Comorbidity of ADHD and Dyslexia

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Comorbidity of ADHD and DyslexiaEva Germanò a , Antonella Gagliano M.D. a & Paolo Curatolo ba Division of Child Neurology and Psychiatry Pediatric Department ofPoliclinico G. Martino, University of Messina, Gazzi-Messina, Italyb Pediatric Neurology Unit, Tor Vergata, University of Rome,Department of Neuroscience, Roma, ItalyVersion of record first published: 16 Aug 2010.

To cite this article: Eva Germanò , Antonella Gagliano M.D. & Paolo Curatolo (2010): Comorbidity ofADHD and Dyslexia, Developmental Neuropsychology, 35:5, 475-493

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Comorbidity of ADHD and Dyslexia

Eva Germanò and Antonella GaglianoDivision of Child Neurology and Psychiatry

Pediatric Department of Policlinico G. Martino, University of MessinaGazzi-Messina, Italy

Paolo CuratoloPediatric Neurology Unit, Tor Vergata, Department of Neuroscience

University of Rome, Roma, Italy

Comorbidity of attention deficit hyperactivity disorder (ADHD) and reading disorder (RD) is fre-quent. Comorbid subjects show a neuropsychological profile characterized by failure of various cog-nitive functions with an additive-effect that can determine more severe functional deficits. ComorbidRD may be a marker for a group of children with ADHD with more severe cognitive deficits, and aworse neuropsychological, academic, and behavioral outcome. The article focuses on the link be-tween RD and ADHD from an epidemiological, genetic, neurofunctional, neuropsychological, andtherapeutic perspective and summarizes the characteristics of the comorbid phenotype.

Reading disability (RD) and attention deficit hyperactivity disorder (ADHD) are two of the mostcommon disorders diagnosed in childhood and each of them occurs in approximately 5% of thepopulation (Diagnostic and Statistical Manual of Mental Disorders–Text Revision; AmericanPsychiatric Association, 2000). Over 80% of children with ADHD and 60% of children with RDmeet the criteria for at least one additional diagnosis (Willcutt & Pennington, 2000a, 2000b). RD,commonly referred to as dyslexia, is defined as an unexpected, specific, and persistent failure toacquire efficient reading skills despite conventional instruction, adequate intelligence, and socio-cultural opportunity (APA, 2000). ADHD is one of the most prevalent developmental disorders,characterized by excessive activity, short attention span, and impulsivity (APA, 2000). Recent ad-vances from neuroimaging and molecular genetics have improved our understanding of theneurobiology of ADHD (Curatolo, Paloscia, D’Agati, Moavero, & Pasini, 2008).

ADHD is a highly comorbid condition (Gillberg et al., 2004; Banaschewski, Neale, Rothen-berger, & Roessner, 2007). Psychiatric comorbidities include oppositional defiant disorder, con-duct disorder, anxiety, and depression (Jensen et al., 2001). Other types of comorbidities reportedare RD, developmental coordination disorder, and language disorder (Gilger, Pennington, &DeFries, 1992; Cohen et al., 2000). Among psychiatric disorders, ADHD is the most frequentlyassociated with dyslexia (Kronenberger & Dunn, 2003). Attention and learning problems usually

DEVELOPMENTAL NEUROPSYCHOLOGY, 35(5), 475–493Copyright © 2010 Taylor & Francis Group, LLCISSN: 8756-5641 print / 1532-6942 onlineDOI: 10.1080/875656412010494748

Correspondence should be addressed to Antonella Gagliano, M.D., Division of Child Neurology and Psychiatry, Pedi-atric Department of Policlinico G. Martino, University of Messina, Via Consolare Valeria, 98125 Gazzi-Messina, Italy.E-mail: [email protected]

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are considered inter-related and on a continuum (Mayes, Calhoun & Crowell, 2000). Between thetwo disorders there is a bidirectional relationship since the comorbidity is very high if one exam-ines children with dyslexia for ADHD (Willcutt & Pennington, 2000a) or children with ADHDfor dyslexia (Sanson, Prior & Smart, 1996). Reading difficulties appears to be strongly relatedwith the predominantly inattentive type of ADHD rather than hyperactivity or impulsivity(Willcutt & Pennington, 2000b). Furthermore, in ADHD subjects a disability in written expres-sion seems more common (Mayes & Calhoun, 2007). Based on Mayes and coll. evidences, chil-dren with reading, math, or spelling deficits plus ADHD have more severe learning and attentionproblems than children with only one of the two conditions. Some studies have suggested thatcomorbid RD may be a marker for a group of children with ADHD with more severe cognitivedeficits; these children are more impaired on both executive and nonexecutive functions (Purvis& Tannock, 2000; Seidman, Biederman, Monuteaux, Coyle, & Faraone, 2001; Willcutt et al.,2001; Willcutt, Doyle, Nigg, Faraone & Pennington, 2005a).

