many similarities to other addictive medications such as cocaine and methamphetamines . Some liIn a sample of 900 college-aged participants, misuse of stimulants was found to be correlated with ADHD symptom severity. In this study, participants with ADHD were 2.90 times more likely to engage in stimulant misuse. Only 31% of individuals with ADHD possessed a stimulant prescription. Therefore, prescription status did not seem to play a significant role in increasing the likelihood of substance misuse. In addition, the results controlled for symptoms of the ODD, a common culprit linked to substance abuse . NotablyLacy et al. revealed an increased likelihood of self-administering cocaine in adolescent rats who previously received amphetamines. After observing this behavior in rats, the researchers concluded that patients on ADHD pharmacotherapy may present with an increased risk for substance misuse . Thus, tA meta-analysis evaluating fMRI studies found that long-term stimulant medication was associated with normal basal ganglia function . Thus, pScreening for ADHD is important however, improved screening criteria are recommended as overdiagnosis of ADHD based on ASRS guidelines has been noted. Non-managed ADHD poses significant adverse long-term outcomes including a greater prevalence of substance abuse. Non-managed ADHD has also shown long-term neuroanatomic alterations which may be irreversible. Current recommendations include using both pharmacologic and psychosocial interventions in the management of comorbid ADHD and SUD. The scientific literature does point in favor that stimulant usage in ADHD may help prevent the development of SUD. This is further supported by fMRI showing improved neuroanatomical function within subcortical structures notably the limbic system. Larger clinical trials looking at neuroanatomical structures in patients on pharmacologic therapy for ADHD with and without SUD are needed. Further studies looking at the long-term reduction in morbidity with control for other psychiatric conditions especially ODD are also needed.


These themes were: Creativity, Being dynamic, Flexibility, Socio-affective skills, and Higher-order cognitive skills. Core symptoms of ADHD such as impulsivity and hyperactivity were also considered positive aspects of ADHD by a minority of participants. After showing our results to a group of additional individuals with ADHD (focus group) they confirmed the identified positive aspects of ADHD. They also helped us with the interpretation of our findings and mentioned certain positive aspects to be a consequence of living with ADHD (being open minded and being honest). In conclusion, experiencing positive aspects seems to be common in ADHD as almost all participants reported positive aspect of ADHD, these aspects cover many different domains. Awareness about ADHD's strengths might help individuals with ADHD and their environment to better cope with, accept or embrace their diagnosis and for example make educational or occupational choices that fit them well. To incorporate these positive aspects in the understanding of ADHD, future research should focus on quantifying strengths in ADHD, and on investigating the link between these aspects and clinical characteristics and how this new knowledge can be implemented in psychoeducation and find its way to education and occupational settings.Research in Attention-deficit/hyperactivity disorder (ADHD) has had a clear focus on treatment and the dysfunction in specific situation associated with the condition. However, self-report, observational and anecdotal evidence indicates that there are also positive aspects associated with ADHD. Research on the potential positive features in individuals with an ADHD diagnosis is still limited, especially studies with larger representative samples. Here we performed qualitative research to identify positive aspects and strengths associated with ADHD in a large convenience sample from the Dutch organization for people with ADHD, dyslexia and dyscalculia. We sent out open-ended questionnaires to the members of the organization, asking what they consider to be positive aspects of their ADHD. From the responses of individuals with ADHD ( Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, occurring in 5.9% of children . ADHD syThat ADHD may be associated with positive aspects, and/or strengths, is relatively unknown and an often neglected aspect in previous scientific literature. Recently, positive aspects of ADHD have gained attention. This fits well with a conceptual shift that is taking hold in the field of neurodevelopmental conditions, and is being championed by caregivers and individuals with those conditions. Slowly our society is starting to focus more on embracing diversity rather than excluding individuals with a diagnosis. “Neurodiversity” is a term that is often linked to this conceptual shift. One key assumption of neurodiversity is that all forms of neurological diversity might be valuable, depending on the environment, and that this diversity