Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation

Alexandra Katherine Isis Yonza; Lechan Tao; Xiao Zhang; Dmitry Postnov; Krzysztof Kucharz; Barbara Lind; Antonios Asiminas; Anpan Han; Victor Sonego; Kayeon Kim; Changsi Cai

doi:10.1016/j.brs.2025.04.015

Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation

Alexandra Katherine Isis Yonza, Lechan Tao, Xiao Zhang, Dmitry Postnov, Krzysztof Kucharz, Barbara Lind, Antonios Asiminas, Anpan Han, Victor Sonego, Kayeon Kim^*, Changsi Cai^*

^*Corresponding author for this work

Department of Clinical Medicine - Center of Functionally Integrative Neuroscience-SKS

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

Introduction: Intracortial microstimulation (ICMS) is widely used in neuroprosthetic brain-machine interfacing, particularly in restoring lost sensory and motor functions. Spiking neuronal activity requires increased cerebral blood flow to meet local metabolic demands, a process conventionally denoted as neurovascular coupling (NVC). However, it is unknown precisely how and to what extent ICMS elicits NVC and how the neuronal and blood flow responses to ICMS correlate. Suboptimal NVC by ICMS may compromise oxygen and energy delivery to the activated neurons thus impair neuroprosthetic functionality. Material and method: We used wide-field imaging (WFI), laser speckle imaging (LSI) and two-photon microscopy (TPM) to study living, transgenic mice expressing calcium (Ca²⁺) fluorescent indicators in either neurons or vascular mural cells (VMC), as well as to measure vascular inner lumen diameters. Result: By testing a range of stimulation amplitudes and examining cortical tissue responses at different distances from the stimulating electrode tip, we found that high stimulation intensities (≥50 μA) elicited a spatial and temporal neurovascular decoupling in regions most adjacent to electrode tip (<200 μm), with significantly delayed onset times of blood flow responses to ICMS and compromised maximum blood flow increases. We attribute these effects respectively to delayed Ca²⁺ signalling and decreased Ca²⁺ sensitivity in VMCs. Conclusion: Our study offers new insights into ICMS-associated neuronal and vascular physiology with potentially critical implications towards the optimal design of ICMS in neuroprosthetic therapies: low intensities preserve NVC; high intensities disrupt NVC responses and potentially precipitate blood supply deficits.

Original language	English
Journal	Brain Stimulation
Volume	18
Issue	3
Pages (from-to)	885-896
Number of pages	12
ISSN	1935-861X
DOIs	https://doi.org/10.1016/j.brs.2025.04.015
Publication status	Published - 1 May 2025

Keywords

Cerebral blood flow
Intracortical microstimulation (ICMS)
Laser speckle imaging (LSI)
Neuroprostheses
Neurovascular coupling (NVC)
Two-photon imaging (TPM)
Vascular mural cells (VMC)

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10.1016/j.brs.2025.04.015

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@article{5a906ea6be99470999f9ea39ada97703,

title = "Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation",

abstract = "Introduction: Intracortial microstimulation (ICMS) is widely used in neuroprosthetic brain-machine interfacing, particularly in restoring lost sensory and motor functions. Spiking neuronal activity requires increased cerebral blood flow to meet local metabolic demands, a process conventionally denoted as neurovascular coupling (NVC). However, it is unknown precisely how and to what extent ICMS elicits NVC and how the neuronal and blood flow responses to ICMS correlate. Suboptimal NVC by ICMS may compromise oxygen and energy delivery to the activated neurons thus impair neuroprosthetic functionality. Material and method: We used wide-field imaging (WFI), laser speckle imaging (LSI) and two-photon microscopy (TPM) to study living, transgenic mice expressing calcium (Ca2+) fluorescent indicators in either neurons or vascular mural cells (VMC), as well as to measure vascular inner lumen diameters. Result: By testing a range of stimulation amplitudes and examining cortical tissue responses at different distances from the stimulating electrode tip, we found that high stimulation intensities (≥50 μA) elicited a spatial and temporal neurovascular decoupling in regions most adjacent to electrode tip (<200 μm), with significantly delayed onset times of blood flow responses to ICMS and compromised maximum blood flow increases. We attribute these effects respectively to delayed Ca2+ signalling and decreased Ca2+ sensitivity in VMCs. Conclusion: Our study offers new insights into ICMS-associated neuronal and vascular physiology with potentially critical implications towards the optimal design of ICMS in neuroprosthetic therapies: low intensities preserve NVC; high intensities disrupt NVC responses and potentially precipitate blood supply deficits.",

keywords = "Cerebral blood flow, Intracortical microstimulation (ICMS), Laser speckle imaging (LSI), Neuroprostheses, Neurovascular coupling (NVC), Two-photon imaging (TPM), Vascular mural cells (VMC)",

author = "{Isis Yonza}, {Alexandra Katherine} and Lechan Tao and Xiao Zhang and Dmitry Postnov and Krzysztof Kucharz and Barbara Lind and Antonios Asiminas and Anpan Han and Victor Sonego and Kayeon Kim and Changsi Cai",

