The effects of intracranial stimulation on local neurovascular responses in humans

Artur Vetkas; Srdjan Sumarac; Samantha Chau; Reese Clinton; Emily Haniff; Alexandre Boutet; Can Sarica; Xilin Liu; Mojgan Hodaie; Taufik A Valiante; Suneil K Kalia; Andres M Lozano; William D Hutchison; Luka Milosevic

doi:10.1016/j.brs.2025.09.018

The effects of intracranial stimulation on local neurovascular responses in humans

Brain Stimul. 2025 Nov-Dec;18(6):1810-1820. doi: 10.1016/j.brs.2025.09.018. Epub 2025 Sep 25.

Authors

Affiliations

¹ Krembil Brain Institute, University Health Network, Canada; Department of Surgery, University of Toronto, Canada.
² Krembil Brain Institute, University Health Network, Canada; Institute of Biomedical Engineering, University of Toronto, Canada.
³ Krembil Brain Institute, University Health Network, Canada.
⁴ Joint Department of Medical Imaging, University of Toronto, Canada.
⁵ Department of Surgery, University of Toronto, Canada.
⁶ Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Canada; KITE, University Health Network, Toronto, Canada.
⁷ Krembil Brain Institute, University Health Network, Canada; Department of Surgery, University of Toronto, Canada; Institute of Medical Sciences, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada.
⁸ Krembil Brain Institute, University Health Network, Canada; Institute of Biomedical Engineering, University of Toronto, Canada; Edward S. Rogers Sr. Department of Electrical and Computer Engineering, University of Toronto, Canada; Institute of Medical Sciences, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada; KITE, University Health Network, Toronto, Canada; Department of Physiology, University of Toronto, Canada.
⁹ Krembil Brain Institute, University Health Network, Canada; Department of Surgery, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada; KITE, University Health Network, Toronto, Canada.
¹⁰ Krembil Brain Institute, University Health Network, Canada; Department of Surgery, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada; Department of Physiology, University of Toronto, Canada.
¹¹ Krembil Brain Institute, University Health Network, Canada; Institute of Biomedical Engineering, University of Toronto, Canada; Institute of Medical Sciences, University of Toronto, Canada; Center for Advancing Neurotechnological Innovation to Application (CRANIA), Toronto, Canada; KITE, University Health Network, Toronto, Canada. Electronic address: luka.milosevic@mail.utoronto.ca.

PMID: 41015260
DOI: 10.1016/j.brs.2025.09.018

Abstract

Background: Deep brain stimulation (DBS) is used to treat neurological and psychiatric disorders by modulating neuronal circuits. However, the effects of electrical stimulation on the neurovascular unit remain poorly understood due to limitations of capturing microvascular changes near implanted leads. This motivated us to investigate the cardioballistic waveform (CBW) as an electrophysiological surrogate of vascular dynamics in response to microstimulation.

Methods: Microelectrode recordings (n = 193; 108 patients) were obtained during DBS implantation surgery from two electrodes (∼600 μm apart) before and after microstimulation through one electrode. Generalized linear mixed models assessed CBW amplitude changes following 1 Hz or 100 Hz stimulation across basal ganglia regions and white matter. Neuronal activity was also analyzed, including phase-locking to the cardiac cycle, firing rates and patterns, and micro-LFP features. An analytical model interpreted CBW amplitudes as pressure-driven vessel wall expansion, enabling estimation of stimulation-evoked vasodilation and cerebral blood flow.

Results: CBW amplitudes increased significantly after 100 Hz stimulation at the stimulating electrode, but not at the non-stimulating electrode or after 1 Hz stimulation. Significant region-specific effects were observed in the ventral intermediate nucleus (Vim; 107 ± 13 %), subthalamic nucleus (STN; 79 ± 7 %), and globus pallidus internus (GPi; 78 ± 8 %), but not in white matter (WM; 50 ± 14 %) or substantia nigra pars reticulata (SNr; 45 ± 8 %). Across 50 recorded single units, 18 (36 %) were phase-locked to the cardiac cycle, but stimulation did not alter phase-locking value, and changes in spiking or micro-LFP features before versus after stimulation did not scale with CBW changes. Modelling showed that the mean 88 % CBW increase across Vim, STN, and GPi corresponds to an acute increase in cerebral blood flow.

Conclusion: CBW recordings reveal that high-frequency DBS evokes region-specific vascular responses which can be modeled as substantial increases in local blood flow, establishing CBW amplitude as a potential biomarker of subcortical hemodynamics, and a potential therapeutic modality.

Keywords: Cardioballistic waveform (CBW); Deep brain stimulation (DBS); Neurovascular dynamics; Vascular reactivity.

MeSH terms

Adult
Aged
Brain* / blood supply
Brain* / physiology
Cerebrovascular Circulation* / physiology
Deep Brain Stimulation* / methods
Electrodes, Implanted
Female
Humans
Male
Microelectrodes
Middle Aged
Neurovascular Coupling* / physiology
Subthalamic Nucleus / physiology