The added value of cognition-targeted exercise versus symptom-targeted exercise for multiple sclerosis fatigue: A randomized controlled pilot trial.

BACKGROUND: Fatigue is considered one of the most common symptoms of multiple sclerosis (MS) and lacks a current standardized treatment. Therefore, the aim of this study was to examine the feasibility and effectiveness of a cognition-targeted exercise versus symptom-targeted exercise for MS fatigue.
METHODS: In this Pilot, parallel-group, randomized controlled trial, sixty participants with multiple sclerosis, were randomly assigned to either a Cognition-Targeted Exercise (CTE) (N = 30, mean age 41) or a Symptom-Targeted Exercise (STE) (N = 30, mean age 42). The participants in the experimental group received eight, 50-minute sessions of weekly Cognitive Behavior Therapy (CBT) in addition to a CTE Program; whereas, participants in the control group received eight, 50-minute sessions of weekly CBT in addition to the standardized physiotherapy program (STE Program). Feasibility was assessed through recruitment rate, participant retention, adherence and safety, in addition to clinical outcome measures, including: (1) Modified Fatigue Impact Scale (MFIS), (2) Work and Social Adjustment Scale (WSAS), (3) Hospital Anxiety and Depression Scale (HADS), and Perceived Stress Scale (PSS). All outcome measures were assessed at baseline (pretreatment), following completion of the eight visit intervention protocol, and at 3-months follow-up.
RESULTS: The recruitment rate was 60% and 93% of participants completed the entire study. The recruited participants complied with 98% of the required visits. No adverse events were recorded. A Generalized Estimation Equation Model revealed a significant difference over time as an interaction term during the post and follow up visit for all clinical outcome measures (p < .001).
CONCLUSION: The addition of CTE to CBT exhibited positive and more lasting influence on MS fatigue outcomes compared to Symptom-Targeted Exercise (STE). Feasibility and efficacy data from this pilot study provide support for a full-scale RCT of CTE as an integral component of Multiple Sclerosis fatigue management.

Introduction

Multiple Sclerosis (MS) is a chronic demyelinating disease of the central nervous system and is broadly known as a common neurologic complication in humans [1]. It is estimated that over 2.5 million people are suffering from this ailment all around the world [2]. It is most prevalent among females, 20 to 40 years of age [3]. The cause has not yet been detected and no definite treatment has been found; however, pharmacological interventions have exhibited some success in the reduction of intensity and recurrence of the disease process [4]. MS represents a wide range of impairments, including: muscle pain and cramping, insentience, cognitive, sensory, vision and speech dysfunction, gastrointestinal excretory problems and fatigue [5]. Complaints of fatigue for people with MS are reported at 76–97% [1]. The causes of fatigue in people with MS have not been clearly defined in the research [6]. Approximately 65% of people with MS reported fatigue-related symptoms as one of the three most bothersome aspects of their symptoms [7], with a profound side effect on health-related quality of life and daily activity performance [8]. Fatigue also interfered with daily activities for people with MS, causing numerous troubles in occupational, educational, economic, recreational and family areas, ultimately producing negative outcomes in social and personal communications and mental health outcomes [9].

Several published reviews have examined the effectiveness of individual types of fatigue management interventions for people with MS. Current review of evidence for pharmacologic intervention trials targeting fatigue in people with MS have shown weak and inconclusive results [7, 10]. In comparison, recent reviews of exercise training [11] and cognitive behavioral therapy (CBT) [12] suggest that these interventions may be beneficial for MS fatigue management.

The body of research investigating the effect of CBT and exercise interventions is expanding, but to our knowledge, there are insufficient studies that examine the combined effect of CBT and exercises to target fatigue for people with Multiple Sclerosis.

While the role of CBT in contributing to the reduction of fatigue severity is well established [13-15], there continues to be controversy regarding the role that physical activity and exercise play in fatigue management [16-21]. No single, optimal exercise modality has been established to address MS fatigue. Furthermore, most studies show variability in subtype exercise choice, depending on specific MS symptoms, level of functional ability and therapist preference. There is a lack of clarity in identification of specific type and components of exercise that should be included in an intervention to achieve positive fatigue management benefits for people with MS [22].

In light of current research findings, we cannot find a clear answer to the question of whether different types of exercise may affect fatigue differently. The purpose of the present study was to determine whether the treatment effect of CBT on fatigue is mediated by adding different exercise approaches (Cognition-Targeted Exercise versus symptom-contingent exercises). Related aims included feasibility outcomes related to rate of recruitment, participant retention and/or completion rate, adherence to treatment allocation and assurance of protocol safety. The results of this study are an important addition to the validation of CBP treatment approaches and interventions that rely upon physical exercise and activity programs in some way to reduce fatigue in people with Multiple Sclerosis.

Methods

Study design and setting

This study was a prospective, assessor-blinded, parallel-group, randomized controlled clinical trial, comparing one group that received CBT plus Cognition-Targeted Exercise (CTE) to a control group receiving CBT plus Symptom-Targeted Exercise (STE). The setting was Farouk Hospital—Egypt. This trial was registered with the Clinical-Trials.gov NCT04699370 where the full protocol can be accessed (https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AJQR&selectaction=Edit&uid=U0005FZM&ts=2&cx=-g5ewh2). The study protocol was approved by the local ethics committee. Informed consents were provided to and obtained from all participants prior to data collection in accordance with relevant guidelines and regulations.

