Neuropsychological and neurobehavioral functioning in Duchenne muscular dystrophy: A review

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Neuropsychological Functioning in DMD 1
Title: Neuropsychological and neurobehavioral functioning in Duchenne muscular
dystrophy: a review
Wanda M. Snowa, Judy E. Andersonb*, Lorna S. Jakobsona*
aDepartment of Psychology, Faculty of Arts, P404 Duff Roblin Building, 190 Dysart Road,
University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2
bDepartment of Biological Sciences, Faculty of Science, Biological Sciences Building, 50 Sifton
Road, University of Manitoba, Winnipeg, Manitoba, Canada R3T 2N2
*indicates equal contributors
Corresponding Author:
Dr. Wanda M. Snow, Department of Psychology
Department of Psychology, P404 Duff Roblin Building, 190 Dysart Road, University of
Manitoba, Winnipeg, Manitoba, Canada R3T 2N2
Telephone: 1-204-250-7617
Fax: 1-204-254-2153
Email: umsnoww@cc.umanitoba.ca; wssnow@mymts.net
Citation:
Snow, W.M., Anderson, J.E. & Jakobson, L.S. (2013). Neuropsychological and neurobehavioral
functioning in Duchenne muscular dystrophy: a review. Neuroscience and Biobehavioral
Reviews, 37, 743-752.

Neuropsychological Functioning in DMD 2
Abstract
Duchenne muscular dystrophy (DMD) is a genetic condition affecting predominantly
boys that is characterized by fatal muscle weakness. While there is no cure, recent therapeutic
advances have extended the lifespan 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 those afflicted. Several lines of evidence
point to central nervous system involvement as an organic feature of DMD, challenging our view
of the disorder as strictly neuromuscular. This report provides a review of the literature on
neuropsychological and neurobehavioral functioning in DMD. Recent research identifying
associations with DMD and neuropsychiatric disorders is also discussed. Lastly, the review
presents implications of findings related to nonmotor aspects of DMD for improving the quality
of life in those affected. While the literature is often contradictory in nature, this review
highlights some key findings for consideration by clinicians, educators and parents when
developing therapeutic interventions for this population.
Keywords: Duchenne muscular dystrophy; dystrophin; neuropsychology; intelligence;
cognition; verbal memory; neurobehavioral; neuropsychiatric; social interaction; autism

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1. Introduction
Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder that
affects approximately one in 3500 male births (Emery, 1991). Mutations within the largest gene
in the human genome, the dystrophin gene, result in a lack of expression of the functional form
of its major protein product, dystrophin (Hoffman et al., 1987). Dystrophin is essential in
maintaining structural integrity of muscle membranes during contraction; its absence results in
muscle fiber damage, chronic inflammation and fibrosis (Wallace and McNally, 2009) that result
in progressive muscle weakness and death, generally in the third decade, due to cardiac and
pulmonary complications.
The physiological mechanisms responsible for fatal muscle pathology in DMD are
relatively well understood, and the disease is classically considered neuromuscular in nature.
Given this, it is perhaps not surprising that, even though the original description of the disorder
by Duchenne (1868) noted decreased intellectual abilities, historically, little attention has been
paid to cognitive or other neurobehavioral characteristics of those afflicted. There is, however,
compelling and cumulative evidence to argue for a primary central nervous system (CNS)
involvement in DMD, both at the cellular level and from a clinical perspective, such that some
argue that DMD should be regarded as a disorder of brain and muscle, as opposed to one that is
primarily muscular in origin (Hendriksen et al., 2009).
Dystrophin is present in many brain regions responsible for higher order functions such
as learning and memory, including the cerebral cortex, hippocampus, and cerebellum (Lidov et
al., 1990; Huard and Tremblay, 1992). Dystrophin expression in central neurons, however, is
under the control of various promoters; the P-promotor regulates Purkinje neuron dystrophin
expression, whereas the C-promotor regulates hippocampal and cerebral cortical expression

Neuropsychological Functioning in DMD 4
(Blake et al., 1999; Gorecki et al., 1992). In addition to the full-length dystrophin found in
central neurons and muscle, truncated dystrophin isoforms are also located in the peripheral and
central nervous system, including Dp71, Dp116, Dp140, and Dp260 (see Perronnet and Vaillend,
2010 for review). In the brains of those with DMD, dystrophin is absent (Kim et al., 1995). At
autopsy, brains devoid of dystrophin exhibit neuropathology, including gliosis, neuronal loss
(Dubowitz and Crome, 1969), heterotopias, and cortical thickening (Rosman and Kakulas, 1966).
Neuroimaging studies, although few in number, reveal abnormalities in brain function among
those with DMD. A study using positron emission topography (PET) demonstrated reduced
glucose metabolism in those with DMD, specifically in areas that are typically rich in dystrophin
(e.g., cerebral cortex and cerebellum; Lee et al., 2002). In the motor cortex, local
synchronization of spontaneous activity of neural networks is reduced in those with DMD, as
measured by resting-state functional magnetic resonance imaging (RS-fMRI) (Lv et al., 2011).
Further, a study using transcranial magnetic stimulation (TMS) found hypoexcitability in the
motor cortex of those with DMD (Di Lazzaro et al., 1998).
Although secondary to evaluating possible life-saving or even curative treatments for the
muscular aspects of the disorder, thorough understanding of the neuropsychological and
neurobehavioral consequences of DMD is exceedingly well justified. Firstly, psychosocial and
cognitive functioning have a major impact on quality of life. Especially among school-aged
boys, deficits in cognitive abilities and their consequences on academic performance can
negatively affect self-esteem and self-confidence -- of particular importance in a population
already dealing with a devastating and functionally isolating physical condition. Secondly,
neurobehavioral and psychosocial functioning can impact understanding of and adherence to
medical treatments. For example, steroids are the current gold-standard treatment prescribed to

