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The main goal of the present study was the identification of cellular phenotypes in attention-deficit-/hyperactivity disorder (ADHD) patient-derived cellular models from carriers of rare copy number variants (CNVs) in the PARK2 locus that have been previously associated with ADHD. Human-derived fibroblasts (HDF) were cultured and human-induced pluripotent stem cells (hiPSC) were reprogrammed and differentiated into dopaminergic neuronal cells (mDANs). A series of assays in baseline condition and in different stress paradigms (nutrient deprivation, carbonyl cyanide m-chlorophenyl hydrazine (CCCP)) focusing on mitochondrial function and energy metabolism (ATP production, basal oxygen consumption rates, reactive oxygen species (ROS) abundance) were performed and changes in mitochondrial network morphology evaluated. We found changes in PARK2 CNV deletion and duplication carriers with ADHD in PARK2 gene and protein expression, ATP production and basal oxygen consumption rates compared to healthy and ADHD wildtype control cell lines, partly differing between HDF and mDANs and to some extent enhanced in stress paradigms. The generation of ROS was not influenced by the genotype. Our preliminary work suggests an energy impairment in HDF and mDAN cells of PARK2 CNV deletion and duplication carriers with ADHD. The energy impairment could be associated with the role of PARK2 dysregulation in mitochondrial dynamics.
The cell—cell signaling gene CDH13 is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression. CDH13 regulates axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of CDH13 on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the CDH13 gene in humans is sparse. Therefore, we tested for association of a functional intronic CDH13 SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of CDH13 is associated with personality traits and impacts neural processing during working memory tasks. Thus, CDH13 might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Risk stratification for bipolar disorder using polygenic risk scores among young high-risk adults
(2020)
Objective: Identifying high-risk groups with an increased genetic liability for bipolar disorder (BD) will provide insights into the etiology of BD and contribute to early detection of BD. We used the BD polygenic risk score (PRS) derived from BD genome-wide association studies (GWAS) to explore how such genetic risk manifests in young, high-risk adults. We postulated that BD-PRS would be associated with risk factors for BD.
Methods: A final sample of 185 young, high-risk German adults (aged 18–35 years) were grouped into three risk groups and compared to a healthy control group (n = 1,100). The risk groups comprised 117 cases with attention deficit hyperactivity disorder (ADHD), 45 with major depressive disorder (MDD), and 23 help-seeking adults with early recognition symptoms [ER: positive family history for BD, (sub)threshold affective symptomatology and/or mood swings, sleeping disorder]. BD-PRS was computed for each participant. Logistic regression models (controlling for sex, age, and the first five ancestry principal components) were used to assess associations of BD-PRS and the high-risk phenotypes.
Results: We observed an association between BD-PRS and combined risk group status (OR = 1.48, p < 0.001), ADHD diagnosis (OR = 1.32, p = 0.009), MDD diagnosis (OR = 1.96, p < 0.001), and ER group status (OR = 1.7, p = 0.025; not significant after correction for multiple testing) compared to healthy controls.
Conclusions: In the present study, increased genetic risk for BD was a significant predictor for MDD and ADHD status, but not for ER. These findings support an underlying shared risk for both MDD and BD as well as ADHD and BD. Improving our understanding of the underlying genetic architecture of these phenotypes may aid in early identification and risk stratification.
