Review

Cognitive impairment in multiple sclerosis

Nancy D Chiaravalloti, John DeLuca

Multiple sclerosis (MS) is a progressive disease of the CNS that is characterised by widespread lesions in the brain Lancet Neurol 2008; 7: 1139–51
and spinal cord. MS results in motor, cognitive, and neuropsychiatric symptoms, all of which can occur independently Neuropsychology and
of one another. The common cognitive symptoms include deficits in complex attention, efficiency of information Neuroscience Laboratory,
Kessler Medical Rehabilitation
processing, executive functioning, processing speed, and long-term memory. These deficits detrimentally affect many
Research and Education Center,
aspects of daily life, such as the ability to run a household, participate fully in society, and maintain employment— West Orange, NJ, USA
factors that can all affect the overall quality of life of the patient. The increased use of neuroimaging techniques in (N D Chiaravalloti PhD,
patients with MS has advanced our understanding of structural and functional changes in the brain that are J DeLuca PhD); Departments of
Physical Medicine and
characteristic of this disease, although much remains to be learned. Moreover, examination of efforts to treat the
Rehabilitation
cognitive deficits in MS is still in the early stages. (N D Chiaravalloti, J DeLuca) and
Neurology and Neurosciences
Introduction the course of the disease, with a ratio of 1∙3:1 (women to (J DeLuca), University of
Medicine and Dentistry of
Multiple sclerosis (MS) is a progressive disease of the men) in primary-progressive MS.11 New Jersey, New Jersey Medical
CNS and is characterised by the production of widespread In this paper, we review the current understanding of School, NJ, USA
lesions, or plaques, in the brain and spinal cord. These cognitive impairment in MS and describe the common Correspondence to:
lesions and plaques affect the myelin sheath, thus cognitive profile, the factors that contribute to cognitive John DeLuca, Kessler Medical
causing inhibition of axonal transmission. Inflammatory dysfunction, and the effect of such impairments on daily Rehabilitation Research and
Education Center, 1199 Pleasant
demyelination has traditionally been seen as the main life. In addition, we review cognitive and pharmacological
Valley Way, West Orange,
disease process in MS; however, axonal damage or loss is treatments for cognitive deficits, followed by contributions NJ 07052, USA
increasingly being documented to occur early in the from structural and functional imaging techniques to the jdeluca@kmrrec.org
disease and to result in permanent disability.1–3 Whether understanding of cognitive impairments in MS.
grey matter pathology is independent of that seen in
white matter, is a result of axonal injury in the white Cognitive deficits in MS
matter, or is simply similar to the pathology seen in the Since the 1980s, research has indicated that cognitive
white matter is debated.4 Because of the widespread impairment is a common concomitant of MS, with
development of the plaques, MS results in a broad range prevalence rates ranging from 43% to 70%12–14 at both the
of symptoms, which include motor, cognitive, and earlier and later stages of the disease.15,16 MS detrimentally
neuropsychiatric problems,5 and no two individuals with affects various aspects of cognitive functioning, including
MS have exactly the same symptom profile or disease attention,17,18 information processing efficiency,17,19,20
course.6 In addition, cognitive deficits can occur executive functioning,21–23 processing speed,24 and long-
independently of physical disability, which complicates term memory.5,25,26 Processing speed, and visual learning
their identification and recognition.7 This wide variability and memory seem to be most commonly affected in MS
in symptoms and disease course hampers understanding (in 51∙9% and 54∙3%, respectively; figure 1).13,14 Areas of
of the disease process and identification of effective cognition that are not usually affected are “simple”
treatments. Although the precise cause of MS is not yet attention (eg, repeating digits) and essential verbal skills
known, it is currently thought to be the result of (eg, word naming and comprehension).13 Although most
immunological, genetic, and viral factors.8 studies indicate that general intelligence remains intact
Four clinical courses of MS have been identified on the in patients with MS,27 other investigations have detected
basis of the rate of progression of the disease.9 Relapsing- slight but significant decrements.13 Overt dementia is
remitting MS is characterised by periods in which rare in MS,28 and the more common clinical presentation
symptoms are exacerbated and full recovery is noted is one of specific and subtle cognitive deficits that can
between attacks. About 80% of individuals with relapsing- vary substantially among patients.28
remitting MS later develop secondary-progressive MS;9
in this type of MS, the symptoms gradually worsen with Long-term memory
or without occasional relapses or minor remissions. Long-term memory refers to the ability to learn new
Progressive-relapsing MS is characterised by a progressive information and to recall that information at a later time
decline after onset of the disease, with some acute periods point.29 Long-term memory is one of the most consistently
of symptom relapse. There might or might not be impaired cognitive functions in MS and is seen in
recovery from these acute periods. Finally, primary- 40–65% of patients.25 Early work on memory impairment
progressive MS has a continuous and gradual worsening in MS suggested that difficulty in retrieval from long-
of the symptoms with no distinct exacerbation or term storage was the primary cause for the deficit in
remission of symptoms. Although epidemiological long-term memory.30–32 More recently, however, research
studies indicate that women are about twice as likely to has shown that the primary memory problem is in the
have MS than are men,10 this association is affected by initial learning of information.26,33,34 Patients with MS

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 Review

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MS and healthy controls to reach criterion* on the open-trial selective

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reminding test
Cognitive domain
Patients with MS needed substantially more trials to reach criterion relative to the
healthy controls, which is indicative of deficits in verbal acquisition in MS. Adapted
Figure 1: Frequency of impairment in 291 patients with MS by cognitive domain from DeLuca J et al,26 with permission from Taylor and Francis. *Criterion was
Data from Benedict RH et al.14 correct recall of ten words in two consecutive trials.