Neuropsychological Functioning in DMD 5
delay disease progression. The most commonly reported reason for the discontinuation of
steroids, however, are the mood and behavioral side effects (Poysky and Behavior in DMD
Study Group, 2007). Understanding the neuropsychological and behavioral profile of those with
DMD from an early age can assist in distinguishing behavioral and emotional issues associated
with the disorder from those arising secondary to steroid treatment, and may prove helpful in
improving adherence. Other medical advances in the treatment of DMD have increased the
lifespan for those afflicted; this has resulted in an adult population with DMD for whom longer-
term neuropsychological and neurobehavioral ramifications of living with the disorder are
unknown (Rahbek et al., 2005). The best way to ensure that those diagnosed with DMD develop
adequate emotional, social, and cognitive skills as adults is to improve our ability to identify
problems in these areas early on so that available interventions may be started as soon as
possible.
The central aim of this review is to provide a critical description of the literature detailing
neuropsychological and neurobehavioral functioning in those with DMD. Overall functioning in
DMD is multifactorial and includes a complex interplay of factors that is currently poorly
understood. For the purposes of this review, however, neuropsychological and neurobehavioral
functioning in DMD will be discussed according to: 1) general intellectual functioning and
specific cognitive deficits, 2) psychosocial and behavioral functioning, and 3) comorbidities with
neuropsychiatric illnesses. As the vast majority of studies examining non-motor functioning in
DMD have focused on the cognitive profile, particular emphasis will be given to this area of
functioning. Lastly, we present a discussion of the implications of these finding for researchers,
clinicians, parents and educators committed to reducing the burden of disease and improving
quality of life for those affected by this disorder.

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2. Intellectual Functioning in DMD
2.1. General Intellectual Functioning
Reduced overall intellectual functioning is a consistent finding in the clinical literature on
DMD. Cohen et al. (1968) reported an increased prevalence of intellectual disability in DMD
relative to the general population (20.9% versus 3%, respectively) using intelligence quotient
(IQ) scores. The validity of the study was limited, however, due to the fact that some IQ scores
were estimated from physician, teacher, or parent reports rather than by 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 intellectual disability in DMD relative to unaffected siblings. Moreover, mean
scores for the Full Scale Intelligence Quotient (FSIQ), which includes scores from both verbal
and performance subtests, were approximately one standard deviation below mean sibling FSIQ
scores in the DMD group. Such findings rule out socioeconomic factors, such as family income
and parents’ education levels, as primary factors affecting intellectual functioning, as both those
with DMD and their siblings shared these known correlates of intelligence. FSIQ scores were not
significantly correlated with disease severity, nor did they progressively worsen with age,
suggesting that impaired intellectual functioning is not secondary to muscle degeneration or the
environmental impediments it may place on a child, including possible reduced educational and
social opportunities; in both cases, scores would be expected to decline with age and the
progression of muscle pathology. Together, these early findings pointed to a primary, organic
cause of decreased intellectual functioning in DMD due to CNS involvement, even prior to

Neuropsychological Functioning in DMD 7
reports identifying the dystrophin protein, its localization to specific brain areas, and its absence
in those with DMD.
To elucidate the extent to which both the primary motor deficits and any consequential
environmental deprivation negatively impact intellectual function, Ogasawara (1989) compared
FSIQ scores of two groups of boys raised in the same residential school – one group with DMD
and another with spinal muscular atrophy (SMA), another fatally progressive neuroskeletal
disorder. FSIQ scores were reliably lower in those with DMD relative to those with SMA. This
result provides arguably the strongest support for a primary intellectual deficit in DMD that is
not attributable to sequelae of musculoskeletal dysfunction and motor impairment, including
reactive responses to the disorder, or social or environmental deprivation.
2.2. Verbal vs. Performance IQ
Although reports of global intellectual deficits have been described in the literature on
DMD, considerable debate remains as to whether there is any selective impairment in verbal or
non-verbal intellectual abilities. In some reports, those with DMD have been found to score
similarly on the verbal IQ (VIQ) and Performance IQ (PIQ) scales (Black, 1973) and to score
similarly to their unaffected siblings on both measures (Donders & Taneja, 2009). However,
most studies suggest that those with DMD tend to perform more poorly on the verbal than the
performance measures of intelligence tests, although the size of the discrepancy between VIQ
and PIQ measures varies across studies (Dorman et al., 1988; Karagan and Zellweger, 1978;
Karagan, 1979; Leibowitz and Dubowitz, 1981; Marsh and Munsat, 1974). It is important to
note, however, that even when this pattern is observed overall, there can be considerable

Neuropsychological Functioning in DMD 8
variability within this diagnostic group -- with many individuals with DMD actually showing
lower PIQ than VIQ scores, rather than the reverse (see Marini et al., 2007).
In what can be regarded as the most inclusive study examining intellectual ability in
DMD, and the relationship between FSIQ, VIQ and PIQ within this group, Cotton et al. (2001)
conducted a meta-analysis with data from 32 studies carried out between 1960 and 1999 in
which IQ data were collected. The FSIQ, VIQ, and PIQ scores for 1,146 males with DMD (age 2
to 27 years) were analyzed to determine the level of general intellectual impairment and the
prevalence of intellectual disability associated with DMD. Also evaluated was the degree, if any,
to which verbal intelligence was particularly affected in DMD. IQ scores are standardized such
that the mean score within a given age group is set to 100, with a standard deviation of 15.
Cotton et al. compared DMD group means on all three IQ scales to the relevant population mean
of 100 and found that, although all three measures were normally distributed, those with DMD
scored roughly one standard deviation below the population mean on each scale (MFSIQ = 80.2,
MVIQ = 80, MPIQ = 85.4). In addition, 34.8% of those with DMD had scores indicative of
intellectual disability. The mean VIQ-PIQ discrepancy was normally distributed but was
significantly larger than expected in the general population at -5.1 (SD = 14.4). The results of the
meta-analysis substantiated decades of earlier research demonstrating decreased general
intellectual functioning and an increased rate of intellectual disability in those with DMD, and
supported the conclusion that verbal intellectual abilities are slightly more vulnerable than
performance-based skills in this populations.
Investigators interested in studying intellectual abilities in DMD do need to consider the
impact that motor disability may have on test performance. This is particularly true during
completion of the subtests comprising the PIQ scale, as these subtests are often timed and require

