Multiple Sclerosis and Related Disorders 49 (2021) 102770

Contents lists available at ScienceDirect

Multiple Sclerosis and Related Disorders

journal homepage: www.elsevier.com/locate/msard

Original article

Does cognitive training improve attention/working memory in persons

with MS? A pilot study using the Cogmed Working Memory
Training program
Mervin Blair a, Daphne Goveas a, Ajmal Safi a, Connie Marshall b, Heather Rosehart c,
Steven Orenczuk d, Sarah A. Morrow c, *
a
Lawson Health Research Institute, Clinical Neuropsychiatry & Therapeutic Brain Stimulation Research, Ontario Shores Centre for Mental Health Sciences, 550
Wellington Rd, London, ON, Canada
b
Parkwood Institute, Rehabilitation Program, 550 Wellington Rd, London, ON, Canada
c
Western University, Department of Clinical Neurological Sciences and, Parkwood Institute, Department of Cognitive Neurology London Health Sciences Center, London,
ON Canada
d
Parkwood Institute, Veterans Care Program, 550 Wellington Rd, London, ON, Canada

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Cognitive deficits, especially in attention, are common in persons with MS (PwMS) and are asso­
Multiple sclerosis ciated with clinically meaningful outcomes, such as work disability and lower quality of life (QOL). In this study,
Cognitive impairment we aimed to determine whether Cogmed Working Memory Training (CWMT) improves attention/working
Cognitive rehabilitation
memory in PwMS displaying impairment in these domains.
Attention
Methods: This single blind, randomized controlled, pilot study compared the effects of CWMT, a five-week evi­
Working memory
Executive function denced-based computer-assisted training program that is supported by weekly meetings with a coach, to standard
Depression medical care (treatment as usual). We recruited PwMS from one MS center (London (ON) Canada), aged 18-64,
with an Expanded Disability Status Scale (EDSS) score of ≤ 7.0, and a visual acuity (corrected) of at least 20/70.
Potential subjects had to demonstrate impaired attention on at least two of three measures (Paced Auditory Serial
Addition Test [PASAT], Symbol Digit Modalities Test [SDMT], and/or DKEFS Color-Word Interference Test);
these measures also served as the primary study outcomes. Subjects were randomized to either the CWMT or
treatment as usual. Secondary cognitive outcomes included other measures of attention, memory, as well as a
self-reported cognitive function measure. Self-reported measures of mood (depression and anxiety), pain, and
QOL were also included as other secondary outcomes. Subjects received assessments at baseline, post-treatment,
and 6-month follow-up, or an equivalent time period for the treatment as usual group. The two groups were
compared at baseline on background measures using independent samples t-tests, Chi-Square tests, and Mann-
Whitney U tests. To analyze primary and secondary outcomes, a non-parametric approach was used due the
small sample size and that many of our outcomes did not meet assumptions for parametric analyses. Friedman’s
test was conducted followed by post hoc pairwise comparisons within each group using Wilcoxon Signed-Rank
tests with Bonferroni corrected post hoc contrasts, which allowed us to examine for differences between time
points.
Results: Of 30 subjects, 15 were assigned to CWMT. Significant training effects were noted in 1 of 3 primary
attentional outcomes (DKEFS Color-Word Interference Test), 2 of 3 secondary attentional outcomes (Letter-
Number Sequencing, Digit Span), and 1 mood scale (Hospital Anxiety and Depression scale (HADS) - Depression
Subscale), ps < .025. No significant changes were observed in the treatment as usual group.
Conclusion: This pilot study demonstrates that cognitive training with CWMT has the potential to improve
attention/working memory in PwMS, as well as a potential positive effect on mood, in PwMS. Further explo­
ration of this intervention in PwMS with attention/working memory impairment is warranted.

* Corresponding author at: LHSC-UH, 339 Windermere Rd, London, ON CANADA, N6A 5A5.
E-mail address: Sarah.morrow@lhsc.on.ca (S.A. Morrow).

