{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T22:38:33Z","timestamp":1769726313696,"version":"3.49.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T00:00:00Z","timestamp":1706659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Psychiatry"],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Transcranial Magnetic Stimulation (TMS) is used for <jats:italic>in vivo<\/jats:italic> assessment of human motor cortical excitability, with application of TMS pulses over the motor cortex resulting in muscle responses that can be recorded with electromyography (EMG) as Motor Evoked Potentials (MEPs). These have been widely explored as potential biomarkers for neuropsychiatric disorders but methodological heterogeneity in acquisition, and inherent high variability, have led to constraints in reproducibility. Normalization, consisting in scaling the signal of interest to a known and repeatable measurement, reduces variability and is standard practice for between-subject comparisons of EMG. The effect of normalization on variability of MEP amplitude has not yet been explored and was assessed here using several methods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Three maximal voluntary isometric contractions (MVICs) and 40 MEPs were collected from the right hand in healthy volunteers, with a retest session conducted 4 to 8\u2009weeks later. MEP amplitude was normalized using either external references (MVICs) or internal references (extreme MEPs). Iterative re-sampling of 30 normalized MEPs per subject was repeated 5,000 times to define, for each normalization method, distributions for between-subject coefficients of variation (CV) of the mean MEP amplitude. Intra-class correlation coefficients (ICC) were used to assess the impact of normalization on test\u2013retest stability of MEP amplitude measurements.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In the absence of normalization, MEPs collected from the right hand of 47 healthy volunteers were within reported values regarding between-subject variability (95% confidence intervals for the CV: [1.0567,1.0577]) and showed good temporal stability (ICC\u2009=\u20090.77). Internal reference normalization substantially reduced between-subject variability, by values of up to 64%, while external reference normalization had no impact or increased between-subject variability. Normalization with the smallest references reduced test\u2013retest stability, with use of the largest references resulting in slight reduction or improvement of ICCs. Internal reference normalization using the largest MEPs was found to be robust to several sensitivity analyses.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Internal, but not external, reference normalization reduces between-subject variability of MEP amplitude, and has a minimal impact on within-subject variability when conducted with the largest references. Additional research is necessary to further validate these normalization methods toward potential use of MEPs as biomarkers of neuropsychiatric disorders.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fpsyt.2024.1279072","type":"journal-article","created":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T04:23:32Z","timestamp":1706675012000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reducing motor evoked potential amplitude variability through normalization"],"prefix":"10.3389","volume":"15","author":[{"given":"Francisco","family":"Faro Viana","sequence":"first","affiliation":[]},{"given":"Gon\u00e7alo","family":"Cotovio","sequence":"additional","affiliation":[]},{"given":"Daniel Rodrigues","family":"da Silva","sequence":"additional","affiliation":[]},{"given":"Carolina","family":"Seybert","sequence":"additional","affiliation":[]},{"given":"Patr\u00edcia","family":"Pereira","sequence":"additional","affiliation":[]},{"given":"Artur","family":"Silva","sequence":"additional","affiliation":[]},{"given":"Filipe","family":"Carvalho","sequence":"additional","affiliation":[]},{"given":"Albino J.","family":"Oliveira-Maia","sequence":"additional","affiliation":[]}],"member":"1965","published-online":{"date-parts":[[2024,1,31]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1016\/S0140-6736(85)92413-4","article-title":"Non-invasive magnetic stimulation of human motor cortex","volume":"325","author":"Barker","year":"1985","journal-title":"Lancet"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1016\/j.jad.2003.09.014","article-title":"Motor cortical excitability and clinical response to rTMS in depression","volume":"82","author":"Fitzgerald","year":"2004","journal-title":"J Affect Disord"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"117","DOI":"10.1186\/s41983-020-00255-3","article-title":"Motor disability in patients with multiple sclerosis: transcranial magnetic stimulation study","volume":"56","author":"Mohy","year":"2020","journal-title":"Egyptian J Neurol, Psychiatry and Neurosurgery"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"339","DOI":"10.3389\/fneur.2019.00339","article-title":"Fatigue in multiple sclerosis: general and perceived fatigue does not depend on corticospinal tract dysfunction","volume":"10","author":"Mordillo-Mateos","year":"2019","journal-title":"Front Neurol"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1192\/bjp.174.5.449","article-title":"Reduced cortical excitability in depression: impaired post-exercise motor