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The 14-3-3 protein family are molecular chaperones involved in several biological functions and neurological diseases. We previously pinpointed YWHAZ (encoding 14-3-3ζ) as a candidate gene for autism spectrum disorder (ASD) through a whole-exome sequencing study, which identified a frameshift variant within the gene (c.659-660insT, p.L220Ffs*18). Here, we explored the contribution of the seven human 14-3-3 family members in ASD and other psychiatric disorders by investigating the: (i) functional impact of the 14-3-3ζ mutation p.L220Ffs*18 by assessing solubility, target binding and dimerization; (ii) contribution of common risk variants in 14-3-3 genes to ASD and additional psychiatric disorders; (iii) burden of rare variants in ASD and schizophrenia; and iv) 14-3-3 gene expression using ASD and schizophrenia transcriptomic data. We found that the mutant 14-3-3ζ protein had decreased solubility and lost its ability to form heterodimers and bind to its target tyrosine hydroxylase. Gene-based analyses using publicly available datasets revealed that common variants in YWHAE contribute to schizophrenia (p = 6.6 × 10−7), whereas ultra-rare variants were found enriched in ASD across the 14-3-3 genes (p = 0.017) and in schizophrenia for YWHAZ (meta-p = 0.017). Furthermore, expression of 14-3-3 genes was altered in post-mortem brains of ASD and schizophrenia patients. Our study supports a role for the 14-3-3 family in ASD and schizophrenia.
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.
Background: The risk for major depression and obesity is increased in adolescents and adults with attention-deficit / hyperactivity disorder (ADHD) and adolescent ADHD predicts adult depression and obesity. Non-pharmacological interventions to treat and prevent these co-morbidities are urgently needed. Bright light therapy (BLT) improves day–night rhythm and is an emerging therapy for major depression. Exercise intervention (EI) reduces obesity and improves depressive symptoms. To date, no randomized controlled trial (RCT) has been performed to establish feasibility and efficacy of these interventions targeting the prevention of co-morbid depression and obesity in ADHD. We hypothesize that the two manualized interventions in combination with mobile health-based monitoring and reinforcement will result in less depressive symptoms and obesity compared to treatment as usual in adolescents and young adults with ADHD.
Methods: This trial is a prospective, pilot phase-IIa, parallel-group RCT with three arms (two add-on treatment groups [BLT, EI] and one treatment as usual [TAU] control group). The primary outcome variable is change in the Inventory of Depressive Symptomatology total score (observer-blinded assessment) between baseline and ten weeks of intervention. This variable is analyzed with a mixed model for repeated measures approach investigating the treatment effect with respect to all three groups. A total of 330 participants with ADHD, aged 14 – < 30 years, will be screened at the four study centers. To establish effect sizes, the sample size was planned at the liberal significance level of α = 0.10 (two-sided) and the power of 1-β = 80% in order to find medium effects. Secondary outcomes measures including change in obesity, ADHD symptoms, general psychopathology, health-related quality of life, neurocognitive function, chronotype, and physical fitness are explored after the end of the intervention and at the 12-week follow-up.
Discussion: This is the first pilot RCT on the use of BLT and EI in combination with mobile health-based monitoring and reinforcement targeting the prevention of co-morbid depression and obesity in adolescents and young adults with ADHD. If at least medium effects can be established with regard to the prevention of depressive symptoms and obesity, a larger scale confirmatory phase-III trial may be warranted.
Trial registration: German Clinical Trials Register, DRKS00011666. Registered on 9 February 2017. ClinicalTrials.gov, NCT03371810. Registered on 13 December 2017.
Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium
(2017)
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.
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.
Attention-deficit/hyperactivity disorder (ADHD) is highly heritable and the most common neurodevelopmental disorder in childhood. In recent decades, it has been appreciated that in a substantial number of cases the disorder does not remit in puberty, but persists into adulthood. Both in childhood and adulthood, ADHD is characterised by substantial comorbidity including substance use, depression, anxiety, and accidents. However, course and symptoms of the disorder and the comorbidities may fluctuate and change over time, and even age of onset in childhood has recently been questioned. Available evidence to date is poor and largely inconsistent with regard to the predictors of persistence versus remittance. Likewise, the development of comorbid disorders cannot be foreseen early on, hampering preventive measures. These facts call for a lifespan perspective on ADHD from childhood to old age. In this selective review, we summarise current knowledge of the long-term course of ADHD, with an emphasis on clinical symptom and cognitive trajectories, treatment effects over the lifespan, and the development of comorbidities. Also, we summarise current knowledge and important unresolved issues on biological factors underlying different ADHD trajectories. We conclude that a severe lack of knowledge on lifespan aspects in ADHD still exists for nearly every aspect reviewed. We encourage large-scale research efforts to overcome those knowledge gaps through appropriately granular longitudinal studies.
