Probing the Brain-Body Connection Using Transcranial Magnetic Stimulation (TMS): Validating a Promising Tool to Provide Biomarkers of Neuroplasticity and Central Nervous System Function

Arthur R Chaves, Nicholas J Snow, Lynsey R Alcock, Michelle Ploughman, Arthur R Chaves, Nicholas J Snow, Lynsey R Alcock, Michelle Ploughman

Abstract

Transcranial magnetic stimulation (TMS) is a non-invasive method used to investigate neurophysiological integrity of the human neuromotor system. We describe in detail, the methodology of a single pulse TMS protocol that was performed in a large cohort of people (n = 110) with multiple sclerosis (MS). The aim was to establish and validate a core-set of TMS variables that predicted typical MS clinical outcomes: walking speed, hand dexterity, fatigue, and cognitive processing speed. We provide a brief and simple methodological pipeline to examine excitatory and inhibitory corticospinal mechanisms in MS that map to clinical status. Delayed and longer ipsilateral silent period (a measure of transcallosal inhibition; the influence of one brain hemisphere's activity over the other), longer cortical silent period (suggestive of greater corticospinal inhibition via GABA) and higher resting motor threshold (lower corticospinal excitability) most strongly related to clinical outcomes, especially when measured in the hemisphere corresponding to the weaker hand. Greater interhemispheric asymmetry (imbalance between hemispheres) correlated with poorer performance in the greatest number of clinical outcomes. We also show, not surprisingly, that TMS variables related more strongly to motor outcomes than non-motor outcomes. As it was validated in a large sample of patients with varying severities of central nervous system dysfunction, the protocol described herein can be used by investigators and clinicians alike to investigate the role of TMS as a biomarker in MS and other central nervous system disorders.

Keywords: biomarker; cognition; corticospinal excitability; fatigue; hand function; multiple sclerosis; neuroplasticity; transcranial magnetic stimulation; walking function; walking speed.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Basic Neurophysiological Principles of Transcranial Magnetic Stimulation (TMS). Electrical current produced by the stimulator travels via an insulated wire and reaches the stimulator coil (e.g., figure of eight coil) (A). The direction of flow of the electrical current within the coil (black arrows) is able to generate a perpendicular magnetic field (blue dotted lines), that (B) passes through the scalp painlessly and activates corticospinal neurons in the primary motor area by electromagnetic induction. (C) TMS elicits descending corticospinal volleys from the brain to the spinal cord by directly activating pyramidal tract neurons or indirectly via interneurons that synapse on the pyramidal tract (D- and I-waves, respectively); these signals elicit a motor evoked potential (MEP) in the contralateral muscle under investigation (e.g., first dorsal interosseous muscle). (D) TMS-induced MEPs are recorded via electromyography (EMG), with recording electrodes placed over the belly of the target muscle. (E) Offline analysis of corticospinal excitability (e.g., MEP peak-to-peak amplitude) and intracortical inhibition (e.g., cortical silent period (CSP) duration; MEP onset to return of EMG background activity), and corticomotoneuronal conduction speed (e.g., MEP latency; time from TMS stimulus to MEP onset) from a TMS-elicited MEP recorded by EMG of the first dorsal interosseous muscle with a participant performing a tonic voluntary contraction (e.g., pinch grip). Original figure © Arthur R. Chaves (created on Autodesk® Sketchbook® free software).
Figure 2
Figure 2
Parameters and Neurophysiology of the Excitatory and Inhibitory Recruitment Curves. Excitatory recruitment curves (eREC) are investigated by applying a varying range of transcranial magnetic stimulation (TMS) intensities [i.e., maximal stimulator output percentage (MSO%), e.g., 100–155% of Motor Threshold] and investigating the subsequent increases in motor evoked potential (MEP) amplitude (Volts). A linear or sigmoidal (Boltzmann’s) plot between MEP amplitude (y-values) versus the TMS intensities used (x-values) will determine the REC parameters [i.e., slope, and r-squared (R2)]. When muscle tone (tonic voluntary contraction) is performed by the participant during the REC assessment, the TMS variable cortical silent period (CSP), a biomarker of intracortical inhibition, can be investigated and the inhibitory REC (iREC) can be assessed. Overall excitation and inhibition are assessed by calculating the area under the curve using the trapezoid rule.
Figure 3
Figure 3
Finding the Hotspot and Creating a Motor Map. Guided using neuronavigation software, a 6 cm × 7 cm grid is placed on the motor area to assist with finding the first dorsal interosseous primary motor area representation corresponding to the right hand (A). Blue dots (12 mm apart) represent the pre-determined targets in which the experimenter performed 2–3 transcranial magnetic stimulation (TMS) stimulations. (B) A “heat map” is built using the neuronavigation software (Brainsight, Rogue Research Inc, Montreal, QC, Canada) demonstrating the primary motor area’s first dorsal interosseous muscle representation from a single multiple sclerosis (MS) participant (female, 31 years-old, presenting with no disability [expanded disability status scale (EDSS) 0].
Figure 4
Figure 4
Deriving data from a contralateral Transcranial Magnetic Stimulation (TMS)-induced Motor Evoked Potential (MEP). Representative MEP from contralateral hand muscle showing background electromyography (EMG) activity (tonic contraction) before the TMS stimulus (0.10 s on the timescale). EMG change is evaluated based on ±2 SD from the mean indicated as dashed lines. MEP latency, peak-to-peak MEP amplitude, and length of the cortical silent period (CSP is derived during offline analysis.
Figure 5
Figure 5
Deriving data from a Transcranial Magnetic Stimulation (TMS)-induced Ipsilateral Silent Period (iSP). Representative ipsilateral silent period (iSP) from ipsilateral hand muscle, during maximal pinch grip, showing electromyography (EMG) activity before the TMS stimulus (0.10 s on the timescale). EMG activity is briefly suppressed after TMS stimulus. During offline analysis, iSP onset latency, duration, depth, and area under the curve (AUC) can be calculated.
Figure 6
Figure 6
Recruitment of Participants.
Figure 7
Figure 7
Corticospinal Excitability (CSE) Differences Between Hemispheres. (A) Considering all participants in the same analysis, significantly lower CSE was noted in the hemisphere corresponding to the weaker than to the stronger hand. When separating participants into groups of higher (EDSS ≥ 3) vs. lower (EDSS < 3) level of disability, (B) only the group with higher level of disability demonstrated significantly higher active motor threshold (AMT) (i.e., lower CSE) in the hemisphere corresponding to the weaker compared to the stronger hand. (C) No significant difference between hemispheres was noted for AMT in the group with lower level of disability. Error bars represent one standard deviation (±SD) of the mean. EDSS, expanded disability status scale (MS severity; 0 = no disability, to 10 = death due to MS).
