Orderly recruitment of motor units under optical control in vivo
Open accessAbstract
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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Optical stimulation promotes the ability to orderly recruit muscle fibers, meaning slower motor units can be activated first.
“In fact, optical stimulation promotes the ability to orderly recruit the muscle fibers, meaning that the slower motor units can be activated first [130].”
From Interfaces with the peripheral nervous system for the control of a neuroprosthetic limb: a review (2020) · cites this paper as [130]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Millisecond-timescale, genetically targeted optical control of neural activity
Boyden, E. S., Zhang, F., Bamberg, E., Nagel, G., & Deisseroth, K. A. (2005) · Nature Neuroscience · doi:10.1038/nn1525 · Cited by 4,831 · see citing works
Self-citationFUNCTIONAL SIGNIFICANCE OF CELL SIZE IN SPINAL MOTONEURONS
Henneman, E., Somjen, G., & Carpenter, D. O. (1965) · Journal of Neurophysiology · doi:10.1152/jn.1965.28.3.560 · Cited by 2,294 · see citing works
Safety and Efficacy of Gene Transfer for Leber's Congenital Amaurosis
Maguire, A. M., Simonelli, F., Pierce, E. A., Pugh, E. N., Mingozzi, F., Bennicelli, J., Banfi, S., Marshall, K. A., Testa, F., Surace, E. M., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802315 · Cited by 2,145 · see citing works
Effect of gene therapy on visual function in Leber’s congenital amaurosis
Bainbridge, J. W. B., Smith, A. J., Barker, S. S., Robbie, S., Henderson, R., Balaggan, K., Viswanathan, A., Holder, G. E., Stockman, A., Tyler, N., et al. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa0802268 · Cited by 1,924 · see citing works
Physiological types and histochemical profiles in motor units of the cat gastrocnemius
Burke, R. E., Levine, D. N., Tsairis, P., & Zajac, F. E. (1973) · The Journal of Physiology · doi:10.1113/jphysiol.1973.sp010369 · Cited by 1,549 · see citing works
Relation between size of neurons and their susceptibility to discharge
Henneman, E. (1957) · Science · doi:10.1126/science.126.3287.1345 · Cited by 1,227 · see citing works
Molecular and Cellular Approaches for Diversifying and Extending Optogenetics
Gradinaru, V., Zhang, F., Ramakrishnan, C., Mattis, J., Prakash, R., Diester, I., Goshen, I., Thompson, K. R., & Deisseroth, K. A. (2010) · Cell · doi:10.1016/j.cell.2010.02.037 · Cited by 999 · see citing works
Self-citationModels of recruitment and rate coding organization in motor-unit pools.
Fuglevand, A. J., Winter, D. A., & Patla, A. E. (1993) · Journal of Neurophysiology · doi:10.1152/jn.1993.70.6.2470 · Cited by 988 · see citing works
The orderly recruitment of human motor units during voluntary isometric contractions
Milner‐Brown, H. S., Stein, R. B., & Yemm, R. (1973) · The Journal of Physiology · doi:10.1113/jphysiol.1973.sp010192 · Cited by 912 · see citing works
Mammalian Motor Units: Physiological-Histochemical Correlation in Three Types in Cat Gastrocnemius
Burke, R. E., Levine, D. N., Zajac, F. E., Tsairis, P., & Engel, W. K. (1971) · Science · doi:10.1126/science.174.4010.709 · Cited by 790 · see citing works
Circuit-breakers: optical technologies for probing neural signals and systems
Zhang, F., Aravanis, A. M., Adamantidis, A., de Lecea, L., & Deisseroth, K. A. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2192 · Cited by 623 · see citing works
Self-citationBi-stable neural state switches
Berndt, A., Yizhar, O., Gunaydin, L. A., Hegemann, P., & Deisseroth, K. A. (2008) · Nature Neuroscience · doi:10.1038/nn.2247 · Cited by 601 · see citing works
Self-citationBurkholder, T. J., Fingado, B., Baron, S., & Lieber, R. L. (1994) · Journal of Morphology · doi:10.1002/jmor.1052210207 · Cited by 527 · see citing works
Red-shifted optogenetic excitation: a tool for fast neural control derived from Volvox carteri
