Testing for Neuropsychological Endophenotypes in Siblings Discordant for Attention-Deficit/Hyperactivity Disorder

Bidwell, L. Cinnamon; Willcutt, Erik G.; DeFries, John C.; Pennington, Bruce F.

doi:10.1016/j.biopsych.2007.04.003

Cited by 163 publications

(155 citation statements)

References 51 publications

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“…2,3 The phenotype consists of extreme manifestations of continuous traits, including hyperactivity, impulsivity, and dysfunction in executive and self-regulatory skills that involve working memory, temporal organization, planning, organizing, maintaining focus, effort and motivation. 4,5 Brain studies of patients with ADHD have shown abnormalities in frontal-striatal and cerebellar circuitry. 6,7 Although dopaminergic and noradrenergic medications are clinically effective, 8 animal models provide support for the involvement of additional molecular pathways.…”

Section: Introductionmentioning

confidence: 99%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

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Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

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Section: Introductionmentioning

confidence: 99%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

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“…One of the most robust cognitive markers, affecting a large proportion of patients across different tasks and settings, is increased intraindividual reaction time variability (RTV e.g., Kalff et al, 2003;Klein et al, 2006;Scheres et al, 2001;van Meel et al, 2005). Indeed, Bidwell et al, (2007) have shown that RTV is also increased in unaffected dizygotic twins of children with ADHD when compared to control twinpairs, while further evidence for the heritability of this marker comes from the molecular genetics research of Bellgrove and colleagues (Bellgrove et al, 2005) who report an association between the dopamine transporter gene and RTV in ADHD.…”

Section: Introductionmentioning

confidence: 99%

Altered spontaneous low frequency brain activity in Attention Deficit/Hyperactivity Disorder

et al. 2010

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Background: Resting brain activity appears altered in Attention Deficit/Hyperactivity Disorder (ADHD). The default mode interference hypothesis (Sonuga-Barke & Castellanos, 2007) postulates that patterns of spontaneous very low frequency brain activity, typical of the resting brain, cause attention lapses in ADHD when they remain unattenuated following the transition from rest to active task performance. Here we test this hypothesis using DC-EEG.Methods: DC-EEG recordings of very low frequency brain activity (<1.5 Hz) were compared for 16 male children with ADHD and 16 healthy controls during both rest and active task performance (two-choice reaction time task).Results: A previously identified very low frequency resting network of electrodes was replicated. At rest ADHD children showed less EEG power in very low frequency bands (i.e., .02-.2 Hz). They also showed less attenuation of power at these frequency bands during restto-task transition. Reduced attenuation was associated with a number of measures of performance.Discussion: We confirmed the existence of altered very low frequency brain activity in ADHD.ADHD children may have deficits both in maintaining a resting brain when needed and 'protecting' an active brain from the intrusion of resting state brain activity.

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“…A recent review concluded that, on the basis of existing data, one of the most robust motivational markers in ADHD was a preference for smaller sooner (SS) over larger later (LL) rewards (Luman, Oosterlaan, & Sergeant, 2005). This pattern of choice has been shown in most (e.g., Antrop et al, 2006;Bitsakou, Psychogiou, Thompson, & Sonuga-Barke, 2009;Dalen, SonugaBarke, & Remington, 2004;Hoerger & Mace, 2006;Kuntsi, Oosterlaan, & Stevenson, 2001;Schweitzer & Sulzer-Azaroff, 1995;Solanto et al, 2001;Sonuga-Barke, Taylor, Sembi, & Smith, 1992), but not all (Bidwell, Willcutt, DeFries, & Pennington, 2007;Scheres et al, 2006;Solanto et al, 2007) studies of ADHD using SS versus LL choice paradigms. A recent meta-analysis reported a pooled effect size for case-control differences of a similar magnitude to those seen for executive function measures .…”

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Delay and reward choice in ADHD: An experimental test of the role of delay aversion.

et al. 2009

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Children with attention deficit/hyperactivity disorder (ADHD) choose smaller sooner (SS) over larger later (LL) rewards more than controls. Here we assess the contributions of impulsive drive for immediate rewards (IDIR) and delay aversion (DAv) to this pattern. We also explore the characteristics of, and the degree of familiality in, ADHD SS responders. We had 360 ADHD probands; 349 siblings and 112 controls (aged between 6 to 17 years) chose between SS (1 point after 2 s) and LL reward (2 points after 30 s) outcomes on the Maudsley Index of Delay Aversion (Kuntsi, Oosterlaan, Stevenson, 2001): Under one condition SS choice led to less overall trial delay under another it did not. ADHD participants chose SS more than controls under both conditions. This effect was larger when SS choice reduced trial delay. ADHD SS responders were younger, had lower IQ, more conduct disorder and had siblings who were more likely to be SS responders themselves. The results support a dual component model in which both IDIR and DAv contribute to SS choice in ADHD. SS choice may be a marker of an ADHD motivational subtype. (PsycINFO Database Record (c) 2009 APA, all rights reserved).

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Testing for Neuropsychological Endophenotypes in Siblings Discordant for Attention-Deficit/Hyperactivity Disorder

Abstract: Background: Neurocognitive deficits associated with attention-deficit/hyperactivity disorder (ADHD) might be useful intermediate endophenotypes for determining specific genetic pathways that contribute to ADHD.

Cited by 163 publications

References 51 publications

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Altered spontaneous low frequency brain activity in Attention Deficit/Hyperactivity Disorder

Delay and reward choice in ADHD: An experimental test of the role of delay aversion.

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