require more repetitions of information to reach a
predetermined learning criterion, but once that
information has been acquired, recall and recognition
are at the same level as for healthy controls (figure 2).26,34
This deficit in learning new information results in poor
decision-making abilities35 and seems to affect prospective
memory abilities.36 Several factors have been associated
with poor learning abilities in people with MS, including
slow processing speed, susceptibility to interference (ie,
difficulty disregarding irrelevant stimuli), executive
dysfunction, and perceptual deficits.
Efficiency of information processing
Information processing efficiency refers to the ability to
maintain and manipulate information in the brain for a
short time period (working memory)37 and to the speed
with which one can process that information (processing
speed). A reduced speed of processing is the most
common cognitive deficit in MS.24,38,39 Tests of processing
speed can be used to predict long-term cognitive decline,
with a pronounced decline in processing speed occurring
over several years of follow-up.39 Such deficits in
processing speed are typically seen concurrently with
other cognitive deficits that are common in MS,24 such as
deficits in working memory and long-term memory;38,40,41
in some studies the extent of memory impairment has
been positively correlated with deficits in processing
speed.24,40,42 One study has shown that processing speed
can predict performance on the everyday tasks component
of the executive function and performance test (discussed
below).43 Therefore, clinicians who assess patients with
MS should be cautious when interpreting deficits in
higher-order cognition (eg, resistance to interference or
executive functioning) when there is a speed of processing
component to task performance.27
Deficits in working memory and speed of processing
affect each other in patients with MS: as the demands on
working memory increase, both deficits in speed of
processing and working memory become more
prominent.44,45 Impairments in working memory have
been detected in the earliest stage of MS46 and across
disease courses.47 Results from recent large sample
studies have shown that people with MS present with a
significantly higher occurrence of deficits in speed of
processing than in working memory, particularly in
patients who have a secondary-progressive course
(figure 3).24 The paced auditory serial addition test
(PASAT), a test of working memory with substantial
demands on processing speed, is a sensitive measure of
cognitive dysfunction in MS and has a sensitivity and
specificity of 74% and 65%, respectively.48 The PASAT is
the cognitive component of the widely used multiple
sclerosis functional composite,49 which is a multi-
dimensional quantitative outcome measure designed
specifically for use in patients with MS.
Performance on tasks of attention is associated with
speed of processing and working memory. Typically,
basic attention tasks (eg, repeating digits) are unaffected
in patients with MS,14 although a deficit has been noted
in at least one study.50 Impairment in sustained attention
is more common51 and specific decrements in divided
attention (ie, tasks in which patients are asked to attend
to several tasks simultaneously, such as identifying
specific targets on a computer screen, while monitoring

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a second task) have been reported in patients with MS.51
Variability in the exact cognitive processes labelled
“attention” makes it difficult to draw conclusions about
the effect of MS on attention processes: for example,
some investigators label a task an “attention” task when it
might more accurately involve processing speed52,53 or
executive control.53 In addition, the involvement of fatigue
is not often accounted for and this factor probably exerts
a considerable effect on the performance of tasks that
demand longer attention spans and that are typically
used to identify deficits in sustained or divided attention.
Finally, differences among studies in the description of
various disease courses could affect conclusions about
attention because the more complex forms of attention
(ie, sustained and divided) are more likely to be affected
by the progressive forms of MS.
Executive functions
Executive functioning refers to the cognitive abilities
needed for complex goal-directed behaviour and
adaptation to environmental changes or demands. This
includes the ability to plan, anticipate outcomes, and
direct resources appropriately.54 Deficits in executive
functions (ie, abstract and conceptual reasoning, fluency,
planning, and organisation) occur in patients with MS,
albeit less frequently than deficits in memory and
information processing efficiency.5,55,56 Drew and
co-workers57 noted that 17% of patients with MS had
difficulties across a range of executive abilities (ie,
shifting, inhibition, and fluency). Fluency tests “evaluate
the spontaneous production of words under restricted
search conditions”,58 such as words that begin with a
specific letter and words from a particular category. Henry
and Beatty59 noted that patients with MS had substantial
deficits in both phonemic and semantic fluency, and
concluded that levels of fluency were sensitive measures
of neurological impairment in MS. Similarly, perseverative
errors (ie, errors that are repeated despite evidence that
they are incorrect) have been repeatedly seen in patients
with MS.60–62 Measures of executive functioning are also
particularly susceptible to the effects of depression in
patients with MS,61,63–65 and this should always be
considered in the interpretation of poor performance on
executive tasks in individuals with MS.