may also have some selective and evolutionary advantages , 15.Although research into positive aspects of ADHD is scarce, three studies aimed to study positive aspects associated with ADHD. Mahdi and colleagues performed a qualitative study to investigate abilities and disabilities in individuals with ADHD in five different countries, by organizing focus groups and interviews with in total 76 individuals with ADHD, and other stakeholders  . In theiIn addition to the qualitative research, there is also quantitative evidence for a link between the positive traits mentioned by individuals with ADHD and the ADHD phenotype. Most of these studies focused on creativity. Creativity is a broad concept and can be divided into different aspects such as convergent and divergent thinking and creative achievements. Divergent thinking, which entails coming up with different solutions for one problem, was found to be associated with ADHD . In addiAlthough the qualitative studies conducted so far offer a great and much needed exploration into the positive aspects of ADHD, they rely heavily on studies in successful adults with ADHD , 18. To via email to anonymously fill out an online questionnaire. The group of members  consists of individuals with an ADHD diagnosis, and/or dyslexia, and/or dyscalculia, and partners and parents of individuals with these classifications. The invitation to participate in the survey was explicitly directed toward individuals with ADHD/dyslexia/dyscalculia and not their relatives. In the survey participants were asked if they have a current ADHD diagnosis (yes/no) and a dyslexia/dyscalculia diagnosis (yes/no). They were also requested to provide basic demographic information about their age, sex, their diagnosis , employment status and about their treatment by a psychiatrist/psychologist or coach (yes currently/no/not anymore/other). Participants were asked to freely report what they considered positive aspects of ADHD and in a subsequent question, what they considered negative aspects of ADHD, with unlimited time. The questionnaire was available between the 15th of November 2019 and the 20th of February 2020. SurveyMonkey was used to collect the data. As our current study had the specific aim to study positive aspects of ADHD, we only used the data from the participants with an ADHD diagnosis.All members of the Dutch organization for people with ADHD, dyslexia or dyscalculia (Impuls & Woortblind) were invited creative, empathic, happy or enthusiastic or quotes such as “always up for something”. The initial analysis consisted of coding those words and quotes, executed by two raters (MH and AOB). The codes are considered the smallest units in the data. In most instances the actual word corresponded with the given code, but in some cases we made a combination of descriptions that were closely linked. For example, when data mentioned “associative”, or “making connections easily”, or “making links quickly” we gave all of these the code: “associative thinking/seeing connections”. Discrepancies between the two coders were resolved by discussing them and deciding on the best code to fit the answer.We extracted the data from SurveyMonkey and imported the output of the open-ended question about the positive aspects of ADHD in ATLAS-ti 9.1.6. The data consisted of answers of one word, such as After the coding process LS, LH, JM, CG, MH discussed the codes and how they could be grouped into subthemes. This was an iterative process and evaluations were done multiple times by discussing the subthemes. Although some codes fit in multiple subthemes, we decided to use the codes only once in the subtheme grouping. In the final step, a similar process was executed to form the themes, please see After we finalized the subthemes and themes, we validated the identified subthemes and themes from our analysis in a focus group session. To recruit participants for this focus group, we placed an advertisement on the website of the Dutch organization for people with ADHD, dyslexia and dyscalculia. These participants had not participated in the original online survey. We presented  to the gt-test, respectively. For sex, we also investigated sex differences per theme by calculating per theme how many men and how many women have reported at least one positive aspect. These are transformed to ratios . The ratios for men and women were compared by performing a Chi-square test, for each theme separately. We used a Bonferroni correction to counteract multiple comparison problems, using a significance threshold of p < 0.01 (0.05/5 themes = 0.01).In addition to the qualitative analysis, we performed exploratory quantitative analysis to further our understanding of the qualitative results. We explored the relationship between the total number of codes that were mentioned by each individual and basic characteristics such as age and sex, by performing Pearson's correlations and To investigate whether employment status was associated with the number of positive aspects mentioned, we performed a group analysis