ADHD females may be less vulnerable to the executive deficits displayed by boys (Seidman etal., 1997), although further studies missed to detect a gender difference on intentional and execu-tive functions (Rucklidge & Tannock, 2002). According to other studies, RD was significantly as-sociated with inattention in both girls and boys, but with hyperactivity/impulsivity (H/I) only inboys (Willcutt & Pennington, 2000a). Furthermore, the hyperactive and impulsive behaviors ex-hibited by boys with RD may be more disruptive than the inattentive behaviors exhibited by girls,and may therefore be a more frequent cause for clinical referrals. According to these authors, thiscondition could partially explain the discrepancy between the gender ratio in referred RD children(approximately 4 boys to 1 girl)

Children with comorbid problems have more secondary problems, such as low self-esteem, be-havioral problems, and dropping out of school, and a worse outcome compared with children diag-nosed with only ADHD or RD (Willcutt et al., 2001). Moreover, individuals with comorbid RD andADHD are at higher risk of other disruptive disorders (Willcutt & Pennington, 2000b). There wassome evidence consistent with the possibility that RD might have effects on behavioral outcome ofcomorbid children; RD might contribute to the persistence of features of conduct disorder in chil-dren with comorbid problems (Chadwick, Taylor, Taylor, Heptinstall, & Danckaerts, 1999). There-fore, early identification and intervention are important to improve the outcome of affected subjects.

In this review we focused on the link between RD and ADHD from an epidemiological, ge-netic, neurofunctional, neuropsychological, and therapeutic perspective and summarized thecharacteristics of the comorbid phenotype.

EPIDEMIOLOGICAL FINDINGS

The comorbidity of ADHD and RD is found in both clinical and community samples (Gilger et al.,1992). These disorders co-occur more often than would be expected on the basis of chance, indi-cating that this comorbidity is not a consequence of selection bias. Although the extent of theoverlap has inevitably varied from study to study depending on the definition of reading disabilityand the criteria used in identifying hyperactivity, the association between them is not really indoubt. In samples of subjects with ADHD, the rate of RD is between 18–45% (August &Garfinkel, 1990; Dykman & Ackerman, 1991; Mayes et al., 2000; Semrud-Clickeman et al., 992;Loo et al., 2004; Wisniewska, Baranowska, & Wendorff, 2007), whereas in samples of RD chil-

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dren, 18–42% also meet criteria for ADHD (Gayan et al., 2005; Gilger et al., 1992; Willcutt &Pennington, 2000b). Table 1 summarizes epidemiological data concerning this association. Thewide variability of overlapping percentage is most likely due to different reasons. First, childrenwith ADHD are assessed with different clinical instruments, and recruited using different diag-nostic criteria (DSM or International Classification of Disease-Tenth Revision [ICD-10]). Fur-thermore, the definition of RD varied from study to study and the most conventional and widelyused indicator of RD (discrepancy between IQ and achievement test scores) is not always used inthe determination of RD. Moreover, the prevalence of dyslexia varies across different cultures de-pending on the complexity of the orthographic rules.

GENETIC FINDINGS

Several family and twin studies have demonstrated that both RD and ADHD are heritable(Dell’homme, Kim, Loo, Yang, & Smalley, 2007; Friedman, Chhabildas, Budhiraja, Willcutt, &Pennington, 2003; Gayan & Olson, 2001; Willcutt, Pennington & DeFries, 2000c). Heritabilityestimates of ADHD are generally in the range of 70–80% (Faraone et al., 2005); the meanheritability for ADHD was shown to be 77% (Biederman, 2005). Similarly high estimates ofheritability have been found for RD (40–60%) (Gayan & Olson, 1999; Ziegler et al., 2005).

Targeted linkage and association analyses and genome scans, carried out independently for RDand ADHD, have identified potential susceptibility loci that may increase the risk of being af-fected with a disorder. To date, linkage analyses in families with dyslexia have identified ninechromosome regions—dyslexia susceptibility 1 (DYX1), dyslexia susceptibility 9 (DYX9)—listed by the HUGO Gene Nomenclature Committee in which the presence of susceptibilitygenes is suspected. Furthermore, linkage findings in dyslexia are relatively consistent across stud-ies in comparison to findings for other neuropsychiatric disorders. This is particularly true forchromosome regions 6p21–p22 (DYX2), 15q21(DYX1), and 1p34–p36 (DYX8) (Chapman etal., 2004; Cope et al., 2005; Grigorenko et al., 2001, 2003).

Six independent genome-wide ADHD linkage scans have been conducted. Several novelgenomic regions might harbor ADHD susceptibility genes, with the most prominent findings on

ADHD AND DYSLEXIA 477

TABLE 1Epidemiological Data

Author Cases RD in ADHD ADHD in RD

August & Garfinkel, 1990 115 boys ADHD 39%Dykman & Ackerman, 1991 182 ADHD 45%Semrud-Clikeman et al., 1992 60 ADHD 38%Ginger et al., 1992 140 RD 39%Willcutt & Pennington, 2000 209 RD 42% in males

18% in femalesMayes et al., 2000 86 ADHD 26%Loo et al., 2004 407 ADHD 18-23%Gayan et al., 2005 505 RD 36%Wisniewska et al., 2007 28 ADHD 18%

ADHD = attention deficit hyperactivity disorder; RD = reading disorder.

