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Rate-dependent depression is impaired in amyotrophic lateral sclerosis

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Abstract

Objective

We investigated rate-dependent depression (RDD) of the Hoffman reflex (H-reflex) in patients with amyotrophic lateral sclerosis (ALS), a degenerative disease with ventral horn involvement.

Patients and methods

In this case–control study, we enrolled 27 patients with ALS and 30 matched healthy control subjects. Clinical and electrophysiological assessments, as well as RDD in response to various stimulation frequencies (0.5 Hz, 1 Hz, 3 Hz and 5 Hz), were compared between groups. Multiple clinical and electrophysiological factors were also explored to determine any underlying associations with RDD.

Results

The ALS group showed a significant loss of RDD across all frequencies compared to the control group, most notably following 1 Hz stimulation (19.1 ± 20.3 vs. 34.0 ± 13.7%, p = 0.003). Among factors that might influence RDD, the enlargement of the motor unit potential (MUP) showed a significant relationship with RDD following multifactor analysis of variance (p = 0.007) and Pearson correlation analysis (ρ =  − 0.70, p < 0.001), while various upper motor neuron manifestations were not correlated with RDD values (p > 0.05).

Conclusion

We report a loss of RDD in patients with ALS. The strong correlation detected between the RDD deficit and increased MUP suggests that RDD is a sensitive indicator of underlying spinal disinhibition in ALS.

Trial registration

ChiCTR2000038848, 10/7/2020 (retrospectively registered), http://www.chictr.org.cn/.

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Data availability

All data included in this study are available from the corresponding author upon request.

Code availability

Not applicable.

References

  1. Hardiman O, Al-Chalabi A, Chio A, Corr EM, Logroscino G, Robberecht W, Shaw PJ, Simmons Z, van den Berg LH (2017) Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3:17071. https://doi.org/10.1038/nrdp.2017.71

    Article  PubMed  Google Scholar 

  2. Misra UK, Kalita J (1998) A study of H reflex in amyotrophic lateral sclerosis. Neurol India 46:119–122

    CAS  PubMed  Google Scholar 

  3. Ishikawa K, Ott K, Porter RW, Stuart D (1966) Low frequency depression of the H wave in normal and spinal man. Exp Neurol 15:140–156. https://doi.org/10.1016/0014-4886(66)90039-2

    Article  CAS  PubMed  Google Scholar 

  4. Nielsen J, Petersen N, Ballegaard M, Biering-Sorensen F, Kiehn O (1993) H-reflexes are less depressed following muscle stretch in spastic spinal cord injured patients than in healthy subjects. Exp Brain Res 97:173–176. https://doi.org/10.1007/BF00228827

    Article  CAS  PubMed  Google Scholar 

  5. Aymard C, Katz R, Lafitte C, Lo E, Penicaud A, Pradat-Diehl P, Raoul S (2000) Presynaptic inhibition and homosynaptic depression: a comparison between lower and upper limbs in normal human subjects and patients with hemiplegia. Brain 123(Pt 8):1688–1702. https://doi.org/10.1093/brain/123.8.1688

    Article  PubMed  Google Scholar 

  6. Sabatier MJ, Wedewer W, Barton B, Henderson E, Murphy JT, Ou K (2015) Slope walking causes short-term changes in soleus H-reflex excitability. Physiol Rep 3:e12308. https://doi.org/10.14814/phy2.12308

    Article  PubMed  PubMed Central  Google Scholar 

  7. Lamy JC, Wargon I, Mazevet D, Ghanim Z, Pradat-Diehl P, Katz R (2009) Impaired efficacy of spinal presynaptic mechanisms in spastic stroke patients. Brain 132:734–748. https://doi.org/10.1093/brain/awn310

    Article  PubMed  Google Scholar 

  8. Marshall AG, Lee-Kubli C, Azmi S et al (2017) Spinal disinhibition in experimental and clinical painful diabetic neuropathy. Diabetes 66:1380–1390. https://doi.org/10.2337/db16-1181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lee-Kubli C, Marshall AG, Malik RA, Calcutt NA (2018) The H-reflex as a biomarker for spinal disinhibition in painful diabetic neuropathy. Curr Diab Rep 18:1. https://doi.org/10.1007/s11892-018-0969-5

    Article  PubMed  PubMed Central  Google Scholar 

  10. Brooks BR, Miller RG, Swash M, Munsat TL, World Federation of Neurology Research Group on Motor Neuron Diseases (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Mot Neuron Disord 1:293–299. https://doi.org/10.1080/146608200300079536

    Article  CAS  Google Scholar 

  11. Makary MM, Weerasekara A, Rodham H et al (2021) Comparison of two clinical upper motor neuron burden rating scales in ALS using quantitative brain imaging. ACS Chem Neurosci 12:906–916. https://doi.org/10.1021/acschemneuro.0c00772

