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The Neuropsychological Profile ofInfantile Duchenne Muscular DystrophyGiovanni Mento Ph.D. a , Vincenza Tarantino a & Patrizia S.Bisiacchi aa Department of General Psychology, University of Padova, Padova,Italy

Available online: 17 Oct 2011

To cite this article: Giovanni Mento Ph.D., Vincenza Tarantino & Patrizia S. Bisiacchi (2011):The Neuropsychological Profile of Infantile Duchenne Muscular Dystrophy, The ClinicalNeuropsychologist, 25:8, 1359-1377

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The Clinical Neuropsychologist, 2011, 25 (8), 1359–1377

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ISSN: 1385-4046 print/1744-4144 online

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The Neuropsychological Profile of Infantile DuchenneMuscular Dystrophy

Giovanni Mento, Vincenza Tarantino, and Patrizia S. BisiacchiDepartment of General Psychology, University of Padova, Padova, Italy

It has been shown that children with Duchenne muscular dystrophy (DMD) exhibit specific

cognitive deficits. However, the neuropsychological profile has not yet been fully

characterized. In order to control for the contribution of motor impairments as a

confounding variable that is usually present when assessing children with muscular

pathologies, we compared children with DMD to a group of children with an autoimmune

pathology that does not entail either brain or cognitive dysfunction but does imply motor

impairment: juvenile rheumatoid arthritis (JRA). An extensive neuropsychological evalu-

ation was administered, including intelligence, perception, language, memory and learning,

attention, executive function, praxis and reasoning. As the main result, in children with

DMD we found significantly lower performances in verbal IQ, verbal short-term memory

and phonological abilities, as well as in praxis and executive functioning domains. A wide

range of cognitive domains, including verbal abilities, executive functioning, and praxis,

must be taken into account when assessing neuropsychological functioning in children with

DMD. In particular, subtle executive function impairment could be considered as a

subclinical marker of cognitive impairment in developmental disorders.

Keywords: Duchenne muscular dystrophy; Juvenile rheumatoid arthritis; Neuropsychological assess-

ment; Executive function; Praxis; Phonological analysis.

INTRODUCTION

Duchenne muscular dystrophy (DMD) is a hereditary, X-linked, andprogressive muscular disorder that affects about 1 in 3200 boys (Emery, 1992;Emery & Muntoni, 2003). It is caused by a genetic mutation responsible for thedisruption of dystrophin (DYS), a protein normally present in many human tissues,especially in muscular ones (Hoffman, Brown, & Kunkel, 1987). Clinically, DMD ischaracterized by a progressive loss of muscle strength, resulting in motor deficitsand even death due to respiratory muscle insufficiency in the most severe cases(Adams & Victor, 2006). Dystrophin has also been demonstrated to be importantfor the functioning of the central nervous system (CNS), although its role has notyet been fully clarified (Anderson, Anderson, Northam, Jacobs, & Mikiewicz, 2002;Anderson, Head, Rae, & Morley, 2002; Mehler, 2000). It seems to be genericallyinvolved in normal synaptic terminal integrity, synaptic plasticity, and regionalcellular signal integration (Blake & Kroger, 2000; Carlson, 1998; Muntoni, Torelli,& Ferlini, 2003), and different forms of brain DYS have been found to be localizedin specific cell types and brain regions (Gorecki et al., 1992; Gorecki, Lukasiuk,

The Clinical Neuropsychologist, 2011, 25 (8), 1359–1377

http://www.psypress.com/tcn

ISSN: 1385-4046 print/1744-4144 online

http://dx.doi.org/10.1080/13854046.2011.617782

The Neuropsychological Profile of Infantile DuchenneMuscular Dystrophy

Giovanni Mento, Vincenza Tarantino, and Patrizia S. BisiacchiDepartment of General Psychology, University of Padova, Padova, Italy

It has been shown that children with Duchenne muscular dystrophy (DMD) exhibit specific

cognitive deficits. However, the neuropsychological profile has not yet been fully

characterized. In order to control for the contribution of motor impairments as a

confounding variable that is usually present when assessing children with muscular

pathologies, we compared children with DMD to a group of children with an autoimmune

pathology that does not entail either brain or cognitive dysfunction but does imply motor

impairment: juvenile rheumatoid arthritis (JRA). An extensive neuropsychological evalu-

ation was administered, including intelligence, perception, language, memory and learning,

attention, executive function, praxis and reasoning. As the main result, in children with

DMD we found significantly lower performances in verbal IQ, verbal short-term memory

and phonological abilities, as well as in praxis and executive functioning domains. A wide

range of cognitive domains, including verbal abilities, executive functioning, and praxis,

must be taken into account when assessing neuropsychological functioning in children with

DMD. In particular, subtle executive function impairment could be considered as a

subclinical marker of cognitive impairment in developmental disorders.

Keywords: Duchenne muscular dystrophy; Juvenile rheumatoid arthritis; Neuropsychological assess-

ment; Executive function; Praxis; Phonological analysis.

INTRODUCTION

Duchenne muscular dystrophy (DMD) is a hereditary, X-linked, andprogressive muscular disorder that affects about 1 in 3200 boys (Emery, 1992;Emery & Muntoni, 2003). It is caused by a genetic mutation responsible for thedisruption of dystrophin (DYS), a protein normally present in many human tissues,especially in muscular ones (Hoffman, Brown, & Kunkel, 1987). Clinically, DMD ischaracterized by a progressive loss of muscle strength, resulting in motor deficitsand even death due to respiratory muscle insufficiency in the most severe cases(Adams & Victor, 2006). Dystrophin has also been demonstrated to be importantfor the functioning of the central nervous system (CNS), although its role has notyet been fully clarified (Anderson, Anderson, Northam, Jacobs, & Mikiewicz, 2002;Anderson, Head, Rae, & Morley, 2002; Mehler, 2000). It seems to be genericallyinvolved in normal synaptic terminal integrity, synaptic plasticity, and regionalcellular signal integration (Blake & Kroger, 2000; Carlson, 1998; Muntoni, Torelli,& Ferlini, 2003), and different forms of brain DYS have been found to be localizedin specific cell types and brain regions (Gorecki et al., 1992; Gorecki, Lukasiuk,

Address correspondence to: Giovanni Mento, Ph.D., Department of General Psychology,

University of Padova, Via Venezia, 8. 35127 Padova (PD), Italy. E-mail: giovanni.mento@unipd.it

Accepted for publication: August 11, 2011. First published online: October 18, 2011.

