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Impaired sleep-associated modulation of post-exercise corticomotor depression in multiple sclerosis
Journal of the Neurological Sciences (Available online 10 May 2015)
To compare the beneficial effect of nap versus rest on the recovery of motor evoked potentials (MEPs) after a fatiguing exercise performed in patients with multiple sclerosis (MS) and healthy controls.
In 12 MS patients and 12 healthy controls, MEPs were recorded from the adductor pollicis muscle before, 10 and 60 min (T0, T10, and T60) after an effort of thumb adduction at 25% of maximal voluntary contraction force for 24 min. After the effort, the subject was maintained at rest or invited to have a nap while monitored with polysomnography. The two sessions (nap and rest) were randomly performed in each subject during the same day. The impact of nap and rest on post-exercise changes in MEP amplitude were studied in each group (patients and controls) and then compared between the two groups.
Although MEP amplitude at baseline was lower in MS patients than in controls, post-exercise corticomotor depression (PECD), expressed as T10/T0 MEP amplitude ratio, was similar in both groups. Regarding MEP amplitude recovery at T60, nap was significantly more beneficial than rest in healthy subjects, but not in MS patients.
Motor recovery from PECD following a fatiguing exercise can be enhanced by sleep (at least a short nap) in healthy subjects. In MS patients, sleep restorative effect is reduced or lost, maybe contributing to the excessive fatigue or fatigability characterized in these patients.
- We found a post-exercise corticomotor depression in multiple sclerosis.
- We found a post-exercise corticomotor depression in healthy subjects.
- Beneficial effect of sleep on motor recovery from corticomotor depression in controls
- Impaired sleep-associated modulation of corticomotor depression in multiple sclerosis
Keywords: Fatigue, Motor evoked potentials, Multiple sclerosis, Sleep, Exercise, Polysomnography.
A severe fatigue syndrome affects the quality of life of 53 to 92% of patients with multiple sclerosis (MS)  . The pathophysiology of fatigue in MS is multidimensional and not well understood. Among other factors, physical fatigue could be a major component of fatigue in MS  . Physical fatigue is the feeling that the effort required to accomplish a task is disproportionally high  . It appears as a reduction in the ability to exert muscle force, regardless of whether or not the task can be really sustained  . Although post-exercise fatigue has peripheral neuromuscular origins  , there is increasing evidence that a central component is involved in MS patients  . Central fatigue represents the failure of the nervous system to drive the muscle to its maximal exertion  . Positron emission tomography studies demonstrated the existence of metabolic disorders involving the white matter and different structures in MS patients with fatigue compared to those in MS patients without fatigue  and .
Most studies on fatigue in MS used subjective self-report questionnaires  and . However, it is possible to objectively appraise post-exercise fatigue associated with changes in motor cortex excitability, by recording the motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation (TMS). In healthy subjects, several studies showed a major reduction of MEP amplitude for a period of several minutes following an exercise , , , and . This post-exercise corticomotor depression (PECD) and the following recovery period have been assessed in several studies performed in MS patients , , and . Patients with MS showed a reduction of voluntary contraction strength and central activation drive during exercise, together with a more marked PECD  and .
Patients with MS are also known to have poor sleep quality and various sleep disturbances, such as insomnia, excessive daytime sleepiness, periodic leg movements, restless legs syndrome, abnormal sleep–wake regulation, sleep disordered breathing, narcolepsy and rapid eye movement sleep behavioral disorder  . Sleep disorders may likely contribute to the fatigue presented by these patients  and . In this study, we examined whether an alteration of the restorative function of sleep could be involved in the particularly marked post-exercise fatigability characterizing these patients.