(The protocol for this trial and supporting CONSORT checklist are available as supporting information; see S1 Checklist and S1 File).

Sample size

Priori sample size calculation indicated that 100 patients per each group were required to detect a minimal clinically important change of 4 points on the MFIS [23] (assuming a level of significance of 5% and a power level of 90%). As a pilot study we used 25 patients per each group and to account for possible participant dropouts, the sample size was increased by 20%.

Participants

Both male and female subjects were included in this study if they aged between 20–50 years, have relapsing remitting or progressive MS and met the following criteria: (1) Diagnostic criteria for MS were confirmed by a neurologist [24]. (2) Being within normal or average dysfunction and excluding those scoring ≥ 6 in the Expanded Disability Status Scale (EDSS); (3) Being identified as a case level of fatigue; fatigue score of 4 or greater on the fatigue Scale [25]. Potential participants were excluded from the study if they had any serious psychiatric disorders including major affective disorder or any chronic illness that may affect their fatigue level.

Allocation and concealment

An independent person blinded to group allocation and not involved in any other aspect of the study performed the randomization in a 1:1 ratio utilizing a method of random permuted blocks of different sizes. A permuted block randomization sequence was generated using a random number generator (www.randomizer.org). Each block was placed in a sequence of consecutively numbered sealed envelopes. Sequentially numbered and sealed opaque envelopes containing the sequence were stored in a locked drawer. For each enrolled participant, the study coordinator (not involved in the preparation of the allocation sequence) retrieved and opened the next sequentially numbered envelope and assigned the participant according to the random allocation scheme.

Intervention protocol

The participants in the experimental group received eight 50-minute sessions of weekly CBT based on van Kessel’s model [26] in addition to a Cognition-Targeted Exercise CTE program; whereas, participants in the control group received eight 50-minute sessions of weekly CBT in addition to a standardized physiotherapy program, consisting of Symptom-Targeted Exercises (STE).

CBT was designed on the basis of van Kessel’s Model. The main objective of this treatment is to challenge all external factors (e.g. behavioral, cognitive, and affective factors) expected to participate in the development and persistence of fatigue in MS patients. The treatment sessions were delivered on an individual basis. Table 1 summerizes the session contents.

Table 1

Summary of CBT sessions.

First session	Overview of causes of MS fatigue; explanation of cognitive behavioral model for MS fatigue.
Second session	Introduction of treatment rationale, which includes an explanation of CBT and how it relates to MS fatigue
Third session	Education on how patterns of rest and activity or over-activity affect the body and fatigue.
	Participants are encouraged to set goals to improve levels of resting, activity, and exercise to set goals to improve levels of resting, activity, and exercise
Fourth session	Information is provided on sleep patterns (sleeping too much or too little) and impact on fatigue and behavioral techniques (basic sleep hygiene)
Fifth session	The concepts of symptom focusing and symptom attribution are introduced, and how these can have an impact on MS fatigue. Alternative explanations of somatic symptoms are discussed,
Six session	The concept of negative thoughts is introduced and impact on fatigue and mood.
Seventh session	Basic stress management and coping with emotions is discussed. Participants are encouraged to set goals for stress management and practicing alternative ways to manage their emotions
Eighth session	The importance of social support for MS patients is discussed, and participant’s personal support systems are reviewed. Participants are encouraged to continue to employ the skills they have learned throughout the manual to manage their fatigue

For Cognition-Targeted Exercise (CTE), all standardized physical therapy exercises were performed in a time contingent rather than in a symptom-contingent way. Goal setting is essentially done together with the patient, focusing on functionality instead of fatigue relief. Progression to the next level was preceded by mentally visualizing the task for enhancement of successful execution of the targeted movement. During the CTE training, the therapist placed great emphasis on patient’s cognitive report of their problems, so that patients will have positive perceptions regarding their illness and treatment outcome. In addition, the patient’s perceptions about each exercise and anticipated consequences of the exercises were discussed during the session.

The standardized physical therapy protocol consisted of eight, half-hour, individualized physiotherapy sessions, over a 4-week period. This program consisted of twice-weekly supervised general aerobic, strengthening and flexibility exercise sessions based on symptom-targeted contingencies. This exercise program is typically implemented in routine clinical practice.

All intervention procedures for the study and control group were delivered individually, face to face, by the same physiotherapist, with 10 years prior experience, who received specialized training and certification in the techniques employed in this study to minimize inter-therapist variation, enhance fidelity and to mimic a clinical oriented patient-physiotherapist relationship. Compliance with the exercise program was calculated as total number of session’s attended/total number of sessions available.

Outcome measures

Multiple outcome measures were collected at baseline (pretreatment), the next day following the completion of the eight visit intervention, and at 3-months follow-up. The order of measurements was the same for all participants. Modified fatigue impact scale (MFIS) was the primary treatment outcome to determine the fatigue level. The MFIS has been recommended by “the fatigue guidelines development panel of the MS Council for Clinical Practice Guidelines”, as the main outcome measures for assessing MS related fatigue [27, 28].

Secondary outcome measures included:

The Work and Social Adjustment Scale. Fatigue-related impairment was assessed using a reliable and valid Work and Social Adjustment Scale [29].

Hospital Anxiety and Depression Scale. Improvements in mood was assessed using a reliable and valid Hospital Anxiety and Depression Scale [30, 31], a commonly used self-report instrument for detecting states of depression and anxiety in patients with medical illnesses.