Zhang, F., Prigge, M., Beyrière, F., Tsunoda, S. P., Mattis, J., Yizhar, O., Hegemann, P., & Deisseroth, K. A. (2008) · Nature Neuroscience · doi:10.1038/nn.2120 · Cited by 526 · see citing works
Self-citationWang, H., Peça, J., Matsuzaki, M., Matsuzaki, K., Noguchi, J., Qiu, L., Wang, D., Zhang, F., Boyden, E. S., Deisseroth, K. A., et al. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0700384104 · Cited by 384 · see citing works
Self-citationPROPERTIES OF MOTOR UNITS IN A HOMOGENEOUS RED MUSCLE (SOLEUS) OF THE CAT
McPhedran, A. M., Wuerker, R. B., & Henneman, E. (1965) · Journal of Neurophysiology · doi:10.1152/jn.1965.28.1.71 · Cited by 323 · see citing works
PROPERTIES OF MOTOR UNITS IN A HETEROGENEOUS PALE MUSCLE (M. GASTROCNEMIUS) OF THE CAT
Wuerker, R. B., McPhedran, A. M., & Henneman, E. (1965) · Journal of Neurophysiology · doi:10.1152/jn.1965.28.1.85 · Cited by 318 · see citing works
Zajac, F. E., & Faden, J. S. (1985) · Journal of Neurophysiology · doi:10.1152/jn.1985.53.5.1303 · Cited by 236 · see citing works
Selective activation of small motor axons by quasitrapezoidal current pulses
Fang, Z.-P., & Mortimer, J. T. (1991) · IEEE Transactions on Biomedical Engineering · doi:10.1109/10.76383 · Cited by 222 · see citing works
The size principle: a rule describing the recruitment of motoneurons
Mendell, L. M. (2005) · Journal of Neurophysiology · doi:10.1152/classicessays.00025.2005 · Cited by 168 · see citing works
Developmental clustering of ion channels at and near the node of Ranvier.
Rasband, M., & Trimmer, J. S. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0326 · Cited by 158 · see citing works
Allen, D. G., & Westerblad, H. (1995) · The Journal of Physiology · doi:10.1113/jphysiol.1995.sp020883 · Cited by 146 · see citing works
Matching between motoneurone and muscle unit properties in rat medial gastrocnemius.
Bakels, R., & Kernell, D. (1993) · The Journal of Physiology · doi:10.1113/jphysiol.1993.sp019596 · Cited by 128 · see citing works
A method to effect physiological recruitment order in electrically activated muscle
Fang, Z.-P., & Mortimer, J. T. (1991) · IEEE Transactions on Biomedical Engineering · doi:10.1109/10.76384 · Cited by 125 · see citing works
Reinnervation and recovery of mouse soleus muscle after long-term denervation
Irintchev, A., Draguhn, A., & Wernig, A. (1990) · Neuroscience · doi:10.1016/0306-4522(90)90236-w · Cited by 117 · see citing works
Gordon, T., Thomas, C. K., Munson, J. B., & Stein, R. B. (2004) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/y04-081 · Cited by 98 · see citing works
Manipulation of Muscle Force with Various Firing Rate and Recruitment Control Strategies
Zhou, B.-H., Baratta, R. V., & Solomonow, M. (1987) · IEEE Transactions on Biomedical Engineering · doi:10.1109/tbme.1987.326037 · Cited by 91 · see citing works
Thrasher, T. A., Graham, G. M., & Popović, M. R. (2005) · Artificial Organs · doi:10.1111/j.1525-1594.2005.29076.x · Cited by 90 · see citing works
al‐Amood, W. S., Lewis, D. M., & Schmalbruch, H. (1991) · The Journal of Physiology · doi:10.1113/jphysiol.1991.sp018749 · Cited by 74 · see citing works
Cope, T. C., & Clark, B. D. (1991) · Journal of Neurophysiology · doi:10.1152/jn.1991.66.4.1127 · Cited by 63 · see citing works
The sizes of motoneurons supplying hindlimb muscles in the mouse
McHanwell, S., & Biscoe, T. J. (1981) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.1981.0062 · Cited by 62 · see citing works
Retrograde Labeling in Peripheral Nerve Research: It Is Not All Black and White
Hayashi, A., Moradzadeh, A., Hunter, D. A., et al. (2007) · Journal of Reconstructive Microsurgery · doi:10.1055/s-2007-992344 · Cited by 59 · see citing works
Selective fatigue of fast motor units after electrically elicited muscle contractions