Figure 8
Figure 8
Differences in the Excitatory Recruitment Curve (eREC). (A) With all participants in the same analysis, when compared to the hemisphere corresponding to the stronger hand, the hemisphere corresponding to the weaker hand demonstrated significantly lower motor evoked potential (MEP) amplitudes (µV) at the transcranial magnetic stimulation (TMS) intensities of 135–155% of the AMT (*, p < 0.05). When groups were stratified based on levels of disability, (B) only the group with higher level of disability (EDSS) ≥ 3) demonstrated lower MEP amplitudes in the weaker hand (**, p < 0.01) at the intensities of 145 and 155% of the active motor threshold (AMT), whereas (C) no statistically significant difference between hemispheres was noted across MEP amplitudes (105–155% of AMT) in the group with lower level of disability (EDSS < 3). (D) With all participants in the same analysis, the eREC parameters of overall excitation (AUC, area under the curve), gain (slope), and accuracy (R2) were significantly lower in the weaker compared to the stronger hand. When separating participants into groups based on disability levels, (E) the group with a higher level of disability (EDSS ≥ 3) demonstrated significantly lower excitatory recruitment curve gain (slope), overall excitation (AUC), and accuracy (R2) in the hemisphere corresponding to the weaker hand when compared to the stronger hand. (F) In the group with a lower level of disability, overall excitation (AUC) and gain (slope) did not significantly differ between hemispheres, whereas accuracy (R2) was significantly lower in the hemisphere corresponding to the weaker hand. Error bars represent one standard deviation (±SD) of the mean. EDSS, expanded disability status scale (MS severity; 0 = no disability, to 10 = death due to MS).
Figure 9
Figure 9
Differences in the Inhibitory Recruitment Curve (iREC). (A) With all participants in the same analysis, significantly longer cortical silent period (CSP) duration was noted in the hemisphere corresponding to the weaker hand compared to the stronger hand across all the iREC intensities. (B) In participants with a higher level of disability (EDSS) ≥ 3), CSP duration was significantly longer in the weaker compared to the stronger hand at TMS intensities of 105–145% of the active motor threshold (AMT). (C) In participants with a lower level of disability (EDSS < 3), CSP duration was significantly longer in the weaker compared to the stronger hand at the TMS intensities of 105–125% of AMT (A–C). In all participants, as well groups based on higher and lower level of disability, overall inhibition (AUC) was significantly higher in the weaker compared to the stronger hand. ***, p < 0.001, **, p < 0.010, *, p < 0.050. Error bars represent one standard deviation (±SD) of the data mean. EDSS, expanded disability status scale (MS severity; 0 = no disability, to 10 = death due to MS).
Figure 10
Figure 10
Transcranial magnetic stimulation (TMS) Variables that Most Strongly Predict Clinical Outcomes. AMT, active motor threshold; CSP, cortical silent period; iSP, ipsilateral silent period; MEP, motor evoked potential; RMT, resting motor threshold; SDMT, symbol digit modality test.

References

    1. Group B.D.W. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin Pharm. 2001;69:89–95. doi: 10.1067/mcp.2001.113989.
    1. Boyd L.A., Hayward K.S., Ward N.S., Stinear C.M., Rosso C., Fisher R.J., Carter A.R., Leff A.P., Copland D.A., Carey L.M., et al. Biomarkers of stroke recovery: Consensus-based core recommendations from the Stroke Recovery and Rehabilitation Roundtable. Int. J. Stroke. 2017;12:480–493. doi: 10.1177/1747493017714176.
    1. Bielekova B., Martin R. Development of biomarkers in multiple sclerosis. Brain. 2004;127:1463–1478. doi: 10.1093/brain/awh176.
    1. Dalgas U., Hvid L.G., Kwakkel G., Motl R.W., de Groot V., Feys P., Op’t Eijnde B., Coote S., Beckerman H., Pfeifer K., et al. Moving exercise research in multiple sclerosis forward (the MoXFo initiative): Developing consensus statements for research. Mult. Scler. 2020;26:1303–1308. doi: 10.1177/1352458520910360.
    1. Carotenuto A., Iodice R., Petracca M., Inglese M., Cerillo I., Cocozza S., Saiote C., Brunetti A., Tedeschi E., Manganelli F., et al. Upper motor neuron evaluation in multiple sclerosis patients treated with Sativex(®) Acta Neurol. Scand. 2017;135:442–448. doi: 10.1111/ane.12660.
    1. Ploughman M., Austin M.W., Glynn L., Corbett D. The effects of poststroke aerobic exercise on neuroplasticity: A systematic review of animal and clinical studies. Transl. Stroke Res. 2015;6:13–28. doi: 10.1007/s12975-014-0357-7.
    1. Ziemssen T., Akgun K., Bruck W. Molecular biomarkers in multiple sclerosis. J. Neuroinflamm. 2019;16:272. doi: 10.1186/s12974-019-1674-2.
    1. Barnett Y., Garber J.Y., Barnett M.H. MRI biomarkers of disease progression in multiple sclerosis: Old dog, new tricks? Quant. Imaging Med. Surg. 2020;10:527–532. doi: 10.21037/qims.2020.01.04.
    1. Filippi M., Preziosa P., Banwell B.L., Barkhof F., Ciccarelli O., De Stefano N., Geurts J.J.G., Paul F., Reich D.S., Toosy A.T., et al. Assessment of lesions on magnetic resonance imaging in multiple sclerosis: Practical guidelines. Brain. 2019;142:1858–1875. doi: 10.1093/brain/awz144.
    1. Rossini P.M., Burke D., Chen R., Cohen L.G., Daskalakis Z., Di Iorio R., Di Lazzaro V., Ferreri F., Fitzgerald P.B., George M.S., et al. Non-invasive electrical and magnetic stimulation of the brain, spinal cord, roots and peripheral nerves: Basic principles and procedures for routine clinical and research application. An updated report from an I.F.C.N. Committee. Clin. Neurophysiol. 2015;126:1071–1107. doi: 10.1016/j.clinph.2015.02.001.