Finally, the perception of stress. Was measured using a valid and reliable Perceived Stress Scale [32, 33].

The main feasibility outcomes included recruitment rate, retention or completion rate, adherence rate and safety. Recruitment rate was a simple ratio of the number of identified participants vs. those who actually agreed. Whereas, the completion rate was indicated by the number of participants that completed the entire study. Adherence rate was quantified by the number of treatments made vs. the total recommended. For safety assessment, the number and nature of adverse events were recorded on a weekly basis during the intervention period and at every month during the follow up period. All participants were assessed by two physiotherapists, who have at least 10 years’ experience in neurorehabiliation and were not the same therapist who provided the intervention protocol. Assessors were blinded to group allocation to prevent any bias.

Data analysis

The statistical procedure depended on the principle of intention to treat for between-groups comparisons. The normal distribution of all descriptive statistics baseline variables was determined using the Kolmogorov–Smirnov test; where continuous data is noted as mean with standard deviation (SD) in the text and tables. Equality of variance was assessed with Levene’s test; attaining a 95% confidence level, p-value > 0.05. To follow up and compare the effects of the 2 alternative treatments over 3 months, we examined the results using a generalized Estimation Equation (GEE) Model. The statistical analysis was performed using the SPSS statistical software system The SPSS Statistics 26 ® (IBM Corp.) and RStudio IDE. (RStudio, Inc.).

Results

The experimental and control groups were similar for age, gender, EDSS score and all outcome measures. The baseline participant demographics of all patients are shown in Table 2.

Table 2

Baseline participant demographics.

	Cognition-targeted group (n = 30)	Symptom-targeted group (n = 30)
Age(y)	41 ± 6	42 ± 4
	Range 47–65	Range 45–64
Weight(kg)	59 ± 9	60 ± 8
Gender (%)
Male	5	4
Female	25	26
EDSS score	4.5	4.3
Marital status
Married	22	20
Single	1	2
Widow /divorced	7	8
Employment status
Working	27	28
retired	3	2
Educational level
University or higher	19	18
High school	2	1
Junior high school or less	9	11
Disease duration, years, mean (SD)	12±4	11±3
Disease course (RRMS/SPMS),	28/2	29/1
Medication at enrolment
Interferon	6	8
Fingolimod	15	12
Natalizumab	9	10

EDSS: Expanded Disability Status Scale. RRMS: relapsing remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; SD: standard deviation.

Feasibility

Recruitment

The exclusion criteria for this study removed 40% of individuals initially interested in participation, resulting in a recruitment rate of 60%. One hundred participants were initially screened and 60 subjects were found to be eligible to enroll in the study. In total, 60 (100%) participants completed the first follow-up at 4 weeks of treatment and 56 (93%) completed the entire study including the 3-month follow-up after the four week intervention. A diagram of participant retention and randomization throughout the study is shown in Fig 1. The study adherence rate was relatively consistent for both groups. Ninety-eight percent of participants in the CTE group attended 100% of the intervention sessions. In the STE group, 95% of participants attended 100% of sessions. Participant illness accounted for 98% and illness in a family member accounted for 2% of missed appointments. No adverse effects were identified during the 12-week intervention period. Only one participant was hospitalized for 3 days because of a generalized infection unrelated to the study.

Fig 1

Flow chart.

A generalized Estimation Equation (GEE) Model was developed and used to examine the influence of CTE over STE on changes in Modified Fatigue Impact scale (MFIS), Work and social Adjustment scale (WSAS), Hospital Anxiety Scale (HAS) and Perceived Stress Scale (PSS). Pre-treatment scores were considered as reference values for estimating the post and follow up changes among groups. Models selected were chosen according to the least quasi-likelihood under the independence model criterion.

A Generalized Estimation Equation Model revealed a significant difference over time as an interaction term during the post and follow up visit for. Regarding the Hospital Anxiety Scale (HAS), an increase by 0.32 units was reported as a main effect for the CTE compared to STE group. However this observed effect was found to be reduced significantly over the post and follow up visits in response to CTE by -3.96 and -4.45, respectively. There was also a non-significant decrease by -1.08 units as a main effect of CTE, compared to STE group. This decrease remained consistent with the null hypothesis even after considering the time factor for the post treatment visit. However, the interaction effect of CTE at the follow up visit showed a significant decrease by -4.616 units. (The data are available as supporting information; see S1 Data).

Discussion

This randomized controlled trial compared the outcomes of fatigue, work and social adjustment, hospital anxiety, depression, and perceived stress scale between a group that received the Cognition-Targeted Exercise (CTE) coupled with Cognitive Based Therapy (CBT) to that of a group that received Symptom-Targeted Exercise (STE) coupled with CBT. The adherence to treatment assignment during the 4-week, intervention period and compliance with follow-up were acceptable, with no serious adverse events. The between group analysis revealed a significant difference over time as an interaction term during the post and follow up visit. In the cognition-targeted exercise group, the amount of Modified Fatigue Impact Scale (MFIS) and other management outcomes related to work and social adjustment, hospital anxiety and perceived stress improved significantly and this improvement was maintained at the 3-month follow-up. In contrast, the STE group revealed significantly less differences in fatigue level and other management outcomes between baseline and 4-weeks of treatment, and at the 3-month follow-up fatigue scores increased again (Table 3).

Table 3

GEE model for unit change from baseline to 4- week post treatment and the 3-month follow-up, cognition-targeted.

