Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental condition characterized by diminished attentional control. Critically, these difficulties are related to negative consequences in real-life functioning both during development and into adulthood. There is now growing evidence that modulating the underlying neural circuits related to attention can improve behavior and brain function in children with ADHD. We have previously shown that game-based digital therapeutics targeting a key neural marker of attention–midline frontal theta (MFT)–yield positive effects on attentional control in several populations. However, the effects of such digital therapeutics in children with ADHD and no other comorbidities has not been yet examined. To address this gap, we assessed a sample of 25 children with ADHD (8–12 years old) on neural, behavioral, and clinical metrics of attention before and after a 4-week at-home intervention on an iPad targeting MFT circuitry. We found that children showed enhancements on a neural measure of attention (MFT power), as well as on objective behavioral measures of attention and parent reports of clinical ADHD symptoms. Importantly, we observed relationships between the neural and behavioral cognitive improvements, demonstrating that those children who showed the largest intervention-related neural gains were also those that improved the most on the behavioral tasks indexing attention. These findings provide support for using targeted, digital therapeutics to enhance multiple features of attentional control in children with ADHD.Study registration: ClinicalTrials.gov registry (NCT03844269) https://clinicaltrials.gov/ct2/show/NCT03844269. Attention-deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental conditions affecting children, with an estimated 6.1 million youth aged 2–17 years 9.4%) in the United States ever having received this diagnosis , 4. Impo% in the The current recommended treatments for ADHD include pharmacological and behavioral therapies , 9. AlthNeuroRacer, remediated age-related neural deficits in MFT and had positive effects on related objective behavioral metrics of attention and other cognitive control abilities in healthy older adults [NeuroRacer–AKL-T01. We showed that AKL-T01 improved MFT and behavioral measures of attentional control in children with comorbid sensory processing disorder (SPD) and inattention symptoms [Video game-based interventions that target the underlying neural mechanisms of attentional control abilities are one example of neuromodulation for ameliorating cognitive dysfunction. Several studies have previously investigated the efficacy of multi-tasking training delivered by a video-game based experience, where participants simultaneously perform a perceptual discrimination task (similar to a go/no-go task) and a sensory motor navigation task. This work has demonstrated that multi-tasking training that targets midline frontal theta (MFT) circuitry can improve behavior and brain function across a range of populations. MFT (4-7Hz) power is a well-described neural signature of attention and broader cognitive control abilities that has been associated with signaling the need for increased attention in a variety of contexts , 15. Usir adults . Next, wsymptoms . These csymptoms . Finallysymptoms . This trsymptoms . ImportaThus, while there is growing evidence that AKL-T01 can improve objective behavioral metrics of attentional control in youth with attention difficulties, the underlying neural changes associated with these improvements have not yet been examined in children with ADHD who do not have other comorbidities. AKL-T01 may be particularly effective at improving neural markers of attentional control (MFT) in this population, given the overlap of this circuit with brain regions affected in those with ADHD. Specifically, MFT is believed to be generated by the midcingulate cortex, a brain network hub with strong interconnections to various cortical and sub-cortical regions . MFT sigTo address this gap, we sought to examine intervention-related changes in a neural marker of attentional control (MFT) in a cohort of children meeting diagnostic criteria for ADHD. Specifically, we examined AKL-T01 improvements in a broad, heterogenous population of children with ADHD and did not selectively include those with objective attention difficulties at baseline, as other AKL-T01 studies . Our priIn this study, we enrolled 28 children with a confirmed ADHD diagnosis (based on DSM-5 criteria), between March 2019 to February 2020. Characterization of clinical ADHD symptoms in children often relies upon parent report questionnaires for ease of administration –24. As sExclusion criteria were brain malformation or injury, movement disorders, psychiatric conditions , and hearing impairment. In addition, children had to be off antipsychotic or ADHD medications  for the duration of the study and a washout period of at least 30 days prior to initiation. Further, children had to score ≥ 70 on the Perceptual Reasoning Index (PRI) on the Wechsler Intelligence Scale for Children–Fifth Edition and had to be able to comply with all testing and requirements. Participants who were eligible were then assessed with a battery of behavioral and neural outcome measures, both prior to and no later than 7 days after the 4-week AKL-T01 intervention.Participants were recruited from online parent groups, the Sensory Neurodevelopment and Autism Program research registry, and Cortica Healthcare, Marin Center. The study is registered with ClinicalTrials.gov (NCT03844269) as a prospective trial and has approval through WIRB Copernicus Group . Participants’ primary caregivers provided written consent on behalf of their child and children provided informed assent.Participants performed a perceptual discrimination task that assessed selective attention abilities with concurrent electroencephalography (EEG) recording, as in our previous work . The perElectroencephalography (EEG) activity was recorded with a BioSemi ActiveTwo 64-channel EEG acquisition system in conjunction with BioSemi ActiView software (Cortech-Solutions). Signals were amplified and digitized at 1024 Hz with a 16-bit resolution. Anti-aliasing filters were applied and the data were band-pass filtered between 0.01–100 Hz during acquisition. Data was preprocessed using Analyzer software , with blinks and eye-movement artifacts removed through an independent component analysis, as were epochs with excessive peak-to-peak deflections (± 100 μV).The cleaned EEG data were exported into EEGLAB for event-related spectral perturbation (ERSP) analysis. As in our previous work , 18, epoResults), and (3) the last three windows (‘late’: 760–880 ms). We created these longer, 120 ms composite bins (as opposed to looking at singular 40 ms time points) to better account for multiple comparison concerns and potential deviations at each of these a priori composite time windows.All ERSP data was segmented into 40 ms time bins from -400 ms to +880 ms, where time 0 represents the onset of the target stimulus. Here, we focused on post-stimulus ERSP changes in peak MFT, as in our previous work . In addiTo assess objective behavioral improvements from AKL-T01, we used two computerized tasks to probe components of attentional control abilities.In addition to intervention-related neural changes during the perceptual discrimination task, we assessed concurrent changes in task performance. We quantified changes in response time (RT) and response time variability (RTV), in line with our previous work in children .NeuroRacer and AKL-T01 studies [To further index improvements in attentional control, we assessed changes on a visual continuous performance task (CPT) similar to the Test of Variables of Attention (TOVA ) used in studies , 18, 20. studies , 32. Wor studies , 34. UnlParticipants and Design). In addition, we assessed intervention-related changes of clinical ADHD inattention symptoms by re-administering this scale to the same parent/caregiver after the intervention and analyzing changes in symptom severity on the inattention subscale.The Vanderbilt is a standardized clinical parent-report survey used to assess ADHD symptoms. Parent reports of clinically significant inattention symptoms  were used for inclusion criteria in this study to demonstrate ADHD symptomatology  at an adaptive and personalized degree of difficulty. In brief, the AKL-T01 intervention is a self-guided at-home intervention that involves both a perceptual discrimination targeting task, in which users respond to the instructed stimulus targets and ignore the stimulus distractors (similar to a go/no-go task), and a sensory motor navigation task, in which users continuously adjust their location to interact with or avoid positional targets. Performance in each task is assessed during single and multitask conditions.The AKL-T01 intervention was preloaded and administered on iPad Mini 2 tablets . Children were instructed to complete 5 ‘missions’ at least 5 days per week for 4 weeks for a total of approximately 25 minutes of gameplay per day (at least 100 missions). Adherence was monitored remotely by study coordinators using an electronic dashboard created by Akili. If a participant had more than two incomplete days of the intervention, a reminder phone call was made to the parents, while also providing support and feedback to the parents and children with the intervention. Additionally, AKL-T01 generates automatic reminders. After a participant completed 20 sessions of the AKL-T01 intervention, a follow-up research appointment was scheduled with the parents. All