https://doi.org/10.1016/j.msard.2021.102770
Received 10 November 2020; Received in revised form 6 January 2021; Accepted 14 January 2021
Available online 17 January 2021
2211-0348/© 2021 Elsevier B.V. All rights reserved.
M. Blair et al.
1. Introduction
Multiple Sclerosis (MS) is well known to be associated with cognitive
impairment (CI) and is estimated to affect 40-65% of persons with MS
(PwMS) (Rao et al., 1991a). CI has been detected as early as the first
demyelinating episode, prior to a confirmed diagnosis of MS (Feuillet
et al., 2007; Glanz et al., 2007). The most frequently observed impair­
ments are in information-processing speed, attention/working memory,
and episodic memory (Rao et al., 1991a). Thus, PwMS often present with
difficulty multi-tasking, shifting attention or staying on task. Verbal
fluency and executive function can also be involved, but less frequently,
resulting in difficulties with word-finding and inability to do abstract
reasoning and often have concrete thinking (Chiaravalloti & DeLuca,
2008). In contrast, general intelligence and language abilities are rela­
tively spared (Rao, 1995). Longitudinal studies demonstrate a slowly
progressive insidious course, rather than a relapsing-remitting pattern,
and suggest these deficits are unlikely to remit (Amato et al., 2001;
Kujala et al., 1997; Schwid et al., 2007). Since the onset and progression
can be subtle, many patients present once significant deficits are present,
when the possibility of impairment is raised either at work or at home, or
signs of impairment are easily apparent (Chiaravalloti & DeLuca, 2008).
CI is the most common reason for work disability and contributes to
lower reported quality of life and poor social functioning (Rao et al.,
1991b; Benedict et al., 2005)
MS is also well known to be associated with disorders of mood, such
as depression and anxiety. Importantly, research shows that CI is often
related to mood function in MS, and this relationalship may depend on a
host of patient-specific factors (e.g., coping strategy, stress, self-efficacy)
(Arnett et al., 1999).
Given the high rates of CI in PwMS and the consequent impact on
other aspects of functioning (e.g., mood), improving cognitive func­
tioning in PwMS represents an important therapeutic target. Cognitive
rehabilitation is typically used to reduce cognitive deficits or their
harmful impact on activities of daily living. As mentioned previously,
attention is commonly affected, and attention/working memory is often
inter-related with other deficits in PwMS (e.g., processing speed)
(Chiaravalloti and DeLuca, 2008). It has also been shown in the general
population to constrain high level thinking (e.g., problem solving,
complex reasoning, comprehension, general intellectual ability) (Con­
way et al., 2007). Thus, better strategies to improve or maintain
cognitive function in PwMS are urgently needed.
Research on cognitive rehabilitation typically employs computer-
assisted programs with or without additional neuropsychology sup­
port/structure for patients. According to a recent Cochrane review
(Rosti-Otajärvi et al., 2014), investigations into cognitive rehabilitation
in MS are few and pooled analyses that combined multiple studies
yielded non-significant findings across various cognitive domains,
including attention/working memory. Despite a number of negative
findings (Solari et al., 2004; Tesar et al., 2005), more recent work in MS
has showed promise in improving attention/working memory, as well as
recruitment of relevant brain networks, particularly when more rigorous
criteria are used (Cerasa et al., 2013; Filippi et al., 2012). Emotional and
more ecological outcomes (e.g., mood, fatigue, and quality of life) are
also receiving more attention in the literature, despite some conflicting
findings (Rosti-Otajärvi et al., 2014; Mitolo et al., 2015). Thus, any
benefits observed from cognitive rehabilitation of attention/working
memory in MS are preliminary, especially given limitations in research
thus far. Research that focus on a specific aspect of cognitive function
typically yields better outcomes as opposed to multi-faceted/modal in­
terventions, which can be difficult to quantify.
Cogmed Working Memory Training (CWMT) method is an
evidenced-based computer-assisted training method that combines
computerized adaptive training with additional supports, including a
certified training coach (allied health professional) who monitors
training progress and ensures compliance through weekly meetings
(Shinaver 3rd et al., 2014). This approach has been investigated in
2
Multiple Sclerosis and Related Disorders 49 (2021) 102770
various populations that exhibit attentional/working memory deficits,
such as brain injury, attention deficit hyperactivity disorder, and older
adults (including mild cognitive impairment) (Shinaver 3rd et al., 2014),
but it has not been studied in PwMS. Thus, the aim of this work was to
determine whether cognitive training of attention/working memory in
PwMS using CWMT improves (1) three attentional/working memory
outcomes compared to standard medical care and (2) a host of cognitive
and emotional/ecological aspects of functioning that are likely relevant
to achieve and maintain gains. Primary outcomes used are validated
measures of attention/working memory in PwMS, namely the Paced
Auditory Serial Addition Test (PASAT) and Symbol Digit Modalities Test
(SDMT), both of which are part of the Minimal Assessment of Cognitive
Function in MS (MACFIMS) battery (developed by consensus and vali­
dated to assess cognitive dysfunction in PwMS; Benedict et al., 2002)
and a modified Stroop task (DKEFS Color-Word Interference Test;
Morrow, 2013). The second aim was exploratory to examine whether
CWMT has any impact on other cognitive (e.g., memory function) and
emotional/ ecological domains (e.g., depression, fatigue, quality of life),
especially as the latter have shown inconsistent gains using other
cognitive training paradigms in MS (Mitolo et al., 2015).
2. Materials And Methods
2.1. Design and Setting
This single (assessor)-blinded study recruited subjects from the
London (ON) MS Clinic, a tertiary care MS clinic in London (ON),
Canada. Subjects were randomized to either a computer-assisted
training (CWMT) group or a standard medical care group (treatment-
as-usual (TAU)). Primary and secondary cognitive outcome measures
were assessed during an initial screening (baseline), post-treatment, and
at six months’ follow-up.
All subjects provided written informed consent. This study was
reviewed and approved by the University of Western Ontario (Western)
Health Sciences Ethics Review Board (HSREB).
2.2. Intervention
The CWMT method consists of 25 training sessions conducted online.
Each subject completes eight exercises daily, approximately 30-45 mi­
nutes for the entire session. The program lasts five weeks with five
sessions every week. The CWMT program uses an adaptive training
approach in which the difficulty level of the training is adjusted in real
time (trial by trial basis) based on the trainee’s performance. The costs of
CWMT ranges by number of usage and site license (see details on http
s://www.cogmed.com/). Study authors were provided access to
Cogmed services/training programs at no cost for the purpose of this
study.
Each session consists of various tasks that target different aspects of
working memory. Specifically, each session involves training on visuo­
spatial working memory tasks (e.g., remembering the position of objects
in a 4 × 4 Grid) as well as verbal working memory tasks (e.g., remem­
bering phonemes, letters, or digits). Reinforcement is built into the
program (e.g., small weekly rewards for completing the training
sessions).
Each subject was assigned a CWMT qualified coach who was
responsible for providing structure, motivation, and feedback on
training progress in order to optimize training gains. Cogmed coaches
underwent multi-hour online training provided by Cogmed to become
certified, which involved review of Cogmed tasks, Cogmed embedded
scales (cognitive progress/training indicators and self-report scales of
attention difficulties, training motivation, and training goals), training
schedules, how to use the website to track training gains, and how to
provide feedback throughout the training. Cogmed coaches were over­
seen by a regulated health care professional who operated as a quality
assurance representative. Following an initial in-home visit by the coach
M. Blair et al.
to oversee the first training session, each participant’s performance was
tracked online and reviewed by the subject and his/her coach in once
per week phone meetings throughout the five-week period (total of 5
phone interactions). At the end of training, the coach summarized the
training together with the participant and provided feedback data from
rating scales embedded in the Cogmed program and the Cogmed
Coaching Center. Cogmed qualified practitioners (SAM and SO) oversaw
the entire training program and provided consultation to the Cogmed
coaches.
All measures were administered by a trained psychometrist, blinded
to the group status of the subjects. MS clinical and physical functioning
were evaluated by an MS neurologist (SAM). Computer-assisted training
of attention/working memory was completed with the CMWT program.
A trained psychometrist (CM) and neuropsychology fellow (MB) served
as training coaches, with study oversight/monitoring by qualified health
practitioners (SM and SO).
2.3. Patient population
Consecutive PwMS attending the London (ON) MS, or its’ affiliative