Neuropsychological Functioning in DMD 9
graphomotor and/or constructional skills that might be compromised in those with reduced motor
strength. To control for effects on intellectual functioning related to motor impairment, some
investigators interested in DMD have included age-matched comparison groups of children with
motor impairments arising from other conditions. Despite showing similar levels of motor
impairment and comparable PIQ scores, children with DMD have been found to exhibit
significantly lower VIQ scores than children with either SMA (Billard et al., 1992), or those with
juvenile rheumatoid arthritis (Mento et al., 2011). These data indicate that, within the age groups
studied, motor impairment has not been a major confound in studies examining the VIQ-PIQ
discrepancy in DMD.
This conclusion gains strength from studies exploring possible age-related changes in
intellectual functioning in DMD. It is important to conduct studies of this nature as, due to the
progressive nature of the disease, affected individuals show gradual deterioration in motor
function due to progressive weakness and joint instability associated with the functional
deterioration of muscle. Given the progressive loss in motor function, we might expect PIQ
scores (and, therefore, FSIQ scores) to decrease over time in those with DMD. However, the
literature provides little support for this prediction. Thus, in both cross-sectional (Dorman et al.,
1988) and longitudinal studies (Prosser et al., 1969), FSIQ and PIQ have been found to remain
stable in DMD. Interestingly, this may not be the case for VIQ, although results in this regard are
variable. Some authors find no relationship between age and VIQ (Dorman et al., 1988;
Leibowitz & Dubowitz, 1981), while others find that VIQ 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 scores from multiple studies
described in their earlier work (Cotton et al., 2001), Cotton et al. (2005) performed a meta-

Neuropsychological Functioning in DMD 10
analysis to examine age-related changes in intellectual functioning in DMD. Although there was
a relationship between age and disease severity, as expected, with more of the older DMD
groups exhibiting advanced motor impairment, the various age groups did not differ with respect
to PIQ or FSIQ scores. On the other hand, verbal function, as measured by VIQ scores, was
significantly higher in the older DMD groups, relative to the younger groups. As a result of this
age-related change in verbal function, a “closing of the gap” between verbal and performance
measures was evident, with the size of the VIQ-PIQ discrepancy declining significantly across
the age groups -- being largest in the youngest group (age nine and under) and smallest in the
oldest group (20 years and older).
To summarize, despite inconsistencies in the literature, the majority of studies suggest
that, from a population perspective, verbal intelligence is particularly susceptible to impairment
in the absence of brain dystrophin. Although the work of Cotton and colleagues (2005) suggests
that the verbal impairment may lessen over time, this cannot be verified without longitudinal
studies documenting the developmental trajectory of intellectual functioning in this population.
2.3. Specific Cognitive Deficits in DMD
Despite the well-documented intellectual deficits seen in DMD, there is considerable
variability in intellectual functioning in this group. To explain this variability and, in so doing,
gain a deeper appreciation of the role of dystrophin in brain development and function, it is
important to move beyond global IQ measures or other composite scores and look at how those
with DMD perform on tests assessing specific cognitive abilities. In the following section, we
review some of the work that has been done in this area.

Neuropsychological Functioning in DMD 11
2.3.1. Specific Deficits Identified using a Neuropsychological Approach
Dorman et al. (1988) carried out one of the first studies designed to provide a detailed,
neuropsychological evaluation of those affected by DMD. Fifteen adolescent males completed a
battery of 16 motor-free tests used to assess performance in five cognitive domains: 1)
simultaneous processing, 2) sequential processing, 3) auditory analysis, 4) expressive speech,
and 5) receptive speech. Using normative data for comparison, the researchers established a
cutoff score of one standard deviation below the mean to identify individuals with DMD who
were performing below expectations. Based on this criterion, deficiencies were identified in three
out of four measures assessing sequential learning with verbal stimuli; these included a test for
recall of digits and tests involving sentence repetition and word order. Deficiencies in
simultaneous visuospatial processing were less apparent, with below-criterion scores being
observed in only one of four measures. Neither expressive nor receptive language skills were
impaired in this sample.
In other research, a variety of different groups have been used to control for a range of
potential confounds. Three studies have incorporated an SMA group, to control for effects
associated with motor impairment. In the first of these, Whelan (1987) administered a test battery
that included the subtests from the verbal and performance scales of the Wechsler Intelligence
Scale for Children-Revised (WISC-R; Wechsler, 1974). In addition, the Peabody Picture
Vocabulary Test-Revised (PPVT-R; Dunn, 1981) was used to assess receptive language skills.
On each trial in this test, the examiner says a word, and the participant is required to point to one
of four pictures that corresponds to the spoken word. The Raven Coloured Matrices (Raven,
1965) was used to measure non-verbal intelligence. In this test, respondents are asked to identify
the item that would complete a presented pattern. Finally, participants completed tests of verbal

Neuropsychological Functioning in DMD 12
memory (Digit Span from the WISC-R; Sentence Memory Test, Benton, 1965) and non-verbal
memory (the Target Test; Reitan and Davison, 1974). No significant group differences were
seen on any of the tests in the battery. Despite this, within-group comparison of the DMD boys
revealed deficits with memory, as they performed poorly on tests of immediate verbal and non-
verbal memory compared to their performance on other cognitive tests. This result was
consistent with the findings of Ogasawara (1989), who reported that children with DMD
performed significantly more poorly than those with SMA on the Digit Span, a test (from the
Wechsler intelligence scales) used to assess immediate verbal memory. Evidence of a specific
verbal memory impairment was also provided by Billard et al. (1992). In this study, the DMD
group performed worse than the SMA control group on story recall, and nearly half of the DMD
group also exhibited reading disabilities, which were not seen in the SMA group.
Several groups have used typically-developing children as controls. Anderson et al.
(1988) found evidence of memory deficits in DMD boys compared to age-matched controls.
These difficulties were seen both in visual memory (when boys were asked to indicate the
correct serial positioning of pictures presented to them) and in immediate verbal memory (Digit
Span from the WISC-R). In other work, Cotton et al. (1998) compared those with DMD to
controls matched for age, VIQ, and depression using a battery of neuropsychological tests
assessing a number of cognitive domains, including: 1) receptive language, 2) verbal and non-
verbal memory, 3) visuospatial skills, 4) attention, and 5) verbal fluency. Although the DMD
group performed comparably to controls in most areas, deficits were seen in the areas of non-
verbal memory and attention.
Hinton and colleagues put forth an elegant series of studies attempting to elucidate the
core neurocognitive deficit(s) associated with DMD using unaffected-sibling controls as a