data, except for the AKL-T01 intervention, was collected at the Cortica Neurodevelopment Centers, Marin Campus.a priori hypotheses about unique effects of electrode, all MFT analyses presented are collapsed along the factor of electrode . In addition to this approach with a within-subjects factor of time-window, we also interrogated each 120 ms window separately, given that MFT activity at these windows may reflect different ongoing cognitive processes throughout the duration of the task trials. To do so, we conducted 3 separate ANOVAs for each time window, with a within-subjects factor of session (pre and post).Changes in our primary outcome metric—neural measures of attentional control (MFT EEG power)—were assessed with a repeated-measures ANOVA with within-subjects factors of session (pre and post), composite 120 ms time-windows , and electrode . Given that we aimed to replicate our previous analytical approaches and had no Improvements on exploratory metrics of attentional control tasks and survey-based measures were assessed with paired t-tests comparing pre- and post-intervention performance. When examining intervention-related changes, we calculated gain scores for each metric, where higher values indicate improvements in performance or neural activity. To examine relationships between neural improvements and behavioral and clinical improvements, we performed Pearson correlations between neural and cognitive and clinical gains scores. For statistically significant correlations, we also report the strength of the correlation as ‘very strong’ (r = 0.9–1.0), ‘strong’ (r = 0.70–0.89), ‘moderate’ (r = 0.40–0.69), ‘weak’ (r = 0.10–0.39), or ‘negligible’ (r < 0.10).All statistical analyses were conducted using SPSS 24.0 (SPSS Inc.). We report significant effects at a threshold of p ≤ 0.05 and also report marginal ‘trends’ at p ≤ 0.10. Further, effect sizes for intervention-related changes are reported as Cohen’s d, where 0.2 = small effect, 0.5 = medium effect, and 0.8 = large effect . We did Twenty-eight participants meeting our inclusion and exclusion criteria were enrolled in the study. Twenty-five of these participants successfully completed the assessments and intervention . Of the 3 participants that did not complete the study, one participant withdrew during the pre-intervention baseline assessments and two participants did not complete the intervention . The 25 a priori hypotheses that the intervention may affect the cognitive processes occurring at each window differently, we next examined each 120 ms composite window separately. To do so, we conducted 3 repeated-measures ANOVAs with a within-subjects factor of session, separately for each time window. We found increases in the early  = 7.53, p = 0.01, d = 0.62) and late  = 4.51, p = 0.046, d = 0.52) time windows. There was a numerical increase in MFT activity at the peak time period of 160–280 ms following stimulus onset, however in contrast to our previous work [To interrogate effects of AKL-T01 on overall attention-related neural activity during the perceptual discrimination task, we conducted a repeated-measures ANOVA on the MFT EEG data, with within-subjects factors of session (pre and post) and 120 ms composite time-window . We observed a main effect of session,  = 4.76, p = 0.04, d = 0.44), suggesting that there was a general increase in MFT following the intervention . We did ous work , 18, thiFor the perceptual discrimination task, we observed an improvement on response time (RT)  = 3.35, p = 0.003, d = 0.62), suggesting that participants performed faster on this measure following AKL-T01 . HoweverFor the sustained attention task, we did not observe improvements on RT or RTV  = 0.35, p = 0.73, d = 0.09 and t = 0.14, p = 0.89, d = 0.03, respectively). However, we did observe an improvement on tau  = 2.09, p = 0.048, d = 0.46), suggesting that participants had fewer attentional lapses following AKL-T01  (see S2 We confirmed that intervention-related changes on these measures were not driven by changes in basic motoric speed (see Supplementary Information). Briefly, basic response time (BRT) changes were not related to any other training-related neural or behavioral changes, but had a marginal relationship with clinical inattention symptoms. Further, controlling for BRT changes did not affect results for clinical inattention improvements after AKL-T01 (see below).To test whether AKL-T01 led to changes in ADHD inattention symptoms, we examined changes in our clinical outcome measure–the inattention subscale of the Vanderbilt parent report. After the AKL-T01 intervention, parents observed significantly fewer ADHD inattention symptoms  = 5.32, p < 0.001, d = 1.25), suggesting that participants had fewer clinical inattention symptoms following the intervention . FurtherTo examine associations between training-related neural changes and the observed behavioral and clinical improvements, we performed correlations between neural gain scores at the three composite time-windows and improvements on the behavioral and survey-based assessments . NotablyThe present findings demonstrate that a targeted, digital therapeutic (AKL-T01) can have wide-ranging positive effects on several metrics of attention in a heterogenous population of children with ADHD. Specifically, our primary analyses show that AKL-T01 enhances midline frontal theta (MFT), a well-established EEG-based measure of attentional control. Further, our exploratory analyses demonstrate that AKL-T01 improves performance on computerized tasks of attention as well as clinical ADHD symptoms from parent reports. Here, we discuss the possible mechanisms of these intervention-related enhancements.First, we demonstrate that AKL-T01 increases MFT broadly following post-stimulus presentation in children with ADHD, suggesting that these patients are better able to engage control functions and monitor ongoing cognitive processes to support attention-centric performance. Other neuromodulatory approaches, such as neurofeedback training, have also pointed to similar plasticity of MFT, by showing that targeted neurofeedback can broadly enhance MFT activity during training as well as during ‘baseline’ periods . CriticaIn addition to general MFT improvements during task performance, we also observed that these neural changes were most pronounced in the early and late stages of the perceptual discrimination task trials. Examining each time window separately, MFT changes were most evident immediately following stimulus presentation (‘early’) and in preparation for the upcoming task trial (‘late’), although it should be noted that we did not observe a formal statistical interaction between session and time window for these analyses. Early processing (approximately 100 ms post-stimulus presentation) is thought to reflect initial orienting of attentional resources –43, whilIn addition to the intervention-related neural improvements in MFT activity, we also replicate previous work demonstrating that AKL-T01 can improve both behavioral and clinical measures of attention in children with inattention difficulties , 20. We Critically, improvements on these computerized measures were also related to improvements on our EEG-based metric of attention (MFT activity), particularly for the ‘early’ and ‘peak’ time windows. These results suggest that there are benefits to including neuroimaging markers as an adjunct to assessing behavioral and clinical outcome measures, and further point to a potential underlying neural mechanism of the observed changes in behavior. Interestingly, these correlational results also point to individual differences in intervention-related improvements–children that exhibit the greatest neural changes are those that improve the most behaviorally. These findings signal the potential importance for developing personalized interventions that enhance improvements at the individual patient level.Finally, we also found that AKL-T01 improved clinical measures of ADHD–the Vanderbilt parent report used for inclusion criteria of ADHD inattention symptoms. This finding is consistent with previous work using AKL-T01 interventions in children with attention difficulties and indicate that, in this study, children with ADHD had fewer parent-reported symptoms of inattention after the intervention. Notably, almost half (44%) of the children no longer met inclusion criteria for Vanderbilt inattention symptoms after the intervention. This is in line with our previous report that 33% of children with SPD and inattention showed this level of improvement following training . These rNeuroRacer intervention in older adults [While this study represents an effort to expand our understanding of intervention-related neural enhancements in a population of children meeting clinical ADHD criteria, future work is warranted to address limitations of this current study. First, comparisons to a mechanistic or placebo control group would help elucidate the extent of such intervention-related improvements, as in previous work . Second,r adults , suggestr adults . Future The present findings contribute to the recent burst of empirical work aiming to demonstrate the efficacy of various digital health technologies. Here, we provide supporting evidence for the efficacy of one such digital therapeutic in remediating attentional control difficulties in children with ADHD. We show that AKL-T01 improves behavioral and clinical metrics of attention, replicating previous work , 20. ImpS1 Checklist(DOC)Click here for additional data file.S1 Protocol(PDF)Click here for additional data file.S1 File(DOCX)Click here for additional data file.