facilitation with transcranial magnetic stimulation","volume":"174","author":"Shajahan","year":"1999","journal-title":"Br J Psychiatry"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"175","DOI":"10.1007\/s10877-020-00464-4","article-title":"Low-dose Droperidol suppresses transcranial electrical motor-evoked potential amplitude: a retrospective study","volume":"35","author":"Deguchi","year":"2021","journal-title":"J Clin Monit Comput"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"126","DOI":"10.1016\/j.jad.2019.04.067","article-title":"The effect of psychotropic drugs on cortical excitability and plasticity measured with transcranial magnetic stimulation: implications for psychiatric treatment","volume":"253","author":"Minzenberg","year":"2019","journal-title":"J Affect Disord"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"2758","DOI":"10.1038\/sj.npp.1301122","article-title":"Modulation of human motor cortex excitability by single doses of amantadine","volume":"31","author":"Reis","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"2926","DOI":"10.1111\/bcp.15232","article-title":"Transcranial magnetic stimulation as biomarker of excitability in drug development: a randomized, double-blind, placebo-controlled, cross-over study","volume":"88","author":"Ruijs","year":"2022","journal-title":"Br J Clin Pharmacol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1017\/S1461145703003705","article-title":"Motor-evoked potential amplitudes elicited by transcranial magnetic stimulation do not differentiate between patients and Normal controls","volume":"6","author":"Grunhaus","year":"2003","journal-title":"Int J Neuropsychopharmacol"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1191\/1352458505ms1163oa","article-title":"Motor cortex excitability and fatigue in multiple sclerosis: a transcranial magnetic stimulation study","volume":"11","author":"Liepert","year":"2005","journal-title":"Mult Scler J"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1001","DOI":"10.1007\/s00415-008-0818-6","article-title":"Enhanced Corticomotor excitability with dynamic fatiguing exercise of the lower limb in multiple sclerosis","volume":"255","author":"Thickbroom","year":"2008","journal-title":"J Neurol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"858","DOI":"10.1016\/j.clinph.2012.01.010","article-title":"A practical guide to diagnostic transcranial magnetic stimulation: report of an IFCN committee","volume":"123","author":"Groppa","year":"2012","journal-title":"Clin Neurophysiol"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/0168-5597(93)90115-6","article-title":"Variability of motor potentials evoked by transcranial magnetic stimulation","volume":"89","author":"Kiers","year":"1993","journal-title":"Electroencephalogr Clin Neurophysiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1016\/S1388-2457(01)00633-2","article-title":"Transcranial magnetic stimulation Coregistered with MRI: a comparison of a guided versus blind stimulation technique and its effect on evoked compound muscle action potentials","volume":"112","author":"Gugino","year":"2001","journal-title":"Clin Neurophysiol"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"790","DOI":"10.1016\/j.neuroimage.2008.09.040","article-title":"Comparison of navigated and non-navigated transcranial magnetic stimulation for motor cortex mapping, motor threshold and motor evoked potentials","volume":"44","author":"Julkunen","year":"2009","journal-title":"Neuroimage"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"566","DOI":"10.3389\/fphys.2018.00566","article-title":"Intermuscular coherence between surface EMG signals is higher for monopolar compared to bipolar electrode configurations","volume":"9","author":"Mohr","year":"2018","journal-title":"Front Physiol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1123\/jab.13.2.135","article-title":"The use of surface electromyography in biomechanics","volume":"13","author":"Luca","year":"1997","journal-title":"J Appl Biomech"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"e86380","DOI":"10.1371\/journal.pone.0086380","article-title":"Optimization of the transcranial magnetic stimulation protocol by defining a reliable estimate for corticospinal excitability\u2019 edited by Hugo Theoret","volume":"9","author":"Cuypers","year":"2014","journal-title":"PloS One"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"1071","DOI":"10.1016\/j.clinph.2015.02.001","article-title":"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","volume":"126","author":"Rossini","year":"2015","journal-title":"Clin Neurophysiol"},{"key":"ref21","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1002\/0471732877.emd097","article-title":"Electromyography","volume-title":"Encyclopedia of medical devices and instrumentation","author":"Luca","year":"2006"},{"key":"ref22","doi-asserted-by":"crossref","DOI":"10.5772\/49957","article-title":"Normalization of EMG signals: To normalize or not to normalize and what to normalize to?","volume-title":"Computational intelligence in electromyography analysis - a perspective on current applications and future challenges","author":"Halaki","year":"2012"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"102438","DOI":"10.1016\/j.jelekin.2020.102438","article-title":"Consensus for experimental Design in Electromyography (CEDE) project: amplitude normalization matrix","volume":"53","author":"Besomi","year":"2020","journal-title":"J