Background: Genes related to cell adhesion pathway have been implicated in the genetic architecture of attention-deficit/hyperactivity disorder (ADHD). Cell adhesion molecule 1, encoded by CADM1 gene, is a protein which facilitates cell adhesion, highly expressed in the human prefrontal lobe. This study aimed to evaluate the association of CADM1 genotype with ADHD, executive function, and regional brain functions.Methods: The genotype data of 10-tag single nucleotide polymorphisms of CADM1 for 1,040 children and adolescents with ADHD and 963 controls were used for case–control association analyses. Stroop color–word interference test, Rey–Osterrieth complex figure test, and trail making test were conducted to assess “inhibition,” “working memory,” and “set-shifting,” respectively. A subsample (35 ADHD versus 56 controls) participated in the nested imaging genetic study. Resting-state functional magnetic resonance images were acquired, and the mean amplitude of low-frequency fluctuations (mALFF) were captured.Results: Nominal significant genotypic effect of rs10891819 in “ADHD-alone” subgroup was detected (P = 0.008) with TT genotype as protective. The results did not survive multiple testing correction. No direct genetic effect was found for performance on executive function tasks. In the imaging genetic study for the “ADHD-whole” sample, rs10891819 genotype was significantly associated with altered mALFF in the right superior frontal gyrus . Specifically, the mALFFs in T-allele carriers were consistently higher than GG carriers in ADHD and control groups. Endophenotypic correlation analyses indicated a significant negative correlation between “word interference time” in Stroop (shorter “word interference time” indexing better inhibitory function) and mALFF in the rSFG . Finally, mediation analysis confirmed significant indirect effects from “rs10891819 genotype ” via “mALFF (rSFG)” to “inhibition (“word interference time”)” .Conclusions: Our study offered preliminary evidence to implicate the roles of CADM1 in relation to prefrontal brain activities, inhibition function, and ADHD, indicating a potential “gene–brain–behavior” relationship of the CADM1 gene. Future studies with larger samples may specifically test these hypotheses generated by our exploratory findings. CADM1) gene.Attention-deficit/hyperactivity disorder (ADHD)—characterized by developmentally inappropriate levels of inattention, hyperactivity, and impulsivity—is one of the most common childhood neurodevelopmental disorders with an estimated worldwide prevalence of 5% . It is aCADM1 gene, is a member of the immunoglobulin superfamily with cell adhesion properties, which promote axonal growth, neuronal migration, pathfinding, and synaptic formation in the developing nervous system and is also involved in the formation of neural networks  displayed increased daytime activity, decreased rest, and nocturnal hyperactivity, and strikingly, these anomalies were reversed by amphetamine. Moreover, higher levels of impulsive and aggressive behaviors were also present, such as jumping out of their cages and attacking other mice, i.e., behaviors consistent with other rodent models of ADHD  and A755C(Y251S)—were found in autism spectrum disorder probands and their family members , all of which represent the most relevant common brain regions identified by neuroimaging studies of ADHD  and potential relevance to ADHD, no genetic variants of CADM1 have achieved the postulated genome-wide significance (P < 10-8) or been represented among the genome-wide association studies (GWAS) top hits—in either the meta-analysis or primary GWAS of ADHD , instead of conventional diagnostic phenotypes. As an exploratory and hypotheses-generating study, we therefore considered it best to interrogate brain circuitry anomalies by applying an atheoretical probe along the domain continuum. In contrast to task-related fMRI, resting-state fMRI (rs-fMRI) permits evaluation of brain activities without prior theoretical assumptions, representing a more appropriate method to capture spontaneous regional neural activity as indexed by mean amplitude of low-frequency fluctuation (mALFF).Intriguingly, despite different strands of compelling evidence on the implicated roles of CADM1 gene in relation to ADHD psychiatric phenotypes, neurocognitive endophenotypes, and regional brain circuitry activities. Second was to test whether the domain approach guided by RDoC could be an alternative avenue to elucidate “gene–brain–behavior” relationships of the CADM1 gene by a series of domain-specific probes on different intermediate phenotypes within one single study, instead of relying on traditional diagnostic phenotypes alone. In other words, as an exploratory and hypotheses-generating study, we sought to explore the possible “gene–brain–behavior” relationship between CADM1 genetic polymorphism, brain circuitries activities, and executive tasks performance relevant to ADHD. We postulated that the “domain-based” analyses for complex relationships could yield findings with finer specificity than conventional phenotypes.There were two key objectives of this study. First was to examine the association of In total, 2,003 individuals  participated in the current study. All ADHD probands were recruited from the child psychiatric clinics at Peking University Sixth Hospital/Institute of Mental Health. Psychiatric diagnoses of ADHD and comorbidities were assessed and classified according to Diagnostic and Statistical Manual of Mental Disorders, 4th Edition criteria  by trainThe inclusion criteria for ADHD probands included: 1) having a Diagnostic and Statistical Manual of Mental Disorders, 4th Edition ADHD diagnosis; 2) aged between 6 and 16 years; 3) with a full-scale IQ ≥ 70, as measured by the Chinese version of Wechsler Intelligence Scale for Children ; and 4) A subsample of 35 ADHD cases and 56 healthy controls (aged between 8 and 16 years) was recruited for the nested imaging genetic study. To control for potential confounders relevant to this imaging genetic study, more stringent inclusion and exclusion criteria were introduced. Additional exclusion criteria were post-traumatic stress disorder, enuresis, and encopresis [captured by Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime version (Chinese-translated version) ]. ParticThis project was approved by the Ethics Committee of Peking University Sixth Hospital/Institute of Mental Health. Written informed consents were sought and obtained from parents for the child participants and from adult participants.CADM1 gene. The final set of 10-tag SNPs  according to the standard Affymetrix protocol. Samples of cases and controls were added in equal proportion to each chip to avoid batch effects. The Affymetrix 6.0 array included 96 single nucleotide polymorphisms (SNP) probes of tag SNPs Table 1 Executive function measures were ascertained in the subsample of ADHD and child control.Stroop Color–Word Interference test: The test included four conditions: i) color naming ; ii) word reading ; iii) color inhibition ; iv) word inhibition . The “color interference time” denotes the average time (in seconds) taken to complete each trial of condition 3 subtracted by condition 2, and “word interference time” denotes the average time (in seconds) taken to complete each trial of condition 4 subtracted by condition 1. In this study, color and word interference time scores are analyzed to represent “inhibition” of executive function (function .Rey–Osterrieth complex figure test (RCFT): RCFT evaluates visuospatial construction ability, visual working memory, and organizational skills. Participants were asked first to inspect and then copy the RCFT figure. After 30 s  and 20 min , they were asked to recall and reproduce the figure from memory without any visual cues or prompt. Both immediate and delayed scores were rated according to i) the structure recalled  and ii) detailed accuracy reproduced . “Forgotten” scores (for “structure” and for “detail”) were generated by subtracting respective “delay” scores from “immediate” scores. This yielded two set of scores: “structure forgotten score” and “detail forgotten score,” indicating the information that was lost during the 20-min interval. These discrepancy scores were analyzed in this study to represent “visual working memory” of executive function (function .Trail making test: This test was used to assess “set-shifting.” It includes two parts: i) number sequencing trail making; ii) number–letter switching trail making. The time taken to complete each part was recorded. The “set-shifting time” was represented by the time discrepancy taken for part 2 subtracted by the time taken to complete part 1  with a standard 12-channel head coil in the Imaging Center for Brain Research, Beijing Normal University. Participants while awake were instructed to remain still and relaxed with eyes closed during the 30-min period of rs-fMRI scanning, and a head strap and foam pads were used to minimize head movements. Functional images were acquired using an echo-planar imaging sequence with the following parameters: 33 axial slices, thickness/skip = 3.5/0.7 mm, repetition time = 2,000 ms, echo time = 30 ms, flip angle = 90°, matrix = 64 × 64, field of view = 200 × 200 mm, and 240 volumes. T1-weighted anatomical images were acquired with the following parameters: 128 slices, slice thickness = 1.33 mm, repetition time = 2,530 ms, inversion time (TI) = 1,100 ms, echo time = 3.39 ms, flip angle = 7°, matrix = 256 × 256, and field of view = 256 × 256 mm.Analysis of the rs-fMRI data was performed using Data Processing & Analysis for Brain Imaging (DPABI) 4.4 toolbox (DPABI_V3.1) . The preALFF, regional homogeneity, and degree centrality are the three most commonly used methods for “voxel-wise whole-brain” analysis in rs-fMRI . The intThe power spectrum was obtained by fast Fourier transform of the pretreated time courses, and the averaged square root across a frequency band of 0.01–0.08 Hz was calculated as ALFF . ALFF ofChi-square tests were applied for the categorical variable (sex), and independent sample t-tests were applied for continuous variables (age and IQ scores).Demographic and clinical characteristics were compared between ADHD and control groups. P < 0.05), further genotypic comparisons under recessive and dominant models were conducted. Furthermore, we repeated the earlier analyses by stratifying the full ADHD sample (i.e. the "ADHD-whole" sample)into “ADHD-comorbid” and “ADHD-alone” subsamples to account for potential heterogeneity related to comorbidities within the