Visual perceptual functions
Visual perceptual functions not only include the
recognition of a visual stimulus, but also the ability to
perceive the characteristics of that stimulus accurately.
Compared with studies on long-term memory and
information processing efficiency, there has been little
work on visual perceptual processing. Up to about a
quarter of people with MS might have deficits in visual
perceptual functions.66 Difficulties in primary visual
processing (eg, from optic neuritis) in MS can have a
detrimental effect on visual perceptual processing,
although perceptual deficits that are independent of
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Review
80
Impairment in processing speed
Impairment in working memory
70
60
Percentage of patients impaired
50
40
30
20
10
0
Secondary-progressive MS Relapsing-remitting MS
Figure 3: Percentage of patients with secondary-progressive MS or relapsing-
remitting MS who have impairments in speed of processing and working
memory
In this sample of 215 patients with MS, considerably more patients had
impairments in speed of processing than in working memory. Adapted from
DeLuca J et al,24 with permission from Taylor and Francis.
primary visual or other cognitive abnormalities can also
occur.66 Primary visual problems can contribute to
difficulties on higher-order cognitive tasks that have
visual demands.67
Assessment of cognitive functioning
Given the high occurrence of cognitive dysfunction in
patients with MS, adequate assessment and diagnosis of
these deficits is essential. Clinicians and researchers
have used various tests of cognitive functioning to
identify the deficits commonly seen in these patients. As
the cognitive deficits in MS frequently fall within specific
cognitive domains and can be subtle and vary considerably
among patients,28 a carefully selected neuropsychological
test battery is essential. Various batteries have been
recommended for use, although many have been
criticised for their emphasis on brevity rather than
comprehensiveness and thus often fail to identify
cognitive deficits accurately.68,69 However, other tests have
been deemed too comprehensive because areas that are
not typically affected by MS are assessed and these tests
are thus inefficient in terms of cost and time.70
Consequently, an International Conference of MS Experts
resulted in the development of the minimal assessment
of cognitive function in MS test battery, which is now
recommended for use with patients with MS. This battery
is composed of seven tests that assess word fluency,
visuospatial ability, verbal memory, visuospatial memory,
processing speed, working memory, and executive
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 Review
function, and has been shown to be sensitive to the
cognitive profiles characteristic of patients with MS.14 In
an effort to increase the availability of screening
assessments, researchers have also started to investigate
the validity of internet-based cognitive testing.71
Other factors that affect cognitive performance
Disease-related factors
Cognitive impairment can be seen irrespective of the
duration of disease and is only mildly associated with
physical disability.72,73 However, the course of the disease
does play a part in the pattern of cognitive dysfunction in
MS. Progressive MS generally results in more severe
cognitive impairment than does relapse-remitting MS;74,75
however, in these data the course of the disease was
confounded with duration of disease. For example, about
50% of individuals with untreated relapsing-remitting
MS will develop secondary-progressive MS within
10–15 years of onset.76 Thus, by definition, disease duration
and the extent of neurological disability (measured using
the expanded disability status scale) are greater in patients
with a secondary-progressive course compared with
relapsing-remitting MS. In the few studies that have
distinguished between patients with primary-progressive
MS and patients with secondary-progressive MS,
significantly greater cognitive dysfunction was seen in
the secondary-progressive MS group.23,39,40,77,78
Few studies have examined the characteristics of
cognitive decline in MS over time. Such studies have
methodological difficulties, such as a solely cross-sectional
design or short follow-up periods. In one study,79 cognition
was assessed in individuals with MS who were examined
initially at enrollment and then after 4 and 10 years. As the
disease progressed, the percentage of patients with
cognitive impairment tended to increase, although, even
after 10 years, most patients did not have cognitive
impairment. Similar results were found in another 10-year
follow-up study,80 in which no significant change in
performance on tests of memory and semantic retrieval
were seen over the study period. However, on tests of
working memory and processing speed, 27–44% of
patients showed a decline over time.
Depression
Research has shown a link between emotional symptoms
and cognitive functions in many people with neurological
disorders. Depression is common in MS and is thought
to interfere considerably with cognitive and non-cognitive
activities.81 The relation between depression and cognitive
functioning is not clear:82 although results from several
studies have shown depression to be associated with
neuropsychological functioning in patients with MS,83,84
other investigations have not shown such a relation.26,85,86
In a critical review of the literature, Arnett and
co-workers82 concluded that when studies are adequately
powered and include a representative sample of people
with MS, a positive link has been consistently noted
1142
between depression and cognitive functioning.