    Article  CAS  PubMed  Google Scholar 

  12. Bohannon RW, Smith MB (1987) Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 67:206–207

    Article  CAS  Google Scholar 

  13. Nandedkar SD, Barkhaus PE, Stålberg EV, Neuwirth C, Weber M (2018) Motor unit number index: guidelines for recording signals and their analysis. Muscle Nerve 58:374–380. https://doi.org/10.1002/mus.26099

    Article  PubMed  Google Scholar 

  14. Jerath N, Kimura J (2019) F wave, A wave, H reflex, and blink reflex. Handb Clin Neurol 160:225–239. https://doi.org/10.1016/B978-0-444-64032-1.00015-1

    Article  PubMed  Google Scholar 

  15. Mekhael W, Begum S, Samaddar S, Hassan M, Toruno P, Ahmed M, Gorin A, Maisano M, Ayad M, Ahmed Z (2019) Repeated anodal trans-spinal direct current stimulation results in long-term reduction of spasticity in mice with spinal cord injury. J Physiol 597:2201–2223. https://doi.org/10.1113/JP276952

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Toda T, Ishida K, Kiyama H, Yamashita T, Lee S (2014) Down-regulation of KCC2 expression and phosphorylation in motoneurons, and increases the number of in primary afferent projections to motoneurons in mice with post-stroke spasticity. PLoS ONE 9:e114328. https://doi.org/10.1371/journal.pone.0114328

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sabbahi M, Etnyre B, Al-Jawayed IA, Hasson S, Jankovic J (2002) Methods of H-reflex evaluation in the early stages of Parkinson’s disease. J Clin Neurophysiol 19:67–72. https://doi.org/10.1097/00004691-200201000-00009

    Article  CAS  PubMed  Google Scholar 

  18. Pivik RT, Mercier L (1981) Spinal motoneuronal excitability in hyperkinesis: H-reflex recovery function and homosynaptic depression during wakefulness. J Clin Neuropsychol 3:215–236. https://doi.org/10.1080/01688638108403127

    Article  CAS  PubMed  Google Scholar 

  19. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424:938–942. https://doi.org/10.1038/nature01868

    Article  CAS  PubMed  Google Scholar 

  20. Sánchez-Brualla I, Boulenguez P, Brocard C, Liabeuf S, Viallat-Lieutaud A, Navarro X, Udina E, Brocard F (2018) Activation of 5-HT receptors restores KCC2 function and reduces neuropathic pain after spinal cord injury. Neuroscience 387:48–57. https://doi.org/10.1016/j.neuroscience.2017.08.033

    Article  CAS  PubMed  Google Scholar 

  21. Lee-Kubli CA, Calcutt NA (2014) Altered rate-dependent depression of the spinal H-reflex as an indicator of spinal disinhibition in models of neuropathic pain. Pain 155:250–260. https://doi.org/10.1016/j.pain.2013.10.001

    Article  PubMed  Google Scholar 

  22. Boulenguez P, Liabeuf S, Bos R, Bras H, Jean-Xavier C, Brocard C, Stil A, Darbon P, Cattaert D, Delpire E, Marsala M, Vinay L (2010) Down-regulation of the potassium-chloride cotransporter KCC2 contributes to spasticity after spinal cord injury. Nat Med 16:302–307. https://doi.org/10.1038/nm.2107

    Article  CAS  PubMed  Google Scholar 

  23. Fuchs A, Ringer C, Bilkei-Gorzo A, Weihe E, Roeper J, Schutz B (2010) Downregulation of the potassium chloride cotransporter KCC2 in vulnerable motoneurons in the SOD1-G93A mouse model of amyotrophic lateral sclerosis. J Neuropathol Exp Neurol 69:1057–1070. https://doi.org/10.1097/NEN.0b013e3181f4dcef

    Article  CAS  PubMed  Google Scholar 

  24. Branchereau P, Martin E, Allain AE, Cazenave W, Supiot L, Hodeib F, Laupenie A, Dalvi U, Zhu H, Cattaert D (2019) Relaxation of synaptic inhibitory events as a compensatory mechanism in fetal SOD spinal motor networks. Elife 8:e51402. https://doi.org/10.7554/eLife.51402

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Martin E, Cazenave W, Allain AE, Cattaert D, Branchereau P (2020) Implication of 5-HT in the dysregulation of chloride homeostasis in prenatal spinal motoneurons from the G93A mouse model of amyotrophic lateral sclerosis. Int J Mol Sci 21:1107. https://doi.org/10.3390/ijms21031107

    Article  CAS  PubMed Central  Google Scholar 

  26. Modol L, Mancuso R, Ale A, Francos-Quijorna I, Navarro X (2014) Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons. Front Cell Neurosci 8:7. https://doi.org/10.3389/fncel.2014.00007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Huynh W, Simon NG, Grosskreutz J, Turner MR, Vucic S, Kiernan MC (2016) Assessment of the upper motor neuron in amyotrophic lateral sclerosis. Clin Neurophysiol 127:2643–2660. https://doi.org/10.1016/j.clinph.2016.04.025

