Anhedonia is apparent in different mental disorders and is suggested to be related to dysfunctions in the reward system and/or affect regulation. It may hence be a common underlying feature associated with symptom severity of mental disorders.N = 557).We constructed a cross-sectional graphical Least Absolute Shrinkage and Selection Operator (LASSO) network and a relative importance network to estimate the relationships between anhedonia severity and the severity of symptom clusters of major depressive disorder (MDD), anxiety sensitivity (AS), attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) in a sample of Dutch adult psychiatric patients (Both these networks revealed anhedonia severity and depression symptom severity as central to the network. Results suggest that anhedonia severity may be predictive of the severity of symptom clusters of MDD, AS, ADHD, and ASD. MDD symptom severity may be predictive of AS and ADHD symptom severity.The results suggest that anhedonia may serve as a common underlying transdiagnostic psychopathology feature, predictive of the severity of symptom clusters of depression, AS, ADHD, and ASD. Thus, anhedonia may be associated with the high comorbidity between these symptom clusters and disorders. If our results will be replicated in future studies, it is recommended for clinicians to be more vigilant about screening for anhedonia and/or depression severity in individuals diagnosed with an anxiety disorder, ADHD and/or ASD. Comorbidity between major depressive disorder (MDD), anxiety disorders, attention-deficit hyperactivity disorder (ADHD), and autism spectrum disorder (ASD) is high  to develop the Research Domain Criteria (RDoC) framework. The goal of RDoC is to explore transdiagnostic, underlying dimensions of psychopathology across a broad range of disorders , close to clinical practice  is an observational, cross-sectional study of Dutch adult (age >17 years) patients who were diagnosed with one or more of the following disorders: mood disorders, anxiety disorders, ADHD, or ASD, and possibly a comorbid substance use disorder. The study included mostly outpatients , but eligible inpatients were also allowed to participate.This study used data of the ongoing MIND-Set study , conducted at the Department of Psychiatry of the Radboud university medical center (Radboudumc) and the Donders Institute, Nijmegen, The Netherlands. The MIND-Set study  than females. The mean age was approximately 39 years . Educational level was reasonably distributed being low for 81 participants (14.5%), medium for 209 participants (37.5%), high for 206 participants (36.9%), unknown for 36 participants (6.5%), and 19 participants (3.4%) did not fulfill any graduation. Within this sample, 232 participants (41.6%) were diagnosed with MDD, 176 participants (31.5%) were diagnosed with an anxiety disorder, 215 participants (38.5%) were diagnosed with ADHD, and 133 participants (23.8%) were diagnosed with ASD. Of the 176 participants with anxiety disorders, 38 participants (21.5%) were diagnosed with panic disorder, 6 participants (3.4%) were diagnosed with agoraphobia, 16 participants (9.0%) were diagnosed with obsessive compulsive disorder (OCD), 48 participants (27.2%) were diagnosed with PTSD, 36 participants (20.4%) were diagnosed with GAD, 50 participants (28.4%) were diagnosed with a social phobia, 15 participants (8.5%) were diagnosed with a specific phobia, and 19 participants (10.7%) were diagnosed with an anxiety disorder not otherwise specified (NOS).The current study excluded two patients as they did not meet the inclusion criteria for the current study . This resulted in a final analytical sample of 557 patients. This sample included slightly more males , neuropsychological tests, and neuro-imaging measures followed. These measures are not part of the current study. The MIND-Set study has been approved by the local medical ethics committee (Commissie Mensgebonden Onderzoek Arnhem – Nijmegen). The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant national and institutional committees on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.never) to 4 . The anhedonia factor correlated significantly with the SCID item representing anhedonia according to the DSM-IV, rs(441) = 0.536, p < 0.001. In the current sample, the internal consistency of the factor was good (α = 0.87).Seven items which represent an anhedonia factor in the Outcome Questionnaire OQ-45-2;, are useI do not feel sad’ and 3 indicating ‘I feel sad nearly all the time’). In the current sample, the internal consistency of the IDS-SR was good (α = 0.86).The Inventory of Depressive Symptomatology Self-Report  to 4 (extremely much). In the current sample, the internal consistency of the ASI was good (α = 0.86).The Anxiety Sensitivity Index  to 3 (very much/very frequently). In the current sample, the internal consistency of the CAARS-SS was good (α = 0.88).The Conners' Adult ADHD Rating Scale, Short Version  to 4 . In the current sample, the internal consistency of the AQ-50 was excellent (α = 0.90). The mean values and standard deviations for all measures are described in The 50-item Autism Spectrum Quotient . As data collection is still ongoing, the de-identified dataset is available upon request from the first author. We computed two types of networks: a graphical LASSO network to visualize the associations between the symptom clusters and a relative importance network to assess directionality.All analyses were conducted in the R programming environment , by using the R packages qgraph package implements the graphical LASSO regularization in combination with extended Bayesian information criterion (EBIC) model selection. Graphical LASSO uses a tuning parameter (γ) to control the degree to which regularization is applied. This tuning parameter controls the trade-off between including false-positive edges and removing true edges. The tuning parameter is advised to be set between zero and 0.5  between 0 and 1 . There was no missing data on ASI and CAARS-SS items. The network was estimated using complete pairwise observations .Several features are immediately apparent. First, depression symptom severity emerged as a central node, connected to anhedonia, AS, and ADHD symptom severity. Anhedonia severity also emerged as a central node, connected to depression, ADHD, and ASD symptom severity. ADHD symptom severity and AS symptom severity were also connected, as well as AS and ASD symptom severity. The correlation matrix with all the regularized partial correlation coefficients is presented in online Supplementary Table S2. Bootstrapped CI's for the edges indicate that most edges were fairly stable, as demonstrated by relatively narrow CI's . The bootstrapped significance test  revealed that the edges between the symptom severity clusters of anhedonia and depression, depression and AS, depression and ADHD, and between ADHD and ASD were significantly stronger than at least half of the other edges in the network.These dynamics are further reflected in the centrality indices . Depression severity showed the highest level of betweenness, closeness and strength. ADHD symptom severity showed high levels of betweenness and closeness. Anhedonia severity showed a high strength value. The CS-coefficients were 0.75 for strength, 0.59 for closeness, and 0.21 for betweenness. The values of strength and closeness are above the recommended threshold between 0.25 and 0.5, suggesting that these are the most stable centrality indices. The CS-coefficient for betweenness is below the recommended threshold and should thus be interpreted more cautiously  are presented in online Supplementary Table S3. We found that depression severity was strongly predictive of anhedonia (lmg = 0.75), AS (lmg = 0.53) and ADHD (lmg = .36) symptom severity. Anhedonia was predictive of depression (lmg = 0.62), ASD (lmg = 0.25), ADHD (lmg = 0.20), and AS (lmg = .15) symptom severity. Although anhedonia strongly predicted AS (lmg = .15), AS predicted ADHD severity as well (lmg = 0.21), which in turn predicted anhedonia severity (lmg = 0.11). Moreover, ADHD symptom severity was strongly predictive of ASD symptom severity (lmg = 0.54). The bootstrapped CIs for the edges indicated again that the edges were fairly stable .These relationships are also reflected in the centrality indices . DepressThe anhedonia and depression severity nodes may be measuring overlapping constructs . This could have inflated edge weights and centrality, which makes it difficult to ensure that the strong connection between the nodes is not due to their conceptual overlap , its use limits the generalizability and perhaps the reliability and validity of our results because this is not validated. Hence, our results should be interpreted with caution and replication of these findings with validated anhedonia measures, such as the SHAPS  indicates that participants psychological distress is of clinical significance, based on the recommended Dutch cut-off (i.e. cut-off score = 55; De Jong, Nugter, Lambert, & Burlingame, Our study has several limitations as well. First, anhedonia was measured using the anhedonia factor structure of the OQ-45 (Minami et al., These limitations notwithstanding, this study offers unique insights on plausible relationships between anhedonia severity and severity of symptom clusters that merit further study. While our results are mostly hypothesis-generating, they suggest anhedonia as a common underlying transdiagnostic psychopathology feature, predictive of the severity of symptom clusters of depression, AS, ADHD, and ASD. Thus, anhedonia may be associated with the high comorbidity between these symptom clusters and disorders. Moreover, our results suggest that depression severity is predictive of the severity of symptom clusters of AS and ADHD. If our results will be replicated in future studies, it is recommended for clinicians to be more vigilant about screening for anhedonia and/or depression severity in individuals diagnosed with an anxiety disorder, ADHD and/or ASD. Future studies should investigate whether a focus on anhedonia, as a potential underlying transdiagnostic psychopathology feature associated with symptom severity of depression, AS, ADHD and ASD, is therapeutically efficacious.


