Search

Human brain mapping 43(1), 37-55 (2022). doi:10.1002/hbm.25029 special issue: "Special Issue: The ENIGMA Consortium: the first 10 years / Issue Edited by: P.M. Thompson, N. Jahanshad, L. Schmaal, J.A. Turner, A. Winkler, S.I. Thomopoulos, G.F. Egan, P. Kochunov", Published by Wiley-Liss, New York, NY

Despite a growing literature on the complex bidirectional relationship of ADHD and substance use, reviews specifically focusing on alcohol are scarce. ADHD and AUD show a significant genetic overlap, including genes involved in gluatamatergic and catecholaminergic neurotransmission. ADHD drives risky behavior and negative experiences throughout the lifespan that subsequently enhance a genetically increased risk for Alcohol Use Disorders (AUD). Impulsive decisions and a maladaptive reward system make individuals with ADHD vulnerable for alcohol use and up to 43 % develop an AUD; in adults with AUD, ADHD occurs in about 20 %, but is vastly under-recognized and under-treated. Thus, routine screening and treatment procedures need to be implemented in AUD treatment. Long-acting stimulants or non-stimulants can be used to treat ADHD in individuals with AUD. However, it is crucial to combine medical treatment for ADHD with pharmacotherapy and psychotherapy for AUD, and other comorbid disorders. Identification of individuals at risk for AUD, especially those with ADHD and conduct disorder or oppositional defiant disorder, is a key factor to prevent negative outcomes.

Variations in SLC9A9 gene expression and protein function are associated with multiple human diseases, which range from Attention-deficit/hyperactivity disorder (ADHD) to glioblastoma multiforme. In an effort to determine the full spectrum of human disease associations with SLC9A9, we performed a systematic review of the literature. We also review SLC9A9's biochemistry, protein structure, and function, as well as its interacting partners with the goal of identifying mechanisms of disease and druggable targets. We report gaps in the literature regarding the genes function along with consistent trends in disease associations that can be used to further research into treating the respective diseases. We report that SLC9A9 has strong associations with neuropsychiatric diseases and various cancers. Interestingly, we find strong overlap in SLC9A9 disease associations and propose a novel role for SLC9A9 in neuropsychiatric comorbidity. In conclusion, SLC9A9 is a multifunctional protein that, through both its endosome regulatory function and its protein-protein interaction network, has the ability to modulate signaling axes, such as the PI3K pathway, among others.

Na+/H+ Exchanger 9 (NHE9) is an endosomal membrane protein encoded by the Solute Carrier 9A, member 9 gene (SLC9A9). SLC9A9 has been implicated in attention deficit hyperactivity disorder (ADHD), autism spectrum disorders (ASDs), epilepsy, multiple sclerosis and cancers. To better understand the function of NHE9 and the effects of disease-associated variants on protein–protein interactions, we conducted a quantitative analysis of the NHE9 interactome using co-immunoprecipitation and isobaric labeling-based quantitative mass spectrometry. We identified 100 proteins that interact with NHE9. These proteins were enriched in known functional pathways for NHE9: the endocytosis, protein ubiquitination and phagosome pathways, as well as some novel pathways including oxidative stress, mitochondrial dysfunction, mTOR signaling, cell death and RNA processing pathways. An ADHD-associated mutation (A409P) significantly altered NHE9’s interactions with a subset of proteins involved in caveolae-mediated endocytosis and MAP2K2-mediated downstream signaling. An ASD nonsense mutation in SLC9A9, R423X, produced no-detectable amount of NHE9, suggesting the overall loss of NHE9 functional networks. In addition, seven of the NHE9 interactors are products of known autism candidate genes (Simons Foundation Autism Research Initiative, SFARI Gene) and 90% of the NHE9 interactome overlap with SFARI protein interaction network PIN (p

