Introduction

Dystrophic myotonias (DMs) are multi-system hereditary diseases with an estimated prevalence of 3–15 per 100000 [1,2], characterized by myotonic symptoms, muscle weakness and atrophy, extra-muscular involvement, cognitive impairment, and dysmorphisms. There are two main DMs forms: Myotonic dystrophy type 1 (DM1), which is the most common adult form of muscular dystrophy (due to a CTG-repeat expansion of at least 50 repeats in the non-coding 3' UTR of the myotonic dystrophy protein kinase(DMPK)-gene) [3], and Myotonic dystrophy type 2 (DM2), which is an autosomal dominant disorder caused by mutations in the zinc finger protein 9(ZNF9)-gene [4]. Within the multisystem involvement, DM1 implies central nervous system abnormalities. In fact, on brain magnetic resonance imaging (MRI), DM1 patients show hyperintense lesions involving the periventricular and deep white matter on T2-weighted sequences, dilated Virchow-Robin spaces [5], and an asymmetric and patchy subcortical white matter involvement [6–8].

Given that DM1 is a multi-system disorder, it requires a multi-disciplinary approach, including effective rehabilitation programs that can help to maintain patient’s quality of life, as well as maximize patient’s physical and psychosocial functions. An effective rehabilitation program can also minimize secondary medical comorbidity, prevent or limit physical deformity, and allow the patient to integrate into society. The study of central nervous system neuroplasticity has significantly contributed to the development of patient-tailored rehabilitative programs for motor function recovery in different neurological conditions [9]. In fact, it is possible to harness the residual plasticity of the brain to maximize functional recovery through, e.g., physical therapy and neuromodulation approaches [9,10]. Therefore, the knowledge of cortical plasticity in DM1 patients could be helpful to personalize the rehabilitative program to the single patient, harnessing the plasticity potential to foster motor recovery, also by implementing neuromodulation strategies [9,11]. Nonetheless, there are few neurophysiological data on the central nervous system available in defined myopathies, including DM1. It has been reported that functional involvement of corticospinal pathway [12,13], subclinical signs of cortical disinhibition [14], disinhibition in the somatosensory cortex [15], elevated central motor thresholds [16], and a deficit of the voluntary movement mechanism [17] can be found in several types of myopathy.

Herein, we performed a transcranial magnetic stimulation (TMS) study aimed at investigating central conduction time, sensory-motor plasticity, and cortical excitability in patients with DM1, in an attempt to find plasticity abnormalities that could be helpful to define patient-tailored motor rehabilitative programs in patients with DM1.

Materials and methods

Subjects

Seven patients with a clinical, genetic, and electromyographic evidence of DM1, without clinical or laboratory evidence of other neurological disorders or diseases affecting the peripheral nervous system, without taking drugs modifying muscles and nerve excitability, and with no contraindications to TMS, were consecutively included in the study during the follow-up visits. They were recruited at IRCCS Centro Neurolesi “Bonino-Pulejo” of Messina (Italy) between November 2016 and February 2017. Clinical-demographic characteristics are reported in Table 1. Seven normal individuals were enrolled as a control group (two males, five females, mean age of 24±5 years). The study was reviewed and approved by the Ethics Committee of IRCCS Centro Neurolesi “Bonino-Pulejo” of Messina (Italy) before the study began. The study has been conducted according to the principles expressed in the Declaration of Helsinki. All subjects gave their written informed consent to study participation.

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Table 1. DM1 clinical-demographic characteristics.

https://doi.org/10.1371/journal.pone.0178470.t001

Results

All the recruited patients completed the experimental procedure, without reporting any adverse effects during or after the experiments.

Fig 1 Illustrates the baseline TMS findings on RMT, cortical and cervical MEP, and CSP. As compared to HC, cortical MEP latency was delayed in latency (p = 0.002), smaller in amplitude (p<0.001), and largely abnormal in morphology (polyphasic and desynchronized responses). There were no significant differences concerning cervical MEP latency, amplitude, and morphology, CSP and RMT (each p = 0.4). Consequently, CMCT was increased in DM1 patients (p<0.001).

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Fig 1. Cortical excitability and central motor conduction time.

RMT resting motor threshold; MEP motor evoked potential; CMCT central motor conduction time; CSP cortical silent period; HC healthy control; DM1 myotonic dystrophy type 1.

https://doi.org/10.1371/journal.pone.0178470.g001

Noteworthy, we found significant rPAS aftereffects (time×group×muscle F = 2.4, p = 0.01), which consisted of a MEP amplitude increase in both the muscles tested in DM1 patients (time×muscle F = 0.4, p = 0.8; time effect F = 84, p<0.001), up to T3 (each post-hoc t-test p<0.001) (Fig 2), whilst a preserved topographic specificity (i.e., MEP amplitude increase limited to the FDI muscle) was found in HC (F = 99, p<0.001) up to T3 (each post-hoc t-test p<0.001) (Fig 2). Further, we found that the increase of rPAS aftereffects in both the muscles tested at T2 (in which we had the most relevant amplitude increase) in DM1 individuals were both correlated with baseline MEP amplitude (APB r = 0.953, p = 0.001; FDI r = 0.894, p = 0.007), differently from HC individuals (both muscles p = 0.9) (Fig 3). No correlations were found between the electrophysiological parameters and the clinical-demographic characteristics. The dataset is provided in S1 Table.