� 2011 Psychology Press, an imprint of the Taylor & Francis group, an Informa business

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Szklarczyk, & Kaczmarek, 1998; Tian et al., 1996; Uchino, Teramoto, Naoe, Miike,et al., 1994; Uchino, Teramoto, Naoe, Yoshioka, et al., 1994). In particular, DYShas been found to be highly localized in the pyramidal cells of both the cerebralcortex and the hippocampus, as well as in the Purkinje cells of the cerebellar cortex(Kim, Wu, Xu, & Black, 1992; Tian et al., 1996).

Since the discovery of DMD in the nineteenth century by Duchenne (1868),general intellectual impairments have been associated with its clinical profile,although for many years this assumption was under debate since it was believed thatthese intellectual impairments could largely be a result of psychosocial and/or pooreducational stimulation (Lincoln & Staples, 1977; Morrow & Cohen, 1954; Schoelly& Fraser, 1955). Over the following years, the incidence of mental retardation inDMD was reported as ranging between 20% (Benson & Hunter, 1987) and 50%(Bethlem, 1980; Rapaport et al., 1992; for a review, see Cotton, Crowe, &Voudouris, 1998). Furthermore, the mean full scale IQ score was reported to varyaround one standard deviation below the average score (Anderson, Routh, &Ionasescu, 1988; Dorman, Hurley, & D’Avignon, 1988; Leibowitz & Dubowitz1981; Michalak & Opas, 1997; Ogasawara, 1989; Prosser, Murphy, & Thompson,1969; Rapaport et al., 1992) and the normal range (Bushby et al., 1995; Mearig,1979; Morrow & Cohen, 1954; Rutter, 1966; Sollee, Latham, Kindlon, & Bresnan,1985). A first possible explanation for these inconsistent results could be ascribed tothe limitations of the general intelligence tests employed in these studies forestimating IQ. Indeed, although requiring the integration of a broad range ofcognitive abilities (perception, memory, attention, and language, for example) inorder to demonstrate normal intellectual performances, intelligence tests did notprovide specific measures of these single underlying cognitive functions (Wicksell,Kihlgren, Melin, & Eeg-Olofsson, 2004).

More recently the use of specific neuropsychological tests has enabledclinicians to single out selected deficits in a restricted range of cognitive domainsassociated with infantile DMD (Anderson et al., 1988; Billard et al., 1992; Billard,Gillet, Barthez, Hommet, & Bertrand, 1998; Cotton et al., 1998; Hinton, De Vivo,Nereo, Goldstein, & Stern, 2000, 2001; Wicksell et al., 2004; for reviews, seeAnderson, Head, et al., 2002; Cyrulnik & Hinton, 2008). Overall, investigatorsidentified poor verbal short-term memory as the main cognitive problem of childrenwith DMD (Anderson et al., 1988; Billard et al., 1992; Karagan, 1979; Karagan &Zellweger, 1978; Marsh, & Munsat, 1974; Whelan, 1987), while visuo-spatial andattentive functions were relatively spared (Hinton et al., 2001). Interestingly, thisoccurred despite a normal level of intelligence (Hinton et al., 2000). For instance,significantly low performances were reported in tests of story recall (Billard et al.,1992; Hinton et al., 2000, 2001; Wicksell et al., 2004), sentence repetition (Billardet al., 1992; Hinton, Fee, Goldstein, & De Vivo, 2007), and verbal digit span tasks(Billard et al., 1998; Hinton et al., 2000, 2001; Ogasawara, 1989; Wicksell et al.,2004). Of note, some authors argued that altered verbal memory processing mighthave accounted for the other cognitive deficits that were equally observed in thesepatients, such as poor expressive language, and reading and verbal fluencydifficulties (Cotton et al., 1998; Karagan & Zellweger, 1978; Leibowitz & Dubowitz,1981; Marsh & Munsat, 1974; Smith, Sibert, & Harper, 1990; Whelan, 1987).Children with DMD have also been reported to show more difficulties than their

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healthy peers in remembering stories, repeating back digits, and following long

verbal statements as a consequence of their inability to hold and manipulate

phonological information in their immediate memory store. Thus it has been

suggested that the nature of the impaired cognitive profile observed in the infantile

DMD population may stem from a limited phonological storage, and possibly also

poor rehearsal ability (Hinton et al., 2000).Although there is consistent evidence of a verbal core deficit, it should

nonetheless be noted that the majority of neuropsychological studies in children

with DMD have mainly focused on three cognitive domains only, namely verbal

abilities, memory, and visuospatial processing (Cotton et al., 1998). In comparison,

few studies have extensively assessed additional functions in the same clinical

samples, such as perception, attention, executive functions, and praxis.

