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Neuroscience and Biobehavioral Reviews 37 (2013) 743–752

Contents lists available at SciVerse ScienceDirect

Neuroscience and Biobehavioral Reviews

jou rn al h om epage: www.elsev ier .com/ locate /neubiorev

eview

europsychological and neurobehavioral functioning in Duchenne muscularystrophy: A review

anda M. Snowa,∗, Judy E. Andersonb,1, Lorna S. Jakobsona,1

Department of Psychology, Faculty of Arts, P404 Duff Roblin Building, 190 Dysart Road, University of Manitoba, Winnipeg, Manitoba R3T 2N2, CanadaDepartment of Biological Sciences, Faculty of Science, Biological Sciences Building, 50 Sifton Road, University of Manitoba, Winnipeg, Manitoba R3T 2N2, Canada

r t i c l e i n f o

rticle history:eceived 1 February 2013eceived in revised form 21 March 2013ccepted 22 March 2013

eywords:uchenne muscular dystrophyystrophineuropsychology

a b s t r a c t

Duchenne muscular dystrophy (DMD) is a genetic condition affecting predominantly boys that is charac-terized by fatal muscle weakness. While there is no cure, recent therapeutic advances have extended thelifespan of those with DMD considerably. Although the physiological basis of muscle pathology is well-documented, less is known regarding the cognitive, behavioral, and psychosocial functioning of thoseafflicted. Several lines of evidence point to central nervous system involvement as an organic feature ofDMD, challenging our view of the disorder as strictly neuromuscular. This report provides a review ofthe literature on neuropsychological and neurobehavioral functioning in DMD. Recent research identify-ing associations with DMD and neuropsychiatric disorders is also discussed. Lastly, the review presents

ntelligenceognitionerbal memoryeurobehavioraleuropsychiatricocial interaction

implications of findings related to nonmotor aspects of DMD for improving the quality of life in thoseaffected. While the literature is often contradictory in nature, this review highlights some key findingsfor consideration by clinicians, educators and parents when developing therapeutic interventions for thispopulation.

© 2013 Elsevier Ltd. All rights reserved.

utism

ontents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7432. Intellectual functioning in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 744

2.1. General intellectual functioning . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7442.2. Verbal vs. performance IQ . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7452.3. Specific cognitive deficits in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 745

2.3.1. Specific Deficits Identified using a Neuropsychological Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7453. Psychosocial and neurobehavioral functioning in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7484. Neuropsychiatric disorders in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7485. Implications of neuropsychological and neurobehavioral findings in DMD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7496. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 750

. Introduction

Duchenne muscular dystrophy (DMD) is an X-linked recessiveenetic disorder that affects approximately one in 3500 male births

∗ Corresponding author. Tel.: +1 204 250 7617; fax: +1 204 254 2153.E-mail address: wssnow@mymts.net (W.M. Snow).

1 Equal contributors.

149-7634/$ – see front matter © 2013 Elsevier Ltd. All rights reserved.ttp://dx.doi.org/10.1016/j.neubiorev.2013.03.016

(Emery, 1991). Mutations within the largest gene in the humangenome, the dystrophin gene, result in a lack of expression of thefunctional form of its major protein product, dystrophin (Hoffmanet al., 1987). Dystrophin is essential in maintaining structuralintegrity of muscle membranes during contraction; its absenceresults in muscle fiber damage, chronic inflammation and fibro-

sis (Wallace and McNally, 2009) that result in progressive muscleweakness and death, generally in the third decade, due to cardiacand pulmonary complications.

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The physiological mechanisms responsible for fatal muscleathology in DMD are relatively well understood, and the disease

s classically considered neuromuscular in nature. Given this, it iserhaps not surprising that, even though the original description ofhe disorder by Duchenne (1868) noted decreased intellectual abili-ies, historically, little attention has been paid to cognitive or othereurobehavioral characteristics of those afflicted. There is, how-ver, compelling and cumulative evidence to argue for a primaryentral nervous system (CNS) involvement in DMD, both at the cel-ular level and from a clinical perspective, such that some arguehat DMD should be regarded as a disorder of brain and muscle,s opposed to one that is primarily muscular in origin (Hendriksent al., 2009).

Dystrophin is present in many brain regions responsible forigher order functions such as learning and memory, includinghe cerebral cortex, hippocampus, and cerebellum (Lidov et al.,990; Huard and Tremblay, 1992). Dystrophin expression in cen-ral neurons, however, is under the control of various promoters;he P-promotor regulates Purkinje neuron dystrophin expression,hereas the C-promotor regulates hippocampal and cerebral cor-

ical expression (Blake et al., 1999; Gorecki et al., 1992). In additiono the full-length dystrophin found in central neurons and muscle,runcated dystrophin isoforms are also located in the periph-ral and central nervous system, including Dp71, Dp116, Dp140,nd Dp260 (see Perronnet and Vaillend, 2010 for review). In therains of those with DMD, dystrophin is absent (Kim et al., 1995).t autopsy, brains devoid of dystrophin exhibit neuropathology,

ncluding gliosis, neuronal loss (Dubowitz and Crome, 1969), het-rotopias, and cortical thickening (Rosman and Kakulas, 1966).euroimaging studies, although few in number, reveal abnormal-

ties in brain function among those with DMD. A study usingositron emission topography (PET) demonstrated reduced glucoseetabolism in those with DMD, specifically in areas that are typ-

cally rich in dystrophin (e.g., cerebral cortex and cerebellum; Leet al., 2002). In the motor cortex, local synchronization of sponta-eous activity of neural networks is reduced in those with DMD, aseasured by resting-state functional magnetic resonance imaging

RS-fMRI) (Lv et al., 2011). Further, a study using transcranial mag-etic stimulation (TMS) found hypoexcitability in the motor cortexf those with DMD (Di Lazzaro et al., 1998).