Exercise versus symptom-targeted exercise for multiple sclerosis fatigue.

Modified Fatigue Impact	GEE coefficient	95% confidence interval	Standard error	Wald	p-value
(Intercept)	49.6	47.49 To 51.71	1.08	2117.9	<0.001
Cognition-targeted	-2.16	-6.04 To 1.72	1.98	1.19	0.2747
Post	-6.32	-8.93 To -3.71	1.33	22.47	<0.001
Follow	-4.3	-7.44 To -1.15	1.61	7.15	<0.001
Cognition-targeted: post	-12.88	-17.31 To -8.45	2.26	32.4	<0.001
Cognition-targeted: follow	-15.32	-20.3 To -10.34	2.54	36.35	<0.001
Work and Social Adjustment Scale	GEE coefficient	95% confidence interval	Standard error	Wald	p-value
(Intercept)	18.28	17.15 1 To 9.408	0.576	1008.74	<0.001
Cognition-targeted	-1.36	-2.91 To 0.186	0.789	2.97	0.08468
Post	-2.96	-4.69 To -1.231	0.882	11.26	0.00079
Follow	-2.367	-4.17 To -0.561	0.921	6.6	0.01020
Cognition-targeted: post	-3.68	-5.82 To -1.537	1.094	11.33	0.00076
Cognition-targeted: follow	-5.162	-7.40 To -2.923	1.142	20.41	<0.001
Hospital Anxiety	GEE coefficient	95% confidence interval	Standard error	Wald	p-value
(Intercept)	15.08	14.16 To 16	0.47	1031.12	< 2e-16
Cognition-targeted	0.32	-0.858 To 1.498	0.601	0.28	0.59449
Post	-1.72	-3.108 To -0.332	0.708	5.9	0.01517
Follow	-1.863	-2.922 To -0.803	0.541	11.87	0.00057
Cognition-targeted: post	-3.96	-5.682 To -2.238	0.879	20.31	<0.001
Cognition-targeted: follow	-4.45	-5.967 To -2.933	0.774	33.06	<0.001
Perceived Stress	GEE coefficient	95% confidence interval	Standard error	Wald	p-value
(Intercept)	22.12	20.36 2 To 3.878	0.897	608.41	<0.001
Cognition-targeted	-1.08	-3.48 To 1.321	1.225	0.78	0.3779
post	-2.64	-5.01 To -0.266	1.211	4.75	0.0293
follow	-1.772	-4.51 To 0.961	1.394	1.62	0.2038
Cognition-targeted: post	-3.04	-6.43 To 0.348	1.729	3.09	0.0786
Cognition-targeted: follow	-4.616	-8.05 To -1.179	1.753	6.93	0.0085

Symptom-targeted Exercise was the reference value.

To our knowledge, there is no study that has evaluated the comparative effectiveness of cognition-targeted exercise and symptom-targeted exercise. So far, few existing studies have compared the effects of different exercise approaches that have heterogeneous results [34]. There is a substantial body of research showing that the level of physical activity is an effective component in chronic fatigue management for patients with MS [16, 35]. However, according to Wiborg et al. [13], the effect of CBT on fatigue “is not mediated by a persistent increase in physical activity”. The results of our study are also consistent with earlier research on CBT for chronic fatigue in which a reduction in fatigue was associated with a change in illness beliefs and not the physical activity level [20, 21].

Diverse results related to exercise approach in patients with MS found in comparative literature may be one explanation for the lack of consensus for interventions for reducing fatigue. Previous studies have challenged the behavioral, and cognitive factors that play a role in the development and persistence of fatigue in MS patients. Other studies focused only on the physical fitness status. The majority of previous studies investigated non-fatigued groups of patients with MS [34], thus the level of evidence from this group of studies may be limited and not generalizable to patients with MS and fatigue [36-40].

However, no clear explanation is available for the superiority of CTE, the plausible mechanism behind the positive effect on MS fatigue, which is based on the theory that excessive physiological motor fatigue is mainly central in origin, rather than a consequence of intramuscular changes. It, logically, follows that when patients learned of their ability to increase their level of physical activity, despite their symptoms, the belief of having little control over their condition may have, also, changed [13]. This explanation is also consistent with other studies that highlighted the role of changing the illness belief as an important factor in fatigue reduction [21, 41]. In light of the findings of this study, changing illness-related cognitive behaviors may also play a more crucial role in CBT for Chronic Fatigue Syndrome (CFS) compared to a focus on sole increase in physical activity.

CBT is based upon the principle that physical, behavioral, cognitive, and affective responses and functions interact with one another with mutual effects [1]. Therefore, the addition of CTE, which focuses on the patient’s awareness of the connection between body and cognitive belief systems, may contribute toward a change in other systems (e.g. affective and physical response), resulting in a greater reduction in symptoms of fatigue for patients with MS, than those achieved by CBT, alone.