Atypicalities in perception and interpretation of faces and emotional facial expressions have been reported in both autism and attention-deficit/hyperactivity disorder (ADHD) during childhood and adulthood. Investigation of face processing during young adulthood (18 to 25 years), a transition period to full-fledged adulthood, could provide important information on the adult outcomes of autism and ADHD.N = 566). The groups were based on the Diagnostic Interview for ADHD in Adults 2.0 (DIVA-2) and the Autism Diagnostic Observation Schedule-2 (ADOS-2). We analyzed ERPs from two passive viewing tasks previously used in childhood investigations: (1) upright and inverted faces with direct or averted gaze; (2) faces expressing different emotions.In this study, we investigated event-related potentials (ERPs) related to visual face processing in autism, ADHD, and co–occurring autism and ADHD in a large sample of young adults (Across both tasks, we consistently found lower amplitude and longer latency of N170 in participants with autism compared to those without. Longer P1 latencies and smaller P3 amplitudes in response to emotional expressions and longer P3 latencies for upright faces were also characteristic to the autistic group. Those with ADHD had longer N170 latencies, specific to the face-gaze task. Individuals with both autism and ADHD showed additional alterations in gaze modulation and a lack of the face inversion effect indexed by a delayed N170.Alterations in N170 for autistic young adults is largely consistent with studies on autistic adults, and some studies in autistic children. These findings suggest that there are identifiable and measurable socio-functional atypicalities in young adults with autism. The transition from adolescence to adulthood  can highlight particular challenges for individuals with autism and attention-deficit/hyperactivity disorder (ADHD). Young adults seek to achieve independence and in doing so, they encounter an increase in social and executive demands alongside a reduction in parental scaffolding  for a reWhile challenges in social functioning have traditionally been more associated with autism , ADHD isPossibly due to their evolutionary relevance, cognitive and neural processing of faces and emotional expressions occurs rapidly, reflecting prioritization in the human brain . Due to The N170 is one of the most studied ERPs in autism and is considered among the most promising ERPs related to the disorder . The N17The earlier face-sensitive P1 component, measured at occipital sites, is believed to reflect the processing of low-level features of faces, including color and contrast and early perception of emotion . StudiesThe relatively late central/parietal P3 is associated with more controlled contextual evaluation and is modulated by emotional expressions , 33. AtyThe aim of the present study is to investigate neural correlates of visual face processing in young adults with ADHD, autism and co-occurring autism and ADHD. Identifying objective indicators of socio-emotional functioning such as ERPs to faces and emotional expressions in young adulthood might help to understand outcomes in ADHD and autism during this critical period of development. Participants completed two passive viewing tasks: one designed to examine neural correlates to viewing upright and inverted faces with direct or averted gaze , 37–39; This study was conducted with full ethical approval from King’s College London Psychiatry, Nursing and Midwifery Research Ethics Subcommittee (RESCMR-16/17-2673). All participants signed consent forms prior to participation and were from the Individual Differences in Electroencephalography in young Adults Study (IDEAS) a subsample of the Twins Early Development Study (TEDS) , 43.Since the main aim of IDEAS was to understand the variation observed between ADHD and autism in young adulthood, the sample was enriched for high levels of autistic and/or ADHD traits based on childhood and adolescent measures meaning the proportion of individuals with ADHD and autism in this sample is higher than a sample selected randomly from the general population  and resting state for each participant within the same session using a wireless and portable 64-channel system . An online high-pass filter of 0.1 Hz was used during the acquisition and the sampling rate was 500 Hz. The order in which these tasks were delivered were counterbalanced across the whole sample (but kept constant within each twin pair). In this study the findings from two tasks related to visual face processing–here named the EoE and face-gaze tasks–were analyzed and presented.The EoE task, so named as it involves presentation of 10 grayscale faces of a male and a female (in young adulthood), each expressing one of five emotions . The images were taken from the NimStim set of facial expressions  see Sup, 40.The second task  involved presentation of nine color images of three female faces, three looking directly at the participant and six having an averted gaze (either looking right or left). Each of these nine faces were presented either in upright or inverted orientation on a gray background see Figure 1 in Grice et al. , and FigEEGLAB  and cust1  for more than 15% of the time were marked as bad channels. Following average referencing, Adaptive Mixture Independent Component Analysis (AMICA) was used to calculate the ICA components  with nsg1 . Based o1 . This exIn this study we used peak amplitudes of ERP components to allow a more direct comparison with relevant childhood studies  and to investigate latencies in addition to amplitudes , 31. TheOutliers were excluded based on the 2*IQR (interquartile range) criterion. Missing ERP variables for each subject  were imputed separately for each task with the Multivariate Imputation by Chained Equations (mice) R package . The varCognitive ability was not included in the models because previous studies indicate that lower average cognitive ability is integral to the ASD phenotype and correcting for this could lead to artefactual positive or negative results –62.post-hoc tests with pooled datasets, we re-ran the linear mixed models with post hoc pairwise comparisons (using Bonferroni’s adjustment) on a single imputed dataset, selected always as the first of the 50 imputed datasets. Main and interaction effects consistently showed the same pattern across pooled and single imputed datasets, as well as across imputed and complete case datasets, so here we only report the results from the single imputed dataset. Effect sizes as indexed by Cohen’s d (dz) were calculated using the R package emmeans for the post-hoc t-tests and we report these values throughout the section “3. Results”. Cohen’s d values indicate the following effect sizes: dz = 0.20, small effect, dz = 0.50, medium effect, dz = 0.80, large effect . Moreover, in the EoE task, only arousal-related effects  and valence-related effects  are reported. All significant findings are summarized in Effects involving autism and ADHD are reported below. Effects not related to autism and ADHD, and those related to hemisphere lateralization, are in line with previous literature and are included in the Event-related potential waveforms for the P1 component are shown in F = 4.082, p = 0.044], with females showing shorter latencies than males, and was kept in the model while age was not significant and thus excluded. A main effect of autism emerged , where autism+ individuals showed longer latency than autism- individuals  = 2.581, p = 0.035] . Both autism-  and autism+  individuals showed shorter latency in the joy condition compared to neutral condition. Autism- individuals also showed a shorter latency specific to the anger condition compared to neutral condition . Similarly, there was an interaction effect between ADHD and emotion  , as well as longer latency for neutral compared to joy . All other main effects and interactions involving autism or ADHD  were not significant.Sex was a significant covariate  : autism+= 0.042] , where AF = 5.335, p = 0.021], where autism- individuals showed overall greater amplitude than autism+ individuals across all emotions  = 4.265, p = 0.039], with females showing shorter latencies than males, and was kept in the model while age was not significant and was thus excluded. There was a group interaction  . Another interaction emerged between autism and emotion , and ADHD and emotion , which were further moderated by an interaction between autism, ADHD and emotion  ; ADHD-only individuals showed longer latency for disgust compared to joy ; autism+ADHD individuals showed longer latency for anger and disgust compared to neutral , as well as anger and disgust compared to joy ; autism-only individuals showed longer latency in the neutral condition compared to autism+ADHD . All other main effects and interactions involving autism or ADHD were not significant.Sex was a significant covariate [= 0.002] , where i< 0.001] : compariF = 4.297, p = 0.039]  = 3.956, p = 0.047]  but autism+ individuals did not show the same pattern. An interaction emerged between ADHD and orientation   = 6.132, p = 0.013], however no post-hoc tests were significant. All other main effects and interactions involving autism or ADHD  were not significant.Age and sex were not significant covariates and were excluded from the model. There was an interaction between autism and orientation [= 0.047] , where a= 0.028] , howeverF = 7.973, p = 0.005], where autism- individuals showed greater amplitude than autism+ individuals  = 22.364, p < 0.001] , but autism- individuals showed greater amplitude for inverted faces compared to autism+ individuals . All other main effects and interactions involving autism or ADHD were not significant.Age and sex were not significant covariates and were excluded from the model. There was a main effect of autism  , where bF = 12.65, p < 0.001], with females showing shorter latencies than males, and was kept in the model while age was not significant and was excluded from the model. There was a main effect of autism , where autism- individuals showed shorter latency compared to autism+ individuals  = 5.677, p = 0.017], where