ADHD phenotype, given the concerns raised about such effects on genetic association in the literature . In addition, further logistic regression analyses were conducted to adjust the potential confounding effects with age, sex, and 10 principal components derived from the multidimensional scaling procedure for the Affymetrix 6.0 genotyping data  was performed using SPSS. The executive function measures  were entered as dependent variables in the general linear model, while genotypes were entered as independent variables, with age, sex, IQ, and ADHD diagnoses set as covariates. Whenever genetic main effects were detected, P < 0.05 .Statistical analyses of mALFF were performed in DPABI . A mixedThe correlations between regional mALFF alteration and executive functions (EF) indexes were conducted in those brain regions using Pearson correlation. Sex, age, IQ, and ADHD diagnoses were controlled as covariates.If the correlation reached significance, moderation and mediation effects were evaluated using the PROCESS macro of SPSS . First, http://www.braineac.org).To explore the potential biological functions of the SNPs identified in our first analysis, we further examined the patterns of expression quantitative trait loci (eQTL) based on the data from the UK Brain Expression Cohort (Ps < 0.05).The demographic and clinical characteristics of participants for both the association study and nested imaging genetic study are summarized in P = 0.008) and the recessive model with TT genotype as protective  .For the “gene-EF” analyses, performances on all executive function measures were poorer in the ADHD group compared with controls. However, no genotypic main effect of rs10891819 was detected for the “ADHD-whole,” “ADHD-alone,” or “ADHD-comorbid” grouping (Ps > 0.05).The genotypic distributions of rs10891819 in the nested study were: 19, 12, and 4 carriers of GG, GT, and TT genotypes in the “ADHD-whole” group (n = 35) and 37, 13, and 6 carriers in control group (n = 56). However, when stratified by comorbidities, no TT genotype carriers were found in the “ADHD-alone” subgroup. Subsequently, the GT and TT genotypes were combined to form the “T-allele carrier” group for imaging genetic analyses. Further details on sample characteristics were given in t = 3.85, corrected P < 0.05, also see Post hoc analyses stratifying ADHD and control participants into two separate groups detected the same pattern: T-allele carriers showed significantly higher levels of mALFF than GG carriers in the ADHD group  and in the control group   for T-allele carriers when compared with GG carriers (peak Ps < 0.05).When the ADHD cases were stratified into “ADHD-alone” and “ADHD-comorbid” subgroups and then combined with the participants from control group, respectively , the genotypic effect of rs10891819 remained significant in the rSFG region, with higher levels of mALFF shown in T-allele carriers compared with GG carriers  and executive function measures were conducted in the combined sample of ADHD participants and controls. The results showed a negative correlation between mALFF in the rSFG and “word interference time” in the STROOP test  on the relationship between genotype (X) and word interference time (Y) was evaluated. The level of mALFF (moderator) was significantly associated with word interference time, but there was no significant mALFF*genotype interaction in relation to word interference time , 95% CI = -3.39 to -22.73, P = 0.006], but the path from genotype to word interference time did not reach statistical significance. The bias-corrected bootstrap 95% CI indicated that the indirect path through mALFF was significant [B = -2.61 (SE = 1.07), 95% CI = -0.48 to -4.72, P = 0.009) offering support that mALFF mediated the path between genotype and word interference time , genotype (X), and word interference time (Y). In the mediation model, the path from genotype to mALFF was significant [B = 0.20 (SE = 0.04), 95% CI = 0.12 to 0.27, CADM1 expression level , the minor G allele of the SNP rs10891819 was associated with higher CADM1 gene in relation to ADHD psychiatric phenotypes, neurocognitive endophenotypes, and regional brain circuitry activities. There are four key findings.Our study examined the association of The first key finding was a marginal significant genotypic effect of rs10891819 detected only in the “ADHD-alone” subgroup, with TT genotype as protective, though the association did not survive Bonferroni correction. Second, in the nested imaging genetic study, rs10891819 genotype was significantly associated with altered spontaneous regional brain activities during rs-fMRI, in the rSFG region. More specifically, the mALFF activities in the T-allele carriers were consistently higher than GG carriers in both ADHD and control groups. Third, endophenotypic correlation analyses detected a significant negative correlation between “word interference time” in Stroop and mALFF activity in the rSFG, that is: higher spontaneous regional brain activities in the rSFG were correlated with better performance in inhibition task (as indexed by shorter “word interference time”). Fourth, our mediation analysis confirmed a significant three-way effect (supported by a significant Sobel test for “indirect-only mediation”) from “gene” to “brain activity” to “inhibition task”—potentially representing a “gene–brain–behavior” relationship. The significant indirect effects involved two paths: from rs10891819 genotype  to brain activation in the rSFG (higher activities) and from rSFG to Stroop inhibition task (better performance).CADM1 genotype and its association with higher brain activation in the context of better performance in inhibition task. These two strands of findings are consistent with each other, suggestive that the detected CADM1 genotypic effects confer better cognitive function and therefore protection, rather than elevating the risks of impaired cognitive processes or phenotypic expression of ADHD. Our preliminary findings could also indicate that CADM1 genotypes may not directly elevate the risk of ADHD expression and therefore would be consistent with our predictions derived from ADHD GWAS, which did not detect genome-wide significant associations with the “disorder phenotype.”In other words, we only detected a protective effect of CADM1 gene by a series of domain-specific probes on different intermediate phenotypes within one single study, instead of relying on traditional diagnostic phenotypes alone. The SNP rs10891819 showed marginal association (TT genotype as protective) in the “ADHD-alone” subsample. The detected association was not found in the “ADHD-comorbid” or the whole (unstratified) sample. This could represent a spurious chance finding . If such findings were replicated, our findings may offer support for the RDoC conceptual framework that privileges brain circuitries (in relation to genes and endophenotypes) over the clinical phenotypes as the primary anchor for investigation.Our second aim was to test whether the domain approach guided by RDoC could be an alternative avenue to elucidate “gene–brain–behavior” relationships of the  finding  or a weaCADM1 gene encodes cell adhesion molecule 1, which influences a wide range of neural functions, including neuronal development, myelination, synaptic formation, plasticity, and integrity of neuronal networks  was associated with a higher CADM1 expression level. However, the reverse pattern of minor allele of rs10891819 was observed in our Chinese Han participants   and at the level of pathway–pathway interaction . Moreover, the genotypic effect of CADM1 on rSFG and subsequent relationship with inhibition function reported by our research might be the consequence of CADM1*DAT1 gene–gene interaction. ADHD is likely a disorder involving multiple causal genes of small effects and interactions. To elucidate this possibility, future study with DAT1 and other genotypes can unpack more fully the effects and theoretical implications of CADM1*DAT1 and other gene–gene interactions.Interestingly, rs10891819 is located in intron 9 of t review . Evidentt review . TherefoCADM1 gene on ADHD, and it should be regarded as a hypothesis-generating study. Second, the scope was limited by the small sample size, especially after stratification by comorbidities status. Our preliminary findings should be treated with caution and needed to be replicated in other samples. More specifically, Caucasian samples may show an opposite effect; given G-allele is the minor allele conferring higher CADM1 expression in Caucasian population. Future replication studies should therefore be vigilant of potential divergent functional effects of a given minor allele on cellular, brain, functional, and behavioral expression. Third, the participants in our controls recruited in the gene–behavior association analyses included both adults and children. Genotypes do not change with age, and healthy adult samples without childhood history of psychiatric disorders can be used as controls. Further validation analyses in children-only samples could overcome this limitation. In addition, if some adults failed to recall or disclose childhood disorders accurately, contamination of the controls by ADHD cases would reduce the statistical power of the sample, biasing the results toward the null hypothesis rather than leading to spurious positive findings. Fourth, there were multiple testing and comparison in our study. Our significant findings could be spurious and arose by chance. However, the directions of significant findings converged meaningfully in line with theoretical and biological plausibility, regarding the protective effect of the rs10891819 genotype, higher PFC activation, better cognitive function, and their mediating relationship. It remained likely that a weak genetic signal initially detected by candidate gene association approach was amplified through subsequent domain iterations as guided by RDoC approach. Fifth, we could only detect the effect of an “indirect-only mediation”  may be able to provide a fuller explanation. Furthermore, mediation and moderation analyses by future studies could be utilized in a gene–environment interaction model justified by a plausible biological theory , the National Key Basic Research Program of China (973 program 2015CB856405), Beijing Municipal Science & Technology Commission (No.Z161100000516032), the National Natural Science Foundation of China , Beijing Natural Science Foundation (7172245), and the Capital Foundation of Medical Developments (CFMD:2016-2-4113).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.


