{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T13:14:58Z","timestamp":1784121298249,"version":"3.55.0"},"reference-count":42,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T00:00:00Z","timestamp":1695859200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001778","name":"Deakin University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001778","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Physiology"],"published-print":{"date-parts":[[2023,11]]},"abstract":"<jats:sec><jats:title>Abstract<\/jats:title><jats:p>Increased amplitude of persistent inward currents (PICs) is observed in pre\u2010symptomatic genetically modified SOD1 mice models of amyotrophic lateral sclerosis (ALS). However, at the symptomatic stage this reverses and there is a large reduction in PIC amplitude. It remains unclear whether these changes in PICs can be observed in humans, with cross\u2010sectional studies in humans reporting contradictory findings. In people with ALS, we estimated the PIC contribution to self\u2010sustained firing of motoneurons, using the paired\u2010motor unit analysis to calculate the \u0394frequency (\u0394<jats:italic>F<\/jats:italic>), to compare the weaker and stronger muscles during the course of disease. We hypothesised that, with disease progression, \u0394<jats:italic>F<\/jats:italic>s would relatively increase in the stronger muscles; and decline in the weaker muscles. Forty\u2010three individuals with ALS were assessed in two occasions on average 17\u00a0weeks apart. Tibialis anterior high\u2010density electromyograms were recorded during dorsiflexion (40% of maximal capacity) ramped contractions, followed by clinical tests. \u2206<jats:italic>F<\/jats:italic> increased from 3.14 (2.57, 3.71)\u00a0peaks per second (pps) to 3.55 (2.94, 4.17)\u00a0pps on the stronger muscles (0.41 (0.041, 0.781)\u00a0pps, standardised difference (<jats:italic>d<\/jats:italic>)\u00a0=\u00a00.287 (0.023, 0.552), <jats:italic>P<\/jats:italic>\u00a0=\u00a00.030). \u2206<jats:italic>F<\/jats:italic> reduced from 3.38 (95% CI 2.92, 3.84)\u00a0pps to 2.88 (2.40, 3.36)\u00a0pps on the weaker muscles (\u22120.50 (\u22120.80, \u22120.21)\u00a0pps, <jats:italic>d<\/jats:italic>\u00a0=\u00a00.353 (0.138, 0.567), <jats:italic>P<\/jats:italic>\u00a0=\u00a00.001). The ALSFRS\u2010R score reduced 3.9 (2.3, 5.5) points. These data indicate that the contribution of PICs to motoneuron self\u2010sustained firing increases over time in early stages of the disease when there is little weakness before decreasing as the disease progresses and muscle weakness exacerbates, in alignment with the findings from studies using SOD1 mice.\n<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/png\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/tjp15746-gra-0001-m.png\"><jats:alt-text>image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><\/jats:sec><jats:sec><jats:title>Key points<\/jats:title><jats:p><jats:list list-type=\"bullet\">\n<jats:list-item><jats:p>Research on mouse model of amyotrophic lateral sclerosis (ALS) suggests that the amplitude of persistent inward currents (PICs) is increased in early stages before decreasing as the disease progresses.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>Cross\u2010sectional studies in humans have reported contradictory findings with both higher and lower PIC contributions to motoneuron self\u2010sustained firing.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>In this longitudinal (\u223c17\u00a0weeks) study we tracked changes in PIC contribution to motoneuron self\u2010sustained firing, using the \u0394<jats:italic>F<\/jats:italic> calculation (i.e. onset\u2010offset hysteresis of motor unit pairs), in tibialis anterior muscles with normal strength and with clinical signs of weakness in people with ALS.<\/jats:p><\/jats:list-item>\n<jats:list-item><jats:p>\u0394<jats:italic>F<\/jats:italic>s decreased over time in muscles with clinical signs of weakness. The PIC contribution to motoneuron self\u2010sustained firing increases before the onset of muscle weakness, and subsequently decreases when muscle weakness progresses.<\/jats:p><\/jats:list-item>\n<\/jats:list><\/jats:p><\/jats:sec>","DOI":"10.1113\/jp285181","type":"journal-article","created":{"date-parts":[[2023,9,28]],"date-time":"2023-09-28T13:52:49Z","timestamp":1695909169000},"page":"4723-4735","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Longitudinal changes in intrinsic motoneuron excitability in amyotrophic lateral sclerosis are dependent on disease progression"],"prefix":"10.1113","volume":"601","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4667-4257","authenticated-orcid":false,"given":"Gabriel S.","family":"Trajano","sequence":"first","affiliation":[{"name":"School of Exercise and Nutrition Sciences, Faculty of Health Queensland University of Technology (QUT)  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3788-3700","authenticated-orcid":false,"given":"Lucas B. R.","family":"Orssatto","sequence":"additional","affiliation":[{"name":"Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Faculty of Health Deakin University  Geelong Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2704-8517","authenticated-orcid":false,"given":"Pamela A.","family":"McCombe","sequence":"additional","affiliation":[{"name":"Department