MS Cognitive Clinic, who reported cognitive difficulties were
approached regarding interest in this study. PwMS diagnosed with
RRMS, PPMS, and SPMS, age 18-64 with Expanded Disability Status
Scale (EDSS) (Kurtzke, 1983) score of ≤ 7.0, and a visual acuity (cor­
rected) of at least 20/70 were included. This information was only
collected once (at study screening; note: the screening visit turned into a
baseline visit for those who met study eligibility criteria). Attention/­
working memory deficits were screened for using the PASAT (Rao et al.,
1991a), SDMT (Smith, 1982), and the DKEFS Color-Word Interference
Test (Delis et al., 2001). PwMS with a z-score lower than -1.5 on at least
2 of the 3 measures were characterized as showing attention/working
memory deficits (i.e. worse than 1.5 standard deviations below the
mean) (Benedict et al., 2002). These subjects were enrolled in the study,
providing exclusion criteria were not met: no clinical rela­
pse/corticosteroid treatment for at least 1 month prior to study entry,
daily marijuana use, loss of visual acuity, a history of bipolar disorder or
other psychiatric illness.
2.4. Outcome measures
Data on the following outcome measures were collected at baseline
and then at post-treatment and 6-month follow-up. Primary outcome
measures assessed attention/working memory deficits and included
PASAT, SDMT, and a modified Stroop task (DKEFS Color-Word Inter­
ference Test).
Additional cognitive, emotional and other measures were adminis­
tered (secondary outcomes). Additional cognitive measures focused on
attention were included: Wechsler Memory Scale-III Spatial Span (WMS-
III SS) (Wechsler, 1997a) and Wechsler Adult Intelligence Scale-III
(WAIS-III) (Wechsler, 1997b) attention subtests (Arithmetic,
Letter-Number Sequencing, Digit Span). Other cognitive assessments
comprised two measures of memory function: California Verbal
Learning Test 2nd edition (CVLT2) (Benedict et al., 2002), a measure of
auditory/verbal episodic memory; and Brief Visual Memory Test -
Revised (BVMT-R) (Benedict et al., 2002), a measure of visual-spatial
memory. Lastly, the Victoria Symptom Validity Test, a cognitive effort
measure, was added. Emotion/other assessment measures included
were the following: Beck Depression Inventory –Fast Screen (BDI-FS)
(Beck et al., 2000), Hospital Anxiety and Depression scale (HADS)
(Honarmand and Feinstein, 2009), Fatigue Severity Scale (FSS) (Krupp
et al., 1989), Dysexecutive Questionnaire (DEX) (Wilson et al., 1996),
Cognitive Failures Questionnaire (Alschuler et al., 2012), Brief COPE
(Carver, 1997), Short Form Health Survey (SF-36) (Vickrey et al., 1995),
Multiple Sclerosis Neuropsychological Screening Questionnaire (MSNQ)
self-report form (Benedict et al., 2003), Perceived Deficits Questionnaire
(PDQ) (Sullivan et al., 1990), and the Numeric Pain Rating Scale (NPRS)
3
Multiple Sclerosis and Related Disorders 49 (2021) 102770
(Auschler et al., 2012).
2.5. Statistical Analyses
The CWMT and TAU groups were compared at baseline on back­
ground measures using independent samples t-tests, Chi-Square tests,
and Mann-Whitney U tests. To analyze primary and secondary out­
comes, a non-parametric approach was taken because our sample size
was small and many of our outcomes did not meet assumptions for
parametric analyses (e.g., normal distributions). Our primary outcomes
were SDMT, PASAT, and DKEFS Color-Word Interference Test. Sec­
ondary cognitive measures comprised WAIS-III attention subtests
(Arithmetic, Digit span, Letter-Number Sequencing), WMS-III SS, and
truncated subtests of CVLT-2 (total immediate recall) and BVMT-R (total
immediate recall). Other outcomes included BDI-FS, HADS, FSS, DEX,
CFQ, Brief COPE, SF-36, MSNQ, PDQ, and NPRS. Within each group,
Friedman’s test was used to examine for differences in primary and
secondary outcomes across the three time points of assessment (base­
line, post-intervention, 6-month follow-up) using an alpha level of .025
(2-tailed to adjust for examining each group separately i.e., 0.5 divided
by 2) as the significance criterion. Post hoc pairwise comparisons within
each group were conducted with Wilcoxon Signed-Rank tests to examine
for differences between time points; to investigate secondary outcomes,
we adopted a more conservative approach by performing a Bonferroni
correction with an adjusted alpha of .017 (alpha of .05 divided by 3 for
three-time comparisons). SPSS Statistics 23 was used for all analyses.
3. Results
We identified 30 subjects who demonstrated attention/working
memory deficits, were eligible to participate in the study and who signed
informed consent; 15 were randomized to the CWMT group. However,
four patients in the CWMT group withdrew consent before initiating
training. The remaining 11 patients were able to adhere to the 5-week
training regimen as tracked by Cogmed coaches on a weekly basis
throughout the Cogmed online portal for coaches. Two patients in the
TAU group withdrew consent prior to study completion. An additional
two patients in the TAU group withdrew consent prior to conducting the
6-month follow-up assessment. Accordingly, we collected complete data
on 11 patients in each of the CWMT and TAU groups (22 subjects in
total) (Fig. 1). Demographic information is provided in Table 1.
There was no difference between groups in age (t(28) = .36, p = .72),
years of education, (t(28) = 1.07, p = .30), years since MS diagnosis, (t
(28) = .38, p = .70), EDSS, (U = 95.5, p = .48), reported gender (χ2(1) =
1.43, p = .23). There were no significant differences on the primary
outcome scores: SDMT (U = 106, p = .79), PASAT (U = 110, p = .92),
and DKEFS Color-Word Interference (U = 104.5, p = .74) (Tables 1 and
2). Scores on secondary outcomes were similar across groups (ps > .05).
On the VSVT hard subtest, the CWMT group obtained a lower score,
indicating lower effort on testing, relative to the TAU group at baseline
(U = 45, p = .008). No group difference was observed for the VSVT at
post-treatment and 6-month follow-up (ps > .05). Examination of each
group separately across the study time points with Wilcoxon Signed-
Rank tests showed no change in each group’s VSVT scores (ps > .05).
For the CWMT group, analyses on primary outcomes using Fried­
man’s test revealed a significant effect across time for the DKEFS Color-
Word Interference test (χ2(2) = 8.14, p = 0.02), but not for the SDMT
(χ2(2) = 0.14, p = .93) or PASAT (χ2(2) = 3.56, p = .17) (Fig. 2;
Table 2). Post hoc pairwise comparisons with Wilcoxon signed-Rank
tests for the DKEFS Color-Word Interference test indicated a signifi­
cant improvement in scores from baseline to post-treatment (Z = 2.41, p
= .016, d = 0.27) but not from baseline to 6-month follow-up (Z = 2.20,
p = .03, d = 0.30), or post-treatment to 6-month follow-up, (Z = .32, p =
.75, d = 0.04, Bonferroni corrected). Analyses on secondary cognitive
outcomes for the CWMT group using Friedman’s test revealed signifi­
cant effects across time on the WAIS-III Letter-Number Sequencing (χ2
M. Blair et al.
Fig. 1. Flow chart illustrating the recruitment process and number of patients present at each assessment time point for each study group.
(2) = 8.79, p = .01) and Digit Span (Backwards subtest) (χ2(2) = 8.67, p
= .01). Post hoc comparisons showed improved scores from baseline to
post-treatment on Digit Span (Backwards subtest) (Z = 2.75, p = .01, d
= 0.69), whereas Letter-Number Sequencing scores across visits did not
reach significance (ps > .016; Bonferroni corrected alpha level). Ana­
lyses on other secondary outcomes for the CWMT group using Fried­
man’s test did not reveal significant effects across time for BDI-FS (χ2(2)
= 6, p = .049) but it did for the HADS-Depression subscale (χ2(2) = 7.58,
p = .02), a slightly more in-depth depression screen. Post hoc compar­
isons showed improved scores from baseline to 6-month follow-up on
the HADS-Depression subscale (Z = 2.44, p = .015, d = 0.63).
For the TAU group, analyses on primary outcomes using Friedman’s
test showed no significant effects across time for the DKEFS Color-Word
Interference test (χ2(2) = 1.76), SDMT (χ2(2) = 1.72), or PASAT (χ2(2)
= 5.19, ps > .05) (Fig. 2; Table 2). Similarly, no significant findings were
observed for secondary outcomes for the TAU group (ps > .05) (Table 2).
4
Multiple Sclerosis and Related Disorders 49 (2021) 102770
4. Discussion
In this randomized, single blinded, treatment as usual (TAU) control
study, we examined the effectiveness of an evidence-based approach to
cognitive rehabilitation of working memory, namely the CWMT method,
in PwMS. We also explored potential secondary training effects in
emotion and other domains. In the CWMT group, we found a significant
training effect in one of three primary attentional outcomes (DKEFS
Color-Word Interference test), which measures interference control, and
in two of the three secondary attentional outcomes (Digit span, Letter-
Number Sequencing). We also found a significant improvement in
depressive symptoms (measured by the HADS-Depression subscale). No
significant changes were observed in the TAU group. These findings
demonstrate the utility of CWMT in attention/working memory in
PwMS as well as secondary effects in emotional aspects of functioning,
namely depressive symptoms. We cannot rule out the possibility that
weekly interactions with the coach provided to the CWMT group (initial
home visit, 5 weekly phone calls to review training) did not play a role in
improving their mood scores.
M. Blair et al. Multiple Sclerosis and Related Disorders 49 (2021) 102770