Attention-deficit/hyperactivity disorder (ADHD) is a common, highly heritable neurodevelopmental disorder. Genetic loci have not yet been identified by genome-wide association studies. Rare copy number variations (CNVs), such as chromosomal deletions or duplications, have been implicated in ADHD and other neurodevelopmental disorders. To identify rare (frequency ≤1%) CNVs that increase the risk of ADHD, we performed a whole-genome CNV analysis based on 489 young ADHD patients and 1285 adult population-based controls and identified one significantly associated CNV region. In tests for a global burden of large (>500 kb) rare CNVs, we observed a nonsignificant (P=0.271) 1.126-fold enriched rate of subjects carrying at least one such CNV in the group of ADHD cases. Locus-specific tests of association were used to assess if there were more rare CNVs in cases compared with controls. Detected CNVs, which were significantly enriched in the ADHD group, were validated by quantitative (q)PCR. Findings were replicated in an independent sample of 386 young patients with ADHD and 781 young population-based healthy controls. We identified rare CNVs within the parkinson protein 2 gene (PARK2) with a significantly higher prevalence in ADHD patients than in controls (P=2.8 × 10(-4) after empirical correction for genome-wide testing). In total, the PARK2 locus (chr 6: 162 659 756-162 767 019) harboured three deletions and nine duplications in the ADHD patients and two deletions and two duplications in the controls. By qPCR analysis, we validated 11 of the 12 CNVs in ADHD patients (P=1.2 × 10(-3) after empirical correction for genome-wide testing). In the replication sample, CNVs at the PARK2 locus were found in four additional ADHD patients and one additional control (P=4.3 × 10(-2)). Our results suggest that copy number variants at the PARK2 locus contribute to the genetic susceptibility of ADHD. Mutations and CNVs in PARK2 are known to be associated with Parkinson disease.
New innovative neuropsychological tests in attention deficit hyperactivity disorder ADHD have been proposed as objective measures for diagnosis and therapy. The current study aims to investigate two different commercial continuous performance tests (CPT) in a head-to-head comparison regarding their comparability and their link with clinical parameters. The CPTs were evaluated in a clinical sample of 29 adult patients presenting in an ADHD outpatient clinic. Correlational analyses were performed between neuropsychological data, clinical rating scales, and a personality-based measure. Though inattention was found to positively correlate between the two tests (r = 0.49, p = 0.01), no association with clinical measures and inattention was found for both tests. While hyperactivity did not correlate between both tests, current ADHD symptoms were positively associated with Nesplora Aquarium’s motor activity (r = 0.52 to 0.61, p < 0.05) and the Qb-Test’s hyperactivity (r = 0.52 to 0.71, p < 0.05). Conclusively, the overall comparability of the tests was limited and correlation with clinical parameters was low. While our study shows some interesting correlation between clinical symptoms and sub-scales of these tests, usage in clinical practice is not recommended.
The quantified behavioral test - a confirmatory test in the diagnostic process of adult ADHD?
(2020)
The differential diagnosis of attention deficit hyperactivity disorder (ADHD) in adulthood is complicated by comorbid disorders, but also by the overlapping of main symptoms such as inattentiveness, impulsivity, and hyperactivity with other disorders. Neuropsychological tests like continuous performance tests (CPT) try to solve this dilemma by objectively measurable parameters. We investigated in a cohort of n=114 patients presenting to an ADHD outpatient clinic how well a commercially available CPT test (QbTest®) can differentiate between patients with ADHD (n=94) and patients with a disconfirmed ADHD diagnosis (n=20). Both groups showed numerous comorbidities, predominantly depression (27.2% in the ADHD group vs. 45% in the non-ADHD group) and substance-use disorders (18.1% vs. 10%, respectively). Patients with ADHD showed significant higher activity (2.07 ± 1.23) than patients without ADHD (1.34 ± 1.27, dF=112; p=0.019), whereas for the other core parameters, inattention and impulsivity no differences could be found. Reaction time variability has been discussed as a typical marker for inattention in ADHD. Therefore, we investigated how well ex-Gaussian analysis of response time can differentiate between ADHD and other patients, showing, that it does not help to identify patients with ADHD. Even though patients with ADHD showed significantly higher activity, this parameter differed only poorly between patients (accuracy AUC 65% of an ROC-Curve). We conclude that CPTs do not help to identify patients with ADHD in a specialized outpatient clinic. The usability of this test for differentiating between ADHD and other psychiatric disorders is poor and a sophisticated analysis of reaction time did not decisively increase the test accuracy.
