ADHD among adolescents with intellectual disabilities: Pre-pathway influences

https://doi.org/10.1016/j.ridd.2013.02.025Get rights and content

Abstract

Children and adolescents with intellectual disabilities (ID) are at heightened risk for developing ADHD. However, the validity of ADHD as a diagnosis for youth with ID remains controversial. To advance research on validity, the present study examined the hypothesized precursors to ADHD in typically developing adolescents (TD) and adolescents with ID, specifically with regard to family history of ADHD, molecular genetics, and neuropsychological functioning. Results indicated that youth ADHD symptoms were related to parental ADHD symptoms regardless of the adolescent's cognitive functioning. Additionally, findings suggested that the DRD4 genetic variant and adolescent set-shifting abilities were related to adolescent ADHD symptoms independent of cognitive functioning. This study provides an initial investigation of the biological correlates of ADHD among youth with ID.

Highlights

► Youth with intellectual disability (ID) are at heightened risk for developing ADHD. ► We examined “pre-pathway” factors thought to underlie a diagnosis of ADHD. ► Youth ADHD symptoms were associated with parental ADHD symptoms. ► DRD4 genetic variant predicted ADHD symptoms in ID and typically developing samples. ► Set-shifting abilities were also related to ADHD symptoms in both samples.

Introduction

Youth with intellectual disabilities (ID) are at least three times as likely to have a mental disorder as typically developing (TD) children, with attention-deficit/hyperactivity disorder (ADHD) constituting the most frequent comorbid diagnosis (Baker et al., 2010, Dekker et al., 2002, deRuiter et al., 2008, Emerson and Hatton, 2007, Neece et al., 2011b). However, the validity of ADHD among people with ID is controversial given that previous students have documented a negative correlation between ADHD symptoms and IQ (Goodman et al., 1995, Rapport et al., 1999). However, the degree to which ADHD symptoms are inherent to ID is not clear. The goal of the current study was to further examine the validity of ADHD among adolescents with moderate to borderline ID, focusing on “pre-pathway” influences, or factors thought to precede or underlie the diagnosis of ADHD (Tellegen, 1988).

A groundbreaking paper by Robins and Guze (1970) described five phases necessary to establish the diagnostic validity of psychiatric illness: clinical descriptions, laboratory findings, exclusion of other disorders, follow-up study, and family study. These criteria have since been expanded such whereby diagnostic validity necessitates a consistent pattern of data across clinical correlates (e.g. behavioral phenotypes), family history, developmental course, and treatment response (Antshel, Phillips, Gordon, Barkley, & Faraone, 2006). Consistent with the methodology outlined in Robins and Guze (1970), a previous study with the current sample of adolescents with and without ID examined the clinical presentation of ADHD (i.e. prevalence, sex differences, and comorbidity) and evaluated its validity based on symptom presentation, developmental course, and associated functional impairment (Neece, Baker, Crnic, & Blacher, 2012). Findings suggested that adolescents with ID were at elevated risk for ADHD (risk ratio: 3.4:1) compared to their typically developing peers and the symptoms endorsed, trajectory of the disorder, and levels of impairment were comparable among adolescents with and without ID, providing preliminary support for the validity of ADHD in this population of adolescents.

More recently, a “second standard” of validation has emerged where clinical description and epidemiological criteria must be further substantiated by elucidation of the etiology, pathophysiology, and underlying mechanisms (e.g. candidate genes) the disorder (Andreasen, 1995). Thus, the present study investigated “pre-pathway” influences, or potential causal factors for ADHD among youth with and without ID (Tellegen, 1988). Specifically, we examined similarities and differences among typically developing (TD) adolescents and adolescents with ID with regard to several theoretically derived and biologically plausible factors across multiple domains including family history of ADHD, molecular genetics, and neuropsychological factors (working memory, response inhibition, and set-shifting).