Table 1 adaptive responding function in which task difficulty gradually in­

Group demographics of study subjects. creases slightly above an individual’s current capacity to support
Cogmed Working Treatment as p- attentional remediation (Shinaver 3rd et al., 2014). In our study, the
Memory Training Usual value CWMT group demonstrated cognitive training benefits at post treat­
n 15 15 - ment, but not at follow-up, on one of three primary attentional out­
†
Sex (M:F) 3:12 6:9 .23 comes. In particular, the CWMT group significantly managed cognitive
§
Age 51.07(7.29) 52.13(8.71) .72 interference (incongruent stimuli on DKEFS Color-Word Interference) to
M(SD) accurately process and respond to relevant stimuli. This finding is
MS type 9:6:0 8:6:1 -
(RRMS: SPMS: PPMS)
consistent with that of Cerasa et al. (2013) who also demonstrated that
§
Education 13.13(1.13) 13.73(1.87) .30 an intensive computer-based program specifically tailored for impaired
M(SD) attentional abilities improved some aspects of cognitive functioning
Years since MS 14.87(8.47) 16.25(10.94) .70 (improvement in Stroop test scores). Additionally, Filippi et al. (2012)
§

diagnosis
observed enhanced performance in attention abilities assessed by the
M(SD)
‡
Expanded Disability 4.5(1.5-7) 4(2-6.5) .48 Stroop task in PwMS using the RehaCom computer program. Our
Status Scale observed small to moderate effect size (d = .27) is in a similar range as
Median(range) observed in meta-analytic work examining gains in the Stroop task
†
Based on Chi-square analysis; following CWMT and other working memory interventions (mean d =
§
Based on independent samples t-test; .32, 95% confidence interval [0.11, .53]; Melby-Lervåg & Hulme, 2013).
‡
Based on Mann-Whitney U test. The training gains we observed in attention measures were not sustained
at follow-up, and like many other studies in this field, highlights the
Cognitive rehabilitation literature in PwMS thus far have highlighted questionable durability of cognitive training in MS (Rosti-Otajärvi et al.,
several drawbacks in studies related to cognitive training in multiple 2014; Mitolo et al., 2015), which may relate to changes in resting state
domains including attention/working memory (Goverover et al., 2018; functional connectivity of related networks (Parisi et al., 2013)
Mitolo et al., 2015). Few studies have assessed the efficacy of in­ Notably, the two primary attentional outcomes in which no cognitive
terventions in multiple domains (including cognition) in the same MS benefit was observed were an attentional measure that emphasizes
sample, and many researchers have highlighted the need for further processing speed, namely SDMT, and an updating working memory
evidence-based cognitive rehabilitation techniques (Goverover et al., measure, namely PASAT. We attribute the positive finding regarding
2018). Thus, in this study, we addressed these drawbacks by conducting cognitive interference control to a near transfer effect, in which cogni­
a randomized control trial using CWMT, following up with patients 6 tive training gains transferred to similar cognitive task; specifically,
months’ post-treatment to determine whether CWMT has lasting relevant trained skills from the CWMT program carried over to the most
training effects, if any; and assessing secondary training effects in similar primary outcome measure (DKEFS Color-Word Interference
emotion and other domains. The CWMT program employs a novel test). However, this was likely not the case for the SDMT and PASAT.

