Local and distant cortical responses to single pulse intracranial stimulation in the human brain are differentially modulated by specific stimulation parameters

Angelique C. Paulk, Rina Zelmann, Britni Crocker, Alik S. Widge, Darin D. Dougherty, Emad N. Eskandar, Daniel S. Weisholtz, R. Mark Richardson, G. Rees Cosgrove, Ziv M. Williams, Sydney S. Cash

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Background: Electrical neuromodulation via direct electrical stimulation (DES) is an increasingly common therapy for a wide variety of neuropsychiatric diseases. Unfortunately, therapeutic efficacy is inconsistent, likely due to our limited understanding of the relationship between the massive stimulation parameter space and brain tissue responses. Objective: To better understand how different parameters induce varied neural responses, we systematically examined single pulse-induced cortico-cortico evoked potentials (CCEP) as a function of stimulation amplitude, duration, brain region, and whether grey or white matter was stimulated. Methods: We measured voltage peak amplitudes and area under the curve (AUC) of intracranially recorded stimulation responses as a function of distance from the stimulation site, pulse width, current injected, location relative to grey and white matter, and brain region stimulated (N = 52, n = 719 stimulation sites). Results: Increasing stimulation pulse width increased responses near the stimulation location. Increasing stimulation amplitude (current) increased both evoked amplitudes and AUC nonlinearly. Locally (<15 mm), stimulation at the boundary between grey and white matter induced larger responses. In contrast, for distant sites (>15 mm), white matter stimulation consistently produced larger responses than stimulation in or near grey matter. The stimulation location-response curves followed different trends for cingulate, lateral frontal, and lateral temporal cortical stimulation. Conclusion: These results demonstrate that a stronger local response may require stimulation in the grey-white boundary while stimulation in the white matter could be needed for network activation. Thus, stimulation parameters tailored for a specific anatomical-functional outcome may be key to advancing neuromodulatory therapy.

Original languageEnglish (US)
Pages (from-to)491-508
Number of pages18
JournalBrain Stimulation
Issue number2
StatePublished - Mar 1 2022
Externally publishedYes

Bibliographical note

Funding Information:
Support included NIH grants MH086400 , DA026297 , and EY017658 to ENE, MH109722 , NS100548 , and MH111872 to ASW, NS100548 to DDD, and ECOR, NINDS K24- NS088568 to SSC and Tiny Blue Dot Foundation to SSC, ACP , and RZ. A United States Department of Energy Computational Sciences Graduate Fellowship [ DE-FG02-97ER25308 ] supported BC . Some of this research was sponsored by the U.S. Army Research Office and Defense Advanced Research Projects Agency ( DARPA ) under Cooperative Agreement Number W911NF-14-2-0045 issued by ARO contracting office in support of DARPA's SUBNETS Program. The views and conclusions contained in this document are those of the authors and do not represent the official policies, either expressed or implied, of the funding sources.

Publisher Copyright:
© 2022 The Authors


  • Cortex
  • Human
  • Intracranial
  • Nonlinear
  • Single pulse electrical stimulation
  • White matter
  • Evoked Potentials/physiology
  • Brain
  • White Matter
  • Humans
  • Electric Stimulation/methods
  • Cerebral Cortex/physiology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, Non-U.S. Gov't


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