of Neurology Royal Brisbane &amp; Women's Hospital  Brisbane Queensland Australia"},{"name":"UQ Centre for Clinical Research The University of Queensland  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4204-5130","authenticated-orcid":false,"given":"Warwick","family":"Rivlin","sequence":"additional","affiliation":[{"name":"Department of Neurology Royal Brisbane &amp; Women's Hospital  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Neurology Royal Brisbane &amp; Women's Hospital  Brisbane Queensland Australia"},{"name":"UQ Centre for Clinical Research The University of Queensland  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2820-8183","authenticated-orcid":false,"given":"Robert D.","family":"Henderson","sequence":"additional","affiliation":[{"name":"Department of Neurology Royal Brisbane &amp; Women's Hospital  Brisbane Queensland Australia"},{"name":"UQ Centre for Clinical Research The University of Queensland  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,9,28]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2020.08.009"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/braincomms\/fcaa018"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2552\/acb1d7"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284192"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-510X(99)00210-5"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws274"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.3109\/17482968.2012.725416"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP283630"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2009.12.041"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(22)01272-7"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP284164"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00024.2001"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1419497111"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2552\/ab5eda"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2007.145078"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1177\/1073858408314986"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1088\/1741-2560\/11\/1\/016008"},{"key":"e_1_2_6_19_1","doi-asserted-by":"publisher","DOI":"10.1109\/TSP.2007.896108"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1523\/ENEURO.0378-20.2021"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP280097"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.3389\/fncir.2014.00081"},{"key":"e_1_2_6_23_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00018.2017"},{"key":"e_1_2_6_24_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00144.2021"},{"key":"e_1_2_6_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(10)61156-7"},{"key":"e_1_2_6_26_1","doi-asserted-by":"publisher","DOI":"10.1002\/mus.24196"},{"key":"e_1_2_6_27_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00665.2003"},{"key":"e_1_2_6_28_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2004.074138"},{"key":"e_1_2_6_29_1","doi-asserted-by":"publisher","DOI":"10.18637\/jss.v082.i13"},{"key":"e_1_2_6_30_1","doi-asserted-by":"publisher","DOI":"10.3389\/fpsyg.2013.00863"},{"key":"e_1_2_6_31_1","unstructured":"Lenth R. V. Buerkner P. Herve M. Love J. Riebl H. &Singmann H.(2021). emmeans: Estimated Marginal Means aka Least\u2010Squares Means \u2010 R package.https:\/\/github.com\/rvlenth\/emmeans"},{"key":"e_1_2_6_32_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP278117"},{"key":"e_1_2_6_33_1","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.30955"},{"key":"e_1_2_6_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/med\/9780199688395.001.0001"},{"key":"e_1_2_6_35_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2022.06.016"},{"key":"e_1_2_6_36_1","doi-asserted-by":"publisher","DOI":"10.1113\/JP283708"},{"key":"e_1_2_6_37_1","doi-asserted-by":"publisher","DOI":"10.1152\/jn.00697.2020"},{"key":"e_1_2_6_38_1","doi-asserted-by":"publisher","DOI":"10.2340\/16501977-0235"},{"key":"e_1_2_6_39_1","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2010.200659"},{"key":"e_1_2_6_40_1","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181b6bbbd"},{"key":"e_1_2_6_41_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(08)70293-X"},{"key":"e_1_2_6_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinph.2018.09.014"},{"key":"e_1_2_6_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2021.10.030"}],"container-title":["The Journal of Physiology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.1113\/JP285181","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,1]],"date-time":"2023-11-01T07:25:06Z","timestamp":1698823506000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.1113\/JP285181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,28]]},"references-count":42,"journal-issue":{"issue":"21","published-print":{"date-parts":[[2023,11]]}},"alternative-id":["10.1113\/JP285181"],"URL":"https:\/\/doi.org\/10.1113\/jp285181","archive":["Portico"],"relation":{},"ISSN":["0022-3751","1469-7793"],"issn-type":[{"value":"0022-3751","type":"print"},{"value":"1469-7793","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,28]]},"assertion":[{"value":"2023-06-20","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-07","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-09-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}