Interestingly, when further specific neuropsychological tests were employed, it

was found that the children performed poorly in the areas of attention and executive

functioning (Anderson et al., 1988; Cotton et al., 1998; De Moura, Valle, Resende,

& Pinto, 2010; Donders & Taneja, 2009; Wicksell et al., 2004). In particular, the

children with DMD failed in several tests that assessed high-order cognitive

abilities, including Verbal Fluency, the Trail Making Test, and the Tower of

London test. These data gave rise to the hypothesis of a more-complex cognitive

profile involving not only verbal memory deficits but also other specific disorders,

and posed the crucial question as to whether aspects other than those strictly related

to verbal processing could also be significantly affected, which would then entail a

more heterogeneous cognitive profile.An important issue in investigating cognitive functioning in infantile DMD is

that it would be somewhat difficult to distinguish between the neurobiological

impacts of DYS depletion on cognitive functioning per se and other confounding

factors, such as motor deficits or poor education and academic levels due to long

periods of hospitalization. In relation to motor impairment, the prevalent muscular

deficits that characterize the clinical profile of children with DMD may significantly

affect their performance in tests, particularly in those requiring motor execution,

such as in writing or, for example, in the Trial Making Test. Although most of the

studies, but not all, employ tasks that require very little motor involvement, the

possibility that physical impairment could, to some extent, alter test performance

still persists. To the best of our knowledge, only two studies (Billard et al., 1998;

Whelan, 1987) have directly addressed these issues, comparing children with DMD

to children with spinal muscular atrophy (SMA), a neurological pathology that also

implies motor impairment. In particular, they respectively assessed general

intelligence and reading abilities (Billard et al., 1998) and general intelligence,

memory, and verbal and non-verbal abilities (Whelan, 1987). However, the results

were quite inconsistent. While Whelan (1987) reported no significant group

differences in the patterns of test-score profiles, indicating that the performances

of the two patient groups were very similar, Billard et al. (1998) found that the

children with DMD exhibited a reading age that was significantly lower than the

SMA children compared to their chronological age. Interestingly, the children with

DMD showed significant impairment in reading non-words, accounting for a

specific deficit in phonological processing. Even in this case, however, the authors

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only focused on verbal and/or memory assessment and did not take intoconsideration other important neuropsychological functions.

The general purpose of this study was to better characterize the cognitiveprofile of infantile DMD by employing an extensive neuropsychological battery thatincluded a large number of tests in order to assess all of the main cognitivefunctions, including general intelligence, reasoning, perceptual discrimination,language, memory and learning, praxis, selective attention, and executive function-ing. In more detail, the specific aims were two-fold: first, to clarify whether or notcognitive deficits in DMD are limited to language-based domains; second, todisambiguate the role of aspects other than cognitive ones, such as motor deficits,on the performance in cognitive tasks. For the first purpose we employed anextensive neuropsychological assessment battery including functions other thanlanguage. For the second purpose we chose to compare the cognitive profile ofDMD children with a group of children who had a pathology that does not involveCNS-related cognitive alterations but which still shows motor impairment. We thencompared children with DMD to an age-matched group of children with juvenilerheumatoid arthritis (JRA). Juvenile rheumatoid arthritis is a chronic disorder thataffects more than 150 out of every 100,000 children, and is mainly characterized byjoint inflammation without showing clinically relevant cognitive impairment(Cassidy & Petty, 2001).

METHOD

Participants

A total of 27 children (DMD: n¼ 14, mean age¼ 99.4 months, SD¼ 40.05,range¼ 48–144; JRA: n¼ 13, mean age¼ 111.2 months, SD¼ 31.4, range¼ 49–144)participated in the study. The children with DMD were, on average, slightlyyounger than the children with JRA, although this difference was not significant(p4.05). All participants were male and were recruited at the Gaslini Children’sHospital of Genoa, Italy. Given that the children came from different Italianregions they were hospitalized for a long period, lasting an average of 1 month,during which time they underwent a series of clinical evaluations to ascertain thediagnosis of DMD or JRA, and the presence of functional and neurologicalimpairments, in addition to a neuropsychological assessment. The diagnosis ofDMD was made on the basis of muscle biopsy, plasma CPK levels, electromyog-raphy, and the absence of neurological signs other than those strictly related toDMD. The diagnosis of JRA was formulated on the basis of chronic signs of jointinflammation (Cassidy & Petty, 2001). Both DMD and JRA groups weremedication-free at the time of cognitive assessment. The severity of motorimpairment was measured by the use of a 0–3 clinical scale administered by aphysician. A score of 0 indicates the absence of impairment, a score of 1 indicatesthe presence of mild motor impairments in the lower limbs but preserveddeambulation, a score of 2 indicates the use of wheelchair but preserved upperlimb dexterity, and a score of 3 indicates the presence of severe disability in bothupper and lower limbs. None of the children scored 3. No difference was observed

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between the groups regarding school attendance before the tests. None of thechildren was reported to have particular academic difficulties.

The local ethics committee approved the study and signed informed consentwas obtained from the parents.

Cognitive assessment

An extensive neuropsychological battery was administered to all children (theBatteria di valutazione neuropsicologica; Bisiacchi, Cendron, Gugliotta, Tressoldi, &Vio, 2005; Gugliotta, Bisiacchi, Cendron, Tressoldi, & Vio, 2009). This battery hasbeen standardized for an Italian population ranging from 4 to 18 years of age andspecifically assesses a broad range of cognitive functions. A total of 26 tests takenfrom BVN battery were grouped together in six domain-coherent clusters, includingperceptual discrimination, language, memory and learning, praxis, selectiveattention, and executive functions. This battery did not require reading skills. Inaddition, we grouped together verbal and performance IQ scores obtained from theWISC/WIPPSI scales (according with age) as well as reasoning scores obtainedfrom the Raven’s Colored Matrices test (Raven, Court, & Raven, 1990) in twoadditional, separate clusters defined as general intelligence and reasoning, respec-tively. Although some of the tests that we constrained within the same cluster areusually employed to assess different aspects of the same cognitive functions, such asshort-term and long-term memory or word learning for memory or comprehensionand phonological processing for language, they were nevertheless included in thesame supra-ordinate category. This allowed us to reduce the number of multivariatecomparisons. The eight domains and the single tests included in each of them aredescribed below.

