scholarly journals Characterization and Mitigation of Model Bias in Parametric Mapping of Dopamine Response to Behavioral Challenge

2021 ◽  
Author(s):  
Michael A Levine ◽  
Joseph B Mandeville ◽  
Finnegan Calabro ◽  
David Izquierdo-Garcia ◽  
Julie C Price ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Step Function ◽  
Binding Potential ◽  
Reference Tissue ◽  
Heaviside Step Function ◽  
Average Bias ◽  
Adult Participants ◽  
Single Target ◽  
First Pass ◽  
Initial Uptake

Compartmental modeling of 11C-raclopride (RAC) is commonly used to measure dopamine response to intra-scan behavioral tasks. Bias in estimates of binding potential (BPND) and its dynamic changes (ΔBPND) can arise when the selected compartmental model deviates from the underlying biology. In this work, we characterize the bias associated with assuming a single target compartment and propose a model for reducing this bias by selectively discounting the contribution of the initial uptake period. Methods: 69 healthy young adult participants were scanned using RAC PET/MR while simultaneously performing a rewarded behavioral task. BPND and ΔBPND were estimated using an extension of the Multilinear Reference Tissue Model (MRTM2) with the task challenge encoded as a Heaviside step function. Bias was estimated using simulations designed to match the acquired data and was reduced by introducing a new model (DE-MRTM2) that reduces the biasing influence of the initial uptake period in the modeled estimation of BPND for both simulations and participant data. Results: Bias in ΔBPND was observed to vary both spatially with BPND and with the assumed value of k4. At the most likely value of k4 (0.13 min-1), the average bias and the maximum voxel bias magnitude in the nucleus accumbens were estimated to be 1.2% and 3.9% respectively. Simulations estimated that debiasing the contribution of the first 27 minutes of acquired data reduced average bias and maximum voxel bias in the nucleus accumbens ΔBPND to -0.3% and 2.4% respectively. In the acquired participant data, DE-MRTM2 produced modest changes in the experimental estimates of striatal ΔBPND, while extrastriatal bias patterns were greatly reduced. DE-MRTM2 also considerably reduced the dependence of ΔBPND upon the first-pass selection of k2'. Conclusion: Selectively discounting the contribution of the initial uptake period can help mitigate BPND- and k4-dependent bias in single compartment models of ΔBPND, while also reducing the dependence of ΔBPND on the first-pass estimation of k2'.

FC10-05 - Attenuated serotonin transporter association between midbrain and nucleus accumbens in major depression

2011 ◽  
Vol 26 (S2) ◽  
pp. 1868-1868
Author(s):  
A. Hahn ◽  
E. Akimova ◽  
D. Häusler ◽  
C. Philippe ◽  
M. Savli ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Serotonin Transporter ◽  
Healthy Subjects ◽  
Reward Processing ◽  
Binding Potential ◽  
Projection Area ◽  
Reference Tissue ◽  
Hedonic Experience ◽  
Image Position ◽  
First Time

IntroductionPatients suffering from major depressive disorder (MDD) exhibit alterations in serotonin transporter (5-HTT) binding clinically reflected by lack of hedonic experience. We recently demonstrated the importance to evaluate interregional relationships of neurotransmitter systems, providing important complementary information on a network level.ObjectiveTo identify interregional 5-HTT relationships between the midbrain raphe region and projection areas in MDD patients compared to controls.MethodsEighteen medication-free patients with MDD and 16 healthy subjects underwent PET using [11C] DASB. 5-HTT binding potential (BPND) maps were computed with the multilinear-reference-tissue-model-2 in PMOD3.1. Voxel-wise linear regression was calculated in SPM8 using midbrain 5-HTT BPND as regressor; group comparisons were assessed by ANOVA (p < 0.001).ResultsHealthy subjects showed positive associations between serotonin transporters located in the midbrain and transporters expressed in the nucleus accumbens bilaterally. Importantly, this relationship was significantly decreased in MDD patients as compared to controls (t = 5.41/4.84, right/left hemisphere; see figure).ConclusionsThis study demonstrates for the first time 5-HTT alterations on a network level in MDD patients between the midbrain and a major projection area. Our results complement previous findings emphasizing the importance of the nucleus accumbens in MDD and indicate a disturbed serotonergic regulation in this key area of reward processing.