ADHD- individuals showed shorter latency than ADHD+ individuals  = 5.417, p = 0.019], which was further moderated by an interaction between autism, ADHD and orientation  , whereas autism+ADHD individuals showed longer latency for upright faces compared to CG individuals . Finally, there was an interaction between autism, ADHD and direction  , and CG individuals showed longer latency for averted than direct gaze . All other main effects and interactions involving autism or ADHD  were not significant.Sex was a significant covariate  : the com= 0.043] : CG indiAge and sex were not significant covariates and were excluded from the model. All main effects and interactions involving autism or ADHD were not significant.F = 9.997, p = 0.002], with females showing shorter latencies than males, and was kept in the model while age was not significant and was excluded from the model. There was an interaction between autism and orientation  , and autism- individuals showed longer latency for upright faces compared to autism+ individuals . All other main effects and interactions involving autism or ADHD were not significant.Sex was a significant covariate [= 0.001] , 8B, wheWe investigated visual face processing in two passive viewing tasks tapping into different aspects of face, gaze and emotion processing in young adults with autism, ADHD, co-occurring autism and ADHD as well as in a comparison group without ADHD or autism. In line with previous studies using these tasks, we found main effects of emotion on P1 latency, N170 amplitude and N170 latency . We furtThe most consistent differences between groups across both tasks were found for the N170 component, where autistic participants showed longer latencies and smaller amplitudes in both tasks in comparison to those without autism. These findings indicate alterations in this neural correlate of face processing for autistic young adults , 64 consEarly studies of the N170 failed to show any effect of emotional expressions on its amplitude or latency , which Specific task differences for the N170 emerged for individuals with co-occurring autism and ADHD, who showed longer N170 latencies compared to comparison group individuals for the direct gaze and not for the averted gaze condition indicating lack of modulation by gaze direction. Similarly, we found that N170 latencies were longer in the co-occurring group compared to the comparison group for upright faces. The existence of this effect only for the upright face condition and not for the inverted faces might indicate that the co-occurring group is less affected by the more challenging inverted face condition. This lack of inversion effect has previously been reported in children with autism . A childIn line with previous studies of adults, autistic participants showed a delayed P1 latency compared to those without autism  . The P1 In our study we observed shorter latencies in females in comparison to males for N170 (in both tasks), P1 (EoE task) and P3 (face-gaze task) components. The findings for N170 and P100 latencies are in line with previous studies, and might support the theory that women are faster in detecting face stimuli and structural face encoding during face processing in comparison to men , 78.Contrary to expectations, young adults with ADHD did not show a reduction in P3 amplitude; however, those with autism showed reduced P3 amplitude compared to those without autism in the EoE task across all emotions. Other P3 effects specific to autism indicated longer latencies for upright faces compared to those without autism. These findings are in contrast to previous studies in both ADHD and autism but there is some evidence from other modalities that facial processing atypicalities exist in autism beyond early processing stages , 80. TheThis study has one of the largest EEG datasets of young adults with ADHD and autism; however, possibly due to use of strict diagnostic criteria (ADOS-2 and DIVA-2), the number of co-occurring ADHD and autism cases  is limitThis study provides a comprehensive examination of the temporal stages of face processing using salient socio-emotional stimuli: emotional expression, face gaze and orientation. We found consistent differences between those with autism and without in the N170 component across stimuli, with the autistic group showing lower amplitude and a delayed peak for N170, in agreement with some previous studies in adulthood. Furthermore, autistic participants had longer P1 latencies and smaller P3 amplitudes in response to emotional expressions and longer P3 latencies for upright faces compared to those without autism. Alterations for the ADHD group were limited to longer N170 latencies, specific to the face-gaze task, overlapping with the same finding in autism. Those with co-occurring autism and ADHD shared these atypicalities with the autism and ADHD participants but had additional differences in gaze modulation and a lack of an inversion effect as indexed by the N170. These findings suggest that there are identifiable and measurable socio-functional atypicalities in young adults with autism and ADHD that could be used along with other measures understand the progression of these conditions. Future work should investigate how much these neurophysiological atypicalities contribute to functional and social outcomes to clarify if they could serve as potential treatment targets in broader remediation interventions .The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by the King’s College London Psychiatry, Nursing and Midwifery Research Ethics Subcommittee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any identifiable images or data included in this article.ÜA, RC, and GM conceived and designed the analysis. ÜA and RC performed the analysis and wrote the initial draft in consultation with GM and CT. GM designed the study and acquired funding. All authors provided feedback on the manuscript, read, and approved the final version of this manuscript.


As a consequence, most of our knowledge is about referred children with ADHD in middle childhood in the age range of 6–12 years. One implication of this is that for a long time ADHD research was not bothered so much by studying causes of ADHD The first paper that I will highlight in this editorial is by Miller et al.  who discThe value of establishing the temporal sequence of personal and environmental alterations leading to a clinical onset of a disease cannot be underestimated. It is one element  in establishing the causality of a risk factor (the risk factor should occur prior to the onset of the disease), and a very important one in observational research. The accumulation of knowledge as to whether a risk factor is (likely) causal is necessary if we want to target the risk factor for interventions: that is, only causal risk factors can actually influence the outcome. Prospective research charting the sequences of personal and environmental alterations in risk during the gradual unfolding of ADHD over time provides opportunities to identify mediators that are useful as intervention targets in particular developmental periods. Also, prospective research may identify protective factors, by comparing children who have the same risk profile  but one group progressing to a full clinical onset of ADHD yet another not. That is, if we only study those who already have an onset of ADHD like we used to do we can never know if onset of ADHD (particularly the impairments experienced by the children) can be prevented, postponed or reduced in severity and thus if and how a developmental trajectory heading toward onset of ADHD can be shifted toward a more favorable outcome.Advances is therefore proud to publish the “Delineating early developmental pathways to ADHD: Setting an international research agenda” from the Early ADHD Consortium.The paper by Miller et al. in this issue of JCPP Advances describes a research agenda for prospective research pre‐onset to ADHD. The authors have formed the Early ADHD Consortium to improve future prospective research on the causes of ADHD. An important factor herein in my view is sample size. Clearly, we need the statistical power coming from large samples to get robust insights into the causes of ADHD: ADHD is a multifactorial condition resulting from the collective influence of multiple personal and environmental risk factors, each contributing a minor part but working in unison to heighten ADHD susceptibility. With none of the risk factors being necessary or sufficient, pathways toward onset of ADHD diverge among children and the to‐be‐expected small effects of any risk factor manifest as even smaller effects when averaged across all children in the study sample. This reasoning on why large samples are needed holds all the more if we are to identify the interplay (interactions) among risk factors. Furthermore, Miller et al. point out that neurodevelopmental alterations likely emerge prior to overt behavioral changes and that we need to understand causal factors at additional levels of understanding  next to the overt behavioral level, emphasizing once more the need for large samples. Team science in consortia to enlarge the sample turned out to be the game changer in the field of genetics, and this should also work out to improve our understanding of the broader  causes of ADHD. JCPP The second paper that I will highlight by Li et al. is also published in JCPP Advances  and focuAs argued, the ideas put forward by Miller et al. are not only relevant pre‐onset to ADHD but throughout the lifespan. To illustrate this further, I want to highlight two aspects specifically. First, as pointed out already, Miller et al. emphasize that environmental risk factors of ADHD in early development may change over time. As an example of altering risk factors over development, maternal immune activation, during pregnancy, may contribute to the risk of a later onset of ADHD . Miller et al. explain that how an exclusive focus on onset of ADHD and the presumption of specificity of risk for this outcome may obscure transdiagnostic patterns and lead to inaccurate causal models. That non‐specificity is ubiquitous and also relevant in the course of ADHD is undisputed. I already cited the example reported by Li et al. on the association of ADHD with CVD amidst similar associations of schizophrenia, substance use disorder, mood, anxiety and stress related disorders with CVD. Similarly, the most recent Genomewide Association Study on ADHD showed high sharing of genetic (concordant and discordant) genetic variants of ADHD with other disorders showing even more than before their strong intertwinement of the genetic architecture  from pregnancy to death, but this is obviously not going to happen. Yet, papers from multidisciplinary research teams working together on different parts of the lifespan, like Miller et al. in the Early ADHD Consortium, and Li et al. in the Timespan consortium, show that we are making good progress in understanding the ADHD lifespan.Catharina A. Hartman: Conceptualization; writing–original draft; writing–review and editing.is part of the TIMESPAN consortium, but not a co‐author on the cited papers. She is also Deputy Editor‐in‐Chief for JCPP Advances.Catharina A. Hartman