Depression affects many aspects of cognitive functioning
in MS, including working memory,87,88 processing speed,89
learning and memory functions,90 abstract reasoning,90
and executive functioning.23,64 The amelioration of
depression could also lead to neuropsychological
improvements in patients with MS.91
Up to 60% of people with MS have depression,92
although efforts to explain its source, from factors such
as effects of drugs, physical disability, cognitive deficits,
fatigue, and disease duration, have not been successful.92
However, depression in patients with MS is less common
in individuals with lesions that are predominantly in the
spinal cord than in patients with brain lesions.93 Recent
studies have shown a relation between depression and
demyelination94–97 with demyelination in some brain
regions appearing to contribute to depression more than
other areas. For example, Sabatini and co-workers98 have
suggested that a disconnection between cortical and
subcortical areas that are important for limbic system
function might contribute to depression in MS. Similarly,
Bakshi and co-workers94 have concluded that a
cortical–subcortical disconnection caused by lesions in
frontal and parietal white matter (independent of
neurological disability), as well as atrophy, might
contribute to depression in individuals with MS. Other
studies have shown a greater number of lesions in the
temporal region in depressed versus non-depressed
individuals with MS.95–97 In addition to differences in
patterns of lesion location, immunological markers (such
as increased T4+ helper/inducer cell counts)99 have also
been associated with depression in MS.82
Fatigue
Fatigue is one of the most common symptoms in MS
and has been reported in over 90% of patients.100 Fatigue
has two components: physical and cognitive101 and,
although difficulties in the accurate assessment of
cognitive fatigue is an obstacle to forming a complete
understanding of the construct, researchers still seek to
better understand the relation between cognitive fatigue
and cognition in MS.101 No association has been found
between subjective reports of fatigue and cognitive
dysfunction.101–103 However, efforts to measure fatigue
objectively have been more successful; decrements in
performance over time in tasks that require sustained
mental effort have suggested that fatigue might affect
performance.101 This pattern has also been noted in
cognitive tasks of working memory103 and visual
vigilance.101
Impairment in oral motor functions
Cognitive tasks that require a rapid spoken response
might be detrimentally affected by impairments in
rudimentary oral motor functions in people with MS.
Decreased performance on tasks that require oral
responses are partially caused by dysarthria in patients
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with MS.104 The assessment of rudimentary oral motor
problems was recommended as part of the minimal
assessment of cognitive function in MS and was further
investigated empirically by Arnett and co-workers.105 In
an effort to minimise the effect of the characteristic slow
motor response of patients with MS on performance of
cognitive tests, researchers and clinicians have frequently
used tasks that do not require motor function for writing
or for manual manipulation. As a result, the primary
response modality in the study of a person with MS tends
to be speech, which is susceptible to oral motor
impairments. Thus, caution is needed in the interpretation
of tasks that could be affected by rudimentary speech
problems to avoid over-diagnosis of problems in higher-
order cognitive processing.
The effect of cognitive impairment on daily
living
Cognitive dysfunction is closely associated with functional
status in MS.106,107 Rao and co-workers108 found that
individuals with MS who were cognitively impaired
participated in fewer social and vocational activities, were
less likely to be employed, had greater difficulties in doing
routine household tasks, and were more vulnerable to
psychiatric illness than individuals with a purely physical
disability. By use of an objective, structured, and
standardised assessment battery designed by occupational
therapists, the executive functions performance test,109
Kalmar and co-workers43 found that cognitive performance
was correlated with objective assessment of activities
during everyday life, whereas subjective assessment of
functional activity was correlated with emotional distress.43
Although performance on the executive functions
performance test does not depend on speed (ie, patients
can take their time), a significant association between
performance on this test and speed of processing was
seen. Performance on tests of processing speed is also
associated with measures of everyday life that require
speeded responses.110 Nagy and co-workers35 have reported
that patients with MS have a reduced ability to make
decisions that could affect functioning during everyday
life, which was mainly caused by deficits in new learning.
Similarly, Kessler and co-workers107 found that considerable
variance in activities of daily living in MS could be
accounted for by the results of ten memory tests,
independent of demographic or physical disability
variables; functional impairment was primarily associated
with difficulties in new learning.107 Functional impairments
that are commonly seen in MS include difficulty in
shopping independently, completing housework, washing
clothes, ironing, completing home repairs, cooking,
driving, and using public transportation.111
Considerable evidence indicates that quality of life
(QoL) is decreased in individuals diagnosed with MS.112
Furthermore, the extent to which an individual has a
poor QoL correlates with deficits in cognitive
functioning,113 depressive symptomatology,114,115 increased
www.thelancet.com/neurology Vol 7 December 2008
Review
disability,116 severity and progression of disease,117–119
disease duration,117 decreased cerebral integrity on MRI,120
and decreased ability to do everyday activities.121 There is
also a lower QoL during periods of relapse compared
with periods of remission.116,122 Cognitive deficits are
detrimental to the QoL and productivity of patients with
MS108,113 and neuropsychological deficits have a large effect
on QoL in particular.113
The onset of MS typically occurs between the ages of
20 and 40 years, when individuals are most active and
productive in many aspects of their lives,123 and frequently
leads to the loss of gainful employment for many
patients.106 Specifically, 40–80% of individuals with MS
are unemployed124–126 and cognitive impairment is a large
contributor to this high rate of unemployment.106,108 Beatty
and co-workers106 have reported five variables that account
for 49% of the variance in employment status in MS,
three of which are measures of cognitive functioning.
