Introduction

Multiple sclerosis (MS) is a progressive neurological disorder of the central nervous system (CNS) characterised by episodes of inflammatory demyelination and axonal deterioration [1]. Neurological damage can result in a spectrum of symptoms including spasticity, depression and cognitive abnormalities. The development of cognitive disturbances is increasingly recognised in individuals with MS and is associated with negative consequences for quality of life (QOL) and an increased prevalence of depression in patients [2]. The pathogenesis of MS is highly complex with the identity of a single unifying cause underlying its aetiology remaining elusive; however, it is believed that an intricate interplay between immunological factors, genetic factors and environmental influences determines susceptibility to the disease [3]. There is currently no cure for MS; however, a number of disease-modifying therapies (DMTs) have been approved which reduce frequency of relapses and long-term accrual of disability [4]. Although the exact mechanism of action of many MS DMTs is not fully elucidated, these medications are thought to act by several therapeutic mechanisms, via immunomodulation, restoration of the blood-brain barrier (BBB) dysfunction and neuroprotection [5]. However, therapies are often partially effective and with risks of side effects such as flu-like symptoms, skin necrosis and liver enzyme elevation [6]. In addition, the observation that disability often continues to worsen despite immunotherapy has prompted patients to seek alternative treatments. Furthermore, effective therapies and interventions that target cognitive dysfunction in individuals with MS are lacking [7].

It is well known that exercise promotes neuroregeneration and plasticity in rodents [8]. Indeed, exercise can combat the clinical development of experimental autoimmune encephalomyelitis (EAE) by targeting dendritic loss [9], CNS cytokines and growth factors [10]. In human studies, data suggests that physical activity can target multiple clinical manifestations in MS. Indeed, there is sufficient evidence to suggest that exercise among MS patients improves aerobic fitness [2], overall mobility [11], QOL and walking ability [12]. Importantly, moderate-intensity exercise has no adverse effects on pain or function in MS patients [13]. However, a body of literature suggests that the therapeutic efficacy of exercise depends on exercise intensity, with response to variability dependent on the type of exercise (cycling/running/swimming), exercise protocol (acute/chronic) and the MS disease status (relapsing-remitting (RR)/progressive) [14].

In this pilot study, we aimed to develop a short (two times/week for 8 weeks) aerobic training programme with multi-target therapeutic potential in individuals with MS. Furthermore, clinical trials of cognitive therapies in MS have not demonstrated clear reproducible improvements in cognitive function in patients [7]. We determined whether short-term cycle ergometer training could ameliorate cognitive disturbances within specific functional domains while simultaneously improving patient QOL and depressive symptomatology.

Materials and methods

Ethical approval

Written informed consent was obtained from each participant and the study received ethical approval from the Clinical Research Ethics committee of the Cork Teaching Hospitals (ECM 3 (xxxxx) 14/04/15 and 4 (o) 01/07/14). The study conformed to the standards set by the Declaration of Helsinki, except for registration in a database.

Study participants

Details of the participant demographics are presented in Table 1. Healthy volunteers and RRMS patients were recruited via Cork University Hospital and the Mercy University Hospital. RRMS patients were also recruited via local advertisements with the MS Ireland Society. The Expanded Disability Status Scale (EDSS) scores were determined by a neurologist and all patients had a RR form of MS with minimal to moderate disability, as defined by the revised McDonald criteria [15, 16]. All patients received neurologist clearance ensuring they were clinically stable at entry to the study. All patients had to meet the revised MacDonald diagnostic criteria for clinically defined MS [16] including patient history, clinical signs and symptoms, physical examination and adjunctive diagnostic tools including MRI. All patients were on immunomodulatory treatment (presented in Table 1). Study participants were screened through a safe participation questionnaire to ensure they were eligible to undertake the study, and an International Physical Activity Questionnaire (IPAQ) [17] was also completed by every study participant. The IPAQ ensured that participant physical activity levels were categorised as low (< 600 METS min/week) for inclusion. Patients with cardiovascular, respiratory, metabolic or autoimmune disease other than MS were excluded. If subjects experienced relapse during the study, or were unable to pedal for 30 min at 60% VO2max, they were excluded from the study. Healthy volunteers with no history of autoimmune, cardiovascular, respiratory or neurodegenerative disease history were included. Healthy control participants were matched on the basis of age, gender, years of education and fitness level. Participants continued their standard medical care during the period of the study and were asked to avoid participation in any additional exercise programmes during the prescribed 8-week exercise programme. All participants continued their normal activities over the period of the study. To monitor this, a weekly physical activity log was completed by all study participants.