Neuropsychological Functioning in DMD 13
comparison group. Their first study (Hinton et al., 2000), involving 80 boys with DMD aged 6 to
16 years and 40 unaffected siblings, was designed to determine if deficits in certain cognitive
domains exist regardless of general intellectual level. Performance was assessed on numerous
tests with a minimal motor component, including subtests from the verbal scale of the Wechsler
Intelligence Scale for Children-III (WISC-III, Wechsler, 1991) and multiple subtests from the
Wide Range Assessment of Memory and Learning (WRAML; Sheslow and Adams, 1990).
Group comparisons were made but, in addition, for each individual, performance across all
subtests was ranked from worst to best, and ranked profiles were subsequently compared
between groups to determine if DMD was associated with a specific neuropsychological profile.
The PPVT-R (Dunn, 1981) provided a proxy measure of verbal intelligence, as scores on this test
correlate highly (r = 0.70) with WISC-R VIQ scores. Probands were divided into those scoring
above and below the median on the PPVT-R, and rank order analyses were performed. As a
group, probands performed more poorly on the WISC-III Digit Span and Comprehension
subtests and on the WRAML Story Memory subtest than their unaffected siblings. These
differences were not accounted for by differences in age. No significant group differences were
detected for the Similarities or Information subtests of the WISC-R or for the Picture Memory,
Verbal, or Visual Learning subtests of the WRAML. Rank order analysis on measures from the
WISC-III revealed a statistically significant consistency in the rank order on performance of
those with DMD, such that performance was worst on Digit Span, followed by Comprehension,
Similarities and Information. Rank order analysis on measures from the WRAML also revealed
a significant consistency of ranking, with the worst performance being seen on Story Memory,
followed by Picture Memory, Verbal Learning, and Visual Learning subtests. The sibling group
did not show consistency in ranking of their scores, but instead showed considerable variability

Neuropsychological Functioning in DMD 14
in performance rankings. To summarize, relative to their unaffected siblings, the DMD group
performed suboptimally on neuropsychological measures of verbal working memory
(specifically Digit Span and Story Memory) irrespective of general intellectual functioning,
whereas memory for pictures and non-verbal stimuli was unaffected.
In a subsequent study, Hinton et al. (2001) excluded from their original cohort DMD
participants for whom there were no sibling controls. By comparing probands to their respective
siblings, they were able to draw more direct comparisons between the abilities of those with and
without brain dystrophin while controlling for various factors that could affect cognitive abilities
(i.e., familial environment, socioeconomic status). The same eight measures from the WISC-III
and WRAML used in the previous study were employed, as well as additional
neuropsychological tests used to gauge functioning in specific cognitive domains including: 1)
verbal skills, 2) visuospatial skills, 3) attention/memory, and 4) abstract conceptual skills.
Measures of academic achievement in reading, writing, and mathematics from the Woodcock-
Johnson Battery (Woodcock and Johnson, 1977) were included. DMD and sibling-control
groups performed similarly on tests of visuospatial skills and attention – a finding that is
consistent with other reports (Cotton et al., 1998; Dorman et al., 1988; Hendriksen and Vles,
2006). While the two groups also obtained comparable scores on subtests in the verbal domain,
paired comparisons revealed that DMD boys performed worse on the last two items of the Token
Test for Children (Disimoni, 1978). In this test, the child is asked to follow verbal directions that
become increasingly lengthy and complex as the test progresses. Given this, the problems
observed in the DMD group may have been related to increased auditory working memory load.
In support of this, boys with DMD also experienced significantly greater difficulty on Digit Span
than their siblings. Post-hoc analysis revealed that probands had particular difficulty recalling

Neuropsychological Functioning in DMD 15
digits in the reverse order in which they were presented – a skill that requires intact auditory
working memory. In addition to the problems described above, individuals with DMD performed
relatively poorly on the Comprehension subtest of the WISC-R. They also performed worse than
sibling controls on all measures of academic achievement. This latter result was subsequently
replicated in other work by this group (Hinton et al., 2004).
2.3.1.1. The Limited Verbal Span Hypothesis of DMD
Based on their findings, Hinton and colleagues (Hinton et al., 2000; Hinton et al., 2001)
concluded that the neuropsychological profile in DMD is characterized by a selective deficit in
verbal working memory skills, as those with DMD consistently fared worse on subtests that
specifically relied on this ability, including Digit Span, Token Test for Children (immediate
memory for information processed in the auditory domain), and Comprehension (memory for
complex verbal information). The authors argued that a decreased ability to keep phonological
information within short-term and working memory stores might have cascading effects on
intellectual functioning (particularly in the verbal domain), and on academic performance.
In later work (Hinton et al., 2004), these authors revised their description of the
characteristic cognitive deficit in DMD, referring to it as a problem affecting “verbal immediate
memory” or “limited verbal span”, rather than their previous description of a specific deficit in
verbal working memory, as difficulties were apparent on tests requiring short-term retention of
verbal information, whether or not on-line manipulation of that information in working memory
was required (see also Mento et al., 2011). Their suggestion that problems storing verbal
information during presentation of classroom instruction would negatively impact all areas of
academic achievement was strengthened by their finding that performance on Digit Span