Children with attention deficit hyperactivity disorder (ADHD) or autism spectrum disorder (ASD) individually and those with co-occurring ADHD and ASD experience higher rates of total anxiety and psychiatric comorbidities such as gender dysphoria and locomotor skills compared to their typically developing (TD) peers. In this study, it was hypothesized that youth with comorbid ADHD and ASD would experience higher levels of overall anxiety, specifically separation, generalized, and social anxiety. A literature review of relevant studies published from 2007 to 2020 was performed, with a search involving key terms such as “Anxiety,” “ADHD” and “ASD'". It was discovered that individuals with ADHD or ASD had higher levels of anxiety compared to their peers. Furthermore, children who have co-occurring ADHD and ASD had more serve levels of anxiety than children with an individual diagnosis of ADHD or ASD. Children with ASD, ADHD, and co-occurring ADHD and ASD had a higher prevalence of gender dysphoria and impaired locomotor skills, which lead to higher levels of psychiatric comorbidities seen in this population. It can be hypothesized psychiatric comorbidities could also have implications for the high anxiety levels seen in this population but further research is needed to confirm this. Attention deficit hyperactivity disorder (ADHD) is a common neurological, and developmental comorbid disorder among youth with autism spectrum disorder (ASD) . HoweverOver the past decade, the number of patients being treated for ADHD has increased worldwide. There has been a rise in patients with ADHD in European countries such as the Netherlands, Denmark, and Spain, while the rates in most European countries are much lower when compared to the US. The use of prescription medications has increased by 30-85% in children who have ADHD along with other comorbidities, such as ASD or pervasive developmental disorder (PDD) . There iWith regard to the response to treatment, there appears to be a consensus among researchers. This entails that comorbidity is qualitatively diverse when compared to the combination of single disorders. Research findings pertaining to patients of various ages with diverse combinations of ASD and ADHD have reported a variance in the rates of co-presentation of anxiety in patients affected by multiple disorders versus patients affected by a single disorder .ADHD has been further classified into three subtypes: ADHD-predominantly inattentive (ADHD-PI), ADHD-predominantly hyperactive-impulsive (ADHD-HI), and ADHD-combined type (ADHD-C). Motor deficits in children with ADHD are well recognized extensively in the ADHD-related literature. The research predominantly suggests that the movement skills of children with the disorder are significantly distinctive in comparison to peers without ADHD . In addiResearch also shows a prevalence of ADHD in certain psychiatric comorbidities. It is especially high in individuals with mood disorders (22%), anxiety disorders (34%), substance use disorders 11%), and most behavioral disorders 15%) . In a st% . In a %, and moSeveral studies have found that comorbid anxiety disorders can even alter cognitive test performances in patients with ADHD. While there have been some failures in replicating these tests, anxiety disorders can affect physiological arousal, apprehension, and tension . CommuniFinally, neurodevelopmental conditions such as ASD and ADHD are found more commonly in transgender individuals . There hIn clinical settings, anxiety is encountered at an increasing rate during school years in patients with ASD. Both children with ADHD or ASD individually and those with comorbid ADHD and ASD experience higher rates of total anxiety when compared to their typically developing (TD) peers . Youths This literature review aims to investigate the possible associations between psychiatric comorbidities and anxiety in patients with individual diagnoses of ADHD or ASD and those with co-occurring ADHD and ASD. It is hypothesized that individuals with ASD, ADHD, or co-occurring ADHD and ASD will face higher levels of anxiety and psychiatric comorbidities that can be directly attributed to their disease. This is the first study to date to examine the relative impact of comorbid ASD and ADHD on specific anxiety symptoms in youths.This article was previously presented as a meeting abstract at the 2019 International Society for Autism Research (INSAR) Meeting on May 2, 2019.Materials and methodsA search was carried out on the databases PubMed, Scopus, and Medline for published and peer-reviewed literature addressing differing anxiety levels in individuals with ASD, ADHD, and co-occurring ASD and ADHD. We also used the same databases to find various published peer-reviewed articles that address various psychiatric comorbidities seen in children with ASD, ADHD, and those with co-occurring ASD and ADHD. Our inclusion criteria were as follows: articles involving children with a diagnosis of ASD, ADHD, or co-occurring ADHD and ASD. The search yielded a total of eight articles that addressed various levels of anxiety in our target population as well as psychiatric comorbidities such as alterations in locomotor skills and gender dysphoria. ResultsA Summary of the literature review is presented in Table DiscussionWe conducted a literature review on the differing levels of anxiety and psychiatric comorbidities in children with ADHD, ASD, and co-occurring diseases. Clinicians have recognized an increased prevalence of anxiety and psychiatric comorbidities such as gender dysphoria and impaired locomotor skills in children with various diagnoses. The levels of anxiety and psychiatric comorbidities appear to be intertwined as cases of gender dysphoria have been observed to cause increased levels of anxiety . AnxietyIn a study conducted by Guttmann-Steintmetz et al., the particular focus was on anxiety symptoms present in boys and in groups with ASD, ADHD, and ADHD + ASD . They alIdentification of ADHD and ASD symptoms can vary based on age and early-life atypicality. Recognizing these symptoms may aid in the prediction of the presence of ADHD, ASD, and anxiety . ShepharSalley et al. reported that people with ASD demonstrated the highest communication and social interaction deficit while those with ASD + ADHD had the second highest deficiency . Those wA study conducted by Jensen et al., found that female children with ADHD had a higher prevalence of anxiety disorder than their male counterparts . The stuPan et al. evaluated the relationship between motor skills in those with ASD and ADHD among children in Taiwan . Motor sAlthough there is evidence of children with ADHD, ASD, and co-occurring ADHD and ASD having higher rates of gender dysphoria the evidence is limited. A review by Thrower et al. found that children with ASD face gender dysphoria at a rate four times higher than the general population. They also found an increased rate of GD in individuals with ADHD as well . This stChildren with ADHD face higher levels of anxiety than others with estimated rates of co-occurring anxiety being between 18% - 32% of children . Ruf et Anxiety is an extensively studied disorder, with a 25% coexistence rate in those with ADHD . Unlike Our findings suggest an association between those with ADHD, ASD, or co-occurring diseases and higher levels of anxiety and psychiatric comorbidities. We believe that the evidence presented will encourage various health professionals to become more vigilant and aware of these associated symptoms in children with confirmed ADHD, ASD, and co-occurring diagnoses. With both ADHD and ASD having an uncertain etiology, it is hard to truly understand why individuals with ADHD and ASD have an increased prevalence of associated anxiety and psychiatric symptoms. This study has a few limitations, including the varying criteria applied for anxiety diagnosis. Some clinicians can attribute anxiety to stressful situations instead of clinical anxiety disorder, which could contribute to a lower overall anxiety diagnosis in this population. Further research is needed to understand the causative factors that link higher levels of anxiety and associated psychiatric symptoms in children with ADHD, ASD, and co-occurring ADHD and ASD. This literature review aimed to evaluate the possible linkage between anxiety and psychiatric comorbidities in individuals with ASD, ADHD, and co-occurring ADHD and ASD. We have found evidence indicating that individuals with ADHD, ASD, or co-occurring ADHD and ASD display higher levels of anxiety and psychiatric comorbidities such as impaired locomotor skills and gender dysphoria. Our findings provide deeper insights into the association between anxiety and comorbid psychiatric symptoms in individuals diagnosed with ADHD, ASD, or co-occurring ADHD and ASD. Further research is needed to truly delineate the associations seen between anxiety and comorbid psychiatric disorders in those with ASD and ADHD as well as aid in gaining a deeper understanding of the treatment models required for treating these conditions.


