The present paper presents a fundamentally novel approach to model individual differences of persons with the same biologically heterogeneous mental disorder. Unlike prevalent case-control analyses, ...that assume a clear distinction between patient and control groups and thereby introducing the concept of an 'average patient', we describe each patient's biology individually, gaining insights into the different facets that characterize persistent attention-deficit/hyperactivity disorder (ADHD).
Using a normative modeling approach, we mapped inter-individual differences in reference to normative structural brain changes across the lifespan to examine the degree to which case-control analyses disguise differences between individuals.
At the level of the individual, deviations from the normative model were frequent in persistent ADHD. However, the overlap of more than 2% between participants with ADHD was only observed in few brain loci. On average, participants with ADHD showed significantly reduced gray matter in the cerebellum and hippocampus compared to healthy individuals. While the case-control differences were in line with the literature on ADHD, individuals with ADHD only marginally reflected these group differences.
Case-control comparisons, disguise inter-individual differences in brain biology in individuals with persistent ADHD. The present results show that the 'average ADHD patient' has limited informative value, providing the first evidence for the necessity to explore different biological facets of ADHD at the level of the individual and practical means to achieve this end.
Serotonin and dopamine are speculated to subserve motivationally opponent functions, but this hypothesis has not been directly tested. We studied the role of these neurotransmitters in probabilistic ...reversal learning in nearly 700 individuals as a function of two polymorphisms in the genes encoding the serotonin and dopamine transporters (SERT: 5HTTLPR plus rs25531; DAT1 3′UTR VNTR). A double dissociation was observed. The SERT polymorphism altered behavioral adaptation after losses, with increased lose-shift associated with L′ homozygosity, while leaving unaffected perseveration after reversal. In contrast, the DAT1 genotype affected the influence of prior choices on perseveration, while leaving lose-shifting unaltered. A model of reinforcement learning captured the dose-dependent effect of DAT1 genotype, such that an increasing number of 9R-alleles resulted in a stronger reliance on previous experience and therefore reluctance to update learned associations. These data provide direct evidence for doubly dissociable effects of serotonin and dopamine systems.
•Double dissociation of effects of SERT and DAT polymorphisms on reversal learning•Serotonin transporter genotype affects lose-shifting, but not perseveration•Dopamine transporter genotype affects perseveration but not lose-shifting•DAT genotype effect on perseveration depends on individual choice history
In a large-scale behavioral genetics study, den Ouden et al. reveal a functional double dissociation of serotonin and dopamine in reversal learning. They show that the variation in serotonin transporter gene alters short-term lose-shifting, whereas the variation in dopamine transporter gene alters long-term experience-based perseveration.
•We present a systematic review of brain imaging genetics studies in ADHD.•We found imaging genetics studies for 13 ADHD candidate genes, mostly DAT1 and DRD4.•First promising results are described, ...however comparability of studies was limited.•Brain imaging genetics can help to map pathways from gene to disease.•We discuss complementary approaches, e.g. integrating findings across levels of organismal complexity and using bioinformatic, cell and animal models.
Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.
Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Decades of research have suggested that brain asymmetry may be altered in psychiatric ...disorders. However, findings have been inconsistent and often based on small sample sizes. There are also open questions surrounding which structures are asymmetrical on average in the healthy population, and how variability in brain asymmetry relates to basic biological variables such as age and sex. Over the last 4 years, the ENIGMA‐Laterality Working Group has published six studies of gray matter morphological asymmetry based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. A population‐level mapping of average asymmetry was achieved, including an intriguing fronto‐occipital gradient of cortical thickness asymmetry in healthy brains. ENIGMA's multi‐dataset approach also supported an empirical illustration of reproducibility of hemispheric differences across datasets. Effect sizes were estimated for gray matter asymmetry based on large, international, samples in relation to age, sex, handedness, and brain volume, as well as for three psychiatric disorders: autism spectrum disorder was associated with subtly reduced asymmetry of cortical thickness at regions spread widely over the cortex; pediatric obsessive–compulsive disorder was associated with altered subcortical asymmetry; major depressive disorder was not significantly associated with changes of asymmetry. Ongoing studies are examining brain asymmetry in other disorders. Moreover, a groundwork has been laid for possibly identifying shared genetic contributions to brain asymmetry and disorders.