Although secondary to evaluating possible life-saving or evenurative treatments for the muscular aspects of the disorder,horough understanding of the neuropsychological and neuro-ehavioral consequences of DMD is exceedingly well justified.irstly, psychosocial and cognitive functioning have a major impactn quality of life. Especially among school-aged boys, deficitsn cognitive abilities and their consequences on academic per-ormance can negatively affect self-esteem and self-confidence

of particular importance in a population already dealing with devastating and functionally isolating physical condition. Sec-ndly, neurobehavioral and psychosocial functioning can impactnderstanding of and adherence to medical treatments. For exam-le, steroids are the current gold-standard treatment prescribedo delay disease progression. The most commonly reported rea-ons for the discontinuation of steroids, however, are the moodnd behavioral side effects (Poysky and Behavior in DMD Studyroup, 2007). Understanding the neuropsychological and behav-

oral profile of those with DMD from an early age can assist inistinguishing behavioral and emotional issues associated with theisorder from those arising secondary to steroid treatment, anday prove helpful in improving adherence. Other medical advances

n the treatment of DMD have increased the lifespan for those

fflicted; this has resulted in an adult population with DMD forhom longer-term neuropsychological and neurobehavioral ram-

fications of living with the disorder are unknown (Rahbek et al.,005). The best way to ensure that those diagnosed with DMD

avioral Reviews 37 (2013) 743–752

develop adequate emotional, social, and cognitive skills as adultsis to improve our ability to identify problems in these areas earlyon so that available interventions may be started as soon as possi-ble.

The central aim of this review is to provide a critical descriptionof the literature detailing neuropsychological and neurobehavioralfunctioning in those with DMD. Overall functioning in DMD ismultifactorial and includes a complex interplay of factors that iscurrently poorly understood. For the purposes of this review, how-ever, neuropsychological and neurobehavioral functioning in DMDwill be discussed according to: 1) general intellectual functioningand specific cognitive deficits, 2) psychosocial and behavioral func-tioning, and 3) comorbidities with neuropsychiatric illnesses. Asthe vast majority of studies examining non-motor functioning inDMD have focused on the cognitive profile, particular emphasis willbe given to this area of functioning. Lastly, we present a discussionof the implications of these finding for researchers, clinicians, par-ents and educators committed to reducing the burden of diseaseand improving quality of life for those affected by this disorder.

2. Intellectual functioning in DMD

2.1. General intellectual functioning

Reduced overall intellectual functioning is a consistent find-ing in the clinical literature on DMD. Cohen et al. (1968) reportedan increased prevalence of intellectual disability in DMD rela-tive to the general population (20.9% versus 3%, respectively)using intelligence quotient (IQ) scores. The validity of the studywas limited, however, due to the fact that some IQ scores wereestimated from physician, teacher, or parent reports rather thanby psychometrically-sound measures of intelligence. Nonetheless,estimates of global intellectual functioning by Prosser et al. (1969),using the Wechsler Intelligence Scale for Children (WISC; Wechsler,1949) and Wechsler Adult Intelligence Scale (WAIS; Wechsler,1939), replicated the finding of increased prevalence of intellectualdisability in DMD relative to unaffected siblings. Moreover, meanscores for the Full Scale Intelligence Quotient (FSIQ), which includesscores from both verbal and performance subtests, were approxi-mately one standard deviation below mean sibling FSIQ scores inthe DMD group. Such findings rule out socioeconomic factors, suchas family income and parents’ education levels, as primary factorsaffecting intellectual functioning, as both those with DMD and theirsiblings shared these known correlates of intelligence. FSIQ scoreswere not significantly correlated with disease severity, nor did theyprogressively worsen with age, suggesting that impaired intellec-tual functioning is not secondary to muscle degeneration or theenvironmental impediments it may place on a child, including pos-sible reduced educational and social opportunities; in both cases,scores would be expected to decline with age and the progres-sion of muscle pathology. Together, these early findings pointedto a primary, organic cause of decreased intellectual functioning inDMD due to CNS involvement, even prior to reports identifying thedystrophin protein, its localization to specific brain areas, and itsabsence in those with DMD.

To elucidate the extent to which both the primary motordeficits and any consequential environmental deprivation nega-tively impact intellectual function, Ogasawara (1989) comparedFSIQ scores of two groups of boys raised in the same residentialschool – one group with DMD and another with spinal muscularatrophy (SMA), another fatally progressive neuroskeletal disorder.

FSIQ scores were reliably lower in those with DMD relative to thosewith SMA. This result provides arguably the strongest support fora primary intellectual deficit in DMD that is not attributable tosequelae of musculoskeletal dysfunction and motor impairment,

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ncluding reactive responses to the disorder, or social or environ-ental deprivation.

.2. Verbal vs. performance IQ

Although reports of global intellectual deficits have beenescribed in the literature on DMD, considerable debate remainss to whether there is any selective impairment in verbal or non-erbal intellectual abilities. In some reports, those with DMD haveeen found to score similarly on the verbal IQ (VIQ) and Per-ormance IQ (PIQ) scales (Black, 1973) and to score similarly toheir unaffected siblings on both measures (Donders and Taneja,009). However, most studies suggest that those with DMD tend toerform more poorly on the verbal than the performance meas-res of intelligence tests, although the size of the discrepancyetween VIQ and PIQ measures varies across studies (Dorman et al.,988; Karagan and Zellweger, 1978; Karagan, 1979; Leibowitz andubowitz, 1981; Marsh and Munsat, 1974). It is important to note,owever, that even when this pattern is observed overall, therean be considerable variability within this diagnostic group – withany individuals with DMD actually showing lower PIQ than VIQ

cores, rather than the reverse (see Marini et al., 2007).In what can be regarded as the most inclusive study examin-

ng intellectual ability in DMD and the relationship between FSIQ,IQ and PIQ within this group, Cotton et al. (2001) conducted

meta-analysis with data from 32 studies carried out between960 and 1999 in which IQ data were collected. The FSIQ, VIQ,nd PIQ scores for 1146 males with DMD (age 2–27 years) werenalyzed to determine the level of general intellectual impairmentnd the prevalence of intellectual disability associated with DMD.lso evaluated was the degree, if any, to which verbal intelligenceas particularly affected in DMD. IQ scores are standardized such

hat the mean score within a given age group is set to 100, with atandard deviation of 15. Cotton et al. compared DMD group meansn all three IQ scales to the relevant population mean of 100 andound that, although all three measures were normally distributed,hose with DMD scored roughly one standard deviation below theopulation mean on each scale (MFSIQ = 80.2, MVIQ = 80, MPIQ = 85.4).

n addition, 34.8% of those with DMD had scores indicative of intel-ectual disability. The mean VIQ–PIQ discrepancy was normallyistributed but was significantly larger than expected in the gen-ral population at −5.1 (SD = 14.4). The results of the meta-analysisubstantiated decades of earlier research demonstrating decreasedeneral intellectual functioning and an increased rate of intellec-ual disability in those with DMD and supported the conclusionhat verbal intellectual abilities are slightly more vulnerable thanerformance-based skills in this populations.

