Exercising Impacts on Fatigue, Depression, and Paresthesia in Female Patients with Multiple Sclerosis : Medicine & Science in Sports & Exercise

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Exercising Impacts on Fatigue, Depression, and Paresthesia in Female Patients with Multiple Sclerosis


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Medicine & Science in Sports & Exercise 48(5):p 796-803, May 2016. | DOI: 10.1249/MSS.0000000000000834
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Multiple sclerosis (MS) is the commonest chronic autoimmune demyelinating and inflammatory disease of the CNS. Demyelination in association with axonal damage leads to the slowing or blockage of nerve signals, resulting in typical MS symptoms such as visual problems, feeling tired (fatigue), pain (37), sensations of tingling, tickling, pricking, and burning (paresthesia), and problems of movement and balance (25). Often, there are aftereffects such as depression, and the incidence of depression in patients with MS is 40%–50% higher than in the general population (15). Furthermore, excessive fatigue severely reducing physical activity (PA) and exercising is experienced by at least two-thirds of people with MS (4). Up to 87% of patients with MS also report paresthesia (16,21).

The standard treatment for MS involves immune regulatory medication (16); antidepressants are prescribed to cope with secondary effects such as depression (14,28), whereas fatigue is increasingly treated with stimulants such as modafinil and methylphenidate. However, there is growing evidence that PA and exercising (EXTR) can also have a positive influence on the well-being and psychological functioning of patients with MS (2). The aim of the present study was therefore to test the hypotheses that EXTR intervention programs have a positive impact on fatigue, depression, and paresthesia in patients with MS.

As regards the influence of PA and EXTR on the physical health and psychological functioning of patients with MS, within the last two decades, there has been a paradigm shift away from avoidance of PA (2,12) and in favor of encouraging patients with MS to adopt a physically more active lifestyle. Giesser (12) concluded that PA and EXTR have the potential to counteract a broad variety of comorbidities arising from inactivity, such as obesity, metabolic syndrome, osteoporosis, diabetes, and hypertension. Furthermore, Pilutti et al. (29) analyzed 17 randomized control trials of the effects of PA and EXTR on patients with MS and observed a slightly reduced risk of relapse of MS attacks and no increased risk for adverse events or earlier MS attacks.

Motl (24) and Asano et al. (1) identified three main factors explaining why patients with MS are less active than healthy people: fatigue, impairment, and lack of time. Although lack of time seems to be a common reason for people not to exercise, impairment and fatigue are MS-specific issues. As regards impairment, there is some evidence of a negative feedback loop in that acute PA may lead to immediate impairment and physical and mental discomfort. However, there is agreement that the impairments and discomfort are due to an acute increase in body temperature and not to PA as such (Uhthoff phenomenon, cf. [39]).

As regards fatigue, this is a core symptom of MS and understood as increased physical and psychological tiredness. Pilutti et al. (29) reported mixed results as regards the influence of PA and EXTR on fatigue. Although some studies have found a beneficial effect of PA and EXTR on fatigue, others have not. Pilutti et al. (29), however, claimed that EXTR might have a small but significant benefit on fatigue and at the least no worsening of fatigue with any kind of exercising. More specifically, Oken et al. (26) reported a positive impact of yoga on fatigue; similarly, Sutherland and Andersen (36) observed a positive influence of regular aquatic exercise on fatigue. However, research into the effects of yoga and aquatic exercising on patients with MS remains scarce. Accordingly, one aim of the present study was to further examine the influence of a standardized yoga program and an aquatic exercise program on fatigue in patients with MS compared with a nonexercise control condition.

Patients with MS report experiencing depressive symptoms (14). For instance, Sadovnick et al. (32) reported that at least 50% of patients with MS also reported symptoms of depression. Although there is extensive evidence that exercising reduces symptoms of major depression (e.g., [14,23,24,35]), Feinstein et al. (10), in their recent review of such exercise training effects on depression of patients with MS, concluded that results are mixed with some studies reporting a positive influence although other studies failing to do so. However, Feinstein et al. (10) noted that none of these studies had depression as the primary outcome measure and none had assessed symptoms of depression via validated questionnaires. In the light of these observations in the present study (1), symptoms of depression were one of the chief outcomes considered, and (2) depression was assessed via the Beck Depression Inventory (6), a highly standardized, validated, and internationally accepted self-rating tool.