2.1. Patients and controls
From January 2012 to June 2013, we consecutively enrolled 30 patients who complained of fatigue from the cohort of MS patients followed in the Department of Neurology of Henri Mondor Hospital (Créteil, France). Inclusion criteria were: (i) definite diagnosis of MS according to the 2010 revised Mc Donald criteria  ; (ii) age between 18 and 70 years; (iii) Expanded Disability Status Scale (EDSS)  score between 0 and 6; (iv) Fatigue Severity Scale (FSS)  score superior to 1; (v) absence of relapses for the last three months; and (vi) no therapeutic change during the last month. Exclusion criteria were: (i) EDSS higher than 6; (ii) clinical sleep apnea syndrome (apnea–hypopnea index (AHI)  ≥ 10/h of sleep); (iii) severe restless legs syndrome (International Restless Legs Syndrome Rating Scale (IRLS-RS)  score > 20); and (iv) benzodiazepine or antidepressant drug intake, including selective serotonin reuptake inhibitors. A polysomnography (PSG) was performed in all patients to identify sleep disorders.
Fifteen volunteers were recruited as healthy controls. Inclusion criteria were: (i) age between 18 and 70 years and (ii) absence of sleep complaint. Exclusion criteria were: (i) travel over more than four lag time 3 months before the procedure; (ii) night shift work; (iii) suspected sleep apnea syndrome; and (iv) benzodiazepine or antidepressant drug intake. The study received local IRB approval and all subjects gave written and informed consent.
2.2. Study design
Three sessions of MEP recordings before and after exercise were performed during the same day. The first session started at 9 am by measuring resting motor threshold (RMT) and MEP amplitude on the non-dominant hand (see below) at baseline (T0). Then, maximal voluntary contraction force (MVC) of thumb adduction was measured with a dynamometer, while the hand was maintained flat on a horizontal plane. The average MVC value was calculated from three trials. Then, exercise was performed by maintaining thumb adduction constant for 6 min at 25% of MVC against the dynamometer, under visual feedback and encouragement by the examiner. Four 6-min efforts were realized, separated by 1 min of rest between each. In preliminary experiments performed on healthy volunteers, this set of 4 efforts was able to produce PECD as revealed by MEP size reduction, which was maximal at 10 min after the exercise and lasted for more than 1 h. Therefore, MEP recordings were performed 10 and 60 min after exercise (T10, T60).
One objective of the study was to determine the respective influence of nap and rest on the recovery from PECD. To this end, we performed a second session of MEP recordings before and after exercise in the afternoon, at 2 pm, and we managed a 50-min period of nap or rest between T10 and T60 in each condition. To avoid bias due to daytime, the order of nap and rest was randomized between the morning and afternoon sessions in the series of patients and controls.
2.3. MEP recording
MEPs were recorded on the adductor pollicis (AP) muscle of the non-dominant hand, with one self-adhesive surface electrode placed at the internal palmar aspect of the thenar compartment and the reference at the proximal phalanx of the thumb. Single-pulse TMS was performed using a C-100 circular coil connected to a MagPro R30 magnetic stimulator (MagVenture, Farum, Denmark; distr. Mag2Health, France). The coil was placed at the vertex, tangentially to the skull, with the A/B face chosen for preferentially stimulating the motor cortex contralateral to MEP recordings. A special attention was paid to keep the placement of the coil during and between each session constant, benefiting from the hole in the center of the coil to place it always at the same place, indicated by a mark on a cap covering subject's head. MEPs were recorded using a Dantec Keypoint electromyogram (EMG) machine (Natus France, Paris, France) with a bandpass filter of 10–2,000 Hz. For all recordings, patients and subjects were seated comfortably in an armchair with auditory feedback of EMG activity to ensure good muscle relaxation.
First, the RMT was determined, as the minimum stimulation intensity required for obtaining a response of at least 50 μV half the time  . Then, all experiments were performed at an intensity of 120% of RMT with the AP muscle fully relaxed. At each time point (T0, T10, and T60) in each condition (nap and rest), the average MEP amplitude was calculated from a series of 8 trials of cortical stimulation ( Fig. 1 ). The investigator who measured MEPs was blinded for the nap/rest condition (single-blind cross-over study). Finally, at T0 and T60, we recorded the maximal amplitude (Mmax) of the compound muscle action potential (CMAP) of the AP muscle to mixed median + ulnar nerve stimulation at the wrist (to take into account dual innervation of this thenar region by both the median and ulnar nerves).
