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Cross-scale effects of neural interactions during human neocortical seizure activity

  1. Stephan A. van Gilsb,1
  1. aDepartment of Pediatrics, University of Chicago, Chicago, IL 60637;
  2. bDepartment of Applied Mathematics, MIRA Institute for Biomedical Engineering and Technical Medicine, University of Twente, Enschede 7500AE, The Netherlands;
  3. cDepartment of Neurology, Columbia University, New York, NY 10032;
  4. dDeptartment of Neurology and Clinical Neurophysiolgy, Medisch Spectrum Twente, Enschede 7500AE, The Netherlands;
  5. eClinical Neurophysiology Group, MIRA Institute for Biomedical Engineering and Technical Medicine, University of Twente, Enschede 7500AE, The Netherlands;
  6. fDepartment of Neurological Surgery, Columbia University, New York, NY 10032
  1. Edited by Terrence J. Sejnowski, Salk Institute for Biological Studies, La Jolla, CA, and approved August 11, 2017 (received for review February 14, 2017)


We show how small-scale (less than millimeters2) neuronal dynamics relates to network activity observed across wide areas (greater than centimeters2) during certain network states, such as seizures. Simulations show how macroscopic network properties can affect frequency and amplitude of ictal oscillations. Additionally, the seizure dynamic suggests that one neuronal function, feedforward inhibition, plays different roles across scales: (i) inhibition at the small-scale wavefront fails, allowing seizure activity to propagate, but (ii) at macroscopic scales, inhibition of the surrounding territory is activated via long-range intracortical connections and creates a distinct pathway to a postictal state. Ultimately, our modeling framework can be used to examine meso- and macroscopic perturbations and evaluate strategies to promote transitions between ictal and nonictal network states.


Small-scale neuronal networks may impose widespread effects on large network dynamics. To unravel this relationship, we analyzed eight multiscale recordings of spontaneous seizures from four patients with epilepsy. During seizures, multiunit spike activity organizes into a submillimeter-sized wavefront, and this activity correlates significantly with low-frequency rhythms from electrocorticographic recordings across a 10-cm-sized neocortical network. Notably, this correlation effect is specific to the ictal wavefront and is absent interictally or from action potential activity outside the wavefront territory. To examine the multiscale interactions, we created a model using a multiscale, nonlinear system and found evidence for a dual role for feedforward inhibition in seizures: while inhibition at the wavefront fails, allowing seizure propagation, feedforward inhibition of the surrounding centimeter-scale networks is activated via long-range excitatory connections. Bifurcation analysis revealed that distinct dynamical pathways for seizure termination depend on the surrounding inhibition strength. Using our model, we found that the mesoscopic, local wavefront acts as the forcing term of the ictal process, while the macroscopic, centimeter-sized network modulates the oscillatory seizure activity.


  • ?1T.L.E., K.D., W.v.D., and S.A.v.G. contributed equally to this work.

  • ?2To whom correspondence may be addressed. Email: teissa{at}uchicago.edu or koen.dijkstra{at}utwente.nl.
  • ?3Present address: Department of Neurology, Weill Cornell Medical College, New York, NY 10021.

  • ?4Present address: Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY 10029.

  • Author contributions: T.L.E., K.D., C.A.S., W.v.D., and S.A.v.G. designed research; T.L.E., K.D., R.G.E., R.R.G., G.M.M., and C.A.S. performed research; T.L.E., K.D., C.B., M.J.A.M.v.P., W.v.D., and S.A.v.G. analyzed data; and T.L.E., K.D., M.J.A.M.v.P., C.A.S., W.v.D., and S.A.v.G. wrote the paper.

  • The authors declare no conflict of interest.

  • Data deposition: Human data will be shared on request in compliance with the Health Insurance Portability and Accountability Act (HIPAA) law. All other code and data has been deposited on GitHub and can be accessed at http://www.danielhellerman.com/kodi66/Cross-Scale-Effects.

  • This article is a PNAS Direct Submission.

  • This article contains supporting information online at www.danielhellerman.com/lookup/suppl/doi:10.1073/pnas.1702490114/-/DCSupplemental.

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