(1) General intelligence. A general index of cognitive functioning was obtained bygiving the children general intelligence tests appropriate for their age. Childrenolder than 6 years undertook the Wechsler Intelligence Scale for Children(WISC-R; Orsini, 1997; Wechsler, 1986), whereas younger children undertookthe Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R; Orsini &Picone, 1996; Wechsler, 1989).

(2) Reasoning. The Raven’s Colored Progressive Matrices were employed toevaluate general reasoning abilities (Pruneti et al., 1996).

(3) Perceptual discrimination. (i) Auditory discrimination: this test measures theability to perceive and discriminate between auditory stimuli. The children wererequired to judge whether two orally presented non-words were the same ordifferent. This test encompasses either phonologically similar (such as ‘‘bavi–bavi’’) or different (such as ‘‘tuno–suno’’) items. (ii) Visual discrimination: thegoal of this test was to investigate the ability to discriminate and detectdifferences between nine meaningless pictures in order to find the item thatmatched a given target.

(4) Language. (i) Phonemic segmentation and (ii) Phonemic fusion: these testsinvestigate the ability to process phonemes. In particular the children wererequired to decompose orally presented words into syllables or to composewords starting from singularly presented syllables. (iii) Non-word repetition: the

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ability to perceive and reproduce auditory stimuli was assessed by asking the

children to repeat orally presented non-words (i.e., ‘‘letro’’). (iv) Naming: in this

task the participants had to name 20 pictures of common objects as fast as they

could, even though the response time was not considered for the final score.

This test is specifically designed to evaluate three representational systems,

namely structural, semantic, and phonological systems (Bisiacchi et al., 2005;

Caramazza, Bervdt, & Brownwell, 1982). (v) Syntactic comprehension: here the

children were required to choose one picture among a series of four representing

the sentence read by the examiner. The syntactic complexity of the sentences

increased item by item.(5) Memory and learning. Verbal and visuospatial short- and long-term memory

abilities were assessed by means of different groups of tests, as follows:

(i) Forward digit span, in which the participants had to repeat an increasing

series of numbers in exactly the same order as they had been told. (ii) Corsi’s

block tapping test, in which they had to reproduce the exact spatial sequence of

an increasing series of irregularly placed cubes tapped by the examiner.

(iii) Associated word-pair learning (AWPL) in which the children were required

to learn a list of orally presented pairs of non-semantically associated words, for

example ‘‘oro–cavallo’’ (‘‘gold–horse’’); then, after being orally presented with

the first word of the pair, they had to recall the associated word. (iv) Picture

naming and recall (PNR) which includes a first phase of picture naming and a

second phase of picture recall. The participants were shown a series of pictures

of objects (for example, a pen, a ring, a pipe) and were asked to recall the names

of these objects after a short delay. (v) Immediate verbal list learning (IVLL) in

which the children were required to learn a list of orally presented words and to

recall them immediately after. The verbal list was repeated and reinforced eight

times after each recall attempt by the children. The overall performance was

measured by summarizing the scores obtained across the eight single list

repetition trials. (vi) Delayed verbal list learning (DVLL) in which the same list

as in the IVLL test had to be recalled without reinforcement after a 30-minute

delay.(6) Praxis. Six sub-tests are included in this battery, with the aim of assessing the

ability to execute limb and bucco-facial gestures and motor sequences both to a

verbal command and in imitation. The following sub-scales are included:

(i) Meaningful movement execution to a verbal command – upper limbs (MME-

Uls), with items that examine the ability to execute known limb gestures

described by a verbal command (i.e., the sign of the military salute); (ii)

Meaningless movement execution to a verbal command – upper limbs (MLME-

Uls), with items that examine the ability to execute meaningless limb gestures

given by a verbal command (for example ‘‘touch the tip of the nose with the

index finger’’); (iii) Bucco-facial movement execution to a verbal command (ME-

BF), in which the children were required to execute bucco-facial movements

(i.e., to whistle); (iv) Meaningful movements to imitation – upper limbs (MMI-

Uls), in which the children were required to imitate meaningful gestures

produced by the examiner; (v) Meaningless movements to imitation – upper limbs

(MLMI-ULs), which required them to reproduce meaningless gestures made by

1364 GIOVANNI MENTO ET AL.

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the examiner; (vi) Bucco-facial movements to imitation (MI-BF), whichevaluated the ability of the children to imitate bucco-facial movements.

(7) Selective attention. Two subtests were administered which require the ability todiscriminate a meaningless visual target from among distracters. (i) Selectivevisual attention: in this test the children had to select an abstract symbol thatmatched a target from among distracters. (ii) Selective auditory attention: in thistest the children had to select and respond to a target word from among a list ofwords that were rapidly presented by an auditory modality.

(8) Executive functioning. Standardized tasks specifically designed to measureworking memory, planning, inhibition, set shifting, and fluency were admin-istered. (i) Tower of London (TOL), in which the children had to movedifferent-colored beads across three pegs from an initial configuration to atarget position in as few moves as possible. This test seems to be sensitive to awide range of executive function components, including overall planning andinhibition (Shallice, 1982). (ii) Backward digit span, in which they had to repeatan increasing series of numbers in the reverse order to which they had been told.Besides passively holding the numbers in memory, this task requires participantsto manipulate this information and to inhibit inappropriate responses in orderto produce the right sequence, thus engaging working memory resources.(iii) Phonemic fluency and (iv) Semantic fluency, which required the children toretrieve words that began with a particular phoneme or letter (i.e., C, S, P); or toretrieve words that belonged to a particular category (i.e., animals). Both ofthese fluency tests were based on phoneme stems in order to make the taskeasier for younger children. These tests measure the capacity to strategicallyaccess the verbal mnestic store while inhibiting words that do not conform tothe rules of the task (Anderson, Anderson, et al., 2002). They have been claimedto be two of the most sensitive measures of frontal lobe dysfunction (Stuss &Benson, 1986). (v) The Elithorn maze perception test, which required theparticipants to find and draw a pathway, using a pencil, which passed throughthe greatest possible number of dots without crossing from one path to another.Each pattern is designed so that there is only one correct series of dots throughwhich the pathway can pass, although there may be several alternative routesthrough the correct series (Elithorn, 1955).