In contrast to Feinstein et al. (10), Ensari et al. (9), in their review, were able to identify small but positive effects of PA and EXTR on symptoms of depression in patients with MS; they reported effect sizes of 0.36. Given the limited amount of research on this specific topic, and given that about 50% of patients with MS report symptoms of depression, a further aim of the present study was therefore to investigate to what extent regular yoga exercising and aquatic exercising might reduce symptoms of depression among patients with MS.

About 87% of patients with MS report experiencing paresthesia (16,21), that is, abnormal sensations just about anywhere in the body. These include tingling, prickling, pins and needles, electrical-type buzzing, burning, skin crawling, itching, partial numbness (like feeling through tent cloth), and a variety of neuropathic pains. Despite the high prevalence rate of paresthesia (up to 87%, cf. [16,21]), to the best of our knowledge, no research has examined whether an EXTR program such as yoga or aquatic exercises results in any change in paresthesia in patients with MS. Accordingly, the third aim of the present study was to investigate to what extent yoga or aquatic exercise affects paresthesia in patients with MS compared with a nonexercise control condition.

In the present study, we examined two specific types of EXTR, namely, yoga and aquatic exercise.

Although Oken et al. (26) reported beneficial effects of yoga on symptoms of MS (see also Rogers and MacDonald [31]), Cramer et al. (8), in their systematic review and meta-analysis, were less enthusiastic; they argued that randomized control trials were scarce, and methods and study designs varied considerably between studies. Likewise, Frank and Larimore (11) observed that methodological issues (sample size, duration, frequency, and intensity of yoga sessions) made it difficult to conclude that yoga has a robust impact on the symptoms or psychological well-being of patients with MS. Furthermore, Sandroff et al. (34) found that, in patients with MS, treadmill walking but not cycling or yoga impacted positively on cognitive performance. To counter previous limitations in study design, one further aim of the present study was to compare a yoga program with a nonexercise condition but also to another EXTR intervention, namely, aquatic exercising.

As regards the influence of aquatic exercise on core symptoms of MS (33), Sutherland and Andersen (36) and Kargarfard et al. (17) found positive influences on fatigue, whereas Roehrs and Karst (30) reported an improved quality of life. However, the extent to which aquatic exercise has a positive influence on depression or paresthesia has not yet been investigated. A further aim of the present study was therefore to investigate the impact of aquatic exercising on fatigue, depression, and paresthesia.

In conclusion, there is emerging evidence that EXTR positively influences fatigue in patients with MS and that the influence of EXTR on depression in patients with MS remains unclear, and so far, no study has investigated the extent to which EXTR may positively impact on paresthesia. To fill these gaps in our knowledge, the aims of the present study were to investigate the influence of EXTR and, more specifically, of yoga and aquatic exercising on fatigue, depression, and paresthesia in patients with MS compared with a nonexercise condition.

The following two hypotheses were formulated: 1) Following Cooney et al. (7), Rogers and MacDonald (31), and Ensari et al. (9), we expected improvements in symptoms of depression in patients undergoing an EXTR program for 8 wk compared with a nonexercise control group (2). Following Oken et al. (26), Sutherland and Andersen (36), Pilutti et al. (29), and Giesser (12), we expected reductions in fatigue in patients undergoing an EXTR program compared with the nonexercise control condition. We treated as exploratory the extent to which an EXTR program alters paresthesia compared with a nonexercise control condition.