    Article  PubMed  Google Scholar 

  28. Babu S (2020) Upper motor neuron burden measurement in motor neuron diseases: does one scale fit all? Muscle Nerve 61:431–432. https://doi.org/10.1002/mus.26836

    Article  PubMed  Google Scholar 

  29. Chang YX, Zhao Y, Pan S, Qi ZP, Kong WJ, Pan YR, Li HR, Yang XY (2019) Intramuscular injection of adenoassociated virus encoding human neurotrophic factor 3 and exercise intervention contribute to reduce spasms after spinal cord injury. Neural Plast 2019:3017678. https://doi.org/10.1155/2019/3017678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Swash M, Czesnik D, de Carvalho M (2019) Muscular cramp: causes and management. Eur J Neurol 26:214–221. https://doi.org/10.1111/ene.13799

    Article  CAS  PubMed  Google Scholar 

  31. Mazzini L, Balzarini C, Gareri F, Brigatti M (1997) H-reflex changes in the course of amyotrophic lateral sclerosis. Electroencephalogr Clin Neurophysiol 104:411–417. https://doi.org/10.1016/s0168-5597(97)00071-3

    Article  CAS  PubMed  Google Scholar 

  32. de Carvalho M, Swash M (2016) Lower motor neuron dysfunction in ALS. Clin Neurophysiol 127:2670–2681. https://doi.org/10.1016/j.clinph.2016.03.024

    Article  PubMed  Google Scholar 

  33. Fukushima Y, Yamashita N, Shimada Y (1982) Facilitation of H-reflex by homonymous Ia-afferent fibers in man. J Neurophysiol 48:1079–1088. https://doi.org/10.1152/jn.1982.48.5.1079

    Article  CAS  PubMed  Google Scholar 

  34. Andrews JA, Shefner JM (2019) Clinical neurophysiology of anterior horn cell disorders. Handb Clin Neurol 161:317–326. https://doi.org/10.1016/B978-0-444-64142-7.00057-6

    Article  PubMed  Google Scholar 

  35. Amendola J, Durand J (2008) Morphological differences between wild-type and transgenic superoxide dismutase 1 lumbar motoneurons in postnatal mice. J Comp Neurol 511:329–341. https://doi.org/10.1002/cne.21818

    Article  PubMed  Google Scholar 

  36. Howells J, Matamala JM, Park SB, Garg N, Vucic S, Bostock H, Burke D, Kiernan MC (2018) In vivo evidence for reduced ion channel expression in motor axons of patients with amyotrophic lateral sclerosis. J Physiol 596:5379–5396. https://doi.org/10.1113/JP276624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Caress JB, Ciarlone SL, Sullivan EA, Griffin LP, Cartwright MS (2016) Natural history of muscle cramps in amyotrophic lateral sclerosis. Muscle Nerve 53:513–517. https://doi.org/10.1002/mus.24892

    Article  PubMed  Google Scholar 

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Acknowledgements

Dr Rayaz Malik and Dr Andrew Marshall helped improve the scientific rigour of the study.

Funding

This work was supported by the Shanghai Municipal Health Commission [grant number ZHYY-ZXJHZX-1–201701]. Dr Calcutt was supported by grant #1–17-ICTS-062 from the American Diabetes Association.

Author information

Author notes

  1. Xiajun Zhou and Ze Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, Renji Hospital, Shanghai Jiaotong University School of Medicine, 160 Pujian Road, Pudong, Shanghai, 200127, China

    Xiajun Zhou, Ze Wang, Zhi Lin, Desheng Zhu, Chong Xie & Yangtai Guan

  2. Department of Neurology, Shanghai International Medical Center, Shanghai, 201318, China

    Ying Zhu

  3. Department of Pathology, University of California San Diego, San Diego, CA, 92093, USA

    Nigel A. Calcutt

Authors
  1. Xiajun Zhou
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  7. Nigel A. Calcutt
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  8. Yangtai Guan
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Contributions

Xiajun Zhou: conceptualization, methodology, resources, writing — original draft preparation. Ze Wang: data curation, formal analysis, resources, writing — original draft preparation. Zhi Lin: data curation, methodology, formal analysis. Ying Zhu: conceptualization, data curation, methodology. Desheng Zhu: formal analysis, writing — review and editing. Chong Xie: resources, data curation, writing — review and editing. Nigel A. Calcutt: conceptualization; writing, review and editing; supervision. Yangtai Guan: supervision, project administration.

Corresponding author

Correspondence to Yangtai Guan.

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Ethics approval

This study was performed according to the principles of the Declaration of Helsinki, and it was approved by the Institutional Review Board of Renji Hospital, Shanghai Jiaotong University School of Medicine (#KY2020-056).

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Informed consent was obtained from all individual participants included in the study.

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Subjects signed informed consent regarding publishing their data.

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Zhou, X., Wang, Z., Lin, Z. et al. Rate-dependent depression is impaired in amyotrophic lateral sclerosis. Neurol Sci 43, 1831–1838 (2022). https://doi.org/10.1007/s10072-021-05596-2

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