2.4. Rest and nap
The 50-min period of nap or rest was performed under PSG recordings. In the rest condition, the subjects were allowed to sit and read or relax, but not to fall asleep. If any feature of sleepiness or micro-sleep was found in PSG, i.e. at least one epoch of stage 1 sleep, the session was excluded from the analysis. In the nap condition, the subjects were asked to fall asleep within 20 min, to obtain total sleep duration of at least 30 min. If the subject was not able to fall asleep within 20 min, the experiment was interrupted and the session was excluded from the analysis. In all cases, the rest or nap period was stopped after 50 min, possibly waking up the sleeping subjects.
PSG recordings included eight-channel electroencephalographic (EEG) montage, electro-oculogram (EOG), electrocardiogram (ECG), and submental and tibial EMGs, using surface electrodes and standard techniques. The sleep patterns were analyzed according to Rechstchaffen and Kales criteria revised by the American Academy of Sleep Medicine (AASM)  . Sleep stages and latencies were visually scored by a trained investigator.
Finally, all participants were asked to fill out the Epworth Sleepiness Scale (ESS)  to identify excessive diurnal sleepiness in eight situations. Quality of sleep was evaluated by administering the Pittsburgh Sleep Quality Index (PSQI)  . Fatigue was evaluated by the FSS  . Perceived exhaustion after exercise was evaluated by the Perceived Exhaustion Scale (PES) (Borg's scale)  .
2.5. Statistical analyses
Since not all data passed the normality test, as assessed by the Kolmogorov–Smirnov test, nonparametric tests were used. First, baseline demographic data between MS patients and controls were compared using the Mann–Whitney test for quantitative variables (age, force, ESS, FSS, PSQI, and PES scores) and the Fisher test for qualitative variable (gender). Second, regarding the nap, sleep latency and duration were compared between MS patients and controls, also using the Mann–Whitney test.
Regarding MEP recordings, post-exercise MEP amplitudes at T10 and T60 were normalized to baseline MEP values (T0) to provide a T10/T0 MEP amplitude ratio to appraise the effect of exercise and a T60/T0 ratio to appraise the influence of nap or rest. For the MEP variables, (T0, T10/T0, and T60/T0), all comparisons between patients and controls were performed using the Mann–Whitney test, as well as for the T60/T0 CMAP amplitude ratio. In each group (patients or controls), the comparisons between two time points (T0 versus T10 or T60) or regarding MEP variables (T0, T10, T60, T10/T0, and T60/T0) between the rest and the nap conditions, were performed using the Wilcoxon matched pairs test.
Finally, the correlation between T60/T0 MEP amplitude ratio and sleep latency and duration in the nap condition was analyzed using the Spearman rank-correlation test. Values were expressed as mean ± sem (standard error of the mean). In all cases, the level of statistical significance was set at p < 0.05. This alpha level was preserved, since the significance of the comparisons between groups was not affected by multiple comparisons adjustments according to the Benjamini–Hochberg procedure with usual false discovery rate of 0.25.
3.1. Patients and controls
From the 30 enrolled MS patients with fatigue, only 12 patients (aged from 27 to 69 years) completed the study. Five patients did not present PECD (MEP size decrease) at T10. Five patients presented excessive daytime sleepiness, defined as at least one epoch of stage 1 sleep in the rest condition. Finally, 8 patients were not able to fall asleep within 20 min in the nap condition. These 18 patients were totally excluded from any analysis. The clinical data of the 12 analyzed patients are presented in Table 1 (#1 to #12).