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chromosomes 5p and 17p being detected in several studies (Arcos-Burgos et al., 2004; Ashersonet al., 2008; Bakker et al., 2003; Faraone et al., 2007; Fisher et al., 2002a, 2002b; Ogdie et al.,2003).

There is some overlap between linkage regions suggested by genome-wide linkage analyses ofRD and ADHD, which might be explained by pleiotropy for these disorders. These regions in-clude 1p36, 2q22–35, 3p12–q13, 4q12–13, 6p21–22, 6q12–14, 13q22–33, and 15q15–21 (see Ta-ble 2). However, some regions, positively associated to ADHD or dyslexia, are also associated toother developmental disorder, such as autism. As some studies suggest, the chromosome regions6q, 2q, 3p, and 15q are likely to contain risk genes for autism (Duvall et al., 2007; Muhle,Trentacoste, & Rapin, 2004). These pattern of results reduce the specificity of overlap betweenlinkage regions described for RD and ADHD. Furthermore, it is important to underline that link-age of both disorders to the same chromosomal region do not automatically implies that the samegene is involved. Some studies do not support a common genetic basis between ADHD and dys-lexia. Marino et al. (2003) tested within-family association and linkage disequilibrium betweenfour genetic markers at DRD4, DRD3, DRD2, and DAT loci, and dyslexia, in a sample of 130 Ital-ian dyslexic children, 16.9% of whom had comorbid ADHD. No evidence of either association orlinkage disequilibrium was found in the total sample or in the comorbid subgroup. Hsiung,Kaplan, Petryshen, Lu, and Field (2004) investigated DRD4 as a candidate gene for dyslexia bytesting for linkage and association with 14 markers at and around the DRD4 locus on chromosome11p15.5. However, linkage disequilibrium analysis showed no significant evidence for associa-tion between dyslexia and DRD4 or HRAS. In particular, dyslexic subjects showed no significantincrease of the DRD4 7-repeat allele associated with ADHD.

The bivariate heritability between RD and ADHD is more pronounced for the inattentivesymptoms of ADHD than the hyperactive/impulsive ones (Willcutt et al., 2003). The 1p36 regionmay harbor a pleiotropic quantitative trait locus affecting both inattention and dyslexia (Zhou etal., 2008).

Bivariate twin analyses suggest that comorbidity between RD and ADHD may be largely dueto common genetic influences (Light, Pennington, Gilger, & DeFries, 1995; Stevenson et al.,1993; Willcutt & Pennington, 2000b). The ADRA2A gene (Stevenson, Pennington, Gilger,DeFries, & Gillis, 2005) or chromosomal regions (6p21.3; Willcutt et al., 2002) may play a role insusceptibility for both the conditions.


TABLE 2Overview of Risk Loci Shared by RD and ADHD Identified in Linkage Studies

Chromosome RD ADHD

1p36 DYX8 (de Kovel et al., 2007) Zhou et al., 20082q22-35 Rasking et al., 2005 Romanos et al., 20083p12-q13 DYX5 (Nopola-Hemmi et al., 2001) Bakker et al., 20034q12-13 Fisher et al., 2002 Arcos-Burgos et al., 20046p21-22 DYX2 (Grigorenko et al., 2003) Willcutt et al., 20026q 12-14 DYX4 (Petryshen et al., 2001) Ogdie et al., 200313q22-33 Fisher et al., 2002a; Igo et al., 2006 Bakker et al., 200315q15-21 DYX1 (Chapman et al., 2004) Bakker et al., 2003

Approximately LOD scores >1. ADHD = attention deficit hyperactivity disorder; RD = reading disorder.

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Some studies with genome-wide investigations have been conducted which aimed at identify-ing chromosomal loci with pleiotropic effects on dyslexia and ADHD. In the Colorado sample,families with dyslexia having ADHD problems showed evidence for linkages in chromosome re-gions 14q32, 13q32, and at 20q11 (Gayan et al., 2005).

In families with ADHD, evidence for linkage is shown for reading ability in regions 10q32, 16p12,and 17q22 (Loo et al., 2004). These loci may have pleiotropic effects on both RD and ADHD. Therefore,supposedly distinct diagnoses such as RD and ADHD may be due in part to pleiotropic nes that entailrisk for more than one disorder (Willcutt, Pennington, Olson, & Defries, 2007). Thus, pleiotropicgenes may be the rule, rather than the exception, in the aetiology of complex characters. Nevertheless,multiple endophenotypes have to interact to determine the finally observed abnormal phenotype.