Study Design and Procedure

Female patients diagnosed with MS were recruited from the MS center of the Imam Reza Hospital of Kermanshah (Iran) during the fall of 2014. Eligible patients were fully informed about the study aims and procedure, and about the confidential nature of data selection and data handling, and gave their written informed consent. Next, neurologists, psychiatrists, and psychologists not otherwise involved in the study performed a brief medical check and psychiatric interview to ensure that only patients meeting the inclusion criteria (see below) were enrolled in the study. Furthermore, psychologists not otherwise involved in the study and completely blind as regards patients’ assignment distributed and collected patients’ self-rating questionnaire both at the beginning and at the end of the study.

Additionally, neurologists not otherwise involved in the study and completely blind as regards patients’ assignment to the study conditions ascertained at the beginning and at the end of the study, and once a week, whether there were any changes in the state of MS (primary-progressive, secondary-progressive, relapsing-remitting, progressive-relapsing) or further aggravations in the clinical course of the MS. Immune modulatory treatment was fully established and kept constant 4 wk before starting the study and throughout its subsequent execution.

Patients were randomly assigned to the nonexercise control condition, yoga condition, or aquatic exercising condition. At the beginning, participants completed questionnaires covering sociodemographic, illness-related, and anthropometric information (see below). At the beginning and at the end of the study 8 wk later, patients also completed self-rating questionnaires related to fatigue, depression, and paresthesia (see below). The local ethics committee approved the study which was conducted in its entirety in accordance with the ethical standards laid down in the Declaration of Helsinki.


Seventy-two female patients were approached, 13 (18%) did not agree to participate, and five did not meet the inclusion criteria. Accordingly, a total of 54 (75%) female outpatients with MS took part in the study.

Inclusion criteria were as follows: 1) diagnosed and approved diagnosis of MS, as ascertained by neurologists, patients’ reports, and medical records; 2) female; 3) age between 25 and 50 yr; 4) Expanded Disability Status Scale ≤6 (19); 5) one of the following types of MS, as ascertained by a neurologist not otherwise involved in the study: primary-progressive secondary-progressive; relapsing-remitting progressive-relapsing; 6) stable, regular, and monitored pharmacological treatment of MS (immune modulatory treatments). Exclusion criteria were as follows: 1) not meeting the inclusion criteria as described above; 2) unable or unwilling to complete the questionnaires; 3) unable or unwilling to follow the intervention; 4) psychiatric disorder such as severe depression, substance abuse, eating disorders, and similar; 5) being pregnant or breastfeeding, or willing to become pregnant during the study; 6) being treated with psychopharmaca such as antidepressants, stimulants, mood stabilizers, antipsychotics, narcotics, or similar; 7) relapse/MS attack within the last 2 months; 8) possible risk of relapse during the study; 9) being currently under treatment involving yoga or any other kind of PA; 10) being currently under psychotherapeutic treatment; 11) known somatic issues such as cardiovascular disease, arthritis, diabetes, or orthopedic issues, which would have impeded participation in a PA program.


Patients were randomized to one of the three study conditions. To do so, 54 chips with three different colors (18 red, 18 blue, and 18 green) were put in an opaque box and stirred. A psychologist not otherwise involved in the study drew the chips: patients with red chips were assigned to the nonexercise condition, patients with blue chips were assigned to the aquatic exercising, and patients with green chips were assigned to the yoga condition.



Participants completed the Fatigue Severity Scale (18). It consists of nine items, and answers are given on seven-point rating scales ranging from 1 (not at all) to 7 (definitively/almost always), with higher mean scores reflecting greater fatigue (Cronbach’s alpha = 0.91).

Self-report of depressive symptoms: Beck Depression Inventory

Patients completed the Beck Depression Inventory (3), in which the patients self-reported symptoms of depression. The questionnaire consists of 21 items and asks about different dimensions such as depressive mood, loss of appetite, sleep disorders, and suicidality. Answers are given on four-point Likert scales with the anchor points 0 (“as always”/“no change”) to 3 (“not able anymore”/“dramatic change”) and with higher scores reflecting greater severity of depressive symptoms (Cronbach’s alpha = 0.89). Additionally, values were categorized as follows: 0–9, no or minimal depression; 10–18, mild depression; 19–29, moderate depression; 30–63, severe depression.