Electromyogr Kinesiol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1016\/j.jelekin.2011.11.009","article-title":"Evaluation of electromyography normalisation methods for the Back squat","volume":"22","author":"Balshaw","year":"2012","journal-title":"J Electromyogr Kinesiol"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.clinph.2023.04.014","article-title":"Replicability of motor cortex-excitability modulation by intermittent Theta burst stimulation","volume":"152","author":"Seybert","year":"2023","journal-title":"Clin Neurophysiol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"2008","DOI":"10.1016\/j.clinph.2009.08.016","article-title":"Safety, ethical considerations, and application guidelines for the use of transcranial magnetic stimulation in clinical practice and research","volume":"120","author":"Rossi","year":"2009","journal-title":"Clin Neurophysiol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"2299","DOI":"10.1093\/cercor\/bhr003","article-title":"Circadian modulation of GABA-mediated cortical inhibition","volume":"21","author":"Lang","year":"2011","journal-title":"Cereb Cortex"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"11828","DOI":"10.1038\/ncomms11828","article-title":"Circadian regulation of human cortical excitability","volume":"7","author":"Ly","year":"2016","journal-title":"Nat Commun"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"1118","DOI":"10.1016\/j.brs.2021.07.013","article-title":"Day-to-day variability in motor threshold during rTMS treatment for depression: clinical implications","volume":"14","author":"Cotovio","year":"2021","journal-title":"Brain Stimul"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"709368","DOI":"10.3389\/fnins.2021.709368","article-title":"TMS motor mapping methodology and reliability: a structured review","volume":"15","author":"Sondergaard","year":"2021","journal-title":"Front Neurosci"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2892","DOI":"10.1016\/j.clinph.2016.04.001","article-title":"Optimal number of pulses as outcome measures of Neuronavigated transcranial magnetic stimulation","volume":"127","author":"Chang","year":"2016","journal-title":"Clin Neurophysiol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1016\/j.clinph.2015.03.002","article-title":"Ongoing cumulative effects of single TMS pulses on corticospinal excitability: an intra- and inter-Block investigation","volume":"127","author":"Pellicciari","year":"2016","journal-title":"Clin Neurophysiol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1532","DOI":"10.1109\/83.862633","article-title":"Adaptive wavelet thresholding for image Denoising and compression","volume":"9","author":"Chang","year":"2000","journal-title":"IEEE Trans Image Process"},{"key":"ref34","first-page":"24","article-title":"Performance analysis of Savitzky-Golay smoothing filter using ECG signal","volume":"1","author":"Awal","year":"2011","journal-title":"Int J Computer and Info Technol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"633224","DOI":"10.3389\/fneur.2020.633224","article-title":"Time-frequency representation of motor evoked potentials in brain tumor patients","volume":"11","author":"Machetanz","year":"2021","journal-title":"Front Neurol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"385","DOI":"10.1515\/cdbme-2019-0097","article-title":"An efficient ECG Denoising method using discrete wavelet with Savitzky-Golay filter","volume":"5","author":"Samann","year":"2019","journal-title":"Current Directions in Biomed Engineer"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1998","DOI":"10.1002\/jssc.202000013","article-title":"Wavelet transforms in separation science for Denoising and peak overlap detection","volume":"43","author":"Wahab","year":"2020","journal-title":"J Sep Sci"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.brs.2014.01.004","article-title":"Inter- and intra-individual variability following intermittent Theta burst stimulation: implications for rehabilitation and recovery","volume":"7","author":"Hinder","year":"2014","journal-title":"Brain Stimul"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"2531","DOI":"10.1007\/s00221-020-05887-8","article-title":"Neck rotation modulates motor-evoked potential duration of proximal muscle cortical representations in healthy adults","volume":"238","author":"McCambridge","year":"2020","journal-title":"Exp Brain Res"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1016\/j.jcm.2016.02.012","article-title":"A guideline of selecting and reporting Intraclass correlation coefficients for reliability research","volume":"15","author":"Koo","year":"2016","journal-title":"J Chiropr Med"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"263","DOI":"10.3389\/fnagi.2017.00263","article-title":"Reproducibility of single-pulse, paired-pulse, and intermittent Theta-burst TMS measures in healthy aging, Type-2 diabetes, and Alzheimer\u2019s disease","volume":"9","author":"Fried","year":"2017","journal-title":"Front Aging Neurosci"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"447","DOI":"10.3389\/fnins.2019.00447","article-title":"Test\u2013retest reliability of the effects of continuous Theta-burst stimulation","volume":"13","author":"Jannati","year":"2019","journal-title":"Front Neurosci"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"1022","DOI":"10.1162\/jocn_a_01100","article-title":"Interindividual