NEUROIMAGING FINDINGS

Many abnormalities in different brain regions have been reported in ADHD, including smaller totalbrain volumes and reduced volumes in the right frontal lobe, right caudate nucleus, cerebellar hemi-spheres, and cerebellar vermis (Castellanos et al., 2002; Mackie et al., 2007; Valera, Faraone,Murray, & Seidman, 2007). Functional imaging studies by Single Photon Emission Computed To-mography (SPECT) and positron emission tomography (PET) uncovered anomalies in the frontallobes and in the basal ganglia of individuals with ADHD (Ernst, 2003). Functional magnetic reso-nance imaging (fMRI) studies show decreased functioning of dorsolateral prefrontal cortex anddorsal anterior midcingulated cortex on tasks requiring inhibitory control (Bush et al., 2008;Rubia et al., 1999; Tamm, Menon, Ringel, & Reiss, 2004; Zang et al., 2005) and hypoactivation inthe right inferior prefrontal cortex and in the precuneus and posterior cingulated cortex on inhibi-tory-tasks (Rubia, Smith, Brammer, Toone, & Taylor, 2005). Other recent studies show reducedactivation of temporal lobes, basal ganglia, and parietal lobe (Rubia, Smith, Brammer, & Taylor,2007; Silk et al., 2005; Smith, Taylor, Brammer, Toone, & Rubia, 2006; Vance et al., 2007).

There is substantial evidence of brain abnormalities in dyslexia too (Shaywitz et al., 1998).Structural imaging findings include reduced volumes in the inferior frontal gyrus (pars triangularis),in the right anterior cerebellar lobe (Eckert et al., 2003) and in the temporal lobes (Vinckenbosk,Robichon, & Eliez, 2005), less gray matter volume in the left and right fusiform gyrus, in the bilat-eral anterior cerebellum and in the right supramarginal gyrus (Kronbichler et al., 2008).

fMRI studies, examining phonological processing in dyslexic adults and children, have consis-tently found a disruption of 2 left hemisphere posterior brain systems, 1 parietal-temporal(Shaywitz et al., 2002; Temple et al., 2001), the other occipital-temporal, with compensatory en-gagement of anterior systems around the inferior frontal gyrus (Hoeft et al., 2007) and a posterior(right occipital-temporal) system (for review, see Temple, 2002 and Shaywitz, 2006).

Shared biological processes may underlie reading and ADHD. A common neural mechanismmight be a variation in cerebral lateralization, particularly related to language processing. Supportfor such a mechanism is evident from brain-imaging studies of dyslexic and ADHD individuals, inwhom reversed asymmetry of hemisphere structures such as planum temporale, caudate nucleus,and frontal lobes have been observed (Foster, Hynd, Morgan, & Hugdahl, 2002; Pueyo et al., 2000).

Lower cerebellar volume has been found in ADHD (Castellanos et al., 2002); lower cerebellarvolume in anterior lobe (Eckert et al., 2003) and less gray matter volume have been found in thecerebellum in dyslexia (Kronbichler et al., 2008).


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Recent studies have found dysfunctions in temporal regions in ADHD individuals (Smith et al.,2006; Rubia et al., 2007) and, in particular, reduced activation in temporal lobe regions (Shafritz etal., 2004); differences of activation in the same areas are associated with neural deficits in dyslexia(Temple et al., 2001; Shaywitz et al., 2002; Kronbichler et al., 2006; Hoeft et al., 2007).

Striatal dysfunctions have been often observed in both ADHD and RD (Shafritz et al., 2004). Agreat number of studies have examined the neuroanatomic and neurofunctional variables inADHD and in dyslexic subjects (Table 3). However, to date there are no detailed neuroimagingstudies of the comorbid phenotype. It could be possible to find different and specific neurologicalpattern in subjects with both disorders, instead of a summation of the two disorders. It is wellknown that disorders like ADHD and RD are the result of a dysfunction in neural networks, not inlocalized structures. Thus, future researches using Magnetic Resonance Spectroscopy (MRS) andfMRI are needed to elucidate the underlying neural circuits of the comorbid phenotype.

NEUROPSYCHOLOGICAL FINDINGS

ADHD Phenotype

Individuals with ADHD present difficulties on a variety of neurocognitive measures: problemsolving, planning orienting, alerting, cognitive flexibility, sustained attention, response inhibi-tion, and visual working memory (WM) (Voeller, 2004).

Based on similarities between ADHD symptoms and the behavioral sequelae of frontal lobe in-juries, several authors have proposed that ADHD is attributable to a deficit in executive functions


TABLE 3Functional/Structural Neuroimaging Alterations Shared in RD and ADHD

Neuroimaging Alterations RD ADHD

Lower cerebellar volume Eckert et al., 2003; Kronbichler etal., 2008

Berquin et al., 1998; Mostofsky et al.,1998; Castellanos et al., 2002; Hill etal., 2003; Mackie et al., 2007

Dysfunctions in temporal regions Temple et al., 2001; Shaywitz et al.,2002; Kronbichler et al., 2006;Hoeft et al., 2007

Smith et al., 2006; Rubia et al., 2007;Shafritz et al., 2004

Striatal dysfunction Shafritz et al., 2004 Shafritz et al., 2004; Rubia et al., 2007Asymmetry of hemisphere

structuresPlanum temporale:

Dalby et al., 1998; Eckert andLeonard, 2000; Foster et al., 2000

Lobar asymmetries:Zadina et al., 2006

Caudate nucleus:Hynd et al., 1993; Pueyo et al., 2000;Schrimsher et al., 2002; Pineda et al.,2002; Uhlíkova et al., 2007

Putamen nucleus:Wellington et al., 2006

Globus pallidus:Uhkikova et al., 2007

Prefrontal cortical convolution:Li et al., 2007

Frontal lobe:Pueyo et al., 2000

ADHD = attention deficit hyperactivity disorder; RD = reading disorder.