Left–right asymmetry of the human brain is one of its cardinal features, and also a complex, multivariate trait. Over the last four years, the ENIGMA‐Laterality Working Group has published six studies of grey matter morphological asymmetry in health and disease, based on total sample sizes from roughly 3,500 to 17,000 individuals, which were between one and two orders of magnitude larger than those published in previous decades. Here we review the findings from these six studies.
Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disorder and may persist into adulthood. Working memory and attention deficits have been reported to persist from ...childhood to adulthood. How neuronal underpinnings of deficits differ across adolescence and adulthood is not clear. In this study, we investigated gray matter of two cohorts, 486 adults and 508 adolescents, each including participants from ADHD and healthy controls families. Two cohorts both presented significant attention and working memory deficits in individuals with ADHD. Independent component analysis was applied to the gray matter of each cohort, separately, to extract cohort-inherent networks. Then, we identified gray matter networks associated with inattention or working memory in each cohort, and projected them onto the other cohort for comparison. Two components in the inferior, middle/superior frontal regions identified in adults and one component in the insula and inferior frontal region identified in adolescents were significantly associated with working memory in both cohorts. One component in bilateral cerebellar tonsil and culmen identified in adults and one component in left cerebellar region identified in adolescents were significantly associated with inattention in both cohorts. All these components presented a significant or nominal level of gray matter reduction for ADHD participants in adolescents, but only one showed nominal reduction in adults. Our findings suggest although the gray matter reduction of these regions may not be indicative of persistency of ADHD, their persistent associations with inattention or working memory indicate an important role of these regions in the mechanism of persistence or remission of the disorder.
Numerous brain disorders demonstrate structural brain abnormalities, which are thought to arise from molecular perturbations or connectome miswiring. The unique and shared contributions of these ...molecular and connectomic vulnerabilities to brain disorders remain unknown, and has yet to be studied in a single multi-disorder framework. Using MRI morphometry from the ENIGMA consortium, we construct maps of cortical abnormalities for thirteen neurodevelopmental, neurological, and psychiatric disorders from N = 21,000 participants and N = 26,000 controls, collected using a harmonised processing protocol. We systematically compare cortical maps to multiple micro-architectural measures, including gene expression, neurotransmitter density, metabolism, and myelination (molecular vulnerability), as well as global connectomic measures including number of connections, centrality, and connection diversity (connectomic vulnerability). We find a relationship between molecular vulnerability and white-matter architecture that drives cortical disorder profiles. Local attributes, particularly neurotransmitter receptor profiles, constitute the best predictors of both disorder-specific cortical morphology and cross-disorder similarity. Finally, we find that cross-disorder abnormalities are consistently subtended by a small subset of network epicentres in bilateral sensory-motor, inferior temporal lobe, precuneus, and superior parietal cortex. Collectively, our results highlight how local molecular attributes and global connectivity jointly shape cross-disorder cortical abnormalities.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, of-ten persistent into adulthood and accompanied by reactive aggression. Associations of diet and the ...gut-microbiome with ADHD as well as emotional behaviors suggest potential clinical rele-vance of both. However, studies on diet and the gut-microbiome in human reactive aggression are lacking, and should investigate the interaction between diet and the gut-microbiome leading to behavioral changes to assess their potential clinical relevance. In this study, we investigated the interaction of diet and gut-microbiota with adult ADHD and reactive aggression in 77 adults with ADHD and 76 neurotypical individuals. We studied the relationships of ADHD and reactive ag-gression with dietary patterns, bacterial community and taxonomic differences of 16S-sequenced fecal microbiome samples, and potential mediating effects of bacterial genus abundance on signifi-cant diet-behavior associations. The key findings include: (1) An association of high-energy intake with reactive aggeression scores (pFDR = 4.01 × 10−02); (2) Significant associations of several genera with either reactive aggression or ADHD diagnosis with no overlap; and (3) No significant mediation effects of the selected genera on the association of reactive aggression with the high-energy diet. Our results suggest that diet and the microbiome are linked to reactive aggression and/or ADHD individually, and highlight the need to further study the way diet and the gut-microbiome inter-act.
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