    1. Ziemann U., Reis J., Schwenkreis P., Rosanova M., Strafella A., Badawy R., Muller-Dahlhaus F. TMS and drugs revisited 2014. Clin. Neurophysiol. 2015;126:1847–1868. doi: 10.1016/j.clinph.2014.08.028.
    1. Cirillo J., Mooney R.A., Ackerley S.J., Barber P.A., Borges V.M., Clarkson A.N., Mangold C., Ren A., Smith M.C., Stinear C.M., et al. Neurochemical balance and inhibition at the subacute stage after stroke. J. Neurophysiol. 2020;123:1775–1790. doi: 10.1152/jn.00561.2019.
    1. Groppa S., Oliviero A., Eisen A., Quartarone A., Cohen L.G., Mall V., Kaelin-Lang A., Mima T., Rossi S., Thickbroom G.W., et al. A practical guide to diagnostic transcranial magnetic stimulation: Report of an IFCN committee. Clin. Neurophysiol. 2012;123:858–882. doi: 10.1016/j.clinph.2012.01.010.
    1. Ridding M.C., Rothwell J.C. Stimulus/response curves as a method of measuring motor cortical excitability in man. Electroencephalogr. Clin. Neurophysiol. 1997;105:340–344. doi: 10.1016/S0924-980X(97)00041-6.
    1. Devanne H., Lavoie B.A., Capaday C. Input-output properties and gain changes in the human corticospinal pathway. Exp. Brain Res. 1997;114:329–338. doi: 10.1007/PL00005641.
    1. Capaday C. Neurophysiological methods for studies of the motor system in freely moving human subjects. J. Neurosci. Methods. 1997;74:201–218. doi: 10.1016/S0165-0270(97)02250-4.
    1. Carson R.G., Nelson B.D., Buick A.R., Carroll T.J., Kennedy N.C., Cann R.M. Characterizing changes in the excitability of corticospinal projections to proximal muscles of the upper limb. Brain Stimul. 2013;6:760–768. doi: 10.1016/j.brs.2013.01.016.
    1. Talelli P., Ewas A., Waddingham W., Rothwell J.C., Ward N.S. Neural correlates of age-related changes in cortical neurophysiology. NeuroImage. 2008;40:1772–1781. doi: 10.1016/j.neuroimage.2008.01.039.
    1. Potter-Baker K.A., Varnerin N.M., Cunningham D.A., Roelle S.M., Sankarasubramanian V., Bonnett C.E., Machado A.G., Conforto A.B., Sakaie K., Plow E.B. Influence of Corticospinal Tracts from Higher Order Motor Cortices on Recruitment Curve Properties in Stroke. Front. Neurosci. 2016;10:79. doi: 10.3389/fnins.2016.00079.
    1. Kemlin C., Moulton E., Leder S., Houot M., Meunier S., Rosso C., Lamy J.C. Redundancy among parameters describing the input-output relation of motor evoked potentials in healthy subjects and stroke patients. Front. Neurol. 2019;10:535. doi: 10.3389/fneur.2019.00535.
    1. Kukke S.N., Paine R.W., Chao C.C., de Campos A.C., Hallett M. Efficient and reliable characterization of the corticospinal system using transcranial magnetic stimulation. J. Clin. Neurophysiol. 2014;31:246–252. doi: 10.1097/WNP.0000000000000057.
    1. Wilkinson L., Koshy P.J., Steel A., Bageac D., Schintu S., Wassermann E.M. Motor cortex inhibition by TMS reduces cognitive non-motor procedural learning when immediate incentives are present. Cortex. 2017;97:70–80. doi: 10.1016/j.cortex.2017.10.001.
    1. Clarkson A.N., Huang B.S., Macisaac S.E., Mody I., Carmichael S.T. Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke. Nature. 2010;468:305–309. doi: 10.1038/nature09511.
    1. Yacyshyn A.F., Woo E.J., Price M.C., McNeil C.J. Motoneuron responsiveness to corticospinal tract stimulation during the silent period induced by transcranial magnetic stimulation. Exp. Brain Res. 2016;234:3457–3463. doi: 10.1007/s00221-016-4742-1.
    1. Hupfeld K.E., Swanson C.W., Fling B.W., Seidler R.D. TMS-induced silent periods: A review of methods and call for consistency. J. Neurosci. Methods. 2020;346:108950. doi: 10.1016/j.jneumeth.2020.108950.
    1. Škarabot J., Mesquita R.N.O., Brownstein C.G., Ansdell P. Myths and methodologies: How loud is the story told by the transcranial magnetic stimulation-evoked silent period? Exp. Physiol. 2019;104:635–642. doi: 10.1113/EP087557.
    1. Snow N.J., Wadden K.P., Chaves A.R., Ploughman M. Transcranial Magnetic Stimulation as a Potential Biomarker in Multiple Sclerosis: A Systematic Review with Recommendations for Future Research. Neural Plast. 2019;2019:6430596. doi: 10.1155/2019/6430596.
    1. Wassermann E.M., Fuhr P., Cohen L.G., Hallett M. Effects of transcranial magnetic stimulation on ipsilateral muscles. Neurology. 1991;41:1795–1799. doi: 10.1212/WNL.41.11.1795.
    1. Ferbert A., Priori A., Rothwell J.C., Day B.L., Colebatch J.G., Marsden C.D. Interhemispheric inhibition of the human motor cortex. J. Physiol. 1992;453:525–546. doi: 10.1113/jphysiol.1992.sp019243.
    1. Di Pino G., Pellegrino G., Assenza G., Capone F., Ferreri F., Formica D., Ranieri F., Tombini M., Ziemann U., Rothwell J.C., et al. Modulation of brain plasticity in stroke: A novel model for neurorehabilitation. Nat. Rev. Neurol. 2014;10:597–608. doi: 10.1038/nrneurol.2014.162.
    1. Llufriu S., Blanco Y., Martinez-Heras E., Casanova-Molla J., Gabilondo I., Sepulveda M., Falcon C., Berenguer J., Bargallo N., Villoslada P., et al. Influence of corpus callosum damage on cognition and physical disability in multiple sclerosis: A multimodal study. PLoS ONE. 2012;7:e37167. doi: 10.1371/journal.pone.0037167.
    1. Neva J.L., Lakhani B., Brown K.E., Wadden K.P., Mang C.S., Ledwell N.H., Borich M.R., Vavasour I.M., Laule C., Traboulsee A.L., et al. Multiple measures of corticospinal excitability are associated with clinical features of multiple sclerosis. Behav. Brain Res. 2016;297:187–195. doi: 10.1016/j.bbr.2015.10.015.