In the treatment of adult attention-deficit/hyperactivity disorder (ADHD) the importance of psychological interventions in combination with pharmacotherapy is widely accepted in contemporary clinical routine. The natural course of the disorder seems to justify additional psychological interventions because even in patients who are highly compliant to pharmacotherapy full remission is not always achieved. The aim of the present study was to analyze the contribution of psychotherapy to the treatment of adult ADHD patients. In a randomized controlled study, the efficacy of a combined treatment of psychotherapy with pharmacotherapy is compared to pharmacological intervention alone. After initiation and stabilization of treatment with methylphenidate (MPH) in all subjects randomization to the two different treatment conditions was done. Afterwards both groups underwent treatment for about 10–12 weeks, the experimental group receiving sessions of cognitive-behavioral therapy (CBT) whereas the control group only received medication and standard clinical management (SCM). ADHD symptoms differed statistically during time but not between the two different treatment conditions. This result was the same for the single ADHD symptoms—inattention, hyperactivity, impulsivity, and emotional symptoms—and also for impairment. Individual standardized ADHD specific CBT program was not able to outperform SCM. Attention-deficit/hyperactivity disorder (ADHD) beginning in childhood has been accepted to persist in ~50% of cases into adulthood . With a ADHD is a multi-factorial disorder that is associated with a tremendous financial burden, increased stress to families, and adverse academic and vocational outcomes . Across Psychotherapeutic treatment of adult ADHD is considered as part of a comprehensive multimodal therapy program which is based on pharmacological treatment. According to NICE , 13 pharMultimodal Treatment of Attention Deficit Hyperactivity Disorder (MTA) study likewise documented that a comprehensive behavior therapy program is also effective, albeit less than medication. A multimodal program which combined medication and behavioral interventions results in the greatest overall improvement . Even in the case of an excellent therapeutic response these problems do not disappear immediately. Demoralization caused by long lasting disappointment and reoccurring frustration is frequently present and has to be considered in therapy . Based oDespite of the continuous general demand for multimodal treatment, the data presented are still insufficient. An important element of almost all existent studies is pharmacological treatment usually with MPH which is in accordance with today's state of knowledge. Psychotherapy on its own does not seem to be as efficacious as pharmacotherapy which is comprehensible considering the current knowledge about etiology and pathology of this disorder.SMD = 0.76, 95% CI , p = 0.006) and superior to active control groups with a small to moderate effect size  in reducing ADHD symptoms post-intervention  shows some evidence in the psychological treatment of ADHD. Different un- and controlled CBT studies reported some treatments effect like ADHD symptom reduction e.g., , 35–39].–39.35–39rvention .In conclusion, recent empirical data about psychotherapeutic treatments of patients with ADHD indicate that psychotherapy might be efficacious in the treatment of adult ADHD. However, it is not possible at the present time to give a concluding appraisal of the efficacy of a combined pharmacological and psychotherapeutic intervention in comparison to a purely pharmacological treatment due to major deficits of studies. Trying to summarize the problems of the studies, two problem areas can be identified: problems concerning content and concepts , and problems concerning methodological aspects .General aim of the study was to evaluate the contribution of psychotherapy to the treatment of adult ADHD patients. The primary objective of the randomized controlled study was to evaluate the efficacy of multimodal therapy (treatment group: medication + psychotherapy) compared with medication alone (control group: medication) in adult subjects with ADHD. We expected that the multimodal treatment shows a greater success in treatment than medication alone. Secondary objectives were: assessment of the stability of the change in follow-up, assessment of the benefits with regard to impairments in daily life, and assessment of the quality of the psychotherapy.A total of 50 individuals who came to the ADHD Special Consultations Unit of the Outpatient Department of the University of Basel Psychiatric Clinics (UPC) between 2010 and 2015 were recruited for this randomized controlled study. Five men and two women dropped out before being randomized to one of the two treatment groups. Finally, the data of 43 ADHD patients were analyzed.Male and female patients with a diagnosis of ADHD according to DSM-IV criteria, with symptoms before 7 years that continue to meet these criteria at the time of assessment, were enrolled in the study. ADHD was not diagnosed if the symptoms were better accounted for by another psychiatric disorder . All individuals fulfilled all general criteria for a treatment with MPH in accordance with the existing guidelines , 13 and Subjects with clinically significant unstable medical or neurological conditions like hypertension and other cardiac diseases, hyperthyroidism, epilepsy, tic-disorder, or any other severe somatic disorder were excluded from the study. Also, individuals with unstable psychiatric disorders apart from ADHD like moderate to severe mood or anxiety disorders, schizophrenia, with an addiction to or abuse of cocaine, heroin, or other opioids, designer drugs, tranquilizers, other sedatives, or alcohol, and those consuming THC more than two joints a week or more than eight joints a month were also excluded. Addiction to or abuse of nicotine and/or caffeine were documented but were not exclusion criteria. Acute psychiatric symptoms like suicidality, psychotic exacerbations, manic episode, known non-response or allergy to MPH, pregnant, or breast-feeding women were also exclusion criteria. Finally, individuals who received CBT within the last 2 years could not participate in the study.All subjects presenting to obtain a diagnosis, underwent a comprehensive diagnostic assessment to assess the existence of the diagnosis of adult ADHD and possible comorbid disorders  und Axis-II disorders ; used to assess comorbid disorders, administered only at pre-treatment.Structured interview based on the DSM-IV criteria and used for assessing diagnosis retrospectively or confirming a currently obvious disorder.With respect to the determination of the pathology there is no generally accepted instrument until now which could be considered as a gold standard . TherefoEighteen items rating scale according to the DSM-IV criteria; four-point rating scale (severity or frequency of the symptoms), clinician administered.Twenty-six items rating scale based on DSM-IV criteria.Sixty-six items; four-point rating scale (severity or frequency of the symptoms), scoring: inattention/memory problems, hyperactivity/restlessness, impulsivity/emotional lability, problems with self-concept, DSM-IV inattentive symptoms, DSM-IV hyperactive symptoms, DSM-IV ADHD symptoms total, ADHD index.Structured interview according to the criteria of Paul H. Wender; seven syndromes , more adequate to assess the symptomatology in adults.Twenty-two items self-rating scale; 18 items according to DSM-IV/ICD-10; 4 items to assess aspects like impairment, beginning of symptomatology.ADHD symptomatology is always related to more or less remarkable impairments in different functional areas of life. Despite significant impairments related to adult ADHD, little is known about how ADHD symptomatology and functional impairments impact quality of life in patients with this disorder see , 53]. Es. Es53)].Global self-rating scale to assess in work, social life or leisure activities and home-life or family responsibilities.Twenty-nine items self-rating scale; four domains: life productivity, psychological health, relationships, life outlook.The SWE is a unidimensional scale containing 10 items which are answered on a four-point scale.The RSES is a unidimensional scale containing 10 items which measure “global self-esteem.” Each of the 10 items is answered on a four-point scale.The questionnaire by Schneider et al.  was applThe questionnaire addresses central aspects of the therapeutic process. The scale, containing 29 items, is filled out by the patient, respectively, the therapist. The following areas are covered: progress within the therapy sessions, progress outside the therapy sessions, quality of therapy relation, therapy satisfaction, and emotion in the therapy. The function of this questionnaire is to register the progression of the therapy and eventually to provide more details about the interpretation of the results found in this study.All subjects received a standard treatment with MPH which was administered as follows: initiation of treatment with 20 mg Ritalin® LA 20 mg/day; up-titration of Ritalin® every fourth day up to a level of 0.5–1.3 mg/kg bodyweight/day; stabilization of final dosage for at least 2 weeks and no increase of dosage from then of more than 10% of the final dosage. If Ritalin® LA did not show sufficient clinical effects or was not tolerated Concerta® was used as a second choice. The initial dosage was Concerta® 18 mg/day, followed by an up-titration as outlined above.No other stimulants apart from long-acting MPH were used in the study. No non-stimulant medication was initiated. Subjects on non-stimulant medication with a known effect on ADHD symptoms could participate in the study if they fulfilled the following conditions: stable dosage for the last 3 months previous to baseline investigation, sufficient remaining symptoms for ADHD diagnosis. In these subjects MPH was administered in addition to the existing medication. Subjects on non-stimulant medication for other medical or psychiatric conditions could participate if their medication was administered on a stable dosage for at least 3 months and the underlying disorder is remitted to a clinically not significant level of symptoms. In addition, this particular medication must not interfere with MPH.As soon as subjects were on a clinically sufficient dosage of MPH and on a stable level for at least 2 weeks, they were randomized to either multimodal therapy or medication alone. At the end of the study there was a short clinical check-up again and adequacy of medication was controlled again. Afterwards subjects were referred to their physicians or to a specialist for ADHD if they wished to continue treatment.The main outcome measure concerning initiation and dosage adjustment of MPH was a reduction of 30% or more in the sum score of the investigator-rated CAARS. As soon as patients reach this level of individual reduction in sum scores their dosage was not increased any further. If subjects remained stable on this dosage for at least 2 weeks they were randomized to one of the two treatment groups in the study.The psychotherapeutic program was a cognitive-behavioral program designed for single-settings