Study limitations and strategies for improvement

Our study strengths include successful blinding of the outcome assessors, a limited loss to follow-up, and high compliance rate for both of our groups. However, we propose several limitations of this study, pointing to necessary future research work on this topic. First, our project only included a short-term follow-up of 3-months after intervention was terminated. It is unclear how long the identified fatigue related changes would remain and whether patient compliance may also be an issue. Second, because we chose participants with a scoring of less than six in the expanded disability status scale to investigate, it is unknown how our study results might relate to people with MS who have higher levels of disability. Third, within the resource constraints of a pilot investigation, only a small sample size was feasible. While our study had statistically significant findings and raised the possibility of Cognition-Targeted Exercise CTE benefits, no reliable conclusions about mood effects of CTE can be drawn from such a small sample. As Button et al. [42] emphasize, “a study with low statistical power reduces the likelihood that a statistically significant result reflects a true effect.” Thus, replication studies with larger sample sizes are critical to further evaluating any potential mood effects of this type of exercise. Despite of the above mentioned limitations, the present study can be regarded as a positive step toward finding and adopting non-pharmacological interventions to ameliorate fatigue levels in patients with Multiple Sclerosis.

Conclusion

The addition of the Cognition-Targeted Exercise (CTE) to Cognitive-Behavioral Therapy (CBT) revealed positive and more lasting influence on multiple sclerosis management outcomes compared to those received CBT with Symptom-Targeted Exercises (STE). Feasibility and efficacy data from this pilot study provide support for a full-scale RCT based on CTE as an integral component of Multiple Sclerosis fatigue management.

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1 Jul 2021

PONE-D-21-18476

The Added Value of Cognition-targeted Exercise Versus Symptom-targeted Exercise for Multiple Sclerosis Fatigue: Randomized Controlled Trial

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Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance].

COMMENTS: The effect size is taken from a pilot study with total n=10 (i.e., 5 subjects in each group assuming 1:1 allocation ratio, which is too small to yield any useful/meaningful statistic) [Sample size section (line 163-7): The effect size estimate regarding the primary outcome MFIS, was obtained from a pilot study in which 10 participants underwent a similar protocol. The effect size for the differences between the groups was estimated to be 0.79. Accordingly, given a significance level of 5% and statistical power of 80%, 25 patients for each treatment arm were needed. To compensate for potential attrition, we increased the sample size by 20%.giving a total number of 30 patients per group]. The effect size used to estimate required sample size seems to be very large {unreasonably large}. In such (psychological therapy) studies [The objective of this study was to explore the added value effect of cognition-targeted exercise versus symptom-targeted exercise for MS fatigue], the effect size achieved/attained/seen is generally (in most cases) is of small to ‘medium’ level.

By referring to table-2 on page 158 of J. Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 even for medium effect size you need n=64 per group (type-I error=0.05, power=80%).

{Please note that the ‘effect size’ assumed should have some valid basis (exact published reference needs to be quoted) &/or reasonable/realistic, else the study is very likely ‘not to be able to’ detect a difference despite its presence}

Note that ‘The general linear model with repeated measures’ is not a technique originally developed (for testing interaction terms it is definitely nice, however, not) for between groups comparison. Direct between groups comparison techniques are available. Remember that though the measures/tools used are appropriate [e.g. modified fatigue impact scale (MFIS), work and social adjustment scale, hospital anxiety and depression scale, perceived stress scale] most of them yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double (for example, a Visual Analogue Scales VAS score or say ‘depression’ score)}]. Then application of suitable non-parametric test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (i.e. normal)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s) [suitable / most desired/applicable], but should be used whenever/wherever they are available. [Assumptions of ‘general linear model with repeated measures’ are unlikely to be fulfilled making their use invalid]

What is in lines 174-5 (we examined the results using 2 way repeated measures anova) is not reflected properly in tables [2 & 3]. Why there are two ‘P’ values [one each in column 4 & 5, row 4]. Application of repeated measures ANOVA yields only one ‘P’ (for each parameter/variable), in my knowledge. Then which test it is? If it is done after getting a significant ‘F’ by repeated measures ANOVA, then is not that “multiple testing” which requires adjustment in ‘P’? What the CI [in column 4 & 5, row 4] is for? Is it for difference in means? What is the interpretation? Moreover, one should use ‘to’ in/while presenting CI {example, [-5.9 -3.6] should be [-5.9 to -3.6]}.

It is well-known that while reporting [findings from] ‘Clinical Trial’ follow CONSORT guidelines. Even word ‘CONSORT’ or important items {like Random Sequence generation (Item 8a), Allocation concealment (Item 9)} of/in CONSORT checklist are not found [since your article type is ‘Clinical Trial’, you are supposed to cover these items in the report].

Two limitations of this study pointed out in lines 254-7 are not (unfortunately) the only ones. As pointed out in ‘important note’ above “This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ should be assessed separately/independently. In my opinion, to rescue this article (which is quite possible), lot of re-vision is needed. Therefore, I have to unfortunately recommend ‘major revision’.

Reviewer #2: Title

What did you need in the title

Discuss What do you mean here by added value?

The CBT used too much and published before, what was the new in your study

What is your question and answer here?

Abstract:

The background needs to be shortened.

Methods section is poorly framed. It has to be re-written.