There is considerable evidence that ADHD cosegregates, suggesting the potential heritability of individual differences in ADHD. Rates of ADHD among first-degree relatives are two to four times higher among ADHD probands, across ADHD subtypes, relative to non-ADHD controls (Faraone, Biederman, & Friedman, 2000). To our knowledge, no study to date has examined the family history of ADHD among relatives of children or adolescents with ID and ADHD. This is due in part of the fact that most genetic studies of ADHD exclude children with ID. However, it is clearly an important area of inquiry in terms of examining the validity of ADHD as a diagnosis for children and adolescents with ID. Family studies may reveal that it takes less familial risk for ADHD to be expressed in individuals with ID. It may also be that a different pattern of psychiatric disorders is present in families of children and adolescents with ID and ADHD. However, if adolescent ADHD functioning is associated with parental ADHD symptoms independent of the adolescent's cognitive functioning, this further supports the notion that ADHD is the same or similar disorder among adolescents with ID.

The underlying dimensions of ADHD are substantially heritable (h2 = .6–.9; Faraone et al., 2005, Nigg and Nikolas, 2008, Rietveld et al., 2004, Simonoff et al., 1998) indicating that about 70% of the variance in ADHD symptoms is accounted for by some sort of genetic influences. Thus, additive genetic influences, including variance attributable to gene × environment interaction (G × E), account for a significant majority of individual differences in ADHD. As a result, research on ADHD has rapidly moved into molecular genetic studies to identify the possible genes involved in ADHD. Molecular genetic studies of ADHD have tested a variety of candidate genes that may be involved in the development of this disorder, many of which influence the availability of dopamine in the prefrontal cortex. There is a strong empirical rationale for this approach given that dopamine neurotransmission is implicated in key dimensions of ADHD, including working memory, inhibition, and attention across human and rodent models (Nigg, 2001, Sergeant et al., 2002, Willcutt et al., 2005). Moreover, dopaminergic genes are also plausibly associated with ADHD because these genes are directly related to the site of pharmacological action of stimulant medication, which is the most common pharmacotherapy for ADHD (i.e., frontostriatal brain regions; Biederman, 1997).

We focused on two genetic variants that are involved in dopamine neurotransmission and may be implicated ADHD. The DRD4 gene, which produces a blunted response to dopamine (Van Tol, Wu, Guan, & Ohara, 1992), has demonstrated the most consistent association with ADHD across numerous meta-analytic studies (Faraone et al., 2001, Loo et al., 2010, Wu et al., 2012), and, thus, was examined in our sample of adolescents with and without ID. The dopamine transporter gene (DAT1) may be the candidate that is the most biologically plausible given that stimulant medications inhibit the dopamine transporter thereby increasing extracellular dopamine (Li and Lee, 2012, Spencer et al., 2007). Some previous studies have found an association between the DAT1 gene and ADHD (Brookes et al., 2006, Chen et al., 2003, Cook et al., 1995, Faraone et al., 2005, Loo et al., 2008, Loo et al., 2010, Todd et al., 2005), while others have not (Li, Sham, Owen, & He, 2006). However, given the strong theoretical basis for the association between DAT1 and ADHD this variant was also examined in the current study. To the authors’ knowledge this study is the first to examine molecular genetics in children or adolescents with ADHD and ID, specifically investigating whether two of the susceptibility genes that have been most implicated in ADHD (DRD4 and DAT1) are also associated with this disorder in a sample of adolescents with ID.

Executive function (EF) deficits represent putative mechanisms through which the underlying pathophysiology ADHD eventuates in disorder (i.e. endophenotypes). EF refers to the strategic allocation of attention and responses and consists of a set of cognitive processes such as planning, working memory, attention, problem solving, verbal reasoning, inhibition, mental flexibility, and monitoring of actions (Nigg & Nikolas, 2008). These abilities are necessary to effectively suppress a prepotent response (e.g. cognition, behavior) in the service of achieving a higher-order goal (Barkley, 1997, Willcutt et al., 2005). In addition to ADHD symptoms, deficits in EF have also been associated with impairments in functional outcomes (Barkley et al., 2006, Biederman et al., 2006). The present study examined four domains of EF; verbal working memory, spatial working memory, response inhibition, and set shifting, all of which have been found to be impaired in children and adolescents with ADHD (Barkley, 1997, Nigg, 2009).