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(EF) (Barkley, 1997). Barkley proposed the Inhibition model, a comprehensive theory that recog-nizes in deficient inhibitory control the core deficit of ADHD that secondarily disrupts other EFprocesses (Barkley, 1997; Shanahan, Pennington, & Willcutt, 2008), particularly response inhibi-tion, vigilance, WM, and planning (Willcutt et al., 2005a). Empirical evidence suggests multipledeficits of WM, with a greater impairment of spatial central executive WM rather than verbal cen-tral executive WM (Martinussen, Hayden, Hogg-Johnson, & Tannock, 2005). However, EFweaknesses are neither necessary, nor sufficient to explain all cases of ADHD since not all sub-jects with ADHD show neuropsychological deficits (Willcutt et al., 2005a ).

An alternative model presents ADHD as resulting from impaired signalling of delayed rewardsarising from disturbance in motivational processes (Sonuga-Barke, 1994). Other patterns of impair-ment in non-inhibitory domains such as state regulation (Cognitive-energetic model, Sergeant,2005; Sergeant et al., 1999) and temporal processing (Castellanos & Tannock, 2002) were found.

Neuropsychological findings emphasize particular components of a unified self-regulatorysystem, which emerges from the infant to toddler years, consolidates from the preschool to earlychildhood years, and continues to mature through adolescence. The self-regulatory abilities of thechild depend on the mutual interplay of: strength of the affective response to incentive; state regu-lation; ability to redirect attention or suppress responses to regulate affect and behavior (executivefunctions); emerging language abilities (Nigg, 2005).

These evidences provide the idea of neuropsychologically heterogeneous nature of the disor-der (Nigg, 2006; Sonuga-Barke, 2005; Willcutt et al., 2005b), and support the likelihood that mul-tiple neurodevelopmental pathways underpin this disorder, highlighting the need for theoreticalmodels of ADHD to combine motivational and cognitive elements.

RD Phenotype

Several theories have been proposed for the cause of dyslexia.The dominant phonological deficit explanation suggests that dyslexia is a language-based dis-

order characterised by difficulties in single-word decoding (Orton, 1995) and phonological pro-cessing (Snowling, 2000) that prevents learning of letter and phoneme associations. According tothis theory, affected individuals have specific difficulties in perceiving and segmenting pho-nemes, leading to difficulties in establishing a connection between phonemes and graphemes(Ramus et al., 2003). However, the purely phonological theory of dyslexia cannot account forlow-level visual, sensory, and motor coordination deficits reported in many subjects.

The magnocellular deficit theory accounts for disturbances in visual processing (Eden, Van-Meter, Rumsey, & Zeffiro, 1996); this theory proposes that in a proportion of individuals withdyslexia, the perception of visual, rapid moving stimuli and stimuli of low spatial frequency andlow contrast is impaired. This hypothesis in its dominant version assumes degraded visual inputdue to poor binocular fixation as the cause of the reading difficulties. This deficit is associated, atthe central nervous system level, with impaired sensitivity of cells within the retinocorticalmagnocellular pathway (Stein, 2001).

The automaticity/cerebellar deficit hypothesis suggests that the automatization of cognitiveprocesses and motor control in the cerebellum is disturbed in individuals with dyslexia (Nicolson,Fawcett, & Dean, 2001). The role of the cerebellum in the pathogenesis of dyslexia stems from theconceptualization of dyslexia as a learning disorder, in which failure to acquire and automatizereading and writing skills might be the most prominent symptom. (Fawcett & Nicholson, 1999).


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Comorbid Phenotype and Hypotheses to Explain Comorbidity

Several clinical researches and theoretical accounts have been proposed in the past to understandthe neuropsychological correlates of comorbid phenotypes and to explain comorbidity betweenADHD and RD. For each competing hypothesis, a different neuropsychological profile of thecomorbid phenotype, related to RD-only and the ADHD-only phenotypes, has been described.

A first hypothesis suggested that RD may cause the symptoms of ADHD as a consequence offrustrations elicited by difficulties with reading (Pisecco, Baker, Silva, & Brooke, 1996). Accord-ing to this hypothesis, comorbid phenotype exhibits the neuropsychological deficits of RD onlyand the behavioral characteristics of both disorders, since the RD genotype, under particular envi-ronmental conditions, mimics the ADHD phenotype (Phenocopy hypothesis; Pennington, Grois-ser & Welsh, 1993). Consequently, it was assumed that comorbid subjects had the sameneuropsychological weakness exhibited by subjects with the first disorder only. Further studiesdid not support this hypothesis (Nigg, Hinshaw, Carte, & Treuting, 1998; Rucklidge & Tannock,2002; Willcutt et al., 2001) and it became increasingly clear that comorbid RD and ADHD chil-dren exhibited the combination of the deficits in the RD-only and ADHD-only subjects group.

