Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.

Aggression and deficient cognitive control problems are widespread in psychiatric disorders, including major depressive disorder (MDD). These abnormalities are known to contribute significantly to the accompanying functional impairment and the global burden of disease. Progress in the development of targeted treatments of excessive aggression and accompanying symptoms has been limited, and there exists a major unmet need to develop more efficacious treatments for depressed patients. Due to the complex nature and the clinical heterogeneity of MDD and the lack of precise knowledge regarding its pathophysiology, effective management is challenging. Nonetheless, the aetiology and pathophysiology of MDD has been the subject of extensive research and there is a vast body of the latest literature that points to new mechanisms for this disorder. Here, we overview the key mechanisms, which include neuroinflammation, oxidative stress, insulin receptor signalling and abnormal myelination. We discuss the hypotheses that have been proposed to unify these processes, as many of these pathways are integrated for the neurobiology of MDD. We also describe the current translational approaches in modelling depression, including the recent advances in stress models of MDD, and emerging novel therapies, including novel approaches to management of excessive aggression, such as anti-diabetic drugs, antioxidant treatment and herbal compositions.

We usually look at an object when we are going to manipulate it. Thus, eye tracking can be used to communicate intended actions. An effective human-machine interface, however, should be able to differentiate intentional and spontaneous eye movements. We report an electroencephalogram (EEG) marker that differentiates gaze fixations used for control from spontaneous fixations involved in visual exploration. Eight healthy participants played a game with their eye movements only. Their gaze-synchronized EEG data (fixation-related potentials, FRPs) were collected during game’s control-on and control-off conditions. A slow negative wave with a maximum in the parietooccipital region was present in each participant’s averaged FRPs in the control-on conditions and was absent or had much lower amplitude in the control-off condition. This wave was similar but not identical to stimulus-preceding negativity, a slow negative wave that can be observed during feedback expectation. Classification of intentional vs. spontaneous fixations was based on amplitude features from 13 EEG channels using 300 ms length segments free from electrooculogram contamination (200..500 ms relative to the fixation onset). For the first fixations in the fixation triplets required to make moves in the game, classified against control-off data, a committee of greedy classifiers provided 0.90 ± 0.07 specificity and 0.38 ± 0.14 sensitivity. Similar (slightly lower) results were obtained for the shrinkage LDA classifier. The second and third fixations in the triplets were classified at lower rate. We expect that, with improved feature sets and classifiers, a hybrid dwell-based Eye-Brain-Computer Interface (EBCI) can be built using the FRP difference between the intended and spontaneous fixations. If this direction of BCI development will be successful, such a multimodal interface may improve the fluency of interaction and can possibly become the basis for a new input device for paralyzed and healthy users, the EBCI “Wish Mouse”.

The role of altered brain mitochondrial regulation in psychiatric pathologies, including Major Depressive Disorder (MDD), has attracted increasing attention. Aberrant mitochondrial functions were suggested to underlie distinct inter-individual vulnerability to stress-related MDD syndrome. In this context, insulin receptor sensitizers (IRSs) that regulate brain metabolism have become a focus of recent research, as their use in pre-clinical studies can help to elucidate the role of mitochondrial dynamics in this disorder and contribute to the development of new antidepressant treatment. Here, following 2-week chronic mild stress (CMS) using predation, social defeat, and restraint, MDD-related behaviour and brain molecular markers have been investigated along with the hippocampus-dependent performance and emotionality in mice that received the IRS dicholine succinate (DS). In a sucrose test, mice were studied for the key feature of MDD, a decreased sensitivity to reward, called anhedonia. Based on this test, animals were assigned to anhedonic and resilient-to-stress-induced-anhedonia groups, using a previously established criterion of a decrease in sucrose preference below 65%. Such assignment was based on the fact that none of control, non-stressed animals displayed sucrose preference that would be smaller than this value. DS-treated stressed mice displayed ameliorated behaviours in a battery of assays: sucrose preference, coat state, the Y-maze, the marble test, tail suspension, and nest building. CMS-vulnerable mice exhibited overexpression of the inflammatory markers Il-1β, tnf, and Cox-1, as well as 5-htt and 5-ht2a-R, in various brain regions. The alterations in hippocampal gene expression were the closest to clinical findings and were studied further. DS-treated, stressed mice showed normalised hippocampal expression of the plasticity markers Camk4, Camk2, Pka, Adcy1, Creb-ar, Nmda-2r-ar, and Nmda-2r-s. DS-treated and non-treated stressed mice who were resilient or vulnerable to anhedonia were compared for hippocampal mitochondrial pathway regulation using Illumina profiling. Resilient mice revealed overexpression of the mitochondrial complexes NADH dehydrogenase, succinate dehydrogenase, cytochrome bc1, cytochrome c oxidase, F-type and V-type ATPases, and inorganic pyrophosphatase, which were decreased in anhedonic mice. DS partially normalised the expression of both ATPases. We conclude that hippocampal reduction in ATP synthesis is associated with anhedonia and pro-inflammatory brain changes that are ameliorated by DS.

Gangliosides are glycosphingolipids, which are abundant in brain, are known to modulate ion channels and cell-to-cell communication. Deficiencies can result in aberrant myelination and altered immune responses, which can give rise to neurodevelopmental psychiatric disorders. However, to date, little mechanistic data is available on how ganglioside deficiencies contribute to the behavioural disorders. In humans, the loss of lactosylceramide-alpha-2,3-sialyltransferase (ST3Gal5) leads to a severe neuropathology, but in ST3Gal5 knock-out (St3gal5−/−) mice the absence of GM3 and associated a-, b- and c-series gangliosides is partially compensated by 0-series gangliosides and there is no overt behavioural phenotype. Here, we sought to examine the behavioural and molecular consequences of GM3 loss more closely. Mutants of both sexes exhibited impaired conditioned taste aversion in an inhibitory learning task and anxiety-like behaviours in the open field, moderate motor deficits, abnormal social interactions, excessive grooming and rearing behaviours. Taken together, the aberrant behaviours are suggestive of an autism spectrum disorder (ASD)-like syndrome. Molecular analysis showed decreased gene and protein expression of proteolipid protein-1 (Plp1) and over expression of proinflammatory cytokines, which has been associated with ASD-like syndromes. The inflammatory and behavioural responses to lipopolysaccharide (LPS) were also altered in the St3gal5−/− mice compared to wild-type, which is indicative of the importance of GM3 gangliosides in regulating immune responses. Together, the St3gal5−/− mice display ASD-like behavioural features, altered response to systemic inflammation, signs of hypomyelination and neuroinflammation, which suggests that deficiency in a- and b-series gangliosides could contribute to the development of an ASD-like pathology in humans.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N_total = 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.