Working memory requires the ability to encode, tore, manipulate, and retrieve information, typically in the face of interference. Working memory is influenced by dopaminergic functioning (Goldman-Rakic, 1993) and may be one mediator of the relationship between the genetic factors discussed earlier and ADHD. Biologically, verbal and spatial working memory are regulated by the left hemisphere and right hemisphere, respectively (Baddeley, 1998, Jonides et al., 1993, Paulesu et al., 1993) suggesting that these two facets are empirically separable. Meta-analyses of at least 20 studies found modest effect sizes for verbal working memory deficits in ADHD (d = 0.43 in Martinussen, Hayden, Hogg-Johnson, & Tannock, 2005 and d = 0.54 in Willcutt et al., 2005). Although fewer studies have examined spatial working memory in children and adolescents with ADHD, the meta-analyses available have found fairly large effect sizes for spatial working memory (d = 1.06 in Martinussen et al., 2005 and d = 0.72 in Willcutt et al., 2005). Despite research indicating that they are distinct constructs, no study to the best of our knowledge has examined verbal and spatial working memory separately in a sample of persons with ID.

Limited findings investigating working memory in youth with ID have focused on children generally finding that children with ID exhibit more working memory deficits than age-matched TD youth. However, these children typically perform similarly or even better than children matched for mental age (Henry and MacLean, 2002, Jarrold and Baddeley, 1997, Jarrold et al., 2000, Rosenquist et al., 2003, Van der Molen et al., 2007) suggesting that cognitive functioning alone cannot fully account for the variance in performance on assessments of working memory. Similar findings with our sample of adolescents would support the notion that ADHD may be a construct that is separate and distinct from IQ.

Response inhibition refers to individual differences in the ability to suspend a response during an active moment-to-moment behavior (Nigg & Nikolas, 2008). In studies of response inhibition, neuroimaging and brain injury studies converge around the primacy of circuitry in the inferior frontal gyrus and the caudate in the basal ganglia (Nigg & Nikolas, 2008). Using the Logan stop task (Logan & Cowan, 1984), meta-analytic evidence suggests children with ADHD exhibit impaired response inhibition (d = 0.61; Willcutt et al., 2005). One study found that adults with ADHD and ID made significantly more commission errors on a continuous performance test compared to adults with ADHD alone, even with statistical control of IQ. Thus, adults with comorbid ADHD and ID may show cognitive profiles reflecting a “double deficit” (Rose, Bramham, Young, Paliokostas, & Xenitidis, 2009). No study to the best of our knowledge has examined a similar construct of response inhibition among children or adolescents with ID.

Set shifting, also referred to as task shifting or cognitive shifting, is the mental process of re-directing one's focus of attention away from one fixation point and toward another fixation point. These abilities likely involve attentional networks in the prefrontal cortex; however, different areas of the prefrontal cortex have been implicated (e.g. lateral prefrontal cortex; Dove, Pollmann, Schubert, Wiggins, Cramon, 2000; inferior prefrontal cortex; Konishi et al., 1998). ADHD is reliably associated with impaired cognitive flexibility, including poor set shifting compared to control children (effect size for set-shifting d = 0.65; Boonstra, Oosterlaan, Sergeant, & Buitelaar, 2005; d = 0.46, Willcutt et al., 2005).

Despite the large number of studies examining neuropsychological functioning among youth with ADHD, very little research has examined the cognitive parameters of children and adolescents with ADHD and ID. This may be because participants with ID may be less likely to understand the tasks or less able to sustain attention long enough to complete neuropsychological evaluation. Some have argued against examining neuropsychological deficits in the context of general cognitive delays (Pennington and Bennetto, 1998, Pulsifer, 1996). However, research suggests that among youth with ID, there is significant variability in neuropsychological profiles and strengths/weaknesses can be identified, especially among youth with mild or borderline ID (Swillen et al., 1999, Udwin and Yule, 1991). If EF deficits are a distinct characteristic of ADHD, one would expect ADHD functioning to be associated with set shifting abilities, and other aspects of executive functioning, above and beyond the child's intellectual functioning.