Statistical analyses

The non-parametric Kruskal-Wallis test was performed on data related to thelevel of neurological and motor impairment severity, as scored by the clinical scale,in order to establish the presence of differences between the DMD and JRA groups.To correct for the effect of the age we transformed the raw scores obtained from theBVN as well as from Raven’s reasoning test into normalized z-scores for eachparticipant by using the normative data for each test. Furthermore, we calculatedage-corrected scores for general intelligence tests (WISC or WPPSI). The z-scoresobtained from the single BVN tests were grouped into six clusters representingdifferent cognitive domains (perceptual discrimination, language, memory andlearning, praxis, selective attention, and executive functions), whereas the standard

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scores obtained from the Raven’s colored matrices test and from the WISC/WPPSIbattery were grouped into two separate additional clusters. The resulting eightclusters were then entered in separate multivariate analyses of variance(MANOVAs). The combined effect of multiple measures was analyzed in orderto individuate the presence of overall group differences across cognitive domains(Palmieri, Manara, Bello, Mento, Lazzarini et al., 2011; Wicksell et al., 2004).Furthermore the MANOVA also returned univariate analyses of variance(ANOVAs), in which the mean scores of each single test within each cognitivedomain were compared between the groups. This allowed us to statistically verifythe presence of significant group differences within each test composing a cognitivedomain. A Bonferroni correction was used for multiple comparisons. The effect sizewas estimated by calculating the partial eta square (Z2

p).

RESULTS

The mean test scores for each group and the results of the statistical analysesare reported in Table 1. No differences were found between groups regarding thelevel of impairment severity (p4.05), meaning that the DMD and JRA groupscould be considered comparable regarding motor function.

As a general consideration, the mean performance of both groups for each testwas largely within 1.5 standard deviations, (except for Auditory discrimination,where DMD reported scores below 2 standard deviations), meaning that all childrenshowed performances within the normative ranges. Nevertheless, while JRA groupalways showed mean z-scores close to zero, children with DMD reported scoresbelow 1 standard deviation in some of the tests employed (Table 1), accounting formore deficient performances than age-level expectations. As an example, the JRAgroup mean on the Verbal IQ tests was 96, then within normal limits, whereas thePerformance IQ was 86, that is around 1 SD below age level expectations.

Overall, the MANOVAs revealed the presence of statistically significantbetween-group differences in perceptual discrimination, F(2, 24)¼ 6.08; p5 .01;Z2p¼ .34, language, F(5, 16)¼ 4.06; p5 .02; Z2

p¼ .56, and executive functiondomains, F(5, 16)¼ 5.34; p5 .005; Z2

p¼ .62, accounting for the general difficultiesof the DMD group in such cognitive domains. In addition the ANOVAs performedon single tests within each of the eight cognitive domain clusters revealed significantdifferences between the groups in the tests described below.

General intelligence

The children with DMD obtained full scale IQ scores of around 1 SD belowthe normative mean. The performance IQ did not significantly differ between thetwo groups, whereas verbal IQ was significantly lower in children with DMD thanin children with JRA, F(1, 25)¼ 5.09, p5 .05; Z2

p¼ .20.

Abstract reasoning

With regard to general abstract reasoning there was no difference between themean scores of the groups as measured by Raven’s Colored Progressive matrices.

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Table 1. Mean test scores and related group statistics

