The role of double dissociation studies in the search for candidate Endophenotypes for the comorbidity of attention deficit hyperactivity disorder and reading disability
ABSTRACT The neuropsychological underpinnings of Attention Deficit Hyperactivity Disorder (ADHD) and Reading Disability (RD) and their comorbidity may be studied usefully with the double dissociation design. The results of studies using the double dissociation method may be linked to the search for an endophenotype of ADHD and RD and their comorbidity. This endophenotype may eventually shed more light on the genetic origins of both ADHD and RD and their comorbidity. Executive functioning appears to be a candidate endophenotype of the comorbidity of ADHD and RD. Future studies, it is argued, should combine both the double dissociation design with the Additive Factor Method in this endeavour. Additionally, more attention needs to be given to the subtypes of ADHD, RD, and their association with Dyscalculia to determine useful endophenotype(s).
- SourceAvailable from: Penelope Collins[show abstract] [hide abstract]
ABSTRACT: The relationships among working memory, inhibitory control, and reading skills were studied in 966 individuals, 6—49 years old. In addition to a standardized measure of word recognition, they received a working memory (listening span) task in the standard, blocked format (three sets containing two-, three-, or four-item trials) or in a mixed format (three sets each containing two-, three-, and four-item trials) to determine whether scores derived from the standard format are influenced by proactive interference. Intrusion errors were investigated in order to determine whether deficits in working memory were associated with the access, deletion, or restraint functions of inhibitory control. The results indicated that deficits in working memory were characteristic of individuals with reading disabilities at all ages. These deficits may be associated with the access and restraint functions of inhibition. Working memory skills increased until the age of 19. The blocked format showed a gradual decline in adulthood whereas the mixed format did not. The different patterns suggest that the decline in working memory skills associated with aging may result from growing inefficiencies in inhibitory control, and not diminished capacity.Memory & Cognition 04/2012; 28(1):8-17. · 1.92 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: In an attempt to validate the current DSM-IV criteria for attention-deficit/hyperactivity disorder (ADHD) in females and to determine whether symptoms are continuously distributed or categorically discrete, the authors performed factor and latent class analysis on ADHD symptom data from a large general population of adolescent female twins (1,629 pairs). A structured diagnostic assessment of DSM-IV ADHD was completed with at least one parent of 1,629 pairs by telephone. ADHD symptoms from 1,549 pairs were subjected to latent class and factor analysis. Latent class and factor analyses were consistent with the presence of separate continuous domains of inattention (ATT), hyperactivity-impulsivity (H-I), and combined ATT with H-I problems. Severe latent classes corresponding to the predominantly inattentive, predominantly hyperactive-impulsive, and combined types were identified with lifetime prevalence estimates of 4.0%, 2.2%, and 3.7%, respectively. Membership in the severe ATT class predicted academic problems, family problems, and referral to health care providers. Membership in the H-I and combined classes also predicted impaired social relationships. These results suggest that DSM-IV ADHD subtypes can be thought of as existing on separate continua of inattention, hyperactivity-impulsivity, and combined type problems. Membership in any of there severe ADHD latent classes did not preclude academic excellence, but it was associated with different types of impairment and health care-seeking behavior. These data have implications in the areas of diagnosis, classification, treatment, and research.Journal of the American Academy of Child & Adolescent Psychiatry 09/1998; 37(8):848-57. · 6.97 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: There is widespread support for the notion that subgroups of dyslexics can be identified who differ in their reading profiles: Developmental phonological dyslexia is characterized by poor nonword reading, while developmental surface dyslexia is distinguished by a particular difficulty in reading irregular words. However, there is much less agreement about how these subtypes, and particularly the surface dyslexic pattern, are to be accounted for within theoretical models of the reading system. To assist in addressing this issue, the heritability of reading deficits in dyslexic subtypes was examined using a twin sample. Subjects' scores on (a) an exception word reading task and (b) a nonword reading task were used to create a subtype dimension, and surface and phonological dyslexic subgroups were selected from the ends of this distribution. Reading deficits were found to be significantly heritable in both subgroups. However, the genetic contribution to the group reading deficit was much greater in the phonological dyslexics than in the surface dyslexics. The finding of differential genetic etiology across subtypes suggests that there is at least partial independence in the development of the cognitive processes involved in reading exception words and nonwords. Also, the results support accounts of surface dyslexia which emphasize a strong environmental contribution.Journal of Experimental Child Psychology 03/1999; 72(2):73-94. · 3.12 Impact Factor
International Journal of Disability, Development and Education
Vol. 53, No. 2, June 2006, pp. 177–193
ISSN 1034-912X (print)/ISSN 1465-346X (online)/06/020177–17
© 2006 Taylor & Francis
The Role of Double Dissociation
Studies in the Search for Candidate
Endophenotypes for the Comorbidity of
Attention Deficit Hyperactivity
Disorder and Reading Disability
Christien G. W. de Jong*, Jaap Oosterlaan and
Joseph A. Sergeant
Vrije Universiteit, The Netherlands
Taylor and Francis LtdCIJD_A_171583.sgm10.1080/10349120600716158International Journal of Disability, Development and Education1034-912X (print)/1465-346X (online)Original Article
2006Taylor & Francis 532 000000June 2006Christiende Jongcgw.firstname.lastname@example.org
The neuropsychological underpinnings of Attention Deficit Hyperactivity Disorder (ADHD) and
Reading Disability (RD) and their comorbidity may be studied usefully with the double dissociation
design. The results of studies using the double dissociation method may be linked to the search for
an endophenotype of ADHD and RD and their comorbidity. This endophenotype may eventually
shed more light on the genetic origins of both ADHD and RD and their comorbidity. Executive
functioning appears to be a candidate endophenotype of the comorbidity of ADHD and RD.