    1. Beaulieu L.D., Milot M.H. Changes in transcranial magnetic stimulation outcome measures in response to upper-limb physical training in stroke: A systematic review of randomized controlled trials. Ann. Phys. Rehabil. Med. 2018;61:224–234. doi: 10.1016/j.rehab.2017.04.003.
    1. Hayward K.S., Neva J.L., Mang C.S., Peters S., Wadden K.P., Ferris J.K., Boyd L.A. Interhemispheric Pathways Are Important for Motor Outcome in Individuals with Chronic and Severe Upper Limb Impairment Post Stroke. Neural Plast. 2017;2017:4281532. doi: 10.1155/2017/4281532.
    1. Iodice R., Manganelli F., Dubbioso R. The therapeutic use of non-invasive brain stimulation in multiple sclerosis—A review. Restor. Neurol. Neurosci. 2017;35:497–509. doi: 10.3233/RNN-170735.
    1. Criste G., Trapp B., Dutta R. Axonal loss in multiple sclerosis: Causes and mechanisms. Handb. Clin. Neurol. 2014;122:101–113. doi: 10.1016/B978-0-444-52001-2.00005-4.
    1. Dutta R., Trapp B.D. Relapsing and progressive forms of multiple sclerosis: Insights from pathology. Curr. Opin. Neurol. 2014;27:271–278. doi: 10.1097/WCO.0000000000000094.
    1. Mahad D.H., Trapp B.D., Lassmann H. Pathological mechanisms in progressive multiple sclerosis. Lancet Neurol. 2015;14:183–193. doi: 10.1016/S1474-4422(14)70256-X.
    1. Trapp B.D., Vignos M., Dudman J., Chang A., Fisher E., Staugaitis S.M., Battapady H., Mork S., Ontaneda D., Jones S.E., et al. Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: A retrospective study. Lancet Neurol. 2018;17:870–884. doi: 10.1016/S1474-4422(18)30245-X.
    1. Miller D.H., Leary S.M. Primary-progressive multiple sclerosis. Lancet Neurol. 2007;6:903–912. doi: 10.1016/S1474-4422(07)70243-0.
    1. Lublin F.D. New multiple sclerosis phenotypic classification. Eur. Neurol. 2014;72(Suppl. 1):1–5. doi: 10.1159/000367614.
    1. Kappos L., De Stefano N., Freedman M.S., Cree B.A.C., Radue E.W., Sprenger T., Sormani M.P., Smith T., Haring D.A., Meier D.P., et al. Inclusion of brain volume loss in a revised measure of ‘no evidence of disease activity’ (NEDA-4) in relapsing-remitting multiple sclerosis. Mult. Scler. 2016;22:1297–1305. doi: 10.1177/1352458515616701.
    1. Davis S.L., Wilson T.E., White A.T., Frohman E.M. Thermoregulation in multiple sclerosis. J. Appl. Physiol. 2010;109:1531–1537. doi: 10.1152/japplphysiol.00460.2010.
    1. Bollaert R.E., Motl R.W. Physical and Cognitive Functions, Physical Activity, and Sedentary Behavior in Older Adults With Multiple Sclerosis. J. Geriatr. Phys. Ther. 2019;42:304–312. doi: 10.1519/JPT.0000000000000163.
    1. Motl R.W., Gappmaier E., Nelson K., Benedict R.H. Physical activity and cognitive function in multiple sclerosis. J. Sport Exerc. Psychol. 2011;33:734–741. doi: 10.1123/jsep.33.5.734.
    1. Carrieri L., Sgaramella T.M., Bortolon F., Stenta G., Fornaro L., Cracco A., Perini F., Soresi S. Determinants of on-the-job-barriers in employed persons with multiple sclerosis: The role of disability severity and cognitive indices. Work. 2014;47:509–520. doi: 10.3233/WOR-131623.
    1. Ben Ari Shevil E., Johansson S., Ytterberg C., Bergstrom J., von Koch L. How are cognitive impairment, fatigue and signs of depression related to participation in daily life among persons with multiple sclerosis? Disabil. Rehabil. 2014;36:2012–2018. doi: 10.3109/09638288.2014.887797.
    1. Heesen C., Böhm J., Reich C., Kasper J., Goebel M., Gold S.M. Patient perception of bodily functions in multiple sclerosis: Gait and visual function are the most valuable. Mult. Scler. 2008;14:988–991. doi: 10.1177/1352458508088916.
    1. Paltamaa J., Sarasoja T., Leskinen E., Wikström J., Mälkiä E. Measures of physical functioning predict self-reported performance in self-care, mobility, and domestic life in ambulatory persons with multiple sclerosis. Arch. Phys. Med. Rehabil. 2007;88:1649–1657. doi: 10.1016/j.apmr.2007.07.032.
    1. Chaves A.R., Devasahayam A.J., Riemenschneider M., Pretty R.W., Ploughman M. Walking Training Enhances Corticospinal Excitability in Progressive Multiple Sclerosis—A Pilot Study. Front. Neurol. 2020:11. doi: 10.3389/fneur.2020.00422.
    1. Thompson A.J., Banwell B.L., Barkhof F., Carroll W.M., Coetzee T., Comi G., Correale J., Fazekas F., Filippi M., Freedman M.S., et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17:162–173. doi: 10.1016/S1474-4422(17)30470-2.
    1. Kurtzke J.F. Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS) Neurology. 1983;33:1444–1452. doi: 10.1212/WNL.33.11.1444.
    1. Rossi S., Hallett M., Rossini P.M., Pascual-Leone A. Safety of TMS Consensus Group. Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research. Clin. Neurophysiol. 2009;120:2008–2039. doi: 10.1016/j.clinph.2009.08.016.
    1. Benedict R.H., DeLuca J., Phillips G., LaRocca N., Hudson L.D., Rudick R., Multiple Sclerosis Outcome Assessments C. Validity of the Symbol Digit Modalities Test as a cognition performance outcome measure for multiple sclerosis. Mult. Scler. 2017;23:721–733. doi: 10.1177/1352458517690821.
    1. Drake A.S., Weinstock-Guttman B., Morrow S.A., Hojnacki D., Munschauer F.E., Benedict R.H. Psychometrics and normative data for the Multiple Sclerosis Functional Composite: Replacing the PASAT with the Symbol Digit Modalities Test. Mult. Scler. 2010;16:228–237. doi: 10.1177/1352458509354552.