Previous studies have suggested that Attention Deficit Hyperactive Disorder (ADHD) affect individuals across their lifespan, especially in relation to employment. The purpose of this review was to synthesize the results from studies examining the prospective association of ADHD diagnosis in childhood and later education, earnings and employment, compared to children without an ADHD diagnosis. A review protocol was prospectively registered with PROSPERO (ID = CRD42019131634). The findings were reported according to the PRISMA guidelines. The systematic review is based on a structured and preplanned analysis of original prospective longitudinal studies. A total of 2505 potential records were identified, two through backward search. Six papers met the inclusion criteria. One paper was assessed as good, four as fair and one as poor quality. The studies indicated that ADHD diagnosis affected the nature of the individual’s attachment to the labour market across different labour market attachment outcomes. Adults with persisting symptoms, had significantly more problems at work. Even if ADHD symptoms desist in adulthood, the negative impact of earlier ADHD symptoms can still be seen on occupational outcomes. Significantly fewer probands had a Bachelor’s degree compared to controls. Based on one good quality study and four fair quality studies, it is indicated that patients with childhood diagnosed ADHD, generally experience employment of lower quality compared with peers, in relation to income, education and occupational attainment. The overall level of evidence is rated as poor.The online version contains supplementary material available at 10.1186/s13034-021-00386-2. Attention Deficit Hyperactive Disorder (ADHD) is the most frequently registered psychiatric diagnosis among children and adolescents, and the diagnosis is three times more prevalent among boys than among girls . Girls aADHD is diagnosed according to the DSM-5   and the Although most frequently diagnosed during the school years, ADHD is now acknowledged to affect individuals across the lifespan . ADHD isOur hypothesis is that ADHD can affect learning and psychological wellbeing and negatively affect education and later labour market participation. Given the high prevalence of ADHD, this would imply that a large group of youths will not reach the same economic and educational level as peers.The aim of this study is to describe existing knowledge on prospective associations between ADHD in youth (6–17 years old) and future employment.A review protocol was prospectively registered with PROSPERO (ID = CRD42019131634). The findings were reported according to the PRISMA guidelines for systematic reviews.A systematic review was performed of prospective longitudinal studies addressing the impact of childhood ADHD diagnosis on later labour market attainment.MEDLINE, Web of Science, PsycINFO and The Cochrane Library (Cochrane Database of Systematic Reviews) were used for systematic searching in December 2018 and again in November 2020. A research librarian helped develop the search strategy. The search terms used were “Attention Deficit Disorder with Hyperactivity”, “attention deficit disorder” or “ADHD”, combined with “adult” and “occupations”, “work”, “employment” or “workplace”.References were imported into Covidence. Title and abstract screening, full-text screening and data extraction were performed independently by two of the authors of this paper. The inclusion criteria were set to include quantitative prospective longitudinal studies, in English, Danish, Swedish and Norwegian. The study population included adults who were diagnosed with ADHD/ADD at age 6–18 years and comparable ADHD/ADD-free controls. No timeframe was set. Studies performed in low- and middle-income countries were excluded in order to increase homogeneity of labour market regimes. If the population included adults not in working age (> 60 years), the study was also excluded. All the included studies needed to have age- and sex-matched comparison participants without ADHD/ADD. Finally, backward searching of reference lists of the located studies were performed. References in systematic reviews on similar topics were also screened to localize further relevant studies.Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies, from the National Heart, Lung, and Blood Institute  was usedThe first author (MSC) used a data extraction sheet, to extract data from each of the included studies. Afterwards the second author (ML) checked the data. Disagreements were solved through discussion. The collected information included author name, publication date, objectives, study design, study period, follow-up, population, inclusion/exclusion criteria, variables of interest, measurement, statistical methods, participants, confounders, outcome data, main results and limitations.A PRISMA flow diagram of the search results and reasons for study exclusion can be found in Additional file The initial literature search provided 2505 references. After removal of duplicates, 2028 references were left for title and abstract screening. Of these, 30 references were relevant for full text screening, and of these four articles were included. Backward searching of reference lists of the located studies, provided two more relevant articles. Screening of the studies included in previous reviews on similar topics did not provide further relevant articles. The search was repeated in November 2020, yielding an additional 15 studies eligible for screening. No additional studies were included following abstract and full-text screening. The search yielded a new systematic review with relevance for this review, but the studies included did not fulfill the inclusion criteria for the present review.Table The six studies were published between 1993 and 2017 (median 2015). The combined study populations of the included studies totaled 2268 individuals, of which 1380 were probands and 888 were controls. However, two studies  were basAge at inclusion of study participants ranged from six to seventeen years of age. Two studies did not report gender distribution but included both females and males, n = 717 for both studies , 16. Of The quality appraisal of the 6 papers resulted in one paper assessed as good quality , four asDue to low quantity of included studies, heterogeneous outcomes and generally low quality of the included studies, meta-analysis and test for heterogeneity was not deemed feasible.Occupational attainment was assessed using different measures; (un)employment, number of jobs, average job length, times fired or quit, employment level/rank, occupation/industry.Two studies used self-reported job changes “total number of times fired or quit” , 16. RoyInformation about problems at work was obtained using a project-derived structured interview. Owens et al. found that girls with persistent ADHD across all study waves showed significantly more problems at work than the other groups  . Accordip = 002, scale score range 1–9), also after controlling for total number of psychiatric disorders other than ADHD , or in current salary levels [probands 2087 (SD = 1896) controls 1167 (SD = 1420) (p = 0.023)] [p = 0.03) [Among 140 girls with ADHD and 88 age- and ethnicity-matched comparison girls 0.023)] . Finallyp = 0.02) at follow-up [Biederman et al. was the only study that reported Socioeconomic Status (SES) at follow-up (16 years follow-up). SES was measured using the 5-point Hollingshead scale, with high score equaling low SES. At follow-up, the mean age was 27.4 years old. Biederman and colleagues followed 79 boys with ADHD and 90 controls and found that participants with ADHD in childhood that were financially independent, had significantly lower personal SES (mean 1.7 SD = 0.8) than controls (mean 1.4 SD = 0.6)  versus 3.2 SD 1.4) among the controls (p < 0.001) . This fi among thThree papers addressing associations between ADHD and receiving a university degree were based on two underlying studies: Two papers were based on The Multimodal Treatment Study of Children with ADHD , 16 and According to Roy and colleagues, the chance for probands to obtain a bachelor’s degree decreased with ADHD symptoms severity measured with the SNAP  scale, where a 1-step increase on the 4-category SNAP scale assessed at baseline had an OR of 0.69  for obtaining a bachelor’s degree in adulthood . Based oMannuzza and colleagues found similar associations among children referred to a child psychiatric clinic and diagnosed with ADHD, compared to a ADHD-free group of matched controls: 12% of probands had complete a bachelor’s degree or higher at follow-up, compared to 49% of controls (p < 0.001) .Owens and colleagues showed higher educational functioning scores among controls than among probands. The educational functioning was reported by the participants, clinicians and the participants parents. All groups had the highest educational functioning score among controls, and the score was lowest among the “persisters”  .Of the six studies meeting inclusion criteria, one was rated of good quality, four of fair, and one of poor quality. Based on the five studies rated fair or good, it is indicated that patients with ADHD generally experience employment of lower quality  and are more likely to receive public assistance.While ADHD is shown to be a significant negative predictor for future occupational outcomes, other factors such as socioeconomic status and test scores can work opposite to this. This suggests that adult outcomes for ADHD patients can be affected. However, it is currently not evident from existing literature, included in this article, which factors positively affect educational and occupational attainment. Given the significant size of the patient population, finding ways to better adult outcomes would have large implications. Overall, the scarcity and quality of the studies meeting inclusion criteria suggest that the level of evidence for the associations targeted in this systematic review is deemed as poor. This should warrant further research addressing which factors and interventions help reduce the long-term vocational effects of childhood ADHD and especially ADD which is not addressed in the present literature.Additional file 1: Figure S1. Search results and reason for study exclusion.