controlling for age and sex and compared individuals who were in employment or were receiving education, with individuals who were unemployed  on the number of positive codes mentioned. Finally, to learn more about the role of treatment on positive aspects in ADHD, we compared the group of people who received treatment (current or past) with those who were not, or had not been in treatment, on the total number of codes mentioned.n = 46) were excluded from qualitative and quantitative analyses because the reasons for leaving these fields blank were unclear. Therefore, the data of 206 participants were included in our final analysis. A full overview of the demographics of the study sample are shown in SD = 12.81). There were more women (n = 129) than men (n = 77) participating in the study and a minority of the study sample had co-existing dyslexia/dyscalculia. A large portion of our sample reported being employed, with unemployment plus disability benefits rates being around 13%. Five participants explicitly reported having no positive aspects related to their ADHD diagnosis (“I don't see any benefits in my case”) and eight participants reported no positive aspects. These subjects were not part of our qualitative analysis, but were part of our quantitative analysis. One participant noted that all aspects of ADHD can be considered as positive without elaborating on these positive aspects. Due to lack of information, we could not incorporate this answer in our qualitative nor in our quantitative analyses.Of the 1,326 members of the Dutch organization for people with ADHD, Impuls & Woortblind, that were sent an email with the invitation to participate, 346 members completed the questionnaire, a response rate of 26%. As we aimed to learn more about the positive aspects of ADHD from individuals with ADHD themselves for this project, we included data from only those with an ADHD diagnosis and not those with dyslexia/dyscalculia without ADHD or those who were relatives of individuals with ADHD. This resulted in excluding 49 individuals who had a diagnosis of dyslexia/dyscalculia without ADHD and 45 individuals who were a family member or a partner of somebody with ADHD but with no current ADHD diagnosis themselves. Participants who did not answer the question about their experiences of positive and negative aspects of ADHD , as these represent positive aspects experienced by only a few participants. A list of low frequency codes can be found in imaginative, creative, resourceful, and associative/seeing connections. Participants in this subtheme mentioned: “Being able to think outside the box” (participant 45), “Creativity in finding solutions” (P14), “Suddenly come up with the craziest ideas that can be brilliant” (P108), “Being able to come up with surprising ideas” (P146), “Always have dreams of what could happen, a rich fantasy” (P129), and “Great problem solving ability” (P26).The first theme that was formed consisted of only the subtheme “creative” and had codes that specified energetic, enthusiastic, up for anything and seeing opportunities. Example quotes from participants for the subtheme “high energy/active” were: “Always having energy for many different things”, (P69), “Being passionate in what you do”, (P30), and “No need for coffee in the morning”, (92). Participants mentioned “Seeing opportunities”, (167)and “Not giving up”, (P36) for the subtheme “positive attitude”. The subtheme “novelty seeking/adventurousness” included quotes like “High degree of curiosity”, (P141), “Dare to take a risk even though it may not go as you hope”, (p81).This theme was composed of the subthemes “high energy/active”, “positive attitude” and “novelty seeking/adventurousness”. Codes that were mentioned in this theme are flexible, broad interests, open minded and quickly getting over fights. Participants in the subtheme “spontaneous/impulsive” mentioned “Being often very spontaneous”, (P154) and “Impulsivity”, (192). Examples of quotes mentioned in the “flexible” subtheme were “Never argue for long because I have forgotten about the cause”, (p124), “Be able to respond to changes”, (P108) and “in my work, I can switch quickly from one task to another”, (P85). The subtheme “open” included quotes like “Broad view of the world”, (P40) and “Many interests”, (P145).The theme flexibility was composed of the subthemes “spontaneous/impulsive”, “flexible” and “open” and consists of codes such as empathic, social, sensitive, and helping/helpful. Example quotes in the subtheme “based on feeling/strong emotions” were “Experience life very intensely with high peaks”, (P141), “I have a huge amount of empathy and emotions”, (P158), “Sharp intuition”, (P133). Quotes mentioned in the subtheme “socially outgoing” were “I can easily make contact with others”, (P75), and “I can get along with different types of people”, (P56). For the subtheme “prosocial/empathic” participants mentioned “Standing up for others”, (P53), “Having a great sense of justice” (P110) and “I have a strong antenna for other people's