Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Technical Report
  • Published:

Orderly recruitment of motor units under optical control in vivo

Nature Medicine volume 16, pages 1161–1165 (2010)Cite this article

Subjects

Abstract

A drawback of electrical stimulation for muscle control is that large, fatigable motor units are preferentially recruited before smaller motor units by the lowest-intensity electrical cuff stimulation. This phenomenon limits therapeutic applications because it is precisely the opposite of the normal physiological (orderly) recruitment pattern; therefore, a mechanism to achieve orderly recruitment has been a long-sought goal in physiology, medicine and engineering. Here we demonstrate a technology for reliable orderly recruitment in vivo. We find that under optical control with microbial opsins, recruitment of motor units proceeds in the physiological recruitment sequence, as indicated by multiple independent measures of motor unit recruitment including conduction latency, contraction and relaxation times, stimulation threshold and fatigue. As a result, we observed enhanced performance and reduced fatigue in vivo. These findings point to an unanticipated new modality of neural control with broad implications for nervous system and neuromuscular physiology, disease research and therapeutic innovation.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ChR2 in mouse sciatic nerve.
Figure 2: Optogenetic control of peripheral nerve.
Figure 3: Orderly recruitment and fatigue resistance with optical stimulation.
Figure 4: Differential recruitment of soleus and lateral gastrocnemius with electrical and optical stimulation.

Similar content being viewed by others

References

  1. Burke, R.E., Levine, D.N., Tsairis, P. & Zajac, F.E. III. Physiological types and histochemical profiles in motor units of the cat gastrocnemius. J. Physiol. (Lond.) 234, 723–748 (1973).

    Article  CAS  Google Scholar 

  2. Henneman, E. Relation between size of neurons and their susceptibility to discharge. Science 126, 1345–1347 (1957).

    Article  CAS  Google Scholar 

  3. Henneman, E., Somjen, G. & Carpenter, D.O. Functional significance of cell size in spinal motoneurons. J. Neurophysiol. 28, 560–580 (1965).

    Article  CAS  Google Scholar 

  4. Gordon, T., Thomas, C.K., Munson, J.B. & Stein, R.B. The resilience of the size principle in the organization of motor unit properties in normal and reinnervated adult skeletal muscles. Can. J. Physiol. Pharmacol. 82, 645–661 (2004).

    Article  CAS  Google Scholar 

  5. Mendell, L.M. The size principle: a rule describing the recruitment of motoneurons. J. Neurophysiol. 93, 3024–3026 (2005).

    Article  Google Scholar 

  6. Bakels, R. & Kernell, D. Matching between motoneurone and muscle unit properties in rat medial gastrocnemius. J. Physiol. (Lond.) 463, 307–324 (1993).

    Article  CAS  Google Scholar 

  7. Singh, K., Richmond, F.J. & Loeb, G.E. Recruitment properties of intramuscular and nerve-trunk stimulating electrodes. IEEE Trans. Rehabil. Eng. 8, 276–285 (2000).

    Article  CAS  Google Scholar 

  8. Fang, Z.P. & Mortimer, J.T. Selective activation of small motor axons by quasi-trapezoidal current pulses. IEEE Trans. Biomed. Eng. 38, 168–174 (1991).

    Article  CAS  Google Scholar 

  9. Lertmanorat, Z. & Durand, D.M. Extracellular voltage profile for reversing the recruitment order of peripheral nerve stimulation: a simulation study. J. Neural Eng. 1, 202–211 (2004).

    Article  Google Scholar 

  10. Hamada, T., Kimura, T. & Moritani, T. Selective fatigue of fast motor units after electrically elicited muscle contractions. J. Electromyogr. Kinesiol. 14, 531–538 (2004).

    Article  Google Scholar 

  11. Zhang, F., Aravanis, A.M., Adamantidis, A., de Lecea, L. & Deisseroth, K. Circuit-breakers: optical technologies for probing neural signals and systems. Nat. Rev. Neurosci. 8, 577–581 (2007).