All the bread samples presented almost similar spectra for major peaks corresponding to wavenumbers in the functional group. The SEM micrographs showed the presence of small and large starch particles with compact structures. Conclusively, rye flour supplementation has a significant impact on the nutritional and structural attributes of the bread.In the present study, four different variants, namely Gp‐1, Gp‐2, Gp‐3, and Gp‐4, were characterized for their nutritional and fatty acid profile. Later on, the nutritionally superior variant was used for bread preparation. Purposely, composite flour was prepared with different ratios of wheat and rye . Furthermore, structural characterization of bread was done using Fourier transform infrared (FTIR) spectroscopy and scanning electron microscopy (SEM). Results showed that the Gp‐2 was more nutritional among the four variants. Furthermore, the spectra of composite flour bread were scanned in the range of 4000–600 cm Rye flour supplementation has a significant impact on the nutritional and structural attributes of the bread. Rye, millet, barley, oats, triticale, maize, and sorghum are some grains grown in many countries. Wheat and rice are the most significant crops in the world, accounting for more than half of all cereal production. All cereals have an embryo (or germ) that holds the genetic material for a new plant and an endosperm that contains starch grains. It is genetically linked to barley and wheat   are present compared with wheat (11%–13%). Arabinoxylan , cellulose (1%–1.7%), and beta‐glucan (1.3%–2.2%) are the main fibers present in the rye grains  is very close to wheat among cereal grains. The husk on both grains is generally removed by threshing. The pericarp and testa, which contain the germ and endosperm , are the outermost layers of the bare kernel  in many countries. Sour and dark bread, crisp bread, flakes for porridges, loaf bread with sifted rye flour, and breakfast cereals are the most common rye dishes . Afterward, these were heated at 80°C for 2 h. After cooling the samples at room temperature, samples were transferred into test tubes and 1 ml of petroleum ether was added thrice in each test tube. Two milliliters of distilled water was added to the test tube and mixed by using a vortex mixer. For the complete formation of layers, 5–10 min stay time was given to the samples. The upper layer was removed and run in GC‐FID. For further analyses, flame ionization detector, Agilent DB‐5 with methyl polysiloxane polymer phase column, and nitrogen gas (N) as a carrier gas at a flow rate of 1.3 ml/min were used.The fatty acid profile of rye was determined by GC‐FID as described by Medeiros and Simoneit . Briefly2.4Among four variants, the nutritionally superior rye variant was selected for the preparation of composite flour and later on for bread preparation Table .2.52.5.1The ingredients, composite flour (rye+wheat), compressed fresh yeast, sugar, salt, improver, shortening, and water, were mixed with a mixer, and bread was prepared with a straight dough method at Ayub Agriculture Research Institute Faisalabad, Pakistan, using method no. 10–10.03 AACC   and scanning electron microscopy (SEM).2.7.1As stated in the Instruction Manual IR Prestige‐21, functional components of each sample were identified using FTIR. The Shimadzu Fourier transform infrared spectrophotometer‐FTIR 8400 S was used to determine functional units. The scanned sample traveled through infrared, where it was detected as a continuous wave by a computer‐connected detector and the spectrum of the tested sample was reported. Typically, samples were scanned in the absorbance range of 600–4000 cm‐1. As the basis of spectrum type, the findings of the investigation included the chemical structure, molecular binding form, and specific functional groups of the examined material .The bread was sputter‐coated using gold in a sputter coater after being mounted on a stub with double‐sided sticky tape (JEC‐3000FC). A scanning electron microscope  was used to image the samples (800) at a 5‐kV accelerating voltage. The images were recorded as previously described by .The resultant data were statistically analyzed by CRD using Minitab statistical package described by Steel, . The res33.1The results regarding the proximate analysis of rye are shown in Table The crude protein content in the various rye content ranged from 9.13% to 9.56%. Gp‐3 showed the maximum protein content (9.56%); meanwhile, minimum protein content (9.13%) was noticed in the Gp‐1. The crude fat content ranged from 1.73% to 1.86% in the different rye flours. The maximum crude fat content (1.86%) was noticed in the Gp‐2, whereas the lowest (1.73%) was observed in the Gp‐4. The crude fiber in the rye flour ranged from 2.5% to 2.8%. The maximum crude fiber content (2.8%) was present in the Gp‐2, while the lowest (2.5%) was noticed in the Gp‐1. The nitrogen‐free extract (NFE) in the rye flours ranged from 76.5% to 78.13%. The maximum NFE (78.13%) was observed in the Gp‐1, whereas the lowest amount (76.5%) was presented in the Gp‐3. These results are in accordance with the finding of Drakos et al.  who inve3.2The results concerning the fatty acid content of rye are shown in Table 3.33. The control bread (T0) showed the maximum bread loaf volume (236.31 cm3), whereas the T2 (231.3 cm3) presented the lowest bread loaf volume. As the rye flour in the bread increases, the loaf volume decreases just because of the high fiber content in the rye flour. The water activity of the bread ranged from 0.932 to 0.945. The maximum water activity of the bread was noticed in the T2 (0.945), whereas T1 (0.932) showed the lowest water activity. Bread's water activity reveals the microbiological growth's lower limit in terms of water availability. The moisture content of the bread ranged from 35.3% to 41.2%. The maximum moisture content (41.2%) was present in the T2, while the lowest moisture content (35.3%) was noticed in the T0. The ash content in the bread ranged from 0.8% to 1.2%. The maximum ash content (1.2%) was present in the T2, whereas minimum ash content (0.8%) was observed in the T1. The crude protein in the bread ranged from 9.7% to 11.6%. The maximum crude protein content (11.6%) was present in the T2; meanwhile, the lowest (9.7%) was noticed in the T0. The crude fat in all the samples of bread ranged from 3.3% to 4.2%. The maximum crude fat content (4.2%) was present in the T2, whereas minimum crude fat content (3.3%) was observed in the T0. The crude fiber content of the bread ranged from 2.9% to 8.1%. The T2 bread sample showed the highest amount of crude fiber (8.1%), whereas the lowest crude fiber content was (2.9%) in T0. The nitrogen‐free extract (NFE) ranged from 74% to 83% in the bread samples. The maximum NFE content (83%) was shown in the T0, whereas the lowest content NFE was (74%) in T2. The results are in accordance with the findings of Sankhon et al.  and the unique pattern also called fingerprint region (1200–600 cm–1)  spectroscopic analysis was conducted to support the proximate data for possible variation in the composition of major fractions such as moisture, proteins, fats, and saccharides of composite bread Figure . The spe–1 majorly contributed by the symmetric stretching vibrations of the C–H bonds of the –CH2/–CH3 alkyl groups. These peaks are reportedly suggesting the presence of lipids mostly bound ones  shows a more compact structure and low bread volume compared to control. The presence of supplemented rye flour exhibited a significant effect on the micrographs of different bread compared to control. Rye flour supplementation should be used to improve the technological and functional properties of baked products.The authors declare that they do not have any conflict of interest.This study does not involve any human or animal testing.This study does not involve any human testing.This study does not involve any human or animal testing.


Emerging evidence suggests increased risk of several physical health conditions in people with ADHD. Only a few physical conditions have been thoroughly studied in relation to ADHD, and there is little knowledge on associations in older adults in particular. We aimed to investigate the phenotypic and aetiological associations between ADHD and a wide range of physical health conditions across adulthood.We did a register study in Sweden and identified full-sibling and maternal half-sibling pairs born between Jan 1, 1932, and Dec 31, 1995, through the Population and Multi-Generation Registers. We excluded individuals who died or emigrated before Jan 1, 2005, and included full-siblings who were not twins and did not have half-siblings. ICD diagnoses were obtained from the National Patient Register. We extracted ICD diagnoses for physical conditions, when participants were aged 18 years or older, from inpatient (recorded 1973–2013) and outpatient (recorded 2001–13) services. Diagnoses were regarded as lifetime presence or absence. Logistic regression models were used to estimate the associations between ADHD (exposure) and 35 physical conditions (outcomes) in individuals and across sibling pairs. Quantitative genetic modelling was used to estimate the extent to which genetic and environmental factors accounted for the associations with ADHD.4 789 799 individuals were identified (2 449 146 [51%] men and 2 340 653 [49%] women), who formed 4 288 451 unique sibling pairs  and 1 841 303 family clusters . The mean age at end of follow-up was 47 years ; ethnicity data were not available. Adults with ADHD had increased risk for most physical conditions (34 [97%] of 35) compared with adults without ADHD; the strongest associations were with nervous system disorders  and respiratory diseases . Sex-stratified analyses showed similar patterns of results in men and women. Stronger cross-disorder associations were found between full-siblings than between half-siblings for nervous system, respiratory, musculoskeletal, and metabolic diseases (p<0·007). Quantitative genetic modelling showed that these associations were largely explained by shared genetic factors (60–69% of correlations), except for associations with nervous system disorders, which were mainly explained by non-shared environmental factors.This mapping of aetiological sources of cross-disorder overlap can guide future research aiming to identify specific mechanisms contributing to risk of physical conditions in people with ADHD, which could ultimately inform preventive and lifestyle intervention efforts. Our findings highlight the importance of assessing the presence of physical conditions in patients with ADHD.Swedish Research Council; Swedish Brain Foundation; Swedish Research Council for Health, Working Life, and Welfare; Stockholm County Council; StratNeuro; EU Horizon 2020 research and innovation programme; National Institute of Mental Health. ADHD is a neurodevelopmental disorder with an estimated worldwide prevalence of 3–7% in childhood and adolescence,Evidence before this studyWe searched Medline for systematic reviews published, with no language restrictions, between database inception and Jan 1, 2021, on the association between adult ADHD and physical health conditions, using the search terms “systematic review”, “ADHD” or “attention deficit hyperactivity disorder”, “adult”, and “physical disease” or “somatic disease”. We identified the most recent systematic review on the topic  and updated it with an additional 19 studies retrieved using the same search strategy and syntax in the Medline database. The available body of research shows that only a few physical conditions have been thoroughly studied in relation to adult ADHD. Emerging evidence, however, suggests increased risk of several physical conditions in people with ADHD. Physical conditions that have shown robust and replicated association with ADHD include obesity, sleep disorders, and asthma, mostly in children. A small number of studies have suggested tentative associations between ADHD and age-related diseases. However, findings have been mixed as not all studies have shown an association, and several studies have been limited by small samples and retrospective reports. Consequently, there is little detailed knowledge on physical diseases in ADHD beyond young-to-middle adulthood.Added value of this studyTo our knowledge, this is the first large-scale register-based study of phenotypic and aetiological associations between ADHD and a broad range of physical health conditions across adulthood. We found that adults with ADHD were