    1. Mathiowetz V., Weber K., Kashman N., Volland G. Adult norms for the Nine Hole Peg Test of finger dexterity. Occup. Ther. J. Res. 1985;5:24–38. doi: 10.1177/153944928500500102.
    1. Feys P., Lamers I., Francis G., Benedict R., Phillips G., LaRocca N., Hudson L.D., Rudick R., Outcome M.S. The Nine-Hole Peg Test as a manual dexterity performance measure for multiple sclerosis. Mult. Scler. 2017;23:711–720. doi: 10.1177/1352458517690824.
    1. Chaves A.R., Wallack E.M., Kelly L.P., Pretty R.W., Wiseman H.D., Chen A., Moore C.S., Stefanelli M., Ploughman M. Asymmetry of Brain Excitability: A New Biomarker that Predicts Objective and Subjective Symptoms in Multiple Sclerosis. Behav. Brain Res. 2019;359:281–291. doi: 10.1016/j.bbr.2018.11.005.
    1. Chaves A.R., Devasahayam A.J., Kelly L.P., Pretty R.W., Ploughman M. Exercise-Induced Brain Excitability Changes in Progressive Multiple Sclerosis: A Pilot Study. J. Neurol. Phys. Ther. 2020;44:132–144. doi: 10.1097/NPT.0000000000000308.
    1. Bohannon R.W. Comfortable and maximum walking speed of adults aged 20–79 years: Reference values and determinants. Age Ageing. 1997;26:15–19. doi: 10.1093/ageing/26.1.15.
    1. Palmer E., Ashby P. Corticospinal projections to upper limb motoneurones in humans. J. Physiol. 1992;448:397–412. doi: 10.1113/jphysiol.1992.sp019048.
    1. Yao B., Klein C.S., Hu H., Li S., Zhou P. Motor Unit Properties of the First Dorsal Interosseous in Chronic Stroke Subjects: Concentric Needle and Single Fiber EMG Analysis. Front. Physiol. 2018;9:1587. doi: 10.3389/fphys.2018.01587.
    1. Fritz N.E., Keller J., Calabresi P.A., Zackowski K.M. Quantitative measures of walking and strength provide insight into brain corticospinal tract pathology in multiple sclerosis. Neuroimage. Clin. 2017;14:490–498. doi: 10.1016/j.nicl.2017.02.006.
    1. DeLuca G.C., Ebers G.C., Esiri M.M. Axonal loss in multiple sclerosis: A pathological survey of the corticospinal and sensory tracts. Brain. 2004;127:1009–1018. doi: 10.1093/brain/awh118.
    1. Thickbroom G.W., Byrnes M.L., Archer S.A., Kermode A.G., Mastaglia F.L. Corticomotor organisation and motor function in multiple sclerosis. J. Neurol. 2005;252:765–771. doi: 10.1007/s00415-005-0728-9.
    1. Li X., Holobar A., Gazzoni M., Merletti R., Rymer W.Z., Zhou P. Examination of Poststroke Alteration in Motor Unit Firing Behavior Using High-Density Surface EMG Decomposition. IEEE Trans. Bio-Med. Eng. 2015;62:1242–1252. doi: 10.1109/TBME.2014.2368514.
    1. Singh A.M., Duncan R.E., Neva J.L., Staines W.R. Aerobic exercise modulates intracortical inhibition and facilitation in a nonexercised upper limb muscle. BMC Sports Sci. Med. Rehabil. 2014;6:23. doi: 10.1186/2052-1847-6-23.
    1. Walsh J.A., Stapley P.J., Shemmell J.B.H., Lepers R., McAndrew D.J. Global Corticospinal Excitability as Assessed in A Non-Exercised Upper Limb Muscle Compared Between Concentric and Eccentric Modes of Leg Cycling. Sci. Rep. 2019;9:19212. doi: 10.1038/s41598-019-55858-5.
    1. Vucic S., Kiernan M.C. Transcranial Magnetic Stimulation for the Assessment of Neurodegenerative Disease. Neurotherapeutics. 2017;14:91–106. doi: 10.1007/s13311-016-0487-6.
    1. Ni Z., Chen R. Transcranial magnetic stimulation to understand pathophysiology and as potential treatment for neurodegenerative diseases. Transl. Neurodegener. 2015;4:22. doi: 10.1186/s40035-015-0045-x.
    1. Di Lazzaro V., Oliviero A., Saturno E., Pilato F., Insola A., Mazzone P., Profice P., Tonali P., Rothwell J.C. The effect on corticospinal volleys of reversing the direction of current induced in the motor cortex by transcranial magnetic stimulation. Exp. Brain Res. 2001;138:268–273. doi: 10.1007/s002210100722.
    1. Hannah R., Rothwell J.C. Pulse Duration as Well as Current Direction Determines the Specificity of Transcranial Magnetic Stimulation of Motor Cortex during Contraction. Brain Stimul. 2017;10:106–115. doi: 10.1016/j.brs.2016.09.008.
    1. Fonov V., Evans A.C., Botteron K., Almli C.R., McKinstry R.C., Collins D.L., Brain Development Cooperative G. Unbiased average age-appropriate atlases for pediatric studies. NeuroImage. 2011;54:313–327. doi: 10.1016/j.neuroimage.2010.07.033.
    1. Collins D.L., Neelin P., Peters T.M., Evans A.C. Automatic 3D intersubject registration of MR volumetric data in standardized Talairach space. J. Comput. Assist. Tomogr. 1994;18:192–205. doi: 10.1097/00004728-199403000-00005.
    1. Jonker Z.D., van der Vliet R., Hauwert C.M., Gaiser C., Tulen J.H.M., van der Geest J.N., Donchin O., Ribbers G.M., Frens M.A., Selles R.W. TMS motor mapping: Comparing the absolute reliability of digital reconstruction methods to the golden standard. Brain Stimul. 2019;12:309–313. doi: 10.1016/j.brs.2018.11.005.
    1. Möller C., Arai N., Lücke J., Ziemann U. Hysteresis effects on the input-output curve of motor evoked potentials. Clin. Neurophysiol. 2009;120:1003–1008. doi: 10.1016/j.clinph.2009.03.001.
    1. Centeno C., Medeiros D., Beck M.M., Lugassy L., Gonzalez D.F., Nepveu J.F., Roig M. The effects of aging on cortico-spinal excitability and motor memory consolidation. Neurobiol. Aging. 2018;70:254–264. doi: 10.1016/j.neurobiolaging.2018.06.035.
