A linear model for estimation of neurotransmitter response profiles from dynamic PET data

Abstract

The parametric ntPET model (p-ntPET) estimates the kinetics of neurotransmitter release from dynamic PET data with receptor-ligand radiotracers. Here we introduce a linearization (lp-ntPET) that is computationally efficient and can be applied to single-scan data. lp-ntPET employs a non-invasive reference region input function and extends the LSRRM of Alpert et al. (2003) using basis functions to characterize the time course of neurotransmitter activation. In simulation studies, the temporal precision of neurotransmitter profiles estimated by lp-ntPET was similar to that of p-ntPET (standard deviation ~3 min for responses early in the scan) while computation time was reduced by several orders of magnitude. Violations of model assumptions such as activation-induced changes in regional blood flow or specific binding in the reference tissue have negligible effects on lp-ntPET performance. Application of the lp-ntPET method is demonstrated on [11C]raclopride data acquired in rats receiving methamphetamine, which yielded estimated response functions that were in good agreement with simultaneous microdialysis measurements of extracellular dopamine concentration. These results demonstrate that lp-ntPET is a computationally efficient, linear variant of ntPET that can be applied to PET data from single or multiple scan designs to estimate the time course of neurotransmitter activation.

Creating Dynamic Images of Short-lived Dopamine Fluctuations with lp-ntPET: Dopamine Movies of Cigarette Smoking

“…Specifically, we have demonstrated that our models predict dopamine concentrations over time from PET data in rats that are in good agreement with simultaneously acquired microdialysis measurements 4,7 . Advantages : The most recent of our models have been either linear and non-parametric (np-ntPET) 1 or linear and parametric (lp-ntPET) 7 . The latter model derives from an earlier linear model introduced by Alpert et al 20 .…”

“…Conventional methods for PET analysis estimate time-invariant kinetic model parameters which cannot capture short-term fluctuations in neurotransmitter release. Our analysis - yielding a dopamine movie - is based on our work with kinetic models and other decomposition techniques that allow for time-varying parameters 1-7 . This aspect of the analysis – temporal-variation- is key to our work.…”

“…Modeling identifies the time-varying function that best describes the dopamine effect on 11 C-raclopride uptake. The statistical step compares the fit of our (lp-ntPET) model 7 to a conventional model 9 . Masking restricts treatment to those voxels best described by the new model.…”

News and views on in-vivo imaging of neurotransmission using PET and MRI

“…Similar decreases in [ 11 C]raclopride receptor binding have also been shown during emotional processing tasks and executive inhibition tasks 73,74 . Several kinetic modeling approaches have been proposed to accurately analyze such experiments that use a within-scan challenges with just one radiotracer injection 72,75 . Overall, such methods enable the imaging of dopaminergic neurotransmission in the live human brain 76 .…”

“…Towards this goal, models that include a dynamic association rate as part of the kinetic model have been developed 72,75 . To date, these models have been successfully applied for the detection of dopamine release or exogenous D2 receptor binding using the radiotracer [ 11 C]raclopride for evaluating cigarette smoking 62,120 or drug injections 50 .…”