at increased risk of numerous physical conditions, across nervous system, respiratory, musculoskeletal, metabolic, circulatory, gastrointestinal, genitourinary, and skin disease groups, compared with adults without ADHD. Although there is little research on the associations between ADHD and age-related diseases, due to the scarcity of lifespan data sources, we showed that ADHD is linked to increased risk of cardiovascular disease, Parkinson's disease, and dementia. Quantitative genetic modelling showed that numerous associations were largely explained by shared genetic factors, with the exception of associations with nervous system and age-related diseases. These findings provide aetiological insights into the co-occurrence of ADHD and physical diseases.Implications of all the available evidenceDetailed management guidelines for adults with ADHD and co-occurring physical diseases are scarce. However, emerging research findings have shown an increased risk of physical diseases in adult patients with ADHD, which highlights the importance of assessing the presence of physical conditions in these patients. Identifying co-occurring physical conditions could have important implications for treating adults with ADHD and for benefiting the long-term health and quality of life of patients. Emerging aetiological research findings can also be used to guide future research aiming to identify specific mechanisms contributing to risk of physical conditions in people with ADHD, which could ultimately inform preventive and lifestyle intervention efforts.A register study in Denmark published in 2020 showed that behavioural disorders  were significantly associated with a range of subsequent physical conditions. Associations with physical conditions were generally of similar or greater magnitude than associations between physical conditions and other psychiatric disorders.Only a few studies have investigated whether aetiological factors underlying ADHD are shared with physical conditions. The few available quantitative and molecular genetic studies have revealed weak-to-moderate genetic associations between ADHD and conditions such as obesity, diabetes, asthma, epilepsy, and migraines.Higher risk of physical conditions in siblings of individuals with ADHD indicates that familial factors shared among siblings contribute to the co-occurrence of disorders. Differences in the magnitude of association across full-siblings and maternal half-siblings can point to the source of familial coaggregation . Full-siblings share on average 50% of their segregating genes, whereas half-siblings share 25%. Full-siblings and maternal half-siblings tend to share environmental factors, as they are often reared in the same household. Thus, a greater association in full-siblings than in half-siblings suggests that shared genetic factors contribute to the association between conditions.We aimed to investigate the phenotypic and aetiological associations between ADHD and a wide range of physical health conditions, and to examine the extent to which any observed associations are primarily genetic or environmental in origin, by estimating individual associations, familial coaggregation, and genetic and environmental contributions to the associations.We did a register study in Sweden and identified full-sibling and maternal half-sibling pairs born between Jan 1, 1932, and Dec 31, 1995, through the Population and Multi-Generation Registers.ICD diagnoses were obtained from the National Patient Register,We based our data on an existing register linkage; we identified 35 relevant common physical conditions, and these were categorised into eight broader disease groups on the basis of ICD-10 structure . AnalyseFor the co-occurrence and familial coaggregation analysis, we used logistic regression to estimate the associations between ADHD and physical conditions, by comparing the risk of physical conditions (outcomes) in individuals with and without ADHD (exposure). We fitted logistic regression models in full-siblings and maternal half-siblings separately, to examine the associations between ADHD in individuals  and physical conditions in their siblings . Associations are presented as odds ratios (ORs) with 95% CIs. Statistical comparisons of the ORs in full-sibling and maternal half-sibling cohorts were made, and significance was determined based on a false discovery rate-corrected p value at a threshold set at p=0·007.In sensitivity analyses, we examined whether the identified familial associations between ADHD and physical conditions could be explained by direct effects of one condition on the other. This was examined in the full-sibling cohort, by adjusting for ADHD in the outcome individuals. If ORs remained significant after adjustment, the contribution of common familial risk factors to ADHD and the physical condition would be further supported. Detailed description of this rationale has been provided elsewhere.Analyses included sex and birth year of both relatives as covariates to adjust for different follow-up lengths and cohort effects. Data management was done using SAS version 9.4, and analyses were run using Stata version 16.0. A cluster robust sandwich estimator was used to remove distributional assumptions and correct CIs for dependence of family data.Quantitative genetic modelling was used to estimate the contribution of genetic and environmental factors to the associations between ADHD and physical conditions. We selected conditions that showed significantly stronger associations with ADHD across full-siblings than maternal half-siblings, as this suggests genetic factors contribute to the cross-disorder covariance. The liability-threshold model was used, where an underlying normally distributed liability of disease is assumed.Analyses included sex and birth year as covariates, and models were fitted using the weighted least-squares method in OpenMx version 2.15.5. Because half-siblings tend to display higher rates of disorders than full-siblings,The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.4 789 799 individuals were identified , who formed 4 288 451 unique sibling pairs  and 1 841 303 family clusters .The full cohort included 2 449 146 (51%) men and 2 340 653 (49%) women, and the mean age at end of follow-up was 47 years , respiratory (2·49 [2·40–2·59]), musculoskeletal (2·03 [1·97–2·09]), and metabolic (2·02 [1·96–2·09]) diseases. The associations between ADHD and these four disease groups were significantly stronger between full-siblings than between maternal half-siblings  of 35 physical conditions studied, and associations were strongest with nervous system disorders (particularly sleep disorders), and respiratory, musculoskeletal, and metabolic diseases. Similar patterns of associations with physical disorders were found in men and women. Several conditions within these disease groups have been linked with ADHD previously, often in smaller clinical studies. There is little research on associations between ADHD and age-related diseases, due to the scarcity of lifespan data sources, but we showed that ADHD is linked with increased risk of cardiovascular disease, Parkinson's disease, and dementia (1·32–2·44 times increased odds).Between-sibling analyses showed that full-siblings of individuals with ADHD were at increased risk for numerous physical conditions, suggesting that shared familial factors contributed to the co-occurrence of the conditions. This inference was further supported by sensitivity analyses where we found that most significant associations remained after adjusting for ADHD in the sibling of the exposure individual. If these physical conditions were simply a consequence of behaviours driven by ADHD  we would expect the associations to disappear after adjusting for ADHD in the sibling. However, as the associations remained significant, this finding supports the idea that ADHD and these physical conditions share aetiological components.Significantly stronger associations with ADHD were found between full-siblings than between half-siblings for nervous system, respiratory, musculoskeletal, and metabolic disease groups, suggesting that the shared familial liability is partly due to genetics. Quantitative genetic modelling showed that these associations were largely explained by shared genetic factors. These findings are consistent with reports of genetic correlations between ADHD and obesity and diabetes from genome-wide association studies.It is also important to highlight associations that showed no evidence of shared familial liability. Between-sibling associations were not significant between ADHD and Parkinson's disease, dementia, inflammatory bowel disease, coeliac disease, rheumatoid arthritis, eczema, pulmonary disease, or atrial fibrillation. One possible explanation for no association with these conditions is limited statistical power due to low cross-disorder concordances. These are especially low for late-onset diseases, by contrast with ADHD which has childhood-onset and has only recently been commonly diagnosed in Sweden,Our findings can guide future research on physical conditions in patients with ADHD. Whereas the co-occurrence of ADHD and several physical conditions implicated shared genetic factors, other conditions showed evidence that suggests unique environmental or directional effects. These findings highlight important directions for future research on more targeted biological mechanisms and modifiable risk factors, which could be informative for diagnosis, prevention, and treatment of physical conditions in patients with ADHD.This is, to our knowledge, the first large-scale study using a representative population cohort to examine phenotypic and aetiological associations between ADHD and a wide range of clinically assessed physical conditions across adulthood. It is important, however, to interpret results in the context of the limitations of the study. We relied on register-based diagnoses, and therefore findings rely on diagnosed patients who are potentially more severely affected than individuals who do not receive or seek health-care support. Furthermore, we did not directly test the effect of ADHD medication on physical conditions, as information on medication was not available before 2005. However, ADHD medications were not licensed for treatment in adults in Sweden before 2008,During the follow-up period, there were changes in diagnostic practices for ADHD Adult ADHD only became a commonly diagnosed disorder in Sweden in the past decade, which probably explains the lower prevalence in our study 1·3%) than in previous survey studies in adults.