Several investigations have noted that 50–80% of patients
with MS are unemployed within 10 years of disease
onset,124–128 and this number is frequently attributed to
deficits in cognition:106,108 as physical disability and
demographic factors account for less than 14% of the
variance in employment status in patients with MS,128
cognitive problems are thought to account for much of
the variance.129 Deficits in various domains of cognitive
impairment have been blamed for this difficulty in
maintaining employment, particularly information
processing efficiency, memory performance,106 and
executive dysfunction.45 Benedict and co-workers14 have
found that poor cognitive performance—particularly on
measures of processing speed, verbal memory, and
executive functioning—predicted vocational status, even
after the effects of age, education, sex, depression, and
disease course were taken into account. Similarly, Rao
and co-workers108 noted that cognitive impairment was
important in determining the work status of individuals
with MS, even when groups were matched on several
measures of disease severity (the expanded disability
status scale scores, disease course, and disease duration).
Thus, MS results in considerable disruptions to the lives,
lifestyles, employment status, and yearly earnings of
affected individuals,128–130 which has a detrimental effect
on personal, occupational, and social functioning, thereby
affecting overall QoL. Although physical disability is
important for the performance of everyday activities, it
cannot account for the extent of difficulties that
individuals with MS encounter for many everyday
activities, particularly in those activities that require a
substantial cognitive load.
Treatment of cognitive deficits
Cognitive rehabilitation
There have been few studies on the treatment of cognitive
deficits so far,131 and several authors have highlighted the
need for additional effective neuropsychological
rehabilitation techniques in MS.132,133 The few cognitive
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Total scores on the Hopkins verbal learning test—revised 4

3
2 been seen with simple repetition of information.149 Non-
1 specific cognitive protocols have also been examined in
0 patients with MS and cognitive benefits have been noted
–1
Baseline to immediate
–2 follow-up
–3
–4
–5
Experimental group
–6 Control group
Figure 4: Hopkins verbal learning test—revised change scores for the
moderately impaired group
Participants in the experimental group showed an increase in verbal learning
scores from baseline to immediate follow-up and from baseline to long-term
follow-up. Participants in the control group showed no meaningful change
during the same assessment period. Adapted from Chiaravalloti ND et al,140
with permission from SAGE Publications.
rehabilitation programmes available for MS aim to
improve attentional deficits,134 communication skills,135
and memory impairments.136–138 Although some studies
have detected a benefit of cognitive rehabilitation for
individuals with MS,137–140 other investigations have not
shown any improvement.141,142 In a comprehensive
evidence-based review of the available data on the use of
cognitive rehabilitation for patients with MS, O’Brien
and co-workers concluded that, although this research is
still in its infancy, there have been some well designed
studies that can provide a foundation from which to
advance the field.143
A few studies have examined the efficacy of attention
remediation protocols for the treatment of patients with
MS. Although results from some studies have not shown
benefits of the specific training programme studied,141,142
other investigations have shown some objective
benefit.134,144 We know of only two studies on the cognitive
rehabilitation of executive functions in patients with MS:
one that detected a significant treatment effect145 and
another that found no treatment effect.141 Learning and
memory have received the most attention with regard to
cognitive rehabilitation in MS. Building on earlier
work,136,138 Chiaravalloti and co-workers140 did a double-
blind randomised placebo-controlled trial of the modified
“story memory technique” to improve learning and
memory in 28 individuals with mixed subtypes of MS
(figure 4). A significant effect of the treatment on list
learning performance was seen, particularly among those
with a moderate-to-severe memory impairment. Although
less rigid in design, some studies have also shown some
benefit of memory rehabilitation programmes in patients
with MS;142 however, others have failed to document any
benefit.136,138 Although not part of structured treatment
protocols, researchers have also started to examine the
effect of specific memory-enhancing techniques in
patients with MS. Techniques such as self-generated
learning146,147 and spaced learning148 can improve learning
and memory considerably in MS, whereas no benefit has
in some studies137,150 but not in others.151
Baseline to long-term The conclusions that can be made from available
follow-up
studies are limited by the methodological problems, such
as baseline differences among groups,137 the use of a
qualitative rather than quantitative research design,135
and reliance on case studies.136 There is an important
clinical need for methodologically rigorous research into
cognitive rehabilitation in patients with MS: the ideal
study would be an adequately powered placebo-controlled,
randomised clinical trial.