Patients rated their degree of paresthesia on a 10-point visual analogue scale ranging from 0 (no sensations at all) to 10 (severe sensations).



Yoga sessions took place in the gym hall of the hospital. Sessions took place three times a week for about 60 min for eight consecutive weeks under the supervision of a certified yoga instructor (Hatha yoga). During the sessions, when appropriate, participants could talk to each other. Yoga sequences for beginners were instructed; a typical session consisted of centering: breathing exercises, meditation; sun salute; different and increasingly demanding standing postures; supported head and shoulder stands; different twists and bends; corpse pose at the end of the session.

Aquatic exercising

Aquatic exercising took place in the rehabilitation center of the hospital. The exercise program for the aquatic training group included a series of water activities undertaken for a period of 8 wk with three sessions per week and 1 h per session (water: 28°C–30°C). Generally, sessions were organized and supervised by a certified instructor not otherwise involved in the study as follows: warming up, 10-min walking, stretching, and gymnastics; 40-min power endurance activities such as relay races, crossing the pool alone or as team competition, strength training, and similar; 10-min cooling down, relaxing, stretching, and breathing exercises. During the session, participants were free to chat to each other.

Activities for controls

Participants in the nonexercise condition met two to three times a week in the hospital for about 60 to 90 min. They were free to talk to physicians and hospital staff, to complete everyday duties, to participate in occupational therapy, and to meet and to talk to other patients. In establishing and emphasizing components of attention and social contact for patients in the nonexercise condition, we ensured that possible effects of EXTR could not be explained in terms of differences in extent of social contacts with other patients, experts, or hospital staff.

Statistical Analyses

Sociodemographic, illness-related, and anthropometric dimensions between the three groups were compared with χ2 tests and one-factorial ANOVA. To calculate changes in fatigue, depression, and paresthesia between the groups and over time, three ANOVA procedures for repeated measures were performed with the group (controls, aquatic exercising, and yoga), time (baseline vs end of study), and group–time interaction as independent factors, and fatigue, depression, and paresthesia as dependent variables. Where appropriate, post hoc analyses with Bonferroni–Holm corrections for P values were performed.

A series of χ2 tests and one odds ratio calculation were performed to calculate the risk of experiencing minimal, mild, or moderate depression at the end of the study.

To calculate the direct and indirect associations between depression, fatigue, and paresthesia at the end of the study, a series of both bivariate and partial correlations was performed.

The level of significance was set at alpha = 0.05. Effect sizes for F-tests were indicated with the partial eta squared (η2p), with 0.059 ≥ η2p ≥ 0.01 indicating small [S], 0.139 ≥ η2p ≥ 0.06 indicating medium [M], and η2p ≥ 0.14 indicating large [L] effect sizes. All computations were performed with SPSS® 22.0 (IBM Corporation, Armonk, NY) for Apple Mac®.


Sociodemographic, illness-related, and anthropometric information

Table 1 reports all descriptive and statistical indices of sociodemographic, illness-related, and anthropometric dimensions for participants in each of the three study conditions.

Descriptive and inferential statistics for sociodemographic, illness-related, and anthropometric data separately for patients with adjuvant yoga, with adjuvant aquatic exercise, or without active intervention.

Patients did not differ descriptively or statistically between the study conditions; that is to say, no descriptive or statistical differences were found for age, weight, duration of MS, status of MS (degree of disability and current type of disability), civil status, educational background, or current occupation. Accordingly, sociodemographic dimensions, illness-related dimensions, and anthropometric dimensions were not entered into the equations as confounders.

Fatigue, depression, and paresthesia at the beginning of the study and 8 wk later, and separately for the three treatment conditions (control, aquatic exercising, and yoga)

Table 2 reports all descriptive and statistical indices for the dimensions fatigue, depression, and paresthesia separately for the factors time, group, and time–group interaction. Note that statistical indices are not reported in the text.

