Deficits in tongue motor control are linked to microstructural brain damage in multiple sclerosis: a pilot study

Articulatory dysfunction and swallowing disorders are common in multiple sclerosis (MS) and affect up to 60 % of patients [1‐3]. The tongue is critically involved in both articulatory function and swallowing. Consequently, it has been suggested that tongue motor function might serve as a surrogate for dysarthria and dysphagia [4, 5]. Indeed, MS patients display reduced tongue muscle strength, premature fatigue, and slowing during repetitive movements even before clinical dysarthria emerges [6]. However, it is not known how these deficits are linked to overall disease burden and the neuropathological substrate of the disease.

Diffusion tensor imaging (DTI) has evolved as a reliable method to quantify the severity of brain tissue damage in MS. Specifically, reductions of the fractional anisotropy (FA) in the cerebral white matter have consistently been reported in MS patients [7]. In this vein, we have found previously that decreased FA in the cerebral white matter adjacent to sensory and visual cortices was linked to increased grip force variability in patients with MS [8].

Here, we utilized a force transducer based experimental setup to objectively quantify deficits in the fine motor control of the tongue in a cohort of MS patients and explored whether these deficits were associated with overall clinical disability and brain microstructural integrity.

We found an increased variability of force output and concurrent reductions of the applied mean force during an isometric tongue protrusion task in MS patients. These findings are in line with previous studies reporting reductions of the voluntary force output and increased force variability in MS patients in a variety of motor tasks [8 ,13, 14]. We have found earlier that the variability of force output showed higher sensitivity than the mean applied force in assessing alterations of motor hand function in MS and other neurological conditions, particularly when deterioration of motor performance was still mild [8, 15, 16]. Along these lines, it is noteworthy that TFV but not TF was associated with overall disability and also exhibited stronger correlations with FA measures. These findings further support the hypothesis of force variability being superior over mean applied force to quantify motor dysfunction and its association to microstructural brain damage in MS [8].

FA measures the degree to which overall diffusion of water molecules can be described as anisotropic. FA ranges from 0–1, where 0 indicates completely isotropic diffusion with no contribution of anisotropic diffusion. FA typically is high (i.e. diffusion is predominantly anisotropic) in brain regions rich in myelinated fibers such as the pyramidal tract or corpus callosum and relatively low (i.e. diffusion is predominantly isotropic) in gray matter areas [17]. While other DTI metrics (e.g. axial and radial diffusivity) have been reported in addition to FA, the latter might be the DTI measure best established and most widely utilized to assess white matter integrity and its association with clinical disability in MS (see e.g.[17, 18] for review). We deliberately chose to measure FA for correlational analyses with behavioral data based on our prior findings. In the latter study, we explored the association of altered hand motor function with cerebral white matter integrity. We found that only FA in the white matter adjacent to the primary sensory and visual cortices, but not other DTI measures, i.e. mean diffusivity, axial diffusivity and radial diffusivity, correlated with quantitative measures of hand motor function, suggesting that FA might be most sensitive to assess white matter damage associated with motor dysfunction.

Supporting these findings, TFV was inversely correlated with FA in the posterior limb of the internal capsule expanding to the brain stem, whereas TF showed a positive correlation with FA in this region. Thus, decreased microstructural white matter integrity was indicative of abnormally high tongue force variability and reduced total force output in the MS patients. The posterior portion of the internal capsule mainly incorporates cortico fugal motor fibers comprising the pyramidal and corticobulbar tracts, and somatosensory fibers. The motor fibers have a somatotopic organization with the tongue being located in the anterior part of the posterior limb [19, 20]. Hence, structural damage of this structure, particularly its anterior portion, is likely to affect tongue function by disrupting motor output from the motor cortex to the tongue [21].

Dysphagia and dysarthria are common in MS. A recent meta-analysis conducted by Guan et al. showed that at least one third of MS patients suffer from dysphagia [22]. Similar estimates have been suggested for dysarthria in MS patients [1]. Dysphagia can emerge in very early disease stages in ambulatory patients, and constitutes a major hazard in severely affected patients. Several studies established a close relationship between overall clinical disability and the presence of dysphagia, suggesting that dysphagia is most pronounced in clinically severely affected patients with an EDSS of 6.5 or higher [2, 3]. Whereas dysphagia is associated with overall clinical disability, it seems that the MS subtype is not a strong predictor of dysphagia [23]. However, reports are equivocal and some authors suggest that patients with progressive MS forms (SPSS and PPMS) are more likely to develop dysphagia compared to patients with RRMS [24]. Similarly, the severity of dysarthria has been found to correlate well with overall disease burden [25], even though subtle signs of dysarthria have been revealed in MS patients without manifest speech disorder [1]. In line with these findings, we found that MS patients with high EDSS scores exhibited pronounced variability of tongue force output.

We acknowledge several limitations of this study. Because of the limited sample size we could not explore potential differences in FA and its correlation with tongue function for the MS subtypes in the current set of data. Moreover, the correlations observed do not necessarily imply a causal relationship of structure and function and the specificity of the findings reported remains unclear because healthy controls did not undergo MRI. That said, the strong and symmetric correlations of TFV with FA in a region crucial to tongue motor function are intriguing and indicate a link of increased TFV to the neuropathological substrate of the disease. Previous reports suggest that both dysarthria and dysphagia are associated with overall disease burden rather than alterations of single functional systems or subtype of MS [22, 26]. That being said, for future studies, it might be worthwhile to additionally apply clinical rating scales specifically assessing dysphagia and dysarthria. Finally, we note that FA is very sensitive to microstructural brain changes per se [11, 27], but is limited in characterizing the pathological processes underpinning these structural alterations. For example, FA changes in afferent pathways can be caused by both potentially reversible demyelination and irreversible axonal degeneration in patients with MS [28]. A multi-modal imaging approach including myelin sensitive MRI techniques might help to better understand the pathological processes underlying microstructural tissue damage [29, 30].

Our findings suggest that the quantitative motor (Q-Motor) measurement of tongue function might proof useful as a non-invasive and cost efficient method to assess motor dysfunction in MS in addition to categorical scales such as the EDSS. Avoidance of inter- and intra-rater variability and lack of site-effects due to the pre-calibration of sensors applied may increase sensitivity and reliability, e.g., in small proof-of-concept studies. In line with prior studies [8, 9] TFV was a more sensitive surrogate of motor dysfunction and more robustly linked to overall disease burden and microstructural brain integrity than TF. Prospective studies are warranted to prove the utility of TFV to assess longitudinal changes of motor phenotype and cerebral microstructure in patients with MS.