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Fig 2. Repetitive paired associative stimulation aftereffects.

FDI first dorsal interosseous; APB abductor pollicis brevis; HC healthy control; DM1 myotonic dystrophy type 1; rPAS repetitive paired associative stimulation; * indicates a significant change of MEP amplitude from baseline (T0). Square bracket indicates the topographic specificity of rPAS aftereffects only in HC.

https://doi.org/10.1371/journal.pone.0178470.g002

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Fig 3. Scatterplots of the correlation between motor evoked potential at baseline and repetitive paired associative stimulation aftereffects at T2.

FDI first dorsal interosseous; APB abductor pollicis brevis; HC healthy control; DM1 myotonic dystrophy type 1.

https://doi.org/10.1371/journal.pone.0178470.g003

Discussion

The novelty of our data consists of the demonstration of wide abnormalities of sensorimotor plasticity in DM1 individuals, beyond corticospinal tract abnormalities (i.e., MEP amplitude reduction and CMCT increase). It has been proposed that MEP alterations may result from muscular atrophy [25], whereas the increase of CMCT may depend on a subtle lesion in the corticospinal tract, accounting for either a reduction in the number of descending volleys or a temporal dispersion of the descending volleys (that could determine a longer time to achieve the temporal summation necessary for the activation of spinal motorneurons) [12]. In addition, DM1 patients show reduced connectivity in large frontoparietal networks, frontal white matter alterations [6–8], and increased parietal-cerebellar connectivity, which have been interpreted as compensatory reorganization phenomena [26]. In keeping with these issues, the abnormally increased sensorimotor plasticity in DM1 we found may be interpreted as a compensatory phenomenon to maintain a sufficient corticospinal output [27]. In fact, the lack of topographic specificity and the increase of rPAS aftereffects were both correlated with baseline MEP amplitude, differently from HC individuals [24], and there were no abnormalities of RMT and CSP. About that, the mutation of DMPK-gene may involve primarily cell shape determination, the regulation of actin-myosin contractility, and the nuclear envelope stability rather than the modulation of the activity of voltage-gated ion channels [28]. These may altogether determine a more structurally involvement of brain cell functions, thus justifying corticospinal tract alterations rather than cell membrane dis-excitability.

Alternatively, rPAS abnormality may reflect a use-dependent plasticity [29–32], implying that myopathic patients perform greater efforts for various activities of daily living, thus explaining the easy fatigability of such individuals. Furthermore, muscular dystrophy may itself change sensory feedback from muscle spindles, which could modify sensorimotor plasticity [12,33]. Hence, rPAS abnormalities may also be considered as an additional epiphenomenon of a multisystem syndrome as the DM1 is.

It should be further investigated whether central nervous system alterations may yield to more severe DM1 symptoms. Indeed, we did not find any correlation between neurophysiological parameters and the degree of clinical impairment, as observed by other authors [34]. Hence, the severity of the electrophysiological changes does not correlate with the degree of muscular atrophy and weakness in DM1. Such data suggests that the central nervous system motor dysfunctions are independent of the primitive muscle damage and are part of the manifestations of the disease. However, these data need to be confirmed in larger sample size studies.

Thanks to the advances in technical supports, such as electrical wheelchairs, home ventilation, and canes, rehabilitation management of these patients went from maintaining walking abilities as long as possible (with physiotherapy, stretching, and braces) to improving upper limb function, taking into account that many technical and electronic supports require a certain ability of the upper limbs [9]. The knowledge and the possibility to shape cortical plasticity to improve upper limb motor function by using conventional and non-conventional (e.g. neurorobotics and non-invasive neuromodulation) protocols arose great interest in neurorehabilitation [9,35]. Therefore, our data could be used to design patient-tailored rehabilitation program and identify the patients who may benefit from neuromodulation approach, in an attempt to restore the abnormal cortical plasticity related to DM1 and improve neurorehabilitation outcomes. Moreover, the possibility to shape neuroplasticity in patients with DM1 may be of notable importance, given that a maladaptive plasticity can worsen the clinical phenotype and the motor recovery, and make the patient more disabled [36].

In conclusion, our findings suggest that patients with DM1 present an involvement of motor descending pathways and cortical sensory-motor plasticity that are independent from primitive muscle damage (i.e., they belong to the wide spectrum of the DM1 multisystem dysfunctions). Overall, such findings should be taken into account to manage these patients better and to establish a more individualized and functional therapeutic approach, as an abnormal plasticity may negatively affect the motor function rehabilitation outcome. Indeed, the knowledge of cortical plasticity in DM1 patients could be helpful to predict the motor outcome, to follow patient’s rehabilitation progress, and to harness the residual plasticity in order to foster motor recovery by implementing neuromodulation strategies.

Supporting information