Background: Well-trained primary school teachers should be competent in recognizing attention deficit hyperactivity disorder (ADHD) in students and be able to assist in providing care and support.Objectives: This study intends to assess primary school teachers' knowledge of ADHD and evaluate the effectiveness of a short-term educational intervention. Methods: A quasi-experimental quantitative study was conducted among primary school teachers in Jazan, Saudi Arabia. A two-hour educational intervention was designed and run in six schools using a specific knowledge rating scale before and after the application of the intervention. Results: A total of 150 primary school teachers were included in this study, of which 64% were males, 51.3% were in the age group of 40-49 years, and 28% had teaching experience of more than 20 years. Regarding ADHD knowledge, the pre-intervention knowledge of the general criteria, symptoms and diagnosis, and treatment was considered adequate in 3.3%, 16.7%, and 2.7% of the participants, respectively, which improved post-intervention to 22%, 54.7%, and 19.3%, respectively. There was a significant association between the pre-intervention knowledge of the general criteria and the gender and between the knowledge of symptoms and diagnosis and the attendance of ADHD workshop by the participants. Also, there was a significant association between the participants' age, residence experience, attendance of ADHD workshops, and the general criteria and treatment domains.Conclusions: Most primary school teachers in Jazan have insufficient knowledge of ADHD. Using a knowledge improvement intervention can substantially improve the teachers’ knowledge. Therefore, it is necessary to incorporate thoughtful knowledge improvement programs into the educational curricula for teachers. The most common neuro-behavioral disease affecting children is attention deficit hyperactivity disorder (ADHD), which affects 3.4-7.2% of children globally and 2.7-16.4% of children in Saudi Arabia . There aBecause most children spend more time in school and interact with teachers than with their parents or healthcare professionals, primary school teachers have taken responsibility for assessing children's academic and behavioral difficulties and providing immediate assistance shortly after early detection. Interventions for ADHD teacher training have been designed to increase teachers' understanding of the disorder, prepare them to foster a supportive learning environment, and help them develop problem-solving tactics . Recent , this study aims to assess the knowledge of ADHD among primary school teachers in the Jazan region of Saudi Arabia and evaluate the impact of the socio-demographic variables on the knowledge before and after interventional educational lectures.There is a reasonable effort in Saudi Arabia to diagnose, manage, and raise awareness of ADHD. For example, the Saudi Ministry of Health started a national School-Based Screening Program (NSBSP) to examine children's many health conditions, including ADHD . MoreoveStudy design and participantsThis quantitative quasi-experimental study was conducted in the city of Jazan, the capital of the Jazan region in the Kingdom of Saudi Arabia, between February and June 2023. The study was conducted among primary school teachers, both male and female, in six schools. The study was approved by the Standing Committee for Scientific Research, Jazan University (HAPO-10-Z-001) .This study included all teachers in the selected primary schools who agreed to participate, and excluded the teachers who did not match the inclusion criteria, refused to participate, or did not complete the questionnaire. The minimum sample size was 150 participants, calculated by an online sample size calculator , a margiData collection tool and the collection procedureData collection was done with the help of a questionnaire that had questions on demographic information , previous experience and knowledge regarding ADHD; the last section assessed the participants' knowledge using the Knowledge of Attention Deficit Disorders Scale (KADDS) that was created by Sciutto and colleagues in 2000 to assess knowledge gaps and common misconceptions among parents of children with ADHD, educators of those children, and other clinical and educational professionals . The 36 The participants filled out an informed consent that demonstrated the purpose and the method of the study; then, they received the questionnaire to be filled out before the educational intervention. Because of the time constraints, the educational interventional program was prepared as a two-hour lecture that contained the basic knowledge of ADHD regarding general features, symptoms, warning signs, diagnosis, and treatment, which enabled the participants to answer all the given questions in the KADDS questionnaire. The authors prepared the lecture in an uncomplicated, understandable PowerPoint  format with visual illustrations to attract the participants. The participants were permitted to ask questions after the demonstration to ensure their understanding of the concepts in the lecture. Then, the same questionnaire was used to assess teachers' knowledge of ADHD immediately following the interventional educational lecture was concluded.Knowledge ScoreEach correct answer in the questionnaire was one mark; wrong answers and "do not know" got zero marks. This calculation gave a score of 0-36 and then converted to percentages. The score was not normally distributed, so we calculated 25% and 75% of the data, and the knowledge was categorized into Poor (< 25%), Fair (25-75%), and Adequate (> 75%) .Data presentation and statistical analysisIBM SPSS Statistics for Windows, Version 23.0  was used for data analysis. Initially, all information gathered via questionnaire was then coded into variables. Frequencies were used to give a general overview of the data. Descriptive and inferential statistics involving the Pearson Chi-square test, one-way ANOVA, Fisher's exact test, and the Mc-Nemar-Bowker test were used to present the results. A p-value of less than 0.05 was considered statistically significant.In total, 150 primary school teachers were included in this study. The participants' characteristics are shown in Table Regarding ADHD knowledge, Mc-Nemar's test for correlated proportions was applied with matched pre- and post-intervention pairs in the three domains. The pre-intervention knowledge regarding the general criteria domain, symptoms and diagnosis domain, and treatment domain was considered adequate (> 75%) in 3.3%, 16.7%, and 2.7% of the participants, respectively, which improved post intervention to 22%, 54.7%, and 19.3%, respectively, in the three domains. Also, the poor ADHD knowledge (< 25%) revealed a statistically significant improvement post intervention among the participants in the three domains (p = 0.000), as shown in Table One-way ANOVA was used to assess if there were any statistically significant differences between the means of the three domains and the demographic variables of the participants. As shown in Table The Fisher's exact test and Pearson chi-square were used to assess whether there is a statistically significant relationship between demographic variables and the knowledge of ADHD. Age group, gender, educational level, and years of experience were significantly related to ADHD knowledge domains, as shown in Table This study aimed to assess the knowledge of primary school teachers working in Jazan, Saudi Arabia, before and after implementing an educational intervention on ADHD. The common incorrect KADDS items that showed poor knowledge were the estimates suggesting that ADHD occurs in approximately 15% of school-age children (42%), the possibility for an adult to be diagnosed with ADHD (40.7%), and the fact that ADHD children are more compliant with their fathers than with their mothers (37.3%). Also, 32.7% of the participants thought that ADHD is primarily the result of ineffective parenting, and 30.7% thought that treatment for ADHD that focuses mainly on punishment is the most effective in reducing the symptoms of ADHD.Before the intervention, most teachers (73.3%) showed adequate knowledge that symptoms of ADHD must manifest before the age of seven to be diagnosed. Additionally, two-thirds (66.7%) of the teachers knew that children who frequently fidget or seem restless in two or more settings (such as at home and school) must exhibit relevant symptoms of ADHD. These outcomes aligned with research conducted in the cities of Madinah and Makkah regarding primary teacher knowledge and showed similar teachers' concepts ,19.Similar to previous Saudi studies, about 48% of the participants had a wrong concept before the intervention that reducing dietary intake of sugar and food additives was one modality of reducing ADHD symptoms . HoweverThe results of the current study have indicated that the educational intervention had a substantial influence on teachers' knowledge regarding ADHD, confirming earlier studies that have shown the value of short-term programs in raising teachers' understanding of ADHD . The finThis poor pre-intervention knowledge among teachers was associated with gender and the previous attendance of training workshops; this result is consistent with the last Saudi studies that confirmed that the previous training positively influences knowledge ,24. HoweThe current study highlights teacher training and examines the effectiveness of available short-term educational intervention resources for ADHD. However, several limitations must be taken into account when evaluating our findings. First, because of the limited duration of the intervention, it could not studied whether the long-term benefits could be influenced by the teacher's attention span and general mood over such a short period; it also reduces reassurance beyond the intervention's expanded learning outcome. Second, because the questionnaire was self-reported, participants may have overestimated their understanding of ADHD, which may be one reason for the wrong rate of adequate knowledge. Moreover, we grouped the incorrect and 'don't know' answers together and assigned them the same score, making it challenging to distinguish teachers' intention of not answering from poor knowledge. Lastly, the relatively small sample size and the study being conducted in a single city and only in public schools limit the generalizability of the results, so more extensive research is warranted in the future to validate the results. Teachers play a crucial role in helping manage ADHD-affected children as they usually spend significant time with children and can promptly observe the behavioral changes in ADHD children. In this study, the teachers' knowledge regarding ADHD showed considerable improvement after implementing an educational intervention. Although most previous research in Saudi Arabia has shown that there is still insufficient knowledge, wrong perception, and lack of positive attitude surrounding ADHD among teachers, such short-term educational intervention can participate in improving their knowledge in cost-effective ways. The teacher's knowledge and motivation for dealing with children with ADHD would be enhanced by attending training workshops and integrating the particular education course into the instructors' educational curriculum.