Background: Autism spectrum disorder (“autism”) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, but its potential as a neural stratification marker has not been widely examined. Methods: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS (European Autism Interventions—A Multicentre Study for Developing New Medications) Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical control subjects as well as a replication dataset from ABIDE (Autism Brain Imaging Data Exchange) (513 individuals with autism, 691 neurotypical subjects) using a promising approach that moves beyond mean group comparisons. We derived gray matter voxelwise laterality values for each subject and modeled individual deviations from the normative pattern of brain laterality across age using normative modeling. Results: Individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language, motor, and visuospatial regions, associated with symptom severity. Language delay explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged, with individuals with autism with language delay showing more pronounced rightward deviations than individuals with autism without language delay. Conclusions: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism and indicate that atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.
Background: Autism Spectrum Disorder (henceforth ‘autism’) is a highly heterogeneous neurodevelopmental condition with few effective treatments for core and associated features. To make progress we need to both identify and validate neural markers that help to parse heterogeneity to tailor therapies to specific neurobiological profiles. Atypical hemispheric lateralization is a stable feature across studies in autism, however its potential of lateralization as a neural stratification marker has not been widely examined.
Methods: In order to dissect heterogeneity in lateralization in autism, we used the large EU-AIMS Longitudinal European Autism Project dataset comprising 352 individuals with autism and 233 neurotypical (NT) controls as well as a replication dataset from ABIDE (513 autism, 691 NT) using a promising approach that moves beyond mean-group comparisons. We derived grey matter voxelwise laterality values for each subject and modelled individual deviations from the normative pattern of brain laterality across age using normative modeling.
Results: Results showed that individuals with autism had highly individualized patterns of both extreme right- and leftward deviations, particularly in language-, motor- and visuospatial regions, associated with symptom severity. Language delay (LD) explained most variance in extreme rightward patterns, whereas core autism symptom severity explained most variance in extreme leftward patterns. Follow-up analyses showed that a stepwise pattern emerged with individuals with autism with LD showing more pronounced rightward deviations than autism individuals without LD.
Conclusion: Our analyses corroborate the need for novel (dimensional) approaches to delineate the heterogeneous neuroanatomy in autism, and indicate atypical lateralization may constitute a neurophenotype for clinically meaningful stratification in autism.
Background: Marked sex differences in autism prevalence accentuate the need to understand the role of biological sex-related factors in autism. Efforts to unravel sex differences in the brain organization of autism have, however, been challenged by the limited availability of female data.
Methods: We addressed this gap by using a large sample of males and females with autism and neurotypical (NT) control individuals (ABIDE; Autism: 362 males, 82 females; NT: 409 males, 166 females; 7-18 years). Discovery analyses examined main effects of diagnosis, sex and their interaction across five resting-state fMRI (R-fMRI) metrics (voxel-level Z > 3.1, cluster-level P < 0.01, gaussian random field corrected). Secondary analyses assessed the robustness of the results to different pre-processing approaches and their replicability in two independent samples: the EU-AIMS Longitudinal European Autism Project (LEAP) and the Gender Explorations of Neurogenetics and Development to Advance Autism Research (GENDAAR).
Results: Discovery analyses in ABIDE revealed significant main effects across the intrinsic functional connectivity (iFC) of the posterior cingulate cortex, regional homogeneity and voxel-mirrored homotopic connectivity (VMHC) in several cortical regions, largely converging in the default network midline. Sex-by-diagnosis interactions were confined to the dorsolateral occipital cortex, with reduced VMHC in females with autism. All findings were robust to different pre-processing steps. Replicability in independent samples varied by R-fMRI measures and effects with the targeted sex-by-diagnosis interaction being replicated in the larger of the two replication samples – EU-AIMS LEAP.
Limitations: Given the lack of a priori harmonization among the discovery and replication datasets available to date, sample-related variation remained and may have affected replicability.
Conclusions: Atypical cross-hemispheric interactions are neurobiologically relevant to autism. They likely result from the combination of sex-dependent and sex-independent factors with a differential effect across functional cortical networks. Systematic assessments of the factors contributing to replicability are needed and necessitate coordinated large-scale data collection across studies.
Competing Interest Statement: ADM receives royalties from the publication of the Italian version of the Social Responsiveness Scale Child Version by Organization Speciali, Italy. JKB has been a consultant to, advisory board member of, and a speaker for Takeda/Shire, Medice, Roche, and Servier. He is not an employee of any of these companies and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, or royalties. CFB is director and shareholder in SBGneuro Ltd. TC has received consultancy from Roche and Servier and received book royalties from Guildford Press and Sage. DM has been a consultant to, and advisory board member, for Roche and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. TB served in an advisory or consultancy role for Lundbeck, Medice, Neurim Pharmaceuticals, Oberberg GmbH, Shire, and Infectopharm. He received conference support or speakers fee by Lilly, Medice, and Shire. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press; the present work is unrelated to these relationships. JT is a consultant to Roche. The remaining authors declare no competing interests.