Demographic profile of patients is not mentioned. P value are all .0005 – please check again

poorly Key words and not illustrative (type of technique or therapy you used )

Introduction:

1. Explain the rationale of the study. Please delete information unrelated to objective so that the section is short and sweet. Kindly focus on three elements of introduction.

a. What is known about the topic? (Background)

b. What is not known? (The research problem)

c. Why the study was done? (Justification)

2. Objective is not clear as mentioned above.

Write on

patients with multiple sclerosis

cognitive behavioral model of MS fatigue

Symptom-targeted Exercise

objective of the current study

Methods

Totally unclear

Rewrite by these consequences

-Study design, setting, sample size, Participant (inclusion and exclusion criteria),

-Which stage of MS you select –mention if the patients have any symptoms or remission –the patient under treatment during the study (mention all with its side effect )

-Intervention (explain CBT)

- Comparison. Ethics and end point

LINE 101-102

psychological disorders or any chronic illness that may affect their fatigue

discus what are you mean here

LINE 103

A third person blinded to group allocation

Where were the 1st and 2nd person

Line 110- 111 (explain CBT )

The subjects in the experimental group received eight 50-minute sessions of weekly CBT based on van Kessel’s model

CONSORT 2010 checklist need revision pages not accurate for each element

13a and 13b not covered in page 8

Page 8 include (data analysis and results )

Results

P value are all P<0.0005 in the 1st paragraph page 9 and 0.001 in the tables clarify please (why same results for all values )

Also in table 1 gender (numbers not clear )30-25 v 29-26

I think statistics need readjustment completely

Discussion:

The discussion section needs to be written and described scientifically after correction needed for results

References

Rewrite again

Most reference are old like (5,8,13,14,18,20,30) and not completed (volumes and issues ) like (33,34,35,29,26,15,1)

Reviewer #3: This work explores a novel target for the treatment of fatigue in patients with MS, and I congratulate the authors for their efforts to carry out this trial.

As additional data, it would be interesting to know the proportion of patients with different MS phenotypes recruited in the study, and if there were differences in the response to therapy in the different clinical forms.

In addition, it would be interesting to know if the patients who intervened were under immunomodulatory treatment, and what type of treatment, since we know that interferons can cause fatigue

Finally, an English correction by a native speaker would be recommended.

**********

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Submitted filename: renamed_d18a7.docx

Click here for additional data file.

26 Aug 2021

Comments

Comments Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

Responses Done as suggested

Comments We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions.

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Response There is now restriction and we have uploaded the data file

Comments Please amend your manuscript to include your abstract after the title page.

Response Done s suggested

Comments Reviewer #1: Important note: This review pertains only to ‘statistical aspects’ of the study and so ‘clinical aspects’ [like medical importance, relevance of the study, ‘clinical significance and implication(s)’ of the whole study, etc.] are to be evaluated [should be assessed] separately/independently. Further please note that any ‘statistical review’ is generally done under the assumption that (such) study specific methodological [as well as execution] issues are perfectly taken care of by the investigator(s). This review is not an exception to that and so does not cover clinical aspects {however, seldom comments are made only if those issues are intimately / scientifically related & intermingle with ‘statistical aspects’ of the study}. Agreed that ‘statistical methods’ are used as just tools here, however, they are vital part of methodology [and so should be given due importance].

COMMENTS: The effect size is taken from a pilot study with total n=10 (i.e., 5 subjects in each group assuming 1:1 allocation ratio, which is too small to yield any useful/meaningful statistic) [Sample size section (line 163-7): The effect size estimate regarding the primary outcome MFIS, was obtained from a pilot study in which 10 participants underwent a similar protocol. The effect size for the differences between the groups was estimated to be 0.79. Accordingly, given a significance level of 5% and statistical power of 80%, 25 patients for each treatment arm were needed. To compensate for potential attrition, we increased the sample size by 20%.giving a total number of 30 patients per group]. The effect size used to estimate required sample size seems to be very large {unreasonably large}. In such (psychological therapy) studies [The objective of this study was to explore the added value effect of cognition-targeted exercise versus symptom-targeted exercise for MS fatigue], the effect size achieved/attained/seen is generally (in most cases) is of small to ‘medium’ level.

By referring to table-2 on page 158 of J. Cohen’s paper “A power primer” in Psychological Bulletin, 1992, vol.:112, pp 155-159 even for medium effect size you need n=64 per group (type-I error=0.05, power=80%).

{Please note that the ‘effect size’ assumed should have some valid basis (exact published reference needs to be quoted) &/or reasonable/realistic, else the study is very likely ‘not to be able to’ detect a difference despite its presence}

Response I totally agree that this pilot small sample may be not representative for actual differences and may leads to a lack of representativeness in the study sample

And accordingly we changed our design to Randomized pilot trial

And recalculate the sample size based on the published minimal clinical difference for the primary outcome

Comments Note that ‘The general linear model with repeated measures’ is not a technique originally developed (for testing interaction terms it is definitely nice, however, not) for between groups comparison. Direct between groups comparison techniques are available. Remember that though the measures/tools used are appropriate [e.g. modified fatigue impact scale (MFIS), work and social adjustment scale, hospital anxiety and depression scale, perceived stress scale] most of them yield data that are in [at the most] ‘ordinal’ level of measurement [and not in ratio level of measurement for sure {as the score two times higher does not indicate presence of that parameter/phenomenon as double (for example, a Visual Analogue Scales VAS score or say ‘depression’ score)}]. Then application of suitable non-parametric test(s) is/are indicated/advisable [even if distribution may be ‘Gaussian’ (i.e. normal)]. Agreed that there is/are no non-parametric test(s)/technique(s) available to be used as alternative in all situation(s) [suitable / most desired/applicable], but should be used whenever/wherever they are available. [Assumptions of ‘general linear model with repeated measures’ are unlikely to be fulfilled making their use invalid]

Response To follow up and compare the effects of the 2 alternative treatments over 3 months, we examined the results using a generalized Estimation Equation (GEE) Model .