Investigators interested in studying intellectual abilities in DMDo need to consider the impact that motor disability may have onest performance. This is particularly true during completion of theubtests comprising the PIQ scale, as these subtests are often timednd require graphomotor and/or constructional skills that mighte compromised in those with reduced motor strength. To controlor effects on intellectual functioning related to motor impairment,ome investigators interested in DMD have included age-matchedomparison groups of children with motor impairments arisingrom other conditions. Despite showing similar levels of motormpairment and comparable PIQ scores, children with DMD haveeen found to exhibit significantly lower VIQ scores than chil-ren with either SMA (Billard et al., 1992), or those with juvenileheumatoid arthritis (Mento et al., 2011). These data indicate that,ithin the age groups studied, motor impairment has not been a

ajor confound in studies examining the VIQ–PIQ discrepancy inMD.

This conclusion gains strength from studies exploring possi-le age-related changes in intellectual functioning in DMD. It is

avioral Reviews 37 (2013) 743–752 745

important to conduct studies of this nature as, due to the pro-gressive nature of the disease, affected individuals show gradualdeterioration in motor function due to progressive weakness andjoint instability associated with the functional deterioration ofmuscle. Given the progressive loss in motor function, we mightexpect PIQ scores (and, therefore, FSIQ scores) to decrease overtime in those with DMD. However, the literature provides little sup-port for this prediction. Thus, in both cross-sectional (Dorman et al.,1988) and longitudinal studies (Prosser et al., 1969), FSIQ and PIQhave been found to remain stable in DMD. Interestingly, this maynot be the case for VIQ, although results in this regard are variable.Some authors find no relationship between age and VIQ (Dormanet al., 1988; Leibowitz and Dubowitz, 1981), while others find thatVIQ either decreases (Black, 1973) or increases (Miller et al., 1985;Prosser et al., 1969) as a function of age.

Using the same compiled data set of DMD intelligence scoresfrom multiple studies described in their earlier work (Cotton et al.,2001), Cotton et al. (2005) performed a meta-analysis to examineage-related changes in intellectual functioning in DMD. Althoughthere was a relationship between age and disease severity, asexpected, with more of the older DMD groups exhibiting advancedmotor impairment, the various age groups did not differ withrespect to PIQ or FSIQ scores. On the other hand, verbal function, asmeasured by VIQ scores, was significantly higher in the older DMDgroups, relative to the younger groups. As a result of this age-relatedchange in verbal function, a “closing of the gap” between verbal andperformance measures was evident, with the size of the VIQ–PIQdiscrepancy declining significantly across the age groups – beinglargest in the youngest group (age nine and under) and smallest inthe oldest group (20 years and older).

To summarize, despite inconsistencies in the literature, themajority of studies suggest that, from a population perspective,verbal intelligence is particularly susceptible to impairment in theabsence of brain dystrophin. Although the work of Cotton et al.(2005) suggests that the verbal impairment may lessen over time,this cannot be verified without longitudinal studies documentingthe developmental trajectory of intellectual functioning in this pop-ulation.

2.3. Specific cognitive deficits in DMD

Despite the well-documented intellectual deficits seen in DMD,there is considerable variability in intellectual functioning in thisgroup. To explain this variability and, in so doing, gain a deeperappreciation of the role of dystrophin in brain development andfunction, it is important to move beyond global IQ measures orother composite scores and look at how those with DMD perform ontests assessing specific cognitive abilities. In the following section,we review some of the work that has been done in this area.

2.3.1. Specific Deficits Identified using a NeuropsychologicalApproach

Dorman et al. (1988) carried out one of the first studies designedto provide a detailed, neuropsychological evaluation of thoseaffected by DMD. Fifteen adolescent males completed a battery of16 motor-free tests used to assess performance in five cognitivedomains: (1) simultaneous processing, (2) sequential processing,(3) auditory analysis, (4) expressive speech, and (5) receptivespeech. Using normative data for comparison, the researchersestablished a cutoff score of one standard deviation below themean to identify individuals with DMD who were performingbelow expectations. Based on this criterion, deficiencies were iden-

tified in three out of four measures assessing sequential learningwith verbal stimuli; these included a test for recall of digits andtests involving sentence repetition and word order. Deficienciesin simultaneous visuospatial processing were less apparent, with

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elow-criterion scores being observed in only one of four measures.either expressive nor receptive language skills were impaired in

his sample.In other research, a variety of different groups have been used

o control for a range of potential confounds. Three studies havencorporated an SMA group to control for effects associated with

otor impairment. In the first of these, Whelan (1987) adminis-ered a test battery that included the subtests from the verbal anderformance scales of the Wechsler Intelligence Scale for Children-evised (WISC-R; Wechsler, 1974). In addition, the Peabody Pictureocabulary Test-Revised (PPVT-R; Dunn and Dunn, 1981) was used

o assess receptive language skills. On each trial in this test, thexaminer says a word, and the participant is required to pointo one of four pictures that corresponds to the spoken word. Theaven Coloured Matrices (Raven, 1965) was used to measure non-erbal intelligence. In this test, respondents are asked to identifyhe item that would complete a presented pattern. Finally, par-icipants completed tests of verbal memory (Digit Span from the

ISC-R; Sentence Memory Test, Benton, 1965) and non-verbalemory (the Target Test; Reitan and Davis, 1974). No significant

roup differences were seen on any of the tests in the battery.espite this, within-group comparison of the DMD boys revealedeficits with memory, as they performed poorly on tests of immedi-te verbal and non-verbal memory compared to their performancen other cognitive tests. This result was consistent with the findingsf Ogasawara (1989), who reported that children with DMD per-ormed significantly more poorly than those with SMA on the Digitpan, a test (from the Wechsler intelligence scales) used to assessmmediate verbal memory. Evidence of a specific verbal memorympairment was also provided by Billard et al. (1992). In this study,he DMD group performed worse than the SMA control group ontory recall, and nearly half of the DMD group also exhibited readingisabilities, which were not seen in the SMA group.

