Navigated Trancranial Magnetic Stimulation in Amyotrophic Lateral Sclerosis Jakob Udby Blicher1,2 MD PhD, Birger Johnsen1 MD PhD, Hatice Tankisi1 MD PhD, Alexander Hess1 MD, Anders Fuglsang-Frederiksen1 MD DMSc 1

Aarhus University Hospital, Department of Clinical Neurophysiology, Norrebrogade 44, 8000 Aarhus C,

Denmark 2

Aarhus University, Center of Functionally Integrative Neuroscience, Norrebrogade 44, 8000 Aarhus C,

Denmark Corresponding author: Jakob Udby Blicher Aarhus University, Center of Functionally Integrative Neuroscience, Norrebrogade 44, Building 10G, 8000 Aarhus C, Denmark email: [email protected] Running title: Navigated TMS in ALS Keywords: Transcranial Magnetic Stimulation, MRI, Amyotrophic lateral sclerosis, Neuronavigation, Cortical excitability

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process which may lead to differences between this version and the Version of Record. Please cite this article as an ‘Accepted Article’, doi: 10.1002/mus.24512

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Navigated Transcranial Magnetic Stimulation (nTMS) allows for online anatomical guided TMS, using the patient’s own structural MRI scan. This allows mapping of the cortical area corresponding to the measured motor evoked potentials (MEPs). Recently Chervyakov et al. reported their results with using nTMS to access upper motor neuron (UMN) deficits in amyotrophic lateral sclerosis (ALS)1. Clinically there is a need for a reliable and sensitive physiological method for assessing UMN abnormality,2 since current techniques are often not sufficiently sensitive in early ALS3. Consequently, the paper by Chervyakov et al. has attracted some attention4. The authors investigated 30 ALS patients, most of them (25) in advanced disease stages, and concluded that nTMS is a promising method for assessing UMN function. The conclusion is based on a correlation between cortical map size, as measured by nTMS, and disease severity. However, the authors also report a significant correlation between disease severity and resting motor threshold (rMT), a TMS measure of cortical excitability shown previously to correlate with disease severity5. The authors did not clarify whether the nTMS map volume represents a new independent predictor of injury severity or simply co-varies with rMT. The question is of importance, since rMT is much easier and faster to access. Moreover, a more detailed description of the mapping method is warranted. Judging from the figures, the cortical area covered and the depth at which the brain is visualized during stimulation differ between subjects. In the example shown in figure 1 many of the borders of the stimulated area are marked as above threshold MEPs, and thus it is unknown whether the map would extend beyond the investigated area. This could potentially result in significant bias between exams, and standardization of the mapping procedure with well-defined borders of below threshold MEPs should be performed. Finally, the study does not quantify lower motor neuron (LMN) function, and the effects of LMN loss on nTMS measures are not discussed. The MEP elicited by TMS relies on an intact connection from motor cortex to muscle, and any injury along this pathway could result in inability to elicit MEPs. Consequently, cortical map size measured by nTMS may be decreased due to LMN loss, or it may be increased as a result

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of compensatory cortical plasticity. Accordingly, changes in cortical map size cannot necessarily be considered as evidence of UMN affection. In conclusion, nTMS could potentially be a new useful biomarker for assessing UMN deficits in ALS. The study by Chervyakov et al. shows that the technique is applicable in patients with a range of disease severities, but it fails to show whether the technique is superior to other TMS measures, such as rMT, paired-pulse,6, 7 or triple stimulation techniques8 for detection of UMN abnormality. Future studies will have to clarify whether the technique can contribute to the diagnostic challenge in early motor neuron disease.

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References

1. Chervyakov AV, Bakulin IS, Savitskaya NG, Arkhipov IV, Gavrilov AV, Zakharova MN, Piradov MA. Navigated transcranial magnetic stimulation in amyotrophic lateral sclerosis. Muscle Nerve 2014.

2. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, Mills K, Mitsumoto H, Nodera H, Shefner J, Swash M. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol 2008; 119:497503.

3. Mills KR. The natural history of central motor abnormalities in amyotrophic lateral sclerosis. Brain 2003; 126:2558-2566.

4. Chase A. Motor neuron disease: Evaluation of ALS via transcranial magnetic stimulation. Nat Rev Neurol 2014; 10:485.

5. Mills KR, Nithi KA. Corticomotor threshold is reduced in early sporadic amyotrophic lateral sclerosis. Muscle Nerve 1997; 20:1137-1141.

6. Ziemann U, Winter M, Reimers CD, Reimers K, Tergau F, Paulus W. Impaired motor cortex inhibition in patients with amyotrophic lateral sclerosis. Evidence from paired transcranial magnetic stimulation. Neurology 1997; 49:1292-1298.

7. Blicher JU, Jakobsen J, Andersen G, Nielsen JF. Cortical Excitability in Chronic Stroke and Modulation by Training: A TMS Study. Neurorehabil Neural Repair 2009; 23:486-493.

8. Furtula J, Johnsen B, Frandsen J, Rodell A, Christensen PB, Pugdahl K, Fuglsang-Frederiksen A. Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI. J Neurol 2013; 260:1535-1544.

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Navigated transcranial magnetic stimulation in amyotrophic lateral sclerosis.

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