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Low-frequency cortical activity is a neuromodulatory target that tracks recovery after stroke

Nature Medicinevolume 24pages12571267 (2018) | Download Citation


Recent work has highlighted the importance of transient low-frequency oscillatory (LFO; <4 Hz) activity in the healthy primary motor cortex during skilled upper-limb tasks. These brief bouts of oscillatory activity may establish the timing or sequencing of motor actions. Here, we show that LFOs track motor recovery post-stroke and can be a physiological target for neuromodulation. In rodents, we found that reach-related LFOs, as measured in both the local field potential and the related spiking activity, were diminished after stroke and that spontaneous recovery was closely correlated with their restoration in the perilesional cortex. Sensorimotor LFOs were also diminished in a human subject with chronic disability after stroke in contrast to two non-stroke subjects who demonstrated robust LFOs. Therapeutic delivery of electrical stimulation time-locked to the expected onset of LFOs was found to significantly improve skilled reaching in stroke animals. Together, our results suggest that restoration or modulation of cortical oscillatory dynamics is important for the recovery of upper-limb function and that they may serve as a novel target for clinical neuromodulation.

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This work was supported by awards from the National Institute of Neurological Disorders and Stroke, NIH (Pathway to Independence Award to T.G., 1K99NS097620), A*STAR (fellowship to L.G.), Department of Veterans Affairs, Veterans Health Administration (VA Merit: 1I01RX001640 to K.G., Career Development Award: 7IK2BX003308 to D.S.R.) and National Institute of Mental Health, NIH (5R01MH111871 to K.G.); and start-up funds from the UCSF Department of Neurology to K.G.; and a Career Award for Medical Scientists from the Burroughs Wellcome Fund to D.S.R. (1015644). K.G. also holds a Career Award for Medical Scientists from the Burroughs Wellcome Fund (1009855) and an Independent Scientist Award (1K02NS093014) from the National Institute of Neurological Disorders and Stroke, NIH. This human work was also supported by a grant from the NIH (R37NS21135 to R.T.K.).

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Author notes

  1. These authors contributed equally: Dhakshin S. Ramanathan, Ling Guo, Tanuj Gulati.


  1. Neurology Service, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

    • Dhakshin S. Ramanathan
    • , Ling Guo
    • , Tanuj Gulati
    • , Gray Davidson
    • , April K. Hishinuma
    • , Seok-Joon Won
    • , Raymond A. Swanson
    •  & Karunesh Ganguly
  2. Mental Health Service, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA

    • Dhakshin S. Ramanathan
    •  & Gray Davidson
  3. Department of Psychiatry, University of California, San Francisco, San Francisco, CA, USA

    • Dhakshin S. Ramanathan
    •  & Gray Davidson
  4. Mental Health Service, VA San Diego Health System, San Diego, San Diego, CA, USA

    • Dhakshin S. Ramanathan
  5. Department of Psychiatry, University of California, San Diego, San Diego, CA, USA

    • Dhakshin S. Ramanathan
  6. Neuroscience Graduate Program, University of California, San Francisco, San Francisco, CA, USA

    • Ling Guo
  7. Department of Neurology, University of California, San Francisco, San Francisco, CA, USA

    • Tanuj Gulati
    • , April K. Hishinuma
    • , Seok-Joon Won
    • , Raymond A. Swanson
    •  & Karunesh Ganguly
  8. Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, CA, USA

    • Robert T. Knight
  9. Department of Psychology, University of California, Berkeley, Berkeley, CA, USA

    • Robert T. Knight
  10. Department of Neurosurgery, University of California, San Francisco, San Francisco, CA, USA

    • Edward F. Chang


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For the rodent experiments, D.S.R., L.G., T.G., S.-J.W. and K.G. conceived and designed the experiments. R.A.S. provided input on the design of the stroke models. D.S.R., L.G., T.G., G.D., A.K.H. and S.-J.W. performed the experiments. D.S.R., L.G., G.D. and T.G. analyzed the data. For the human experiments, T.G., K.G., E.F.C. and R.T.K. were involved in data collection. D.S.R. analyzed the data. D.S.R., L.G., T.G. and K.G. wrote the manuscript. All authors contributed to editing and revising the manuscript.

Competing interests

D.S.R., T.G. and K.G. filed a PCT Patent Application for Systems Methods and Devices for Closed Loop Methods To Enhance Motor Recovery After Stroke.

Corresponding author

Correspondence to Karunesh Ganguly.

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