Table 2
Means and standard deviations of primary and secondary outcome measures at assessment time points for each study group.
Cogmed Working Memory Training Treatment as Usual
Baseline Post-treatment 6-month follow up p-value Baseline Post-treatment 6-month follow up p-value
M(SD) M(SD)

Primary outcomes
PASAT 27.73(14.43) 37.18(12.11) 35.18(10.69) .17 28.07(12.66) 30.08(11.01) 33.91(12.20) .08
SDMT 39.20(9.58) 40.91(6.02) 39.73(7.51) .93 39.60(7.94) 41.85(9.54) 40.64(9.79) .42
DKEFS Color-Word Interference 25.07(10.26) 27.82(10.30) 28.27(10.87) .02* 26.13(5.17) 29.08(5.89) 29.73(4.32) .41
Secondary outcomes
CVLT2 Total Immediate Recall 40.67(10.08) 46(15.74) 46.55(13.53) .18 42.47(10.23) 47.15(12.89) 45(13.09) .27
BVMT-R Total Immediate Recall 17.20(7.06) 18.18(9.88) 19.27(10.43) .70 19.40(8.77) 19.46(9.77) 17.64(8.38) .81
VSVT-Easy 23.67(0.82) 23.73(0.65) 22.91(2.7) .66 23.86(0.54) 23.62(0.65) 24(0) .09
VSVT-Hard 19.60(3.92) 20.73(3.61) 20.64(5.30) .32 22.57(1.99) 22.62(1.26) 22.45(1.44) .76
WMS-III Spatial Span (Forward) 6.67(1.80) 6.27(1.68) 6.09(1.22) .42 6.67(1.59) 6.62(1.81) 6.82(1.47) .81
WMS-III Spatial Span (Backward) 5.87(2.00) 6.73(2.10) 6.18(1.66) .61 6.27(2.02) 6.38(1.85) 6.45(1.51) .89
WAIS-III Arithmetic 10.80(2.96) 11.73(3.23) 12(3) .80 10.87(3.66) 12.23(3.47) 11(2.61) .08
WAIS-III Letter-Number Sequencing 7.07(2.99) 9.18(2.86) 8.45(2.58) .01* 7.33(2.80) 8.08(2.33) 7.82(3.28) .38
WAIS-III Digit Span (Forward) 9.20(2.04) 9.09(2.07) 9.18(2.32) .84 9.67(1.63) 9.08(1.19) 8.82(1.66) .13
WAIS-III Digit Span (Backward) 5.07(1.28) 6.18(1.89) 6.09(1.3) .01* 4.73(1.28) 5.62(1.19) 5.36(1.86) .39
MSNQ 34.07(12.47) 30.18(17.85) 28.55(15.16) .30 27.27(9.07) 29.85(8.14) 29.91(10.83) .68
BDI-FS 4.67(2.85) 4.27(4.38) 2.64(3.26) .049* 3.73(2.84) 3.54(3.93) 2.73(3.52) .13
FSS mean score 4.82(1.76) 4.94(1.68) 4.89(2.26) .14 5.23(1.16) 5.09(1.32) 5.18(1.26) .68
HADS Anxiety Subscale 8.53(3.56) 7.36(4.41) 7.09(4.35) .90 6.40(3.36) 4.08(2.72) 6.09(4.95) .26
HADS Depression Subscale 7.27(3.99) 5.73(3.95) 4.73(4.03) .02* 5.53(3.14) 5.31(3.01) 4.91(3.15) .48
SF-36 57.20(19.01) 53.91(20.07) 56.45(23.79) .31 51.13(17.46) 48.92(18.21) 44.55(12.78) .37
DEX 27.67(16.47) 24.64(20.73) 23.09(17.68) .25 23.27(11.44) 19.31(8.50) 20.55(10.82) .74
CFQ 44.53(15.84) 44.55(29.26) 42.36(24.25) .40 39(17.87) 33.08(20.63) 36.45(20.54) .61
Brief COPE 61.67(9.13) 60.18(8.17) 63.91(13.85) .08 64.93(13.97) 62.62(13.09) 64.91(12.49) .23
PDQ 40.53(12.95) 37(24.38) 37.82(24.19) .47 33.47(13.87) 29.62(16.02) 30.73(15.74) .30
NPRS 3.52(2.15) 4.25(2.59) 4.14(2.28) .63 2.87(2.21) 2.73(2.81) 2.64(2.98) .97

PASAT = Paced Auditory Serial Addition Test; SDMT = Symbol Digit Modality Test; DKEFS = Delis-Kaplan Executive Function System; CVLT2 = California Verbal
Learning Test Second Edition; BVMT-R = Brief Visuospatial Memory Test – Revised; VSVT = Victoria Symptom Validity Test; WMS-III = Wechsler Memory Scale Third
Edition; WAIS = Wechsler Adult Intelligence Scale; MSNQ = Multiple Sclerosis Neuropsychological Screening Questionnaire; BDI-FS = Beck Depression Inventory-Fast
Screen; FSS = Fatigue Severity Scale; HADS = Hospital Anxiety and Depression Scale; SF-36 = 36-item Short Form Health Survey; DEX = Dysexecutive questionnaire;
CFQ = Cognitive Failure Questionnaire; PDQ = Perceived Deficits Questionnaire; NPRS = Numeric Pain Rating Scale.
*Significant results using Friedman’s test, p < .05.

