Cell-type dependence of effects from transcranial electric brain stimulation
- 1Department of Physics, Norwegian University of Life Sciences, Ås, Norway
- 2Department of Physics, University of Oslo, Oslo, Norway
Abstract
There is an urgent need for better treatment options for many neurological conditions, including Alzheimer’s disease, Parkinson’s disease, depression, and epilepsy. Transcranial electrical stimulation (tES) is a non-invasive, safe, inexpensive, and promising method that could address some of this unmet need. The therapeutic value of tES has been well demonstrated, but the effect is highly variable. To enable tES to reach its full potential requires a better understanding of how tES modulates neural activity so that tES treatments can be tailored to specific neurological conditions and individual patients. The neural response to tES is, however, highly complex, and the parameter space involved in optimizing tES treatments is daunting. This has made it difficult to obtain general insights into how tES modulates neural activity, and a central challenge lies in the cell-type-specific and frequency-dependent nature of these responses. In this study, we investigated cell-type-specific neuronal responses to tES over a broad frequency range, using a large database of biophysically detailed neuron models. We found that pyramidal cells respond strongly to low-frequency tES, but their responses drop sharply with frequency. In contrast, inhibitory neurons show a smaller reduction and, on average, become more responsive than pyramidal cells above ~60 Hz. By leveraging a reciprocity theorem we demonstrated that the effect of tES on a given cell-type is proportional to the frequency-dependent current-dipole moment that determines the EEG-signal contribution of this cell-type. We further identified the dendritic asymmetry as key in determining tES responses across the frequency spectrum. Counterintuitively, we also found that while total cell length increases tES sensitivity at low frequencies, it can have the opposite effect at high frequencies. Furthermore, we derived an analytical formula for idealized neuron models which can approximately predict the tES sensitivity of different cell types at any given frequency. By characterizing the role of morphology and stimulation frequency in determining tES responses of single cells, this is an important step towards a better understanding of tES at the fundamental level. These results also provide an efficient and accurate method for characterizing and comparing the tES responses of different neural populations across the frequency spectrum, which facilitates optimizing tES for cell-type specific targeting. Author summary: Transcranial electric stimulation (tES) is a promising, non-invasive treatment for several neurological conditions. It is, however, difficult to optimize, and its therapeutic effect is highly variable. A central challenge is predicting how tES affects neural activity, which is complicated by the cell-type-specific and frequency-dependent nature of tES responses. Here we investigated cell-type specific tES responses across a broad frequency range. We found that pyramidal cells respond strongly to low frequency tES, but their sensitivity drops sharply as frequency increases. In contrast, inhibitory neurons maintain responsiveness, becoming more sensitive than pyramidal cells above ~60 Hz. Using a reciprocity theorem, we demonstrated that a cell’s tES response is proportional to its frequency-dependent current-dipole moment. We identified the key role of dendritic asymmetry in determining these responses. Counterintuitively, while greater cell length increases low-frequency sensitivity, it can reduce high-frequency sensitivity. Finally, we derived an analytical formula to predict the tES sensitivity of idealized neuron models at any frequency. These findings advance our fundamental understanding of tES, and provide an efficient method to characterize neural responses at the single-cell level. This paves the way for improved tES optimization and cell-type specific targeting by facilitating efficient and accurate investigations of tES at the network level.
Related
- Fear learning–induced brain dynamics predict individual extinction memory expression following transcranial magnetic stimulation
- Digital-twin optimized transcranial temporal interference electrical stimulation alters rat brain activity patterns and metabolism including deep structures
- Improved inhibitory control following combined transcranial direct current stimulation (tDCS) and cognitive training in individuals with traumatic brain injury and impulsivity
- Weak electric fields of deep brain stimulation can entrain spiking in multi-compartment cortical neuron models
- Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome
BibTeX
@article{dahle2026celltype,
title = {{Cell-type dependence of effects from transcranial electric brain stimulation}},
author = {Susanne Dahle and Gaute T. Einevoll and Torbjørn V. Ness},
journal = {PLOS Computational Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pcbi.1014895},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014895},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Cell-type dependence of effects from transcranial electric brain stimulation
AU - Susanne Dahle
AU - Gaute T. Einevoll
AU - Torbjørn V. Ness
PY - 2026
DA - 2026/10/22
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014895
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014895
AB - There is an urgent need for better treatment options for many neurological conditions, including Alzheimer’s disease, Parkinson’s disease, depression, and epilepsy. Transcranial electrical stimulation (tES) is a non-invasive, safe, inexpensive, and promising method that could address some of this unmet need. The therapeutic value of tES has been well demonstrated, but the effect is highly variable. To enable tES to reach its full potential requires a better understanding of how tES modulates neural activity so that tES treatments can be tailored to specific neurological conditions and individual patients. The neural response to tES is, however, highly complex, and the parameter space involved in optimizing tES treatments is daunting. This has made it difficult to obtain general insights into how tES modulates neural activity, and a central challenge lies in the cell-type-specific and frequency-dependent nature of these responses. In this study, we investigated cell-type-specific neuronal responses to tES over a broad frequency range, using a large database of biophysically detailed neuron models. We found that pyramidal cells respond strongly to low-frequency tES, but their responses drop sharply with frequency. In contrast, inhibitory neurons show a smaller reduction and, on average, become more responsive than pyramidal cells above ~60 Hz. By leveraging a reciprocity theorem we demonstrated that the effect of tES on a given cell-type is proportional to the frequency-dependent current-dipole moment that determines the EEG-signal contribution of this cell-type. We further identified the dendritic asymmetry as key in determining tES responses across the frequency spectrum. Counterintuitively, we also found that while total cell length increases tES sensitivity at low frequencies, it can have the opposite effect at high frequencies. Furthermore, we derived an analytical formula for idealized neuron models which can approximately predict the tES sensitivity of different cell types at any given frequency. By characterizing the role of morphology and stimulation frequency in determining tES responses of single cells, this is an important step towards a better understanding of tES at the fundamental level. These results also provide an efficient and accurate method for characterizing and comparing the tES responses of different neural populations across the frequency spectrum, which facilitates optimizing tES for cell-type specific targeting. Author summary: Transcranial electric stimulation (tES) is a promising, non-invasive treatment for several neurological conditions. It is, however, difficult to optimize, and its therapeutic effect is highly variable. A central challenge is predicting how tES affects neural activity, which is complicated by the cell-type-specific and frequency-dependent nature of tES responses. Here we investigated cell-type specific tES responses across a broad frequency range. We found that pyramidal cells respond strongly to low frequency tES, but their sensitivity drops sharply as frequency increases. In contrast, inhibitory neurons maintain responsiveness, becoming more sensitive than pyramidal cells above ~60 Hz. Using a reciprocity theorem, we demonstrated that a cell’s tES response is proportional to its frequency-dependent current-dipole moment. We identified the key role of dendritic asymmetry in determining these responses. Counterintuitively, while greater cell length increases low-frequency sensitivity, it can reduce high-frequency sensitivity. Finally, we derived an analytical formula to predict the tES sensitivity of idealized neuron models at any frequency. These findings advance our fundamental understanding of tES, and provide an efficient method to characterize neural responses at the single-cell level. This paves the way for improved tES optimization and cell-type specific targeting by facilitating efficient and accurate investigations of tES at the network level.
SN - 1553-7358
SN - 1553-734X
ER -