Neuropsychological Functioning in DMD 16
significantly predicted scores on all three measures of academic achievement (reading, writing
and math), whereas motor impairment and degree of parent-rated behavioral problems did not
(Hinton et al., 2004). Based on their own work and that of others, Hinton and colleagues further
contended that the deficits in immediate verbal memory seen in DMD result from aberrations
within the cerebro-cerebellar loops, and further argue that DMD may be considered a cerebellar
disorder. The cerebellum receives input from multiple regions of the CNS, and cerebellar
neurons project to nearly all portions of the motor system (Thach et al., 1992) as well as to non-
motor areas of the cerebral cortex (Strick et al., 2009). These anatomical connections between
the cerebellum and the cerebral cortex form essentially “closed-loops”, with distinct and separate
motor and non-motor circuits (Kelly and Strick, 2003). Hinton and colleagues theorized that an
absence of dystrophin in the cerebellum negatively impacts the maintenance and development of
phonological memory stores and rehearsal of information specifically through this cerebro-
cerebellar loop associated with non-motor function (Cyrulnik and Hinton, 2008).
While appealing, the hypothesis of a specific neuropsychological profile characterized by
limited verbal span in DMD (Cyrulnik and Hinton, 2008; Hinton et al., 2000; Hinton et al., 2001;
Hinton et al., 2004) has not been universally supported. In a recent study, Donders and Taneja
(2009) used the Children’s Memory Scale (Cohen, 1997) to assess both immediate and delayed
memory for visual and verbal material among boys with DMD and their unaffected siblings.
Those with DMD did not show deficits in immediate memory, as would be predicted by the
limited verbal span hypothesis. However, they did exhibit difficulties with delayed memory for
both types of materials. After controlling for FSIQ, however, only differences in delayed verbal
recall remained significant. The authors noted that Hinton and colleagues did not examine
delayed memory in their research (Hinton et al., 2000; Hinton et al., 2001).

Neuropsychological Functioning in DMD 17
2.3.1.2. Deficits in Executive Function in DMD
Although there is considerable evidence to support the view that limited verbal span is a
cardinal feature of the neurocognitive profile of DMD, there are also data to suggest that DMD
may be associated with impairments in executive functioning. Executive functions include
components such as working memory, planning, inhibition (of competing thoughts, actions, or
attention), and set shifting (i.e., flexibility in switching between mental states or tasks). In a
comprehensive study of neuropsychological functioning DMD, Mento et al. (2011) noted
consistent deficits in planning and inhibition in children with DMD as compared to those with
juvenile rheumatoid arthritis, as evidenced by performance on the Tower of London test
(Shallice, 1982) and the Elithorn maze perception test (Elithorn, 1955). Deficits on these same
tests and on another test tapping into these same skills (Trail Making Test; War Department,
1944) have also been reported in DMD by Wicksell et al. (2004) in a study that employed a
control group of typically-developing children.
In other work, parents reported that boys with DMD displayed more deficits on the Shift
subscale of the Behavior Rating Inventory of Executive Function (BRIEF; Gioia et al., 2000)
than unaffected siblings (Donders and Taneja, 2009). Boys with DMD also performed worse,
overall, on the Delis-Kaplan Executive Function Battery (Delis et al., 2001), although these
differences were not significant when FSIQ was added as a covariate.
The fact that executive dysfunction has been reported in those with DMD in these studies
and others (see Anderson et al., 1988; Cotton et al., 1998) that utilized a number of different
control groups (i.e. children with a motor impairment; typically developing children; unaffected
siblings) suggests that deficits in this domain may be a central feature of the disorder. Given the

Neuropsychological Functioning in DMD 18
presence of executive dysfunction in multiple studies, including their own, Mento et al. (2011)
argued that the limited verbal span hypothesis of DMD (Hinton et al., 2004) is insufficient to
account for the range of deficits reported in the literature. Rather, Mento and colleagues
suggested that those with DMD may exhibit a broader deficit in higher-order cognitive
processing capabilities, including executive function, and noted that impairment in such
capabilities is a general finding in studies of cognition in DMD. By comparison, deficits in
immediate verbal memory, although a common finding in the literature, have not been
universally reported (see Donders and Taneja, 2009). Deficits in executive function in those
with DMD would be consistent with an absence of dystrophin in brain regions implicated in
higher-order processing and executive functions, such as the cerebral cortex, specifically
prefrontal regions (Spencer-Smith and Anderson, 2009). It is important to note, however, that the
cerebellum is activated during the completion of tasks that assess components of executive
function, such as the Tower of London, leading some to conclude that the cerebellum may be a
key component of the neural network that drives executive function (see Stoodley, 2012 for
review). Anatomically, the cerebellum receives input from and projects to prefrontal regions
(Kelly and Strick, 2003) that are implicated in executive function. Although studies have
confirmed the presence of dystrophin in cortical pyramidal neurons (Lidov et al., 1990), there are
no detailed studies investigating its specific localization in cerebral cortical regions outside the
major lobular divisions (i.e., prefrontal regions). Such studies are essential if we are to elucidate
the role of dystrophin in the brain and fully appreciate the consequences of its absence on
cognition.
2.3.1.3. Summary

Neuropsychological Functioning in DMD 19
The literature on specific cognitive deficits in DMD yields somewhat inconsistent results.
While the majority of studies indicate that expressive and receptive language are both preserved,
as is visuospatial processing, findings in other areas are less clear. Although memory deficits are
frequently reported, in some studies these deficits are evident with stimuli presented verbally,
whereas in others, they are found with both verbal and visual materials, or not at all. Some of the
inconsistencies reported in the literature likely arise from the fact that different researchers have
used different control or comparison groups (i.e., groups with SMA or juvenile rheumatoid
arthritis; typical control groups matched for various factors; unaffected siblings) and different
assessment tools. However, studies examining higher-order cognitive abilities, including
executive function, consistently report impairments in these domains in those with DMD.
Although there is compelling evidence for a deficit in immediate verbal memory in DMD, there
is considerable evidence that this deficit forms part of a neuropsychological profile that includes
executive dysfunction as well.
3. Psychosocial and Neurobehavioral Functioning in DMD
Despite the devastating nature of the muscular disorder and its early presentation, little is
known about the psychosocial development of children living with DMD; indeed, there is only a
handful of studies that document neurobehavioral and emotional functioning in this clinical
population. Leibowitz and Dubowitz (1981) examined the degree of emotional disturbance
among those with DMD age 3 to 13, using the Rutter Behaviour Questionnaire (RBQ) Form A
for parents (Rutter et al., 1970), and Form B for teachers (Rutter, 1967). In the RBQs,
respondents are asked a series of questions relating to the child’s behaviour, and the likelihood of
emotional disturbance is inferred from these responses. Of 52 boys with DMD, 19 (36.6 %) met