ADHD is a neurodevelopmental disorder with a long trajectory into adulthood where it is often comorbid with depression, substance use disorder (SUD) or obesity. Previous studies described a dysregulated dopaminergic system, reflected by abnormal reward processing, both in ADHD as well as in depression, SUD or obesity. No study so far however tested systematically whether pathologies in the brain’s reward system explain the frequent comorbidity in adult ADHD. To test this, we acquired MRI scans from 137 participants probing the reward system by a monetary incentive delay task (MIDT) as well as assessing resting-state connectivity with ventral striatum as a seed mask. No differences were found between comorbid disorders, but a significant linear effect pointed toward less left intrastriatal connectivity in patients depending on the number of comorbidities. This points towards a neurobiologically impaired reward- and decision-making ability in patients with more comorbid disorders. This suggests that less intrastriatal connectivity parallels disorder severity but not disorder specificity, while MIDT abnormalities seem mainly to be driven by ADHD.
Background: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. Methods: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. Results: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. Conclusions: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.
Depressive symptoms in youth with ADHD: the role of impairments in cognitive emotion regulation
(2022)
Youth with attention-deficit/hyperactivity disorder (ADHD) are at increased risk to develop co-morbid depression. Identifying factors that contribute to depression risk may allow early intervention and prevention. Poor emotion regulation, which is common in adolescents, is a candidate risk factor. Impaired cognitive emotion regulation is a fundamental characteristic of depression and depression risk in the general population. However, little is known about cognitive emotion regulation in youth with ADHD and its link to depression and depression risk. Using explicit and implicit measures, this study assessed cognitive emotion regulation in youth with ADHD (N = 40) compared to demographically matched healthy controls (N = 40) and determined the association with depressive symptomatology. As explicit measure, we assessed the use of cognitive emotion regulation strategies via self-report. As implicit measure, performance in an ambiguous cue-conditioning task was assessed as indicator of affective bias in the processing of information. Compared to controls, patients reported more frequent use of maladaptive (i.e., self-blame, catastrophizing, and rumination) and less frequent use of adaptive (i.e., positive reappraisal) emotion regulation strategies. This pattern was associated with the severity of current depressive symptoms in patients. In the implicit measure of cognitive bias, there was no significant difference in response of patients and controls and no association with depression. Our findings point to depression-related alterations in the use of cognitive emotion regulation strategies in youth with ADHD. The study suggests those alterations as a candidate risk factor for ADHD-depression comorbidity that may be used for risk assessment and prevention strategies.
Attention-deficit hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder characterized by hyperactivity, impulsivity, and/or inattention, which are symptoms also observed in many rare genetic disorders. We searched for genes involved in Mendelian disorders presenting with ADHD symptoms in the Online Mendelian Inheritance in Man (OMIM) database, to curate a list of new candidate risk genes for ADHD. We explored the enrichment of functions and pathways in this gene list, and tested whether rare or common variants in these genes are associated with ADHD or with its comorbidities. We identified 139 genes, causal for 137 rare disorders, mainly related to neurodevelopmental and brain function. Most of these Mendelian disorders also present with other psychiatric traits that are often comorbid with ADHD. Using whole exome sequencing (WES) data from 668 ADHD cases, we found rare variants associated with the dimension of the severity of inattention symptoms in three genes: KIF11, WAC, and CRBN. Then, we focused on common variants and identified six genes associated with ADHD (in 19,099 cases and 34,194 controls): MANBA, UQCC2, HIVEP2, FOPX1, KANSL1, and AUH. Furthermore, HIVEP2, FOXP1, and KANSL1 were nominally associated with autism spectrum disorder (ASD) (18,382 cases and 27,969 controls), as well as HIVEP2 with anxiety (7016 cases and 14,475 controls), and FOXP1 with aggression (18,988 individuals), which is in line with the symptomatology of the rare disorders they are responsible for. In conclusion, inspecting Mendelian disorders and the genes responsible for them constitutes a valuable approach for identifying new risk genes and the mechanisms of complex disorders.