Hamada, T., Kimura, T., & Moritani, T. (2004) · Journal of Electromyography and Kinesiology · doi:10.1016/j.jelekin.2004.03.008 · Cited by 53 · see citing works
(2000) · PubMed · Cited by 50 · see citing works
Effects of genetic selection and voluntary activity on the medial gastrocnemius muscle in house mice
Zhan, W., Swallow, J. G., Garland, T., Proctor, D. N., Carter, P. A., & Sieck, G. C. (1999) · Journal of Applied Physiology · doi:10.1152/jappl.1999.87.6.2326 · Cited by 46 · see citing works
Lertmanorat, Z., & Durand, D. M. (2004) · Journal of Neural Engineering · doi:10.1088/1741-2560/1/4/003 · Cited by 42 · see citing works
Kan, H. E., Busé-Pot, T., Navío, R. P., Isbrandt, D., Heerschap, A., & HAAN, A. D. (2005) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00040.2005 · Cited by 34 · see citing works
Recruitment Order Among Motoneurons From Different Motor Nuclei
Sokoloff, A. J., Siegel, S. G., & Cope, T. C. (1999) · Journal of Neurophysiology · doi:10.1152/jn.1999.81.5.2485 · Cited by 24 · see citing works
ICFEM 2000. Third IEEE International Conference on Formal Engineering Methods
(2000) · IEEE Transactions on Rehabilitation Engineering · doi:10.1109/86.867869 · Cited by 20 · see citing works
Motor Neuron Inhibition–Based Gene Therapy for Spasticity
McClelland, S., Teng, Q., Benson, L. S., et al. (2007) · American Journal of Physical Medicine & Rehabilitation · doi:10.1097/phm.0b013e31804a83cf · Cited by 12 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Optogenetics in neural systems
Yizhar, O., Fenno, L. E., Davidson, T. J., Mogri, M., & Deisseroth, K. (2011) · Neuron · doi:10.1016/j.neuron.2011.06.004 · Cited by 1,881 · see citing works
Self-citationThe development and application of optogenetics
Fenno, L., Yizhar, O., & Deisseroth, K. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113817 · Cited by 1,822 · see citing works
Self-citationRejuvenation of the muscle stem cell population restores strength to injured aged muscles
Cosgrove, B. D., Gilbert, P. M., Porpiglia, E., Mourkioti, F., Lee, S. P., Corbel, S. Y., Llewellyn, M. E., Delp, S. L., & Blau, H. M. (2014) · Nature Medicine · doi:10.1038/nm.3464 · Cited by 677 · see citing works
Self-citationSensory feedback for limb prostheses in amputees
Raspopovic, S., Valle, G., & Petrini, F. M. (2021) · Nature Materials · doi:10.1038/s41563-021-00966-9 · Cited by 308 · see citing works
A mm-Sized Wireless Implantable Device for Electrical Stimulation of Peripheral Nerves
Charthad, J., Chang, T. C., Liu, Z., Sawaby, A., Weber, M. J., Baker, S., Gore, F., Felt, S. A., & Arbabian, A. (2018) · IEEE Transactions on Biomedical Circuits and Systems · doi:10.1109/tbcas.2018.2799623 · Cited by 230 · see citing works
Optical Control of Muscle Function by Transplantation of Stem Cell–Derived Motor Neurons in Mice
Bryson, J. B., Machado, C. B., Crossley, M., Stevenson, D., Bros-Facer, V., Burrone, J., Greensmith, L., & Lieberam, I. (2014) · Science · doi:10.1126/science.1248523 · Cited by 163 · see citing works
Optogenetic Control of Targeted Peripheral Axons in Freely Moving Animals
Towne, C., Montgomery, K. L., Iyer, S. M., Deisseroth, K., & Delp, S. L. (2013) · PLoS ONE · doi:10.1371/journal.pone.0072691 · Cited by 156 · see citing works
Self-citationBeyond the brain: Optogenetic control in the spinal cord and peripheral nervous system
Montgomery, K. L., Iyer, S. M., Christensen, A. J., Deisseroth, K., & Delp, S. L. (2016) · Science Translational Medicine · doi:10.1126/scitranslmed.aad7577 · Cited by 147 · see citing works
Self-citationA review for the peripheral nerve interface designer
Larson, C. E., & Meng, E. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2019.108523 · Cited by 133 · see citing works
Interfaces with the peripheral nervous system for the control of a neuroprosthetic limb: a review
Yildiz, K. A., Shin, A. Y., & Kaufman, K. R. (2020) · Journal of NeuroEngineering and Rehabilitation · doi:10.1186/s12984-020-00667-5 · Cited by 113 · see citing works