From the 15 enrolled healthy subjects, only 12 subjects (aged from 22 to 58 years) completed the study. Three subjects did not present PECD (MEP size decrease) at T10. These 3 subjects were totally excluded from any analysis. Conversely, the rest and nap conditions were accurate in all subjects. The comparisons between patients and controls regarding demographic data at baseline are presented in Table 2 .
|Controls (n = 12)||MS patients (n = 12)||p value|
|Age||37 ± 3||44 ± 3||0.08|
|Sex ratio (F/M)||6/6||9/3||0.6|
|Force during exercise (25% of MVC) (N)||25 ± 10||28 ± 17||0.2|
|NREM sleep 1 duration (min)||7 ± 1||4 ± 1||0.04|
|NREM sleep 2 duration (min)||18 ± 2||19 ± 3||0.7|
|NREM sleep 3 duration (min)||3 ± 2||3 ± 1||0.7|
|ESS||4.6 ± 0.7||6.6 ± 0.8||0.08|
|FSS||2.1 ± 0.3||4.6 ± 0.4||0.0003 ⁎|
|PSQI||3.3 ± 0.5||7.8 ± 0.8||0.0004 ⁎|
|PES (Session 1)||11.6 ± 0.5||11.6 ± 0.8||0.7|
|PES (Session 2)||11.1 ± 0.4||12.3 ± 0.7||0.4|
⁎ p value of Mann–Whitney test < 0.05.
Briefly, MS patients had higher scores on the FSS and PSQI, indicating a greater fatigue and a poorer quality of sleep compared to controls ( Table 2 ).
3.2. Sleep quantity during naps
In patients, 5 had a nap in the morning and 7 in the afternoon. In controls, 6 had a nap in the morning and 6 in the afternoon. The mean sleep latency was not significantly different between MS patients and controls (12 min ± 2 vs. 9 min ± 1, p > 0.05). The mean nap duration was also similar in MS patients and controls. Naps were composed of NREM sleep only. There was no significant difference for sleep duration and sleep latency between morning and afternoon naps in MS patients (27 min ± 4 vs. 28 min ± 4 and 12 min ± 2 vs. 12 min ± 2, p > 0.05) and in controls (27 min ± 2 vs. 23 min ± 2 and 11 min ± 1 vs. 8 min ± 1, p > 0.05).
3.3. MEP recordings
The mean MEP amplitudes in patients and controls at T0 and the ratios T10/T0 and T60/T0 are presented in Table 3 . First, baseline MEP values at T0 did not differ significantly between the rest and the nap conditions, both in MS patients (690 μV ± 101 vs. 748 μV ± 125, p > 0.05) and in controls (1251 μV ± 251 vs. 1109 μV ± 272, p > 0.05). However, mean MEP amplitude was significantly lower at baseline (T0) in MS patients compared to controls ( Table 3 ).
|Controls (n = 12)||MS patients (n = 12)||p value|
|Baseline MEP amplitude (T0) in rest condition (μV)||1251 ± 251||690 ± 101||0.03 ⁎|
|Baseline MEP amplitude (T0) in nap condition (μV)||1109 ± 272||748 ± 125||0.2|
|Baseline MEP amplitude (T0) in both conditions (μV)||1180 ± 251||719 ± 102||0.02 ⁎|
|Post-exercise MEP amplitude (T10) in rest condition (μV)||512 ± 176||335 ± 59||0.7|
|Post-exercise MEP amplitude (T10) in nap condition (μV)||425 ± 81||411 ± 97||0.5|
|Post-exercise MEP amplitude (T10) in both conditions (μV)||469 ± 176||373 ± 59||0.3|
|Post-rest MEP amplitude (T60) in rest condition (μV)||785 ± 99||635 ± 93||0.3|
|Post-nap MEP amplitude (T60) in nap condition (μV)||1170 ± 142||544 ± 111||0.003 ⁎|
|Post-rest/nap MEP amplitude (T60) in both conditions (μV)||977 ± 99||589 ± 93||0.01 ⁎|
|T10/T0 MEP amplitude ratio in rest condition||0.4 ± 0.05||0.5 ± 0.05||0.06|
|T10/T0 MEP amplitude ratio in nap condition||0.5 ± 0.07||0.5 ± 0.08||0.5|
|T60/T0 MEP amplitude ratio in rest condition||0.8 ± 0.1||0.9 ± 0.1||0.2|
|T60/T0 MEP amplitude ratio in nap condition||1.4 ± 0.2||0.7 ± 0.1||0.008 ⁎|
|T60/T0 CMAP amplitude ratio in rest condition||0.8 ± 1.6||0.8 ± 0.9||0.2|
|T60/T0 CMAP amplitude ratio in nap condition||0.9 ± 0.1||0.8 ± 0.9||0.8|
⁎ p value of Mann–Whitney test < 0.05.
