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Activation of NMDA Receptor Ion Channels by Deep Brain Simulation in the Pig Visualised with[18F]GE-179 PET

Lookup NU author(s): Professor David Brooks

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This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


Abstract

Background No PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-D-aspartate receptor ion channel (NMDAR-IC) function. [1834 F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. Objective To show [1837 F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. Methods Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [1840 F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [1841 F]GE-179 uptake at baseline and then during DBS was measured with PET. Cerebral blood flow (CBF) was measured with [15O]H2O PET at baseline and during DBS and parametric CBF images were generated to evaluate DBS induced CBF changes. Functional effects of injecting the PCP blocker MK-801 were also evaluated. Electrode positions were later histologically verified. Results DBS induced a 47.75% global increase in brain [1847 F]GE-179 uptake (p=0.048) compared to baseline. Global CBF was unchanged by hippocampal DBS. [18F]GE-179 PET detected a 5% higher uptake in the implanted compared with the non-implanted temporo-parietal cortex at baseline (p=0.012) and during stimulation (p=0.022). Administration of MK-801 before DBS failed to block [1850 F]GE-179 uptake during stimulation. Conclusion PET detected a 47.75% increase in global brain [1853 F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support [18F]GE-179 PET providing a use-dependent marker of abnormal NMDAR-IC activation.


Publication metadata

Author(s): Vibholm AK, Landau AM, Alstrup AKO, Jacobsen J, Vang K, Munk OL, Dietz MJ, Orlowski D, Sørensen JCH, Brooks DJ

Publication type: Article

Publication status: Published

Journal: Brain Stimulation

Year: 2020

Volume: 13

Issue: 4

Pages: 1071-1078

Print publication date: 01/07/2020

Online publication date: 03/04/2020

Acceptance date: 30/03/2020

Date deposited: 31/03/2020

ISSN (print): 1935-861X

ISSN (electronic): 1876-4754

Publisher: Elsevier

URL: https://doi.org/10.1016/j.brs.2020.03.019

DOI: 10.1016/j.brs.2020.03.019


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