These findings remained when analyses were restricted to trials (n: 5–13) with children/adolescents, low medication exposure, semi-active controls, or WMT or multiple process training. There was a small improvement in inattention symptoms , which remained when trials were restricted to semi-active controls , and doubled in size when assessed in the intervention delivery setting , suggesting a setting-specific effect. CCT improved WM , but not other neuropsychological  or academic outcomes . Longer-term improvement (at ~6-months) in verbal WM, reading comprehension, and ratings of executive functions were observed but relevant trials were limited in number (n: 5–7). There was no evidence that multi-process training was superior to working memory training. In sum, CCT led to shorter-term improvements in WM, with some evidence that verbal WM effects persisted in the longer-term. Clinical effects were limited to small, setting specific, short-term effects on inattention symptoms.This meta-analysis investigated the effects of computerized cognitive training (CCT) on clinical, neuropsychological and academic outcomes in individuals with attention-deficit/hyperactivity disorder (ADHD). The authors searched PubMed, Ovid, and Web of Science until 19th January 2022 for parallel-arm randomized controlled trials (RCTs) using CCT in individuals with ADHD. Random-effects meta-analyses pooled standardized mean differences (SMD) between CCT and comparator arms. RCT quality was assessed with the Cochrane Risk of Bias 2.0 tool (PROSPERO: CRD42021229279). Thirty-six RCTs were meta-analysed, 17 of which evaluated working memory training (WMT). Analysis of outcomes measured immediately post-treatment and judged to be “probably blinded” (PBLIND; trial  Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental condition characterized by developmentally-inappropriate, persistent, pervasive and impairing inattention and/or hyperactivity/impulsivity symptoms . ADHD meComputerized cognitive training (CCT) has also been investigated as a treatment option for those with ADHD. This is motivated by the notion that ADHD is potentially the result of weaknesses in neuropsychological processes thought to mediate causal pathways between originating causes  and symptom expression . Indeed,most proximal (MPROX) to the intervention setting  and outcomes we judged to be probably blinded . Interestingly, in Cortese et al. (2015) , st. (2015) , 17 and . (2015) , but the. (2015) , only fo. (2015) , 18, or . (2015) , all of different from the intervention setting , which confounds the blinded status of ratings with the setting of intervention delivery, meaning that PBLIND outcomes could be indexing the issue of generalisation, not just outcome assessor bias. Our update addressed this issue through a sensitivity analysis that included only trials with PBLIND outcomes that were measured in the intervention setting. Finally, and importantly, to extend the analyses by Cortese et al. [Because of the relatively small number of high-quality trials with PBLIND outcomes at that time, our prior meta-analyses were unable to provide a solid estimate of the efficacy of CCT, an analysis of whether certain intervention types were better than others, or whether they improved different neuropsychological and academic outcomes. However, since Cortese et al. , which ie et al. , we aimeThis study followed a preregistered protocol , and was reported in line with PRISMA 2020 [We included parallel-arm RCTs with participants of any age that had a clinical ADHD, or equivalent hyperkinetic syndrome, diagnosis as defined by DSM-III/ICD-9 onwards (any subtype/presentation) or were above cut-off on validated ADHD rating scales, regardless of the presence of common-comorbidities. CCTs must have been implemented using fully computer-based procedures with an adaptive component – i.e., training difficulty increased as performance improved. Eligible comparator arms were semi-active (non-adaptive CCT), non-active , or placebo pill. Where trials had two comparator conditions  the condition representing the most rigorous control was selected . All RCTs must have been peer-reviewed and published in an academic journal, and reported a validated outcome measure of ADHD symptoms, neuropsychological processes, and/or academic outcomes. We excluded RCTs with participants with ADHD with a rare comorbidity  that was used as a trial inclusion criterion , or when CCT was only delivered in combination with or adjunct to another distinctive planned active treatment that was administered as part of the trial .We searched PubMed (MEDLINE), OVID , and Web of Science  until 19th January 2022 using variations of terms for ADHD, RCTs, and cognitive training (see Supplement). Database searches were supplemented by hand searching of published relevant systematic reviews or meta-analyses or of references in individual papers.Two authors  independently i) screened all article titles and abstracts; ii) read the full text of articles that passed title/abstract screening to determine final inclusion; iii) extracted relevant data (see Data Items section below) and iv) assessed all eligible reports  with the Risk of Bias (RoB) 2.0 tool . The RoBMeans and standard deviations at all available time points were extracted from validated rating scales/subscales that directly measured ADHD total symptoms or sub-dimensions  or ADHD-relevant neuropsychological outcomes, and academic outcomes. Consistent with previous EAGG protocols, if multiple ADHD outcomes were reported for each assessor, we selected the one for analysis based on the following hierarchy; i) ADHD Rating Scale , ii) SwaFor ADHD-related outcomes we distinguished MPROX from PBLIND ratings. MPROX were ratings from individuals judged to be most proximal to the intervention, which were typically least blinded to intervention allocation . PBLIND outcomes were the most blinded outcome where assessors were judged to be probably unaware of treatment allocation. We judged an outcome assessor to be PBLIND if they were a) distal from the intervention setting, b) independent coders rating in the intervention setting, or c) could be blinded by design even if proximal to the treatment setting . Where multiple PBLIND outcomes were available, we selected the one more distal to the treatment setting  or an independent coder. Outcome assessors were judged to not be PBLIND if the trial design prevented concealment of group allocation  or there was evidence that blinding broke during the trial . MPROX was by definition available for all trials that met the inclusion criteria, while PBLIND was only available for some trials. In some trials, MPROX and PBLIND outcomes were based on the same assessment .For ADHD symptoms, we analysed MPROX and PBLIND outcomes, but our primary analyses were PBLIND outcomes because they provide a more robust and bias-free estimate of CCT effects. For other outcomes , we report MPROX outcomes if sufficient  PBLIND trials were not available. Our primary outcome was PBLIND outcomes of ADHD symptoms  measured at the first time point after the final CCT session . We also report PBLIND assessments of inattention and hyperactivity/Impulsivity symptoms separately. Other outcomes were neuropsychological and academic outcomes at post-assessment or longer-term follow-up . Given the variety of neuropsychological/cognitive outcome measures, wherever possible, we took the pragmatic decision to group outcomes together that we judged to tap the same or similar core constructs, with judgments informed by factor analyses and meta-analytic evidence where possible , 19, 30.g small sample bias adjustment [Q – i.e., chi-squared test – and the magnitude of true heterogeneity relative to random heterogeneity was estimated using the I2 statistic [Effect size estimates were based on standardized mean differences (SMDs), which were calculated as mean baseline- to post-assessment (or follow-up) change in the intervention group minus the mean baseline- to post-assessment (or follow-up) change in the control group divided by the pooled baseline standard deviation with Hedges’ justment , 32. We justment , 33, 34 justment . SMDs wejustment , 36, andtatistic .We conducted pre-specified sensitivity analyses where at least five relevant trials met inclusion criteria. Separate analyses were conducted that included only trials where: (i) there was a semi-active comparator; ii) only a minority  of participants were receiving medication; iii) only WM was targeted; iv) multiple cognitive processes were targeted; v) participants were preselected based on impairment in the trained cognitive domain ; vi) with children/adolescents (<18-years-old); vii) with adults (>18-years); or viii) PBLIND assessment was conducted in the intervention setting. We ran pre-specified meta-regressions with the predictors: mean age  or overall RoB  . Post-hoFinally, publication bias was assessed using Egger’s regression test of small study effects and was carried out only for significant results with all trials included.We used RevMan  to calcun = 22), followed by WLC (n = 11) and TAU (n = 3). Most trials recruited children , followed by adults , and adolescents  (see Supplementary Table n = 17), followed by multi-process training (MPT) (n = 13), attention training (n = 5), and inhibitory control training (n = 1). Most trials administered CCT at home (n = 21), followed by at school (n = 5), in a laboratory setting (n = 3), the clinic/hospital (n = 2), and a mixed setting . Several outcomes were excluded from five out of the 36 eligible RCTs. We excluded i) independent evaluator-rated ASRS from Virta et al (2010) [Of the 359 non-duplicate reports found, 233 were removed at title and abstract screening, leaving 136 to be assessed at full-text for