Second, MEP amplitude decreased from T0 to T10 both in MS patients (from 719 μV ± 102 to 373 μV ± 59, p < 0.05) and in controls (from 1180 μV ± 251 to 469 μV ± 176, p < 0.05). This decrease was similar in patients and controls, as expressed by the T10/T0 MEP amplitude ratio ( Table 3 ). In addition the decrease in MEP amplitude at T10 (T10/T0) did not differ significantly between the rest and the nap conditions, both in MS patients (0.5 ± 0.05 vs. 0.5 ± 0.08, p > 0.05) and in controls (0.4 ± 0.05 vs. 0.5 ± 0.07, p > 0.05).
Regarding the effect of nap and rest, mean MEP amplitude at T60 was significantly higher after nap session compared to rest session in controls (1170 μV ± 142 vs. 785 μV ± 99, p < 0.05), whereas it did not differ significantly between the rest and the nap conditions in MS patients (635 μV ± 93 vs. 544 μV ± 111, p > 0.05). Mean MEP amplitude at T60 was significantly higher after nap session in controls compared to MS patients but similar after rest between patients and controls ( Table 3 ). This was confirmed by the changes in the T60/T0 MEP amplitude ratio. There was a similar recovery in MS patients after nap and rest (0.7 ± 0.1 vs. 0.9 ± 0.1, p > 0.05), whereas MEP recovery was significantly higher after nap than after rest in controls (1.4 ± 0.2 vs. 0.8 ± 0.1, p < 0.05). So, the T60/T0 MEP amplitude ratio was similar between patients and controls after rest, but lower in MS patients than in controls after nap ( Table 3 ). This is illustrated by Fig. 2 .
Regarding Mmax, the T60/T0 CMAP amplitude ratio did not differ between the nap and the rest conditions, both in MS patients and in controls, with no significant difference between MS patients and controls ( Table 3 ).
Finally, there was no correlation between T60/T0 MEP amplitude ratio and sleep latency or duration in the nap condition, either in MS patients or in controls (Spearman test, p > 0.05).
The main result of this study was that the beneficial influence of sleep (during a nap) on PECD was reduced in MS patients compared to healthy subjects. This result supports an alteration of sleep restorative function in MS patients, at least in those complaining of fatigue.
First, we were able to produce PECD in most MS patients and controls, but not all (MEP size did not decrease after exercise in 5/30 MS patients and 3/15 controls). Using a similar approach, various studies have explored the depression of motor cortex excitability in healthy humans, expressed as a transient but profound reduction of MEP amplitude following a fatiguing exercise , , , and . A short but maximal contraction of a hand muscle produces an important PECD starting a few minutes after the end of the effort and lasting for less than 30 min  . However, the amount and duration of MEP size depression depend on the strength and duration of the effort  and . Reducing contraction intensity, e.g., at 20–30% of MVC, but prolonging the effort produces a smaller MEP size decrease but of longer duration. For example, Humphry et al.  showed a reduction of MEP amplitude lasting for at least 50 min after an exercise performed at 20% of MVC for 19 min. A quite similar finding was observed in our study.