and contained several modules which were summarized in a standardized manual , and a maximum of 12 sessions. The manual contained a description of each session of the therapeutic interventions as well as general advices. . Apart from the first two sessions the weekly therapy sessions were identical in structure: discussion of homework given in the previous session, presenting the theme of the current session, presentation of new homework.Discussing homework of the previous session aimed to evaluate therapeutic progress and to control whether therapeutic strategies were used in daily life or not. If problems raised it was necessary to identify the cause and to work out realistic solutions with the patient. The presentation of the content of each session should provide a clear structure for the patient. This seems to be extremely important in the treatment of ADHD , 26. ThePractical parts of the therapy sessions were: exercises, role plays, hand-outs, and work sheets. The therapy set consisted of different basic (B 1–3) and optional modules (O 1–5). Whereas, the basic modules were used with all patients, the application of the optional modules depended on the conclusions from the individual analysis of behavior which meant that the specific problems of the patient were taken into account for the choice of optional modules.Concerning standard clinical management (SCM) we refer to the NIMH-depression study . In the In our study patients in the control group received SCM consisting of medication counseling administered by a psychiatrist. SCM was administered weekly by 30 min sessions. The elements of SCM were written down in a manual to guide the psychiatrist through the standardized procedure similar as described by Fawcett et al. .In SCM apart from evaluating the general state of health and mind as well as effects and side effects of medication, the pulse rate, blood pressure and weight were measured. Also the CAARS was administered to assess the course of ADHD with ongoing medication. The patient was encouraged to report difficulties he experienced since the last visit but he was instructed that he will not receive any psychotherapeutic interventions. The psychiatrist listened and responded empathically but restricted counseling to the above-mentioned items. In the case of severely aggravating difficulties or even suicidality the psychiatrist was obliged to react to the patient's problems in the same way as if the patient was not a study participant. If additional psychotherapeutic counseling, additional medication, or even hospitalization became necessary the patient was withdrawn from the study and received the usual clinical treatment. This procedure ascertained that patient's needs were fully respected and dangerous situations were avoided. Psychiatrists received a didactic training in SCM for at least half a day.group: CBT + MED vs. SCM + MED) and the within-factor , and—for the main hypothesis most relevant—the interaction term (group × time) were conducted. To provide robust outcomes, normalized latent variables were extracted through principal component analysis for the total scores and the different domains of ADHD assessed via CAARS, CAARS-S:S, CAARS-O:L, WRAADDS, and ADHD-SR and for impairments measured by SDS, AAQol, SWE, and RSES. Since this data set does not contain a suitable number of cases for such a procedure to produce stable results, the general data set of the ADHD Special Consultations Unit of the Outpatient Department of the UPC was used to provide the weights of the different subscales. For further information on this data set see  but not of the factor group . Neither did the interaction effect of group and time reach significance . The same pattern was also found for the subdomains of ADHD: inattention, hyperactivity, impulsivity, and emotional symptoms and also for the two latent variables of impairment (see Table To test the main hypothesis ANOVAs between subjects with CBT + MED and SCM + MED were conducted with the within factor p < 0.01), hyperactivity , and emotional symptoms  high correlations but not for impulsivity . The perceived quality of therapy relation and therapy satisfaction correlated significantly with the latent factors of impairment  but not with ADHD symptoms. All correlations are displayed in Table Spearman's correlations were carried out to explore the relationship between CBT process characteristics of the therapy group (progress within therapy) and the changes in symptom and impairment levels. Emotion in therapy showed for the symptoms inattention  in comparison with medication alone (control group). Whereas, the experimental group (CBT + MED) attended individual psychotherapy sessions, the control group (SCM + MED) only received medication and clinical counseling. The current findings do not support the notion that CBT outperforms SCM when added to a pharmacological treatment.The different analyses show a statistically decrease of ADHD symptoms during the time  and an increase of symptoms in the follow-up. However, both groups did not differ significantly in the ratings of ADHD symptoms. The same results were found for the single ADHD domains  and also for impairment in daily life. The assessment of the quality of therapy in the therapy group showed that inattention, hyperactivity, and emotional symptoms correlated high and significantly with the domain emotion in therapy. However, the perceived quality of therapy relation and therapy satisfaction correlated significantly with impairments but not with ADHD symptoms.According to guidelines, psychopharmacological treatment is currently considered as first-line treatment for adults in ADHD , 19, 67.A multimodal approach to the treatment of ADHD is recommended by international guidelines , 13. CBTIn line with the findings of the current study are the results of Philipsen et al.  who howeAn explanation for our results may be that in our sample the medication responded very good. All patients received Ritalin® LA. The second choice of medication (Concerta®) was not used because all patients responded very good to Ritalin® LA. The reduction of ADHD symptoms from baseline to pre-treatment assessment counted for both groups 50%. In comparison Stevenson et al.  reportedIn our study patients in the control group received SCM which elements were standardized and noted in a manual to guide the psychiatrist performing practice care in a professional, emphatical, and optimal way. As a consequence, SCM as an established and well-known procedure in psychiatric settings, in combination with medication, showed similar outcomes than the here presented standardized ADHD psychotherapy program. This program may not have been sufficiently effective to outperform SCM.Cognitive Therapy Adherence and Competence Scale –M = 5.66 [SD = 0.19]) and quality of therapy (M = 5.52 [SD = 0.22]–M = 5.72 [SD = 0.06]) were all above the cutoff of the CTACS (M ≥ 4) which can be interpreted as a good adherence.Whereas, every single psychotherapeutic session was video recorded and supervised, the SCM sessions unfortunately were neither recorded nor supervised. The adherence to the SCM protocol was so not controlled. However, these data could help to understand the interaction between medication, psychotherapy, and attitude to treatment in the different groups. In a smaller sample of the psychotherapy group we analyzed 27 randomly selected psychotherapy sessions of nine patients with the aim to evaluate the treatment adherence of the involved psychotherapists: Two trained independent psychologists rated on the basis of the   the vidOur ADHD psychotherapy program was based on CBT theory and models. Although the elements of our program derive from established and reliable techniques which have been adapted to the special need of ADHD patients, a pilot study may have identified less effective therapeutic interventions giving us the possibility to adjust our program. The therapy set consisted of different basic and optional modules. This set of modules was based on the diagnostic criteria of ADHD and the corresponding results from the literature –62. WherThe standardized ADHD specific CBT program consisted in 10–12 sessions, each lasting 120 min. While the treatment period might be too short to ensure that patients continued to use the new learned skills, the length of each session might be too long. Due to the compact and short treatment patients might be not able to properly develop new functional strategies, enduring behavior, and thinking patterns.A further explanation for our results may be found in the problem activation  and selfThe current study focused on the symptom reduction of ADHD in adults. The structure of the CBT program was a central aspect in the standardized manual. The assessment of the quality of therapy in the therapy group showed that the factor emotion in therapy correlated with ADHD symptoms (except impulsivity). It seems to be beneficial to activate emotion in the therapy session. Furthermore, and more relevant, may be the findings that the quality of relation and therapy satisfaction correlated with impairments. The focus of impairments is crucial in psychotherapy with ADHD patients because of the severe difficulties of those patients on daily functioning , 10. ADHThe aim of our study was to analyze the data of more patients. Unfortunately, it was not possible to include more patients during the defined study time. The small size of both treatment conditions was especially relevant in the questionnaires measuring impairments. The number of filled questionnaires especially in the follow-up evaluation were too small. The package of questionnaires may be too large and must be adjusted for future studies.Attitude to treatment was only measured and controlled in the CBT + MED group and also only with one questionnaire. However, this aspect is important in psychotherapeutic as well as in psychopharmacological treatments  and shouAlthough the two groups did not show a statistically significant difference in comorbid disorders (Axis I and II), there were more patients with a comorbid personality disorder (Axis II) in the CBT + MED group. The presence of these comorbidities might have had a stronger impact on the treatment progress and effects of the experimental group. In future research the control of this aspect is mandatory.The present randomized controlled trial is one of the few studies focusing on ADHD multimodal individual therapy. The here developed standardized ADHD specific CBT program does not suggest that CBT augments significantly the reduction of ADHD symptoms. The CBT program was not able to outperform SCM which is a well-known psychiatric procedure. In further study the role of medication, CBT components, techniques, as well as modules, attitude/adherence to treatment in ADHD psychotherapy and further possible side effects in CBT should be paid more attention. This could help to understand the impact of CBT to reduce ADHD symptoms and functional impairments.This study was carried out in accordance with the recommendations of Ethics Committee of Basel  with written informed consent from all subjects. All subjects gave written informed consent in accordance with the Declaration of Helsinki. The protocol was approved by the Ethics