While impulsivity is a basic feature of attention-deficit / hyperactivity disorder (ADHD), no study explored the effect of different components of the Impulsiveness (Imp) and Venturesomeness (Vent) scale (IV7) on psychiatric comorbidities and an ADHD polygenic risk score (PRS). We used the IV7 self-report scale in an adult ADHD sample of 903 patients, 70% suffering from additional comorbid disorders, and in a subsample of 435 genotyped patients. Venturesomeness, unlike immediate Impulsivity, is not specific to ADHD. We consequently analyzed the influence of Imp and Vent also in the context of a PRS on psychiatric comorbidities of ADHD. Vent shows a distinctly different distribution of comorbidities, e.g., less anxiety and depression. PRS showed no effect on different ADHD comorbidities, but correlated with childhood hyperactivity. In a complementary analysis using principal component analysis with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition ADHD criteria, revised NEO Personality Inventory, Imp, Vent, and PRS, we identified three ADHD subtypes. These are an impulsive–neurotic type, an adventurous–hyperactive type with a stronger genetic component, and an anxious–inattentive type. Our study thus suggests the importance of adventurousness and the differential consideration of impulsivity in ADHD. The genetic risk is distributed differently between these subtypes, which underlines the importance of clinically motivated subtyping. Impulsivity subtyping might give insights into the organization of comorbid disorders in ADHD and different genetic background.
Purpose of Review: Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice.
Recent findings: The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genome-wideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction.
Summary: Knowledge about a patient’s genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.
Structural brain morphometry as classifier and predictor of ADHD and reward-related comorbidities
(2022)
Attention deficit/hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders, and around two-thirds of affected children report persisting problems in adulthood. This negative trajectory is associated with high comorbidity with disorders like obesity, depression, or substance use disorder (SUD). Decreases in cortical volume and thickness have also been reported in depression, SUD, and obesity, but it is unclear whether structural brain alterations represent unique disorder-specific profiles. A transdiagnostic exploration of ADHD and typical comorbid disorders could help to understand whether specific morphometric brain changes are due to ADHD or, alternatively, to the comorbid disorders. In the current study, we studied the brain morphometry of 136 subjects with ADHD with and without comorbid depression, SUD, and obesity to test whether there are unique or common brain alterations. We employed a machine-learning-algorithm trained to classify subjects with ADHD in the large ENIGMA-ADHD dataset and used it to predict the diagnostic status of subjects with ADHD and/or comorbidities. The parcellation analysis demonstrated decreased cortical thickness in medial prefrontal areas that was associated with presence of any comorbidity. However, these results did not survive correction for multiple comparisons. Similarly, the machine learning analysis indicated that the predictive algorithm grouped most of our ADHD participants as belonging to the ADHD-group, but no systematic differences between comorbidity status came up. In sum, neither a classical comparison of segmented structural brain metrics nor an ML model based on the ADHD ENIGMA data differentiate between ADHD with and without comorbidities. As the ML model is based in part on adolescent brains, this might indicate that comorbid disorders and their brain changes are not captured by the ML model because it represents a different developmental brain trajectory.
Beyond well-established difficulties with working memory in individuals with attention deficit hyperactivity disorder (ADHD), evidence is emerging that other memory processes may also be affected. We investigated, first, which memory processes show differences in adults and adolescents with ADHD in comparison to control participants, focusing on working and short-term memory, initial learning, interference, delayed and recognition memory. Second, we investigated whether ADHD severity, co-occurring depressive symptoms, IQ and physical fitness are associated with the memory performance in the individuals with ADHD.
We assessed 205 participants with ADHD (mean age 25.8 years, SD 7.99) and 50 control participants (mean age 21.1 years, SD 5.07) on cognitive tasks including the digit span forward (DSF) and backward (DSB), the Rey Auditory Verbal Learning Test (RAVLT), and the vocabulary and matrix reasoning subtests of the Wechsler Abbreviated Scale of Intelligence. Participants with ADHD were additionally assessed on ADHD severity, depression symptoms and cardiorespiratory fitness. A series of regressions were run, with sensitivity analyses performed when variables were skewed.
ADHD-control comparisons were significant for DSF, DSB, delayed and recognition memory, with people with ADHD performing less well than the control participants. The result for recognition memory was no longer significant in sensitivity analysis. Memory performance was not associated with greater ADHD or depression symptoms severity. IQ was positively associated with all memory variables except DSF. Cardiorespiratory fitness was negatively associated with the majority of RAVLT variables.
Individuals with ADHD showed difficulties with working memory, short-term memory and delayed memory, as well as a potential difficulty with recognition memory, despite preserved initial learning.