Table 1 Demographic data and clinical characteristic on participants at baseline
Full size table

Exercise protocol

The exercise programme was conducted in the Human Physiology Laboratory, Department of Physiology, University College Cork, and consisted of a 30-min exercise session involving cycle ergometry (using a static Monark RT2 Recumbent Bike; Monark Exercise AB, Kroons, Sweden). This was repeated twice a week for 8 weeks. The exercise task was designed such that each study participant exercised at 65–75% age-predicted maximal heart rate. The session involved a 5-min warm-up to reach the target heart rate; work rate was adjusted to maintain this submaximal steady state for 20 min and was followed by a 5 min warm-down at 40% maximal heart rate. Each exercise session was supervised by a CPR/AED certified physiologist and heart rate was monitored throughout.

Aerobic fitness

Cardiorespiratory fitness was determined by estimating maximal oxygen uptake (VO2max) using the Astrand 6-min cycle test [18]. A submaximal exercise test was chosen to avoid an exacerbation of MS symptoms associated with Uhthoff’s phenomenon. A non-invasive monitoring system (Finapres-Finometer MIDI; Smart Medical, Gloucestershire, UK) was used to measure beat-to-beat heart rate and blood pressure throughout the fitness test.

QOL and depressive symptomatology

The QOL of participants was assessed prior to week 1 of training (pre-exercise), and at the end of 8 weeks of training (post-exercise) using the MS Quality of Life-54 (MSQOL-54) questionnaire [19] generating a physical and mental health composite score. The MSQOL-54 is a self-report questionnaire and was completed by subjects without any additional assistance. In our study, the administration time of this instrument was typically 11–18 min. All subjects also completed the self-rated 16-item Quick Inventory of Depressive Symptomatology (QIDS-SR16) questionnaire prior to week 1 of training, and at the end of 8 weeks of training. The total QIDS-SR16 score (0–27) was blindly generated for patients and healthy control participants, producing a quantitative result corresponding to depression severity (0–5 = None; 6–10 = Mild; 11–15 = Moderate; 16–20 = Severe; 21–27 = Very Severe). Study participants attempted and self-administered all the questions. QIDS-SR16 has been implemented in other studies reviewing depressive comorbidity [20].

Cognitive performance

Cognitive performance was assessed using the Cambridge Neuropsychological Test Automated Battery (CANTAB®; Cambridge Cognition, LTD) software prior to week 1 of training, and at the end of 8 weeks of training. All assessments were conducted by a trained test administrator who issued standardised verbal instructions to participants on the use of a portable touchscreen Sahara i440D Slate Tablet PC (Sand Dune Ventures, Tablet Kiosk) running CANTABeclipse™ software (Cambridge, UK), as previously described [21, 22]. The researcher provided verbal instructions to participants from a standardised script and had full control of a keyboard used to start, pause or abort each test. As a test battery of multiple cognitive tests was employed, test order was counterbalanced, using a Latin square design, to avoid effects of fatigue for tests completed later in the session. The cognitive assessment lasted for approximately 45 min. The battery administered involved a motor screening test (as a familiarisation with the CANTAB user interface), a mood rating scale, tests of hippocampal-dependent visuospatial memory (paired associates learning; PAL), sustained attention (rapid visual information processing; RVP) and executive function/cognitive flexibility (attention-switching task; AST).

Statistical analysis

Data were analysed using paired Student’s t test and two-way analysis of variance (ANOVA). When analysis indicated significance, the post hoc Student-Newman-Keuls test was used. Data are expressed as mean ± standard errors of the mean (SEM).