Blood-based microarray studies comparing individuals affected with autism spectrum disorder (ASD) and typically developing individuals help characterize differences in circulating immune cell functions and offer potential biomarker signal. We sought to combine the subject-level data from previously published studies by mega-analysis to increase the statistical power. We identified studies that compared ex vivo blood or lymphocytes from ASD-affected individuals and unrelated comparison subjects using Affymetrix or Illumina array platforms. Raw microarray data and clinical meta-data were obtained from seven studies, totaling 626 affected and 447 comparison subjects. Microarray data were processed using uniform methods. Covariate-controlled mixed-effect linear models were used to identify gene transcripts and co-expression network modules that were significantly associated with diagnostic status. Permutation-based gene-set analysis was used to identify functionally related sets of genes that were over- and under-expressed among ASD samples. Our results were consistent with diminished interferon-, EGF-, PDGF-, PI3K-AKT-mTOR-, and RAS-MAPK-signaling cascades, and increased ribosomal translation and NK-cell related activity in ASD. We explored evidence for sex-differences in the ASD-related transcriptomic signature. We also demonstrated that machine-learning classifiers using blood transcriptome data perform with moderate accuracy when data are combined across studies. Comparing our results with those from blood-based studies of protein biomarkers (e.g., cytokines and trophic factors), we propose that ASD may feature decoupling between certain circulating signaling proteins (higher in ASD samples) and the transcriptional cascades which they typically elicit within circulating immune cells (lower in ASD samples). These findings provide insight into ASD-related transcriptional differences in circulating immune cells. © 2016 Wiley Periodicals, Inc.

This study tested the causal link between Attention Deficit/Hyperactivity Disorder (ADHD) and Internet addiction (IA) and investigated motivational and executive dysfunction as explanatory mechanisms in this association. A sample of 682 young adults completed self-report measures both at Time1 and Time2, six-months apart, including 54 ADHD participants diagnosed by the Conners’ Adult ADHD Rating Scale and the Continuous Performance Test. According to the performance in four cognitive tasks, ADHD participants were classified into three groups based on the dual pathway model of ADHD: executive dysfunction (ED), motivational dysfunction (MD) and combined dysfunction (CD). Participants’ severity of IA symptoms was assessed using the self-report Chen IA Scale. Results indicated that ADHD scores at Time1 predicted IA scores at Time2 but not vice versa. ADHD participants were easier to be IA than controls, while the severity of IA among the three ADHD groups changed differently. The MD and CD groups became more excessively engaged in Internet use over the course of the six-months while the ED group was unchanged. These findings identify ADHD as a potential risk factor for IA and suggest that motivational dysfunction, characterized by an excessive preference for immediate reward over delayed rewards, is a better predictor of IA than executive dysfunction.

The stimulant, methylphenidate (MPH), is commonly used to treat attention deficit hyperactivity disorder (ADHD) and has been increasingly prescribed for school age children and adolescents. Concerns regarding its long-term effects on later substance use disorders (SUDs) have been raised. Previous animal studies have produced contradictory results regarding whether early exposure to MPH increases or protects against SUD in adulthood. The goal of our study was to determine if clinically relevant doses of MPH during adolescence alter cocaine responsiveness in adulthood in a rat model of ADHD, the spontaneous hypertensive rat (SHR). We pretreated SHRs with saline or MPH (2.5 mg/kg once or twice day) via oral gavage during their dark cycle from postnatal day 35 (p35) to p44. Adult rats (p80) were assessed in an eight-session cocaine-conditioned place preference test (CPP). Four doses of cocaine were administered via intraperitoneal injection (i.p.) during the conditioning sessions: 1, 5, 10 and 20 mg/kg. Once per day MPH treatment had a small sensitizing effect on baseline general locomotor activity in a novel environment at p80 as well as a limited suppressive effect on reward-specific locomotor activity as measured by the decreased preference to enter the cocaine-paired chamber. This treatment did not have any effect on the amount of time that rats chose to spend in the cocaine-paired chamber. Twice per day MPH treatment had no effect on locomotion or drug-preference. Our results suggest that MPH treatment of ADHD rats during adolescence does not alter preference for cocaine in adulthood.

Autism spectrum disorders (ASDs) are a group of debilitating neurodevelopmental disorders thought to have genetic etiology, due to their high heritability. The endosomal system has become increasingly implicated in ASD pathophysiology. In an attempt to summarize the association between endosomal system genes and ASDs we performed a systematic review of the literature. We searched PubMed for relevant articles. Simons Foundation Autism Research Initiative (SFARI) gene database was used to exclude articles regarding genes with less than minimal evidence for association with ASDs. Our search retained 55 articles reviewed in two categories: genes that regulate and genes that are regulated by the endosomal system. Our review shows that the endosomal system is a novel pathway implicated in ASDs as well as other neuropsychiatric disorders. It plays a central role in aspects of cellular physiology on which neurons and glial cells are particularly reliant, due to their unique metabolic and functional demands. The system shows potential for biomarkers and pharmacological intervention and thus more research into this pathway is warranted.

Attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) commonly co-occur. With the DSM-5, clinicians are permitted to make an ASD diagnosis in the context of ADHD. In earlier versions of the DSM, this was not acceptable. Both ASD and ADHD are reported to have had substantial increases in prevalence within the past 10 years. As a function of both the increased prevalence of both disorders as well as the ability to make an ASD diagnosis in ADHD, there has been a significant amount of research focusing on the comorbidity between ADHD and ASD in the past few years. Here, we provide an update on the biological, cognitive and behavioral overlap/distinctiveness between the two neurodevelopmental disorders with a focus on data published in the last four years. Treatment strategies for the comorbid condition as well as future areas of research and clinical need are discussed.

This review covers an introduction of traditional Chinese medicine (TCM) in treating attention-deficit/hyperactivity disorder (ADHD), focusing on the traditional theoretic basis from the perspective of TCM regarding ADHD's cause, pathogenesis, methods of syndrome differentiation, and rationale for treatment. The authors present commonly accepted and successfully practiced clinical procedures used in China for diagnosis and treatment of ADHD by TCM clinicians along with the supportive clinical evidence. The authors hope to inspire more research to better understand the mechanisms underlying the therapies and to promote appropriate incorporation of TCM therapies with Western pharmacologic treatment to better help patients with ADHD.

Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders which begin in childhood and persist into adulthood. They cause lifelong impairments and are associated with substantial burdens to patients, families, and society. Genetic studies have implicated the sodium/proton exchanger (NHE) nine gene, Slc9a9, to ASDs and attention-deficit/hyperactivity disorder(ADHD). Slc9a9 encodes, NHE9, a membrane protein of the late recycling endosomes. The recycling endosome plays an important role in synapse development and plasticity by regulating the trafficking of membrane neurotransmitter receptors and transporters. Here we tested the hypothesis that Slc9a9 knock-out (KO) mice would show ADHD-like and ASD-like traits. Ultrasonic vocalization (USV) recording showed that Slc9a9 KO mice emitted fewer calls and had shorter call durations, which suggest communication impairment. Slc9a9 KO mice lacked a preference for social novelty, but did not show deficits in social approach; Slc9a9 KO mice spent more time self-grooming, an indicator for restricted and repetitive behavior. We did not observe hyperactivity or other behavior impairments which are commonly comorbid with ASDs in human, such as anxiety-like behavior. Our study is the first animal behavior study that links Slc9a9 to ASDs. By eliminatingNHE9 activity, it provides strong evidence that lack of Slc9a9leads to ASD-like behaviors in mice and provides the field with a new mouse model of ASDs.

Objective: To clarify the role of oxidative stress and antioxidant activity in ADHD. Method: We examined the association of ADHD and oxidative stress by applying random effects meta-analysis to studies of oxidative stress and antioxidant status in medication naive patients with ADHD and controls. Results: Six studies of a total of 231 ADHD patients and 207 controls met our selection criteria. The association between ADHD and antioxidant status was not significant. We found a significant association between ADHD and oxidative stress that could not be accounted for by publication bias. The significant association lost significance after correcting for intrastudy clustering. No one observation accounted for the positive result. Conclusion: These results are preliminary given the small number of studies. They suggest that patients with ADHD have normal levels of antioxidant production, but that their response to oxidative stress is insufficient, leading to oxidative damage.

ADHD and autism spectrum disorder are common psychiatric comorbidities to each another. In addition, there is behavioral, biological and neuropsychological overlap between the two disorders. There are also several important differences between autism spectrum disorder and ADHD. Treatment strategies for the comorbid condition will also be reviewed. Future areas of research and clinical need will be discussed.

Medications for attention deficit hyperactivity disorder (ADHD) are only partially effective. Ideally, new treatment targets would derive from a known pathophysiology. Such data are not available for ADHD. We combine evidence for new etiologic pathways with bioinformatics data to assess the possibility that existing drugs might be repositioning for treating ADHD. We use this approach to determine if prior data implicating the sodium/hydrogen exchanger 9 gene (SLC9A9) in ADHD implicate sodium/hydrogen exchange (NHE) inhibitors as potential treatments. We assessed the potential for repositioning by assessing the similarity of drug-protein binding profiles between NHE inhibitors and drugs known to treat ADHD using the Drug Repositioning and Adverse Reaction via Chemical-Protein Interactome server. NHE9 shows a high degree of amino acid similarity between NHE inhibitor sensitive NHEs in the region of the NHE inhibitor recognition site defined for NHE1. We found high correlations in drug-protein binding profiles among most ADHD drugs. The drug-protein binding profiles of some NHE inhibitors were highly correlated with ADHD drugs whereas the profiles for a control set of nonsteroidal anti-inflammatory drugs (NSAIDs) were not. Further experimental work should evaluate if NHE inhibitors are suitable for treating ADHD.