Future studies, it is argued, should combine both the double dissociation design with the Additive
Factor Method in this endeavour. Additionally, more attention needs to be given to the subtypes of
ADHD, RD, and their association with Dyscalculia to determine useful endophenotype(s).
Keywords: Attention Deficit Hyperactivity Disorder; Comorbidity, Double dissociation;
Endophenotype; Reading Disability; Subtype
Attention Deficit Hyperactivity Disorder (ADHD) and Reading Disability (RD)
occur together more often than would be expected by chance. Genetic molecular
studies show that the comorbidity of ADHD and RD may have genetic origins
*Corresponding author. Department of Clincial Neuropsychology, Van der Boechorststraat 1,
1081 HV Amsterdam, The Netherlands. Email: email@example.com
C. G. W. de Jong et al.
(Stevenson et al., 2005). However, the results of these studies are not always clear
and are sometimes contradictory. A reason for these unclear and contradictory find-
ings could be that ADHD and RD are heterogeneous disorders—a fact that is not
taken into account in these genetic studies. Identification of endophenotypes could
assist in the search for the genetic base of the comorbidity of ADHD and RD. An
endophenotype could be a neuropsychological marker of a disorder and is a closer
expression of the genotype of the disorder than is the phenotype. It is possible that
subtypes of ADHD and RD have different endophenotypes. If this is so, then it is
also possible they have different genotypes, which would explain the unclear results
of the genetic molecular studies. Given this and the recent interest in determining
the endophenotype of ADHD (Doyle et al., 2005), it is a challenge to the field to
discover those neuropsychological deficits that are distinctive to the two disorders
and those that are common.
This article will discuss neuropsychological studies that test three behavioural
genetic hypotheses about the comorbidity of ADHD and RD. The neuropsychologi-
cal studies that test the three hypotheses all use a double dissociation design. This
article also attempts to provide a brief rationale for a research agenda in the area by
indicating the advantages of combining the strengths of the double dissociation
design with the Additive Factor Method (AFM) in studies of ADHD and RD and
their comorbidity, as well as their association with Dyscalculia.
We begin with a brief account of the comorbidity of ADHD and RD, followed
by a description of the single and double dissociation methods. This is followed by
a section on current findings of studies using these methods that place this
approach in the context of the three behavioural genetic hypotheses of the two
ADHD, RD, Comorbidity, and Endophenotypes
ADHD occurs in approximately 5% of school-aged children (American Psychiatric
Association, 1994) and frequently occurs with other psychiatric and developmental
disorders (Angold, Costello, & Erkanli, 1999). For example, ADHD is often associ-
ated with Learning Disabilities (LD) such as Reading Disability (RD) (Faraone
et al., 1993). Earlier estimates of the comorbidity of RD and ADHD varied widely
(9–80%) (August & Garfinkel, 1989; Halperin, Gittelman, Kline, & Rudel, 1984;
Holborow & Berry, 1986; Lambert & Sandoval, 1980); however, more recent
research estimates the comorbidity of ADHD and RD to be 40% (Shaywitz, Escobar,
Shaywitz, Fletcher, & Makuch, 1992).
Twin studies indicate that both disorders (ADHD and RD) have genetic origins
(Hudziak et al., 1998; Pennington et al., 1991; Rhee, Waldman, Hay, & Levy, 1999;
Sherman, Iacono, & McGue, 1997). However, the exact locations of the possible
genes that may lead to ADHD and/or RD are currently unknown (Faraone et al.,
2005; Rabin, Wen, Hepburn, Lubs, & Feldman, 1993). Some evidence suggests that
ADHD and RD co-occur because of shared genetic factors (Gilger, Pennington, &
DeFries, 1992). However, twin studies and molecular genetic studies of RD and
Endophenotypes of Comorbidity of ADHD and RD
ADHD often have low statistical power to detect genes of small effect, possibly
because of the heterogeneity of both disorders (Faraone, Tsuang, & Tsuang, 1999).