5
M. Blair et al. Multiple Sclerosis and Related Disorders 49 (2021) 102770

Fig. 2. Mean scores (standard error bars) obtained on the DKEFS Colour-Word Interference test, Paced Auditory Serial Addition Test (PASAT) and Symbol Digit
Modalities Test (SDMT) at the different assessment time points for each study group.
*Significant results using Friedman’s test for Cogmed Working Memory Training group, p < .05 (post-hoc revealed significant difference between baseline and
post-treatment).

The SDMT involves reference to a readily available symbol-legend
throughout the task, thereby minimizing the need to hold information
online (Benedict et al., 2017), as opposed to CWMT tasks. As for the
PASAT, this task relies on the sequential working memory updating of
task items as the task proceeds (Tombaugh, 2006). Again, this is dis­
similar from all CWMT tasks which largely involve holding task items
online at each difficulty level of the task (with task items increasing to
optimize the challenge) (Shinaver 3rd et al., 2014; Klingberg, 2010), and
were largely similar to secondary attentional outcomes in which sig­
nificant improvements were observed (Letter-Number sequencing and
Digit Span Backwards). It is of note that the non-significant training
benefit we observed on the PASAT is inconsistent with a few previous
attention/executive functioning training studies (Filippi et al., 2012;
Mattioli et al., 2010; Hancock et al., 2015); however, without in-depth
knowledge of the specifics of the tasks used in these studies, we
cannot rule out the possibility of a near-transfer training effect ac­
counting for the benefits observed on the PASAT.
Considered together, near transfer effects are an important outcome
of cognitive training, which may have implications for activities of daily
living (Lussier et al., 2012), and CWMT intervention may prove to be a
novel therapeutic approach in treating specific cognitive deficits in
PwMS, namely the ability to manage interference/tasks distractions. On
the other hand, human cognition is not commonly receptive to far-
transfer effects. In fact, cognitive training regimens that target specific
domains rarely show an improvement on dissimilar tasks (Chase et al.,
1982, Detterman, 1993; Sala & Gobet, 2017; Simons et al., 2016). In
general, an increasing improvement in cognitive functioning and skills
as shown by an enhanced performance on the trained and related tasks is
expected as a by-product of engaging in relevant domain-specific
cognitively demanding tasks (Simons et al., 2016). This is likely medi­
ated by neural plasticity, with the goal that enhanced cognitive skills
boost everyday skills that rely on them (Karbach & Schubert).
Far-transfer effects of cognitive training may be improved by imple­
menting heterogenous training in which the training context varies be­
tween sessions and variable priority training in which participants vary
the amount of attention given to each task (Lussier et al., 2017). While

