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      ADHD: Reviewing the Causes and Evaluating Solutions

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          Abstract

          Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder in which patients present inattention, hyperactivity, and impulsivity. The etiology of this condition is diverse, including environmental factors and the presence of variants of some genes. However, a great diversity exists among patients regarding the presence of these ADHD-associated factors. Moreover, there are variations in the reported neurophysiological correlates of ADHD. ADHD is often treated pharmacologically, producing an improvement in symptomatology, albeit there are patients who are refractory to the main pharmacological treatments or present side effects to these drugs, highlighting the importance of developing other therapeutic options. Different non-pharmacological treatments are in this review addressed, finding diverse results regarding efficacy. Altogether, ADHD is associated with different etiologies, all of them producing changes in brain development, leading to the characteristic symptomatology of this condition. Given the heterogeneous etiology of ADHD, discussion is presented about the convenience of personalizing ADHD treatment, whether pharmacological or non-pharmacological, to reach an optimum effect in the majority of patients. Approaches to personalizing both pharmacological therapy and neurofeedback are presented.

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          Most cited references214

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          Discovery of the first genome-wide significant risk loci for attention deficit/hyperactivity disorder

          Attention deficit/hyperactivity disorder (ADHD) is a highly heritable childhood behavioral disorder affecting 5% of children and 2.5% of adults. Common genetic variants contribute substantially to ADHD susceptibility, but no variants have been robustly associated with ADHD. We report a genome-wide association meta-analysis of 20,183 individuals diagnosed with ADHD and 35,191 controls that identifies variants surpassing genome-wide significance in 12 independent loci, finding important new information about the underlying biology of ADHD. Associations are enriched in evolutionarily constrained genomic regions and loss-of-function intolerant genes and around brain-expressed regulatory marks. Analyses of three replication studies: a cohort of individuals diagnosed with ADHD, a self-reported ADHD sample and a meta-analysis of quantitative measures of ADHD symptoms in the population, support these findings while highlighting study-specific differences on genetic overlap with educational attainment. Strong concordance with GWAS of quantitative population measures of ADHD symptoms supports that clinical diagnosis of ADHD is an extreme expression of continuous heritable traits.
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            Molecular genetics of attention-deficit/hyperactivity disorder.

            Results of behavioral genetic and molecular genetic studies have converged to suggest that both genetic and nongenetic factors contribute to the development of attention-deficit/hyperactivity disorder (ADHD). We review this literature, with a particular emphasis on molecular genetic studies. Family, twin, and adoption studies provide compelling evidence that genes play a strong role in mediating susceptibility to ADHD. This fact is most clearly seen in the 20 extant twin studies, which estimate the heritability of ADHD to be .76. Molecular genetic studies suggest that the genetic architecture of ADHD is complex. The few genome-wide scans conducted thus far are not conclusive. In contrast, the many candidate gene studies of ADHD have produced substantial evidence implicating several genes in the etiology of the disorder. For the eight genes for which the same variant has been studied in three or more case-control or family-based studies, seven show statistically significant evidence of association with ADHD on the basis of the pooled odds ratio across studies: DRD4, DRD5, DAT, DBH, 5-HTT, HTR1B, and SNAP-25.
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              Brain Imaging of the Cortex in ADHD: A Coordinated Analysis of Large-Scale Clinical and Population-Based Samples

              Neuroimaging studies show structural alterations of various brain regions in children and adults with ADHD, although non-replications are frequent. Our aim is to identify cortical characteristics related to ADHD using large-scale studies. Cortical thickness and surface area (based on the Desikan–Killiany atlas) were compared between cases (n=2246) and controls (n=1934) for children, adolescents, and adults separately in ENIGMA-ADHD, a consortium of 36 centers. To assess familial effects on cortical measures, cases, unaffected siblings, and controls in the NeuroIMAGE study (n=506) were compared. Associations of the attention scale from the Child Behavior Checklist with cortical measures were determined in a pediatric population sample (Generation-R, n=2707). In ENIGMA-ADHD, lower surface area values were found in children with ADHD, mainly in frontal, cingulate, and temporal regions; the largest effect was for total surface area (Cohen’s d =−0.21; p FDR =<0.001). Fusiform gyrus and temporal pole cortical thickness was also lower in children with ADHD. Neither surface area nor thickness differences were found in the adolescents/adult groups. Familial effects were seen for surface area in several regions. In an overlapping set of regions, surface area, but not thickness, was associated with attention problems in Generation-R. Subtle differences in cortical surface area are widespread in children, but not in adolescents and adults with ADHD, confirming involvement of frontal cortex and highlighting regions deserving further attention. Importantly, the alterations behave like endophenotypes in families and are linked to ADHD symptoms in the population, extending evidence that ADHD behaves as a continuous trait in the population. Future longitudinal studies should clarify individual lifespan trajectories that lead to non-significant findings in adolescent/adult groups despite presence of an ADHD diagnosis.
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                Author and article information

                Contributors
                Role: Academic Editor
                Role: Academic Editor
                Journal
                J Pers Med
                J Pers Med
                jpm
                Journal of Personalized Medicine
                MDPI
                2075-4426
                01 March 2021
                March 2021
                : 11
                : 3
                : 166
                Affiliations
                [1 ]División de Ciencias de la Salud, Universidad de Quintana Roo, Chetumal 77039, Quintana Roo, Mexico; lnunez@ 123456uqroo.edu.mx
                [2 ]Laboratorio Efectos Terapéuticos de los Canabinoides, Subdirección de Investigación Biomédica, Hospital General Dr. Manuel Gea González, Calz. de Tlalpan 4800, Belisario Domínguez Secc 16, Tlalpan 14080, Ciudad de México, Mexico; draandreahs@ 123456gmail.com
                Author notes
                [* ]Correspondence: wendyhm@ 123456uqroo.edu.mx ; Tel.: +52-983-8350300 (ext. 241)
                Author information
                https://orcid.org/0000-0002-7744-078X
                https://orcid.org/0000-0001-7400-3325
                https://orcid.org/0000-0002-0274-6899
                Article
                jpm-11-00166
                10.3390/jpm11030166
                7999417
                33804365
                49222176-0003-4059-a9c8-39e2f3d38a2f
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 31 December 2020
                : 23 February 2021
                Categories
                Review

                adhd,heterogeneous etiology,pharmacological treatment,neurofeedback,qeeg informed neurofeedback,treatment personalization

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