In the present study, MEP amplitude was significantly lower at baseline in MS patients compared to controls, but PECD, expressed as the T10/T0 MEP amplitude ratio, was similar in patients and controls. In contrast to previous studies  , we have not been able to demonstrate that PECD, when present, was more marked in MS patients. In fact, patients mostly differed from controls regarding the beneficial impact of sleep on the recovery from PECD.
In our healthy subjects, a short nap after a fatiguing exercise significantly enhances the rate of motor recovery compared to a simple rest. To our knowledge, this is the first study showing evidence of the restorative function of sleep on PECD in healthy subjects. In previous studies, a night's sleep was found to enhance motor corticospinal facilitation induced by 20-Hz repetitive TMS  and performance in motor task  . However, sleep-dependent motor skill improvement may also exist after a short nap  .
Conversely, in MS patients, we did not find that nap was more beneficial than rest on the recovery from PECD. Some MS patients complain of a marked fatigue shortly after awakening and therefore, they found sleep unrefreshing  and . The present results suggest a lack of restorative function of sleep in the context of MS associated with fatigue. Based on various methods of assessment, other studies showed a correlation between poor sleep quality and fatigue in MS patients , , and . Thus, sleep fragmentation could partially explain fatigue in MS, but the disruption of sleep microstructure can result from various causes. In our study, patients with obstructive sleep apnea or severe restless legs syndrome were excluded. We also avoided the effect of the circadian rhythm by randomizing nap and rest between the morning and the afternoon.
However, our study may have bias. First, nap and rest conditions were performed on the same day at 4–5 h interval. Although baseline MEP values at T0 did not differ significantly between the rest and the nap conditions, both in MS patients and in controls, we cannot rule out that motor cortex excitability changes, not revealed by MEP amplitude, may have outlast the first session and produce carry-over effects on the second session. Actually, prolonged modifications of cortical excitability have been previously described following a hand motor task , , , and . A second comment is that MEP size depression was assessed in a fully relaxed muscle and some aspects of central fatigue related to the voluntary motor cortical drive are not reflected by this method  . A third comment refers to the involvement of spinal or peripheral neuromuscular components in post-exercise fatigue. For example, one study suggested that post-exercise fatigue involved a depression of the synaptic transmission between the upper and lower motoneurons at spinal level  . Conversely, Brasil-Neto et al. found in healthy subjects that post-exercise MEP size reduction occurred without any significant change in H-reflex or CMAP amplitude  , suggesting a purely central phenomenon related to a reduced motor cortical output drive, maybe due to an altered excitability of pyramidal cells  . Similar results have been reported by others, in healthy subjects  and  and MS patients  . In the present study, exercise did not impact on Mmax, confirming that the PECD phenomenon was preferentially of central origin, although a combination of neuromuscular and spinal influences could also contribute to this phenomenon  .
In conclusion, our results show that sleep may be beneficial on motor recovery following a fatiguing exercise. This beneficial impact of sleep is significantly reduced in MS patients. This result could be considered as a feature of a poorer quality of sleep in MS, which may be less restorative and potentially involved in the presence of undue fatigue and fatigability, very frequently observed in this disease.
Conflict of interest
There is no conflict of interest.
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a Université Paris Est Créteil, Faculté de Médecine, EA 4391, Créteil F-94010, France
b AP-HP, Groupe Henri Mondor, Service de Physiologie, Explorations Fonctionnelles, Créteil F-94010, France
c AP-HP, Groupe Henri Mondor, Service de Neurologie, Créteil F-94010, France
⁎ Corresponding author at: Service de Physiologie Explorations Fonctionnelles, AP-HP, Groupe Hospitalier Henri Mondor, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil, F-94010, France. Tel.: + 33 149 814 670; fax: + 33 149 814 660.
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