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
Source: PubMed


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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    • "Moreover, they have deficits in timing functions (Noreika et al. 2013) and in 'hot' EF, referring to EF involving motivation and affect such as reward-related decision-making (Kerr & Zelazo, 2004), as measured by temporal discounting (TD) and gambling tasks (Rubia et al. 2009; Noreika et al. 2013). Nonetheless, there is heterogeneity in cognitive impairments, with some patients not showing impairments or only in some cognitive domains which are likely underpinned by different pathophysiological pathways (Sonuga-Barke, 2003; Nigg et al. 2005; Sonuga-Barke et al. 2010). TD tasks require choices between small immediate and larger delayed rewards and measure the extent to which a reward is subjectively discounted when delayed in time, i.e. the sensitivity to temporal delays measured in units of reward (Rubia et al. 2009). "
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    ABSTRACT: Background: Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. Method: Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. Results: Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. Conclusions: The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.
    Full-text · Article · Dec 2015 · Psychological Medicine
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    • "Although earlier models have tried to map specific mental disorders onto their underlying neural substrates, it is becoming increasingly clear that psychiatric disorders are pathophysiologically heterogeneous – with different individuals with the same disorder (or at least meeting the same diagnostic criteria) showing markedly different neuropsychological profiles. This has been perhaps most fully explored in relation to ADHD (Sjowall, Roth, Lindqvist, & Thorell, 2013), where there has been a proposal for neuropsychological subtypes (Faraone et al., 2015; Nigg, Willcutt, Doyle, & Sonuga-Barke, 2005 ). Heterogeneity is also considered an important issue in CD, anxiety, and depression . "
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    ABSTRACT: Background: Ineffective decision making is a major source of everyday functional impairment and reduced quality of life for young people with mental disorders. However, very little is known about what distinguishes decision making by individuals with different disorders or the neuropsychological processes or brain systems underlying these. This is the focus of the current review. Scope and methodology: We first propose a neuroeconomic model of the decision-making process with separate stages for the prechoice evaluation of expected utility of future options; choice execution and postchoice management; the appraisal of outcome against expectation; and the updating of value estimates to guide future decisions. According to the proposed model, decision making is mediated by neuropsychological processes operating within three domains: (a) self-referential processes involved in autobiographical reflection on past, and prospection about future, experiences; (b) executive functions, such as working memory, inhibition, and planning, that regulate the implementation of decisions; and (c) processes involved in value estimation and outcome appraisal and learning. These processes are underpinned by the interplay of multiple brain networks, especially medial and lateralized cortical components of the default mode network, dorsal corticostriatal circuits underpinning higher order cognitive and behavioral control, and ventral frontostriatal circuits, connecting to brain regions implicated in emotion processing, that control valuation and learning processes. Findings and conclusion: Based on clinical insights and considering each of the decision-making stages in turn, we outline disorder-specific hypotheses about impaired decision making in four childhood disorders: attention-deficit/hyperactivity disorder (ADHD), conduct disorder (CD), depression, and anxiety. We hypothesize that decision making in ADHD is deficient (i.e. inefficient, insufficiently reflective, and inconsistent) and impulsive (biased toward immediate over delayed alternatives). In CD, it is reckless and insensitive to negative consequences. In depression, it is disengaged, perseverative, and pessimistic, while in anxiety, it is hesitant, risk-averse, and self-deprecating. A survey of current empirical indications related to these disorder-specific hypotheses highlights the limited and fragmentary nature of the evidence base and illustrates the need for a major research initiative in decision making in childhood disorders. The final section highlights a number of important additional general themes that need to be considered in future research.
    Full-text · Article · Dec 2015 · Journal of Child Psychology and Psychiatry
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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.
    Full-text · Article · Aug 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology
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