Recent conceptualisations of the underpinnings of mental disorders suggest a
search be undertaken for the endophenotypes of ADHD and RD (Almasy &
Blangero, 2001; Doyle et al., 2005; Gottesman & Gould, 2003). An endophenotype
may be a biochemical, neurophysiological, endocrinological, neuroanatomical,
cognitive, or neuropsychological marker(s) of a disorder. To be a candidate
endophenotype, markers should be heritable. An endophenotype is genetically less
complex, has a more direct biological link to the disorder, and is supposed to be
influenced by one or more of the susceptible genes of the disorder. In this article, we
propose to advance the search for the endophenotypes of ADHD and RD by estab-
lishing that neuropsychological studies with this purpose should be conducted using
a double dissociation design.
Neuropsychology and Searching for Endophenotypes
As will become evident from this brief selective review of neuropsychological studies
of both disorders, deficits associated with ADHD and RD show communality more
often than distinctiveness between the disorders (Sergeant, Geurts, & Oosterlaan,
2002). This is somewhat surprising given that the two disorders are hypothesised to
be associated with distinct brain mechanisms. For example, ADHD is suggested to
be a disorder of frontal lobe functioning (Barkley, 1997), the right anterior cingulate
gyrus (Bush et al., 1999) and the cerebellum (Castellanos & Tannock, 2002). In
contrast, magnetic resonance imaging studies have shown RD to be associated with
the planum temporale (Foster, Hynd, Morgan, & Hugdahl, 2002; Hynd, Semrud-
Clikeman, Lorys, Novey, & Eliopulos, 1990). More recently, it has been shown that
leftward asymmetry in the temporal bank of the planum temporale is related to better
coding and storage of semantic material (Kibby et al., 2004). Kibby et al. noted that
the parietal bank morphology is related to coding and storage of phonological mate-
rial, and that the presence of an extra gyrus in the parietal region is associated with
reduced phonological working memory. Thus, at first glance one would expect that
children with ADHD and children with RD would exhibit distinctive patterns of
neuropsychological dysfunction. However, recent neural imaging research indicates
that phonological processing in working memory, apart from requiring dorsolateral
prefrontal functioning, is also dependent upon cerebellar functioning (Desmond,
Gabrieli, Wagner, Ginier, & Glover, 1997). Hence, both ADHD and RD may have
communalities in working memory but dissociations in other brain networks.
In order to disentangle those functional deficits that co-occur and those that
occur separately in ADHD and RD, we propose that a double dissociation design
be employed. A double dissociation between these two disorders would be
supported if ADHD and RD exhibit distinctive profiles on two contrasting neurop-
sychological domains (Pennington, Groisser, & Welsh, 1993; Willcutt, Pennington,
Olson, Chhabildas, & Hulslander, 2005). The results of this type of research have
implications for our understanding of the neuropsychological mechanisms of
C. G. W. de Jong et al.
ADHD and RD and their comorbidity, as well as for our search for endopheno-
types. If the two disorders could be separated on the two contrasting neuropsycho-
logical functions or cognitive domains, this would be evidence that ADHD and RD
have distinct aetiologies. If on the other hand, a double dissociation did not occur
between ADHD and RD, it could be concluded that ADHD and RD have a
To test for a double dissociation of the two disorders, we first need to be able to
identify the neuropsychological deficits of ADHD and RD separately. Research indi-
cates that ADHD may be characterised by several neuropsychological dysfunctions.
An example of a neuropsychological dysfunction of ADHD is a deficit in executive
functioning, particularly in inhibition and working memory (Pennington & Ozonoff,
1996). Other neuropsychological dysfunctions of ADHD indicate working memory
and cerebella deficits, such as difficulties in time perception (Tiffin-Richards, Hassel-
horn, Richards, Banaschewski & Rothenberger, 2004) and deviant sensitivity to
reward and punishment (Luman, Oosterlaan, & Sergeant, 2005). RD, on the other
hand, may be characterised by phonological deficits and naming deficits (Wagner &
Torgesen, 1987; Wolf & Bowers, 2000).