Several groups have used typically-developing children as con-rols. Anderson et al. (1988) found evidence of memory deficits inMD boys compared to age-matched controls. These difficultiesere seen both in visual memory (when boys were asked to indi-

ate the correct serial positioning of pictures presented to them)nd in immediate verbal memory (Digit Span from the WISC-R).n other work, Cotton et al. (1998) compared those with DMD toontrols matched for age, VIQ, and depression using a battery ofeuropsychological tests assessing a number of cognitive domains,

ncluding: 1) receptive language, 2) verbal and non-verbal memory,) visuospatial skills, 4) attention, and 5) verbal fluency. Althoughhe DMD group performed comparably to controls in most areas,eficits were seen in the areas of non-verbal memory and atten-ion.

Hinton and colleagues put forth an elegant series of studiesttempting to elucidate the core neurocognitive deficit(s) associ-ted with DMD using unaffected-sibling controls as a comparisonroup. Their first study (Hinton et al., 2000), involving 80 boys withMD aged 6–16 years and 40 unaffected siblings, was designed toetermine if deficits in certain cognitive domains exist regardless ofeneral intellectual level. Performance was assessed on numerousests with a minimal motor component, including subtests fromhe verbal scale of the Wechsler Intelligence Scale for Children-IIIWISC-III, Wechsler, 1991) and multiple subtests from the Wideange Assessment of Memory and Learning (WRAML; Sheslow anddams, 1990). Group comparisons were made but, in addition,

or each individual, performance across all subtests was rankedrom worst to best, and ranked profiles were subsequently com-ared between groups to determine if DMD was associated with a

pecific neuropsychological profile. The PPVT-R (Dunn and Dunn,981) provided a proxy measure of verbal intelligence, as scoresn this test correlate highly (r = 0.70) with WISC-R VIQ scores.robands were divided into those scoring above and below the

avioral Reviews 37 (2013) 743–752

median on the PPVT-R, and rank order analyses were performed.As a group, probands performed more poorly on the WISC-III DigitSpan and Comprehension subtests and on the WRAML Story Mem-ory subtest than their unaffected siblings. These differences werenot accounted for by differences in age. No significant group differ-ences were detected for the Similarities or Information subtests ofthe WISC-R or for the Picture Memory, Verbal, or Visual Learningsubtests of the WRAML. Rank order analysis on measures from theWISC-III revealed a statistically significant consistency in the rankorder on performance of those with DMD, such that performancewas worst on Digit Span, followed by Comprehension, Similari-ties and Information. Rank order analysis on measures from theWRAML also revealed a significant consistency of ranking, with theworst performance being seen on Story Memory, followed by Pic-ture Memory, Verbal Learning, and Visual Learning subtests. Thesibling group did not show consistency in ranking of their scores,but instead showed considerable variability in performance rank-ings. To summarize, relative to their unaffected siblings, the DMDgroup performed suboptimally on neuropsychological measures ofverbal working memory (specifically Digit Span and Story Memory)irrespective of general intellectual functioning, whereas memoryfor pictures and non-verbal stimuli was unaffected.

In a subsequent study, Hinton et al. (2001) excluded from theiroriginal cohort DMD participants for whom there were no siblingcontrols. By comparing probands to their respective siblings, theywere able to draw more direct comparisons between the abili-ties of those with and without brain dystrophin while controllingfor various factors that could affect cognitive abilities (i.e., famil-ial environment, socioeconomic status). The same eight measuresfrom the WISC-III and WRAML used in the previous study wereemployed, as well as additional neuropsychological tests used togauge functioning in specific cognitive domains including: (1) ver-bal skills, (2) visuospatial skills, (3) attention/memory, and (4)abstract conceptual skills. Measures of academic achievement inreading, writing, and mathematics from the Woodcock–JohnsonBattery (Woodcock and Johnson, 1977) were included. DMD andsibling-control groups performed similarly on tests of visuospa-tial skills and attention – a finding that is consistent with otherreports (Cotton et al., 1998; Dorman et al., 1988; Hendriksen andVles, 2006). While the two groups also obtained comparable scoreson subtests in the verbal domain, paired comparisons revealed thatDMD boys performed worse on the last two items of the TokenTest for Children (DiSimoni, 1978). In this test, the child is askedto follow verbal directions that become increasingly lengthy andcomplex as the test progresses. Given this, the problems observedin the DMD group may have been related to increased auditoryworking memory load. In support of this, boys with DMD alsoexperienced significantly greater difficulty on Digit Span than theirsiblings. Post-hoc analysis revealed that probands had particulardifficulty recalling digits in the reverse order in which they werepresented – a skill that requires intact auditory working mem-ory. In addition to the problems described above, individuals withDMD performed relatively poorly on the Comprehension subtestof the WISC-R. They also performed worse than sibling controlson all measures of academic achievement. This latter result wassubsequently replicated in other work by this group (Hinton et al.,2004).

2.3.1.1. The limited verbal span hypothesis of DMD. Based ontheir findings, Hinton and colleagues (Hinton et al., 2000;Hinton et al., 2001) concluded that the neuropsychologicalprofile in DMD is characterized by a selective deficit in ver-

bal working memory skills, as those with DMD consistentlyfared worse on subtests that specifically relied on this abil-ity, including Digit Span, Token Test for Children (immediatememory for information processed in the auditory domain),