% than inThe heritability of a few health conditions  was slightly lower than in previous reports.In conclusion, we showed that adults with ADHD are at increased risk of a range of physical conditions, across circulatory, metabolic, gastrointestinal, genitourinary, musculoskeletal, nervous system, respiratory, and skin diseases. Most physical conditions showed familial associations with ADHD (mainly from genetic factors). Our findings highlight the need for rigorous medical assessment and care in adult patients with ADHD, and suggest long-term consequences with age-related diseases. We further shed light on the aetiological underpinnings of physical conditions in ADHD, which could guide future research that aims to identify shared biological mechanisms, or modifiable risk factors that contribute to risk of physical conditions in patients with ADHD.https://www.scb.se/en/services/guidance-for-researchers-and-universities/.The Public Access to Information and Secrecy Act in Sweden prohibits us from making individual-level data publicly available. Researchers who are interested in replicating our work can apply for individual-level data through Statistics Sweden at: www.adhdinadults.com, outside of the submitted work. All other authors declare no competing interests. EDR affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned  have been explained.EDR reports grants from FORTE, Ingrid and Thurings Stiftelse, during the conduct of the study; and personal speaker fees from Shire Sweden, a Takeda Pharmaceuticals company, outside of the submitted work. HL has served as a speaker for Evolan Pharma and Shire Sweden and has received research grants from Shire Sweden, outside of the submitted work. IB reports grants from The Swedish Brain Foundation, during the conduct of the study. ML reports personal fees from Johnson and Johnson, and grants from the EU's Horizon 2020, outside of the submitted work. SC reports honoraria and reimbursement for travel and accommodation expenses for lectures from the following non-profit associations: Association for Child and Adolescent Central Health, Canadian ADHD Alliance Resource, British Association of Pharmacology, and Healthcare Convention for Educational Activity on ADHD, during the conduct of the study. SVF has received income, potential income, travel expenses, or continuing education support or research support from Takeda, OnDosis, Tris, Otsuka, Arbor, Alcobra, Aveksham, Enzymotec, Neurovance, Vallon, KemPharm-Corium, Lundbeck, Ironshore, Rhodes, Akili Interactive Labs, Sunovion, Supernus, and Genomind; has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD; receives royalties from books published by Guilford Press, Oxford University Press, and Elsevier; and is programme director of


Previous research has indicated that attention-deficit/hyperactivity disorder (ADHD) isassociated with an increased risk for dementia, but studies are scarce and inconclusive.We aimed to investigate the association between ADHD, and dementia and mild cognitiveimpairment (MCI). Additionally, we aimed to investigate the impact of comorbidconditions, educational attainment, head injuries, other developmental disorders, andsex on the association.The study population consisted of 3,591,689 individuals born between 1932 and 1963,identified from Swedish population-based registers. Cases of ADHD, dementia and MCI weredefined according to ICD diagnostic codes and ATC codes for medication prescriptions. ACox proportional hazards model was used to test the associations between ADHD, anddementia and MCI.Individuals with ADHD had an increased risk for dementia and MCI. After adjusting forsex and birth year, a hazard ratio (HR) was 2.92  fordementia, and 6.21 (5.25–7.35) for MCI. Additional adjustment for psychiatric disorders substantiallyattenuated the associations, HR = 1.62 (1.32–1.98) for dementia, and 2.54 (2.14–3.01)for MCI. Common metabolic disorders , sleepdisorders, head injuries, educational attainment, and other developmental disorders, hada limited impact on the association. The association between ADHD and dementia wasstronger in men.ADHD is a potential risk factor for dementia and MCI, although the risk significantlyattenuates after controlling for psychiatric disorders. Further research is needed toconfirm these findings and to explore underlying mechanisms of the associations. Attention-deficit/hyperactivity disorder (ADHD) is a common, childhood-onsetneurodevelopmental disorder and an important risk factor for many psychiatric ,2 and geStudies in humans –8 and anAdditionally, it has been proposed  that ADHThe current study aimed to extend previous research –8,12 by We used data from multiple Swedish population-based registers. All individuals registeredin Sweden are assigned a unique personal identity number that enables a linkage of theseregisters . The TotThe total cohort consisted of 3,591,689 individuals born between 1932 and 1963, who werealive and resided in Sweden in 2001 . WeexclADHD cases were defined as individuals who received an ICD-9/10 diagnosis from the NPR, or dispWe included a diagnosis of dementia or MCI recorded at age 50 or older to minimize therisk of misdiagnosis with conditions with similar clinical presentations  whendementia/MCI is diagnosed at a younger age .The folThe following variables, associated with ADHD and/or dementia in previous research, wereaddressed as covariate sets: (a) sex ,11 and bWe used a Cox proportional hazards model to test the association of ADHD withdementia/MCI, by comparing the rate of having these disorders between individuals with andwithout ADHD from the age of 50 years, with attained age as the underlying timescale.Since ADHD is defined according to the ICD-10 criteria by a childhood-onset of thesymptoms , we consWe used Wilcoxon two-sample test to evaluate differences in median age of dementia/MCIdiagnosis, and median age in 2013 between individuals with and without ADHD. Whendistribution of frequencies for covariates differed between groups with and without ADHD,we used logistic regression models to inspect associations between ADHD and thecovariates, presented as odds ratios (OR) with 95 % CIs and adjusted for sex and birthyear.To investigate whether the case definition of ADHD based on a confirmed diagnosis wouldaffect the results, we conducted a sensitivity analysis by excluding cases with ADHDmedication prescription only.Main and sensitivity analyses were presented collapsed across sex and stratified by sex.We used SAS version 9.4  for data management and R version 3.6.1 fordata analyses.Z = −9.02, p < 0.0001; for MCI,Z = −11.55, p < 0.0001). At the end of 2013individuals with ADHD were younger than those without ADHD . All covariates were significantly associated with ADHD andMCI  in individuals with ADHD compared with individualswithout ADHD, adjusting for sex and birth year . After sp = 0.01, meaning that the risk of having dementia in women with ADHDwas 42% lower than in men with ADHD. An event rate per 10,000 person years for dementiawas lower in women  than men with ADHD, while the event rates for men and women without ADHD were equal (p = 0.84).The association between ADHD and dementia across all levels of adjustments was strongerin men compared to women , with are equal . On the We performed a sensitivity analysis to investigate whether the results were affected bythe case identification for ADHD that revealed the same pattern of results acrossadjustments for all included covariate sets with overlapping confidence intervals, butsomewhat lower associations of ADHD with dementia/MCI compared to the main analysis(Supplementary Table S2). When case identification of ADHD was based on a diagnosis only,point estimates for dementia attenuated towards the null and became nonsignificant afteradjusting for psychiatric disorders.Since the median age of ADHD and MCI/dementia diagnoses were relatively close in time andto provide further confirmation of the clinical validity of ADHD diagnoses, we conductedtwo post hoc sensitivity analyses, adjusted for sex and birth year, based on more sctrictcase defitions of ADHD by including (a) only cases with at least two confirmed diagnosesof ADHD and (b) only cases with a primary diagnosis of ADHD. Both post hoc sensitivityanalyses yielded results consistent with the main analysis .In this Swedish population-based register study, we found that ADHD was associated with anincreased risk for both dementia and MCI. Psychiatric disorders substantially attenuated theassociations of ADHD with dementia and MCI. Additionally, we demonstrated that theassociation between ADHD and dementia was stronger in men than in women.Our findings support previous studies that identified an increased risk for dementia inpeople with antecedent ADHD –7. One sAdditionally, findings of the current study support a hypothesis that cumulativehealth-compromising factors of ADHD may affect the association between ADHD and dementia. SpecifiOur finding that educational attainment had a limited influence on the association betweenADHD and dementia needs to be interpreted carefully. Individuals with ADHD were more likelyto complete secondary education, but less likely to complete postsecondary/postgraduateeducation compared to those without ADHD. This is somewhat inconsistent with previousstudies that have identified an association between ADHD and lower educational levels . A potenWe found an increased risk for common metabolic  andsleep disorders, and head injuries in individuals with ADHD. Still, these covariates onlyminimally affected the associations of ADHD with dementia/MCI. One study  found thFurther, our findings suggest that the association between ADHD and dementia/MCI may beindependent from other developmental disorders. We were unable to address other early-lifeand neurobiological/genetic explanations to the observed associations . Early-lThe association between ADHD and dementia was somewhat stronger in men, while previousstudies did not address the effect of sex on the association –8, or thThe current study identified a prevalence of clinically diagnosed ADHD of 0.3%. This isnotably lower compared to a pooled prevalence estimate based on validated scales of 2.5% inadults  and 2.2%Some limitations of the current study should be addressed when interpreting its findings.The risk for MCI in people with ADHD was larger than the risk for dementia, and the medianage of diagnosis for ADHD and MCI/dementia were close in time. In older adults, symptoms ofADHD, such as difficulty to organize activities, inability to sustain attention, memoryproblems, behavioral and psychiatric symptoms  may resemble prodromal dementia/MCI .AdditioWe could not investigate separate associations between ADHD and dementia subtypes  due to a smallnumber of individuals with ADHD diagnosed with each subtype. It is plausible that differentsubtypes of dementia, having distinct etiological pathways, are differentially associatedwith ADHD and comorbid disorders. Additionally, ADHD and some subtypes of dementia mightonly share similar clinical presentation; however, underlying mechanisms could be distinctand unrelated . For insWe did not cover behavioral outcomes  of ADHD that could affect the association between ADHD and dementia , since tThe median age of the study population at the end of the follow-up was 63 years, while therisk for dementia substantially increases after the age of 65 , thus, wIn conclusion, the present study suggests that there is an increased risk for dementia andMCI in individuals with ADHD, with the association between ADHD and dementia being strongerin men than in women. These associations substantially attenuate after controlling forcomorbid psychiatric disorders, while common metabolic disorders and sleep disorders, headinjuries, educational attainment, and other developmental disorders, have a limited impact.Since this is a notably understudied topic, more research is of crucial importance toconfirm our findings and investigate underlying mechanisms. Specifically, futureneurobiological and epidemiological studies are needed, which should cover differentsubtypes of dementia, behavioral outcomes of ADHD, and a broader range of socioeconomicvariables and comorbid health conditions.


