Activation of NMDA receptor ion channels by deep brain stimulation in the pig visualised with [18F]GE-179 PET

• Published in: Brain stimulation Vol. 13; no. 4; pp. 1071 - 1078
• Main Authors: Vibholm, Ali Khalidan, Landau, Anne Marlene, Alstrup, Aage Kristian Olsen, Jacobsen, Jan, Vang, Kim, Munk, Ole Lajord, Dietz, Martin Jensen, Orlowski, Dariusz, Sørensen, Jens Christian Hedemann, Brooks, David James
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2020; Elsevier
• Subjects: [15O]H2O; [18F]GE-179; Animals; Brain - diagnostic imaging; Brain - metabolism; DBS; Deep Brain Stimulation; Fluorine Radioisotopes; Male; N-Methylaspartate - metabolism; NMDA receptor; PET; Positron-Emission Tomography - methods; Radiopharmaceuticals; Receptors, N-Methyl-D-Aspartate - metabolism; Swine; [15O]H2O; DBS; NMDA receptor; [18F]GE-179; PET; [F]GE-179; [O]HO
• ISSN: 1935-861X; 1876-4754
• DOI: 10.1016/j.brs.2020.03.019

No PET radioligand has yet demonstrated the capacity to map glutamate N-methyl-d-aspartate receptor ion channel (NMDAR-IC) function. [18F]GE-179 binds to the phencyclidine (PCP) site in open NMDAR-ICs and potentially provides a use-dependent PET biomarker of these ion channels. To show [18F]GE-179 PET can detect increased NMDAR-IC activation during electrical deep brain stimulation (DBS) of pig hippocampus. Six minipigs had an electrode implanted into their right hippocampus. They then had a baseline [18F]GE-179 PET scan with DBS turned off followed by a second scan with DBS turned on. Brain [18F]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. DBS induced a 47.75% global increase in brain [18F]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 [18F]GE-179 uptake during stimulation. PET detected an increase in global brain [18F]GE-179 uptake during unilateral hippocampal DBS while CBF remained unchanged. These findings support that [18F]GE-179 PET provides a use-dependent marker of abnormal NMDAR-IC activation. •NMDA receptor activation during DBS in Pig detected in vivo using [18F]GE-179 PET.•Continuous DBS induced a 47.75 % increase in global uptake detected in vivo by [18F]GE-179 PET.•Global Cerebral Blood Flow was unchanged by continuous DBS.