Neuropsychological Functioning in DMD 20
the clinical cut-off used to indicate emotional disturbance, categorized as antisocial, neurotic, or
mixed in nature, based on scores from the RBQ B for teachers. Similarly, scores of 18 of 55
affected boys (32.7 %) exceeded the cut-off scores indicative of emotional disturbance with the
RBQ A (parents). Younger children were more likely to show evidence of emotional
disturbances compared to older children.
In a subsequent study (Fitzpatrick et al., 1986), the RBQ-B was used to examine
psychosocial adjustment of boys with DMD compared to a control group of boys matched for
age and father’s occupation. Although total mean scores were not significantly different between
groups, those with DMD did score significantly higher on items in the “neurotic” subscale
relative to controls. In addition, while no diagnoses of depressive disorders were made in the
control group, over half of those with DMD met the criterion for a depressive disorder based on
clinical information pooled from parents, teachers, and an interview with a psychiatrist. Those
with DMD were also significantly more likely to express problems with peer relations than
controls during interviews. It should be noted, however, that in subsequent work, Cotton et al.
(1998) did not detect any increased rates of depression among a small sample of 10 boys with
DMD relative to age and VIQ-matched controls; this study utilized a self-reporting measure, the
Beck Depression Inventory (Beck, 1987).
A number of studies examining neurobehavioral functioning in DMD have used the Child
Behaviour Checklist (CBCL; Achenbach, 1991) to identify possible child psychopathology,
based on parental reports. The CBCL consists of 120 items measuring behaviour across two
broad scales (Internalizing Problems and Externalizing Problems) and eight narrow scales
(Social Withdrawal, Somatic Complaints, Anxiety/Depression, Social Problems, Attention
Problems, Thought Problems, Delinquent Behaviour, and Aggressive Behaviour). Using this

Neuropsychological Functioning in DMD 21
assessment tool, Hendriksen and Vles (2006) found no indication of decreased psychosocial
adjustment or behaviour problems among a group of DMD boys, as mean scores on all scales fell
within the normal range defined by the normative data. A different story emerges, however,
when one considers studies in which comparisons have been drawn between parents’ ratings of
children with DMD and their unaffected siblings. Hinton et al. (2004) reported that their DMD
group exhibited more problems on the Total Behaviour Problem Scale than their siblings.
Further, Donders and Taneja (2009) reported that, even after controlling for FSIQ, boys with
DMD scored more poorly on the Social Problems and the Social Withdrawal scales than their
siblings. In this study, data from an additional parental assessment also indicated that children
with DMD experienced more difficulties than siblings in initiating social interactions and in
responding to changes in the social environment. Other research has suggested that those with
DMD score significantly worse on the Social Problems scale than either unaffected siblings or a
comparison group of those with cerebral palsy, independent of their cognitive abilities or motor
impairment (Hinton et al., 2006).
Although the CBCL is often used to examine psychosocial functioning in DMD,
Hendriksen et al. (2009) argue that it may not be the most suitable assessment tool, as it may be
overly sensitive 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 with DMD (aged 5 to 17 years) using the Personal Adjustment and Role
Skills Scale-III (PARS-III; Stein and Jessop, 1990), a parent-report measure of psychosocial
adjustment; they also provided psychometric data validating the use of this tool in DMD.
Compared to a clinical reference group with chronic conditions, those with DMD were rated as
having significantly more difficulty with peer relations and productivity and were rated as being

Neuropsychological Functioning in DMD 22
less dependent, less depressed, and less anxious. Increasing age was significantly associated with
an increase in psychosocial adjustment in the DMD group. However, scores on the peer relation
subscale were negatively associated with increasing age, suggesting that social relations may
worsen over time in those with DMD. To determine the extent to which steroid use affected
psychosocial functioning, data from those with DMD were grouped according to whether the
child did or did not use steroids. No significant differences were detected for the two groups on
this measure of psychosocial functioning. Overall, results of studies using the PARS-III indicate
that those with DMD are not at a significantly greater risk of psychosocial difficulties than those
with other chronic illnesses, although peer relationships in boys with DMD may be adversely
affected over time.
4. Neuropsychiatric Disorders in DMD
In addition to several studies suggesting that the neurobehavioral profile of DMD
includes impairments in social interactions, there is a documented association between DMD and
autism spectrum disorders – a set of disorders characterized by social interaction deficits.
Komoto et al. (1984), in the first report of DMD-autism comorbidity, described a case study of a
five-year old boy with DMD who was later diagnosed with autism. In a later sample of 158
patients representing all known cases of DMD within Massachusetts, Wu et al. (2005) noted a
comorbid diagnosis of autism in six patients; this was a significantly higher rate of comorbidity
(3.8%) than would be expected by chance, based on the prevalence of each disorder separately.
A higher than normal rate of co-occurrence between the two disorders was also reported in an
international sample of 351 males with DMD; in that study, 3.1% of the DMD group received a
comorbid diagnosis of autism according to parental reports (Hendriksen and Vles, 2008).