MANOVA ANOVA DMD JRA

Cognitive domain and test F p-value Z2p F p-value Z2

p M MSE M MSE

General Intelligence 2.46 ns –

Verbal IQ 5.09 5.05 0.20 83.20 4.87 98.08 4.44

Performance IQ 2.67 ns – 84.30 5.32 86.08 4.86

Reasoning

Raven’s Colored Matrices 1.77 ns – –0.25 0.36 0.67 0.37

Perceptual Discrimination 6.20 5.01 0.34

Auditory discrimination 9.60 5.05 0.27 –2.70 0.43 –0.74 0.45

Visual discrimination 2.82 ns – –0.68 0.28 0.05 0.29

Language 4.06 5.02 0.56

Phonemic segmentation 9.99 5.01 0.33 –1.28 0.37 0.41 0.37

Phonemic fusion 0.13 ns – 0.01 0.50 –0.24 0.50

Non-words repetition 1.43 ns – –0.20 0.29 –0.29 0.29

Naming 3.04 ns – –0.90 0.33 0.74 0.33

Syntactic comprehension 0.87 ns – –0.30 0.33 0.13 0.33

Memory and Learning 1.68 ns –

Forward digit span 3.56 ns – –0.32 0.29 0.42 0.26

Corsi’s block tapping test 3.28 ns – –1.42 0.49 –0.21 0.44

AWPL 0.20 ns – –0.22 0.32 –0.42 0.29

PNR 0.02 ns – 0.42 0.35 0.50 0.32

IVLL 6.11 5.05 0.25 –1.35 0.44 0.11 0.40

DVLL 1.43 ns – –0.49 0.30 –0.01 0.27

Praxis 1.81 ns –

MME–Uls 3.58 ns – –0.13 0.28 0.64 0.29

MLME–Uls 1.11 ns – –1.20 0.33 –0.68 0.35

ME–BF 0.68 ns – –0.52 0.33 –0.92 0.34

MMI–Uls 4.25 5.05 0.14 –0.27 0.24 0.45 0.25

MLMI–Uls 6.50 5.02 0.20 –1.19 0.41 0.34 0.43

MI–BF 0.56 ns – –0.14 0.21 0.36 0.21

Attention 0.34 ns –

Selective visual attention 0.03 ns – 0.33 0.48 0.20 0.48

Selective auditory attention 1.97 ns – –0.80 0.43 0.06 0.43

Executive Functions 5.34 5.005 0.62

Backward digit span 0.01 ns – 0.47 0.33 0.42 0.33

Tower of London 11.09 5.01 0.36 –0.64 0.25 0.54 0.25

Phonemic Fluency 5.86 5.05 0.23 –0.78 0.35 0.41 0.35

Semantic Fluency 10.81 5.005 0.35 –1.11 0.24 0.03 0.24

Elithorn Perceptual Maze test 11.49 5.005 0.36 –0.31 0.21 0.72 0.21

M¼Mean scores corrected by age (z–scores or standardized scores); MSE¼Mean Standard Error;

ns¼not–significant, i.e. p4.05; AWPL¼Associated Words’ List Learning; PNR¼Picture naming and

recall; IVLL¼ Immediate Verbal List Learning; DVLL¼Delayed Verbal List Learning;

MME–Uls¼Meaningful Movements Execution to Verbal Command – Upper Limbs;

MLME–Uls¼Meaningless Movements Execution to Verbal Command – Upper Limbs; ME–

BF¼Bucco–Facial Movements Execution to Verbal Commands; MMI–Uls¼Meaningful Movements

to Imitation – Upper Limbs; MLMI–ULs¼Meaningless Movements to Imitation – Upper Limbs;

MI–BF¼Bucco–Facial Movements to Imitation.

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Perceptual discrimination

In the Auditory discrimination test the children with DMD showed signif-icantly lower scores than the children with JRA, F(1, 20)¼ 9.60; p5 .01; Z2

p¼ .28.No between-group differences were found regarding visual discrimination.

Language

The ANOVAs revealed that the children with DMD scored significantly lowerthan the control group in the phonemic segmentation test, F(1, 20)¼ 9.99; p5 .01;Z2p¼ .33, while the performance in all of the other tests was comparable with the

JRA group.

Memory and learning

Among the tests used to investigate memory, children with DMD obtainedsignificantly lower mean scores than children with JRA in the IVLL test,F(1, 20)¼ 6.11; p5 .05; Z2

p¼ .25. No significant differences were found in all ofthe other tests that assessed short or long-term memory, both for verbal and non-verbal stimuli.

Praxis

Compared to children with JRA, the children with DMD showed a poorerperformance in executing meaningless, MLMI-ULs; F(1, 20)¼ 6.50; p5 .02;Z2p¼ .20, and meaningful, MMI-Uls; F(1, 20)¼ 4.25; p5 .05; Z2

p¼ .14, movementsto imitation. No differences were found in the other praxis tasks.

Selective attention

The mean scores of the DMD and JRA groups did not differ in either theselective visual or in the auditory attention tests.

Executive functions

The mean number of correctly reproduced configurations in the Tower ofLondon test was lower in the DMD group compared to the JRA group,F(1, 20)¼ 11.09; p5 .01; Z2

p¼ .36. The phonemic fluency, F(1, 20)¼ 5.86; p5 .05;Z2p¼ .23, semantic fluency, F(1, 20)¼ 10.81; p5 .005; Z2

p¼ .35, and Elithorn mazeperception test results, F(1, 20)¼ 11.49; p5 .005; Z2

p¼ .36, also differed between thegroups, with poorer performances from the DMD children.

DISCUSSION

The general aim of the present study was to characterize the cognitive profileof infantile DMD by means of an extensive neuropsychological battery, whichincluded a large number of tests in order to assess all of the main cognitive domains.

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Specifically we addressed the question of whether cognitive functions other thanverbal ones could be impaired in such a population. Additionally, in order tocontrol for the contribution of motor impairments as a confounding variableusually present when assessing children with muscular pathologies, we comparedchildren with DMD to a group of children with an autoimmune pathology that doesnot entail either brain or cognitive dysfunction but does imply motor impairment:juvenile rheumatoid arthritis (JRA). The two groups were matched for age and thelevel of severity of motor impairment.

As a first result, the MANOVA tests identified three specific cognitivedomains in which the overall performance of the DMD group scored significantlylower than the JRA group: perceptual discrimination, language, and executivefunctions. No overall differences were found in multivariate analyses regardinggeneral intelligence, reasoning, memory and learning, attention, or praxis, indicat-ing that such domains were not largely affected. In particular the mean score in theRaven’s test did not differ between the groups, meaning that children with DMD donot present specific difficulties in abstract logical reasoning, which is consistent withthe results of previous studies (Cotton et al., 1998; Wicksell et al., 2004).

The univariate ANOVAs performed within each cognitive domain confirmedthat the general low performance of DMD children that was observed in theMANOVAs for language, perceptual discrimination, and executive functionsdepended on low performances in some specific tests included in such categories.Indeed, the DMD group showed significantly lower scores in the tests that engagedauditory discrimination and phonological manipulation. On the other hand, theyshowed performances that were as good as those in the JRA group in the languagetests requiring verbal comprehension (i.e., sentence repetition) and production (i.e.,naming). This pattern of results may reflect a specific deficit in phonologicalprocessing, specifically in tasks requiring phonemic manipulation, such as segmen-tation. These data are in line with previously reported findings (Billard et al., 1992,1998; Dorman et al., 1988; Hinton et al., 2000, 2001, 2007; Leibowitz, & Dubowitz,1981). In this regard it may be very important to address in future studies therelationship between phonological abilities and reading acquisition in children withDMD, considering that reading difficulties have been previously reported in such apopulation (Billiard et al., 1998).