Results

Demographic data of study participants

The overall demographics of the study participants are reported in Table 1. A total of 24 individuals were recruited to the study. After screening, 20 individuals met our inclusion criteria. Overall, 19 subjects completed the exercise intervention and pre- and post-assessment sessions, consisting of healthy control participants (n = 10) and RRMS patients (n = 9). One subject within the MS group withdrew from the study before completion due to a bout of cold/flu, exacerbating symptoms and resulting in a relapse. Mean disease symptom duration in the MS cohort was 5.89 ± 1.16 years. The mean age of the healthy control and MS patient cohorts that enrolled in the investigation was 36.00 ± 2.04 years (range 25–44 years) and 35.33 ± 2.12 years (range 27–44 years), respectively. Of the MS patients included in this study, four patients were actively treated with fingolimod, two with natalizumab and one with dimethlyfumarate, glatiramer acetate and beta interferon 1a (Table 1). Two patients took vitamin D supplementation.

Effect of exercise on VO2peak, body weight and BMI

On entry to the study, there was no significant difference in aerobic fitness (VO2max) between healthy subjects (32.70 ± 1.83 ml/min/kg) and MS patients (30.00 ± 1.97 ml/min/kg) (Table 2). Exercise resulted in a significant improvement in aerobic fitness both in healthy participants (p < 0.01) and in the MS cohort (p < 0.01) (Table 2). No significant change was detected in body weight or BMI after the exercise programme in both cohorts (Table 2).

Table 2 Longitudinal changes of parameters in the subgroups at baseline pre-exercise (t1) and at 8 weeks post-exercise (t2)
Full size table

Effect of exercise on disability

The EDSS scores were taken by a neurologist prior to week 1 of training (pre-exercise), and at the end of 8 weeks of training (post-exercise). Although an overall reduction in EDSS was noted in the MS cohort after completion of the programme, this was not statistically significant (2.17 ± 0.40 pre-exercise versus 1.83 ± 0.46 post-exercise, p = 0.19; Table 2).

Exercise improves QOL in MS

Much evidence indicates that QOL is impaired in MS patients [23]. To determine if cycle ergometry improved QOL, the physical health summary score of participants was assessed prior to week 1 of training (pre-exercise), and at the end of 8 weeks of training (post-exercise) using the MSQOL-54 questionnaire. As expected, MS was associated with a lower physical health summary score compared to the control cohort, but importantly, the decline in physical health summary score was reversed following the exercise programme (Fig. 1a). Indeed, post hoc analysis revealed that MS was associated with a significant reduction in physical health prior to the exercise programme, when compared to healthy volunteers (89.47 ± 2.18% healthy control vs. 54.48 ± 5.42% MS, p < 0.001; Fig. 1a). Importantly, exercise promoted a significant improvement in physical health summary score in the MS cohort (54.48 ± 5.42% pre-exercise vs. 72.82 ± 3.23% post-exercise, p < 0.01; Fig. 1a). No change was observed in physical health before and after exercise in healthy volunteers (89.47 ± 2.18% pre-exercise vs. 90.81 ± 2.65% post-exercise). Two-way ANOVA revealed a significant influence of exercise (p < 0.01) and disease status (p < 0.001), in addition to a significant interaction of these factors (p < 0.05) (Fig. 1a).

Fig. 1
figure 1

An 8-week aerobic exercise programme improves the QOL and symptoms of depression in RRMS patients. QOL indices and depressive symptomatology were assessed prior to week 1 of training, and at the end of 8 weeks of training, using the MSQOL-54 questionnaire and the self-rated QIDS-SR16 questionnaire, respectively. Exercise induced an improvement in a physical health summary score, b fatigue levels, c pain levels, d depressive symptomatology and e mental health summary score. Data are presented as the mean ± SEM and are representative of data from healthy volunteers (n = 10) and MS patients (n = 9). ***p < 0.001 compared to healthy individuals pre-exercise training. + p < 0.05, ++ p < 0.01 and +++ p < 0.001 compared to MS individuals pre-exercise training. HC healthy control, MS multiple sclerosis