Another interesting hypothesis explaining comorbidity was proposed: the Cross-assortmenthypothesis (Faraone, Biederman, Lehman, & Keenan, 1993). It suggested that ADHD and RD aretransmitted independently in families and that their co-occurrence may be due to non-randommating. According to this theory, spouses of those with ADHD had significantly higher rates ofRD than spouses of those without ADHD. In keeping with this model, the cognitive profile ofcomorbid phenotype seemed consistent with the additive combination of the deficits of theRD-only and the ADHD-only phenotypes. But following studies suggested that cross-assortmenthypothesis is not likely to provide a sufficient explanation for the larger part of comorbid cases(Doyle, Faraone, DuPrue, & Biederman, 2001; Friedman et al., 2003) and that further studies areneeded to fully understand the neuropsychological correlates of RD-ADHD comorbidity. In theirfirst studies, Pennington and colleagues postulated a significant double dissociation between RDand ADHD (Pennington et al., 1993). With the aim of examining phonological and executive abil-ities, they used a full 2 × 2 (RD × ADHD) design and found data confirming the double dissocia-tion model. According to this model, RD and ADHD were linked with two opposite patterns ofimpairment in two different cognitive domains. Furthermore, a growing amount of evidenceseemed to confirm that comorbid RD and ADHD subjects showed the additive combination of thedeficit associated with each single disorder (Pisecco, Baker, Silva & Broke, 2001; Swanson,Mink, & Bocian, 1999; Willcutt et al., 2001). Hence, the double dissociation hypothesis betweenRD and ADHD explained that ADHD-only subjects appeared impaired on executive abilities, butnot on phonological abilities; RD-only subjects exhibited phonological processing deficits, butnot executive functions deficits (Marzocchi et al., 2008; Purvis & Tannock, 1997; Willcutt et al.,2001) and comorbid subjects showed a sum of the previous deficits (Willcutt et al., 2001). Conse-quently, three independent phenotypes were described: a phoneme awareness/verbal workingmemory deficit for the RD only phenotype, an executive/inhibition deficit for the ADHD onlyphenotype; an additive combination for comorbid phenotype, arising from a coexistence of coreneuropsychological deficits of both disorders. As predicted by this model, a single neuro-psychological deficit is the cause of each disorder: a phonological deficit sustains dyslexia and aninhibition deficit explains ADHD (Pennington et al., 1993). Moreover many studies reportedslower rapid automized naming (RAN) performances in RD and in comorbid phenotype, but not


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in ADHD only phenotype (Felton, Wood, Brown, Campbell, & Harter, 1987; Raberger &Wimmer, 2003; Semrud-Clickeman, Guy, & Griffin, 2000), also in studies carried out in non-al-phabetic language communities (Chan, Hung, Liu, & Lee, 2008). These findings seem to recog-nize RAN impairment as a specific deficit for dyslexic children, supporting double dissociationhypothesis.

More recently, various studies provided an increasing amount of evidence for more cognitivedeficits underlying ADHD and RD, questioning a complete dissociation of the core deficits of twodisorders. In fact, executive function deficits have been demonstrated in children with dyslexia(Purvis & Tannock, 2000; Rucklidge & Tannock, 2002; Willcutt et al., 2001) and subtle deficits inverbal storage and verbal central executive domains were found in ADHD subjects (Martinussen& Tannock, 2006). In addition, dyslexic subjects show a high cognitive impulsivity probably re-lated with a frontal functions impairment (Donfrancesco, Mugnaini, & Dell’Uomo, 2005). Fur-ther studies reported a higher cognitive impulsivity level in comorbid phenotype than in subjectswith ADHD only, characterizing impulsivity as a common factor in both ADHD and RD (Purvis& Tannock, 2000).

In parallel, throughout genetic studies, it became progressively clear that some of the etiologi-cal factors are shared in ADHD and RD and that it is possible to found genetic overlaps betweenthese two disorders (Gayan et al., 2005; Loo et al., 2004). Given that RD and ADHD presentshared genetic risk factors, it is highly probable that they have shared cognitive risk factors aswell.

The cognitive subtype hypothesis (Rucklidge & Tannock, 2002) predicts that the neuro-psychological deficits of the comorbid group are different from the simple additive combinationof the deficits associated with RD-only and the ADHD-only groups since there is a significant in-teraction between RD and ADHD on at least some of the neurocognitive weaknesses. So, individ-uals with RD and ADHD generally seem to have slower naming speed, specifically concerningnaming letters and digits tasks in RD (Wolf & Bowers, 1999) and for objects and colors tasks inADHD (Ghelani, Sidhu, Unesh, & Tannock, 2004; Tannock, Martinussen, & Frijters, 2000).Neuropsychological background of co-occurring dyslexia and ADHD can be understood as theco-existence of phonological short-term memory deficits and central executive deficits (Tiffin-Richards, Hasselhorn, Woerner, Rothenberger, & Banaschewski, 2008), sustaining an incompletedissociation of executive and linguistic functions in dyslexia and ADHD.