Alleviating the multiple problems of children with autism spectrum disorder (ASD) and its comorbid conditions presents major challenges for the affected children, parents, and therapists. Because of a complex psychopathology, structured therapy and parent training are not always sufficient, especially for those patients with intellectual disability (ID) and multiple comorbidities. Moreover, structured therapy is not available for a large number of patients, and pharmacological support is often needed, especially in those children with additional attention deficit/hyperactivity and oppositional defiant, conduct, and sleep disorders. Persistent deficits in the ability to initiate and sustain reciprocal social interaction and social communication,A range of restricted, repetitive, and inflexible patterns of behavior and interests, andA high prevalence of intellectual disability, language impairments, and other comorbid disordersand a number of comorbid conditions such as attention deficit/hyperactivity disorder (ADHD), sleep disorders, convulsions, oppositional defiant disorder (ODD), anxieties, obsessions and compulsions (OCD), depression, and numerous other symptoms and conditions that are discussed as to whether they represent “core” or comorbid problems [Autism spectrum disorder (ASD) is a common , complexproblems . These cproblems . Table 1ASD comprises persons with a very low functional level up to a normal or even supranormal level with relatively low impairment. The disorder may not be cured but largely ameliorated by therapy and guided intrafamilial support , 165. Es“Conventional” pharmacotherapy is targeted to reduce inappropriate behavior and the associated burden for family, school, and the social environment, to limit inattention, impulsivity, and hyperactivity associated with ADHD, and to reduce the risk of seizures. Up to two-thirds of children with ASD are treated with psychotropics, and a third with multiple drugs , 288. NePharmacologic agentsTherapy for common problems of ASD and comorbid disordersOther substances, supplementary and alternative therapies.In order to improve the multiple medical, social, behavioral, learning, or sleep-related problems, a number of drugs have been recommended and studied in clinical trials . In addiWe searched the database PubMed/Medline for the following terms: autism AND pharmacotherapy OR medication, and retrieved 4.248 citations. Restricting the period covered to the years 2000–2019 and the language to English OR French OR German; 3.607 citations remained, including 1120 reviews. Selecting relevant titles, primarily taking into account the contents and quality of the papers, and secondarily the authors, publication media (impact factor), and date (selecting newer references), 223 remained. These were carefully studied in detail and supplemented by 742 additional relevant articles retrieved by specific topic searches that were considered important for understanding during the writing process. This added to 965 references of which 325 were cited in this article, depending on their subjectively estimated significanceIn the following, we will discuss the various groups of pharmaceuticals used in children and adolescents with ASD, namely antipsychotics, antidepressants, and anticonvulsants.Antipsychotics influence dopamine neurotransmission, act sedating in lower, antipsychotic in medium, and narcotic in high doses. First generation antipsychotics (FGA), especially haloperidol, have been shown to influence stereotypic and hyperactive behavior, to reduce temper tantrums and social isolation . FGAs shThis is also true for the SGA clozapine because of its dangerous hematologic side effects . As an aIn normally developing children, selective serotonin antagonists (SSRIs) are effective against depressive symptoms with substance-related differences in effectivity and side effects. SSRIs also act against anxiety disorders in lower dosages and against OCD in higher dosages, compared to the treatment of depression. In children with ASD, SSRIs are widely prescribed, but their therapeutic effect is less evident . Other AA few studies suggest improvements of repetitive and stereotypic behavior with AD therapy in children with ASD , althougght gain . Studiesght gain ), and loIn summary, although AD medication, especially SSRIs, is widely prescribed in children and adolescents, its effectiveness is limited to not evident in children with ASD, and side effects may be more exaggerated in these patients. Therefore, the use of ADs in ASD can generally not be recommended. Because of their widespread use, pharmacologic data on AD medication are nevertheless summarized in Table Anticonvulsants may be used to treat epilepsies, bipolar disorders, and externalizing behavioral problemsThe most commonly used pharmacotherapeutics are valproic acid, lamotrigine, levetiracetam, and ethosuximide , cf. TabPharmacotherapy for patients with ASD aims at reducing inappropriate behavior and the related intrafamiliar and psychological stress, at improving engagement in therapy, health-related quality of life, performance at school and work, social integration and participation, and at treating comorbid problems such as ADHD or seizures , 274. LiASD and ADHD share genetic, neurophysiological, and clinical similarities , 181. BoTreatment of ADHD in patients with ASD should follow the same multimodal algorithms as for ADHD alone and should include psychoeducation , 238, paMedication for ASD/ADHD targets modulating dopamine and epinephrinergic transmitter systems, thereby increasing dopamine availability in frontal areas and striatum, and downregulating dopamine moderators. Usually, two types of medication are distinguished: stimulants  and nonstimulants .Stimulants. Effectiveness and compatibility of methylphenidate, the most frequently used ADHD medication, have multiply been proven in patients with ASD and ADHD, with and without ID [thout ID , 298. Inthout ID , 298 witormal IQ . The efformal IQ . In chilormal IQ , or lisdormal IQ , 145, anEmotional dysregulation (irritability) is a common problem in children with ADHD and with ASD, with rates around 78% for both disorders . StimulaAtomoxetine. The norepinephrine reuptake inhibitor and NMDA receptor antagonist possesses good effectiveness [tiveness , 124 andect size , 244, esect size  or aripiect size  or switcect size , 270 or ect size .Comparing atomoxetine and amphetamine derivates, higher effect sizes of methyplhenidate slow release preparations have been reported . Small bAlpha-2-agonists. Clonidine and extended-release guanfacine are less effective medications against ADHD core symptoms with some antitic potential, pronounced tiredness, and gastrointestinal SE, which may lead to discontinuing the medication. Hyperactivity and impulsivity are improved in about 45% of cases [of cases , 294.Other treatments for ADHD. Mindfulness-based [ss-based , 268 andss-based  have beeDue to the fact that antidepressant medication is of questionable effect in children and adolescents with ASD, their use may generally not be recommended. There is no clear-cut evidence that this recommendation is also valid for patients with severe depression, and the widespread use of antidepressant medication reflects this challenge, especially in the light that the prevalence of comorbid depression in autistic patients is fourfold compared to the nonautistic population . CombiniSuicidality has been reported in 21.3% (7–47%) of patients with ASD , 324. SuBipolar disorders are detected in 6–21% of adult ASD patients , and 30%About 40% of children with ASD present with various anxiety disorders, phobias including social phobia, general, and separation anxiety disorder, and OCD . They alIn general, the treatment methods of choice for fears and OCD are parent training, play therapy, and cognitive behavioral therapy (CBT) , 60. AntMedication may be helpful in inducing and improving disturbed sleep but should be provided with caution: melatonin will improve sleep rhythm in 85% of the children with ASD even in those without disturbed melatonin circadian rhythm at a daily dosage of 1–6 mg given 30 minutes before bedtime , 267. AdOther sleep stimulating agents, like valerian, passion flower, and hops provide placebo support; benzodiazepines, zolpidem, and zaleplon act on GABA receptors, helping in inducing sleep but usually have a long  anxiety . Sleep-iRestless legs syndrome , 28010, Other sleep-stimulating agents, like valerian, passion flower, and hops, provide placebo support; benzodiazepines, zolpidem, and zaleplon act on GABA receptors, helping in inducing sleep but usually have a long nged use . Sleep-iBenzodiazepines, especially those targeting symptoms . The climentclasspt{minimaEpilepsy (more than one convulsion) occurs in about 5–46% of children with ASD, (compared to 1–2% in children not on the spectrum), depending on the clinical sample and the severity of ID . ComorbiMitochondrial respiratory chain defects have been detected as an important link between epilepsy and ASD . In addiGastrointestinal distress related to constitutional, behavioral, and inflammatory causes is frequently observed in children with ASD and may be related to altered ASD severity . AlteratImpulsive aggression and related disruptive behavior, as well as self-injuring behavior are frequently observed in ASD/ADHD and are the leading cause for school suspension, clinical referrals, and ward admissions . PositivIndependently of their intellectual capacity, up to asomnias , 317. Thasomnias , 202. Reasomnias , ADHD/ASasomnias  leading asomnias , 308.Restless legs syndrome , 280, anBehavioral measures , 314 likChronic tic disorders and motor stereotypies are common comorbid movement disorders in children and adolescents with ASD . The preAmong the “newer” pharmacologic concepts , oIn the short term, intranasal oxytocin enhances motivation and attention to social stimuli, improves social initiative, understanding, learning , 22, 176There is only limited evidence for using beta blockers for reducing stress-related autoaggressive behavior  or memanMedical cannabis, especially for ADHD, tics, sleep problems, behavioral problems, and anxiety , 247, maVarious behavioral and functional therapies, such as structured behavioral therapies , 299, coAlternative, “natural” treatments seem less invasive, safer (there are no reports on dangerous action), more intuitive to understand, and easier to procure. Parents are concerned with the safety or side effects (listed in the package leaflet) of medication or are disappointed because conventional medication did not change the core symptoms of ASD . TherefoMost of these therapies are used as an adjunct to conventional therapy. Biologically based therapies , essential fatty acids (25%), melatonin (25%), and probiotics 19%), and discourage withholding (76%) or delaying immunizations (55%), chelation (61%), anti-infectives (57%), or secretin (43%) . It has %, and diConventional therapy, although mostly funded on extensive controlled studies, has its limits, especially when treating irritability and temper tantrums. These problems should be restricted by early behavioral treatment. Unfortunately, these treatments are tedious and not available everywhere. In addition, the question of the impact of comorbid conditions has not been solved as yet.Pharmacologic treatments are not sufficient; the primary ASD treatment, especially for children with intellectual disabilities, will remain structured and functional therapy, as well as parental empowerment and support.Therapies aiming at improving the core symptoms of ASD, such as social communication: novel therapies, e.g., oxytocin, are encumbered with the complex functioning of our social brain, which is outlined in the first days of life or even before.At present, genetically based therapies are not visible on the horizon, mostly because the genetic background of ASD is so complex that it will probably need further years of intensive research to link clinical pictures to genetic variants and establish repair options.Pharmacotherapy in children and adolescents with ASD may be helpful in overcoming otherwise not resolvable behavioral and attentional problems , and, again, walking the tightrope between brightening mood or reducing anxiety or obsessions and compulsions and an increased behavioral activation.Sleep problems are observed in a majority of patients with ASD. Sleep hygiene and bedtime routines should be tried before trying medication, and sleep-related side effects of stimulant therapy should also be considered as a promoting factor of sleep dysfunction. Melatonin is the first-line drug, especially for difficulties in falling asleep. It is effective in about two-thirds and counterbalances inherited melatonin dysfunction. It should be noted that falling asleep with lights on  counteracts the action of melatonin medication.Treatment of ADHD, one of the most prominent comorbid conditions of ASD with overlapping symptoms, is often a key factor in enabling social and intellectual learning, school attendance, and fighting restlessness and impulsivity. Problems are related to the reduced efficacy of pharmacotherapy compared to normotypic patients and a multitude of interacting problems, e.g., bipolar disorder and ADHD.Convulsions, most frequently observed in children with ASD and ID, should be treated like in normally developing children (see Sect. 3.2.1). Attention should be paid to sedation, metabolic, learning inhibition side effects, and, and in adolescents, to teratogenic side effects for the offspring.The rediscovery of the gut–brain axis is a relatively new field of research and might, therefore, be overestimated by parents. More prospective studies will shed light on the effects of dietary and probiotic measures. Alternative treatments are comprehensively largely overestimated for their effects, ranging from dietary to physical and possibly endangering measures. Because alternative “medications” are not controlled for their action in prospective randomized trials, it is difficult to argue against the use of such substances in the general public, mostly because “natural” substances are considered harmless and innocuous (see Sect. 3.4).In summary, we compiled an overview on substances that may be advantageously used in children with ASD with the aim of improving social behavior, learning ability, and quality of life of the children and their environment. The approach is rather defensive, mostly targeting undesired symptoms. Future work and experience should focus on desired changes of core symptoms, on long-term efficacy, on reducing polypragmasia and undesired drug effects, and on avoiding overtreatment, especially if behavioral therapies are available as an alternative. On the other hand, the benefits of carefully prescribed medication should always be recognized.


A significant improvement was reported in half of the patients followed after 1 year, with Clinical Global Impression—Improvement scale (CGI-I) ≤ 3. In all, 233 of 4091 are 18-year-old patients. Conclusions: A ten-year systematic monitoring of models of care was a fruitful shared and collaborative initiative in order to promote significant improvement in clinical practice, providing effective and continuous quality of care. The unique experience reported here should spread.Background: The purpose of this article is to update the diagnostic assessment, therapeutic approach, and 12–18 month follow-up of patients added to the Italian Lombardy Attention Deficit Hyperactivity Disorder (ADHD) Register. Methods: Medical records of patients added to the Registry from 2011 to 2021 were analysed. Results: 4091 of 5934 patients met the criteria for a diagnosis of ADHD, and 20.3% of them presented a familiarity with the disorder. A total of 2879 children (70.4%) had at least one comorbidity disorder, in prevalence a learning disorder (39%). Nearly all (95.9%) received at least one psychological prescription, 17.9% of them almost one pharmacological treatment, and 15.6% a combination of both. Values of ≥5 of the Clinical Global Impression—Severity scale (CGI-S) are more commonly presented by patients with a pharmacological prescription than with a psychological treatment ( Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder that affects 5.9% of children and persists into adulthood for two-thirds of them ,2, with The wide variability depends on the different diagnostic procedures adopted to assess children and the criteria used, and the period of time over which assessment is conducted . The peaA retrospective study based on medical records was conducted. Data were identified from the Regional ADHD Registry. Formal ethical review board approval was not required for the present updating because it was previously approved by the Institutional Review Board of the Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy. Written informed consent was obtained from all patients before data collection. We used the previously described methodology and reported data concerning the local health setting , the chaData were extracted from the database and analyses were updated on 1 April 2021, and data referred to patients added between 2011 and 2021.p < 0.05 was considered to be significant.All data were entered in an SAS/STAT database . Descriptive statistics were computed for the entire study population and for subgroups. The Wilcoxon test was used to compare continuous variables, whereas chi-square tests were used to compare categorical variables. V-Cramer and Wilcoxon effect sizes were calculated . Both vaA total of 7053 children were added to the registry from June 2011 to December 2021, of whom 6188 were children and adolescents accessing the ADHD centres for the first time  for suspected ADHD diagnosis. Most of the patients (5934) had completed the diagnostic assessment . Children = 121, 2%).The characteristics strongly associated with ADHD were lower age, male gender, only child, not born in Italy, adopted, support teacher, lower educational level of parents, unemployed father, ADHD familiarity and psychiatric comorbidity . Accordin = 2311, 56.5%), followed by child training  and teacher training . All training types were proposed to 519 (12.7%) patients. In all, 2485 (61.9%) patients had an ADHD Combined subtype (ADHD-C), whereas 1218 (30.3%) were diagnosed with Inattentive Type (ADHD-I) and 313 (7.8%) Hyperactive Type (ADHD-HI) subtypes. Of all 4091 patients diagnosed with ADHD, 4016 patients received a prescription  received at least one prescription: 3282 (80.2%) received only psychological treatment, 94 (2.3%) only pharmacotherapy and 640 patients (15.6%) received both pharmacological and psychological treatment. A total of 734 patients received a drug prescription, 679 (16.6%) of them methylphenidate (0.5–80 mg daily), of those 21 (0.5%) together with another drug , 23 (0.6%) atomoxetine (10–60 mg daily), and 53 (1.3%) other psychotropic drugs. Among the 3922 (95.9%) patients prescribed psychoeducational treatment, 2631 (64.3%) received at least one type of training intervention , whereas 2820 (68.9%) received other psychological treatment. Parent training was the most frequently proposed psychological treatment  than drug therapy (16.6%), p < 0.0001. Univariate analysis between patients treated with pharmacological and psychological treatment highlighted several significant differences, as reported in Those with an ADHD-C diagnosis were treated more commonly with drug therapy (79.8%) than with psychological treatment (57.9%), Results from the rating scales, filled out by the parents and teachers, were compared in order to highlight differences or similarities about how adults perceived the symptom severity and behavioural problems of the child. The same comparison was made between mothers’ and fathers’ perception .p < 0.0001) than teachers, who reported more behavioural  and emotional problems . Mothers reported more child pathological problems than fathers did on both subscales   and on the CBCL-Total score . Despite these differences, kappa values highlighted a “fair” agreement between parents and teachers (>60%) and “excellent” agreement between mothers and fathers (>85%).The results highlighted that parents tended to perceive more cognitive problems (CPRS-I = 3270, 66.6%; CTRS-I = 2682, 54.6%; Throughout the regional database system, data on patient care from the first access to the diagnosis and data on treatment prescriptions and follow-up visits were systematically collected. As shown in Ten years after the creation of the Lombardy Registry Project, clinical and service assessment data revealed the effectiveness and usefulness of this regional project in providing assistance and continuity of care to ADHD patients and their families. Over the years, the registry was monitored to achieve clinical improvement, using systematic activities and an interactive system evaluation to test the change, according to the main clinical quality improvement features . The cliThe Regional ADHD Registry represents a distinctive tool, a unique experience in the international context, to help guarantee a shared pathway of care in ADHD children. Continuous, systematic monitoring allows resources to be invested appropriately, such as in promoting progressive and significant improvement in clinical practice, ensuring a shared and efficient quality of care. Training initiatives involving clinicians, patients, parents and teachers may be useful in order to raise awareness about the disorder in clinical practice.