Descriptive and inferential statistics for fatigue, symptoms of depression, and paresthesia separately for the factors group (controls, with adjuvant aquatic exercising, and with adjuvant yoga), time (baseline vs end of study), and group–time interaction.

The following overall pattern was observed: At baseline, values for depression, fatigue, and paresthesia did not differ descriptively or statistically between the three study conditions (all F < 1.04, P > 0.34). Fatigue, depression, and paresthesia decreased from the beginning of the study to the end 8 wk later; significant group differences were observed. The significant time–group interactions showed that fatigue, depression, and paresthesia decreased over time in the aquatic exercising and yoga conditions but not in the nonexercise condition (see also Fig. 1). Post hoc analyses with Bonferroni–Holm corrections for P values revealed larger effect sizes for both aquatic exercising and yoga compared with the nonexercise condition, with yoga having a stronger effect than aquatic exercising on fatigue but not on depression or paresthesia.

Paresthesia scores significantly decreased over time (η 2 p = 0.60 [large effect]); the significant time–group interaction (η 2 p = 0.44 [large effect]) showed that paresthesia scores decreased significantly over time in the aquatic exercising group and in the yoga group, but not in the nonexercise group.

Depression, categories.

Depression values were categorized into no/minimal depression, mild depression, moderate depression, and severe depression. All descriptive and statistical indices are reported in Table 3.

Categories of depression separately for baseline and study end and separately for group (controls, aquatic exercising, and yoga).

Although at the beginning of the study there were no differences in categories between the three study conditions, at the end of the study, patients in the aquatic exercise and yoga condition reported either no/minimal or mild depression (all changes statistically significant), whereas depression categories in the nonexercise condition did not change.

In the final step, depression categories were dichotomized into “low depression” (which included no/minimal and mild depression) and “high depression” (which included moderate and severe depression); the three groups were also dichotomized into “control” versus “intervention conditions.” The risk of still being moderately to severely depressed at the end of the study was 35-fold higher in the nonexercise condition than in the intervention conditions (OR, 35.00; CI: 3.91–313.86).

Direct and indirect associations between depression, fatigue, and paresthesia at the end of the study

The following correlations were observed: fatigue and depression, r = 0.58***; controlling for paresthesia, rp = 0.47***; fatigue and paresthesia, r = 0.39***; controlling for depression, rp = 0.04; depression and paresthesia, r = 0.63***; controlling for fatigue, rp = 0.53*** (*** = p < 0.001). The three dimensions were interrelated, though depression explained the association between fatigue and paresthesia.


The key findings of the present study are that, compared with the nonexercise condition, both aquatic exercising and yoga had positive effects on fatigue, depression, and paresthesia among female patients with MS.

Two hypotheses and one research question were formulated, and each of these is considered in turn.

Our first hypothesis was there would be a reduction in fatigue after an EXTR program when compared with a nonexercise condition, and this hypothesis was supported. Therefore, our findings are in accord with those studies reporting a positive impact of EXTR on fatigue (12,29). However, we believe that the present data add to the current literature for at least three reasons: 1) data were gathered from a clinical trial, 2) patients were randomly assigned to the study condition, and 3) yoga and aquatic exercising had the same impact on fatigue compared with the nonexercise condition. We hold therefore that both yoga and aquatic exercising are suitable to counteract one of the most disturbing side effects of MS, namely, fatigue.

Our second hypothesis was that EXTR would positively impact on depression, and again, this was fully supported. The present findings therefore confirm those from previous research (9,11,15,35) but also add to the literature in at least three ways: 1) unlike previous studies (Feinstein et al. [10]; Ensari et al. [9]), depression was the main outcome variable; 2) in contrast to Ensari et al. (11) who reported maximum effect sizes of 0.36, we observed large effect sizes (η2p) in the range 0.39–0.79; 3) as reported in Table 3, by the end of the study, patients in the intervention groups reported either no/minimal or mild depression; in contrast, the risk at the end of the study of reporting moderate to severe depression was 35-fold higher in the nonexercise condition compared with the intervention conditions.