Although the MANOVAs revealed no overall differences between the groupsin domains other than language, perceptual discrimination, and executive func-tioning, the ANOVA performed on the single tests revealed additional groupdifferences. In this regard the intellectual profile of children with DMD wascharacterized by significantly lower verbal IQ scores, whereas no differences werefound between the groups in the performance IQ. This result is in line with most ofthe studies that reported worse scores in verbal than in intelligence performance inDMD (Anderson et al., 1988; Dorman et al., 1988; Leibowitz & Dubowitz, 1981;Michalak & Opas, 1997; Ogasawara, 1989; Prosser, 1969; Rapaport et al., 1992). Ofnote, both groups obtained a performance IQ score of around 1 SD below thenormative mean. This result is probably attributable to motor impairments.Furthermore, concerning the memory and learning domain, univariate ANOVAsshowed that the performances of children with DMD were poorer in the picturenaming and recall test (PNR), which is a task that requires the naming of pictures

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and the recall of these names after a short retention delay. Consistent with previous

reports that showed children with DMD to have short-term verbal memory deficits

(Cotton et al., 1998; Wicksell et al., 2004), we found children with DMD to be

impaired in the immediate but not in the long-term recall. According to some

authors, a limited verbal span may be the basis of this impairment in children with

DMD (Cyrulnik & Hinton, 2008). No differences were reported between the groups

in tests engaging long-term verbal memory (i.e., associated word-pair learning) or

visuo-spatial memory (Corsi’s test). Interestingly, children with DMD also

performed significantly worse in some subtests of the praxis domain, which

required the execution of meaningful and meaningless movements with the upper

limbs to imitation, whereas they correctly executed meaningful and meaningless

gestures to a verbal command, as well as bucco-facial movements. The difficulty in

the implementation of both known and unknown gestures may be associated with a

deficit in planning motor sequences. The fact that motor sequences were performed

worse to imitation than to a verbal command suggests that linguistic and semantic

aspects may facilitate the retrieval and production of motor actions in this

pathological population, both with and without meaning. As far as we know, praxis

has never been evaluated in the DMD population, although it may provide

important insights into the interplay between cognitive and motor processes. In this

regard it would be interesting to further investigate the mechanisms underlying the

relationship between motor and cognitive impairments, which could be critical in

such a clinical population.Neither visual scores nor auditory selective attention test scores were

significantly different between the groups. On the contrary, the performance of

the children with DMD in the executive functioning tasks evaluating visuo-spatial

planning, problem solving (Tower of London and Elithorn maze tests), and verbal

fluency (Phonemic and Semantic fluency) was poorer compared to the JRA group.

Interestingly these results suggest that, although no difficulties were present in the

children with DMD when they were required to simply attend to specific stimuli

among others, as required in the selective attention tests, they nonetheless showed

difficulties in processing stimuli that demanded a higher cognitive control. This was

the case in the tasks that necessitated holding and manipulating information

(working memory), shifting from one cognitive set to another (set shifting), and

inhibiting unsuccessful strategies (Tower of London), for example. In this regard the

Tower of London test has previously been reported to discriminate between controls

and children with DMD, with the latter needing more time and a larger number of

moves to correctly reach the final configuration (Wicksell et al., 2004). Likewise,

they obtained lower scores in the verbal fluency test, i.e., they showed difficulties in

retrieving words from the lexicon, presumably because they failed to adopt efficient

strategies to access phonologically and semantically cued words. Finally, in the

Elithorn maze test, they encountered some difficulties in correctly planning the

visuo-spatial strategy, as they spent more time and showed more errors in

identifying the best pathway for successfully completing the task.The poorer performances observed across several executive functioning tasks,

which engaged either verbal or visuo-spatial modalities, suggests a high-order global

cognitive impairment. Importantly, the effect sizes of the group difference in the

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executive functioning domain were large (Clark-Carter, 1997), meaning that thisarea is affected to a greater extent.

Compared to previous studies that assessed cognitive functioning in childrenwith DMD, our results show that executive functioning difficulties may exist inaddition to the lower-level phonological and verbal short-term memory impair-ments already described in the literature. Indeed, after the initial claim of a specificverbal deficit core (Cotton et al., 1998; Hinton et al., 2000), evidence of additionaldeficits in infantile DMD in executive functioning, memory, and visuo-spatialabilities has been reported. In this regard Cotton et al. (1998) were the first topurposely investigate executive functions (EF) in children with DMD, examiningthe ability to efficiently and effectively employ strategies for word list generation aswell as the participants’ attention and capacity to substitute symbols for numbers.In both instances the performance of the participants with DMD was significantlypoorer than the controls. In line with these results, Hinton et al. (2001) reportedworse performances in children with DMD compared to their siblings in tests thatassessed abstract/conceptual skills, such as comprehension and similarity subtestsfrom the WISC-III (Wechsler, 1991). Even though this sub-scale cannot beconsidered a specific EF test, the authors considered it to assess high-order,conceptual reasoning. More recently, Wicksell et al. (2004) assessed EFs in childrenwith DMD by using specific tests, such as the Trail Making Test (TMT) A and B,Rey complex figure planning, the Tower of London and verbal fluency tests. Byusing a MANOVA statistical approach similar to that employed in the presentstudy, they also found that the DMD group performed significantly worse in allaspects of executive functioning in addition to memory and learning problems.Finally, Donders and Taneja (2009) used some of the tests from the Delis-KaplanExecutive Function System battery (D-KEFS; Delis, Kaplan, & Kramer, 2001),including letter, category, and design fluency. However, group differences were onlystatistically significant for the Shift score. Comparing the different studies it shouldbe noted that there is no complete agreement on which tests are to be employed inorder to assess executive functioning. In this regard some authors categorized thetests that assess high-order cognitive functioning as belonging to the EF spectrum(Donders & Taneja, 2009), to abstract/conceptual tasks (Hinton et al., 2001), or tocomplex attention (Cotton et al., 1998) tasks. Nevertheless, these conceptualdifferences in the results seem to converge towards a general compromising of suchabilities, both in the verbal (i.e., Phonological and Semantic fluency tests) and thenon-verbal (i.e., Tower of London, Trial Making tests) domains, makingthe impairment of high-order intellectual abilities a common finding in all of thestudies that investigated cognitive domains other than the verbal one ininfantile DMD.

