In our study, we assessed MM in mildly to moderately affected patients with relapsing-remitting MS (EDSS ≤ 3.5 (mean 1.5 ± 1.2)) and compared them with healthy controls.
Our results indicated that MS patients had more frequently and pronounced MM compared to healthy controls. The high interrater agreement, in line with Magne et al. (17), emphasized the usability of the Woods and Teuber scale for assessing MM.
The FSMC is a patient-reported outcome measure for measuring mental and physical fatigue in MS patients (15). In our study, there was a moderate correlation between all three FSMC scores and the EDSS. Patients with higher scores of MM on the Woods Teuber Scale (> 1) had significantly higher FSMC sum scores and motor scales, as well as numerically higher scores in the FSMC cognitive scale, compared to patients with lower scores. There was no significant difference in age, duration of the disease, or EDSS between the two groups, ruling out these parameters as confounding factors.
A possible explanation for the correlation of MM and motor fatigue in MS patients may be that both symptoms may origin in similar brain areas, involving neuronal dysfunction and reorganization. Several studies (14, 19, 20) have shown altered cerebral activation in MS-related fatigue, with increased activation required for performing motor tasks in MS patients with fatigue, including the cingulate gyri (21), that also showed overactivation in Parkinson patients with MM (3). Overactivation of the (posterior) cingulate cortex might be part of a network disruption in MS patients, possibly involving a compensatory inhibitory network to inhibit MM.
We selected mildly to moderately affected MS patients since previous examinations had shown that severely affected patients with paralytic, spastic, or atactic debilitations either would not be able to perform the investigation for MM, or the MM would be masked due to the patients’ existing debilitations. Furthermore, TMS studies were not possible in more severely affected patients due to our TMS protocol, which requires maximum voluntary contraction of the APB.
Our study focused on MM as a clinical sign and reliably detected and quantified MM in MS patients and controls through bedside testing. Although some studies in the literature have investigated the invisible mirror activity through electromyography (EMG), testing MM through bedside testing provided sufficient information for our study.
We did not study the correlation between MM and the age of patients or the duration of the disease, since age and disease duration (mean age 31.8 ± 12.7 years, mean disease duration 4.4 ± 6.4 years) were quite homogenously distributed. In patients with longer disease duration or elderly patients, bedside testing of MM may be constrained due to disability (e.g. spasticity) or age-related limitations interfering with MM testing. Whether results may be different in older patients and those with a longer disease duration may be subject to further studies.
About 70% of healthy controls in our study exhibited mild MM (MM = 1). MM in healthy individuals are also described in the literature, and only the involuntary synkinetic MM of the opposite limb should be considered pathologic (1). Our study did not identify any MM > 1 in the control group, consistent with the literature. Mayston et al. (2) however, were unable to detect subtle MM (MM = 1) in adults using EMG, despite employing the same test as in our study. In our study, participants performed the testing with their eyes closed, as we had observed increased occurrences of subtle MM prior to the study in the absence of visual control. Mayston et al. (2) did not document whether the testing was conducted with eyes open or closed in their study, so their results cannot be compared easily to ours.
In our TMS studies, we investigated the silent period according to Hübers et al. (9). Our results were in line with the normal values documented in their study. There was no significant difference in the latency and duration of the silent period between patients and controls in our study and no correlation was found between MM and the latency and the duration of the silent period in MS patients. Tataroglu et al. (10) found a prolongation of the silent period duration in 78% of their patients with definite MS who were more severely affected (mean EDSS 2.8 vs. 1.5 in our study) and investigated the silent period in the legs but did not analyze it separately in the arms. Some patients with higher EDSS scores and the presence of paralysis/spasticity may not be able to undergo silent period investigation through maximal voluntary contraction according to our protocol. Therefore, we decided to study upper extremity movements, often less affected especially in patients with spinal lesions.
One aim of our study was to investigate the morphology of the corpus callosum in MS patients with MM, as it is the most important commissural structure. We examined the CCA and CCI in patients and controls to determine possible corpus callosum atrophy. Consistent with a study by Granberg et al. (11), we found significant reductions in CCA in MS patients, and a non-significant reduction in CCI. It should be noted that patients in the Granberg study were more severely affected and had a longer disease duration than those in our study.
We did not observe any differences in CCI or CCA between the groups with MM 0/1 and MM > 1 using MRI and we found no correlation between MM and CCI and CCA.
A possible explanation for the increased MM in MS patients may be altered functional pathways in the corpus callosum due to strategically located demyelinating plaques, resulting in interhemispheric inhibition dysfunction even before any morphological changes in commissural fibers are established. Cabib et al. (7) investigated mirror activity in MS patients using EMG and found enhanced EMG activity in contralateral homologous muscles, as well as significant diffusivity changes in the corpus callosum via diffusion tensor imaging in MRI studies, not measured in our routine MRI. Similarly, in ALS patients with MM, Wittstock et al. (22) did not find diffusion changes in the corpus callosum despite prolongation of latency or loss of the silent period in MEP studies, suggesting that disruptions in transcallosal pathways, as measured through TMS, may precede microstructural alterations in the corpus callosum. In contrast, in our study we observed a co-occurrence of increased MM and morphological changes in the corpus callosum (reduced nCCA) in MS patients, which precedes functional changes measured by TMS, not different between patients and controls.
Other structures than the corpus callosum may contribute to the origin of MM in MS patients. Liu et al. (1) reported a deactivation of a non-mirroring inhibitory network in Parkinson patients (dorsolateral prefrontal cortex, presupplementary motor area) – areas that may also be affected by juxtacortical inflammatory lesions in MS patients. Functional magnetic resonance imaging (fMRI) studies in poststroke patients (23) have reported increased activity in the non-lesioned sensorimotor cortex, with MM in the non-paretic hand attributed to activity in the contralesioned sensorimotor area via the crossed corticospinal tract - a possible mechanism in patients with MM. We observed a non-significantly higher volume of juxtacortical and periventricular lesions in patients with MM > 1 compared to patients with MM 0/1. It would be of interest whether lesion volume in specific areas (e.g. the dorsolateral prefrontal cortex and the presupplementary motor area) may contribute to MM. However, no specific cortical areas causing MM have been identified so far.