    Article  CAS  Google Scholar 

  12. Boyden, E.S., Zhang, F., Bamberg, E., Nagel, G. & Deisseroth, K. Millisecond-timescale, genetically targeted optical control of neural activity. Nat. Neurosci. 8, 1263–1268 (2005).

    Article  CAS  Google Scholar 

  13. Wang, H. et al. High-speed mapping of synaptic connectivity using photostimulation in channelrhodopsin-2 transgenic mice. Proc. Natl. Acad. Sci. USA 104, 8143–8148 (2007).

    Article  CAS  Google Scholar 

  14. Rasband, M.N. & Trimmer, J.S. Developmental clustering of ion channels at and near the node of Ranvier. Dev. Biol. 236, 5–16 (2001).

    Article  CAS  Google Scholar 

  15. Zajac, F.E. & Faden, J.S. Relationship among recruitment order, axonal conduction velocity and muscle-unit properties of type-identified motor units in cat plantaris muscle. J. Neurophysiol. 53, 1303–1322 (1985).

    Article  CAS  Google Scholar 

  16. Fuglevand, A.J., Winter, D.A. & Patla, A.E. Models of recruitment and rate coding organization in motor-unit pools. J. Neurophysiol. 70, 2470–2488 (1993).

    Article  CAS  Google Scholar 

  17. Kan, H.E. et al. Lower force and impaired performance during high-intensity electrical stimulation in skeletal muscle of GAMT-deficient knockout mice. Am. J. Physiol. Cell Physiol. 289, C113–C119 (2005).

    Article  CAS  Google Scholar 

  18. Zhan, W.Z. et al. Effects of genetic selection and voluntary activity on the medial gastrocnemius muscle in house mice. J. Appl. Physiol. 87, 2326–2333 (1999).

    Article  CAS  Google Scholar 

  19. McPhedran, A.M., Wuerker, R.B. & Henneman, E. Properties of motor units in a heterogeneous pale muscle (m. gastrocnemius) of the cat. J. Neurophysiol. 28, 85–99 (1965).

    Article  CAS  Google Scholar 

  20. Burkholder, T.J., Fingado, B., Baron, S. & Lieber, R.L. Relationship between muscle fiber types and sizes and muscle architectural properties in the mouse hindlimb. J. Morphol. 221, 177–190 (1994).

    Article  CAS  Google Scholar 

  21. Cope, T.C. & Clark, B.D. Motor-unit recruitment in the decerebrate cat: several unit properties are equally good predictors of order. J. Neurophysiol. 66, 1127–1138 (1991).

    Article  CAS  Google Scholar 

  22. Milner-Brown, H.S., Stein, R.B. & Yemm, R. The orderly recruitment of human motor units during voluntary isometric contractions. J. Physiol. (Lond.) 230, 359–370 (1973).

    Article  CAS  Google Scholar 

  23. Allen, D.G. & Westerblad, H. The effects of caffeine on intracellular calcium, force and the rate of relaxation of mouse skeletal muscle. J. Physiol. (Lond.) 487, 331–342 (1995).

    Article  CAS  Google Scholar 

  24. al-Amood, W.S., Lewis, D.M. & Schmalbruch, H. Effects of chronic electrical stimulation on contractile properties of long-term denervated rat skeletal muscle. J. Physiol. (Lond.) 441, 243–256 (1991).

    Article  CAS  Google Scholar 

  25. Burke, R.E., Levine, D.N. & Zajac, F.E. Mammalian motor units: physiological-histochemical correlation in three types in cat gastrocnemius. Science 174, 709–712 (1971).

    Article  CAS  Google Scholar 

  26. Sokoloff, A.J., Siegel, S.G. & Cope, T.C. Recruitment order among motoneurons from different motor nuclei. J. Neurophysiol. 81, 2485–2492 (1999).