Full size image

We next assessed the impact of the 8-week exercise programme on subscales within the MSQOL-54 questionnaire, targeting fatigue and pain, both pre-exercise and post-exercise (Fig. 1b, c). Fatigue is one of the most commonly reported and debilitating symptoms in MS [24]. Furthermore, evidence indicates a high incidence of pain in MS patients, with up to 50% of patients experiencing this symptom [25]. Post hoc analysis revealed that MS patients experienced elevated fatigue when compared to healthy volunteers (Fig. 1b). Indeed, MSQOL-54 data indicated that energy levels were higher in healthy volunteers on entry to the study when compared to MS patients (64.78 ± 3.78% control vs. 32.56 ± 3.96% MS, p < 0.001; Fig. 1b). Post hoc analysis revealed that exercise did not significantly impact energy levels in the healthy control cohort (64.78 ± 3.78% pre-exercise vs. 74.00 ± 3.92% post-exercise); however, exercise induced a significant improvement in the energy levels in MS patients (32.56 ± 3.96% pre-exercise vs. 50.44 ± 5.58% post-exercise, p < 0.001; Fig. 1b).

At entry to the study, MSQOL-54 instrument data identified enhanced pain levels in MS patients, compared to healthy participants (2.22 ± 1.11% control vs. 29.39 ± 7.82% MS, p < 0.001; Fig. 1c). Post hoc analysis revealed that exercise did not alter the pain level indicated by healthy volunteers (2.22 ± 1.11% pre-exercise versus 2.22 ± 1.11% post-exercise; Fig. 1c); however, exercise reduced the percentage pain level indicated by MS patients (29.39 ± 7.82% pre-exercise versus 12.41 ± 4.80% (Fig. 1c).

Overall, these findings indicate that the 8-week exercise programme undertaken in this study can improve physical health scores and energy levels in RRMS patients. The data also indicate that the short-term ergometry programme has the proclivity to reduce the pain levels experienced by MS patients.

Exercise reduces depressive symptomatology in MS

All subjects in the study completed the self-rated QIDS-SR16 questionnaire as an indicator of depressive symptomatology, prior to week 1 of training, and at the end of 8 weeks of training. Two-way ANOVA revealed a significant influence of exercise (p < 0.05) and disease status (p < 0.001), in addition to a significant interaction of these factors (p < 0.05; Fig. 1d). The mean QIDS-SR16 total score in MS patients’ entry to the study was 8.67 ± 1.76 (mean ± SEM), indicating mild depression in this cohort (Fig. 1d). Indeed, on entry to the study, six MS patients (66.7%) experienced depressive symptoms, three patients presented with mild depression, one presented with moderate depression and two presented with severe depression, as indicated by the QIDS-SR16. In contrast, one control subject (10%) presented with mild depression. Overall, post hoc analysis determined that MS patients’ total QIDS-SR16 scores (8.67 ± 1.76; mean ± SEM) were significantly higher compared to healthy volunteers (2.22 ± 0.62; mean ± SEM; p < 0.001, Fig. 1d), indicating increased depressive symptomatology in MS patients. Importantly, post hoc analysis also determined that completion of the 8-week exercise programme promoted a significant reduction in depressive symptomatology among MS patients (8.67 ± 1.76 pre-exercise vs. 4.22 ± 0.62 post-exercise; p < 0.05; Fig. 1d).