Page 9

Comments What is in lines 174-5 (we examined the results using 2 way repeated measures anova) is not reflected properly in tables [2 & 3]. Why there are two ‘P’ values [one each in column 4 & 5, row 4]. Application of repeated measures ANOVA yields only one ‘P’ (for each parameter/variable), in my knowledge. Then which test it is? If it is done after getting a significant ‘F’ by repeated measures ANOVA, then is not that “multiple testing” which requires adjustment in ‘P’? What the CI [in column 4 & 5, row 4] is for? Is it for difference in means? What is the interpretation? Moreover, one should use ‘to’ in/while presenting CI {example, [-5.9 -3.6] should be [-5.9 to -3.6]}.

Response This part was rewritten again

Comments It is well-known that while reporting [findings from] ‘Clinical Trial’ follow CONSORT guidelines. Even word ‘CONSORT’ or important items {like Random Sequence generation (Item 8a), Allocation concealment (Item 9)} of/in CONSORT checklist are not found [since your article type is ‘Clinical Trial’, you are supposed to cover these items in the report].

Response We added the required information in Page 5

Comments Two limitations of this study pointed out in lines 254-7 are not (unfortunately) the only ones.

Response We added more relevant limitations

Page 13

Comments Reviewer #2: Title

What did you need in the title

Discuss What do you mean here by added value?

The CBT used too much and published before, what was the new in your study

What is your question and answer here?

Response I explained the rationale behind this study in the introduction part

Comments Abstract:

The background needs to be shortened.

Methods section is poorly framed. It has to be re-written.

Demographic profile of patients is not mentioned. P value are all .0005 – please check again

poorly Key words and not illustrative (type of technique or therapy you used )

Response Done as suggested

Comments Introduction:

1. Explain the rationale of the study. Please delete information unrelated to objective so that the section is short and sweet. Kindly focus on three elements of introduction.

a. What is known about the topic? (Background)

b. What is not known? (The research problem)

c. Why the study was done? (Justification)

2. Objective is not clear as mentioned above.

Write on

patients with multiple sclerosis

cognitive behavioral model of MS fatigue

Symptom-targeted Exercise

objective of the current study

Response Done as suggested

Comments Methods

Totally unclear

Rewrite by these consequences

Study design, setting, sample size, Participant (inclusion and exclusion criteria),

-Which stage of MS you select –mention if the patients have any symptoms or remission –the patient under treatment during the study (mention all with its side effect )

-Intervention (explain CBT)

- Comparison. Ethics and end point

Response I rewrote this part following these suggested arrangement and added more details for CBT

Medications at enrolment and types of MS were summarized at table 2

Comments LINE 101-102

psychological disorders or any chronic illness that may affect their fatigue

discus what are you mean here

Response It is a typo error

I meant her psychiatric disorders.

Page 5 line 120

especially Previous cross-sectional studies have demonstrated a close association between chronic fatigue and psychiatric disorders.

Skapinakis P, Lewis G, Meltzer H. Clarifying the relationship between unexplained chronic fatigue and psychiatric morbidity: results from a community survey in Great Britain. Am J Psychiatry. 2000;157:1492–1498. [PubMed]

Lawrie SM, Pelosi AJ. Chronic fatigue syndrome in the community. Prevalence and associations. Br J Psychiatry. 1995;166:793–797

Comments LINE 103

A third person blinded to group allocation

Where were the 1st and 2nd person

Response The term "third person" refers to someone else, i.e., not the treatment provider or assessor .

And anyway I have changed to an independent person page 5

Line 123 To avoid any confusion

Comments Line 110- 111 (explain CBT )

The subjects in the experimental group received eight 50-minute sessions of weekly CBT based on van Kessel’s model

Response We added more details for CBT table 1

Comments CONSORT 2010 checklist need revision pages not accurate for each element

13a and 13b not covered in page 8

Page 8 include (data analysis and results )

Response Adjusted as suggested

Comments Results

P value are all P<0.0005 in the 1st paragraph page 9 and 0.001 in the tables clarify please (why same results for all values )

Also in table 1 gender (numbers not clear )30-25 v 29-26

I think statistics need readjustment completely

Response We rewrote this part as suggested

Comments Discussion:

The discussion section needs to be written and described scientifically after correction needed for results

Response Done as suggested

Comments References

Rewrite again

Most reference are old like (5,8,13,14,18,20,30) and not completed (volumes and issues ) like (33,34,35,29,26,15,1)

Response Done as suggested

Comments Reviewer #3: This work explores a novel target for the treatment of fatigue in patients with MS, and I congratulate the authors for their efforts to carry out this trial.

As additional data, it would be interesting to know the proportion of patients with different MS phenotypes recruited in the study, and if there were differences in the response to therapy in the different clinical forms.

In addition, it would be interesting to know if the patients who intervened were under immunomodulatory treatment, and what type of treatment, since we know that interferons can cause fatigue

Finally, an English correction by a native speaker would be recommended.

Response Done as suggested

Submitted filename: Response to Reviewers (1).docx

Click here for additional data file.

7 Sep 2021

PONE-D-21-18476R1The added value of cognition-targeted exercise versus symptom-targeted exercise for multiple sclerosis fatigue: a randomized controlled pilot trialPLOS ONE

Dear Dr. Moustafa,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Please submit your revised manuscript by Oct 22 2021 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Walid Kamal Abdelbasset, Ph.D.