There is some evidence from twin research and family research that executive
functioning, and working memory in particular, are heritable, which makes execu-
tive functioning deficits candidates for the endophenotype of ADHD (Ando, Ono, &
Wright, 1995; Fan, Wu, Fosella, & Posner, 2001). Phonological skills are also influ-
enced by genetic factors, and deficits in phonological skills may be a possible candi-
date endophenotype of RD (Castles, Datta, Gayan, & Olson, 1999). Here, we
review double dissociation studies in which executive functions and the executive
function of working memory—in particular, timing, naming, and phonological
skills—have been studied in ADHD and RD. These double dissociation studies
examine the neuropsychological underpinnings of the comorbidity of ADHD and
RD, and are a first phase in determining the endophenotype.
First, we will describe the double dissociation methodology used in the studies
that are discussed in this article. Second, studies using a single dissociation design,
which are the basis for double dissociation studies, will be noted. Double dissocia-
tion studies can be used to investigate whether neuropsychological variables that
have been identified as associated with ADHD and RD in single dissociation studies
show overlap on distinctiveness with respect to the two disorders. Third, the double
dissociation methodology will be linked to three behavioural genetic hypotheses
related to the comorbidity of RD and ADHD. Finally, the results of the behavioural
genetic studies will be reviewed to suggest ways in which double dissociation
research in ADHD and RD can be improved and thus increase the likelihood of
uncovering the endophenotype of the two disorders.
Single and Double Dissociation Methodology and the AFM
In this section we define the methodological terms, and then identify the principles
that we hope will be applied in discovering the endophenotypes of ADHD and RD.
Endophenotypes of Comorbidity of ADHD and RD
We will illustrate this using previous research conducted by one of the authors and
other colleagues with children with LD and children with ADHD (van der Meere,
van Baal, & Sergeant, 1989) and use a figure based on the data from that publication
for this purpose.
Single dissociation studies compare two or more groups with one another using a
single task as the dependent measure. The double dissociation method, on the other
hand, requires two tasks to be employed (e.g., the tasks depicted in the left and right
panels of Figure 1) to determine whether one of the two tasks, here a working
memory task, shows an interaction with one clinical group (here the LD group), but
not the other clinical group (the ADHD group). This would be expressed as a statis-
tically significant interaction between groups with task. The findings in Figure 1
suggest that a working memory deficit is specific to LD and a motor selection deficit
is specific to ADHD.
The double task methodology has been applied in previous studies of ADHD and
RD, but these studies have used only a single level of task difficulty (see later). As
Figure 1 makes clear, at the level of difficulty of WMI and Motor 1, there is no
difference between the ADHD and RD groups, and both groups are different from
the control group. In contrast, if only tasks at the difficulty level of WM2 and Motor
2 had been used, all three groups would be distinguishable. The results of using
experimental tasks with a single level of difficulty clearly fail to present a complete
picture, and the evidence represented in Figure 1 indicates the need to include tasks
with more than one level of difficulty in double dissociation research.
Use of multi-task difficulty levels is a sine qua non of the AFM (Sternberg, 1969).
The clinical application of the AFM states that if a task variable with increasing task
demands separates a clinical group from the control or other clinical group, then the
neuropsychological process operationalised by the task variable is defective
Figure 1.The double dissociation methodology in combination with the AFM used in van der Meere et al.’s (1989) study of children with ADHD, children with LD, and controls with two tasks (a working memory task and a motor task) at two levels of difficulty. The y axis represents reaction times, with slower times indicating greater difficulty with the task.
Meere et al.’s (1989) study of children with ADHD, children with LD, and controls with two tasks
(a working memory task and a motor task) at two levels of difficulty. The y axis represents reaction
times, with slower times indicating greater difficulty with the task.
The double dissociation methodology in combination with the AFM used in van der
C. G. W. de Jong et al.
(Sergeant, 2005; Sergeant, Oosterlaan, & van der Meere, 1999; Sergeant & van der
Meere, 1990). This process is identified by the interaction between group and task.
If the reader examines Figure 1, three types of differences between the clinical and
control groups can be observed. First, in both panels the clinical groups are signifi-
cantly different from the controls. Second, there is an interaction (slope difference)
between groups and task level: clinical groups do less well with increasing task
demands than the controls. Third, there is a three-way interaction of group with task
level and type of task. If only one level of task had been used, the specific process
deficit would not have been revealed because there would have been no task slope
effect present. It is the combination of double task methodology and AFM that we
propose is essential for the discovery of the endophenotypes of ADHD and RD.