    Article  CAS  Google Scholar 

  27. Hayashi, A. et al. Retrograde labeling in peripheral nerve research: it is not all black and white. J. Reconstr. Microsurg. 23, 381–389 (2007).

    Article  Google Scholar 

  28. Thrasher, A., Graham, G.M. & Popovic, M.R. Reducing muscle fatigue due to functional electrical stimulation using random modulation of stimulation parameters. Artif. Organs 29, 453–458 (2005).

    Article  Google Scholar 

  29. Fang, Z.P. & Mortimer, J.T. A method to effect physiological recruitment order in electrically activated muscle. IEEE Trans. Biomed. Eng. 38, 175–179 (1991).

    Article  CAS  Google Scholar 

  30. Zhou, B.H., Baratta, R. & Solomonow, M. Manipulation of muscle force with various firing rate and recruitment control strategies. IEEE Trans. Biomed. Eng. 34, 128–139 (1987).

    Article  CAS  Google Scholar 

  31. Zhang, F. et al. Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri. Nat. Neurosci. 11, 631–633 (2008).

    Article  Google Scholar 

  32. Berndt, A., Yizhar, O., Gunaydin, L.A., Hegemann, P. & Deisseroth, K. Bi-stable neural state switches. Nat. Neurosci. 12, 229–234 (2009).

    Article  CAS  Google Scholar 

  33. Bainbridge, J.W. et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N. Engl. J. Med. 358, 2231–2239 (2008).

    Article  CAS  Google Scholar 

  34. Maguire, A.M. et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N. Engl. J. Med. 358, 2240–2248 (2008).

    Article  CAS  Google Scholar 

  35. McClelland, S., Teng, Q., Benson, L.S. & Boulis, N.M. Motor neuron inhibition–based gene therapy for spasticity. Am. J. Phys. Med. Rehabil. 86, 412–421 (2007).

    Article  Google Scholar 

  36. Gradinaru, V. et al. Molecular and cellular approaches for diversifying and extending optogenetics. Cell 141, 154–165 (2010).

    Article  CAS  Google Scholar 

  37. Irintchev, A., Draguhn, A. & Wernig, A. Reinnervation and recovery of mouse soleus muscle after long-term denervation. Neuroscience 39, 231–243 (1990).

    Article  CAS  Google Scholar 

  38. McHanwell, S. & Biscoe, T.J. The sizes of motoneurons supplying hindlimb muscles in the mouse. Proc. R. Soc. Lond. B Biol. Sci. 213, 201–216 (1981).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank R. Barretto and D. Wetmore for technical assistance and K. McGill, Z. Lateva, R. Lieber, D. Lin and F. Zajac for fruitful discussions. This work was supported by a Stanford Bio-X Interdisciplinary Initiatives award (S.L.D. and K.D.), the National Alliance for Research on Schizophrenia and Depression (K.R.T.), and the Stanford–US National Institutes of Health Medical Scientist Training Program (M.E.L.).

Author information

Authors and Affiliations

  1. Department of Bioengineering, Stanford University, Stanford, California, USA

    Michael E Llewellyn, Kimberly R Thompson, Karl Deisseroth & Scott L Delp

  2. Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, USA

    Karl Deisseroth

  3. Department of Mechanical Engineering, Stanford University, Stanford, California, USA

    Scott L Delp

Authors
  1. Michael E Llewellyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kimberly R Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karl Deisseroth
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Scott L Delp
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.E.L. conducted the experiments, performed the analysis and wrote the manuscript. K.R.T. performed the imaging experiments and wrote the manuscript. S.L.D. and K.D. supervised the project and wrote the manuscript.

Corresponding authors

Correspondence to Karl Deisseroth or Scott L Delp.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Methods (PDF 435 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Llewellyn, M., Thompson, K., Deisseroth, K. et al. Orderly recruitment of motor units under optical control in vivo. Nat Med 16, 1161–1165 (2010). https://doi.org/10.1038/nm.2228

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm.2228

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing