**3. Discussion**

The studies reviewed here show that most TMS measurements vary considerably from study to study. The cause of this variability remains unclear, but the methodological problem of TMS and technical factors, including the relatively small sample size in most studies or the difficulty of many patients (especially children) to achieve complete muscle relaxation, can explain this variability. Several TMS studies have provided electrophysiological evidence for abnormal motor cortical excitability and/or plasticity in patients with different myopathies. Applications of TMS to characterize musculoskeletal pathophysiology in patients with myopathies appear to be safe and can be developed in valuable biomarkers.

In a first study of patients with MD, TMS has been reported to have subclinical central motor conduction abnormalities suggesting that the integrity of the corticospinal tract is also affected. This deficiency was considered one of the multisystem manifestations of muscle disease, regardless of muscle pathology [12]. However, these preliminary results were not confirmed by successive studies in other myopathies.

The reviewed TMS studies showed that it is possible to detect changes in motor cortex excitability in myopathy patients. The most important finding is a significant reduction in SICI compared to healthy controls.

In adult patients with various types of myopathies, including FSHD and LGMD, the mechanisms of intracortical inhibition are reduced. This finding has been interpreted as a compensatory mechanism within the central nervous system that helps patients with myopathy to regain muscle power. SICI deficiency in FSHD may be explained by overexpression of the gene encoding the diazepam binding inhibitor (DBI), which is expected to attenuate the effects of GABA on GABAA receptors by acting on the benzodiazepine binding site [20]. Thus, DBI can determine a reduction in SICI, a phenomenon that depends largely on intracortical GABAA inhibitory mechanisms. It is interesting to note that a decrease in initial intracortical inhibition may prevent the subsequent use of this compensatory mechanism within the central nervous system in fatiguing muscle exercises as can be seen in healthy subjects [17]. Reduced baseline SICI in MD can be considered compensatory because of peripheral weakness, whereas in fibromyalgia syndrome, reduced SICI should rather be considered as an indicator of primary central disinhibition. Also in DM1 patients, TMS revealed abnormalities in cortical excitability, thus suggesting the occurrence of intracortical dysfunction [18]. These results are consistent with the autopsy and neuroimaging studies showing that dysfunction of the brain can be accompanied by structural changes. As a result, a disturbance of neuronal architecture was detected in the autopsy of the brain [21]. In addition, a three-dimensional magnetic resonance imagingcontrolled study demonstrated cerebral parenchymatrophy and hyperintensive lesions of the white matter [22], and PET scans showed a hypoperfusion in the prefrontal, temporal, and parieto-occipital lobes as well as in the basal ganglia, supporting the hypothesis of brain dysfunction in patients with DM1 [23].

In DM1 patients reduced intracortical facilitatory mechanisms (ICF) were found too [18]. Further, CNS excitability properties were markedly altered at the baseline and were not prone to be further impaired after a fatiguing exercise. Adjusting the cortical and neuromuscular features to the initial change may prevent increased fatigue after exercise performed with a maximum voluntary contraction percentage. The authors hypothesized that fatigue in MD patients may be mainly due to peripheral factors related to muscle pathology. Thus, MD patients were probably unable to reach the required force level of 50% of their maximal grip force for enough time to determine a reduction of corticospinal excitability, a marker of

**57**

*Electrophysiological Assessment of CNS Abnormalities in Muscular Dystrophy*

central fatigue [24]. This may explain the lack of reduced MEP amplitudes after

in patients with hereditary myopathies, whereas a single study on TMS in an acquired colchicine myopathies showed normal corticospinal excitability.

It is interesting to note that central compensatory mechanisms can be observed

Many patients with dystrophinopathies (DMD and BMD) also suffer from cognitive impairment, learning difficulties, and variable mental retardation in addition to progressive muscle weakness [1–3]. The role played by the absence or disruption of dystrophin within the central nervous system is unclear, and the pathogenic conditions leading to mental retardation in MD patients are still unknown. TMS investigation of cortical function in DMD patients did not delineate a clear picture of motor cortical abnormalities and led even to contradictory results. Yayla et al. did not report any motor cortical abnormalities [6], and Di Lazzaro et al. reported higher MT for magnetic than for electrical stimulation in four DMD patients [7]. As already discussed, methodological reasons, as well as the small sample size of the

During 5 Hz-rTMS in BMD patients, MEP facilitation as observed in healthy subjects was reduced in contrast to the above-reported study of Yayla et al. [6, 9]. 5 Hz-rTMS MEP facilitation reflects mechanisms of short-term plasticity within the motor cortex that probably differ from those involved in the paired-pulse TMS facilitation and are likely related to an enhancement in the activity of I-wave generating circuits [25]. Intracortical facilitation in paired-pulse TMS is a complex phenomenon reflecting the activity of still poorly defined cortical circuits indepen-

The results of the study of Golaszewski et al. indicate impaired cortical plasticity in glutamate-dependent excitation circuits in mentally retarded BMD patients consistent with the results of several experimental studies indicating abnormal glutamatergic transmission in muscle diseases caused by mutations within the dystrophin-encoding gene [9]. In particular, the product of the dystrophin gene, dystrophin-71, in glutamate receptor signaling and possibly clustering, appears to be involved [27]. Besides, dystrophin-deficient mdx mice are more resistant to kainic acid-induced seizures but not to GABA antagonist-induced seizures compared with control mice. In the mdx mice, the kainic acid receptor density in the brain was found to be significantly lower than in the control mice*,* although the density of muscarinic cholinergic receptors, another important neurotransmitter receptor for cognitive function, was normal. The disruption of the dystrophin complex may lead to an instability of kainate-type glutamate receptors on the synaptic membranes

It is important to note that the rTMS approach cannot be used to study cortical plasticity in children with DMD because the safety guidelines for the TMS application have been updated in the research and clinical environments [29]. The updated guidelines recommend that children should not be used as subjects for rTMS without compelling clinical reasons. Alternatively, the paired associative stimulation (PAS) technique can be applied in MD children that provide information about different aspects of cortical plasticity. So far, PAS has not yet been applied in myopathy patients and MD children [30]. No study has measured cortical responsiveness or

Integrated approaches using TMS in conjunction with high-density EEG may reveal altered cortical plasticity and functional connectivity across different neuronal networks, similar to several other neurological and psychiatric disorders.

TMS can also affect brain function during repeated administration. rTMS can modulate cortical excitability and induce long-lasting neuroplastic changes [31, 32]. rTMS has been used for therapeutic purposes in patients with many neurological

*DOI: http://dx.doi.org/10.5772/intechopen.86256*

latter study, may account for these discrepancies.

dent from those involved in I-wave generation [26].

with resulting inefficient neurotransmission in DMD patients [28].

plasticity outside the motor cortex.

fatiguing exercise in these patients.

#### *Electrophysiological Assessment of CNS Abnormalities in Muscular Dystrophy DOI: http://dx.doi.org/10.5772/intechopen.86256*

central fatigue [24]. This may explain the lack of reduced MEP amplitudes after fatiguing exercise in these patients.

It is interesting to note that central compensatory mechanisms can be observed in patients with hereditary myopathies, whereas a single study on TMS in an acquired colchicine myopathies showed normal corticospinal excitability.

Many patients with dystrophinopathies (DMD and BMD) also suffer from cognitive impairment, learning difficulties, and variable mental retardation in addition to progressive muscle weakness [1–3]. The role played by the absence or disruption of dystrophin within the central nervous system is unclear, and the pathogenic conditions leading to mental retardation in MD patients are still unknown. TMS investigation of cortical function in DMD patients did not delineate a clear picture of motor cortical abnormalities and led even to contradictory results. Yayla et al. did not report any motor cortical abnormalities [6], and Di Lazzaro et al. reported higher MT for magnetic than for electrical stimulation in four DMD patients [7]. As already discussed, methodological reasons, as well as the small sample size of the latter study, may account for these discrepancies.

During 5 Hz-rTMS in BMD patients, MEP facilitation as observed in healthy subjects was reduced in contrast to the above-reported study of Yayla et al. [6, 9]. 5 Hz-rTMS MEP facilitation reflects mechanisms of short-term plasticity within the motor cortex that probably differ from those involved in the paired-pulse TMS facilitation and are likely related to an enhancement in the activity of I-wave generating circuits [25]. Intracortical facilitation in paired-pulse TMS is a complex phenomenon reflecting the activity of still poorly defined cortical circuits independent from those involved in I-wave generation [26].

The results of the study of Golaszewski et al. indicate impaired cortical plasticity in glutamate-dependent excitation circuits in mentally retarded BMD patients consistent with the results of several experimental studies indicating abnormal glutamatergic transmission in muscle diseases caused by mutations within the dystrophin-encoding gene [9]. In particular, the product of the dystrophin gene, dystrophin-71, in glutamate receptor signaling and possibly clustering, appears to be involved [27]. Besides, dystrophin-deficient mdx mice are more resistant to kainic acid-induced seizures but not to GABA antagonist-induced seizures compared with control mice. In the mdx mice, the kainic acid receptor density in the brain was found to be significantly lower than in the control mice*,* although the density of muscarinic cholinergic receptors, another important neurotransmitter receptor for cognitive function, was normal. The disruption of the dystrophin complex may lead to an instability of kainate-type glutamate receptors on the synaptic membranes with resulting inefficient neurotransmission in DMD patients [28].

It is important to note that the rTMS approach cannot be used to study cortical plasticity in children with DMD because the safety guidelines for the TMS application have been updated in the research and clinical environments [29]. The updated guidelines recommend that children should not be used as subjects for rTMS without compelling clinical reasons. Alternatively, the paired associative stimulation (PAS) technique can be applied in MD children that provide information about different aspects of cortical plasticity. So far, PAS has not yet been applied in myopathy patients and MD children [30]. No study has measured cortical responsiveness or plasticity outside the motor cortex.

Integrated approaches using TMS in conjunction with high-density EEG may reveal altered cortical plasticity and functional connectivity across different neuronal networks, similar to several other neurological and psychiatric disorders.

TMS can also affect brain function during repeated administration. rTMS can modulate cortical excitability and induce long-lasting neuroplastic changes [31, 32]. rTMS has been used for therapeutic purposes in patients with many neurological

*Muscular Dystrophies*

**3. Discussion**

myopathies.

The studies reviewed here show that most TMS measurements vary considerably

In a first study of patients with MD, TMS has been reported to have subclinical central motor conduction abnormalities suggesting that the integrity of the corticospinal tract is also affected. This deficiency was considered one of the multisystem manifestations of muscle disease, regardless of muscle pathology [12]. However, these preliminary results were not confirmed by successive studies in other

The reviewed TMS studies showed that it is possible to detect changes in motor cortex excitability in myopathy patients. The most important finding is a significant

In DM1 patients reduced intracortical facilitatory mechanisms (ICF) were found too [18]. Further, CNS excitability properties were markedly altered at the baseline and were not prone to be further impaired after a fatiguing exercise. Adjusting the cortical and neuromuscular features to the initial change may prevent increased fatigue after exercise performed with a maximum voluntary contraction percentage. The authors hypothesized that fatigue in MD patients may be mainly due to peripheral factors related to muscle pathology. Thus, MD patients were probably unable to reach the required force level of 50% of their maximal grip force for enough time to determine a reduction of corticospinal excitability, a marker of

In adult patients with various types of myopathies, including FSHD and LGMD, the mechanisms of intracortical inhibition are reduced. This finding has been interpreted as a compensatory mechanism within the central nervous system that helps patients with myopathy to regain muscle power. SICI deficiency in FSHD may be explained by overexpression of the gene encoding the diazepam binding inhibitor (DBI), which is expected to attenuate the effects of GABA on GABAA receptors by acting on the benzodiazepine binding site [20]. Thus, DBI can determine a reduction in SICI, a phenomenon that depends largely on intracortical GABAA inhibitory mechanisms. It is interesting to note that a decrease in initial intracortical inhibition may prevent the subsequent use of this compensatory mechanism within the central nervous system in fatiguing muscle exercises as can be seen in healthy subjects [17]. Reduced baseline SICI in MD can be considered compensatory because of peripheral weakness, whereas in fibromyalgia syndrome, reduced SICI should rather be considered as an indicator of primary central disinhibition. Also in DM1 patients, TMS revealed abnormalities in cortical excitability, thus suggesting the occurrence of intracortical dysfunction [18]. These results are consistent with the autopsy and neuroimaging studies showing that dysfunction of the brain can be accompanied by structural changes. As a result, a disturbance of neuronal architecture was detected in the autopsy of the brain [21]. In addition, a three-dimensional magnetic resonance imagingcontrolled study demonstrated cerebral parenchymatrophy and hyperintensive lesions of the white matter [22], and PET scans showed a hypoperfusion in the prefrontal, temporal, and parieto-occipital lobes as well as in the basal ganglia, supporting the hypothesis of brain dysfunction in patients with DM1 [23].

from study to study. The cause of this variability remains unclear, but the methodological problem of TMS and technical factors, including the relatively small sample size in most studies or the difficulty of many patients (especially children) to achieve complete muscle relaxation, can explain this variability. Several TMS studies have provided electrophysiological evidence for abnormal motor cortical excitability and/or plasticity in patients with different myopathies. Applications of TMS to characterize musculoskeletal pathophysiology in patients with myopathies

appear to be safe and can be developed in valuable biomarkers.

reduction in SICI compared to healthy controls.

**56**

and psychiatric disorders because it can induce long-term modulation of brain activity in the target brain region and across brain networks via transcranial induction of electrical currents in the brain. rTMS involves mechanisms of synaptic plasticity, and, recently, an association between rTMS-induced aftereffects and the induction of synaptic plasticity has been demonstrated [33]. Since abnormal cortical excitability and neuroplastic changes may play a role in the clinical expression of myopathies (including muscle weakness and fatigue), their modulation by rTMS may have a therapeutic potential. If the abovementioned changes affect motor control, treatment, or rehabilitation, strategies based on these abnormalities can help to improve the outcome of myopathy patients in neurorehabilitation.

In summary, only a few studies have used TMS for the electrophysiological characterization of cortical involvement in neuromuscular diseases. However, TMS may be promising as an electrophysiological biomarker in patients with muscular dystrophy and other myopathies, in identifying potential therapeutic targets and in monitoring the effects of suspected pharmacological applications. Neuromodulation by rTMS may have a therapeutic potential in the future to induce synaptic plasticity as a compensatory neurobiological mechanism for progressive muscle weakness to improve treatment outcome.