Moreover, it was observed that the comorbid group may differ from the simple additive combi-nation of the deficits associated with RD and ADHD in consequence of specific additional cogni-tive weakness, such as rapid naming and reaction times, forming an unique cognitive subtypemore clinically impaired (specific subtype hypothesis, Rucklidge & Tannock, 2002). In concor-dance with this model a unique deficit in RAN tasks and more severe impairment on verbal work-ing memory (WM), in comparison to pure phenotypes, were described in the comorbid phenotype(Bental & Tirosh, 2007). Latest findings seem to recognize WM and RAN impairment as possiblespecific deficits for comorbid children. Another important impairment described in comorbidphenotype is the processing speed deficit that appears to be related to both RD and ADHD(Shanahan et al., 2006; Willcutt et al., 2005b). It seems a shared cognitive risk factor that could ex-plain the comorbidity of ADHD and RD, and which could represent the most promising candidateas a neuropsychological endophenotype (Willcutt et al., 2005b).

Altogether, a set of hypotheses has been based on a deterministic etiological cognitive modelfor RD and ADHD, focused on a single cognitive cause (Single cognitive deficit model, Penning-


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ton et al., 1993). Comorbid phenotype does not exhibit a specific weakness on any functions thatare not impaired in at least one of the other two groups (Willcutt et al., 2005b). This raises the is-sue that each disorder may result from a different combination of cognitive deficits, some sharedand some not shared. Thus far, different pathways may lead up to the comorbid ADHD + RDphenotype.

However, most of the findings, taken together, lead to reject the simple cognitive deficit modelof ADHD and RD and to conclude that the overlap of more factors produce comorbidity (Penning-ton, 2006). Finding a shared cognitive risk factor between two comorbid disorders is consistentwith multiple deficit hypothesis of both disorders (Shanahan et al., 2006). The aetiology of com-plex behavioral disorders involves the interaction of multiple risk and protective factors, whichcan be either genetic or environmental (Multiple deficit model, Pennington, 2006; Sonuga-Barke,2005).

The development of behavioral symptoms that define these disorders is based on the balancebetween risk and protective factors. Thus the relation between RD and ADHD might be attribut-able to common etiological influences that increase susceptibility to both disorders (Common eti-ology model, Willcutt et al., 2003; Willcutt et al., 2005b; Willcutt et al., 2007).

Table 4 summarizes the neuropsychological correlates and the models or hypothesis for RD +ADHD comorbidity.

TREATMENT OPTIONS

Effective intervention programs for dyslexia provide children with systematic instruction in criti-cal components of reading: phonemic awareness, phonics, fluency, vocabulary, and comprehen-sion strategies (Shaywitz, Gruen, & Shaywitz, 2007). Proper treatment plans are necessary toguide parents and to offer adequate coping strategies (Lagae, 2008). An essential component ofthe management of dyslexia in students in secondary school incorporates the provision of extratime and assistive technology aids (Shaywitz et al., 2007). Evidence-based treatments for ADHDinclude a combination of pharmacological and behavioral interventions. The use of a multimodaltreatment is currently considered the most appropriate approach (Kaiser, Hoza, & Hurt, 2008). Abroad set of interventions including behavioral therapy and parent training, school consultation,and academic interventions are recommended (Wolraich et al., 2005). In children with ADHDand RD comorbid condition treatment approaches must address both disorders. They need a com-plete psychoeducational treatment program (cognitive–behavioral training and phonological pro-grams) that may be useful for reducing behavioral and reading problems.

Identification and treatment of any comorbid psychiatric issues and involvement of the familyin the treatment processes are an important part of intervention. An early treatment can remediate,and may prevent, reading difficulties in primary school-aged children since it can change the tra-jectory in terms of language, reading skills, and self-esteem (Sundheim & Voeller, 2004).

Multiple studies have shown short-term effects of Methylphenidate (MPH) on the coresymptoms of ADHD, cognitive laboratory tasks and academic performance in children withADHD (Spencer et al., 1996; Wilens & Spencer., 2000). MPH improves reading performance inchildren with ADHD and comorbid dyslexia (Bental & Tirosh, 2008; Keulers et al., 2007;Shafritz et al., 2004). These data support a possible influence of MPH on cognitive attentionfunctions related to reading skills in the comorbid group. Several explanations for the effects of


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MPH on academic learning have been proposed: improved ability to selectively attend to rele-vant stimuli (Balthazor, Wagner, & Pelham, 1991) and better efficiency of specific and/or gen-eral cognitive processes (Keulers et al., 2007). fMRI findings (Shafritz et al., 2004) demonstrateneural dysfunction and neural effects of MPH in adolescents with ADHD or RD during the per-formance of attention tasks. MPH increase striatal activation for both ADHD and RD adoles-cents (Shafritz et al., 2004).