A Meshless Local Petrov-Garlerkin Method for Solving the Biharmonic Equation

2014 ◽  
Vol 931-932 ◽  
pp. 1488-1494
Author(s):  
Supanut Kaewumpai ◽  
Suwon Tangmanee ◽  
Anirut Luadsong
Keyword(s):  
Relative Error ◽  
Biharmonic Equation ◽  
Interpolation Method ◽  
Step Function ◽  
Special Treatment ◽  
Maximum Relative Error ◽  
Heaviside Step Function ◽  
Treatment Techniques ◽  
Point Interpolation Method ◽  
Point Interpolation

A meshless local Petrov-Galerkin method (MLPG) using Heaviside step function as a test function for solving the biharmonic equation with subjected to boundary of the second kind is presented in this paper. Nodal shape function is constructed by the radial point interpolation method (RPIM) which holds the Kroneckers delta property. Two-field variables local weak forms are used in order to decompose the biharmonic equation into a couple of Poisson equations as well as impose straightforward boundary of the second kind, and no special treatment techniques are required. Selected engineering numerical examples using conventional nodal arrangement as well as polynomial basis choices are considered to demonstrate the applicability, the easiness, and the accuracy of the proposed method. This robust method gives quite accurate numerical results, implementing by maximum relative error and root mean square relative error.

scholarly journals Quantification of Ligand PET Studies using a Reference Region with a Displaceable Fraction: Application to Occupancy Studies with [11C]-DASB as an Example

2011 ◽  
Vol 32 (1) ◽  
pp. 70-80 ◽  
Author(s):  
Federico E Turkheimer ◽  
Sudhakar Selvaraj ◽  
Rainer Hinz ◽  
Venkatesha Murthy ◽  
Zubin Bhagwagar ◽  
...  
Keyword(s):  
Specific Binding ◽  
Normal Subjects ◽  
Volume Of Distribution ◽  
Binding Potential ◽  
Accurate Estimation ◽  
Data Sets ◽  
Reference Region ◽  
Reference Tissue ◽  
Positron Emission ◽  
Definition Of

This paper aims to build novel methodology for the use of a reference region with specific binding for the quantification of brain studies with radioligands and positron emission tomography (PET). In particular: (1) we introduce a definition of binding potential BPD = DVR–1 where DVR is the volume of distribution relative to a reference tissue that contains ligand in specifically bound form, (2) we validate a numerical methodology, rank-shaping regularization of exponential spectral analysis (RS-ESA), for the calculation of BPD that can cope with a reference region with specific bound ligand, (3) we demonstrate the use of RS-ESA for the accurate estimation of drug occupancies with the use of correction factors to account for the specific binding in the reference. [11C]-DASB with cerebellum as a reference was chosen as an example to validate the methodology. Two data sets were used; four normal subjects scanned after infusion of citalopram or placebo and further six test—retest data sets. In the drug occupancy study, the use of RS-ESA with cerebellar input plus corrections produced estimates of occupancy very close the ones obtained with plasma input. Test-retest results demonstrated a tight linear relationship between BPD calculated either with plasma or with a reference input and high reproducibility.

scholarly journals Synthesis and preclinical evaluation of [11C]MTP38 as a novel PET ligand for phosphodiesterase 7 in the brain

2020 ◽  
Author(s):  
Naoyuki Obokata ◽  
Chie Seki ◽  
Takeshi Hirata ◽  
Jun Maeda ◽  
Hideki Ishii ◽  
...  
Keyword(s):  
Arterial Input Function ◽  
Inflammatory Diseases ◽  
Input Function ◽  
Binding Potential ◽  
Dependent Manner ◽  
Reference Tissue ◽  
Molar Activity ◽  
The Brain

AbstractPurposePhosphodiesterase (PDE) 7 is a potential therapeutic target for neurological and inflammatory diseases, although in-vivo visualization of PDE7 has not been successful. In this study, we aimed to develop [11C]MTP38 as a novel positron emission tomography (PET) ligand for PDE7.Methods[11C]MTP38 was radiosynthesized by 11C-cyanation of a bromo precursor with [11C]HCN. PET scans of rat and rhesus monkey brains and in-vitro autoradiography of brain sections derived from these species were conducted with [11C]MTP38. In monkeys, dynamic PET data were analyzed with an arterial input function to calculate the total distribution volume (VT). The non-displaceable binding potential (BPND) in the striatum was also determined by a reference tissue model with cerebellar reference. Finally, striatal occupancy of PDE7 by an inhibitor was calculated in monkeys according to changes in BPND.Results[11C]MTP38 was synthesized with radiochemical purity ≥ 99.4% and molar activity of 38.6 ± 12.6 GBq/μmol. Autoradiography revealed high radioactivity in the striatum and its reduction by non-radiolabeled ligands, in contrast with unaltered autoradiographic signals in other regions. In-vivo PET after radioligand injection to rats and monkeys demonstrated that radioactivity was rapidly distributed to the brain and intensely accumulated in the striatum relative to the cerebellum. Correspondingly, estimated VT values in the monkey striatum and cerebellum were 3.59 and 2.69 mL/cm3, respectively. The cerebellar VT value was unchanged by pretreatment with unlabeled MTP38. Striatal BPND was reduced in a dose-dependent manner after pretreatment with MTP-X, a PDE7 inhibitor. Relationships between PDE7 occupancy by MTP-X and plasma MTP-X concentration could be described by Hill’s sigmoidal function.ConclusionWe have provided the first successful preclinical demonstration of in-vivo PDE7 imaging with a specific PET radioligand. [11C]MTP38 is a feasible radioligand for evaluating PDE7 in the brain and is currently being applied to a first-in-human PET study.