    1. Kidgell D.J., Pearce A.J. What has transcranial magnetic stimulation taught us about neural adaptations to strength training? A brief review. J. Strength Cond. Res. Natl. Strength Cond. Assoc. 2011;25:3208–3217. doi: 10.1519/JSC.0b013e318212de69.
    1. Bailey A.Z., Mi Y.P., Nelson A.J. Short-latency afferent inhibition in chronic spinal cord injury. Transl. Neurosci. 2015;6:235–243. doi: 10.1515/tnsci-2015-0025.
    1. Leon-Sarmiento F.E., Rizzo-Sierra C.V., Bayona E.A., Bayona-Prieto J., Doty R.L., Bara-Jimenez W. Novel mechanisms underlying inhibitory and facilitatory transcranial magnetic stimulation abnormalities in Parkinson’s disease. Arch. Med Res. 2013;44:221–228. doi: 10.1016/j.arcmed.2013.03.003.
    1. Werhahn K.J., Behrang-Nia M., Bott M.C., Klimpe S. Does the recruitment of excitation and inhibition in the motor cortex differ? J. Clin. Neurophysiol. 2007;24:419–423. doi: 10.1097/WNP.0b013e3181379a69.
    1. Lenzi D., Conte A., Mainero C., Frasca V., Fubelli F., Totaro P., Caramia F., Inghilleri M., Pozzilli C., Pantano P. Effect of corpus callosum damage on ipsilateral motor activation in patients with multiple sclerosis: A functional and anatomical study. Hum. Brain Mapp. 2007;28:636–644. doi: 10.1002/hbm.20305.
    1. Davidson T., Tremblay F. Age and hemispheric differences in transcallosal inhibition between motor cortices: An ispsilateral silent period study. BMC Neurosci. 2013;14:62. doi: 10.1186/1471-2202-14-62.
    1. Kuo Y.-L., Dubuc T., Boufadel D.F., Fisher B.E. Measuring ipsilateral silent period: Effects of muscle contraction levels and quantification methods. Brain Res. 2017;1674:77–83. doi: 10.1016/j.brainres.2017.08.015.
    1. Meyer B.-U., Röricht S., Gräfin von Einsiedel H., Kruggel F., Weindl A. Inhibitory and excitatory interhemispheric transfers between motor cortical areas in normal humans and patients with abnormalities of the corpus callosum. Brain. 1995;118:429–440. doi: 10.1093/brain/118.2.429.
    1. Kesar T.M., Eicholtz S., Lin B.J., Wolf S.L., Borich M.R. Effects of posture and coactivation on corticomotor excitability of ankle muscles. Restor. Neurol. Neurosci. 2018;36:131–146. doi: 10.3233/RNN-170773.
    1. Finisguerra A., Maffongelli L., Bassolino M., Jacono M., Pozzo T., D’Ausilio A. Generalization of motor resonance during the observation of hand, mouth, and eye movements. J. Neurophysiol. 2015;114:2295–2304. doi: 10.1152/jn.00433.2015.
    1. Tobimatsu S., Sun S.J., Fukui R., Kato M. Effects of sex, height and age on motor evoked potentials with magnetic stimulation. J. Neurol. 1998;245:256–261. doi: 10.1007/s004150050215.
    1. Livingston S.C., Friedlander D.L., Gibson B.C., Melvin J.R. Motor evoked potential response latencies demonstrate moderate correlations with height and limb length in healthy young adults. Neurodiagn. J. 2013;53:63–78.
    1. Schättin A., Gennaro F., Egloff M., Vogt S., de Bruin E.D. Physical Activity, Nutrition, Cognition, Neurophysiology, and Short-Time Synaptic Plasticity in Healthy Older Adults: A Cross-Sectional Study. Front. Aging Neurosci. 2018;10:242. doi: 10.3389/fnagi.2018.00242.
    1. Mang C.S., Snow N.J., Campbell K.L., Ross C.J., Boyd L.A. A single bout of high-intensity aerobic exercise facilitates response to paired associative stimulation and promotes sequence-specific implicit motor learning. J. Appl. Physiol. 2014;117:1325–1336. doi: 10.1152/japplphysiol.00498.2014.
    1. Rosenkranz K., Kacar A., Rothwell J.C. Differential modulation of motor cortical plasticity and excitability in early and late phases of human motor learning. J. Neurosci. 2007;27:12058–12066. doi: 10.1523/JNEUROSCI.2663-07.2007.
    1. Fleming M.K., Newham D.J. Reliability of Transcallosal Inhibition in Healthy Adults. Front. Hum. Neurosci. 2016;10:681. doi: 10.3389/fnhum.2016.00681.
    1. Daskalakis Z.J., Molnar G.F., Christensen B.K., Sailer A., Fitzgerald P.B., Chen R. An automated method to determine the transcranial magnetic stimulation-induced contralateral silent period. Clin. Neurophysiol. 2003;114:938–944. doi: 10.1016/S1388-2457(03)00038-5.
    1. Schmierer K., Irlbacher K., Grosse P., Roricht S., Meyer B.U. Correlates of disability in multiple sclerosis detected by transcranial magnetic stimulation. Neurology. 2002;59:1218–1224. doi: 10.1212/WNL.59.8.1218.
    1. Giovannelli F., Borgheresi A., Balestrieri F., Zaccara G., Viggiano M.P., Cincotta M., Ziemann U. Modulation of interhemispheric inhibition by volitional motor activity: An ipsilateral silent period study. J. Physiol. 2009;587:5393–5410. doi: 10.1113/jphysiol.2009.175885.
    1. Jung P., Ziemann U. Differences of the ipsilateral silent period in small hand muscles. Muscle Nerve. 2006;34:431–436. doi: 10.1002/mus.20604.
    1. Harris-Love M.L., Morton S.M., Perez M.A., Cohen L.G. Mechanisms of short-term training-induced reaching improvement in severely hemiparetic stroke patients: A TMS study. Neurorehabilit. Neural Repair. 2011;25:398–411. doi: 10.1177/1545968310395600.
    1. Sheskin D.J. Handbook of Parametric and Nonparametric Statistical Procedures. 3rd ed. CRC Press; New York, NY, USA: 2003.
    1. Kirkland M.C., Wallack E.M., Rancourt S.N., Ploughman M. Comparing three dual-task methods and the relationship to physical and cognitive impairment in people with multiple sclerosis and controls. Mult. Scler. Int. 2015;2015:650645. doi: 10.1155/2015/650645.