Pharmacological interventions
Two pharmacological approaches have been examined in
an effort to improve cognitive deficits in patients with
MS: disease-modifying therapies and pharmacological
treatments specifically targeted at improving cognition.
Disease-modifying therapies are drugs that alter the
disease course of MS. Although many studies have
examined the efficacy of various disease-modifying
therapies in MS, not all trials have included cognition as
an outcome variable and, when they do, cognition tends
to be a secondary outcome; it is therefore difficult to deter-
mine the effect of the drug on cognitive function from
these studies. In such studies, the cognitive status of
included participants is commonly comparable to that of
healthy individuals.152 In one study, a significant beneficial
effect of interferon beta-1a was shown for processing
speed, and learning and memory.153 Interferon beta-1b
has shown some mild benefit for cognitive function,154,155
whereas research on glatiramer acetate has shown no
effect on cognition.152 However, glatiramer acetate has
been found to improve fatigue in patients with MS,
which resulted in fewer absences from work.156,157
Researchers have also examined the benefit of
pharmacological treatments specifically targeted at
improving cognition. Acetylcholinesterase inhibitors
were originally developed to treat cognitive decline in
Alzheimer’s disease. The study of acetylcholinesterase
inhibitors in individuals with MS dates back to 1988,
when Leo and co-workers158 noted an improvement in
verbal memory with physostigmine in a double-blind,
placebo-controlled study; a similar effect was seen by
Unverzgagt and co-workers.159 However, both studies had
methodological limitations: the former had a small
sample and the latter did not have a control group. In
addition, the short half-life and considerable adverse
effects of physostigmine have tempered enthusiasm for
the drug. Donepezil has received the most research
attention in efforts to improve cognition in MS and
improvements in memory dysfunction in MS have been
seen with this drug.160 However, methodological problems,

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such as no placebo-control group, have limited the
conclusions that could be drawn from earlier studies.161,162
A recent double-blind, placebo-controlled randomised
clinical trial with 69 individuals with MS showed that
donepezil improved objective memory performance on
list learning, as well as subjective ratings and clinician
ratings of memory abilities.163,164
Stimulant drugs have also been investigated in
patients with MS. Amantadine hydrochloride is
commonly used to treat fatigue in MS and has shown
modest benefit.165 However, studies of the efficacy of
amantadine for treating the cognitive deficits in MS
have not shown an effect.166 In addition, in a randomised
clinical trial of 38 patients with MS no effect of ginkgo
biloba on cognition was seen overall.167 However, a trend
was noted for improved performance on the Stroop test,
which measures resistance from interference and
processing speed.
Although cognitive impairment is a main concomitant
of MS, an effective treatment has not yet been identified;
the strongest evidence suggests that acetylcholinesterase
inhibitors and donezepil in particular are the most
promising drugs. However, many of these studies have
had small samples and few studies have applied optimum
research strategies.160,163 Future research is therefore
necessary to enable a recommendation for pharmacological
therapy for cognitive deficits in patients with MS.
Neuroimaging and cognition
Structural imaging
Structural neuroimaging has become a key element of
diagnosis and care in MS.168 Various techniques designed
to capture brain integrity—MRI being the most widely
used—have shown correlations with cognitive functioning.
Several measures can be obtained by use of MRI,
including whole brain atrophy,169,170 cortical atrophy,171 and
lesion volume.172 Studies have shown that patients with
greater lesion burden have significantly more cognitive
dysfunction than those with less lesion burden.62,95,172,173
Measures of brain atrophy are particularly sensitive in
elucidating the relation between brain integrity and
cognitive status.95,174–176 The width of the third ventricle has
a strong association with cognitive status176 and subcortical
atrophy is more highly correlated with cognition than
whole brain atrophy or lesion load.174,177 The width of the
third ventricle correlates not only with cognitive
performance in MS,176,178 but also provides predictive
validity for cognition.178 Atrophy in the thalamus is a
strong predictor of cognitive dysfunction,178 although this
is not necessarily better than other MRI measures, such
as width of third ventricle or whole brain atrophy. Grey
matter and white matter atrophy have been associated
with performance in particular cognitive skills, which
indicates that atrophy in these distinct tissue types could
result in specific functional deficits. Similarly, left frontal
atrophy has been associated with performance on tests of
verbal memory, whereas right frontal atrophy has been
www.thelancet.com/neurology Vol 7 December 2008
Review
associated with deficits in visual memory and working
memory.179 Neocortical volume correlates with cognitive
performance across a wide range of neuropsychological
measures, and also distinguishes patients with MS with
cognitive impairment from those without cognitive
impairment.178 Thus, measures of central atrophy, such as
lesion load, seem to be more useful than conventional
measures in determining the extent of cerebral change in
MS.178 Longitudinal imaging studies have shown a strong
correlation between changes in cognitive functioning and
an increase in brain atrophy;180,181 moreover, progression of
brain atrophy early in the disease can predict cognitive
impairment 5 years later.170
New technologies can help to maximise our ability to
assess cerebral integrity in MS. Although some studies
that use diffusion-tensor MRI have found a correlation
between functional anisotropy and cognitive perfor-
mance,182 other investigations have found no such
association.183 Measures derived from magnetisation
transfer ratio have also consistently been shown to be
associated with cognition, as documented with many
types of brain tissue, including cortical and subcortical
regions,184 normal-appearing brain tissue on conventional
imaging,185 and normal-appearing white matter.186
Magnetic resonance spectroscopy, which provides a
measure of metabolic changes in the cerebral cortex and
white matter, is also a sensitive indicator of cognitive
functioning in MS, particularly in normal-appearing
white matter.187,188 Multi-slice echo-planar spectroscopic
imaging provides global metabolic measures that can be
used to distinguish between patients with MS with and
without cognitive impairment.189
Functional imaging
Compared with structural imaging, the application of
functional imaging to study brain function is a relatively
new area of research in MS. Initial studies using PET,
single photon emission computed tomography
(SPECT),190–195 and perfusion MRI196 have shown a
reduction in cerebral oxygen use and blood flow in
individuals with MS, and these changes correlate with
cognitive impairment. More recently, functional MRI
(fMRI), which has many advantages over PET and SPECT,
has begun to be used in MS research. The increased use
of functional imaging techniques to study clinical
problems in MS over the past 10 years has provided a
wealth of new knowledge about brain–behaviour relations
in MS. However, this increasing body of new knowledge
must be met with the appropriate scientific scrutiny and
scepticism with regard to interpretation and application.
Functional imaging studies that have investigated
cognitive processes in MS have focused on three main
areas: working memory, attention, and executive
functions. fMRI studies of working memory in MS have
mainly used three verbal working memory cognitive
tasks: the PASAT46 (or a modification of the PASAT
referred to as the mPASAT197), the N-back test,198 and the
1145
 Review
Sternberg protocol.199 Studies that have used the PASAT
and mPASAT have shown that individuals with MS
have bilateral frontal cortical activation,46,197,200,201 by
contrast with the more focal left frontal activation seen
in healthy controls. However, patients with MS also
show considerably greater activation throughout other
brain regions such as bilateral parietal lobes,197,201
bilateral temporal lobes,201 and the right cerebellum200
when compared with healthy controls. In fMRI studies
that have compared individuals with MS with and
without impaired working memory,46,197,201 all have shown
differences in the pattern of cerebral activation between
the two groups, although the specific patterns of cerebral
activation differed among studies. Several method-
ological differences, such as response modality (verbal
vs motor), the use of a control task, and the speed of
stimulus presentation, might account for the variation
in results.
Data from fMRI studies of the 2-back working memory
task consistently suggest that, when performance is
similar among groups, the same cortical regions (frontal
and parietal areas) are activated in participants with MS
and healthy controls.198,202,203 However, although some
results have shown that the magnitude of the activation
is greater in the patients with MS compared with the
healthy controls,198,203 other investigations have shown
lower activation in frontal regions in those with MS.202
By use of the Sternberg protocol, Hillary and co-workers199
found significantly greater activation in the right frontal
and right temporal lobes in individuals with MS than in
healthy controls, with no difference in left hemisphere
activation. Participants with poorer performance
showed increased activation in the right frontal and
right temporal lobes. A similar inverse relation was
shown by Chiaravalloti and co-workers197 between
performance on the PASAT and the level of activation
of the right frontal and parietal regions. However, Li
and co-workers204 found a significant decrease in the
number of voxels activated in the right and left cerebellar
hemispheres in participants with MS compared with
the healthy control group by use of the Sternberg
protocol. This finding suggested that the cognitive
processes of the cerebellum are also disrupted in MS,
possibly caused by a disruption in the pathways from
the cortex to the cerebellum.
Two studies have applied functional neuroimaging
techniques to examine attention in MS, both of which
showed significant differences in patterns of cortical
activation during attention tasks between patients with
MS and healthy controls.205,206 By use of a visual attention
task during fMRI, Penner and co-workers205 showed that
patients with MS who had mild cognitive impairment had
significantly greater activation in the right dorsolateral
prefrontal cortex, right superior temporal gyrus, right
lateral cerebellum, left angular gyrus, and bilateral inferior
parietal cortex than did the control group. Patients with
MS who were severely impaired also had significantly
1146
greater activation in the left inferior parietal lobe than did
the control group. By use of PET, Santa Maria and
co-workers206 showed that, compared with the control
group, patients with MS had significantly less glucose use
in the right anterior cingulate gyrus and increased
activation in the left superior temporal gyrus on an
auditory attention task. Despite methodological
differences, both studies provide evidence for substantial
differences in activation levels between patients with MS
and controls in brain regions that support these cognitive
processes.
Although people with MS have difficulties on tasks of
planning and problem solving (an area of executive
function),21,207,208 we know of only one study that used
fMRI to investigate planning abilities in participants with
MS.209 In this study, similar levels of activation in the
bilateral frontal and parietal lobes were found in patients
and controls in response to a modified version of the
Tower of London test.
Overall, two main patterns of functional cerebral
activity during cognitive functioning in MS can be
identified. First, the blood-oxygenation-level-dependent
responses are frequently seen in patients with MS in
regions where no activation was found in healthy
controls. Second, the regions of cortical activation are
largely similar between patients with MS and healthy
controls, but the level of activation can be increased in
patients with MS. Several explanations for these findings
have been suggested,210 such as cerebral reorganisation201,211
and recruitment of other cortical regions as a
compensatory mechanism to account for the effects of
motor and cognitive impairments related to MS.203,211 Task
difficulty has also been suggested as an explanatory factor
for these findings: the patterns of activation seen in MS
might be caused by recruitment of additional cerebral
resources when the task demands reach a certain
threshold,212 perhaps on the basis of the individual’s
experience of task difficulty. Neuronal integrity (eg,
presence of brain lesions) might also affect the patterns
of activation seen in functional neuroimaging studies,
either directly or indirectly. In fact, Audoin and
co-workers46 noted that the pattern of cerebral activation
in patients with MS performing the PASAT correlated
significantly with severity of brain disease.
Conclusions
Although the cognitive sequelae of MS have only been
recognised as an important symptom over the past few
decades, research has shown that they exert a large effect
on many everyday activities, including social and
emotional function, the ability to do household tasks,
maintenance of gainful employment, and overall QoL.
With the recognition of the importance of cognitive
functioning in MS comes a responsibility on the part of
both clinicians and researchers to seek to increase
understanding of these cognitive deficits, their effect on
other abilities (such as everyday life activities, employment
www.thelancet.com/neurology Vol 7 December 2008

Search strategy and selection criteria
References for this Review were identified through searches
of PubMed and PsycINFO by use of the search term “multiple
sclerosis” in combination with other appropriate targets, such
as “cognition”, “cognitive dissonance”, “comprehension”,
“consciousness”, “intuition”, “mental processing”, “learning”,
“intention”, “higher nervous activity”, “mental fatigue”,
“MRI”, “perception”, “thinking and volition”, “cognitive
impairment”, “cognitive deficits”, “cognitive dysfunction”,
and “executive dysfunction”, up to September, 2008. Further
articles were identified from the reference sections of these
publications. Only papers published in English were reviewed.
Abstracts or unpublished material were excluded.
status, or social participation), the factors that might
affect their presentation, and techniques for improvement.
Both fatigue and depression have been identified as
important contributors to cognitive performance in
patients with MS; therefore, when assessing cognition in
research and clinical settings, these factors need to be
taken into account.
In a broad sense, intact cognitive function is a result of
a complicated network of specific cognitive abilities that
function together in an optimum way. Thus, whether
doing research or treating individual patients with MS,
one must recognise that deficits in basic cognitive
processes, such as processing speed and attention, will
detrimentally affect performance in other areas, such as
executive control and learning and memory, and affect
activities in everyday life. Similarly, motor deficits in
tasks that require a motor response or oral motor
problems in tasks that require an oral response must also
be taken into account.
The investigation of efforts to improve cognitive status
in MS is still in its infancy and future work will be
important to improve the lives of individuals with MS.
Pharmacological and behavioural studies to enhance
cognitive function in MS are scant and there are few
studies that have used appropriate methodological rigor.
Therefore, treatments with proven effectiveness have not
yet been identified. Future research that applies optimum
research strategies is necessary to enable recommend-
ations for either pharmacological therapy or behavioural
interventions for cognitive deficits in MS.
The application of novel measurement criteria in
available technologies and new technologies to
understand further the association between brain
structure and function—as well as their effect on
cognition—is an exciting opportunity to advance our
knowledge of the neurological effects of MS. Both
researchers and clinicians need to keep up to date with
the rapidly changing technology, to apply this technology
in clinically meaningful ways, and to develop optimum
ways to understand the structure and function of the
brain in MS.
www.thelancet.com/neurology Vol 7 December 2008
Review
Contributors
The authors contributed equally to this Review.
Conflicts of interest
We have no conflicts of interest.
Acknowledgments
NDC and JD are supported by grants from the National Institutes of
Health (R01 HD045798, STTR R42 NS050007), the National Institute on
Disability and Rehabilitation Research (H133A070037), and the National
Multiple Sclerosis Society (RG 3330, PP1331).
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