feelings”, (P46).The Socio-affective theme consisted of subthemes “based on feeling/strong emotions”, “socially outgoing” and “prosocial/empathic”. Examples of codes in this theme were: image thinking, attention for detail, intelligent/smart and analytical. Examples of quotes for the subtheme “executive functions/intelligence” were “Super-fast thinking ability”, (P14), “Good long-term memory”, (P175), “See funny stories and pictures in front of me”, (P90), and “Quick to understand”, (P188). For the subtheme “attention” sentences such as “Can focus for a long time on details”, (P11), “Can focus very well if interest is stimulated”, (P28) and “Having an eye for detail”, (P81) were mentioned.The Higher-order cognitive skills theme consisted of the subthemes “executive functions/intelligence” and “attention”. Codes that were used were playful; “Be able to play well”, (P96), versatile; ”Allrounder/generalist”, (P141), honest; “Being honest”, (P158), stress resistant; “Being able to act in stressful situations”, (P144), not boring; “Being a bit crazy”, (P89), sentience; “Notice more in the environment than other people”, (P106), sincere; “Sincere”, (P168), witty/sharp; “Smart and sharp”, (P97) and non-conformist; “The ability to take a deviant point of view”, (P44).A number of codes did not fit in any of the themes and subthemes described above. Therefore, to categorize these codes we added the codes into a subtheme called “other codes”. We mention those codes here followed by one example: A notable finding of our results is that the core symptom domains of ADHD, impulsivity and hyperactivity, are mentioned as positive aspects of ADHD. These symptoms, which are often a reason for individuals with ADHD to seek help, are also seen as positive aspects of ADHD by people with an ADHD diagnosis. Positive aspects such as “energetic” and “enthusiastic” were mentioned and can be linked to the hyperactivity symptoms in ADHD, and codes such as “spontaneous” and “impulsive” can be linked to the impulsivity symptoms in ADHD. The third core symptom domain of ADHD, inattention, was not mentioned as a positive aspect, but the opposite, attention (skills), such as “hyperfocus”, “attention to detail” and “alert” were perceived as positive aspects of ADHD.SD = 10.54)]. The participants of the focus group reported many positive aspects of ADHD, but after checking our data we noticed that they were all already in our code list. All participants agreed that the themes and subthemes were representative of the positive aspects of ADHD.Eight individuals, five women and three men with ADHD responded to the advertisement and were invited to a focus group session. Two people canceled last minute, and therefore the focus group consisted of six participants . Similarly, employment status had no effect on the number of codes reported .When we compared men to women on the total number of codes, we found a significant difference t= 0.009) . No corrCreativity, Being dynamic, Flexibility, Socio-affective skills, and Higher- order cognitive skills. We validated the results in a focus group, and participants identified themselves with the themes that were found, and the way we organized them. Our quantitative analysis showed that being creative, enthusiastic and energetic were positive aspects that were reported most. Women reported more positive aspects than men, and age, employment status and “ever received treatment by a clinician/coach” were not factors that associated with the number of positive aspects mentioned.In the present study we performed qualitative and quantitative analyses on self-reported positive aspects of ADHD in a sample of 206 adults with ADHD. The qualitative analysis delivered 116 codes of positive aspects of ADHD, which were categorized into thirteen subthemes, and five themes. The five themes are creativity was found across all previous studies and also in our study. This, together with the result of our quantitative analysis of creativity being the most reported positive aspect, means that this is a widely recognized strength in ADHD and is not only reported in high functioning adults with ADHD but also in a more general sample of adults with ADHD. The same is true for our subtheme high energy/active (from our theme being dynamic). It is also reported in Mahdi's theme “energy and drive”, and Sedgwick's theme “energy”. Holthe's study also mentioned “high energy” and “determination”. All studies described that this is both physical energy and a source for perseverance. The subtheme novelty seeking/adventurousness (part of our theme being dynamic) was also found in Holthe's study, mentioning “risk taking” specifically. From our theme higher order cognitive skills, and subtheme attention, hyperfocus is a concept that was also found in Mahdi's and Sedgewick's studies. The theme socio-affective skills with the subtheme prosocial/empathic, comes back in the related themes of “agreeableness” and “willingness to assist others” in Mahdi's results and as “humanity” in Sedgewick's results. (Sub)Themes of