When a disorder is valid in different populations, there is an assumption that the same causal factors underlie its presentation across groups. Thus, in an effort to further understand the validity of an ADHD diagnosis for adolescents with ID, we examined pre-pathway factors thought to precede ADHD among adolescents with and without ID. Toward this aim, the following hypotheses were investigated: (1) After controlling for youth IQ, maternal ADHD symptoms will be associated with the adolescent's ADHD symptoms, (b) The homozygous 10-repeat genotype (10/10) of the DAT1 gene and the 7-repeat allele of the DRD4 gene, rigorously implicated in the etiology of ADHD, will be significantly associated with ADHD among adolescents who are typically developing with ADHD and among adolescents with comorbid ADHD and ID, and (c) Adolescent ADHD will be associated with neuropsychological deficits (i.e. working memory, response inhibition, and set shifting) even after controlling for adolescent intellectual functioning.

Section snippets

Participants

Participants were 164 families of youth aged 13 years. They were participating in a longitudinal study of young children, with samples drawn from Southern California (87.9%) and Central Pennsylvania (12.1%). Most families (73.2%, n = 120) had been recruited 10 years earlier, with the intake assessment conducted near the child's 3rd birthday. Another 8 families of children with ID entered the study at child age 5. Additionally, 19 families of TD adolescents and 17 families of adolescents with ID

Preliminary analyses

Adolescent ADHD symptoms were significantly higher in the ID group (Mean CPRS ADHD Score = 16.7; SD = 9.3) compared to the TD group (Mean CPRS ADHD Score = 7.0; SD = 7.8); t = 5.61, p < .001. Additionally, when the relationship between cognitive functioning and ADHD symptomatology was examined using two continuous variables, there was a significant negative correlation between adolescent IQ as measured by the WISC-IV and number of ADHD symptoms (r = −.45, p < .001). These findings are consistent with previous

Discussion

We examined similarities in the hypothesized precursors to ADHD in typically developing adolescents (TD) and adolescents with intellectual disability (ID). Although youth with ID are at very high risk for developing ADHD, no study had systematically investigated the “pre-pathway” factors that may contribute to the development of ADHD in this vulnerable population. Despite innovations in understanding the genetic and neurobiological substrates of ADHD, it is clear that ADHD has multiple causal

Acknowledgements

This paper was based on the activities of the Collaborative Family Study, supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, Grant number: 34879-1459 (Drs. Bruce L. Baker, Jan Blacher, and Keith Crnic PIs). We are indebted to our staff and doctoral student colleagues.

References (81)

  • E. Rose et al.

    Neuropsychological characteristics of adults with comorbid ADHD and borderline/mild intellectual disability

    Research in Developmental Disabilities

    (2009)
  • J.A. Sergeant et al.

    How specific is a deficit of executive functioning for attention-deficit/hyperactivity disorder?

    Behavioural Brain Research Special Issue: Neurobehavioural Mechanisms in ADHD

    (2002)
  • T.J. Spencer et al.

    Efficacy and safety of dexmethylphenidate extended-release capsules in adults with attention-deficit/hyperactivity disorder

    Biological Psychiatry

    (2007)
  • F. Verbruggen et al.

    Response inhibition in the stop-signal paradigm

    Trends in cognitive sciences

    (2008)
  • I.D. Waldman

    Statistical approaches to complex phenotypes: Evaluating neuropsychological endophenotypes for attention-deficit/hyperactivity disorder

    Biological Psychiatry

    (2005)
  • E.G. Willcutt et al.

    Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review

    Biological Psychiatry

    (2005)
  • N.C. Andreasen

    The validation of psychiatric diagnoses: New models and approaches

    American Journal of Psychiatry

    (1995)
  • P.J. Asherson et al.

    Approaches to gene mapping in complex disorders and their application in child psychiatry and psychology

    British Journal of Psychiatry

    (2001)
  • B.L. Baker et al.

    Mental disorders in five-year-old children with or without developmental delay: Focus on ADHD

    Journal of Clinical Child and Adolescent Psychology

    (2010)
  • R.A. Barkley

    ADHD and the nature of self-control

    (1997)
  • Biederman, J. (1997, October). Treatment of ADHD with an emphasis on stimulant medication. Paper given at the...
  • J. Biederman et al.

    Impact of psychometrically defined deficits of executive functioning in adults with attention deficit hyperactivity disorder

    American Journal of Psychiatry

    (2006)
  • A.M. Boonstra et al.