Neuropsychological Functioning in DMD 23
Interestingly, boys with DMD are reported to show a mild impairment at recognizing facial
affect compared to sibling controls (Hinton et al., 2007), a characteristic neuropsychological
deficit in autism. Hinton et al. (2006) found that 33% of a sample of 58 DMD boys exceeded the
cut-off score on an assessment used to screen for autism, and that 87% of those identified at this
initial screening met the diagnostic criterion for autism based on their mothers’ responses to the
Autism Diagnostic Interview-Revised (Lord et al., 1994). None of the unaffected siblings scored
above the screening tool cut-off score. Together, these findings lend strong support for a
proposed link between DMD and autism spectrum disorder.
Comorbidity of DMD with other neuropsychiatric disorders has also been documented,
including attention-deficit hyperactivity disorders (ADHD; 11.7%) and obsessive-compulsive
disorder (4.8%) (Hendriksen and Vles, 2008), with the rates at which these disorders occurred in
the DMD sample being significantly higher than those seen in the general population. As there
was no relationship between corticosteroid use and receiving the diagnosis of ADHD, it is
unlikely that the relatively high rates of this disorder in the DMD sample could be attributed to
effects of steroid treatment on emotional functioning or behaviour.
5. Implications of Neuropsychological and Neurobehavioral Findings in DMD
Several recommendations arise from the literature examining neuropsychological and
neurobehavioral functioning in those with DMD, which may help to reduce the overall burden of
the disease. These include strategies that may assist with earlier diagnoses of the disorder, as
well as specific recommendations to improve functioning for those already diagnosed.
Some researchers have speculated that cognitive deficits, especially within the verbal
domain, may be important early risk markers for DMD. Indeed, there are numerous documented

Neuropsychological Functioning in DMD 24
cases of boys initially referred to speech and language specialists who were subsequently
diagnosed with DMD (Essex and Roper, 2001; Mohamed et al., 2000). Delayed attainment of
both motor and language milestones is more common in those with DMD compared with their
siblings, based on prospective parental reports (Cyrulnik et al., 2007). Additionally, signs of
generalized developmental delay are seen in children with DMD between three to six years of
age (Cyrulnik et al., 2008). These findings may help to improve the design of screening tools that
may assist in the early identification of the disorder. This is important -- as despite our
understanding of the molecular basis of DMD and the nature of disease progression -- diagnosis
is often delayed for this condition, which often results from new mutations in the very large
dystrophin gene (Mohamed et al., 2000; Ciafaloni et al., 2009). Many practitioners and
physicians are unaware that cases of DMD may present with non-motor delays, including delays
in cognitive and language development, before any professional consideration is made of a
diagnosis of DMD based on muscle weakness or specific motor delays (Mohamed et al., 2000).
Both physicians and early educators should be aware of the relationship between early
developmental delays and DMD, as the condition is relatively common in the population (1/3500
live male births). Delayed diagnosis has implications for delaying genetic counselling for parents
and can delay or restrict access to possible therapeutic interventions of benefit for children with
DMD, including not only corticosteroids, but also other interventions designed to support
cognitive and psychosocial development (Mohamed et al., 2000).
Despite the overwhelming evidence of cognitive, psychosocial, and behavioral issues in
DMD (in particular those relating to verbal memory, depression, and social difficulties), it is
important to remember that, from a clinical perspective, only a subset of boys with DMD exhibit
such deficits. In fact, the majority of individuals with DMD function at normal intellectual

Neuropsychological Functioning in DMD 25
levels. Although FSIQ scores are lower at the population level, these scores follow a normal
distribution in this clinical population (Cotton et al., 2001; Cotton et al., 2005; Ogasawara, 1989;
Prosser et al., 1969). As well, the rate of clinical depression appears similar in those with DMD
compared to other boys with chronic health conditions (Hendriksen et al., 2009), despite the
severe and ultimately lethal consequences of the disease. Moreover, although there is an
increased risk of social behavioral problems in DMD, not all DMD boys exhibit social deficits,
and among those who do, some are only mildly affected (displaying impaired peer relations). In
some cases, however, these impairments are extreme and accompanied by impaired language
skills and repetitive or restrictive behaviour patterns at an early age – a pattern of deficits that
may be indicative of an underlying autism spectrum disorder.
The remarkable variability in non-motor deficits in DMD suggests the existence of
clinical heterogeneity in this population. Evidence in support of subtypes comes from a study
that employed a principal component analysis of multiple clinical parameters to identify four
phenotypic subtypes in DMD, based on the degree of intellectual impairment and motor
involvement (Desguerre et al., 2009); Group A: classified as “early infantile DMD” and
categorized by severe motor and intellectual dysfunction; Group B: termed “classical DMD” and
characterized by intermediate intellectual outcomes but poor motor outcome; Group C: coined
“moderate pure motor DMD”, exhibited typical intelligence and delayed motor dysfunction; and
Group D: termed “severe pure motor DMD”, characterized by normal intelligence but poor
motor function .
The dystrophin gene is a very large gene, and a complex system regulates the expression
of a large number of its protein products of heterogeneous localization and variable size (see
Perronnet and Vaillend, 2010 for review). These features of the genetic disorder have prompted

Neuropsychological Functioning in DMD 26
research aimed at identifying particular mutations within the dystrophin gene that are associated
with cognitive impairment. Mutation site has been correlated with the degree of cognitive
impairment in DMD. Thus, distal mutations that affect the shorter isoforms of dystrophin have
been associated with a more severe cognitive phenotype, likely due to the fact that shorter
dystrophin isoforms are produced by transcription and translation of distal regions along the gene
sequence (Taylor et al., 2010). Specifically, mutations affecting Dp140 (Felisari et al., 2000;
Moizard et al., 1998; Taylor et al., 2010; Wingeier et al., 2011) and Dp71 (Moizard et al., 1998;
Moizard et al., 2000) are associated with more severe cognitive dysfunction in DMD, whereas
gene mutations in the initial promoter region of the gene that encode brain-type full-length
dystrophin are compatible with typical intellectual functioning (den Dunnen et al., 1991;
Rapaport et al., 1992). Although research has identified associations between gene-mutation site
and cognitive deficits, there have been no attempts to identify subgroups of mutations that
produce the clinical features of particular behavioral, psychosocial, or emotional profiles (i.e.,
deficits in social interaction, depressive symptomology) that are often reported in DMD. As well,
there are no studies to date showing a link between specific gene mutations in DMD and an
increased risk of developing the reportedly co-morbid neuropsychiatric disorders (i.e., autism
spectrum disorders, ADHD, obsessive-compulsive disorder).
This review suggests that more research is required to identify DMD individuals at risk of
developing the cognitive deficits, emotional and psychosocial issues, and social behavioral
problems seen in this heterogeneous population. Until we have a clearer understanding of who
falls into these high-risk categories, thorough neurodevelopmental and neuropsychological
assessments are warranted soon after the initial diagnosis of DMD (Bushby et al., 2010). Clinical