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nd Comprehension (memory for complex verbal information).he authors argued that a decreased ability to keep phono-ogical information within short-term and working memorytores might have cascading effects on intellectual functioningparticularly in the verbal domain), and on academic perfor-

ance.In later work (Hinton et al., 2004), these authors revised their

escription of the characteristic cognitive deficit in DMD, refer-ing to it as a problem affecting “verbal immediate memory” orlimited verbal span”, rather than their previous description of

specific deficit in verbal working memory, as difficulties werepparent on tests requiring short-term retention of verbal infor-ation, whether or not on-line manipulation of that information

n working memory was required (see also Mento et al., 2011).heir suggestion that problems storing verbal information duringresentation of classroom instruction would negatively impact allreas of academic achievement was strengthened by their find-ng that performance on Digit Span significantly predicted scoresn all three measures of academic achievement (reading, writingnd math), whereas motor impairment and degree of parent-ratedehavioral problems did not (Hinton et al., 2004). Based on theirwn work and that of others, Hinton and colleagues further con-ended that the deficits in immediate verbal memory seen in DMDesult from aberrations within the cerebro-cerebellar loops, andurther argue that DMD may be considered a cerebellar disor-er. The cerebellum receives input from multiple regions of theNS, and cerebellar neurons project to nearly all portions of theotor system (Thach et al., 1992) as well as to non-motor areas

f the cerebral cortex (Strick et al., 2009). These anatomical con-ections between the cerebellum and the cerebral cortex formssentially “closed-loops”, with distinct and separate motor andon-motor circuits (Kelly and Strick, 2003). Hinton and colleaguesheorized that an absence of dystrophin in the cerebellum nega-ively impacts the maintenance and development of phonological

emory stores and rehearsal of information specifically throughhis cerebro-cerebellar loop associated with non-motor functionCyrulnik and Hinton, 2008).

While appealing, the hypothesis of a specific neuropsychologi-al profile characterized by limited verbal span in DMD (Cyrulniknd Hinton, 2008; Hinton et al., 2000; Hinton et al., 2001; Hintont al., 2004) has not been universally supported. In a recent study,onders and Taneja (2009) used the Children’s Memory Scale

Cohen, 1997) to assess both immediate and delayed memoryor visual and verbal material among boys with DMD and theirnaffected siblings. Those with DMD did not show deficits in imme-iate memory, as would be predicted by the limited verbal spanypothesis. However, they did exhibit difficulties with delayedemory for both types of materials. After controlling for FSIQ, how-

ver, only differences in delayed verbal recall remained significant.he authors noted that Hinton and colleagues did not examineelayed memory in their research (Hinton et al., 2000; Hinton et al.,001).

.3.1.2. Deficits in executive function in DMD. Although there isonsiderable evidence to support the view that limited verbalpan is a cardinal feature of the neurocognitive profile of DMD,here are also data to suggest that DMD may be associated withmpairments in executive functioning. Executive functions includeomponents such as working memory, planning, inhibition (ofompeting thoughts, actions, or attention), and set shifting (i.e.,exibility in switching between mental states or tasks). In a com-rehensive study of neuropsychological functioning DMD, Mento

t al. (2011) noted consistent deficits in planning and inhibition inhildren with DMD as compared to those with juvenile rheumatoidrthritis, as evidenced by performance on the Tower of London testShallice, 1982) and the Elithorn maze perception test (Elithorn,

avioral Reviews 37 (2013) 743–752 747

1955). Deficits on these same tests and on another test tappinginto these same skills (Trail Making Test; War Department, 1944)have also been reported in DMD by Wicksell et al. (2004) in a studythat employed a control group of typically-developing children.

In other work, parents reported that boys with DMD displayedmore deficits on the Shift subscale of the Behavior Rating Inventoryof Executive Function (BRIEF; Gioia et al., 2000) than unaffected sib-lings (Donders and Taneja, 2009). Boys with DMD also performedworse, overall, on the Delis-Kaplan Executive Function Battery(Delis et al., 2001), although these differences were not significantwhen FSIQ was added as a covariate.

The fact that executive dysfunction has been reported in thosewith DMD in these studies and others (see Anderson et al., 1988;Cotton et al., 1998) that utilized a number of different controlgroups (i.e. children with a motor impairment; typically devel-oping children; unaffected siblings) suggests that deficits in thisdomain may be a central feature of the disorder. Given the presenceof executive dysfunction in multiple studies, including their own,Mento et al. (2011) argued that the limited verbal span hypothe-sis of DMD (Hinton et al., 2004) is insufficient to account for therange of deficits reported in the literature. Rather, Mento and col-leagues suggested that those with DMD may exhibit a broaderdeficit in higher-order cognitive processing capabilities, includingexecutive function, and noted that impairments in such capabilitiesis a general finding in studies of cognition in DMD. By compar-ison, deficits in immediate verbal memory, although a commonfinding in the literature, have not been universally reported (seeDonders and Taneja, 2009). Deficits in executive function in thosewith DMD would be consistent with an absence of dystrophin inbrain regions implicated in higher-order processing and executivefunctions, such as the cerebral cortex, specifically prefrontal regions(Spencer-Smith and Anderson, 2009). It is important to note, how-ever, that the cerebellum is activated during the completion of tasksthat assess components of executive function, such as the Tower ofLondon, leading some to conclude that the cerebellum may be akey component of the neural network that drives executive func-tion (see Stoodley, 2012 for review). Anatomically, the cerebellumreceives input from and projects to prefrontal regions (Kelly andStrick, 2003) that are implicated in executive function. Althoughstudies have confirmed the presence of dystrophin in cortical pyra-midal neurons (Lidov et al., 1990), there are no detailed studiesinvestigating its specific localization in cerebral cortical regionsoutside the major lobular divisions (i.e., prefrontal regions). Suchstudies are essential if we are to elucidate the role of dystrophin inthe brain and fully appreciate the consequences of its absence oncognition.

2.3.1.3. Summary. The literature on specific cognitive deficits inDMD yields somewhat inconsistent results. While the majority ofstudies indicate that expressive and receptive language are bothpreserved, as is visuospatial processing, findings in other areas areless clear. Although memory deficits are frequently reported, insome studies these deficits are evident with stimuli presented ver-bally, whereas in others, they are found with both verbal and visualmaterials, or not at all. Some of the inconsistencies reported in theliterature likely arise from the fact that different researchers haveused different control or comparison groups (i.e., groups with SMAor juvenile rheumatoid arthritis; typical control groups matchedfor various factors; unaffected siblings) and different assessmenttools. However, studies examining higher-order cognitive abilities,including executive function, consistently report impairments in

these domains in those with DMD. Although there is compellingevidence for a deficit in immediate verbal memory in DMD, thereis considerable evidence that this deficit forms part of a neuropsy-chological profile that includes executive dysfunction as well.

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. Psychosocial and neurobehavioral functioning in DMD

Despite the devastating nature of the muscular disorder and itsarly presentation, little is known about the psychosocial develop-ent of children living with DMD; indeed, there is only a handful of

tudies that document neurobehavioral and emotional functioningn this clinical population. Leibowitz and Dubowitz (1981) exam-ned the degree of emotional disturbance among those with DMDge 3 to 13, using the Rutter Behavior Questionnaire (RBQ) Form Aor parents (Rutter et al., 1970), and Form B for teachers (Rutter,967). In the RBQs, respondents are asked a series of questionselating to the child’s behavior, and the likelihood of emotional dis-urbance is inferred from these responses. Of 52 boys with DMD,9 (36.6%) met the clinical cut-off used to indicate emotional dis-urbance, categorized as antisocial, neurotic, or mixed in nature,ased on scores from the RBQ B for teachers. Similarly, scores of 18f 55 affected boys (32.7%) exceeded the cut-off scores indicativef emotional disturbance with the RBQ A (parents). Younger chil-ren were more likely to show evidence of emotional disturbancesompared to older children.

In a subsequent study (Fitzpatrick et al., 1986), the RBQ-B wassed to examine psychosocial adjustment of boys with DMD com-ared to a control group of boys matched for age and father’sccupation. Although total mean scores were not significantly dif-erent between groups, those with DMD did score significantlyigher on items in the “neurotic” subscale relative to controls. Inddition, while no diagnoses of depressive disorders were maden the control group, over half of those with DMD met the crite-ion for a depressive disorder based on clinical information pooledrom parents, teachers, and an interview with a psychiatrist. Thoseith DMD were also significantly more likely to express problemsith peer relations than controls during interviews. It should beoted, however, that in subsequent work, Cotton et al. (1998) didot detect any increased rates of depression among a small sam-le of 10 boys with DMD relative to age and VIQ-matched controls;his study utilized a self-reporting measure, the Beck Depressionnventory (Beck, 1987).

A number of studies examining neurobehavioral functioning inMD have used the Child Behavior Checklist (CBCL; Achenbach,991) to identify possible child psychopathology, based on parentaleports. The CBCL consists of 120 items measuring behaviorcross two broad scales (Internalizing Problems and Externaliz-ng Problems) and eight narrow scales (Social Withdrawal, Somaticomplaints, Anxiety/Depression, Social Problems, Attention Prob-

ems, Thought Problems, Delinquent Behavior, and Aggressiveehavior). Using this assessment tool, Hendriksen and Vles (2006)

ound no indication of decreased psychosocial adjustment orehavior problems among a group of DMD boys, as mean scoresn all scales fell within the normal range defined by the normat-ve data. A different story emerges, however, when one considerstudies in which comparisons have been drawn between par-nts’ ratings of children with DMD and their unaffected siblings.inton et al. (2004) reported that their DMD group exhibitedore problems on the Total Behavior Problem Scale than their

iblings. Further, Donders and Taneja (2009) reported that, evenfter controlling for FSIQ, boys with DMD scored more poorly onhe Social Problems and the Social Withdrawal scales than theiriblings. In this study, data from an additional parental assess-ent also indicated that children with DMD experienced more

ifficulties than siblings in initiating social interactions and inesponding to changes in the social environment. Other researchas suggested that those with DMD score significantly worse

n the Social Problems scale than either unaffected siblings or

comparison group of those with cerebral palsy, independentf their cognitive abilities or motor impairment (Hinton et al.,006a,b).

avioral Reviews 37 (2013) 743–752

Although the CBCL is often used to examine psychosocial func-tioning in DMD, Hendriksen et al. (2009) argue that it may notbe the most suitable assessment tool, as it may be overly sen-sitive to items related to living with a chronic illness. As such,the CBCL may over-represent psychosocial maladjustment in DMD.These authors examined psychosocial functioning in 287 boys withDMD (aged 5 to 17 years) using the Personal Adjustment and RoleSkills Scale-III (PARS-III; Stein and Jessop, 1990), a parent-reportmeasure of psychosocial adjustment; they also provided psycho-metric data validating the use of this tool in DMD. Compared to aclinical reference group with chronic conditions, those with DMDwere rated as having significantly more difficulty with peer rela-tions and productivity and were rated as being less dependent, lessdepressed, and less anxious. Increasing age was significantly associ-ated with an increase in psychosocial adjustment in the DMD group.However, scores on the peer relation subscale were negatively asso-ciated with increasing age, suggesting that social relations mayworsen over time in those with DMD. To determine the extentto which steroid use affected psychosocial functioning, data fromthose with DMD were grouped according to whether the child didor did not use steroids. No significant differences were detectedfor the two groups on this measure of psychosocial functioning.Overall, results of studies using the PARS-III indicate that thosewith DMD are not at a significantly greater risk of psychosocialdifficulties than those with other chronic illnesses, although peerrelationships in boys with DMD may be adversely affected overtime.

4. Neuropsychiatric disorders in DMD

In addition to several studies suggesting that the neurobehav-ioral profile of DMD includes impairments in social interactions,there is a documented association between DMD and autismspectrum disorders – a set of disorders characterized by socialinteraction deficits. Komoto et al. (1984), in the first report of DMD-autism comorbidity, described a case study of a five-year old boywith DMD who was later diagnosed with autism. In a later sampleof 158 patients representing all known cases of DMD within Mas-sachusetts, Wu et al. (2005) noted a comorbid diagnosis of autismin six patients; this was a significantly higher rate of comorbidity(3.8%) than would be expected by chance, based on the preva-lence of each disorder separately. A higher-than-normal rate ofco-occurrence between the two disorders was also reported in aninternational sample of 351 males with DMD; in that study, 3.1% ofthe DMD group received a comorbid diagnosis of autism accordingto parental reports (Hendriksen and Vles, 2008). Interestingly, boyswith DMD are reported to show a mild impairment at recogniz-ing facial affect compared to sibling controls (Hinton et al., 2007),a characteristic neuropsychological deficit in autism. Hinton et al.(2006a,b) found that 33% of a sample of 58 DMD boys exceededthe cut-off score on an assessment used to screen for autism, andthat 87% of those identified at this initial screening met the diag-nostic criterion for autism based on their mothers’ responses tothe Autism Diagnostic Interview-Revised (Lord et al., 1994). Noneof the unaffected siblings scored above the screening tool cut-offscore. Together, these findings lend strong support for a proposedlink between DMD and autism spectrum disorder.

Comorbidity of DMD with other neuropsychiatric disorders hasalso been documented, including attention-deficit hyperactivitydisorders (ADHD; 11.7%) and obsessive-compulsive disorder (4.8%)(Hendriksen and Vles, 2008), with the rates at which these disor-

ders occurred in the DMD sample being significantly higher thanthose seen in the general population. As there was no relationshipbetween corticosteroid use and receiving the diagnosis of ADHD,it is unlikely that the relatively high rates of this disorder in the

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MD sample could be attributed to effects of steroid treatment onmotional functioning or behavior.

. Implications of neuropsychological and neurobehavioralndings in DMD

Several recommendations arise from the literature examiningeuropsychological and neurobehavioral functioning in those withMD, which may help to reduce the overall burden of the disease.hese include strategies that may assist with earlier diagnoses ofhe disorder, as well as specific recommendations to improve func-ioning for those already diagnosed.

Some researchers have speculated that cognitive deficits, espe-ially within the verbal domain, may be important early riskarkers for DMD. Indeed, there are numerous documented cases

f boys initially referred to speech and language specialists whoere subsequently diagnosed with DMD (Essex and Roper, 2001;ohamed et al., 2000). Delayed attainment of both motor and lan-

uage milestones is more common in those with DMD comparedith their siblings, based on prospective parental reports (Cyrulnik

t al., 2007). Additionally, signs of generalized developmental delayre seen in children with DMD between three to six years of ageCyrulnik et al., 2008). These findings may help to improve theesign of screening tools that may assist in the early identificationf the disorder. This is important – as despite our understanding ofhe molecular basis of DMD and the nature of disease progression

diagnosis is often delayed for this condition, which often resultsrom new mutations in the very large dystrophin gene (Mohamedt al., 2000; Ciafaloni et al., 2009). Many practitioners and physi-ians are unaware that cases of DMD may present with non-motorelays, including delays in cognitive and language development,efore any professional consideration is made of a diagnosis of DMDased on muscle weakness or specific motor delays (Mohamedt al., 2000).

Both physicians and early educators should be aware of theelationship between early developmental delays and DMD, as theondition is relatively common in the population (1/3500 live maleirths). Delayed diagnosis has implications for delaying geneticounseling for parents and can delay or restrict access to possibleherapeutic interventions of benefit for children with DMD, includ-ng not only corticosteroids, but also other interventions designedo support cognitive and psychosocial development (Mohamedt al., 2000).

Despite the overwhelming evidence of cognitive, psychosocial,nd behavioral issues in DMD (in particular those relating to ver-al memory, depression, and social difficulties), it is important toemember that, from a clinical perspective, only a subset of boysith DMD exhibit such deficits. In fact, the majority of individ-als with DMD function at normal intellectual levels. AlthoughSIQ scores are lower at the population level, these scores follow

normal distribution in this clinical population (Cotton et al.,001; Cotton et al., 2005; Ogasawara, 1989; Prosser et al., 1969).s well, the rate of clinical depression appears similar in thoseith DMD compared to other boys with chronic health condi-

ions (Hendriksen et al., 2009), despite the severe and ultimatelyethal consequences of the disease. Moreover, although there is anncreased risk of social behavioral problems in DMD, not all DMDoys exhibit social deficits, and among those who do, some arenly mildly affected (displaying impaired peer relations). In someases, however, these impairments are extreme and accompaniedy impaired language skills and repetitive or restrictive behavior

atterns at an early age – a pattern of deficits that may be indicativef an underlying autism spectrum disorder.

The remarkable variability in non-motor deficits in DMD sug-ests the existence of clinical heterogeneity in this population.

avioral Reviews 37 (2013) 743–752 749

Evidence in support of subtypes comes from a study that employeda principal component analysis of multiple clinical parameters toidentify four phenotypic subtypes in DMD, based on the degree ofintellectual impairment and motor involvement (Desguerre et al.,2009); Group A: classified as “early infantile DMD” and categorizedby severe motor and intellectual dysfunction; Group B: termed“classical DMD” and characterized by intermediate intellectual out-comes but poor motor outcome; Group C: coined “moderate puremotor DMD”, exhibited typical intelligence and delayed motordysfunction; and Group D: termed “severe pure motor DMD”, char-acterized by normal intelligence but poor motor function.

The dystrophin gene is a very large gene, and a complex systemregulates the expression of a large number of its protein productsof heterogeneous localization and variable size (see Perronnet andVaillend, 2010 for review). These features of the genetic disorderhave prompted research aimed at identifying particular muta-tions within the dystrophin gene that are associated with cognitiveimpairment. Mutation site has been correlated with the degree ofcognitive impairment in DMD. Thus, distal mutations that affect theshorter isoforms of dystrophin have been associated with a moresevere cognitive phenotype, likely due to the fact that shorter dys-trophin isoforms are produced by transcription and translation ofdistal regions along the gene sequence (Taylor et al., 2010). Specifi-cally, mutations affecting Dp140 (Felisari et al., 2000; Moizard et al.,1998; Taylor et al., 2010; Wingeier et al., 2011) and Dp71 (Moizardet al., 1998; Moizard et al., 2000) are associated with more severecognitive dysfunction in DMD, whereas gene mutations in the ini-tial promoter region of the gene that encode brain-type full-lengthdystrophin are compatible with typical intellectual functioning(den Dunnen et al., 1991; Rapaport et al., 1992). Although researchhas identified associations between gene-mutation site and cogni-tive deficits, there have been no attempts to identify subgroups ofmutations that produce the clinical features of particular behav-ioral, psychosocial, or emotional profiles (i.e., deficits in socialinteraction, depressive symptomology) that are often reported inDMD. As well, there are no studies to date showing a link betweenspecific gene mutations in DMD and an increased risk of developingthe reportedly co-morbid neuropsychiatric disorders (i.e., autismspectrum disorders, ADHD, obsessive-compulsive disorder).

This review suggests that more research is required to iden-tify DMD individuals at risk of developing the cognitive deficits,emotional and psychosocial issues, and social behavioral problemsseen in this heterogeneous population. Until we have a clearerunderstanding of who falls into these high-risk categories, thor-ough neurodevelopmental and neuropsychological assessmentsare warranted soon after the initial diagnosis of DMD (Bushby et al.,2010). Clinical information of this type should be used to developeffective strategies for treatment and management that are tailoredto a child’s unique neuropsychological and behavioral profile.

It is important for parents and early-childhood educators to bemade aware of the role that deficits in verbal immediate memorymay play in the intellectual functioning and academic achieve-ment of those with DMD. Supports for those with problems in thisarea could involve strategies such as segmenting verbal instruc-tions into smaller components and repeating verbal information(Hinton et al., 2004). In addition, the use of special remedial inter-ventions may help to improve overall academic abilities, includingprograms designed to improve phonological abilities, dictation, andmathematical problem solving. The early clinical presentation ofverbal delays in DMD suggests that speech therapy may be a usefulcomponent of early intervention efforts in particular cases. Addi-tionally, the fact that intellectual problems (when present) are

non-progressive should be emphasized to parents and educatorsso they can provide children with DMD adequate and continuingopportunities to develop their intellectual and cognitive capabili-ties. This may become especially important in later years as muscle

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athology progresses, and these children are able to do less and lesshysically (Polakoff et al., 1998).

As depression is not uncommon in DMD, careful screening forepressive symptoms should be done on a regular basis duringisits with relevant therapists (physicians, occupational therapists,sychologists, etc.), and educators and parents should be madeware of signs of impaired psychosocial adjustment at particu-ar developmental phases. These may include classical depressiveymptoms, such as changes in sleeping patterns or a lack of interestn previously enjoyed activities, as well other behaviors not typ-cally associated with depression, such as aggressiveness (whichs often associated with depression in younger children) (Polakofft al., 1998).

This review identified many studies that document social dif-culties for those with DMD, especially affecting peer relations. It

s unclear whether such difficulties are consequences of decreasedobility, or if they reflect an organic symptom of the disorder – a

ossibility that gains support from studies showing that many boysith DMD exhibit social deficits similar to those seen in autism, aeurodevelopmental disorder with an inherent CNS etiology andharacterized by social difficulties. In either case, educators andarents need to be aware of the higher prevalence of such socialeficits in DMD and offer therapeutic and environmental oppor-unities, such as social skills training, applied behavior analysis,nd/or increased opportunities to engage in social interactions witheers. Moreover, since social isolation and lack of adequate peerupport undoubtedly affect emotional coping, addressing thesessues may also serve to decrease depressive symptoms. Socialnteractions may also be improved by educating peers and schoolersonnel about the disorder. The importance of attending earlyo problems in social interactions is underscored by findings of aignificant association between the degree of social support andeneral psychosocial well-being among boys with DMD; studiesxploring this association indicate that high-quality social inter-ctions are a key factor in shaping psychosocial resilience amonghose with this chronic condition (Fee and Hinton, 2011).

Diagnosticians, educators, and parents should be made awaref the higher-than-expected prevalence of other neuropsychiatricisorders (including ADHD and OCD) in the DMD population, so thatny noted deficits are not simply regarded as secondary sequelaef the primary motor disease, or consequences of living with such ahronic condition. Appropriate interventions could then be offeredhen indicated to pre-empt progression of these disorders. Collec-

ively, such efforts could go a long way to improving the quality ofife for this group of boys and their families and caregivers, who arelready dealing with a devastating physical condition.

. Conclusions

This report aimed to provide a critical and detailed review ofhe literature on neuropsychological and neurobehavioral func-ioning in those with DMD. The literature is often contradictoryn nature, possibly due to methodological constraints, includinghe use of samples of convenience and various control groups asell as the utilization of various assessment tools. Such limitations

re expected in research examining children with a chronic, fatalllness. However, the synthesis of the literature highlights impor-ant, over-arching ideas for consideration. Both general intellectualnd academic abilities are depressed at the population level inMD. While multiple aspects of cognitive functioning are impli-ated in the disorder, verbal abilities, especially those relating to

erbal immediate memory, seem predominantly affected in thisroup; these may be evident even in the absence of an intellectualisability. Moreover, psychosocial mal-adjustment and behavioral

ssues often manifest in DMD, including depression and difficulties

avioral Reviews 37 (2013) 743–752

with social interactions and peer relations. In addition, the inci-dence of neuropsychiatric disorders appears higher among thosewith DMD than in the general population, for reasons that arenot currently known. Finally, this review has found that althoughthere is evidence to suggest that DMD is associated with particularneuropsychological and neurobehavioral characteristics, there isconsiderable heterogeneity in this clinical sample; this fact shouldbe given ample consideration during the development of therapeu-tic interventions.

The use of carefully selected control groups that account forphysical and familial factors, and the use of meta-analytical sta-tistical methods to address sample sizes and representativeness,have expanded our current understanding of neuropsychologicaland behavioral characteristics in DMD. Several lines of evidencehave now converged sufficiently to point to an organic and primaryCNS involvement in DMD that challenges our view of the disorderas being strictly neuromuscular in nature.

This review sought to offer some suggestions for clinicians,educators and parents in light of findings related to intellectual,cognitive, behavioral, and psychosocial functioning. The applica-tion of some of these strategies in the management of this chroniccondition may have the potential to decrease the burden of thedisease and improve the overall quality of life and daily function-ing for those with DMD. Continued research on neuropsychologicaland neurobehavioral functioning in DMD, together with studiesdesigned to elucidate the role of dystrophin within the developingand mature brain at individual, tissue, cellular and sub-cellular lev-els, are expected to expand the available repertoire of treatmentsfor affected boys.

Conflict of interest

The funders did not contribute to the study design, interpreta-tion, or manuscript preparation. The authors declare that they haveno conflict of interest.

Acknowledgements

This work was supported by operating grants from the Mani-toba Institute for Child Health (JEA) and the Natural Sciences andEngineering Research Council (LSJ), and by a Postgraduate Scholar-ship from the Natural Sciences and Engineering Research Council(WMS).

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