Single Dissociation Studies with ADHD and RD
Before discussing studies using the double dissociation design, reports using the
single dissociation design will be reviewed briefly. These studies use a single task in
order to examine whether individuals with ADHD and RD differ in their perfor-
mance. Single dissociation studies can potentially aid in the search for suitable
neuropsychological processes that might differentiate ADHD and RD in the double
ADHD is often associated with deficits in executive functioning (for a review see
Sergeant et al., 2002). Executive functions include planning, evaluation, inhibition
and changing one’s actions. Additional executive functions are working memory and
fluency. Although children with ADHD have difficulties in all these areas of execu-
tive functioning, they especially exhibit deficits in inhibition and working memory
(Barkley, 1997). While executive functioning deficits have been found in children
with ADHD (Pennington & Ozonoff, 1996; Sergeant, Geurts, Huijbregts, Scheres,
& Oosterlaan, 2003), it is unclear, however, whether the comorbidity of LD such as
RD and Dyscalculia with ADHD has an effect on the executive functions of children
with either ADHD or LD, because executive functioning deficits may also occur in
children with only RD (Donfranesco, Mugnaini & Dell’Uomo, 2005). Seidman,
Biederman, Monuteaux, Doyle, and Faraone (2001) examined the executive func-
tions of children with ADHD, with and without LD, in comparison with control
children. They demonstrated that children with both ADHD and LD had more
difficulty with executive functioning compared with children with only ADHD and
control children. When children with ADHD had both Dyscalculia and RD, they
were more impaired than children with ADHD with a single LD. A comorbid learn-
ing disability thus appears to aggravate the executive functioning deficits of children
Working memory deficits have also been shown in children with ADHD (see
Martinussen, Hayden, Hogg-Johnson, & Tannock, 2005, for a meta-analysis).
However, working memory deficits have also been reported in RD (Chiappe, Hasher,
& Siegel, 2000; De Jong, 1998). Douglas and Benezra (1990) studied the nature of
verbal short-term and long-term memory in boys with ADHD and in boys with RD.
Endophenotypes of Comorbidity of ADHD and RD
Boys with ADHD demonstrated both long-term and short-term memory difficulties.
However, they were the most impaired on memory measures that required self-regu-
latory processes or “executive” processing; that is, children with ADHD had more
difficulty organising, using rehearsal strategies, sustaining strategic effort, and
considering response alternatives. In contrast, boys with RD had more difficulty with
memory tasks that demanded verbal processing. A study by Kaplan, Dewey,
Crawford, and Fisher (1998) demonstrated that the long-term memory difficulties of
children with ADHD may be due to inattentiveness rather than reflecting specific
memory deficits. Kaplan et al. studied long-term memory in children with ADHD,
children with RD, and children with both ADHD and RD in order to separate the
influence of inattentiveness from memory. The findings demonstrated that children
with RD and children with both ADHD and RD had difficulties in recalling informa-
tion. However, children with only ADHD did not have difficulty in remembering;
they were impaired on memory tasks that required attention.
Another important process for the identification of the ADHD endophenotype is
timing. Children with ADHD demonstrate time perception deficits (van Meel,
Oosterlaan, Heslenfeld, & Sergeant, 2005; Rubia, Taylor, Taylor, & Sergeant, 1999;
Smith, Taylor, Warner Rogers, Newman, & Rubia, 2002). The role of comorbid RD
in studies with ADHD that examine time perception deficits is, however, unclear.
Tiffin-Richards et al. (2004) studied time reproduction in finger-tapping tasks in
children with ADHD, children with RD, children with both ADHD and RD, and
non-diagnosed controls. The clinical groups did not differ from controls on the time
reproduction tasks. However, children with RD and children with both RD and
ADHD were more impaired in tapping complex rhythms than the ADHD group.
Toplak, Rucklidge, Hetherington, John, and Tannock (2003), in contrast, demon-
strated deficits in duration discrimination and duration estimation in children and
adolescents with ADHD with and without comorbid RD. However, the temporal
information processing issue in ADHD is complex and awaits definitive research
(Toplak, Dockstader, & Tannock, 2006).
An important process in identifying a RD endophenotype is establishing automati-
sation difficulties, which can be observed in tasks that require rapid naming of stim-
uli (Denckla, 1972). Children with ADHD also appear to have difficulties in rapid
naming of stimuli (Tannock, Martinussen, & Frijters, 2000). Raberger and Wimmer
(2002) studied rapid naming and balance in children with ADHD, children with
both ADHD and RD, children with only RD, and controls. Both rapid naming and
balance are thought to be mediated by the cerebellum (Raberger & Wimmer, 2002).
In that study, children with RD with or without ADHD were most impaired at letter
and colour naming. Children with ADHD either with or without RD had poor
balancing skills in comparison with the other groups.
Another process important for RD is phonological processing (Lyon, 1995).
Breier, Gray, Fletcher, Foorman, and Klaas (2002) studied temporal order judge-
ment and discrimination in children with RD, children with ADHD, children
with both ADHD and RD, and non-diagnosed controls. Children with RD demon-
strated a specific deficit in speech perception compared with the ADHD groups,
C. G. W. de Jong et al.
while the ADHD and RD groups did not differ in processing non-speech stimuli.