SLC9A9 (solute carrier family 9, member 9, also known as Na+/H+ exchanger member (NHE9)) is a membrane protein that regulates the luminal pH of the recycling endosome, an essential organelle for synaptic transmission and plasticity. SLC9A9 has been implicated in human attention deficit hyperactivity disorder (ADHD) and in rat studies of hyperactivity. We examined the SLC9A9 gene sequence and expression profile in prefrontal cortex, dorsal striatum and hippocampus in two genetic rat models of ADHD. We report two mutations in a rat model of inattentive ADHD, the WKY/NCrl rat, which affect the interaction of SLC9A9 with calcineurin homologous protein (CHP). We observed an age-dependent abnormal expression of SLC9A9 in brains of this inattentive model and in the Spontaneous Hypertensive Rat (SHR) model of ADHD. Our data suggest a novel mechanism whereby SLC9A9 sequence variants and abnormalities in gene expression could contribute to the ADHD-like symptoms of rat models and possibly the pathophysiology of ADHD in humans.

Background According to DSM-IV there are three subtypes of Attention-Deficit/Hyperactivity Disorder, namely: ADHD predominantly inattentive type (ADHD-PI), ADHD predominantly Hyperactive-Impulsive Type (ADHD-HI), and ADHD combined type (ADHD-C). These subtypes may represent distinct neurobehavioral disorders of childhood onset with separate etiologies. The diagnosis of ADHD is behaviorally based; therefore, investigations into its possible etiologies should be based in behavior. Animal models of ADHD demonstrate construct validity when they accurately reproduce elements of the etiology, biochemistry, symptoms, and treatment of the disorder. Spontaneously hypertensive rats (SHR) fulfill many of the validation criteria and compare well with clinical cases of ADHD-C. The present study describes a novel rat model of the predominantly inattentive subtype (ADHD-PI). Methods ADHD-like behavior was tested with a visual discrimination task measuring overactivity, impulsiveness and inattentiveness. Several strains with varied genetic background were needed to determine what constitutes a normal comparison. Five groups of rats were used: SHR/NCrl spontaneously hypertensive and WKY/NCrl Wistar/Kyoto rats from Charles River; SD/NTac Sprague Dawley and WH/HanTac Wistar rats from Taconic Europe; and WKY/NHsd Wistar/Kyoto rats from Harlan. DNA was analyzed to determine background differences in the strains by PCR genotyping of eight highly polymorphic microsatellite markers and 2625 single nucleotide polymorphisms (SNPs). Results Compared to appropriate comparison strains (WKY/NHsd and SD/NTac rats), SHR/NCrl showed ADHD-C-like behavior: striking overactivity and poor sustained attention. Compared to WKY/NHsd rats, WKY/NCrl rats showed inattention, but no overactivity or impulsiveness. WH/HanTac rats deviated significantly from the other control groups by being more active and less attentive than the WKY/NHsd and SD/NTac rats. We also found substantial genomic differences between the WKY/NCrl and WKY/NHsd rats for eight short tandem repeat loci and 2625 SNPs. About 33.5 percent of the genome differs between the two WKY rat substrains, with large stretches of divergence on each chromosome. Discussion These data provide solid behavioral and genetic evidence that the WKY/NCrl and WKY/NHsd rats should be considered as separate substrains. Moreover, the behavioral features of the WKY/NCrl rat indicate that it should be a useful model for ADHD-PI, the primarily inattentive subtype of ADHD. The SD/NTac and the WH/HanTac rats show significant genetic and/or behavioral differences from WKY/NHsd rats and appear not to be appropriate controls in studies using the SHR/NCrl. The present results support the conclusion that SHR/NCrl is the best validated animal model of ADHD-C. The overactivity, impulsiveness and deficient sustained attention of the SHR/NCrl strain are independent behaviors. Thus, overactivity does not account for this strain's impulsiveness and deficient sustained attention. Finally, the present study shows that great care has to be exercised to select the model and comparison groups.