Next, we examined the extent to which an EXTR might affect paresthesia. The pattern of results suggests that, compared with the nonexercise condition, EXTR positively impacts on paresthesia. In this regard, the results expand on previous literature related to the treatment of paresthesia in patients with MS. But why should an EXTR have this impact? Our speculation was that an EXTR improves blood flow and nerve impulse functioning. Also, given that EXTR generally increases self-control, self-esteem, and coping, it was possible that as a result patients paid less attention to signs of paresthesia. However, as shown in the partial correlation computations, paresthesia seemed to decrease as a function of reduced depression. Therefore, we hypothesize that EXTR impacted indirectly on paresthesia via improved symptoms of depression.

The data available to us did not, unfortunately, shed light on the physiological and psychological mechanisms producing the impressive improvements we observed with respect to fatigue, depression, and paresthesia. Consequently, we need to draw ideas from previous studies about possible mechanisms. Thus, it is conceivable that both yoga and aquatic exercising had influences at the molecular level (22), and that they enhanced neuroplasticity (7). Additionally, it is possible that, on a psychological level, EXTR had positive influences on self-control, self-esteem, coping (20), and self-efficacy, all of which in turn reduced fatigue, depression, and paresthesia. This holds particularly true for yoga: Although yoga aims to enhance the development of the individual’s self-awareness and control of their body and mind, at a behavioral level, it increases health-related quality of life in general while reducing perceived stress (27,28), most probably via a complex set of psychophysiological processes such as are generally observed in relaxation and meditation techniques (27,38).

Despite the new findings, various limitations warrant against overgeneralization (1). The sample sizes are rather small, though we calculated effect sizes, which are insensitive to sample sizes (2). We exclusively assessed female patients but Harbo et al. (13) have reported a true increase in MS among women, but not in men (ratio: from 2.3 to 3.5/1) during the last decade. However, it remains unclear whether this pattern of results is also applicable to male patients (3). Symptoms of depression were exclusively assessed via self-ratings; future studies should also assess symptoms of depression and patient’s behavior, illness severity, and improvements via expert ratings. In this regard, participants were not selected for the presence of key outcomes, though statistical computations showed that at baseline, the three different conditions did not differ in depression, fatigue, and paresthesia (4). Sleep was not assessed; it is possible that the results emerged because of latent but unassessed variables such as sleep quality, which biased two or more dimensions in the same direction (5). No biomarkers were assessed; future studies should focus on inflammatory cytokines as markers of the impact of PA on cellular activity and on MS (6). No data were collected for muscle strength, cardiovascular changes, or gait; future studies should thoroughly and objectively assess changes in these dimensions (7). Total PA over the 8 wk of the study was assessed neither subjectively nor objectively via activity trackers (8). Given the nature and structure of the intervention (yoga, aquatic exercising, and nonexercise condition), patients were not unaware of the study condition, and therefore, we cannot rule out that treatment effects might be due to patient’s expectations and motivation (or disappointments for patients assigned to the nonexercise condition) (9). It remains unclear whether the positive effects of PA were due to a general impact of PA or to more specific components of yoga and aquatic exercise.


Compared with a nonexercise condition, both yoga and aquatic exercising three times a week for eight consecutive weeks positively influenced fatigue, depression, and paresthesia in female patients with MS.

We thank all study participants. Furthermore, we greatly thank Jennifer Kurath (Psychiatric Clinics of the University of Basel, CH) for text editing and Nick Emler (University of Surrey, Surrey, UK) for proofreading the manuscript.

We thank the Board of Public Sports, Physical Education and Management Department of Kermanshah University of Medical Sciences (Kermanshah, Iran), as well as the Research Council of the Medical Sciences University of Kermanshah (Iran), for financial support and approval of the present research (research no. 44854). No sponsors had influence on data gathering, data analyses, or data interpretation, or upon writing and submitting the present manuscript. This study complied with ethical standards.

No funding was received for this manuscript. The authors declare that they have no conflicts of interest.

The results of the present study do not constitute endorsement by the American College of Sports Medicine.


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