positive aspects that, to our knowledge, were found for the first time in our study, are the theme flexibility, and the subthemes positive attitude, strong emotions, and executive functions. This could be due to the relatively large sample that we included which likely captured more positive aspects covering a wider spectrum due to the larger variation of individuals in our sample. In contrast, Sedgwick's study used a sample of 6 high functioning males and Holthe's study included 5 successful women. Themes that were found in Sedgewick's article, but did not come up in our results, are “appreciation of beauty and excellence”, and “sublimation” . This could possibly be due to the differences in participants between the studies. Sedgewick's study included high functioning and highly educated adults who might have more access to art and cultural aspects of life than our community sample. A difference in research methods could also explain this discrepancy as in Sedgwick's study they performed extensive interviews whereas we mainly had one-word quotes and sometimes a short sentence. This might have led to themes with more depth such as the theme of sublimation. Finally, cultural differences could explain differences between samples, as some strengths in one country or culture might not be considered strengths in another country/culture  vs. never having been in treatment by a clinician/coach, did not affect the rate of positive aspects mentioned by individuals with ADHD. We assumed that participants who were not employed or who were receiving disability pensions would possibly be more impaired by their ADHD and therefore might not experience many positive aspects. We also considered that receiving treatment in past or present would lead to increased quality of life and that therefore more positive aspects would arise. Unfortunately, we do not have any additional data on impairment or quality of life in our sample to further unravel these findings. To better understand what it means to report many positive aspects, future research should be dedicated at studying the relationship between the frequency of reported strengths and wellbeing, impairment and quality of life. In addition, we should acknowledge that our treatment variable gave us limited information, for example, we could not specify pharmacological or non-pharmacological treatment. Previous work has provided evidence for pharmacological treatment not affecting the most reported positive aspect, creativity . HoweverIn all, future studies researching positive aspects in ADHD should collect more demographic and clinical information, information about wellbeing and indices of quality of life of the individuals in the study, and possibly also information about the believes and sentiments of ADHD to further our understanding of positive aspects in ADHD.The current study has delivered a list of self-reported positive aspects of ADHD. These were grouped based on the relatedness of the aspects in terms of the meaning of the aspects. There is also the possibility to make a different distinction, based on what the participants of the focus group suggested. For example, there might be positive aspects that are a consequence of living with ADHD such as being open-minded, honest or perseverant. Due to the more advanced age of our sample, we very likely have also captured these positive aspects related to ADHD, that are a result of coping with ADHD. Thus far, little is known about the longitudinal course of positive aspects of ADHD. Future research should aim to explore strengths in individuals with ADHD from an early age, this way, coping mechanisms as a result of having ADHD can be excluded or eliminated.Another group of aspects could be defined as being the counterpart of the deficit aspects of ADHD, originating from the same underlying neurobiological mechanism. This was also proposed in the Dynamic Developmental Model, where adaptive and maladaptive outcomes are evaluated in relation to symptoms of ADHD . Here onThere is also a group of aspects that have, depending on the situation, either a negative consequence or a positive consequence. For example, impulsivity and related characteristics such as spontaneity and novelty seeking, are considered positive aspects of ADHD but are also part of the core ADHD symptoms as defined by international classification systems such as the DSM-5. Dependent on the situation the same characteristic may be beneficial and positive, or detrimental. For instance: acting impulsively in a situation of crisis can be beneficial. Future research using for example digital applications could monitor aspects such as impulsivity throughout the day and identify in which situation impulsivity is beneficial or detrimental. More insights into the situational aspects can lead to better management of these aspects of ADHD and help find a balance between beneficial and detrimental effects.From the above it becomes clear that we do not know much about where the positive aspects originate from. Do they develop together with