However, although the data seem to converge towards a global rather than aspecific cognitive impairment in infantile DMD, some issues remain open regardingthe real nature of the neuropsychological profile in such pathology. Indeed,although short-term verbal memory impairment seems to be a common finding, asmost of these studies reported poor performances in story recall and verbal digitspan (Hinton et al., 2001; Wicksell et al., 2004), poor performances for visuo-spatialtests have also been reported, thus contradicting the idea that cognitive deficits ininfantile DMD are related to the type of stimulus presented (Donders & Taneja,

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2009; Wicksell et al., 2004). Furthermore, poorer long-term memory performancesin both visual and verbal delayed recall tests were also found in children with DMDcompared to their siblings (Donders & Taneja, 2009). It has been suggested (Solleeet al., 1985) that a possible source of variability in the intellectual functioning ofchildren with DMD, for example, the discrepancies observed in the findings forverbal and spatial processing, may be derived from different subtypes of thedisorder (Cotton et al., 2001). In order to address this issue, detailed neuropsycho-logical data would need to be considered in relation to genetic analyses. Anotherissue that may contribute to the different profile of infantile DMD described inliterature is the possible presence of confounding factors, such as parental educationand socio-economical status. Some authors controlled for these variables whencomparing children affected by DMD with their siblings (Donders & Taneja, 2009).Although we did not observe relevant qualitative differences at the time of theanamnesis, we did not specifically address this aspect with quantitative measures.This may comprise a limitation of the present study.

The executive dysfunction observed may presumably be related to an alteredintegration of different perceptual and cognitive functions, which occurs at a higherlevel of processing. As proposed by an integrative theoretical framework recentlyreviewed by Garon, Bryson, and Smith (2008), the interaction of both a centralexecutive attentional core and partially dissociable executive components may bethe basis of the development of higher level abilities (Miyake et al., 2000). Accordingto this framework, the emergence and strengthening of a cortical attentionalnetwork during preschool years and later is hypothesized as promoting thedevelopment of executive functioning.

From a neurobiological point of view, one could speculate that the executivedysfunction observed in DMD children may rely on DYS depletion, which results inthe altered development of the neural network involving integration between theneocortical association cortex and the hippocampal regions, with a potentiallycrucial mediating role for the cerebellum (Cyrulnik & Hinton, 2008; Donders &Taneja, 2009; Hinton et al., 2001; Mehler, 2000). In this regard, in a PET study, Leeet al. (2002) investigated brain glucose metabolism in children with DMD andidentified specific neural structures that showed altered glucose consumption(hypometabolism), including the medial temporal structures, the cerebellumbilaterally, and the sensorimotor and lateral temporal cortices of the righthemisphere.

A recent review by Cyrulnik and Hinton (2008) argued that at the basis of theabnormalities in areas of verbal short-term memory and phonological languageprocessing would be the absence of cerebellar-DYS (here referred to the ‘‘cerebellarhypothesis’’). Cerebellar activation has been well documented in cognitive tasksrequiring phonological processing (Awh et al., 1996; Cabeza et al., 1997; Chen &Desmond, 2005; Crottaz-Herbette, Anagnoson, & Menon, 2004; Honey, Bullmore,& Sharma, 2000; Jonides et al., 1997, 1998; Paulesu, Frith, & Frackowiak, 1993;Schumacher et al., 1996; Smith et al., 1996); on the other hand, it does not appear tobe involved in spatial working memory tasks (Smith et al., 1990). In light of theresults of the present study, however, the hypothesis of a specific cerebellardysfunction as the ‘‘core’’ of selective verbal impairment in DMD, as recentlyproposed by Cyrulnik and Hinton (2008), appears to be only partly satisfactory

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since the heterogeneous neuropsychological profile that we found accounts for awider CNS involvement, presumably implying different cerebro-cerebellar circuitsconnecting the cerebellum to the hippocampus and parietal and frontal corticalareas. Promising neuroimaging tools specifically designed to depict brain connec-tivity, such as diffusion tensor imaging (DTI; Huppi & Dubois, 2006; Le Bihan,2003) and functional connectivity magnetic resonance imaging (fc-MRI;Damoiseaux et al., 2006), could be efficiently applied in DMD in order tosensitively detect the eventual malfunctioning of integration between the differentbrain regions.

In conclusion, the current study only partially supports the view of a selectivedeficit in verbal skills in infantile DMD, as previously suggested by some otherauthors (Hinton et al., 2001, 2007). Indeed, in agreement with other studies(Donders & Taneja, 2009; Wicksell et al., 2004), we reported additional evidence ofcognitive impairment in children with DMD in domains other than language,particularly involving the executive functioning.

As a final consideration, the present findings suggest that executive subclinicaldysfunctions could be considered as a general, rather than specific, marker ofcognitive dysfunction, given that they are common in a broad range of clinicalpopulations that do not share similar etiopathogenetic mechanisms and which arecharacterized by different CNS alterations, such as focal or diffused lesions.

ACKNOWLEDGMENTS

The authors would like to thank all of the children and their families whoparticipated in the study as well as the staff of the Gaslini Children’s Hospital ofGenoa, Italy. There are no known potential conflicts of interest.

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