eligibility. Of these, 94 reports were excluded . This left 42 eligible reports derived from 36 RCTs   because l (2010)  because l (2010) , 48 becal (2010)  because l (2010)  because Of the 36 included trials, 14 reported PBLIND ADHD outcomes  were rated by PBLIND assessors in only four trials and MPROX assessors in thirteen trials . Heterogeneity was zero and non-significant  or laboratory measures of verbal WM , with only the latter showing a benefit in favour of CCT  ; laboratory measures of motor inhibition  and verbal WM , and reading comprehension only . Heterogeneity was small and non-significant in all cases , all of which recruited children aged 9–12-years. Due to an insufficient number of trials, it was not possible to analyse PBLIND outcomes in any one domain or laboratory measures beyond motor inhibition, attention, verbal WM, and reading comprehension. A significant and small benefit favouring CCT relative to control was found in the analysis of MPROX ratings of executive functions (but not ADHD symptoms)  while the significant effects for inattention symptoms increased slightly, remaining significant . The intervention effect for hyperactivity/impulsivity remained non-significant . In these exploratory analyses effects sizes remained small.stand-alone treatment for core ADHD symptoms. In our pre-registered analyses, effects on PBLIND measures of core ADHD features were limited to a significant, but small, short-term effect on inattention symptoms, which was substantially unchanged with variations in experimental control arm. This finding has possible clinical relevance given that inattention may become a more important issue in adulthood [This comprehensive and well-powered meta-analysis found no evidence to support the use of CCT in its current forms as a dulthood . Howeverdulthood . In genedulthood , 15. Equdulthood  and SMD dulthood ). PositiN = 5) in this sensitivity analysis we encourage future trials to explore this issue systematically by varying blinded clinical outcomes measured in the same or different setting to the intervention.The scale of the current meta-analysis - made possible by the large number of new trials published in recent years - provided scope to explore a range of aspects of the effects of CCT for ADHD not possible before. First, against expectation, we found no evidence that MPT was superior to WMT when PBLIND outcomes were employed. Cortese et al.  had founThird, with respect to evidence of the longer-term benefits of CCT, positive effects on WM waned and became non-significant for some outcomes. However, in contrast, there were a number of outcomes where significant, though still small, effects emerged only at follow-up – e.g., objective measures of motor inhibition and reading comprehension and MPROX ratings of executive functioning. These later effects, if confirmed, might represent “sleeper effects” – i.e., effects of CCT become consolidated over time. Such an interpretation remains speculative at this point given the limited number of high risk-of-bias trials on which the findings are based. One other explanation could be that the short-term effects found in WM were in fact later transferred to a positive effect on associated functions  later down the line. These tentative explanations could be a focus in future research along with investigating whether “top-up” interventions are required to prolong the short-term benefit we found.Fourth, as previously reported in our 2015 paper [Fifth, there were too few relevant trials to draw any strong conclusions about the value of CCT for adults with ADHD. One speculation is that the modest, short-term improvements found for inattention symptoms, but not combined ADHD, in children and adolescents might indicate possible benefits to adults for whom inattention becomes especially relevant. However, this would need to be tested specifically in future trials.Sixth, the three exploratory analyses requested during the review process – i.e., restricting analysis to non-commercially funded trials, analysing the PBLIND data collected most proximally rather than most distally, and adding PBLIND parent-rated outcomes from Kofler et al. (2020) – did not change our interpretation of the results, highlighting the robustness of our analyses.We believe that the translational logic of targeting neuropsychological processes thought to mediate ADHD pathophysiology to improve symptoms and/or neuropsychological processes with related improvement in functioning still has viability. However, given the lack of results detailed above, maybe new and innovative training approaches will be required to move the field forward. These may involve targeting different processes, using more focused strategies or different intervention modalities. With regard to the focused strategies, greater benefits may be derived by targeting more basic non-executive functions, like neurophysiological processes that regulate arousal/motivation or emotions , which aN = 348) with a pre-registered trial protocol and analysis plan – so inclusion of these outcomes may have changed our conclusions. The authors found that compared to an semi-active control, CCT targeting attention and cognitive control  led to no improvement in blinded-parent ADHD-RS ratings of ADHD symptoms and BRIEF ratings of executive functioning, but significantly improved TOVA performance – a task-based measure of attention. These results point to potential practice-like gains with transfer limited to the trained cognitive domain, supporting the main conclusions from our meta-analyses. Further, given the size of this study, if ADHD-RS outcomes were included in our primary analysis of PBLIND outcomes, it would likely substantially diminish or even abolish the significant CCT-related improvement in inattention symptoms we found, further supporting our conclusion of the limited clinical benefit of CCT as a standalone treatment for ADHD. We agree with the authors, however, that further investigation into the real-world benefit of AKL-T01 is worthwhile. Finally, our protocol precluded trials with head-to-head comparisons of different interventions. Future analyses should focus on these.There are several limitations to our meta-analysis resulting from the studies available for inclusion. First, the majority of RCTs suffered from biases that were judged to be of some or high risk. For example, high levels of attrition were common - 17 out of 42 reports had dropouts >20% at post-assessment but did not account for this analytically – which may have inflated SMDs. Further, while 14 RCTs reported PBLIND ADHD outcomes, the remaining 22 used WLC/TAU controls and/or MPROX outcomes only, meaning that blinding was unlikely or practically impossible. This raised the risk that outcome assessors were biased by knowledge of group assignment. Future RCTs should improve participant retention or provide evidence that results were not biased by missing data  , 13. SecThere was no empirical support for the use of CCT as a stand-alone intervention for ADHD symptoms based on the largest and most comprehensive meta-analysis of RCTs conducted to date. Small effects, of likely limited clinical importance, on inattention symptoms were found – but these were limited to the setting in which the intervention was delivered. Robust evidence of small-to-moderate improvements in visual-spatial and verbal STM/WM tasks did not transfer to other domains of executive functions or academic outcomes, but these might take time to become apparent. New interventions targeting different processes using different, more ecologically valid, approaches within more focused intervention strategies are required going forward.Supplementary Material


There is equivocal evidence on the presence of oculomotor deficits among children with attention deficit hyperactivity disorder (ADHD), which can be an additional challenge in this population, especially with reading-related tasks. This study aimed to review the deficits in the oculomotor parameters among children with ADHD compared with age-matched controls. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A search of original research articles on various databases was done using key terms, such as “oculomotor deficit,” “attention deficit hyperactivity disorder,” or related terms. We included case-control studies and excluded studies in which children received medications during the test. Twelve original research studies were considered for this review. Ten studies reported data on various types of saccades, two studies reported data on fixation, and one study reported data on pursuit. Among various oculomotor deficits, the forest-plot analysis of an antisaccade task showed that children with ADHD made more direction errors compared to controls. Although independent studies report that ADHD children have poorer performance compared to control populations during oculomotor tasks, there is a lack of evidence to draw a strong conclusion. Children with ADHD are less precise in performing eye movements and need more time to complete the oculomotor tasks than those without ADHD. The overall results provide minimal evidence regarding the presence of various oculomotor deficits in ADHD. Neurobehavioral disorders characterised by the lack of attention, impulsivity, and extremely active and disruptive behaviour in childhood or adulthood are referred to as attention deficit hyperactivity disorder (ADHD) –3. ADHD Oculomotor behaviour involves saccades, smooth pursuit, and fixations . In the Various eye-tracking studies have shown abnormal eye movements in ADHD , 14. TheThe review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines . The revThe aim of this review was to compare the oculomotor parameters in children with and without ADHD. Outcome measures of