Consequently, Breier et al. suggested that children with RD have a deficit in
Various single dissociation studies examining executive functions, memory, time
perception, naming, and phonological skills in children with ADHD or RD or with
ADHD and RD have been reported. These neuropsychological functions seem to be
present in both disorders with the exception of phonological processing. However,
differences or failure to distinguish between ADHD and RD groups in single disso-
ciation studies are difficult to interpret. Although group effects may occur, they do
not implicate a processing deficit. Failures to observe a group difference may occur
due to floor effects. Hence, in order to implicate processing deficiencies, procedures
are required that manipulate the processing demands of the task.
In the next section, the neuropsychological variables noted earlier will be explored
in double dissociation studies of ADHD and RD in the context of studies involving
the behavioural genetic hypotheses of the two disorders. Studies with a double disso-
ciation design may provide greater specificity of dysfunction in both ADHD and RD.
Double Dissociation and Genetic Hypotheses
In the following section we illustrate how the double dissociation design may be used
to test three behavioural genetic hypotheses concerning the comorbidity of ADHD
The three relevant hypotheses are the phenocopy hypothesis, the common aetiol-
ogy hypothesis, and the cognitive subtype hypothesis, and these will be described in
the following. A fourth hypothesis, the cross-assortment hypothesis, will not be
discussed since it does not provide clear predictions for the double dissociation
design (Faraone et al., 1993).
The phenocopy hypothesis proposes that one disorder may lead to a copy of the
symptoms of the other disorder (Pennington et al., 1993). The phenocopy hypothe-
sis is supported when a double dissociation is found between two pure clinical
groups; for example, ADHD and RD and the comorbid group is characterised by
the neuropsychological deficit of one of the two pure groups. Pennington et al.
tested three groups of children—namely, children with ADHD, children with
comorbid ADHD and RD, and children with RD—on a variety of tasks of executive
function and phonological skill. They reported a double dissociation between
ADHD and RD, while the children with only ADHD exhibited executive function-
ing problems and the children with RD exhibited difficulties in phonological func-
tioning. The comorbid group generally reflected the neuropsychological profile of
the RD group. Pennington et al. interpreted their results as indicating that in chil-
dren with ADHD and RD the symptoms of ADHD might occur due to untreated
RD, but they did not really have ADHD.
Endophenotypes of Comorbidity of ADHD and RD
The results of Pennington et al. (1993) have been partially replicated by Närhi
and Ahonen (1995). No double dissociation was observed; that is, children in all
three groups, exhibited executive dysfunctions. The comorbid group exhibited
naming problems, as did the RD group. The difference between the two studies may
be due to the tasks used, task difficulty levels, or the severity of ADHD and RD.
Common Aetiology Hypothesis
The common aetiology hypothesis suggests that ADHD and RD have common
genetic origins. This hypothesis is supported when similar deficits are found in all
the three groups. One common underlying deficit is thought to lead to different
disorders (Willcutt et al., 2005).
Evidence for the common aetiology hypothesis was provided by Willcutt et al.
(2005), who found evidence that children with ADHD demonstrated deficits in
response inhibition, and children with RD had deficits in reading performance.
However, the RD group also demonstrated response inhibition deficits. This latter
finding argues against a double dissociation between ADHD and RD. In addition,
the comorbid group demonstrated deficits in response inhibition and reading. The
children with ADHD, those with RD, and children with both ADHD and RD all
exhibited difficulties in processing speed and verbal working memory. Since the
three groups had overlapping deficits, Willcutt et al. concluded that RD and ADHD
have a common genetic basis.
In order to establish whether ADHD and RD have a common or distinct aetiol-
ogy, Roodenrys, Koloski, and Grainger (2001) investigated working memory mech-
anisms; namely, the phonological loop and the central executive in children with
RD, and in children with both ADHD and RD. Control and attention regulation
processes are said to take place in the central executive (Baddeley & Logie, 1999),
which is required for the retrieval of information in long-term memory and is a
modality-free component of working memory. The phonological loop stores and
rehearses verbal information for a short period to prevent it from decaying (Baddeley
& Logie, 1999). The children with RD exhibited greater difficulty on the phonologi-
cal loop task than the control group, while the comorbid group performed less well
than the control group on two tasks that involved both the phonological loop and the
central executive. Unfortunately, children with only ADHD did not participate in
this study. Thus, this study cannot directly demonstrate that central executive defi-
cits are specific to ADHD. Nevertheless, extension and replication of these findings
would be important for the field.