Given that exercise reduced depressive symptomatology in MS patients (Fig. 1d), we next analysed mental health subscales using the MSQOL-54 questionnaire in healthy control subjects and MS patients at the start of the exercise programme, and following completion of the programme (Fig. 1e). Two-way ANOVA revealed a significant influence of exercise (p < 0.01) and disease status (p < 0.001), in addition to a significant interaction of these factors (p < 0.05) (Fig. 1e). MS was associated with reduced mental health summary score on the MSQOL-54 questionnaire, compared to the control cohort, and importantly, the mental health score in MS patients was improved following the exercise programme (Fig. 1e). Indeed, post hoc analysis revealed that MS was associated with significantly reduced mental health prior to the exercise programme, when compared to healthy volunteers (89.70 ± 2.09% control vs. 61.07 ± 6.73% MS, p < 0.001; Fig. 1e). Importantly, exercise promoted a significant improvement in mental health summary score in the MS cohort (61.07 ± 6.73% pre-exercise vs. 82.51 ± 1.60% post-exercise, p < 0.01; Fig. 1e). No change was observed in mental health scores in the healthy cohort (89.70 ± 2.09% pre-exercise vs. 92.69 ± 0.69% post-exercise; Fig. 1e). These data indicate that the short-term exercise programme undertaken in this study can improve mental health and depressive symptomatology in RRMS patients.

Impact of exercise on cognition

Cognitive performance was assessed using the CANTAB® software prior to week 1 of training, and at the end of 8 weeks of training. Sustained attention, executive function/cognitive flexibility and visuospatial memory were assessed using the RVP, AST and the PAL batteries in CANTAB, respectively.

MS was associated with slower mean latency (Fig. 2a) and a reduction in RVP total hits (Fig. 2b) using CANTAB, compared to the control cohort, and exercise was associated with an improvement in both of these readouts (Fig. 2a, b). Post hoc analysis revealed a significant difference in RVP mean latency (353.1 ± 10.1 ms control vs. 419.3 ± 24.5 ms MS; p < 0.05; Fig. 2a) and RVP total hits (41.9 ± 1.7 control vs. 31.3 ± 3.4 MS; p < 0.01; Fig. 2b) between healthy control and MS groups at baseline. Post hoc analysis determined that exercise in MS patients was associated with a reduction in RVP mean latency towards control levels (419.3 ± 24.5 ms pre-exercise vs. 392.4 ± 20.8 ms post-exercise; Fig. 2a) and an improvement in RVP total hits (31.3 ± 3.4 pre-exercise vs. 36.9 ± 3.3 post-exercise; Fig. 2b).

Fig. 2
figure 2

An 8-week aerobic exercise programme improves cognitive function in RRMS patients. Cognitive function was assessed prior to week 1 of training, and at the end of 8 weeks of training using the CANTAB battery. Exercise induced an improvement in a RVP mean latency, b RVP total hits, c AST mean correct latency, d AST switch cost corrections and e PAL total errors. Data are presented as the mean ± SEM and are representative of data from healthy volunteers (n = 10) and MS patients (n = 9). *p < 0.05 and **p < 0.01 compared to healthy individuals pre-exercise training. AST attention switch task, HC healthy control, MS multiple sclerosis, PAL paired associates learning, RVP rapid visual processing

Full size image

For the AST, MS patients also required significantly more time to respond to the stimuli (mean correct latency) (526.5 ± 20.1 ms control vs. 670.3 ± 48.1 ms MS; p < 0.01; Fig. 2c) and demonstrated longer switch cost latency (i.e. the difference between response latency when a response rule changes versus when it remains the same; 210.3 ± 27.0 ms control vs. 335.5 ± 36.0 ms MS; Fig. 2d) pre-exercise when compared to the healthy volunteers. Exercise improved mean correct latency (670.3 ± 48.1 ms pre-exercise vs. 595.2 ± 59.3 ms; Fig. 2c) and switch cost latency (335.5 ± 36.0 ms pre-exercise vs. 212.3 ± 42.2 ms; Fig. 2d) in MS patients. Healthy participants also made fewer PAL total errors pre-exercise (8.89 ± 1.45 control vs. 17.11 ± 5.90 MS; Fig. 2e), and MS patients showed an improvement in PAL total errors post-exercise (17.11 ± 5.90 pre-exercise vs. 9.63 ± 2.24; Fig. 2e).

These data indicate that MS patients exhibit disturbances within specific cognitive domains, particularly related to sustained attention and executive function/cognitive flexibility, when compared to age-matched healthy volunteers. Data herein also suggest that cycling can improve cognitive function in RRMS patients.