    Executive functioning in adult ADHD: A meta-analytic review

    Psychological Medicine

    (2005)
  • K. Brookes et al.

    The analysis of 51 genes in DSM-IV combined type attention deficit hyperactivity disorder: Association signals in DRD4, DAT1, and 16 other genes

    Molecular Psychiatry

    (2006)
  • C. Chen et al.

    The dopamine transporter gene is associated with attention deficit hyperactivity disorder in a Taiwanese sample

    Molecular Psychiatry

    (2003)
  • D. Cicchetti et al.

    Equifinality and multifinality in developmental psychopathology

    Development and Psychopathology

    (1996)
  • J. Cohen et al.

    Applied multiple regression/correlation analysis for the behavioral sciences

    (2002)
  • C.K. Conners

    The Conners rating scales: Revised. Technical manual

    (2000)
  • C.K. Conners et al.

    Conners adult ADHD rating scales, technical manual

    (1999)
  • S. Deb et al.

    The usefulness of Conners’ rating scales-revised in screening for attention deficit hyperactivity disorder in children with intellectual disabilities and borderline intelligence

    Journal of Intellectual Disability Research Special Issue: Mental Health and Intellectual Disability: XXIV

    (2008)
  • M.C. Dekker et al.

    Emotional and behavioral problems in children and adolescents with and without intellectual disability

    Journal of Child Psychology and Psychiatry

    (2002)
  • K.P. deRuiter et al.

    Development of parent- and teacher-reported emotional and behavioural problems in young people with intellectual disabilities: Does level of intellectual disability matter?

    Journal of Applied Research in Intellectual Disabilities

    (2008)
  • E. Emerson et al.

    Mental health of children and adolescents with intellectual disabilities in Britain

    British Journal of Psychiatry

    (2007)
  • S.V. Faraone et al.

    Meta-analysis of the association between the 7-repeat allele of the dopamine D4 receptor gene and attention deficit hyperactivity disorder

    American Journal of Psychiatry

    (2001)
  • I.R. Gizer et al.

    Relations between multi-informant assessments of ADHD symptoms, DAT1, and DRD4

    Journal of Abnormal Psychology

    (2008)
  • P. Goldman-Rakic

    Dissolution of cerebral cortical mechanisms in subjects with schizophrenia

  • R. Goodman et al.

    The impact of child IQ, parent IQ and sibling IQ on child behavioural deviance scores

    Journal of Child Psychology and Psychiatry

    (1995)
  • L.A. Henry et al.

    Working memory performance in children with and without intellectual disabilities

    American Journal on Mental Retardation

    (2002)
  • C. Jarrold et al.

    Short-term memory for verbal and visuospatial information in Down's syndrome

    Cognitive Neuropsychiatry

    (1997)
  • C. Jarrold et al.

    Verbal short-term memory deficits in Down syndrome: A consequence of problems in rehearsal?

    Journal of Child Psychology and Psychiatry

    (2000)
  • Cited by (13)

    • Resilient parenting of children at developmental risk across middle childhood

      2014, Research in Developmental Disabilities
      Citation Excerpt :

      Therefore, the three specific risk factors we examined here that would be likely to impair positive parenting were child developmental delay (DD), child ADHD or ODD diagnosis, and low family income. These risk factors often present together, with higher prevalence of DD in low SES communities (Emerson, 2012; Leonard & Wen, 2002) and higher prevalence of mental health disorders – most commonly, ADHD and ODD – in children with DD than in typically developing children (Baker, Neece, Fenning, Crnic, & Blacher, 2010; Dekker & Koot, 2003; Neece, Baker, & Lee, 2013). With regard to the risk factor of child DD, our previous work suggested that child DD predicts less positive parenting at child age 3 and again at age 5 (Ellingsen et al., 2013).

    • Aetiology and Pathogenesis

      2022, Textbook of Psychiatry for Intellectual Disability and Autism Spectrum Disorder
    • Validity of dsm‐5 oppositional defiant disorder symptoms in children with intellectual disability

      2021, International Journal of Environmental Research and Public Health
    View all citing articles on Scopus
    View full text