Cognitive Subtype Hypothesis
The cognitive subtype hypothesis suggests that children with both ADHD and
RD have a different form or more severe form of ADHD or RD than children
with either disorder alone (Rucklidge & Tannock, 2002). This hypothesis would
be supported if a double dissociation is found between the groups with a single
C. G. W. de Jong et al.
disorder of ADHD and RD (Rucklidge & Tannock, 2002) and there is evidence
that the comorbid group has greater neuropsychological deficits than groups with a
Willcutt et al. (2001) did find evidence for this hypothesis, reporting a double
dissociation between ADHD and RD; that is, the children with ADHD had difficul-
ties in executive functioning (e.g., inhibition, vigilance, and set sifting). Children
with RD exhibited phonological deficits and verbal working memory deficits.
Children with both RD and ADHD were more impaired on inhibition and phono-
logical measures than the group with only ADHD, only RD, and controls. These
results suggest that ADHD and RD are two separate disorders. The children in the
comorbid group had a more severe subtype of ADHD and RD than the children
with only ADHD and only RD, which is consistent with and provides support for
the cognitive subtype hypothesis.
Rucklidge and Tannock (2002) found additional evidence in support of the cogni-
tive subtype hypothesis. A double dissociation was reported; specifically, naming
and working memory deficits were characteristic of RD, and inhibition deficits were
characteristic of ADHD. In contrast, the comorbid ADHD and RD group exhibited
both inhibition deficits and working memory deficits. The comorbid group exhibited
more severe naming problems in the letter and number conditions than the two
single disorder groups. This finding indicates that the comorbid group had a more
severe automatisation problem than the children with only ADHD or RD, suggest-
ing that automatisation would be a good candidate for future endophenotypic
studies into comorbid ADHD and RD.
McGee, Brodeur, Symons, Andrade, and Fahie (2004) also provided support for
the cognitive subtype hypothesis. They studied time perception and auditory work-
ing memory in children with ADHD, children with comorbid ADHD and RD, and
children with only RD. It was found that children with ADHD had difficulty esti-
mating the duration of a task that they had previously performed. Children with RD
had difficulty with an auditory working memory task. Children with both ADHD
and RD had more difficulty estimating the duration of a task than the single disor-
dered groups, suggesting the importance of time estimation in differentiating
ADHD and RD.
To summarise this section, three behavioural genetic hypotheses concerning the
comorbidity of ADHD and RD have been studied using the double dissociation
method. Executive functions such as working memory, as well as functions such
as timing, naming, and phonological skills, have been studied in ADHD and RD
using the double dissociation design. Taken together, the results of these studies
suggest that executive functioning deficits occur in children with ADHD and children
with both ADHD and RD (Rucklidge & Tannock, 2002; Willcutt et al., 2001).
Nevertheless, there are reports of executive functioning deficits that occur in children
with RD only (Närhi & Ahonen, 1995; Willcutt et al., 2005). The role of timing
and naming deficits is unclear in the comorbidity of ADHD and RD, and requires
further study (McGee et al., 2004; Rucklidge & Tannock, 2002). Furthermore,
phonological deficits do not seem to occur in those with ADHD only and thus
Endophenotypes of Comorbidity of ADHD and RD
provide a potentially fruitful base for neuro-endophenotypic research (Pennington
et al., 1993; Rucklidge & Tannock, 2002; Willcutt et al., 2001).
In the search for a candidate endophenotype of the comorbidity of ADHD and RD,
several studies have been discussed which test for a double dissociation between
ADHD and RD. In the double dissociation studies mentioned earlier, overlap in
executive functioning deficits, particularly in inhibition and working memory, has
been shown in ADHD and RD (Roodenrys et al., 2001; Willcutt et al., 2005). In
contrast, processes such as timing, rapid naming, and phonological skills appear to
separate ADHD and RD (McGee et al., 2004; Rucklidge & Tannock, 2002;
Willcutt et al., 2001).
The double dissociation studies tested three hypotheses regarding the underpin-
nings of ADHD and RD, all of which have been supported in research, even though
these hypotheses are contradictory about the nature of the comorbidity of ADHD
and RD. The results of the neuropsychological double dissociation studies
mentioned earlier in combination with recent genetic studies suggest that the
phenocopy hypothesis regarding the nature of the comorbidity of ADHD and RD
has little support. Recent genetic molecular studies that have shown comorbid
ADHD and RD is associated with contributions of the ADRA2A gene (Stevenson
et al., 2005) might provide support for the cognitive subtype hypothesis. This gene
seems to play an important role in working memory. It appeared in the double
dissociation studies that working memory might be a good candidate endopheno-
type of the comorbidity of ADHD and RD, which seems to be validated by
Stevenson et al. Other genetic research seems to support both the cognitive subtype
hypothesis and the common aetiology hypothesis. Gayán et al. (2005), using bivari-
ate linkage scans, found various genes that have an effect on both ADHD and RD.