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year = "2025",

month = may,

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doi = "10.1016/j.brs.2025.04.015",

language = "English",

volume = "18",

pages = "885--896",

journal = "Brain Stimulation",

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Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation. / Isis Yonza, Alexandra Katherine; Tao, Lechan; Zhang, Xiao et al.
In: Brain Stimulation, Vol. 18, No. 3, 01.05.2025, p. 885-896.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation

AU - Isis Yonza, Alexandra Katherine

AU - Tao, Lechan

AU - Zhang, Xiao

AU - Postnov, Dmitry

AU - Kucharz, Krzysztof

AU - Lind, Barbara

AU - Asiminas, Antonios

AU - Han, Anpan

AU - Sonego, Victor

AU - Kim, Kayeon

AU - Cai, Changsi

PY - 2025/5/1

Y1 - 2025/5/1

N2 - Introduction: Intracortial microstimulation (ICMS) is widely used in neuroprosthetic brain-machine interfacing, particularly in restoring lost sensory and motor functions. Spiking neuronal activity requires increased cerebral blood flow to meet local metabolic demands, a process conventionally denoted as neurovascular coupling (NVC). However, it is unknown precisely how and to what extent ICMS elicits NVC and how the neuronal and blood flow responses to ICMS correlate. Suboptimal NVC by ICMS may compromise oxygen and energy delivery to the activated neurons thus impair neuroprosthetic functionality. Material and method: We used wide-field imaging (WFI), laser speckle imaging (LSI) and two-photon microscopy (TPM) to study living, transgenic mice expressing calcium (Ca2+) fluorescent indicators in either neurons or vascular mural cells (VMC), as well as to measure vascular inner lumen diameters. Result: By testing a range of stimulation amplitudes and examining cortical tissue responses at different distances from the stimulating electrode tip, we found that high stimulation intensities (≥50 μA) elicited a spatial and temporal neurovascular decoupling in regions most adjacent to electrode tip (<200 μm), with significantly delayed onset times of blood flow responses to ICMS and compromised maximum blood flow increases. We attribute these effects respectively to delayed Ca2+ signalling and decreased Ca2+ sensitivity in VMCs. Conclusion: Our study offers new insights into ICMS-associated neuronal and vascular physiology with potentially critical implications towards the optimal design of ICMS in neuroprosthetic therapies: low intensities preserve NVC; high intensities disrupt NVC responses and potentially precipitate blood supply deficits.

AB - Introduction: Intracortial microstimulation (ICMS) is widely used in neuroprosthetic brain-machine interfacing, particularly in restoring lost sensory and motor functions. Spiking neuronal activity requires increased cerebral blood flow to meet local metabolic demands, a process conventionally denoted as neurovascular coupling (NVC). However, it is unknown precisely how and to what extent ICMS elicits NVC and how the neuronal and blood flow responses to ICMS correlate. Suboptimal NVC by ICMS may compromise oxygen and energy delivery to the activated neurons thus impair neuroprosthetic functionality. Material and method: We used wide-field imaging (WFI), laser speckle imaging (LSI) and two-photon microscopy (TPM) to study living, transgenic mice expressing calcium (Ca2+) fluorescent indicators in either neurons or vascular mural cells (VMC), as well as to measure vascular inner lumen diameters. Result: By testing a range of stimulation amplitudes and examining cortical tissue responses at different distances from the stimulating electrode tip, we found that high stimulation intensities (≥50 μA) elicited a spatial and temporal neurovascular decoupling in regions most adjacent to electrode tip (<200 μm), with significantly delayed onset times of blood flow responses to ICMS and compromised maximum blood flow increases. We attribute these effects respectively to delayed Ca2+ signalling and decreased Ca2+ sensitivity in VMCs. Conclusion: Our study offers new insights into ICMS-associated neuronal and vascular physiology with potentially critical implications towards the optimal design of ICMS in neuroprosthetic therapies: low intensities preserve NVC; high intensities disrupt NVC responses and potentially precipitate blood supply deficits.

KW - Cerebral blood flow

KW - Intracortical microstimulation (ICMS)

KW - Laser speckle imaging (LSI)

KW - Neuroprostheses

KW - Neurovascular coupling (NVC)

KW - Two-photon imaging (TPM)

KW - Vascular mural cells (VMC)

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U2 - 10.1016/j.brs.2025.04.015

DO - 10.1016/j.brs.2025.04.015

M3 - Journal article

C2 - 40246195

AN - SCOPUS:105002862161

SN - 1935-861X

VL - 18

SP - 885

EP - 896

JO - Brain Stimulation

JF - Brain Stimulation

IS - 3

ER -

Spatially and temporally mismatched blood flow and neuronal activity by high-intensity intracortical microstimulation

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Keywords

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