Polymer Fiber Probes Enable Optical Control of Spinal Cord and Muscle Function In Vivo
Lu, C., Froriep, U. P., Koppes, R. A., Canales, A., Caggiano, V., Selvidge, J., Bizzi, E., & Anikeeva, P. (2014) · Advanced Functional Materials · doi:10.1002/adfm.201401266 · Cited by 85 · see citing works
Ultraflexible organic light-emitting diodes for optogenetic nerve stimulation
Kim, D., Yokota, T., Suzuki, T., Lee, S., Woo, T., Yukita, W., Koizumi, M., Tachibana, Y., Yawo, H., Onodera, H., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007395117 · Cited by 81 · see citing works
Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy
Yin, J., Yang, L., Xie, Y., Liu, Y., Li, S., Yang, W., Xu, B., Ji, H., Ding, L., Wang, K., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04038-6 · Cited by 72 · see citing works
Closed-loop functional optogenetic stimulation
Srinivasan, S. S., Maimon, B. E., Diaz, M., Song, H., & Herr, H. M. (2018) · Nature Communications · doi:10.1038/s41467-018-07721-w · Cited by 68 · see citing works
Raspopovic, S., Capogrosso, M., Badia, J., Navarro, X., & Micera, S. (2012) · IEEE Transactions on Neural Systems and Rehabilitation Engineering · doi:10.1109/tnsre.2012.2189021 · Cited by 63 · see citing works
A shape-memory and spiral light-emitting device for precise multisite stimulation of nerve bundles
Zheng, H., Zhang, Z., Jiang, S., Yan, B., Shi, X., Xie, Y., Huang, X., Yu, Z., Liu, H., Weng, S., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-10418-3 · Cited by 58 · see citing works
Transdermal optogenetic peripheral nerve stimulation
Maimon, B. E., Zorzos, A. N., Bendell, R., Harding, A., Fahmi, M., Srinivasan, S., Calvaresi, P., & Herr, H. M. (2017) · Journal of Neural Engineering · doi:10.1088/1741-2552/aa5e20 · Cited by 42 · see citing works
Duke, A. R., Peterson, E., Mackanos, M. A., Atkinson, J., Tyler, D., & Jansen, E. D. (2012) · Journal of Neural Engineering · doi:10.1088/1741-2560/9/6/066006 · Cited by 45 · see citing works
Optical control of neuronal excitation and inhibition using a single opsin protein, ChR2
Liske, H., Qian, X., Anikeeva, P., Deisseroth, K., & Delp, S. (2013) · Scientific Reports · doi:10.1038/srep03110 · Cited by 42 · see citing works
Self-citationOptogenetically enhanced axon regeneration: motor versus sensory neuron‐specific stimulation
Ward, P. J., Clanton, S. L., & English, A. W. (2018) · European Journal of Neuroscience · doi:10.1111/ejn.13836 · Cited by 38 · see citing works
- Authors
- Llewellyn, M. E., Thompson, K. R., Deisseroth, K., & Delp, S. L.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Corresponding author
- Deisseroth, Karl
- Delp, Scott L
- Venue
- Nature Medicine
- Published
- 2010-09-26
- Volume
- 16
- Issue
- 10
- Pages
- 1161-1165
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC5839640
- OpenAlex
- W2110181951
- Cited by
- 217
- References
- 40
- Citations by year
- 2026: 4 · 2025: 15 · 2024: 7 · 2023: 15 · 2022: 10 · 2021: 12 · 2020: 9 · 2019: 17 · 2018: 19 · 2017: 14 · 2016: 24 · 2015: 14 · 2014: 15 · 2013: 16 · 2012: 13
- FWCI
- 5.42
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R24HD065690)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neural Engineering
- Physical Sciences › Engineering › Biomedical Engineering › Muscle activation and electromyography studies
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Photoreceptor and optogenetics research
- Keywords
- motor unit recruitment, microbial opsins, neuromuscular electrical stimulation, neuromuscular fatigue, stimulation threshold, neuroprosthetics, neurorehabilitation
- MeSH terms
- Channelrhodopsins, Animals, Electric Stimulation, Electromyography, Mice, Inbred C57BL, Motor Neurons, Muscle Contraction, Peripheral Nerves, Reaction Time, Recruitment, Neurophysiological, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