Committee of Basel .All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Emotional lability (EL) often co-occurs with attention-deficit/hyperactivity disorder (ADHD) in children. However, difficulties of regulating intense emotions in ADHD are still poorly understood. We investigated the potential role of working memory (WM) as a protective factor against EL in children with ADHD by building on models describing the close relationship between WM and regulation of emotions. The parents of 41 children with ADHD and 34 typically developing children (TDC) filled out the emotional control scale (ECS) from the Behavior Rating Inventory of Executive Functioning and the child behavior checklist (CBCL). The children themselves completed the backward conditions of the digit span (DS) and spatial span (SS) tasks as well as the letter–umber sequencing (LNS) task. The results of a stepwise regression analysis confirmed the negative relationship between parent reported EL measured using the ECS and scores on the LNS, when controlling for symptoms of ADHD and oppositional defiant disorder (ODD). WM thus seems to be important for the ability of the children to express emotions in an adaptive and flexible way. We therefore suggest that a poorer WM capacity, which is often found in children with ADHD, may be a predictor of high levels of EL. Attention-deficit/hyperactivity disorder (ADHD) is a frequent neurodevelopmental disorder present in around 5% of children . ProblemBaddeley’s , 2002 WMThe high prevalence of EL difficulties in children and adults with ADHD  has beenOnly one prior study  has, to Supplementary Materials).Therefore, based on the theories of Gross  and PosnTable 1).All participating children had a full-scale intelligence quotient (FSIQ) above 75, however, the children with an ADHD diagnosis had lower FSIQ than the TDC. The study was carried out with the approval of the Regional Ethical Committee for Western Norway (REK-Vest), and written informed consent in accordance with the Declaration of Helsinki was obtained from all parents.The current study included 75 children between 8 and 12 years old, and consisted of 41 children with an ADHD diagnosis and a control group of 34 TDC. There were no group differences in sex or age distributions between the two groups .Exclusion criteria for both groups were an existing ADHD diagnosis and prior use of psychostimulant medicine due to the wish to study cognitive functions that had not been modulated by treatment effects . FurtherWorking memory was assessed with the backward conditions of the DS and the spatial span (SS) tasks, as well as the LNS task . In the Emotional lability was measured with parent information on the emotional control subscale from the Behavior Rating Inventory of Executive Functioning, which “addresses the manifestation of executive functions within the emotional realm and measures a child’s ability to modulate emotional responses. Poor emotional control can be expressed as EL or emotional explosiveness” , p. 18. We used the parent form of the child behavior checklist (CBCL), part of the Achenbach System of Empirically Based Assessment ASEBA; , to inveAll statistical analyses were conducted using IBM SPSS, version 25. Bivariate correlation analyses were conducted among all variables of interest. To test our main hypothesis, we conducted a linear stepwise regression analysis that included EL scores from the ECS as the dependent variable, and age, gender, symptoms of ODD and ADHD, GAI scores, and WM scores of DS, SS, and LNS scores as the independent variables. FSIQ was not included as it has been argued that controlling for it as a covariate is likely to distort findings .The stepwise regression analysis was followed by a moderation analysis as described by Supplementary Materials).To investigate the potential influence of inhibition on the relationship between WM-scores and EL scores from the ECS we repeated the primary stepwise regression with the Stop-Signal Task score as an independent variable together with WM scores, symptoms of ADHD and ODD, age, and gender . Age did, however, not correlate with the DS scores. Gender appeared to only be significantly correlated with the DS scores and not with the other WM scores (LNS and SS). The parent-reported symptoms of EL, ODD and ADHD were not significantly correlated with either age or gender (See Table 2). All three WM scores of LNS, SS, and DS correlated significantly with each other.Preliminary correlational analyses of the relationship between age and the variables of EL and the WM scores , showed that age correlated significantly with the WM scores of SS and LNS (Table 3).All three WM scores of LNS, SS, and DS were inversely correlated with the parent-reported EL scores on the ECS. The forward linear stepwise regression model including the EL scores from the ECS as the dependent variable and the independent variables of age, gender, ADHD symptoms, GAI scores, and the WM scores of LNS, DS, and SS, showed that only symptoms of ODD and the LNS scores significantly predicted the parent-reported scores of EL on the ECS, and not age, gender, GAI, symptoms of ADHD, scores on the DS or scores on the SS .The results of the moderation analysis, investigating the interaction between ADHD diagnostic status and the LNS scores on the EL scores from the ECS, showed that there were no significant interaction between the LNS scores and diagnostic status .The current findings are in line with previous studies in healthy samples e.g.,  in that EL did not appear to be restricted to children with ADHD. Rather this was shown to be a dimensional relationship true for the whole sample. The results, therefore, indicate that the findings regarding a relationship between WM and emotion regulation from studies on typically developing adult populations reviewed in this article are also applicable to children, both with and without ADHD. However, the children with ADHD showed poorer WM capacity on the LNS (and the SS) and a higher frequency of parent-reported EL symptoms than the TDC, indicating that the inverse relationship between EL symptoms and WM capacity may be more significant for their everyday functioning than for the group of TDC. Future studies may therefore want to investigate whether this holds true in other populations with elevated levels of EL, such as in children with anxiety disorders  in combination with well validated and widely accessible questionnaires, thereby obtaining results which are available in, and transferable to, day-to-day clinical practice and may be replicated in many clinical settings. We also regard the use of dimensional analyses as a strength, as these allowed us to investigate the hypothesized pattern of results in both the children with ADHD and the TDC. This is in line with our expectations as the hypothesis was, to a large degree, based on studies of typically developing individuals.The main limitations of this study are the limited sample size and the cross-sectional nature of our data. Due to these limitations all of our participants with high levels of EL belonged to the diagnostic group, thus limiting the generalizability of our conclusions. Furthermore, the use of cross-sectional data does not allow for investigation of the developmental ordering of the children’s difficulties, which would be highly relevant with regards to the model proposed by The current study found support for the hypothesis that WM is a protective factor against elevated levels of EL in children, thus supporting previous findings showing the importance of high  WM capacity in the adaptive display of emotions. The results, if replicated, may represent an approach to understanding the functional heterogeneity associated with ADHD.KP and LS conceived and designed the study. MH, NM, HE, SA, KP, and LS acquired the data. DJ and LS analyzed and interpreted the data. DJ, MH, TE, KP, and LS wrote the manuscript. All authors contributed to manuscript revision, read and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Training in neurofeedback (NF) reduces the symptomatology associated with attention deficit with hyperactivity disorder (ADHD). However, ADHD differs in terms of the type of presentation, i.e., inattentive (ADHD-I), impulsive/hyperactive (ADHD-HI), or combined (ADHD-C). This study examines the efficacy of NF in ADHD presentations. Participants were 64 students (8–12 years old). Cortical activation, executive control, and observed symptomatology by parents were assessed. Results indicated that ADHD-C and ADHD-HI demonstrated greater improvements than ADHD-I. It was concluded that this kind of training produces an improvement and that it is necessary to explore it further in terms of the protocol used. Attention deficit with hyperactivity disorder (ADHD) is understood as a persistent pattern of inattentive, restless, and impulsive behavior which is more frequent and severe than that typically observed in subjects at a similar stage of development . Its preGiven the symptomatology of ADHD and its high prevalence rates ,5, it isSome authors have noted that stimulant medication is effective in reducing ADHD symptoms in 70%–80% of children suffering from ADHD ,10. ThusClinicians frequently use three types of protocols for NF training in ADHD : (1) a cNonetheless, the efficacy of NF could vary depending on the type of ADHD presentation, especially considering the differences between the three types of ADHD. With this in mind, it makes sense to analyze the differential effect of an NF intervention on improvement in the different types of presentation, which is the main aim of this current study. One meta-analysis, which included 15 studies , found tBakhshayesh et al.  comparedThe meta-analysis by Micouland-Franchi, Geoffroy, Fond, Lopez, Bioulac, and Philip  examinedThe efficacy of NF could also vary depending on the measures analyzed . For example, Rossiter  observedThe aim of this current study was to analyze the differential efficacy of NF training on executive control, cortical activation, and observed symptomatology for the ADHD presentation types. To achieve this, we used three groups: subjects with a diagnosis of ADHD-I, ADHD-HI, and ADHD-C. All groups received an NF intervention based on the classic beta-theta protocol (reduce theta and enhance beta). The working hypothesis was that, although all three groups would show improved performance in the assessed variables ), based on previous research ,31 the gM = 9.58; SD = 1.11). They were identified at the Child and Adolescent Psychiatric Service of the Central University Hospital of Asturias, according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition [n = 15, 6 girls and 9 boys), ADHD-HI , and ADHD-C . They all had an IQ of 80 or above  or age (p = 0.515). Differences in terms of gender were significant so this variable was taken as a covariate in subsequent analysis χ2(1) = 6.25, p < 0.012. In addition, 31 participants had pharmacological support , which was taken as a covariate in the analysis linked to gender.Analyses of the participants in this study showed that the sample was homogeneous, with no statistically significant differences in terms of IQ (The assessment was carried out at two different times (before and after treatment) using three kinds