scholarly journals Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

2015 ◽  
Vol 35 (7) ◽  
pp. 1199-1205 ◽  
Author(s):  
Kati Alakurtti ◽  
Jarkko J Johansson ◽  
Juho Joutsa ◽  
Matti Laine ◽  
Lars Bäckman ◽  
...  
Keyword(s):  
High Resolution ◽  
Intraclass Correlation ◽  
Binding Potential ◽  
Reference Tissue ◽  
Retest Reliability ◽  
Positron Emission ◽  
Simplified Reference Tissue Model ◽  
Test Retest Reliability

We measured the long-term test–retest reliability of [11C]raclopride binding in striatal subregions, the thalamus and the cortex using the bolus-plus-infusion method and a high-resolution positron emission scanner. Seven healthy male volunteers underwent two positron emission tomography (PET) [11C]raclopride assessments, with a 5-week retest interval. D2/3 receptor availability was quantified as binding potential using the simplified reference tissue model. Absolute variability (VAR) and intraclass correlation coefficient (ICC) values indicated very good reproducibility for the striatum and were 4.5%/0.82, 3.9%/0.83, and 3.9%/0.82, for the caudate nucleus, putamen, and ventral striatum, respectively. Thalamic reliability was also very good, with VAR of 3.7% and ICC of 0.92. Test-retest data for cortical areas showed good to moderate reproducibility (6.1% to 13.1%). Our results are in line with previous test–retest studies of [11C]raclopride binding in the striatum. A novel finding is the relatively low variability of [11C]raclopride binding, providing suggestive evidence that extrastriatal D2/3 binding can be studied in vivo with [11C]raclopride PET to be verified in future studies.

The Mesoscopic Investigation on Moduli Prediction in Visco-Elastic Particle Reinforced Composites

2008 ◽  
Vol 385-387 ◽  
pp. 329-332
Author(s):  
Xue Zhong Ding ◽  
Li Qiang Tang
Keyword(s):  
Volume Fraction ◽  
Step Function ◽  
Elastic Behavior ◽  
Loading Path ◽  
Elastic Model ◽  
Reinforced Composites ◽  
Heaviside Step Function ◽  
Equivalent Inclusion ◽  
Inclusion Theory ◽  
Elastic Particle

The visco-elastic mechanism of particles reinforced composites has been investigated through revised Eshelby equivalent inclusion theory. A visco-elastic model is applied. Furthermore, by introducing Heaviside step function and Laplace transform, the creep constitutional equation related to strain rate effect is achieved. Finally, by equivalent inclusion theory, introducing secant modulus, the material moduli with time and volume fraction concerning Glass/ED6 particles reinforced materials have been given. The results show that the visco-elastic property of composite material is mainly determined by the visco-elastic behavior of the matrix, which meet experiment results well. It can be concluded from the results that there exits close relationship between the inclusion shape, volume fraction and loading path.

scholarly journals Evaluation of Methods for Generating Parametric (R)-[11C]PK11195 Binding Images

2007 ◽  
Vol 27 (9) ◽  
pp. 1603-1615 ◽  
Author(s):  
Alie Schuitemaker ◽  
Bart NM van Berckel ◽  
Marc A Kropholler ◽  
Reina W Kloet ◽  
Cees Jonker ◽  
...  
Keyword(s):  
Basis Function ◽  
Arterial Input Function ◽  
Parametric Method ◽  
Compartmental Analysis ◽  
Accurate Method ◽  
Graphical Analysis ◽  
Binding Potential ◽  
Reference Tissue ◽  
Parametric Images ◽  
Arterial Blood

Activated microglia can be visualised using ( R)-[11C]PK11195 (1-[2-chlorophenyl]- N-methyl- N-[1-methyl-propyl]-3-isoquinoline carboxamide) and positron emission tomography (PET). In previous studies, various methods have been used to quantify ( R)-[11C]PK11195 binding. The purpose of this study was to determine which parametric method would be best suited for quantifying ( R)-[11C]PK11195 binding at the voxel level. Dynamic ( R)-[11C]PK11195 scans with arterial blood sampling were performed in 20 healthy and 9 Alzheimer's disease subjects. Parametric images of both volume of distribution ( Vd) and binding potential ( BP) were obtained using Logan graphical analysis with plasma input. In addition, BP images were generated using two versions of the basis function implementation of the simplified reference tissue model, two versions of Ichise linearisations, and Logan graphical analysis with reference tissue input. Results of the parametric methods were compared with results of full compartmental analysis using nonlinear regression. Simulations were performed to assess accuracy and precision of each method. It was concluded that Logan graphical analysis with arterial input function is an accurate method for generating parametric images of Vd. Basis function methods, one of the Ichise linearisations and Logan graphical analysis with reference tissue input provided reasonably accurate and precise estimates of BP. In pathological conditions with reduced flow rates or large variations in blood volume, the basis function method is preferred because it produces less bias and is more precise.

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