    1. Akoglu H. User’s guide to correlation coefficients. Turk. J. Emerg. Med. 2018;18:91–93. doi: 10.1016/j.tjem.2018.08.001.
    1. Tabachnick B.G., Fidell L.S. Using Multivariate Statistics. Pearson Education; Boston, MA, USA: 2013.
    1. Vatcheva K.P., Lee M., McCormick J.B., Rahbar M.H. Multicollinearity in Regression Analyses Conducted in Epidemiologic Studies. Epidemiology. 2016:6. doi: 10.4172/2161-1165.1000227.
    1. Salamon S.J., Hansen H.J., Abbott D. How real are observed trends in small correlated datasets? R. Soc. Open Sci. 2019;6:181089. doi: 10.1098/rsos.181089.
    1. Cohen J., Cohen P., West S.G., Aiken L.S. Applied Multiple Regression/Correlation Analysis for the Behavioral Sciences. 3rd ed. Lawrence Erlbaum Associates Publishers; Mahwah, NJ, USA: 2003.
    1. Moore D.S., Notz W.I., Flinger M.A. The Basic Practice of Statistics. 6th ed. W. H. Freeman and Company; New York, NY, USA: 2013.
    1. Cook R.D., Weisberg S. Residuals and Influence in Regression. Chapman and Hall; New York, NY, USA: 1982.
    1. Bollen K.A., Jackman R.W. Regression diagnostics: An expository treatment of outliers and influential cases. Sociol. Methods Res. 1985;13:510–542. doi: 10.1177/0049124185013004004.
    1. Burke S. Missing values, outliers, robust statistics & non-parametric methods. Sci. Data Manag. 1998;1:32–38.
    1. Gelman A., Hill J. Data Analysis Using Regression and Multilevel/Hierarchical Models. Cambridge University Press; Cambridge, UK: 2006.
    1. Li C., Liu F., Peng H., Huang Y., Song X., Xie Q., Li Y., Liu Y. The positive effect of venlafaxine on central motor conduction. Clin. Neurol. Neurosurg. 2018;167:65–69. doi: 10.1016/j.clineuro.2018.02.017.
    1. Santarnecchi E., Rossi S., Bartalini S., Cincotta M., Giovannelli F., Tatti E., Ulivelli M. Neurophysiological Correlates of Central Fatigue in Healthy Subjects and Multiple Sclerosis Patients before and after Treatment with Amantadine. Neural Plast. 2015;2015:616242. doi: 10.1155/2015/616242.
    1. Priori A., Berardelli A., Inghilleri M., Accornero N., Manfredi M. Motor cortical inhibition and the dopaminergic system: Pharmacological changes in the silent period after transcranial brain stimulation in normal subjects, patients with Parkinson’s disease and drug-induced parkinsonism. Brain. 1994;117:317–323. doi: 10.1093/brain/117.2.317.
    1. Rizzo V., Crupi D., Bagnato S., Quartarone A., Benvenga S., Bartolone L., Ghilardi M.F., Trimarchi F., Girlanda P., Battaglia F. Neural response to transcranial magnetic stimulation in adult hypothyroidism and effect of replacement treatment. J. Neurol. Sci. 2008;266:38–43. doi: 10.1016/j.jns.2007.08.031.
    1. Münchau A., Langosch J.M., Gerschlager W., Rothwell J.C., Orth M., Trimble M.R. Mirtazapine increases cortical excitability in healthy controls and epilepsy patients with major depression. J. Neurol. Neurosurg. Psychiatry. 2005;76:527. doi: 10.1136/jnnp.2004.037010.
    1. Mufti M.A., Holtzheimer P.E., III, Epstein C.M., Quinn S.C., Vito N., McDonald W.M. Bupropion decreases resting motor threshold: A case report. Brain Stimul. 2010;3:177–180. doi: 10.1016/j.brs.2009.08.001.
    1. Monte-Silva K., Ruge D., Teo J.T., Paulus W., Rothwell J.C., Nitsche M.A. D2 Receptor Block Abolishes Theta Burst Stimulation-Induced Neuroplasticity in the Human Motor Cortex. Neuropsychopharmacology. 2011;36:2097–2102. doi: 10.1038/npp.2011.100.
    1. Manganotti P., Bortolomasi M., Zanette G., Pawelzik T., Giacopuzzi M., Fiaschi A. Intravenous clomipramine decreases excitability of human motor cortex. A study with paired magnetic stimulation. J. Neurol. Sci. 2001;184:27–32. doi: 10.1016/S0022-510X(00)00495-0.
    1. Schoonheim M.M., Filippi M. Functional plasticity in MS: Friend or foe? Neurology. 2012;79:1418–1419. doi: 10.1212/WNL.0b013e31826d602e.
    1. Rajda C., Pukoli D., Bende Z., Majlath Z., Vecsei L. Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis. Int. J. Mol. Sci. 2017;18:353. doi: 10.3390/ijms18020353.
    1. Murase N., Duque J., Mazzocchio R., Cohen L.G. Influence of interhemispheric interactions on motor function in chronic stroke. Ann. Neurol. 2004;55:400–409. doi: 10.1002/ana.10848.
    1. Zipser C.M., Premoli I., Belardinelli P., Castellanos N., Rivolta D., Heidegger T., Müller-Dahlhaus F., Ziemann U. Cortical excitability and interhemispheric connectivity in early relapsing-remitting multiple sclerosis studied with TMS-EEG. Front. Neurosci. 2018;12:393. doi: 10.3389/fnins.2018.00393.
    1. Nantes J.C., Zhong J., Holmes S.A., Whatley B., Narayanan S., Lapierre Y., Arnold D.L., Koski L. Intracortical inhibition abnormality during the remission phase of multiple sclerosis is related to upper limb dexterity and lesions. Clin. Neurophysiol. 2016;127:1503–1511. doi: 10.1016/j.clinph.2015.08.011.
    1. Vucic S., Burke T., Lenton K., Ramanathan S., Gomes L., Yannikas C., Kiernan M.C. Cortical dysfunction underlies disability in multiple sclerosis. Mult. Scler. 2012;18:425–432. doi: 10.1177/1352458511424308.
    1. Zeller D., Dang S.Y., Stefan K., Biller A., Bartsch A., Saur D., Bendszus M., Rieckmann P., Toyka K.V., Classen J. Functional role of ipsilateral motor areas in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry. 2011;82:578–583. doi: 10.1136/jnnp.2010.219964.
    1. Codecà C., Mori F., Kusayanagi H., Monteleone F., Boffa L., Paolillo A., Bernardi G., Koch G., Centonze D. Differential patterns of interhemispheric functional disconnection in mild and advanced multiple sclerosis. Mult. Scler. 2010;16:1308–1316. doi: 10.1177/1352458510376957.
    1. Wahl M., Hübers A., Lauterbach-Soon B., Hattingen E., Jung P., Cohen L.G., Ziemann U. Motor callosal disconnection in early relapsing-remitting multiple sclerosis. Hum. Brain Mapp. 2011;32:846–855. doi: 10.1002/hbm.21071.
    1. Luscher C., Malenka R.C. NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD) Cold Spring Harb. Perspect. Biol. 2012:4. doi: 10.1101/cshperspect.a005710.
    1. Bliss T.V., Cooke S.F. Long-term potentiation and long-term depression: A clinical perspective. Clinics. 2011;66(Suppl. 1):3–17. doi: 10.1590/S1807-59322011001300002.
    1. Ziemann U., Ilic T.V., Pauli C., Meintzschel F., Ruge D. Learning modifies subsequent induction of long-term potentiation-like and long-term depression-like plasticity in human motor cortex. J. Neurosci. 2004;24:1666–1672. doi: 10.1523/JNEUROSCI.5016-03.2004.
    1. Sale A., Berardi N., Maffei L. Environment and brain plasticity: Towards an endogenous pharmacotherapy. Physiol. Rev. 2014;94:189–234. doi: 10.1152/physrev.00036.2012.
    1. Mang C.S., Campbell K.L., Ross C.J., Boyd L.A. Promoting neuroplasticity for motor rehabilitation after stroke: Considering the effects of aerobic exercise and genetic variation on brain-derived neurotrophic factor. Phys. Ther. 2013;93:1707–1716. doi: 10.2522/ptj.20130053.
    1. Mott D.D., Lewis D.V. The pharmacology and function of central GABAB receptors. Int. Rev. Neurobiol. 1994;36:97–223.
    1. Kullmann D.M., Moreau A.W., Bakiri Y., Nicholson E. Plasticity of inhibition. Neuron. 2012;75:951–962. doi: 10.1016/j.neuron.2012.07.030.
    1. Epstein C.M., Wassermann E.M., Ziemann U., Wolters A., Ziemann U., Benecke R. The Cortical Silent Period. Oxford University Press; New York, NY, USA: 2012.
    1. Classen J., Schnitzler A., Binkofski F., Werhahn K.J., Kim Y.S., Kessler K.R., Benecke R. The motor syndrome associated with exaggerated inhibition within the primary motor cortex of patients with hemiparetic. Pt 4Brain. 1997;120:605–619. doi: 10.1093/brain/120.4.605.
    1. Sale M.V., Ridding M.C., Nordstrom M.A. Factors influencing the magnitude and reproducibility of corticomotor excitability changes induced by paired associative stimulation. Exp. Brain Res. 2007;181:615–626. doi: 10.1007/s00221-007-0960-x.
    1. Klein P.A., Petitjean C., Olivier E., Duque J. Top-down suppression of incompatible motor activations during response selection under conflict. NeuroImage. 2014;86:138–149. doi: 10.1016/j.neuroimage.2013.08.005.
    1. Liepert J., Mingers D., Heesen C., Baumer T., Weiller C. Motor cortex excitability and fatigue in multiple sclerosis: A transcranial magnetic stimulation study. Mult. Scler. 2005;11:316–321. doi: 10.1191/1352458505ms1163oa.
    1. Stagg C.J., Bestmann S., Constantinescu A.O., Moreno L.M., Allman C., Mekle R., Woolrich M., Near J., Johansen-Berg H., Rothwell J.C. Relationship between physiological measures of excitability and levels of glutamate and GABA in the human motor cortex. J. Physiol. 2011;589:5845–5855. doi: 10.1113/jphysiol.2011.216978.
    1. Davey N.J., Smith H.C., Savic G., Maskill D.W., Ellaway P.H., Frankel H.L. Comparison of input-output patterns in the corticospinal system of normal subjects and incomplete spinal cord injured patients. Exp. Brain Res. 1999;127:382–390. doi: 10.1007/s002210050806.
    1. Magistris M.R., Rosler K.M., Truffert A., Myers J.P. Transcranial stimulation excites virtually all motor neurons supplying the target muscle. A demonstration and a method improving the study of motor evoked potentials. Brain. 1998;121:437–450. doi: 10.1093/brain/121.3.437.
    1. Tataroglu C., Genc A., Idiman E., Cakmur R., Idiman F. Cortical relay time for long latency reflexes in patients with definite multiple sclerosis. Can. J. Neurol. Sci. 2004;31:229–234. doi: 10.1017/S0317167100120578.
    1. Tataroglu C., Genc A., Idiman E., Cakmur R., Idiman F. Cortical silent period and motor evoked potentials in patients with multiple sclerosis. Clin. Neurol. Neurosurg. 2003;105:105–110. doi: 10.1016/S0303-8467(02)00127-0.
    1. Zeller D., Aufm Kampe K., Biller A., Stefan K., Gentner R., Schutz A., Bartsch A., Bendszus M., Toyka K.V., Rieckmann P., et al. Rapid-onset central motor plasticity in multiple sclerosis. Neurology. 2010;74:728–735. doi: 10.1212/WNL.0b013e3181d31dcf.
    1. Stampanoni Bassi M., Buttari F., Gilio L., De Paolis N., Fresegna D., Centonze D., Iezzi E. Inflammation and Corticospinal Functioning in Multiple Sclerosis: A TMS Perspective. Front. Neurol. 2020;11:566. doi: 10.3389/fneur.2020.00566.
    1. Caramia M.D., Desiato M.T., Cicinelli P., Iani C., Rossini P.M. Latency jump of “relaxed” versus “contracted” motor evoked potentials as a marker of cortico-spinal maturation. Electroencephalogr. Clin. Neurophysiol. 1993;89:61–66. doi: 10.1016/0168-5597(93)90086-5.
    1. Lemon R.N., Baker S.N., Davis J.A., Kirkwood P.A., Maier M.A., Yang H.S. The importance of the cortico-motoneuronal system for control of grasp. Novartis Found. Symp. 1998;218:202–215. doi: 10.1002/9780470515563.ch11. discussion 215–208.

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa