Causal Heterogeneity in Attention-Deficit/Hyperactivity Disorder: Do We Need Neuropsychologically Impaired Subtypes?

Harvard University, Cambridge, Massachusetts, United States
Biological Psychiatry (Impact Factor: 10.26). 07/2005; 57(11):1224-30. DOI: 10.1016/j.biopsych.2004.08.025
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Before assigning full etiologic validity to a psycopathologic disorder, disease theory suggests that a causal dysfunction in a mechanism within the affect individuals must be identified. Existing theories on attention-deficit/hyperactivity disorder (ADHD) suggest such dysfunctions in cognitive, neuropsychological, or motivational processes in the child. To date, researchers have tested these theories by comparing groups with DSM-defined ADHD to children without ADHD. Using executive functioning as an illustration of an issue that exists across all such theories, this article describes substantial overlaps in the group performance data. Thus only a subgroup may have executive deficits. Noted are other supportive data suggesting multiple pathways to ADHD. The article explores implications and recommends that future theory and research give more consideration to the probability that only a subset of behaviorally defined children will have a deficit in a given neurocognitive mechanism believed to contribute to the disorder. Creation of a provisional set of criteria in DSM-V for defining an "executive deficit type" could stimulate research to validate the first etiologic subtype of ADHD and spur the development of more sophisticated causal models, which in the longer term may give clinicians ways to target and tailor treatments.

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Available from: Joel Thomas Nigg, May 27, 2015
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    • "For example, volumetric differences in cerebellar and subcortical regions have been related to ADHD pathology (Mackie et al., 2007; Seidman, Valera, & Makris, 2005; Valera et al., 2007). Furthermore, an increasing number of studies does not point to one core brain deficit in ADHD, but instead describes widespread neural abnormalities associated with the disorder (Bush, 2010; Coghill, Hayward, Rhodes, Grimmer, & Matthews, 2014; Durston, 2003; Fair, Bathula, Nikolas, & Nigg, 2012; Sonuga- Barke, 2005). This in turn, may underlie the heterogeneity of neurocognitive deficits in individuals with ADHD (Nigg, Willcutt, Doyle, & Sonuga-Barke, 2005; Willcutt, Doyle, Nigg, Faraone, & Pennington, 2005). "
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    ABSTRACT: Background: One neurodevelopmental theory hypothesizes remission of attention-deficit/hyperactivity disorder (ADHD) to result from improved prefrontal top-down control, while ADHD, independent of the current diagnosis, is characterized by stable non-cortical deficits (Halperin & Schulz, 2006). We tested this theory using resting state functional MRI (fMRI) data in a large sample of adolescents with remitting ADHD, persistent ADHD, and healthy controls. Methods: Participants in this follow-up study were 100 healthy controls and 129 adolescents with ADHD combined type at baseline (mean age at baseline 11.8 years; at follow-up 17.5 years). Diagnostic information was collected twice and augmented with magnetic resonance imaging (MRI) scanning at follow-up. We used resting state functional connectivity (RSFC) of the executive control network to investigate whether improved prefrontal top-down control was related to a developmental decrease in ADHD symptoms. In addition, we tested whether non-cortical RSFC, i.e., cerebellar and striatal RSFC, was aberrant in persistent and/or remittent ADHD compared to controls. Results: Higher connectivity within frontal regions (anterior cingulate cortex) of the executive control network was related to decreases in ADHD symptoms. This association was driven by change in hyperactive/impulsive symptoms and not by change in inattention. Participants with remitting ADHD showed stronger RSFC than controls within this network, while persistent ADHD cases exhibited RSFC strengths intermediate to remittent ADHD cases and controls. Cerebellar and subcortical RSFC did not differ between participants with ADHD and controls. Conclusions: In line with the neurodevelopmental theory, symptom recovery in ADHD was related to stronger integration of prefrontal regions in the executive control network. The pattern of RSFC strength across remittent ADHD, persistent ADHD, and healthy controls potentially reflects the presence of compensatory neural mechanisms that aid symptomatic remission.
    Cortex 09/2015; 73:62-72. DOI:10.1016/j.cortex.2015.08.012 · 5.13 Impact Factor
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    • "To investigate heterogeneity in cognitive impairments, we computed the number of deficient test scores for each participant. Similar to previous studies, a deficient score was defined as performance below the 10th percentile of the performance distribution of the control group (Coghill et al., 2013; Nigg et al., 2005b). For variables where higher scores indicated worse performance, deficiency was defined as a score above the 90th percentile of performance distribution of the control group. "
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    ABSTRACT: Attention Deficit/Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N=133, 42% male, mean age 36) and healthy adults (N=132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05-0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
    European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology 08/2015; DOI:10.1016/j.euroneuro.2015.08.010 · 4.37 Impact Factor
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    • "Downloaded by [] at 01:13 26 July 2015 Campbell & von Stauffenberg, 2009). With regard to relations to the two ADHD symptom domains, our finding that working memory deficits are primarily related to inattention is in line with both theoretical formulations and previous empirical data (e.g., Nigg et al., 2005; Wåhlstedt et al., 2008). "
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    ABSTRACT: High levels of ADHD symptoms are related to severe negative outcomes, which underscore the importance of identifying early markers of these behavior problems. The main aim of the present study was therefore to investigate whether neuropsychological deficits in preschool are related to later ADHD symptoms and academic achievement, over and above the influence of early ADHD symptom levels. The present study is unique because it includes a broader range of predictors compared to previous studies and the participants are followed over time for as long as 13 years (i.e., ages 5-18 years). Preschool data included measures of executive functioning and reaction time variability as well as emotional reactivity and emotion regulation of both positive and negative emotions. When controlling for early ADHD symptom levels, working memory, reaction time variability, and regulation of happiness/exuberance were significantly related to inattention whereas regulation of happiness/exuberance and anger reactivity were significantly related to hyperactivity/impulsivity. Furthermore, working memory and reaction time variability in preschool were significantly related to academic achievement in late adolescence beyond the influence of early ADHD symptoms. These findings could suggest that it is possible to screen for early neuropsychological deficits and thereby identify children who are at risk of negative outcomes. Furthermore, our results suggest that interventions need to look beyond executive functioning deficits in ADHD and also target the role of emotional functioning and reaction time variability. The importance of including both the positive and negative aspects of emotional functioning and distinguishing between emotion regulation and emotional reactivity was also demonstrated.
    Child Neuropsychology 07/2015; DOI:10.1080/09297049.2015.1063595 · 2.42 Impact Factor
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