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      Intra-Individual Response Variability Assessed by Ex-Gaussian Analysis may be a New Endophenotype for Attention-Deficit/Hyperactivity Disorder

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          Abstract

          Intra-individual variability of response times (RTisv) is considered as potential endophenotype for attentional deficit/hyperactivity disorder (ADHD). Traditional methods for estimating RTisv lose information regarding response times (RTs) distribution along the task, with eventual effects on statistical power. Ex-Gaussian analysis captures the dynamic nature of RTisv, estimating normal and exponential components for RT distribution, with specific phenomenological correlates. Here, we applied ex-Gaussian analysis to explore whether intra-individual variability of RTs agrees with criteria proposed by Gottesman and Gould for endophenotypes. Specifically, we evaluated if normal and/or exponential components of RTs may (a) present the stair-like distribution expected for endophenotypes (ADHD > siblings > typically developing children (TD) without familiar history of ADHD) and (b) represent a phenotypic correlate for previously described genetic risk variants. This is a pilot study including 55 subjects (20 ADHD-discordant sibling-pairs and 15 TD children), all aged between 8 and 13 years. Participants resolved a visual Go/Nogo with 10% Nogo probability. Ex-Gaussian distributions were fitted to individual RT data and compared among the three samples. In order to test whether intra-individual variability may represent a correlate for previously described genetic risk variants, VNTRs at DRD4 and SLC6A3 were identified in all sibling-pairs following standard protocols. Groups were compared adjusting independent general linear models for the exponential and normal components from the ex-Gaussian analysis. Identified trends were confirmed by the non-parametric Jonckheere–Terpstra test. Stair-like distributions were observed for μ ( p = 0.036) and σ ( p = 0.009). An additional “DRD4-genotype” × “clinical status” interaction was present for τ ( p = 0.014) reflecting a possible severity factor. Thus, normal and exponential RTisv components are suitable as ADHD endophenotypes.

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          Most cited references37

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          Neuroscience of attention-deficit/hyperactivity disorder: the search for endophenotypes.

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            GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia.

            Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.
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              Mean response times, variability, and skew in the responding of ADHD children: a response time distributional approach.

              Response time (RT) distributions from three fixed foreperiod conditions (2, 4, and 8 s) in a warned four-choice RT task were obtained for a group of boys with attention-deficit/hyperactivity disorder, combined type (ADHD; n = 17) and for two groups of normal control boys (age-matched, n = 18, and younger-aged, n = 10). Quantitative measures of distributional shape were derived by fitting the ex-Gaussian distributional model to the individual RT data. Statistical results indicate that the ADHD distributions differ from the age-matched control distributions with respect to the size of the tail (larger for the ADHD boys), but differ from the younger control distributions with respect to the location of the leading edge (slower for the younger control boys). Receiver operating characteristic (ROC) results reveal that the ex-Gaussian exponential component is highly diagnostic of the ADHD boys.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/76069
                URI : http://frontiersin.org/people/u/43464
                URI : http://frontiersin.org/people/u/173592
                URI : http://frontiersin.org/people/u/105828
                URI : http://frontiersin.org/people/u/33196
                Journal
                Front Psychiatry
                Front Psychiatry
                Front. Psychiatry
                Frontiers in Psychiatry
                Frontiers Media S.A.
                1664-0640
                26 November 2014
                12 January 2015
                2014
                : 5
                : 197
                Affiliations
                [1] 1Department of Clinical Laboratories, Pontificia Universidad Católica de Chile , Santiago, Chile
                [2] 2Cognitive Neurosciences Laboratory, Department of Psychiatry, Pontificia Universidad Católica de Chile , Santiago, Chile
                [3] 3Centro de Investigación en Complejidad Social (CICS), Facultad de Gobierno, Universidad del Desarrollo , Santiago, Chile
                [4] 4Medical Technology School, Universidad Mayor , Santiago, Chile
                [5] 5Instituto de Alta Investigación, Universidad de Tarapacá , Arica, Chile
                Author notes

                Edited by: John Vijay Sagar Kommu, National Institute of Mental Health and Neurosciences, India

                Reviewed by: Preeti Jacob, National Institute of Mental Health and Neurosciences, India; Sowmya Bhaskaran T. S., National Institute of Mental Health and Neurosciences, India

                *Correspondence: Marcela Patricia Henríquez-Henríquez, Department of Clinical Laboratories, Pontificia Universidad Católica de Chile, Vicuña Mackena 4686, Santiago 7820436, Chile e-mail: mhenri@ 123456med.puc.cl

                This article was submitted to Child and Neurodevelopmental Psychiatry, a section of the journal Frontiers in Psychiatry.

                Article
                10.3389/fpsyt.2014.00197
                4290481
                25628575
                86f2403e-15dc-4c25-adc3-283d0c4e4981
                Copyright © 2015 Henríquez-Henríquez, Billeke, Henríquez, Zamorano, Rothhammer and Aboitiz.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 November 2014
                : 20 December 2014
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 45, Pages: 8, Words: 6405
                Categories
                Psychiatry
                Original Research

                Clinical Psychology & Psychiatry
                ex-gaussian analysis,adhd,intra-individual variability,endophenotypes,response time

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