of measures: assessment of symptoms (EDAH-assessment), assessment of performance (TOVA), and assessment of cortical activation (QEEG). The EEG spectrum was used for the NF intervention.Scale of assessment of attention deficit with hyperactivity (EDAH) : This scTest of variables of attention (TOVA) : This teQuantified electroencephalography (QEEG). The QEEG assessment of cortical activation was used, which provides the levels of cortical activation through the beta/theta ratio. To record the beta/theta ratio, an electrode is placed on the corresponding cortical areas , and left prefrontal area (Fp1) and two more control electrodes are put on the left and right earlobes. The QEEG was administered to each subject, with open eyes, with a duration of 10 min approximately. An electromyogram system (EMG) should be put on the right forearm to control the level of movement. Participants were requested to remain relaxed, without moving, and to concentrate exclusively on the computer screen. A beta/theta ratio lower than 50% at Cz is related to inattention symptoms. For each part, a ratio below 50% at Fp1 is associated with hyperactivity symptoms. .www.neurocybernetics.com) designed by Howard Lightstone for Neurocybernetics, Inc . In accordance with the description included in a recent study [Neurofeedback (EEG spectrum): The intervention in activation levels was enhanced by means of neurofeedback using the EEG spectrum . All three groups received the neurofeedback intervention. t test for related samples. These differences in improvement were analyzed via a multivariate analysis of covariance (MANCOVA) using the gain (the difference between the pre-treatment and post-treatment scores) as a dependent variable and the group (ADHD type of presentation) as an independent variable. Gender and pharmacological support were used as covariables. Once the covariables were removed, post-hoc multiple Scheffé comparisons were performed to determine which groups had significant differences between them. MANCOVAs were performed to look at the pairwise comparisons more deeply, with the three possible pair comparisons: ADHD-HI vs. ADHD-I, ADHD-HI vs. ADHD-C, and ADHD-I vs. ADHD-C. In these three comparisons the gain in the different measures was taken as the dependent variable and gender and pharmacological support as covariables. We used Cohen’s criterion to interpret effect size, which states that the effect is small when pη2 = 0.01 (d = 0.20), medium when pη2 = 0.059 (d = 0.50), and large when pη2 = 0.138 (d = 0.80) [Firstly, the means and standard deviations for each variable were analyzed. Subsequently, we analyzed the difference between the pre-treatment and post-treatment scores in the three types of presentation using the Student’s  = 0.80) . SPSS veThis study was conducted in accordance with the Helsinki Declaration of the World Medical Association  and was NF training was carried out for 15 min, 3 days a week, for 3 months (36 sessions). The training began with the EEG spectrum rocket game. In the event that the students could not attend a training session, a make-up class was held in the same week in order to ensure that all the participants received three weekly sessions. After 3 months, all the participants were assessed again with the aforementioned instruments (post-treatment assessment) to evaluate the effects of the intervention. Typical NF interventions in ADHD involve 30–40 sessions, each lasting 30–60 min ,38. All the assessment tasks (and the intervention process) were coordinated and guided by the same psychologist, who was a member of the research group.Students with pharmacological support received methylphenidate (one of the most common stimulant medications used to treat ADHD) with the dose set by the child neurologist according to parameters such as weight and height. They started medication after diagnosis at the same time that the NF training was applied. The presence of pharmacological support was taken as a covariate in the specific analysis. The medication was discontinued 1 day before the post-treatment assessment.p ≤ 0.001). The results were statistically significant for all variables except commissions and D prime, measured by TOVA, and AD and H + AD, measured by EDAH (see p = 0.006) and in Fp1 between ADHD-HI and ADHD-I (p = 0.048) as well as between ADHD-I and ADHD-C (p = 0.003). The differences in the gain between the types of presentation were analyzed using MANCOVA , RT (p = 0.003), and ADHD score (p = 0.020); between ADHD-I and ADHD-C in variability (p = 0.005) and ADHD score (p = 0.004); and between ADHD-I and ADHD-HI in variability (p = 0.041) and RT (p = 0.039). In performance, differences were significant between ADHD-HI and ADHD-C for omissions (p ≤ 0.001) and between ADHD-C and ADHD-I (p ≤ 0.001). Finally, for observation symptomatology, differences were significant in the variable H between ADHD-H and ADHD-I  = 11.261, p ≤ 0.001 pη2 = 0.912. The results for each variable are: Cz p = 0.022, pη2 = 0.215; Fp1 p = 0.004, pη2 = 0.324; omissions p = 0.114; commissions p = 0.356; variability p = 0.005, pη2 = 0.306; RT p ≤ 0.001, pη2 = 0.535; D′ p = 0.314 and ADHD score p = 0.931; H p = 0.004, pη2 = 0.313; AD p = 0.046, pη2 = 0.168; H + AD p = 0.878.When the ADHD-HI group was compared to the ADHD-I group, differences were statistically significant F = 2.952, p ≤ 0.007 pη2 = 0.481. Looking at each of the variables, the results are: Cz p = 0.003 pη2 = 0.179; Fp1 p = 0.712; omissions p = 0.009 pη2 = 0.143; commissions p = 0.829; variability p = 0.806; RT p = 0.008 pη2 = 0.146; D′ p = 0.423 and ADHD score p = 0.007 pη2 = 0.152. H p = 0.318; AD p = 0.215; H + AD p = 0.228.In the case of ADHD-HI and ADHD-C, differences were also statistically significant F  = 8.413, p ≤ 0.001 pη2 = 0.704. The results for each variable are: Cz p = 0.375 Fp1 p ≤ 0.001 pη2 = 0.253; omissions p = 0.039 pη2 = 0.084; commissions p = 0.412; variability p = 0.001 pη2 = 0.206; RT p = 0.745; D′ p = 0.037 ηp2 = 0.086 and ADHD score p ≤ 0.001 pη2 = 0.250. H p ≤ 0.001 pη2 = 0.339; AD p = 0.964; H + AD p = 0.040 pη2 = 0.083.Finally, the comparison of ADHD-I and ADHD-C was statistically significant The main goal of this work was to analyze the differential effect of NF on the three presentation types of ADHD. The design was based on analyzing the benefits of this type of intervention in three areas: cortical activation, performance, and observed symptomatology. Firstly, the results showed that, in general, the three presentation types showed improvements in all three areas following the intervention, although these differences were not statistically significant in all cases. In cortical activation, the three types showed a positive improvement. The direction of the differences indicated that this improvement was greater in ADHD-C and ADHD-HI than in ADHD-I in Fp1. In Cz, the improvement was better in ADHD-C and ADHC-I than in ADHD-HI. However, if we focus on effect size, this is largest in ADHD-C followed by ADHD-HI for Cz and in ADHD-C followed by ADHD-I for Fp1. Thus, the results with regard to cortical activation suggest that ADHD-C and ADHD-HI benefit most from the intervention. This may be related to the fact that ADHD-I does not have a major deficit in Fp1, and a similar case occurs for ADHD-HI in Cz . In any In executive control, the profile in the six variables was similar. ADHD-C and ADHD-HI demonstrated better progression than ADHD-I when looking at mean scores. ADHD-C improved more than ADHD-HI except in commissions (the variable associated with impulsivity). Analyzing the progression of each type of presentation, the effect size reflected that the improvement was greater in ADHD-I for omissions and RT (variables related to attention). In the case of ADHD-HI the effect size was greater for variability and D′, and in ADHD-C it was greater for variability and the ADHD score . Given that the Fp1 point (where the intervention was done) is related to inhibition of behavior, hyperactivity, and impulsivity, it is logical that the ADHD-C and ADHD-HI groups improved more than ADHD-I, mainly given that ADHD-I has no major problems associated with impulsivity or hyperactivity, and, hence, the range of improvement is higher for the ADHD-HI and ADHD-C groups. However, children with the inattentive type improved in their RTs and omissions, aspects where children with this specific presentation have more difficulties, and exhibited higher effect sizes in these two variables, reflecting that the intervention in Fp1 also has effects on variables related to inattention. In the case of observed symptomatology measured with EDAH, parents reported good progression after the intervention in the three types of presentation. Again, parents of students with ADHD-C reported better improvement. Parents of students with ADHD-I saw better progression in inattentive symptoms, and parents of ADHD-HI students reported greater improvement in hyperactive impulsivity, as expected. In short, we analyzed differences in the gain (the improvement in scores) in the presentation types of ADHD. The conclusion is that the presentation types have such different profiles of activation and performance that the pre-to-post-test progression varies significantly. The effect size of the pairwise group comparison showed that the ADHD-HI and ADHD-I groups differed mainly in the gain in cortical activation and observed symptomatology but not especially in performance, where the differences were also significant for variability and RT. The ADHD-HI and ADHD-C groups showed greater differences in the gain in performance but the progression of these two types of presentation was very similar without differences in the gain in observed symptomatology. On the other hand, the ADHD-I and ADHD-C groups showed differences in the three kinds of measures: activation (Fp1), performance , and observed symptomatology (hyperactive impulsivity symptoms and inattentive symptoms). In general, one conclusion that we can draw is that although ADHD-C represents the combination of symptoms, this group demonstrates better improvement after the intervention. This could be related to the fact of the initial scores being lower than the other types so there was more room for improvement. Furthermore, the intervention was focused on the Fp1 area, but the improvements in performance were in the variables associated not only with hyperactivity and impulsivity but also the variables associated with inattention . The improvement produced in cortical activation had an effect on performance and on the observed symptoms. As in studies such as Monastra et al. , we saw These results are consistent with previous research in which NF intervention had a positive effect on ADHD symptoms ,25. FurtThe meta-analysis from Hodgson et al.  showed tOne implication of these results is that the intervention must be adapted to the specific profile of the students ,41. It i


Objective: The objective of this study was to assess health-relatedquality of life (HRQoL) in adult ADHD. Method: U.K. residents aged18 to 55 years with ADHD and no major mental health comorbidities completed anonline survey of disorder history, the EuroQoL 5-Dimensions 5-Level (EQ-5D-5L),and the Work Productivity and Activity Impairment Questionnaire: General Health(WPAI:GH). ADHD Rating Scale-IV (ADHD-RS-IV) score was assessed by telephone.Results: In total, 233 participants completed the study . Mean (SD) ADHD-RS-IV total score,EQ-5D utility, and visual analog scale (VAS) scores were 43.5 (7.88), 0.74(.21), and 69.8 (17.76), respectively. Mean (SD) WPAI:GH scoresindicated that health problems caused 45.7% (29.9) overall work impairment and45.8% (28.9) impairment in regular daily activities. Greater work and activityimpairment were both significantly independently associated with lower utilityafter adjusting for age, gender, and somatic comorbidities.Conclusion: Adult ADHD impairs HRQoL, work productivity, andregular daily activities. Recognized as one of the most common psychiatric disorders among children andadolescents, ADHD is also known to persist into adulthood in approximately twothirds of cases . Indeed,Studies conducted in Canada, Europe, Israel, Taiwan, and the United States indicatethat ADHD adversely affects health-related quality of life HRQoL;  in multiHere we present the results of a web-based survey of adults resident in the UnitedKingdom who report a diagnosis of ADHD and no major comorbid mental healthdisorders. The study was designed to evaluate the impact of ADHD on HRQoL using theEuroQoL 5-Dimensions 5-Level (EQ-5D-5L), and on work and regular daily activitiesusing the Work Productivity and Activity Impairment Questionnaire: General Health(WPAI:GH) assessment.Diagnostic and StatisticalManual of Mental Disorders . Informed consent was collected online and all data were anonymizedbefore analysis.SDs  and with 80% power,between two groups of participants of equal size equivalent to a moderate effectsize of ≈0.3 SDs  and, in Eligible participants were aged 18 to 55 years, reported a formal diagnosis ofADHD, were resident in the United Kingdom, and were able to give informedconsent. A specialist patient research and fieldwork agency  used these criteria to identify and contact (via email) individualsfrom their patient community who had previously provided consent to be contactedshould they be potentially eligible for inclusion in a study. These individualshad been recruited through patient associations or through a range oftraditional recruitment activities. Study participants received a £30 voucher orcheck as reimbursement for their time.Diagnostic and Statistical Manual of MentalDisorders  along with questionsabout how long these challenges had been present, and their impact on multipleareas of daily life. Patients whose responses were consistent with theDSM-5 criteria for adult ADHD  address, toensure that each participant was resident in the United Kingdom and completedscreening only once. The self-completed online ADHD assessment was used forscreening purposes only and included questions about participants’ ADHD symptoms the participant description; (b)the EQ-5D-5L; (c) the WPAI:GH; and (d) the ADHD-RS-IV (telephone interview).The participant description comprised questions regarding sociodemographiccharacteristics  and ADHD disorder history . Participants also filled in a checklist to report on the presenceof common chronic medical (somatic) comorbidities known to affect HRQoL: asthma,angina, cancer, chronic heart disease, chronic obstructive pulmonary disease,chronic renal disease, diabetes, rheumatoid arthritis, and other.best possible health) and 0 (dead), whichis weighted using value sets that represent the preferences of the generalpopulation  to 0 . Thus, aThe WPAI:GH is a validated instrument that measures the effect of healthproblems, defined as any physical or emotional problem or symptom, on workproductivity and regular daily activities within the previous 7 days . The fouDSM-IV/5 items: nine for inattentiveness symptoms andnine for hyperactive/impulsive symptoms. The severity of each symptom is ratedon a 4-point scale from 0 (none) to 3(severe), and these values are summed to give the totalscore.The severity of participants’ ADHD symptoms was assessed by trained interviewersvia telephone using the ADHD-RS-IV with adult prompts. The ADHD-RS-IV consistsof the 18 SD, and response frequencies as n(%). The uncertainty in the sample estimates is captured by 95% CIs. Ininferential analyses to examine factors associated with ADHD-RS-IV total scores,EQ-5D utilities, EQ-5D VAS scores, and WPAI:GH outcomes, significance wasassessed using t tests or analyses of variance, as appropriate.Pearson correlation coefficients were used to assess the relationships betweencontinuous variables. Linear regression was used to adjust for the possibleconfounding variables of age, gender, and presence of chronic medicalcomorbidities. These possibly confounding variables were entered first in eachmodel, with subsequent variables added in a stepwise fashion. Significance wastaken throughout at the 5% level (α = .05); however, nominal significance levelsat p < .01 rather than p < .05 areconsidered most reliable owing to the number of tests performed and thedescriptive aims of this research. Analyses were conducted in SPSS v19.0 andStata v14.0, data were cleaned before analysis, and no data imputation wasperformed.In descriptive analyses, responses to individual questions were summarized usingmeans with n =1,072) and not having an ADHD diagnosis from a medical professional(n = 449). Of the 534 individuals who met the initialinclusion criteria and accessed the online ADHD assessment tool, 158 wereexcluded due to responses that were not consistent with theDSM-5 criteria for adult ADHD and 46 closed their webbrowser prematurely. The online survey was completed by 330 individuals, of whom97 were subsequently excluded for not completing the telephone interview(n = 93) or withdrawing from the study (n= 4).The study took place from June 3, 2015, to October 30, 2015; a diagram ofparticipant flow through enrollment, screening, follow-up, and analysis is shownin SD = 9.5), the majority were women(n = 152) and most were of White British ethnicity(n = 180). Approximately one third of participants hadcompleted a university course (n = 78), and one third were infull-time employment (n = 80). All surveys and tools werecompleted in full by the 233 participants.The final sample consisted of 233 participants who completed the online surveyand telephone interview. The sociodemographic characteristics of the 233participants are summarized in SD = 13.1). Overall,51.5% of participants were currently taking medications for ADHD. Someparticipants were also receiving nonpharmacological ADHD treatment (often inaddition to medication), most commonly behavioral therapy (n =19) and individual counseling (n = 18). Approximately 40% ofparticipants reported at least one chronic medical comorbidity, the most commonof which was asthma (n = 48). In the survey, most participants(87.6%) reported experiencing their first symptoms of ADHD before the age of 13years. At screening, however, all 233 participants had reported that symptomshad been present since primary school  and wassignificantly higher in women (44.22 [SD = 7.77]) than in men(41.77 [SD = 7.91]) (p = .023). WhenADHD-RS-IV total scores were compared between groups of participants classifiedby sociodemographic or disease characteristics, greater symptom severity  was also significantly associated with not working(p = .001), not completing school to age 18 years or notcompleting university (p = .005), currently receivingnonpharmacological ADHD treatment (p = .037), and receiving afirst ADHD diagnosis from a psychiatry, psychology, or other service   . NosignSD = 0.21)and 69.81 (SD = 17.76), respectively. These scores arequalitatively lower than the U.K. population norms for adults aged 18 years andover  and similar to those reported by adults aged 75 years and over. Lower utilities were also significantlyassociated with lower work productivity due to health problems , greater activity impairment due to healthproblems , and olderages at first and second ADHD diagnosis . When utilities were compared between groups ofparticipants classified by sociodemographic or disease characteristics, lowerutilities (poorer HRQoL) were significantly associated with not working(p < .001); having chronic medical comorbidities ; receiving a first ADHD diagnosis from apsychiatry, psychology, or other service ; not completing school to age 18 years ornot completing university (p = .033); and older age(p = .012).Lower utilities (poorer HRQoL) were significantly associated with greater ADHDsymptom severity , more work time missed due to health problems , greater impairment while working due to healthproblems , and greateroverall work impairment due to health problems . When EQ-5D VAS scores were compared betweengroups of participants classified by sociodemographic or diseasecharacteristics, lower scores were significantly associated with not working(p < .001) and with having chronic medical comorbidities.Lower EQ-5D VAS scores were associated with greater WPAI:GH activity impairmentdue to health problems (p = .006) and VAS scores (p< .001), and greater overall work impairments due to health problems wereassociated with lower EQ-5D utilities (p = .033). Theregression models indicated that, after controlling for all other factors,utility decreased by .05 points for each additional decade of age(p = .001), men had lower utilities than women , and participants who reported at least onechronic medical comorbidity had lower EQ5D VAS scores than those who did not  in the overall sample of 233 individuals. The135 participants who indicated that they were “currently employed (working forpay)” on the WPAI:GH instrument reported a mean proportion of work time misseddue to health problems of 15.71% (SD = 26.48), a meanimpairment while working due to health problems of 40.59% (SD =27.01), and a mean overall work impairment due to health problems of 45.65%(SD = 29.86).Mean impairment due to health problems of regular daily activities was 45.79%; not working(p = .011); not currently taking ADHD medication(p = .027); receiving a first ADHD diagnosis from apsychiatry, psychology, or other service ; and older age at first ADHD diagnosis. When WPAI:GHoutcomes were compared between groups of participants classified bysociodemographic or disease characteristics, women reported that health problemscaused significantly more impairment while working (p = .025)and of regular daily activities (p = .032) than did men.Participants with at least one chronic medical comorbidity reported that healthproblems caused significantly more impairment while working (p= .032), overall work impairment (p = .024), and activityimpairment (p = .003) than those reporting no medicalcomorbidities. Associations between WPAI:GH and EQ-5D outcomes have already beenreported in the previous section.Significantly greater activity impairment due to health problems was associatedwith greater ADHD symptom severity . Each of the fourWPAI:GH outcomes was significantly independently associated with lower EQ-5Dutility quartile . In addition,more work time missed due to health problems was significantly independentlyassociated with younger age at second ADHD diagnosis (p =.010). The regression models indicated that, after controlling for all otherfactors, women reported that health problems caused more impairment whileworking, overall work