Abstract
407
Objectives Constant infusion of PET tracer can be used to detect the changes between baseline and stimulation period in a single session, which is a suitable technique for the simultaneous PET/MR. The purpose of this study was to evaluate how a pharmacological stimulation using 3,4-methylenedioxymethamphetamine (MDMA) affects the serotonin transporter (SERT), glucose metabolism, and functional connectivity of the rat brain.
Methods Normal Lewis rats (male, 16 weeks old, 295 ± 16 g, n=4) were studied using an integrated PET/MR scanner (7T MR with PET insert) under isoflurane anesthesia (1.5-2% with room air). After overnight fasting, simultaneous PET/MR acquisitions (100min) were performed with bolus and constant infusion of 11C-DASB (bolus 64 ± 18 MBq/0.48ml + 15µl/min, specific radioactivity = 49 ± 18 GBq/µmol) at day1 and with constant infusion of 18F-FDG (total: 117 ± 4.6 MBq/0.8ml) at day3. MDMA (3.2mg/kg), a potent serotonin releasing agent, was administered intravenously 40min after the scan start as a pharmacological stimulation. Echo planar imaging (EPI) sequences (TR: 2000ms, TE: 18ms) were continuously acquired during PET acquisition after anatomical T2 weighted imaging. PET data were reconstructed into 100 frames (1 min data per frame). All PET/MR data were co-registered using SPM12 and volumes of interest were placed using a rat brain atlas (PMOD 3.2). Glucose consumption was evaluated by 18F-FDG uptake using SUV, which was normalized by the injected dose at each time point. Non-displaceable binding potential (BPND) of 11C-DASB was calculated for the evaluation of SERT using the cerebellum gray matter as a reference region. Functional connectivity was evaluated by Pearson’s correlation maps of the functional MRI blood oxygen level dependent (fMRI BOLD) signal and compared among baseline condition (10-40min after the scan start), the early phase of MDMA stimulation (40-70min), and the late phase (70-100min). SUV of 18F-FDG and BPND of 11C-DASB were compared between baseline condition and the late phase by paired t-test.
Results 18F-FDG uptake was significantly increased in the whole brain (SUV: 1.24 ± 0.12 at baseline and 1.48 ± 0.05 in the late phase, p=0.019). Time activity curves of 18F-FDG showed an increased trend after MDMA stimulation and a relatively large increase was observed in the striatum and the insular cortex (1.31 and 1.39 times uptake in the late phase compared to baseline, respectively). BPND of 11C-DASB also showed significant decrease in the whole brain (0.34 ± 0.27 at baseline and 0.19 ± 0.10 in the late phase, p=0.046). Among the brain regions, a large significant decrease of BPND (p<0.05) was observed in the thalamus (0.80 ± 0.54 at baseline, 0.40 ± 0.18 in the late phase), the hypothalamus (0.76 ± 0.43, 0.35 ± 0.17), the superior colliculus (0.90 ± 0.23, 0.43 ± 0.07), the inferior colliculus (0.64 ± 0.12, 0.31 ± 0.09), the midbrain (1.05 ± 0.36, 0.42 ± 0.10), and the pons (0.78 ± 0.53, 0.22 ± 0.21). Correlation maps of the BOLD signal showed dramatic decrease in the whole brain connectivity in the early phase and still decreased in the late phase compared to the baseline.
Conclusions Pharmacological stimulation using MDMA induced increased glucose consumption in the whole brain, decreased binding of SERT due to the inhibitory effect of MDMA, and decreased functional connectivity in the rat brain. Simultaneous PET/MR with constant infusion PET is a promising methodology to evaluate the combination of functional (fMRI) with metabolic (PET) connectivity mapping, cometomics, which allows new insights into brain function research.