Academic Editor

PLOS ONE

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Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

Reviewer #2: Partly

Reviewer #3: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

Reviewer #2: I Don't Know

Reviewer #3: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: (No Response)

Reviewer #2: Yes

Reviewer #3: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: COMMENTS: Not all of the comments made on earlier draft(s) by me are addressed satisfactorily [example: In response to my comments that ‘The general linear model with repeated measures’ is not a technique originally developed for testing the difference between groups, and that ‘assumptions of ‘general linear model are unlikely to be fulfilled making their use invalid’ your response is “To follow up and compare the effects of the 2 alternative treatments over 3 months, we examined the results using a generalized Estimation Equation (GEE)”]. In response to some other comment, you just said that “This part was rewritten again” but WHERE is not indicated.

In short, I am not very happy about the revision. Let the respected editor decide the future course.

Reviewer #2: -

Reviewer #3: THE CHANGES IN THE MANUSCRIPT WERE POSITIVE AND I CONSIDER THAT IT IS IN A CONDITION TO BE PUBLISHED

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

15 Sep 2021

COMMENTS: Not all of the comments made on earlier draft(s) by me are addressed satisfactorily [example: In response to my comments that ‘The general linear model with repeated measures’ is not a technique originally developed for testing the difference between groups, and that ‘assumptions of ‘general linear model are unlikely to be fulfilled making their use invalid’ your response is “To follow up and compare the effects of the 2 alternative treatments over 3 months, we examined the results using a generalized Estimation Equation (GEE)”]. In response to some other comment, you just said that “This part was rewritten again” but WHERE is not indicated.

In short, I am not very happy about the revision. Let the respected editor decide the future course.

Response

At the beginning, I would like to make it clear that I completely agree with the reviewer and that this Generalized estimating equations (GEE) was chosen after consulting a biostatistician . This biostatistician was added to the manuscript based on the required modifications

In this study, We have selected the Generalized estimating equations (GEE) ,which considered as an extension of generalized linear models (GLM) because the major strength of GEE is that they do not require the correct specification of the multivariate distribution

Especially the reviewer 1 has highlighted that a Generalized Linear Mixed Model (GLMM)require some parametric assumptions. And according to literature the Generalized estimating equations (GEE) are a nonparametric way to handle this issue (1)

(1) A Ziegler, M Vens -Generalized estimating equations . Methods of information in medicine, 2010 - thieme-connect.com

And accordingly, we have changed many sections in the manuscript

Data analysis Page 9, line 109-201

Result, page 10, line 220-234

Abstract, line 43-44

reviewer comment

What is in lines 174-5 (we examined the results using 2 way repeated measures anova) is not reflected properly in tables [2 & 3]. Why there are two ‘P’ values [one each in column 4 & 5, row 4]. Application of repeated measures ANOVA yields only one ‘P’ (for each parameter/variable), in my knowledge. Then which test it is? If it is done after getting a significant ‘F’ by repeated measures ANOVA, then is not that “multiple testing” which requires adjustment in ‘P’? What the CI [in column 4 & 5, row 4] is for? Is it for difference in means? What is the interpretation? Moreover, one should use ‘to’ in/while presenting CI {example, [-5.9 -3.6] should be [-5.9 to -3.6]}.

Response :

We have changed the statistical technique used in this study

Instead of GLM we used Generalized estimating equations (GEE)

and accordingly, we have changed the tables completely

Now I believe the analysis technique is properly reflected in the table

reviewer comment

Two limitations of this study pointed out in lines 254-7 are not (unfortunately) the only ones.

Response

We added more relevant limitations

Page 13&14 lines 282 -289

"we propose several limitations of this study, pointing to necessary future research work on this topic. First, our project only included a short-term follow-up of 3-months after intervention was terminated. It is unclear how long the identified fatigue related changes would remain and whether patient compliance may also be an issue. Second, because we chose participants with a scoring of less than six in the expanded disability status scale to investigate, it is unknown how our study results might relate to people with MS who have higher levels of disability. Third, within the resource constraints of a pilot investigation, only a small sample size was feasible. While our study had statistically significant findings and raised the possibility of Cognition-Targeted Exercise CTE benefits, no reliable conclusions about mood effects of CTE can be drawn from such a small sample. As Button et al [43] emphasize, “a study with low statistical power reduces the likelihood that a statistically significant result reflects a true effect.” Thus, replication studies with larger sample sizes are critical to further evaluating any potential mood effects of this type of exercise . Despite of the above mentioned limitations, the present study can be regarded as a positive step toward finding and adopting non-pharmacological interventions to ameliorate fatigue levels in patients with Multiple Sclerosis"

Submitted filename: Response to Reviewers (1).docx

Click here for additional data file.

5 Oct 2021

The added value of cognition-targeted exercise versus symptom-targeted exercise for multiple sclerosis fatigue: a randomized controlled pilot trial

PONE-D-21-18476R2

Dear Dr. Moustafa,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Walid Kamal Abdelbasset, Ph.D.

Academic Editor

PLOS ONE

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: (No Response)

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: (No Response)

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: (No Response)

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

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Reviewer #1: (No Response)

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Reviewer #1: COMMENTS: All of the comments made on earlier draft(s) by me, were/are attended. Now the manuscript is acceptable.

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Reviewer #1: Yes: Dr. Sanjeev Sarmukaddam

28 Oct 2021

PONE-D-21-18476R2

The added value of cognition-targeted exercise versus symptom-targeted exercise for multiple sclerosis fatigue: a randomized controlled pilot trial

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