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.

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'.

Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects

NeuroImage ◽  
2009 ◽  
Vol 47 (2) ◽  
pp. 482-492 ◽  
Author(s):  
Amélie Lothe ◽  
Claudette Boni ◽  
Nicolas Costes ◽  
Philip Gorwood ◽  
Sandrine Bouvard ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Healthy Subjects ◽  
Binding Potential

scholarly journals Tracer Kinetic Modeling of [11C]AFM, a New PET Imaging Agent for the Serotonin Transporter

2013 ◽  
Vol 33 (12) ◽  
pp. 1886-1896 ◽  
Author(s):  
Mika Naganawa ◽  
Nabeel Nabulsi ◽  
Beata Planeta ◽  
Jean-Dominique Gallezot ◽  
Shu-Fei Lin ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Serotonin Transporter ◽  
Emission Tomography ◽  
Binding Potential ◽  
Reference Tissue ◽  
Time Activity ◽  
Tissue Model ◽  
Positron Emission ◽  
Arterial Input Functions ◽  
Tissue Models

[11C]AFM, or [11C]2-[2-(dimethylaminomethyl)phenylthio]-5-fluoromethylphenylamine, is a new positron emission tomography (PET) radioligand with high affinity and selectivity for the serotonin transporter (SERT). The purpose of this study was to determine the most appropriate kinetic model to quantify [11C]AFM binding in the healthy human brain. Positron emission tomography data and arterial input functions were acquired from 10 subjects. Compartmental modeling and the multilinear analysis-1(MA1) method were tested using the arterial input functions. The one-tissue model showed a lack of fit in low-binding regions, and the two-tissue model failed to estimate parameters reliably. Regional time–activity curves were well described by MA1. The rank order of [11C]AFM binding potential ( BPND) matched well with the known regional SERT densities. For routine use of [11C]AFM, several noninvasive methods for quantification of regional binding were evaluated, including simplified reference tissue models (SRTM and SRTM2), and multilinear reference tissue models (MRTM and MRTM2). The best methods for region of interest (ROI) analysis were MA1, MRTM2, and SRTM2, with fixed population kinetic values ( k′2 or b′) for the reference methods. The MA1 and MRTM2 methods were best for parametric imaging. These results showed that [11C]AFM is a suitable PET radioligand to image and quantify SERT in humans.

scholarly journals Quantification of [18F]DPA-714 Binding in the Human Brain: Initial Studies in Healthy Controls and Alzheimer'S Disease Patients

2015 ◽  
Vol 35 (5) ◽  
pp. 766-772 ◽  
Author(s):  
Sandeep SV Golla ◽  
Ronald Boellaard ◽  
Vesa Oikonen ◽  
Anja Hoffmann ◽  
Bart NM van Berckel ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Healthy Subjects ◽  
Volume Ratio ◽  
Information Criterion ◽  
Volume Of Distribution ◽  
Translocator Protein ◽  
Binding Potential ◽  
Reference Tissue ◽  
Time Activity

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([18F] DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [18F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [18F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [18F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution ( VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [18F]DPA-714 cannot be used for separating individual AD patients from heathy subjects, but further studies including TSPO binding status are needed to substantiate these findings.

scholarly journals The association of DAT gene methylation with striatal DAT availability in healthy subjects

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kyoungjune Pak ◽  
Ju Won Seok ◽  
Hyun-Yeol Nam ◽  
Seongho Seo ◽  
Myung Jun Lee ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Healthy Subjects ◽  
Ventral Striatum ◽  
Reward Processing ◽  
Reference Tissue ◽  
Emission Data ◽  
Positive Correlation ◽  
Reward Expectancy ◽  
The Mean ◽  
Reward And Punishment