core ADHD symptoms, or are they causal to having an ADHD diagnosis? There might even be more conceptual groups of positive aspects of ADHD than just the three mentioned above. From the perspective of psychoeducation, it is of high relevance to perform research into the development of the positive aspects of ADHD, as one could imagine that there is a distinction between addressing positive aspects from the “causal” category , from the “positive counterpart” category  or from the “context/situational” category of aspects .Our findings align with current clinical guidelines recommending a multidisciplinary approach for treatment of ADHD, with a range of non-pharmacological treatment options alongside medication if necessary . Our datFinding positive aspects or strengths of individuals with ADHD might also provide other new perspectives for healthcare. First, assessing strengths could become part of the diagnostic process. Ideally, one or more questionnaires could be developed assessing ADHD specific strengths, providing both self and other reports. Second, it paves the way for strength-based interventions and narrative interventions based on positive psychology, complementary to interventions based on symptom reduction. Strength-based interventions have the potential to contribute to beneficial outcomes in various areas of life . Previouvia improving their self-esteem, life satisfaction, wellbeing and health related quality of life. Previous research has shown that strength-use predicts wellbeing and quality of life in the general population  was much higher than the employment rate in a Norwegian sample of individuals with ADHD (24.3%). More than one third of their sample received disability benefits compared to only 8% in our sample . A SwediAnother strength of our study was the participatory evaluation of survey data by members of the focus group. This provided us with meaningful new interpretations of our findings, such as the different categories that might exist within the list op positive aspects that were reported. Participatory research in general has been shown to be advantageous for both researchers and participants, because it leads to more relevant results for both groups .A limitation of our study is the lack of clinical and demographic information of our participants. We did not have information on level of functioning, type and severity of ADHD symptoms, and presence of co-existing conditions . It could be hypothesized that – for example - individuals with ADHD and co-existing depression, may report fewer positive aspects. A study design that incorporates demographic, social and clinical data may explore correlations between clinical characteristics, level of functioning and number and type of positive connotations with ADHD.self-reported- and therefore subjective - positive aspects. Our study does not provide evidence for individuals with ADHD being indeed more driven, empathic, or have more humor (random examples) than individuals without ADHD. Empathy, for example, was reported as a positive aspect of ADHD in our study but also in Mahdi's study, and in quantitative studies investigating self-reported and observant reported empathy was lower in children and adults with ADHD  to identify strengths in ADHD. We need for example quantitative studies with measurements of these strengths and studies using other-report before we can start thinking about incorporating specific strengths into the image of ADHD. The identification of strengths in ADHD can provide implications for the management of ADHD. Awareness about ADHD strengths can help individuals with ADHD and their environment to better cope with, accept or embrace their diagnosis and for example make educational or occupational choices that fit them well. To incorporate these positive aspects in the understanding of ADHD, future research should also focus on investigating the link between these aspects and clinical characteristics and how this new knowledge can be implemented in psychoeducation and find its way to education and occupational settings.martine.hoogman@radboudumc.nl.The datasets presented in this article are not readily available because we do not have consent from our participants to share the data. Data are in Dutch. Please contact the corresponding author for information about using derived data. Requests to access the datasets should be directed to Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.HV, RP, JM, CG, and MH initiated, designed and set-up the study. LS, LH, and MH performed the analysis. JM, CG, and MH reviewed and debated the qualitative results. LS, LH, and MH organized the focus group session with help from HV and RP. LS, LH, JZ, and MH wrote the manuscript with active contributions from all coauthors. All authors contributed to the article and approved the submitted version.MH is supported by a personal Veni grant from the Netherlands Organization for Scientific Research .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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.