Studies have demonstrated an increased risk of accidents and injuries in children, adolescents and adults with attention-deficit/hyperactivity disorder (ADHD). However, little is known about how accident risk may alter over the lifespan. Additionally, it would be important to know if the most common types of accidents and injuries differ in ADHD patients over different age groups. Furthermore, there is increasing evidence of an ameliorating effect of ADHD medication on accident risk. Lastly, the underlying risk factors and causal mechanisms behind increased accident risk remain unclear. We therefore conducted a systematic review focusing on the above described research questions. Our results suggested that accident/injury type and overall risk changes in ADHD patients over the lifespan. ADHD medication appeared to be similarly effective at reducing accident risk in all age groups. However, studies with direct comparisons of accident/injuries and effects of medication at different age groups or in old age are still missing. Finally, comorbidities associated with ADHD such as substance abuse appear to further increase the accident/injury risk.
Exercise interventions in mental disorders have evidenced a mood-enhancing effect. However, the association between physical activity and affect in everyday life has not been investigated in adult individuals with ADHD, despite being important features of this disorder. As physical activity and affect are dynamic processes in nature, assessing those in everyday life with e-diaries and wearables, has become the gold standard. Thus, we used an mHealth approach to prospectively assess physical activity and affect processes in individuals with ADHD and controls aged 14–45 years. Participants wore accelerometers across a four-day period and reported their affect via e-diaries twelve times daily. We used multilevel models to identify the within-subject effects of physical activity on positive and negative affect. We split our sample into three groups: 1. individuals with ADHD who were predominantly inattentive (n = 48), 2. individuals with ADHD having a combined presentation (i.e., being inattentive and hyperactive; n = 95), and 3. controls (n = 42). Our analyses revealed a significant cross-level interaction (F(2, 135.072)=5.733, p = 0.004) of physical activity and group on positive affect. In details, all groups showed a positive association between physical activity and positive affect. Individuals with a combined presentation significantly showed the steepest slope of physical activity on positive affect (slope_inattentive=0.005, p<0.001; slope_combined=0.009, p<0.001; slope_controls=0.004, p = 0.008). Our analyses on negative affect revealed a negative association only in the individuals with a combined presentation (slope=-0.003; p = 0.001). Whether this specifically pronounced association in individuals being more hyperactive might be a mechanism reinforcing hyperactivity needs to be empirically clarified in future studies.
Highligths
• Immune-inflammatory alterations might appear in subjects with ADHD.
• Blood levels of tumor necrosis factor-α might be reduced in individuals with ADHD.
• Individuals with ADHD might show elevated blood levels of interleukin-6.
Abstract
It has been observed that subclinical inflammation might be involved in the pathophysiology of attention deficit/hyperactivity disorder (ADHD). However, studies investigating peripheral blood levels of immune-inflammatory markers have provided mixed findings. We performed a systematic review and meta-analysis of studies comparing unstimulated serum or plasma levels of C-reactive protein (CRP) and cytokines in subjects with ADHD and healthy controls (the PROSPERO registration number: CRD 42021276869). Online searches covered the publication period until 30th Sep 2021 and random-effects meta-analyses were carried out. Out of 1844 publication records identified, 10 studies were included. The levels of interleukin (IL)-6 were significantly higher in studies of participants up to the age of 18 years (k = 10, g = 0.70, 95%CI: 0.10–1.30, p = 0.023) and after including those above the age of 18 years (k = 10, g = 0.71, 95%CI: 0.12–1.31, p = 0.019). In turn, the levels of tumor necrosis factor-α (TNF-α) were significantly lower in subjects with ADHD compared to healthy controls (k = 7, g = −0.16, 95%CI: −0.30 - -0.03, p = 0.020). Individual studies had a high contribution to the overall effect, since the overall effect was no longer significant after removing single studies. No significant differences were found with respect to the levels of CRP, IL-1β, IL-10 and interferon-γ. The present findings indicate that individuals with ADHD tend to show elevated levels of IL-6 and reduced levels of TNF-α. Larger and longitudinal studies recording potential confounding factors and comorbid psychopathology are needed to confirm our findings.