variability and Intraindividual reliability of intermittent Theta burst stimulation-induced neuroplasticity mechanisms in the healthy brain","volume":"29","author":"Schilberg","year":"2017","journal-title":"J Cogn Neurosci"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"376","DOI":"10.1007\/s00221-006-0468-9","article-title":"Variability of motor potentials evoked by transcranial magnetic stimulation depends on muscle activation","volume":"174","author":"Darling","year":"2006","journal-title":"Exp Brain Res"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.neuroscience.2019.04.054","article-title":"The effects of biological sex and ovarian hormones on exercise-induced neuroplasticity","volume":"410","author":"El-Sayes","year":"2019","journal-title":"Neuroscience"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.23736\/s0022-4707.20.10677-7","article-title":"Effects of twelve weeks\u2019 aerobic training on motor cortex excitability","volume":"60","author":"Moscatelli","year":"2020","journal-title":"J Sports Med Phys Fitness"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"242","DOI":"10.1016\/j.neuroscience.2020.03.042","article-title":"A single bout of high-intensity interval exercise increases corticospinal excitability, brain-derived neurotrophic factor, and Uncarboxylated Osteolcalcin in sedentary, healthy males","volume":"437","author":"Nicolini","year":"2020","journal-title":"Neuroscience"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"869","DOI":"10.1139\/apnm-2018-0643","article-title":"Intensity of acute aerobic exercise but not aerobic fitness impacts on corticospinal excitability","volume":"44","author":"MacDonald","year":"2019","journal-title":"Appl Physiol Nutr Metab"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"e0173672","DOI":"10.1371\/journal.pone.0173672","article-title":"Physical activity levels determine exercise-induced changes in brain excitability","volume":"12","author":"Lulic","year":"2017","journal-title":"PloS One"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1321","DOI":"10.1016\/j.clinph.2009.12.040","article-title":"Patients with primary biliary cirrhosis do not show post-exercise depression of cortical excitability","volume":"121","author":"Cerri","year":"2010","journal-title":"Clin Neurophysiol"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"716","DOI":"10.1016\/j.clinph.2015.06.013","article-title":"Atypical cortical drive during activation of the paretic and nonparetic tibialis anterior is related to gait deficits in chronic stroke","volume":"127","author":"Palmer","year":"2016","journal-title":"Clin Neurophysiol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"538","DOI":"10.1212\/WNL.49.2.538","article-title":"Decreased Postexercise facilitation of motor evoked potentials in patients with cerebellar degeneration","volume":"49","author":"Samii","year":"1997","journal-title":"Neurology"},{"key":"ref53","doi-asserted-by":"publisher","first-page":"056040","DOI":"10.1088\/1741-2552\/ac7dfc","article-title":"Detection of motor-evoked potentials below the noise floor: rethinking the motor stimulation threshold","volume":"19","author":"Li","year":"2022","journal-title":"J Neural Eng"},{"key":"ref54","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.jelekin.2018.04.007","article-title":"Maximal voluntary isometric contraction tests for normalizing Electromyographic data from different regions of supraspinatus and infraspinatus muscles: identifying reliable combinations","volume":"41","author":"Alenabi","year":"2018","journal-title":"J Electromyogr Kinesiol"},{"key":"ref55","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1177\/1545968309349939","article-title":"Does functional electrical stimulation for foot drop strengthen corticospinal connections?","volume":"24","author":"Everaert","year":"2010","journal-title":"Neurorehabil Neural Repair"},{"key":"ref56","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1007\/s00415-006-0334-5","article-title":"Motor evoked potentials in multiple sclerosis patients without walking limitation: amplitude vs. conduction time abnormalities","volume":"254","author":"Gagliardo","year":"2007","journal-title":"J Neurol"},{"key":"ref57","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1152\/japplphysiol.00595.2019","article-title":"Effect of fatigue-related group III\/IV afferent firing on Intracortical inhibition and facilitation in hand muscles","volume":"128","author":"Latella","year":"2020","journal-title":"J Appl Physiol"},{"key":"ref58","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1743-0003-2-33","article-title":"Reliability of the biceps Brachii M-wave","volume":"2","author":"Calder","year":"2005","journal-title":"J Neuroeng Rehabil"}],"container-title":["Frontiers in Psychiatry"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2024.1279072\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,1,31]],"date-time":"2024-01-31T04:23:36Z","timestamp":1706675016000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fpsyt.2024.1279072\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,31]]},"references-count":58,"alternative-id":["10.3389\/fpsyt.2024.1279072"],"URL":"https:\/\/doi.org\/10.3389\/fpsyt.2024.1279072","relation":{},"ISSN":["1664-0640"],"issn-type":[{"value":"1664-0640","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,31]]},"article-number":"1279072"}}