Neuropsychological Functioning in DMD 27
information of this type should be used to develop effective strategies for treatment and
management that are tailored to a child’s unique neuropsychological and behavioral profile.
It is important for parents and early-childhood educators to be made aware of the role that
deficits in verbal immediate memory may play in the intellectual functioning and academic
achievement of those with DMD. Supports for those with problems in this area could involve
strategies such as segmenting verbal instructions into smaller components and repeating verbal
information (Hinton et al., 2004). In addition, the use of special remedial interventions may help
to improve overall academic abilities, including programs designed to improve phonological
abilities, dictation, and mathematical problem solving. The early clinical presentation of verbal
delays in DMD suggests that speech therapy may be a useful component of early intervention
efforts in particular cases. Additionally, the fact that intellectual problems (when present) are
non-progressive should be emphasized to parents and educators so they can provide children
with DMD adequate and continuing opportunities to develop their intellectual and cognitive
capabilities. This may become especially important in later years as muscle pathology
progresses, and these children are able to do less and less physically (Polakoff et al., 1998).
As depression is not uncommon in DMD, careful screening for depressive symptoms
should be done on a regular basis during visits with relevant therapists (physicians, occupational
therapists, psychologists, etc.), and educators and parents should be made aware of signs of
impaired psychosocial adjustment at particular developmental phases. These may include
classical depressive symptoms, such as changes in sleeping patterns or a lack of interest in
previously enjoyed activities, as well other behaviours not typically associated with depression,
such as aggressiveness (which is often associated with depression in younger children) (Polakoff
et al., 1998).

Neuropsychological Functioning in DMD 28
This review identified many studies that document social difficulties for those with
DMD, especially affecting peer relations. It is unclear whether such difficulties are consequences
of decreased mobility, or if they reflect an organic symptom of the disorder – a possibility that
gains support from studies showing that many boys with DMD exhibit social deficits similar to
those seen in autism, a neurodevelopmental disorder with an inherent CNS etiology and
characterized by social difficulties. In either case, educators and parents need to be aware of the
higher prevalence of such social deficits in DMD and offer therapeutic and environmental
opportunities, such as social skills training, applied behavior analysis, and/or increased
opportunities to engage in social interactions with peers. Moreover, since social isolation and
lack of adequate peer support undoubtedly affect emotional coping, addressing these issues may
also serve to decrease depressive symptoms. Social interactions may also be improved by
educating peers and school personnel about the disorder. The importance of attending early to
problems in social interactions is underscored by findings of a significant association between
the degree of social support and general psychosocial well-being among boys with DMD; studies
exploring this association indicate that high-quality social interactions are a key factor in shaping
psychosocial resilience among those with this chronic condition (Fee and Hinton, 2011).
Diagnosticians, educators, and parents should be made aware of the higher-than-expected
prevalence of other neuropsychiatric disorders (including ADHD and OCD) in the DMD
population, so that any noted deficits are not simply regarded as secondary sequelae of the
primary motor disease, or consequences of living with such a chronic condition. Appropriate
interventions could then be offered when indicated to pre-empt progression of these disorders.
Collectively, such efforts could go a long way to improving the quality of life for this group of

Neuropsychological Functioning in DMD 29
boys and their families and caregivers, who are already dealing with a devastating physical
condition.
6. Conclusions
This report aimed to provide a critical and detailed review of the literature on
neuropsychological and neurobehavioral functioning in those with DMD. The literature is often
contradictory in nature, possibly due to methodological constraints, including the use of samples
of convenience and various control groups as well as the utilization of various assessment tools.
Such limitations are expected in research examining children with a chronic, fatal illness.
However, the synthesis of the literature highlights important, over-arching ideas for
consideration. Both general intellectual and academic abilities are depressed at the population
level in DMD. While multiple aspects of cognitive functioning are implicated in the disorder,
verbal abilities, especially those relating to verbal immediate memory, seem predominantly
affected in this group; these may be evident even in the absence of an intellectual disability.
Moreover, psychosocial mal-adjustment and behavioral issues often manifest in DMD, including
depression and difficulties with social interactions and peer relations. In addition, the incidence
of neuropsychiatric disorders appears higher among those with DMD than in the general
population, for reasons that are not currently known. Finally, this review has found that although
there is evidence to suggest that DMD is associated with particular neuropsychological and
neurobehavioral characteristics, there is considerable heterogeneity in this clinical sample; this
fact should be given ample consideration during the development of therapeutic interventions.
The use of carefully selected control groups that account for physical and familial factors,
and the use of meta-analytical statistical methods to address sample sizes and representativeness,

Neuropsychological Functioning in DMD 30
have expanded our current understanding of neuropsychological and behavioral characteristics in
DMD. Several lines of evidence have now converged sufficiently to point to an organic and
primary CNS involvement in DMD that challenges our view of the disorder as 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
application of some of these strategies in the management of this chronic condition may have the
potential to decrease the burden of the disease and improve the overall quality of life and daily
functioning for those with DMD. Continued research on neuropsychological and
neurobehavioral functioning in DMD, together with studies designed to elucidate the role of
dystrophin within the developing and mature brain at individual, tissue, cellular and sub-cellular
levels, are expected to expand the available repertoire of treatments for affected boys.
Acknowledgements
This work was supported by operating grants from the Manitoba Institute for Child Health (JEA)
and the Natural Sciences and Engineering Research Council (LSJ), and by a Postgraduate
Scholarship from the Natural Sciences and Engineering Research Council (WMS).
Conflict of Interest: The funders did not contribute to the study design, interpretation, or
manuscript preparation. The authors declare that they have no conflict of interest.
!

Neuropsychological Functioning in DMD 31
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