6
M. Blair et al.
future research is needed to identify any potential far-transfer effects
with respect to CWMT in PwMS, it may be possible that incorporating
heterogenous training into the CWMT intervention could lead to
far-transfer effects in other attentional measures. According to a
comprehensive review by Wollesen and Voelcker-Rehage (2014), factors
that facilitate cognitive as well as motor transfer effects include using
dual task training paradigms (rather than single task interventions),
variable task prioritization, and also appropriate levels of load, task
specificity, intensity and duration. CWMT may owe some of its observed
effects to incorporating some of these factors (e.g., adaptive train­
ing/task load approach).
The CWMT group also demonstrated a reduction in depressive
symptoms as measured by the HADS-Depression subscale, a slightly
more in-dept depression screen compared to the BDI-FS. As research on
the utility of cognitive rehabilitation techniques, especially in the
attentional/executive domain, is still in its infancy (Mitolo et al., 2015),
no definite conclusions can be drawn about their effects on other do­
mains such as emotion functioning, quality of life, fatigue, and views on
one’s abilities (e.g., self-efficacy). Indeed, results in the literature on
these other domains following cognitive rehabilitation have been con­
tradictory and may be related to several factors including a different
types of cognitive rehabilitation, varying inclusion/exclusion criteria,
different outcome measures, and using different control groups (active
vs. passive/TAU groups) (Goverover et al., 2018; Mitolo et al., 2015).
Taking this last consideration into account, our finding of an improve­
ment in depressive symptoms may be attributed to using a waitlist
control group, who did not benefit from the one-time home visit and
weekly telephone check-ins by two allied professionals who served as
CWMT coaches.
This study does have limitations, including a small sample size, a
single-site only, as well as using an unblinded TAU control group. We
adopted a conservative non-parametric approach in this study. How­
ever, a larger study with a similar design as ours may yield stronger
evidence for CWMT through an interaction effect in the context of a
mixed parametric ANOVA. Notably, when we applied this approach to
our current smaller dataset, no significant interaction effects were
observed in our primary outcomes (ps > .05). Thus, as opposed to our
non-parametric approach taken due to the small sample size and data
normality concerns, a future larger study may be more robust to over­
come such limitations. The CWMT group obtained significantly lower
scores on VSVT (an effort measure) compared to the TAU group at
baseline, whereas no differences between the groups were observed at
post treatment and follow up. This between group difference at baseline
relative to later time points opens the possibility that increased effort by
the CWMT group at post treatment contributed to their improved
attention performance. Although this possibility cannot be completely
excluded, it is unlikely since the CWMT group showed no significant
change in VSVT scores, hence no increased effort, from baseline to post
treatment and follow-up testing (within group analysis showed similar
unchanged VSVT scores in the untrained group). It is important to
consider that neuropsychological validity testing is controversial; it
appears to attribute effort to behavior rather than cognitive abilities,
indirectly requires effort to perform using areas of the brain that are
affected in neurological disorders such as MS, and merely attributes
lower test scores to poor effort rather than using neuropsychological
frameworks to interpret test scores (Chafetz et al., 2015).
5. Conclusion
This small, but robust, study demonstrated that CWMT, an evidence-
based approach to cognitive rehabilitation of attention in various non-
MS populations, led to a significant training effect on DKEFS Color-
Word Interference test, a measure of interference control, as well as
improvement in depressive symptoms in PwMS. Like many MS cognitive
training studies, the cognitive gains from CWMT was present following
active treatment and was not sustained over time. Future studies
7
Multiple Sclerosis and Related Disorders 49 (2021) 102770
incorporating neuroimaging measures could be used to determine the
structural and/or functional correlates of these findings as well as
determine whether baseline neural functioning influences training gains
during participation in CWMT tasks. Furthermore, larger sample sizes
should be used to better examine and modify relevant parameters such
as training intensity, booster sessions, and MS-specific factors (e.g., level
of CI or disability).
CRediT authorship contribution statement
Mervin Blair: Conceptualization, Methodology, Formal analysis,
Investigation, Data curation, Writing - original draft, Writing - review &
editing, Visualization. Daphne Goveas: Formal analysis, Writing - re­
view & editing, Visualization. Ajmal Safi: Writing - review & editing,
Visualization. Connie Marshall: Conceptualization, Methodology,
Investigation, Writing - review & editing. Heather Rosehart: Method­
ology, Investigation, Data curation, Writing - review & editing, Project
administration. Steven Orenczuk: Conceptualization, Methodology,
Writing - review & editing, Supervision. Sarah A. Morrow: Conceptu­
alization, Methodology, Formal analysis, Investigation, Resources, Data
curation, Writing - original draft, Writing - review & editing, Supervi­
sion, Project administration.
Conflict of Interest Statement
SAM has, in the past 3 years, served on advisory boards for Biogen
Idec, EMD Serono, Genzyme Canada, Novartis, Roche; has received
Investigator Initiated Grant Funds from Biogen Idec, Novartis, Roche;
has acted as site PI for multi-center trials funded by Novartis, Genzyme,
Roche, and AbbVie.
MB, DG, AS, CM, HR, SO have no disclosures.
References
Alschuler, KN, Jensen, M.P., Ehde, D.M., 2012. Defining mild, moderate, and severe pain
in persons with multiple sclerosis. Pain Medicine 13, 1358–1365. https://doi.org/
10.1111/j.1526-4637.2012.01471.x.
Amato, M.P., et al., 2001. Cognitive dysfunction in early-onset multiple sclerosis: a
reappraisal after 10 years. Archives of Neurology 58 (10), 1602–1606.
Arnett, PA, Higginson, CI, Voss, WD, et al., 1999. Depressed mood in multiple sclerosis:
relationship to capacity-demanding memory and attentional functioning.
Neuropsychology 13, 434–446. https://doi.org/10.1037//0894-4105.13.3.434.
Beck, AT, Steer, R.A., Brown, G.K., 2000. BDI-Fast Screen for medical patients:manual.
Psychological Corporation, San Antonio, TX.
Benedict, RH, DeLuca, J, Phillips, G, et al., 2017. Validity of the Symbol Digit Modalities
Test as a cognition performance outcome measure for multiple sclerosis. Mult Scler
23, 721–733. https://doi.org/10.1177/1352458517690821.
Benedict, RH, Fischer, JS, Archibald, CJ, et al., 2002. Minimal neuropsychological
assessment of MS patients: a consensus approach. Clin Neuropsychol 16, 381–397.
https://doi.org/10.1076/clin.16.3.381.13859.
Benedict, RH, Munschauer, F, Linn, R, et al., 2003. Screening for multiple sclerosis
cognitive impairment using a self-administered 15-item questionnaire. Mult Scler 9,
95–101. https://doi.org/10.1191/1352458503ms861oa.
Benedict, RH, Wahlig, E, Bakshi, R, et al., 2005. Predicting quality of life in multiple
sclerosis: accounting for physical disability, fatigue, cognition, mood disorder,
