# Interrogating the propagation of electrical stimulation across scales in vivo

> **NIH NIH R01** · UNIVERSITY OF COLORADO DENVER · 2024 · $516,545

## Abstract

Project Summary
Intracranial electrical brain stimulation (EBS) remains a central method in the clinic as well as for research in
several animal model systems. However, little is actually known about the ensembles of neurons activated by
typical and clinical intracranial EBS protocols. These stimulation protocols often require a trial-and-error
learning period (during and after invasive neurosurgery) to determine what stimulation parameters are
effective, if any at all are effective. It remains mysterious why some stimulation patterns work in the clinic
while others do not, and what underlying ensembles are activated by various stimulation patterns.
It is known that focal electrical microstimulation activates nearby excitable membranes, including neural
somas, dendrites, and axons. It is also known that the recruited ensemble of neurons may be locally non-
homogenous and that clinical effects may rely more on axons of passage than somatic stimulation. Efforts to
model EBS cannot overcome our current gaps in knowledge about the homogeneity of local propagation and
brain-wide extent of activation. This ambiguity demands a more detailed understanding of local electric field
propagation, particularly in the in vivo mammalian brain. Utilizing recent technological advances, we propose
to fill these gaps empirically with high density electrophysiological monitoring and temporally precise
fluorescent labeling methods, to quantify clinically relevant activation patterns with high spatial resolution
and cell-type specificity.
Here we propose an experimental study in mice, based on a biophysically realistic model of mouse cerebral
cortex, of the spatial and temporal propagation of activation via focal EBS. The study will test the hypothesis
that local electrical stimulation is non-isotropic and cell-type specific. We propose to measure EBS stimulation
with more than 1000 electrodes arranges in three dimensions around a site of stimulation, in combination with
genetic cell type identity through optotagging (Aim 1). To agnostically isolate brain-wide ensembled activated
by EBS, we couple a fluorescent reporter to electrical stimulation for ex vivo whole-brain tissue clearing and
light sheet imaging (Aim 2).

## Key facts

- **NIH application ID:** 10795709
- **Project number:** 4R01NS120850-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Daniel James Denman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $516,545
- **Award type:** 4N
- **Project period:** 2021-07-15 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10795709

## Citation

> US National Institutes of Health, RePORTER application 10795709, Interrogating the propagation of electrical stimulation across scales in vivo (4R01NS120850-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10795709. Licensed CC0.

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