this review were oculomotor parameters, such as saccades, pursuits and fixation deficits.A literature search to identify the publications relevant to the review was done using various electronic databases, such as PubMed, PMC (MEDLINE), Web of Science, Scopus, CINHAL complete, and BMJ. The search terms included “saccade,” “smooth pursuit,” “oculomotor deficit,” “oculomotor problem,” “oculomotor deficit,” “fixation” and “attention hyperactivity disorder.” During the search, appropriate Boolean operators, such as “OR,” “AND” and “NOT,” were used, including Medical Subject Heading (MeSH) terms, to identify the relevant literature. The list of the search strategy used is provided in the Original research articles with ADHD study participants aged ≤18 years, a diagnosis of ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-IV) or DSM-V criteria, primary research outcomes comprising oculomotor parameters, and articles published in English with a case-control study design were included in this review.The exclusion criteria were research studies including participants with any other comorbid disorders, research articles in which the participants were on methylphenidate or Ritalin or any other prescribed medication for ADHD during the time of oculomotor testing or on the day of oculomotor testing.Three authors were involved in the review team. After the initial search in scientific databases, duplicate articles were removed using Mendeley software, and the remaining articles were screened for eligibility. Two authors in the study independently performed title and abstract screening of the included articles. Any disagreement between the two authors in this process was clarified with the third author. Full text of the articles included based on title and abstract screening were assessed for further eligibility as per study inclusion and exclusion criteria. Articles fulfilling the eligibility criteria were reviewed, and data were extracted. The references of all included studies were reviewed for additional relevant publications.The extracted data mainly included study title, year of publication, sample size, participants’ age, study design, nature of oculomotor task and outcome measures for the ADHD and control groups. Microsoft Excel (Version 2013) was used for data extraction and management.I2 statistics. The value of 0% corresponded to no heterogeneity observed, and a larger heterogeneity value related to increasing heterogeneity [I2 value of 25% corresponded to low heterogeneity, 50% corresponded to moderate heterogeneity, and 75% corresponded to high heterogeneity [Review Manager software (RevMan version 5.4.1) was used for statistical analysis . The anaogeneity . The I2 ogeneity .Included studies were assessed for risk of bias by two independent authors using the Modified Newcastle Ottawa scale, a tool for assessing bias in a case-control study , 24. As Based on our search strategies, a total of 92,456 records were identified from the databases listed in the methodology. The number of articles at various levels of screening is provided in the PRISMA flow chart Fig. . After tThe risk of bias assessment table for all included studies is given in Table Study characteristics in terms of sample size, age range, and outcome measures are given in Table p = 0.40) [Prosaccade is the eye movement made towards a peripheral target from the centre of fixation after a cue presentation . In this = 0.40) .In MGS, eye movement is made towards the memorised visual target previously seen in the visual periphery . SeveralI2 value confirms high heterogeneity. The results are inconsistent due to high heterogeneity and confirm that there is variability in latencies among children with ADHD and without ADHD. Therefore, the evidence for worse VGS latency in the ADHD group compared to age-matched controls is inconclusive.VGS are the eye movement made toward a suddenly appearing visual target . AppearaThe studies evaluating VGS accuracy showed that ADHD children had longer accuracy values than children without ADHD, although it was not statistically significant in all studies , 32, 33.I2 value confirms low heterogeneity. In this analysis, the diamond is on the right side of the graph, favouring the results of the control group and depicting that ADHD children made a higher number of direction errors compared to controls.In AS task, eye movement is made in the direction opposite to the visual stimuli presented . In a stThere were limited studies on the comparison of pursuits among children with and without ADHD. One publication evaluated smooth pursuit and found no significant difference between the ADHD and control groups .A study evaluated the tendency of visual fixation for 21 s. In this task, children with ADHD made significant eye movement during the 21 s fixation task compared to controls .Children with ADHD had significantly more fixations with a low rate of reading, resulting in more time to complete reading tasks, than control children .Intrusive saccades are defined as inappropriate saccades made during the fixation period. Such saccades were higher among children with ADHD than in the control group , 15, 30.Very few articles explicitly reported the oculomotor deficits present in the ADHD population compared with age-matched controls. We identified 12 case-control studies where various components of oculomotor deficits were compared between children with ADHD and age-matched controls. ADHD children were evaluated in an unmediated state in all studies included in this review. VGS, AS and MGS were commonly reported oculomotor parameters in those studies.Prosaccade, AS and VGS were assessed based on the response inhibition task. Poor performance in response inhibition tasks is suggestive of frontal lobe deficits , 35, andThe accuracy of MGS was not statistically different between ADHD and control group. Variability in statistical significance of MGS latency reported in two studies could be due to the difference in the delay period used to initiate a MGS after the presentation of a visual target. In one study, a delay period of 1200 msec was used , and in MGS and VGS reflect the function of the cerebellum . VGS hadAS, in terms of accuracy, was not significantly different between children with and without ADHD, but the AS reaction time had a significant difference between both groups. The percentage of direction errors during AS task was higher among the ADHD group than controls. Direction errors attribute to the lack of visual attention in ADHD. The abnormalities in response inhibition contribute to hyperactive, impulsive and off-task behaviour seen in ADHD children . The dirADHD children are very slow and will vary in their response to various tasks, which supports an inability or deficit in preparing responses . AdditioSeveral studies assessed fixation using the distractor , 44, 45,The cerebellar dysfunction and delayed maturation in basal ganglion contribute to impaired spatial attention and voluntary eye movement in ADHD children. They also reduce hand-eye coordination and visual-spatial recognition among ADHD patients . The preI2 value, suggesting the variability across the studies. In the AS task, the percentage of direction errors made was more in ADHD children. Overall, children with ADHD exhibited less precision in making eye movements and required more time to complete the oculomotor task compared to children without ADHD. Although individual studies reported that ADHD children had poorer performance compared to children without ADHD, there is a lack of strong evidence to confirm the presence of oculomotor deficits because of the heterogeneity among the studies. In addition, there is a lack of studies on the assessment of smooth pursuit among ADHD children compared with controls. There is a need for studies with standardised and uniform experimental design to substantiate the oculomotor deficits among children with ADHD.This review witnessed the extent of statistical heterogeneity in the studies reporting VGS latency. The VGS latency was associated with a significantly high Supplemental Material is available at nature.com/eyeSupplemental Material


Cheung, C. H. et al. J. Psychiatr. Res. 2005; 62, 92–100). In these cases, if not treated, ADHD symptoms can cause severe dysfunction , 816–818) often leading to misdiagnosis.ADHD is a neurodevelopmental disorder that occurs in childhood and can persist in adulthood in a percentage of cases ranging from 15% to 70%  and prescribed various drugs but none of these were able to stabilize the psychopathological condition. The clinical history revealed the presence of a pervasive picture of inattention and hyperactivity since childhood which had heavily conditioned the patient’s functioning over time. The inattentive pattern has persisted unchanged over the years, while the hyperactive one has improved leaving room for a stable sense of internal tension and generalized anxiety on which mood fluctuations are cyclically inscribed. A diagnosis of ADHD, combined presentation type, was made by using the DIVA-5. The patient was first prescribed lithium, which was subsequently replaced with valproic acid. After mood stabilization and the reduction of anxious symptoms prolonged-release methylphenidate was added to therapy, obtaining resolution of the clinical picture.Fayyad, J. et al. BJPsych 2007; 190, 402–409). An accurate collection of clinical history can guide the diagnosis and help to address adequate treatment.Almost all adults with ADHD exhibit a lifelong pattern of frequent mood swings and irritability. Given that many mental health practitioners are unfamiliar with emotional lability in adult ADHD, a bipolar, or cluster B/C personality disorder is more likely to be considered as the cause of the mood swings (None Declared