personality, and behavior change. J Neurol Sci 231, 29–34. https://doi.org/
10.1016/j.jns.2004.12.009.
Carver, CS., 1997. You want to measure coping but your protocol’s too long: consider the
brief COPE. Int J Behav Med 4, 92–100. https://doi.org/10.1207/
s15327558ijbm0401_6.
Cerasa, A, Gioia, MC, Valentino, P, et al., 2013. Computer-assisted cognitive
rehabilitation of attention deficits for multiple sclerosis: a randomized trial with
fMRI correlates. Neurorehabil Neural Repair 27, 284–295. https://doi.org/10.1177/
1545968312465194.
Chafetz, MD, Williams, MA, Ben-Porath, YS, et al., 2015. Official Position of the
American Academy of Clinical Neuropsychology Social Security Administration
Policy on Validity Testing: Guidance and Recommendations for Change. Clin
Neuropsychol 29, 723–740. https://doi.org/10.1080/13854046.2015.1099738.
Chiaravalloti, ND, DeLuca, J., 2008. Cognitive impairment in multiple sclerosis. Lancet
Neurology 7, 1139–1151. https://doi.org/10.1016/S1474-4422(08)70259-X.
Conway, AR, Jarrold, C.E., Kane, M.J., Miyake, A., Towse, J.N., 2007. Variation in
working memory. Oxford University Press.
Delis, DC, Kaplan, E., Kramer, J.H., 2001. Delis-Kaplan Executive Funcion System.
Psychological Corporation., San Antonio.
M. Blair et al.
Detterman, D.K., 1993. The case for the prosecution: Transfer as an epiphenomenon. In:
Detterman, D.K., Sternberg, R.J. (Eds.), The case for the prosecution: Transfer as an
epiphenomenon. Transfer on trial: Intelligence, cognition, and instruction 1–24.
Feuillet, L., et al., 2007. Early cognitive impairment in patients with clinically isolated
syndrome suggestive of multiple sclerosis. Mult Scler 13 (1), 124–127.
Filippi, M, Riccitelli, G, Mattioli, F, et al., 2012. Multiple sclerosis: effects of cognitive
rehabilitation on structural and functional MR imaging measures–an explorative
study. Radiology 262, 932–940. https://doi.org/10.1148/radiol.11111299.
Glanz, B.I., et al., 2007. Cognitive dysfunction in patients with clinically isolated
syndromes or newly diagnosed multiple sclerosis. Mult Scler 13 (8), 1004–1010.
Goverover, Y, Chiaravalloti, ND, O’Brien, AR, DeLuca, J., 2018. Evidenced-Based
Cognitive Rehabilitation for Persons With Multiple Sclerosis: An Updated Review of
the Literature From 2007 to 2016. Arch Phys Med Rehabil 99, 390–407. https://doi.
org/10.1016/j.apmr.2017.07.021.
Hancock, LM, Bruce, JM, Bruce, AS, Lynch, SG., 2015. Processing speed and working
memory training in multiple sclerosis: a double-blind randomized controlled pilot
study. J Clin Exp Neuropsychol 37, 113–127. https://doi.org/10.1080/
13803395.2014.989818.
Honarmand, K, Feinstein, A., 2009. Validation of the Hospital Anxiety and Depression
Scale for use with multiple sclerosis patients. Mult Scler 15, 1518–1524. https://doi.
org/10.1177/1352458509347150.
Klingberg, T., 2010. Training and plasticity of working memory. Trends Cogn Sci 14,
317–324. https://doi.org/10.1016/j.tics.2010.05.002.
Krupp, LB, LaRocca, NG, Muir-Nash, J, Steinberg, AD., 1989. The fatigue severity scale.
Application to patients with multiple sclerosis and systemic lupus erythematosus.
Arch Neurol 46, 1121–1123. https://doi.org/10.1001/
archneur.1989.00520460115022.
Kujala, P., Portin, R, Ruutiainen, J., 1997. The progress of cognitive decline in multiple
sclerosis. Brain 120, 289–297.
Kurtzke, JF., 1983. Rating neurologic impairment in multiple sclerosis: an expanded
disability status scale (EDSS). Neurology 33, 1444–1452. https://doi.org/10.1212/
wnl.33.11.1444.
Lussier, M, Bugaiska, A, Bherer, L., 2017. Specific transfer effects following variable
priority dual-task training in older adults. Restor Neurol Neurosci 35 (2), 237–250.
https://doi.org/10.3233/RNN-150581.
Mattioli, F, Stampatori, C, Zanotti, D, Parrinello, G, Capra, R., 2010. Efficacy and
specificity of intensive cognitive rehabilitation of attention and executive functions
in multiple sclerosis. J Neurol Sci 288, 101–105. https://doi.org/10.1016/j.
jns.2009.09.024.
Mitolo, M, Venneri, A, Wilkinson, ID, Sharrack, B., 2015. Cognitive rehabilitation in
multiple sclerosis: A systematic review. J Neurol Sci 354, 1–9. https://doi.org/
10.1016/j.jns.2015.05.004.
Melby-Lervåg, M., Hulme, C., 2013. Is working memory training effective? A meta-
analytic review. Dev Psychol 49, 270–291.
Morrow, SA., 2013. Normative data for the Stroop color word test for a North American
population. Can J Neurol Sci 40 (6), 842–847. https://doi.org/10.1017/
s0317167100015997. Nov.
Multiple Sclerosis and Related Disorders 49 (2021) 102770
Parisi, L, Rocca, MA, Mattioli, F, Copetti, M, Capra, R, Valsasina, P, et al., 2013. Changes
of brain resting state functional connectivity predict the persistence of cognitive
rehabilitation effects in patients with multiple sclerosis. Mult Scler 20 (6), 686–694.
Rao, S.M., 1995. Neuropsychology of multiple sclerosis. Current Opinion in Neurology 8
(3), 216–220.
Rao, SM, Leo, GJ, Bernardin, L, Unverzagt, F., 1991a. Cognitive dysfunction in multiple
sclerosis. I. Frequency, patterns, and prediction. Neurology 41, 685–691. https://
doi.org/10.1212/wnl.41.5.685.
Rao, SM, Leo, GJ, Ellington, L, Nauertz, T, Bernardin, L, Unverzagt, F., 1991b. Cognitive
dysfunction in multiple sclerosis. II. Impact on employment and social functioning.
Neurology 41, 692–696. https://doi.org/10.1212/wnl.41.5.692.
Sala, G., Gobet, F., 2017. Does far transfer exist? Negative evidence from chess, music,
and working memory training. Current Direction in Psychological Science 26,
515–520. https://doi.org/10.1177/0963721417712760.
Schwid, S.R., et al., 2007. Cognitive function in relapsing multiple sclerosis: minimal
changes in a 10-year clinical trial. J Neurol Sci 255 (1-2), 57–63.
Shinaver 3rd, CS, Entwistle, PC, Soderqvist, S., 2014. Cogmed WM training: reviewing
the reviews. Appl Neuropsychol Child 3, 163–172. https://doi.org/10.1080/
21622965.2013.875314.
Simons, D.J., Boot, W.R., Charness, N., Gathercole, S.E., Chabris, C.F., Hambrick, D.Z.,
Stine-Morrow, E.A.L., 2016. Do “brain-training” programs work? Psychological
Science in the Public Interest 17, 103–186. https://doi.org/10.1177/
1529100616661983.
Smith, A., 1982. Symbol Digit Modalities Test: Manual. Western Psychological Services,
Los Angeles.
Solari, Alessandra, et al., 2004. Computer-aided retraining of memory and attention in
people with multiple sclerosis: a randomized, double-blind controlled trial. Journal
of the neurological sciences 99–104.
Sullivan, JJL, Edgley, K., Dehoux, E., 1990. A survey of multiple sclerosis. Part 1:
Perceived cognitive problems and compensatory strategy use. Canadian Journal of
Rehabilitation 4, 99–105.
Tesar, N, Bandion, K, Baumhackl, U., 2005. Efficacy of a neuropsychological training
programme for patients with multiple sclerosis—a randomised controlled trial. Wien
Klin Wochenschr 117, 747–754.
Tombaugh, TN., 2006. A comprehensive review of the Paced Auditory Serial Addition
Test (PASAT). Arch Clin Neuropsychol 21, 53–76. https://doi.org/10.1016/j.
acn.2005.07.006.
Vickrey, BG, Hays, RD, Harooni, R, Myers, LW, Ellison, GW., 1995. A health-related
quality of life measure for multiple sclerosis. Qual Life Res 4, 187–206. https://doi.
org/10.1007/BF02260859.
Wechsler, D., 1997b. Wechsler Adult Intelligence Scale, 3rd ed.
Wechsler, D., 1997a. WMS-III Administration and Scoring Manual.
Wilson, BA., et al., 1996. BADS: Behavioural Assessment of the Dysexecutive Syndrome:
Manual.
Wollesen, B., Voelcker-Rehage, C., 2014. Training effects on motor–cognitive dual-task
performance in older adults. Eur Rev Aging Phys Act 11, 5–24. https://doi.org/
10.1007/s11556-013-0122-z.