They found a new gene, 14q32, that could be implicated in the symptoms of both
ADHD and RD. Other genes that previously seemed to be involved in the single
disorders of ADHD and RD were suggested to have effects on both ADHD and
RD. Other genes that are supposed to be associated with ADHD or RD could not
show bivariate linkage.
The genetic studies could reflect the results of the behavioural genetic hypotheses
tested with the double dissociation design. Genetic research has shown that both
ADHD and RD are heterogeneous disorders. Probably, some subtypes of ADHD
and RD have the same genetic origins, but other subtypes ADHD and RD are sepa-
rate disorders. These genetic studies could assist to differentiate which subtypes of
ADHD and RD show overlap on executive functioning deficits, and which subtypes
of ADHD and RD differ regarding the involvement of executive functioning.
Subtyping of ADHD in future double dissociation studies with ADHD and RD is
important because the subtypes of ADHD have different estimates of comorbidity
with other disorders. ADHD-inattentive subtype (ADHD-IA), for example, seems to
co-occur more often with LD and internalising disorders than with ADHD-Combined
C. G. W. de Jong et al.
(ADHD-C) (Willcutt & Pennington, 2000). Furthermore, the inattentive behaviour
is associated more with RD than with hyperactivity (Weiler, Bernstein, Bellinger, &
Waber, 2000; Willcutt & Pennington, 2000). However, the (neuropsychological)
distinctiveness of ADHD-C and ADHD-IA appears unclear. Klorman et al. (1999)
demonstrated that children with ADHD-C had more difficulty with planning and in
cognitive flexibility than children with ADHD-IA. Nigg, Blaskey, Huang-Pollock, and
Rappley (2002) reported children with the ADHD-C subtype exhibited more diffi-
culties with response inhibition than children with ADHD-IA. In contrast, Geurts,
Verté, Oosterlaan, Roeyers, and Sergeant (2005) reported that the ADHD-C and
ADHD-IA subtypes could not be differentiated from one another on inhibition and
working memory tasks, thus replicating earlier research (Barkley, Grodzinsky, &
DuPaul, 1992; Chhabildas, Pennington, & Willcutt, 2001). A reason for the contra-
dictory results might be that ADHD-IA could be subdivided into two subtypes, so far
overlooked in neuropsychological studies. One type is characterised by a cognitive
sluggish tempo that is reflected in inconsistent alertness, orientation, and daydream-
ing. The other ADHD-IA subtype may be distinguished by distraction problems
(Geurts et al. 2005).
Subtypes of RD have also not been taken into account in double dissociation stud-
ies. Various subtypes may be distinguished in RD; that is, children with RD read
either fast but inaccurately or read slowly but accurately (Bakker, 1979; Manis,
Seidenberg, Doi, McBride-Chang, & Petersen, 1996). Inhibition has been found to
be disturbed in a subtype of children with RD typified as being fast guessers (van der
Schoot, Licht, Horsley, & Sergeant, 2000). It seems that some of the subtypes of RD
show overlap with ADHD.
An additional point of concern in ADHD and RD endophenotypes is that there is
an association with Dyscalculia in both disorders. Dyscalculia co-occurs frequently
with RD and ADHD (Gross-Tsur, Manor & Shalev, 1996). These authors found
that 26% of children with Dyscalculia also had ADHD. The incidence of Dyscalculia
in ADHD was (in that study) five times higher than in the normal population. In 17%
of the children with Dyscalculia, RD was also observed. Children with Dyscalculia
exhibited higher rates of attentional problems than controls on the Child Behavior
Checklist (Achenbach & Edelbrock, 1983; Shalev, Auerbach & Gross-Tsur, 1995).
Dyscalculia may also be characterised by working memory deficits and attention
difficulties similar to those of children with ADHD (Koontz & Berch, 1996; Lindsay,
Tomazic, Levine, & Accordo, 1999; Siegel & Ryan, 1989).
As illustrated by Figure 1, future double dissociation studies should include tasks
with two levels of difficulty to ensure that the process measured by the task can be
determined and any differences between groups exposed. In the majority of studies
mentioned here, tasks with one level were used. With this method only group main
effects could be demonstrated (Chapman & Chapman, 1973). The AFM in combi-
nation with the double dissociation design could further unravel which subtypes of
ADHD and RD overlap and which do not. When these endophenotypes are found,
the search for the genetic origins of ADHD and RD and their comorbidity may be
based on an understanding of the distinctive as well as overlapping functional deficits.
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