impairment, and impairment of regular daily activitiesthan did men  and greater health-related impairments in regular daily activities.Observed mean EQ-5D utility and VAS scores were lower than UK norms for the generalpopulation and similar to those reported by adults aged 75 years and over .ParticiHRQoL is a multidimensional construct of an individual’s perception of the impact ofhis or her health status on physical, psychological, and social functioning. Severalstudies around the world have investigated HRQoL in adults with ADHD, with impactsof ADHD on functioning and HRQoL in adults reported to be similar in severalEuropean and North American countries . PreviouSD = 0.23] and 82.48[SD = 16.96], respectively). Indeed, the present mean utilitiesapproximate to those reported in adults in the general population aged 75 years andover  mapping function  and estaDSM-5 adult ADHD  in severalEuropean countries , and by SD = 0.33] and 63[SD = 21], respectively; The present EQ-5D scores are, however, numerically higher (indicating better HRQoL)than those obtained using the U.K. preference values  by KarlsAs already mentioned, the use of a single, generic HRQoL instrument enables differentconditions to be compared. The present EQ-5D-derived mean utility and VAS values aresimilar to the overall mean scores  self-reported bypatients with selected chronic conditions from National Health Service England’sprimary care Quality Outcomes Framework (QOF) incentive program: asthma, chronicobstructive pulmonary disease, diabetes, epilepsy, heart failure, and stroke . Theyarn = 24) of adults of mean age 66years diagnosed with ADHD later in life indicated that impairments associated withADHD in the professional, economic, social, and emotional domains accumulated withtime  were associated withgreater ADHD symptom severity; greater health-related impairments in work andregular daily activities; not working; having chronic medical comorbidities; beingdiagnosed by a psychiatry, psychology, or other service (vs. a primary care clinicor pediatric service); older age at first or second diagnosis; lack of formalqualifications; and older current age. After adjusting for gender and the presenceof chronic medical comorbidities, increasing age was associated with decreasingutility and VAS score, which worsened by 0.05 and 1.77 points, respectively, foreach additional decade. Increasing age has also been found to be associated withworsening EQ-5D scores in the U.K. population norms . In addiithtime . TogetheSD = 0.28]) or untreated patients (0.67[SD = 0.28]) than for the state describing treatment responders(0.82 [SD = 0.17])  . Althougvailable , this prvailable , making SD= 30.4] and 55.5% [SD = 27.0], respectively, in the U.K. subgroup[n = 101]). A likely explanation could again be the high rateof psychiatric comorbidities in the population recruited by Able et al., with 76.2%of the U.K. subgroup reporting at least one of depression, anxiety/generalizedanxiety disorder, sleep difficulties/insomnia, and other anxiety disorders . This result complements findings from a smallerU.S. study of individuals who met DSM-IV criteria for ADHD inadulthood and were receiving medication (n = 105), in whichsignificant associations between ADHD-RS-IV symptom severity and the work,recreation, and interpersonal domains of the Range of Impaired Functioning Tool(LIFE-RIFT) instrument were reported , in which self-reported asthmaprevalence was significantly higher in adults with ADHD than in those without . Given the additional context about challengingsituations  duringscreening, it might be likely that these participants did, in fact, experience ADHDsymptoms before the age of 12 years. This is consistent with research showing thatdifferences in context (A number of caveats should, however, be considered when interpreting the presentdata. First, the sample included 233 participants, fewer than the original target of300. This level of recruitment allows for the identification of statisticallysignificant differences, at the 5% level, between two groups of participants ofequal size equivalent to a moderate effect size of ≈ 0.35 SDs. In the12 years , and at 12 years , 2017b. context  and in w context  can contDSM-IV Axis II disorder, or arecently diagnosed comorbid Axis I disorder (Finally, and most importantly, adult ADHD often coexists with psychiatriccomorbidities  and the disorder .In summary, the findings of this study isolate and highlight the substantial burdenof ADHD on the HRQoL and productivity of adults in the United Kingdom. For the firsttime, EQ-5D utility is reported for adult ADHD without comorbid mental healthconditions and is demonstrated to be significantly associated with ADHD symptomseverity and to be significantly independently associated with WPAI:GH measures ofimpairment to work and daily activities due to health problems after controlling forage, gender, and chronic medical comorbidities. Given the burden of adult ADHD onpatients, their families, and society, physicians, and other stakeholders shouldseek to implement treatment strategies that improve HRQoL and minimize the impact ofthe disorder on work and daily activities, in addition to reducing ADHDsymptoms.


Children with attention deficit/hyperactivity disorder (ADHD) often continue to exhibit significant impairment in academic, occupational, and social functioning throughout adulthood. In addition, children with ADHD are at increased risk for developing alcoholism and other drug addictions, especially if alcoholism or ADHD exists in other family members. Alcohol and other drug (AOD) abuse may develop earlier in life  when ADHD is accompanied by certain behavioral or mood disorders. The nature of the link between ADHD and AOD use disorder is unknown, although the association may be mediated by the co-occurring disorders just mentioned. In addition, ADHD-related AOD abuse may develop initially as an attempt to alleviate symptoms of mental distress associated with chronic failure, feelings of inadequacy, and conflict with parents and peers. Therapeutic intervention should incorporate both addiction and mental health treatment, including appropriate use of psychiatric medications. Since the beginning of the century, terms such as “hyperactive” have been used to define a heterogeneous group of restless and inattentive children who display learning difficulties. Many such children exhibit the condition now known as attention deficit/hyperactivity disorder (ADHD). Children with ADHD may run about aimlessly, fidget and squirm when seated, and talk excessively. They are often irritable, impatient, and impulsive. Additional symptoms may include difficulty concentrating, forgetfulness, daydreaming, and easy distractibility. The disorder may persist into adulthood, accompanied by significant academic, occupational, and social impairment.The presence of ADHD is an important risk factor for the development of alcoholism and other disorders associated with the use of alcohol and other drugs (AODs).This article explores the co-occurrence  of ADHD and AODD and suggests possible mechanisms that may underlie their association. A discussion of ADHD treatment focuses on the use of medications that can alleviate symptoms of ADHD, thereby potentially affecting the subsequent development of AODD.Diagnostic and Statistical Manual of Mental Disorders (DSM–IV) (The fourth revision of the (DSM–IV)  presents(DSM–IV) .Additional DSM–IV criteria help distinguish ADHD from other disorders or normal temperamental traits. For example, the symptoms must be pervasive  and persistent  and must cause significant impairment in social, academic, or occupational functioning .22ADHD affects from 6 to 9 percent of children and adolescents and up to 5 percent of adults . Data suADHD and AODD occur together in the same person, either simultaneously or sequentially, more often than would be expected by chance . SymptomStudies have identified comorbid ADHD in 25 to 30 percent of certain adolescents with AODD. However, the subjects of the studies were repeat criminal offenders and patients in residential settings who were undergoing treatment for psychiatric and addictive disorders . ConsequEvidence from family studies confirms an association between co-occurring ADHD and AODD. Elevated rates of alcoholism are consistently found in parents of youth with ADHD . ConversThe interpretation of family studies is complicated by the possible influence of prenatal exposure to AODs. For example, the offspring of alcohol- and cocaine-dependent mothers are at increased risk for psychiatric abnormalities, including ADHD . Family AODD appears at an earlier age among adults with, compared with those without, ADHD (mean age 19 versus 22) . In addiADHD also affects the rate of recovery from AODD. In one study, adults with ADHD took more than twice as long as subjects without ADHD to recover from comorbid AODD . In addition, AODD lasted more than 3 years longer in the subjects with ADHD .The underlying mechanisms that link ADHD to AODD remain unknown but may involve complex interactions among biological and psychological factors. Two possible contributory factors of particular significance to risk evaluation and treatment strategy are comorbidity with additional psychiatric disorders and the use of AODs to self-medicate psychological distress.Certain psychiatric conditions frequently co-occur in youth with combined ADHD and AODD . Among tEvidence suggests that some use of AODs represents in part an attempt to ameliorate psychiatric symptoms and their associated subjective states of distress . The acaTreatment of patients with comorbid ADHD and AODD should be based on a thorough evaluation of relevant psychiatric, social, cognitive, educational, and family factors, along with a history of the patient’s AOD use and treatment. The clinician should rule out medical and neurological conditions whose symptoms may overlap with ADHD  or result from AOD use  .The treatment of ADHD and AODD must be considered simultaneously; however, if the addiction is active, it must be treated immediately . DependiMedications play an important role in the long-term treatment of ADHD. The influence of such treatment on the subsequent development of AODD remains unclear and may depend in part on the severity of the underlying condition. Nevertheless, results of preliminary studies suggest that certain medications can alleviate ADHD symptoms in adolescents and adults while reducing co-occurring AOD use or cravings .®, methylphenidate , and pemoline (Cylert®)  . ChildrePsychostimulants themselves are subject to abuse. Of the three psycho-stimulants just mentioned, pemoline has the lowest potential for abuse, followed by methylphenidate and amphetamine . The use®], imipramine [Tofranil® and others], and venlafaxine [Effexor®]) and certain medications commonly prescribed to treat high blood pressure   . The choResearch supports a relationship between ADHD and AODD, with symptoms of ADHD appearing many years before the earliest onset of AOD abuse. AODDs that begin in adolescence run a more severe course than those that appear in adulthood. Therefore, prevention and early treatment strategies should be directed at children with ADHD before AOD use problems develop and become chronic . More st