Discussion

Data from MS studies indicate that various exercise programmes can target mobility [11], muscle strength [26], fatigue [13], mood/depression [27] and cognitive disturbances [2, 28] in patients. However, the impact of exercise is dependent on the type/intensity of exercise training, and hence, there is a clear need to establish a routine exercise protocol that results in targeted clinical improvement in the patient [reviewed in [14]]. Furthermore, therapies and(or) interventions that reduce cognitive disturbances in MS patients are lacking. This pilot study set out to develop a short aerobic training programme with multi-target therapeutic potential in individuals with MS, including targeting cognitive disturbances in MS patients with exercise. The study investigated the characteristics that exist between MS patients and healthy subjects in parameters at baseline, including QOL (physical and mental health summary scores), depressive symptomatology and domains of cognitive function, and determined if a routine cycle ergometer training programme influenced each of these parameters. The findings demonstrate that an 8-week exercise programme (30 min/day, 2 days/week for 8 weeks) is sufficient to improve cardiovascular fitness, QOL, cognitive performance and depression indices, and that this exercise intervention was proven to be a feasible, safe exercise protocol for RRMS patients.

MS diminishes QOL, and while reduced QOL is partly due to physical disability, it is also impacted by depression and cognitive dysfunction [29]. Furthermore, compared to other neurological conditions, MS patients exhibit a higher prevalence of mood disorders, with patients exhibiting high rates of anxiety and depression [30]. Data presented herein support this; however, our findings indicate that 8 weeks of moderate aerobic exercise was sufficient to improve the QOL in MS patients, both in terms of physical and mental health summary scores, while also reducing depressive symptomatology. This is significant as psychological therapies are emerging as key intervention strategies in MS, with evidence indicating that meditation [31], mindfulness-based interventions [32] and Tai Chi [33] are linked with improved mental and physical health in MS patients. This is also important as the management of stress in MS patients has been shown to reduce the number of gadolinium-enhancing brain lesions on MRI and furthermore reduce the number of new or enlarging brain lesions [34]. Furthermore, some data indicate that cumulative stressful life events increase the risk of relapse in individuals with RRMS [35], indicating that specific stressors may influence MS exacerbations. Data presented herein provides evidence that short-term cycle ergometer training is an effective strategy to manage psychological distress (as indicated using QIDS-SR16) and improve physical health in individuals with MS.

For many years, the impact of cognitive decline among MS patients was underestimated, but it is now considered that cognitive impairments affect 40–65% of MS patients, including deficits in sustained attention, information processing speed and visuospatial functions [36]. These neuropsychological abnormalities can occur early and late in the disease and are associated with negative consequences on disability and QOL for patients, as well as their caregivers [37]. Our findings are consistent with this, indicating that MS patients exhibit disturbances related to executive function/cognitive flexibility and sustained attention, when compared to age-matched healthy volunteers. Our data also demonstrate that at discharge from the current exercise programme, the CANTAB battery indicated that exercise improved attention, executive function/cognitive flexibility and visuospatial memory in patients, indicating that a short-term cycling programme can improve cognitive performance in this MS patient cohort. MS is a chronic inflammatory, demyelinating and degenerative disorder of the CNS and is associated with prominent atrophy and brain volume reduction [38, 39], and furthermore, impairments in memory have been linked with brain atrophy in MS [40]. Given that exercise can increase brain volume, particularly in the hippocampus [28], it will be of interest to determine if our exercise programme is associated with alterations in grey and white mater volume and integrity in RRMS patients.

Exercise among MS patients improves mobility [11], QOL and walking ability [12]; however, a body of literature suggests that the therapeutic efficacy of exercise depends on exercise intensity. In addition, there is no effective therapy currently approved to target cognitive disturbances in individuals with MS. Findings herein identify a routine short-term cycle ergometer training intervention as an important strategy to potentially combat multiple symptoms, including cognitive dysfunction, in individuals with RRMS. This study is limited in terms of its sample size, and a follow-up large-scale study will facilitate multivariate analysis to delineate the impact of exercise on specific readouts. Overall, this pilot study has identified an exercise programme worthy of further long-term investigation across various MS population cohorts.