Recent evidence from randomised controlled trials show cognitive effects of polyunsaturatedfatty acids in children with ADHD. The main improvement reported in ADHD sample was in theability to switch and control attention (Sinn, Bryan, & Wilson, 2008). There is little evidence ofefficacy on comorbid phenotype: a reduction of ADHD-related symptoms was described in chil-dren with specific learning difficulties using highly unsaturated fatty acids (HUFA) supple-mentation (Richardson & Puri, 2002). A constitutional inefficiency in the conversion of essentialfatty acid precursor to unsaturated fatty acids has been proposed as a factor not only in ADHD(Stevens et al., 1995) but also in dyslexia and dyspraxia (Stordy, 2000). In these conditions with a


TABLE 4Neuropsychological Correlates and Models for RD + ADHD Comorbidity

Authors Comorbid Phenotype Models and Hypothesis

Pennington et al., 1993 Comorbid group had the symptoms of ADHD,but not the underlying executive deficit

Phenocopy hypothesis

Faraone et al., 1993 The cognitive profile of comorbid phenotype isconsistent with the additive combination ofthe deficits of the RD-only and theADHD-only phenotypes

Cross Assortment hypothesis

Purvis & Tannock, 1997;Willcutt et al., 2001

ADHD subjects are impaired on executiveabilities, but not on phonological abilities; RDsubjects exhibit phonological processingdeficits, but not executive functions deficits;comorbid phenotype arises from an additivecombination of all previousneuropsychological deficits

Double dissociation hypothesis

Rucklidge & Tannock, 2002 Comorbid group was slower with rapid namingand had slower reaction times. It is a specificsubtype, more clinically impaired

Specific subtype hypothesis

Willcutt et al., 2005; Shanahanet al., 2006

Processing speed deficit is a shared cognitivedeficit

Multiple deficit model/Commonaetiology hypothesis

Bental & Tirosh, 2007 Comorbid group shows a more severeimpairment in verbal WM and a unique deficitin rapid naming

Specific subtype hypothesis

Tiffin-Richards et al., 2008 Working memory is a shared cognitive deficit;phonological short-term memory deficits andcentral executive deficits coexist

Multiple deficit model/Commonaetiology hypothesis

Felton et al., 1987; Semrud-Clikeman et al., 2000;Raberger & Wimmer, 2003;Chan et al., 2008

Slower performances in rapid automatizednaming tasks (RAN) in RD and in comorbidphenotype but not in ADHD only phenotype

Double dissociation hypothesis

ADHD = attention deficit hyperactivity disorder; RD = reading disorder; WM = working memory.

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biological basis, phospholipids metabolism looks like a promising paradigm and could help to ac-count for many features that are common not only to these conditions.

FUTURE DIRECTION

The overall pattern of research suggests that ADHD and RD are both related to weakness on mostneurocognitive domains. As noted previously, comorbid children show a phenotype with more se-vere cognitive deficits and worse neuropsychological, academic, and behavioral outcomes, com-pared with children diagnosed with only ADHD or RD. Thus, when a patient receives a diagnosisof ADHD, it is very important to complete the assessment with academic tests in order to identifya potential specific learning disability.

Both behavioral and molecular genetic studies support a partly shared genetic etiology be-tween ADHD and RD and draw the comorbid phenotype as the result of the overlap of risk factorsproducing a high rate of co-occurrence of these disorders. It seems that the ADHD/RD childrenhave difficulty with different aspects of information processing, memory functions, and cognitivespeed. Future research should address to delineate clearly the neuropsychological profile ofcomorbid phenotype, drawing strengths and weaknesses of a unique adverse developmental con-dition.

Recent evidence from an event-related potential study (Dhar, Been, Minderaa, & Althaus,2008) supported the concept that comorbid subjects differ from ADHD in information processingcharacteristics although comorbid subjects are very close to RD in some event-related measures.Measures of task-related neurophysiological and behavioral variables should help to clarify rela-tionships between brain activity and differences in cognitive and behavioral characteristics ofcomorbid phenotype.

Research should also address molecular genetic analyses of this group of patients in order to fa-cilitate the identification of genes for RD, ADHD, and their comorbidity. It has been hypothesizedthat genetic and environmental factors relate to psychiatric disorders, such as ADHD, through theeffect of intermediating, vulnerability traits called endophenotypes. The purpose in determiningcausality and characteristics of comorbid phenotypes would be to establish whether their behav-ioral profiles are genetically related to more stable phenotypes with a clear genetic connection(endophenotype).

Finally, it has also been hypothesized that some male-based neurodevelopmental disorders areassociated with high maternal intrauterine testosterone concentrations (Beech & Beauvois, 2006;James, 2008); future studies could investigate the possible influences of excessive androgen expo-sure in early brain development impairing aspects of RD and ADHD.

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Documents

Comorbidity of ADHD and Dyslexia