Abstract Background DNA methylation inhibits gene expression by preventing transcription factors from binding to DNA. Functioning of nigrostriatal dopaminergic neurons is influenced by the expression of the dopamine transporter (DAT), and genetic variations in the gene encoding DAT contribute to differences in reward processing. We aimed to investigate the action of DAT methylation on DAT protein expression measured by positron emission tomography (PET). Methods The emission data were acquired over 90 min with 50 frames after injection of 18F-FP-CIT using PET. Binding potentials (BPNDs) of ventral striatum, caudate nucleus, putamen were measured with the simplified reference tissue method. Genomic DNA was extracted from subjects’ blood sampling. Methylation of 4 regions in SLC6A3 gene was assessed using bisulfite pyrosequencing. The mean percentage of methylation (%) for each cluster was calculated by taking the average of all CpG site methylation levels measured within the cluster. Subjects were assessed with the Generalized Reward and Punishment Expectancy Scales (GRAPES) that consists of 30 items related with the reward and punishment that individuals expect for their behaviors. Results Thirty-five healthy males, with an age range between 20 and 30 years, and a mean age of 24.4 ± 2.7 years, were included in this study. The mean percentage of methylation (%) from cluster C showed a trend of positive correlation with DAT availability of ventral striatum (rho = 0.3712, p = 0.0281), not significant after correction for multiple comparisons, and a significant correlation with GRAPES A: reward expectancy scale (rho = 0.7178, p < 0.0001). Conclusion DAT methylation from peripheral blood showed a trend of positive correlation with DAT availability of ventral striatum in healthy subjects; however, it was not significant after correction for multiple comparison. The degrees of methylation from cluster C of DAT in peripheral blood were significantly correlated with reward scales of GRAPES A: reward expectancy scale. The association between DAT methylation and DAT expression needs to be investigated further.

Dopaminylation in Psychostimulant use Disorder Protects Against Psychostimulant Seeking Behavior by Normalizing Nucleus Accumbens (NAc) Dopamine Expression

2021 ◽  
Vol 09 ◽  
Author(s):  
Kenneth Blum ◽  
Mark S Gold ◽  
Jean L. Cadet ◽  
David Baron ◽  
Abdalla Bowirrat ◽  
...  
Keyword(s):  
Nucleus Accumbens ◽  
Histone H3 ◽  
D2 Receptor ◽  
Reward Processing ◽  
Allelic Polymorphism ◽  
Cocaine Withdrawal ◽  
Src Signaling ◽  
Chronic Cocaine ◽  
Cocaine Seeking ◽  
Seeking Behavior

Background: Repeated cocaine administration changes histone acetylation and methylation on Lys residues and Deoxyribonucleic acid (DNA) within the nucleus accumbens (NAc). Recently Nestler’s group explored histone Arg (R) methylation in reward processing models. Damez-Werno et al. (2016) reported that during investigator and selfadministration experiments, the histone mark protein-R-methyltransferase-6 (PRMT6) and asymmetric dimethylation of R2 on histone H3 (H3R2me2a) decreased in the rodent and cocaine-dependent human NAc. Overexpression of PRMT6 in D2-MSNs in all NAc neurons increased cocaine seeking, whereas PRMT6 overexpression in D1-MSNs protects against cocaine-seeking. Hypothesis: Hypothesizing that dopaminylation (H3R2me2a binding) occurs in psychostimulant use disorder (PSU), and the binding inhibitor Srcin1, like the major DRD2 A2 allelic polymorphism, protects against psychostimulant seeking behavior by normalizing nucleus accumbens (NAc) dopamine expression. Discussion: Numerous publications confirmed the association between the DRD2 Taq A1 allele (30-40 lower D2 receptor numbers) and severe cocaine dependence. Lepack et al. (2020) found that acute cocaine increases dopamine in NAc synapses, results in histone H3 glutamine 5 dopaminylation (H3Q5dop), and consequent inhibition of D2 expression. The inhibition increases with chronic cocaine use and accompanies cocaine withdrawal. They also found that the Src kinase sig-naling inhibitor 1 (Srcin1 or p140CAP) during cocaine withdrawal reduced H3R2me2a binding. Consequently, this inhibited dopaminylation induced a “homeostatic brake.” Conclusion: The decrease in Src signaling in NAc D2-MSNs, like the DRD2 Taq A2 allele, a well-known genetic mechanism protective against SUD normalized nucleus accumbens (NAc) dopamine expression and decreased cocaine reward and motivation to self-administer cocaine. The Srcin1 may be an important therapeutic target.

Detection and Quantification of 7-Hydroxydehydroepiandrosterone Epimers in Three Body Fluids

2002 ◽  
Vol 67 (1) ◽  
pp. 10-18 ◽  
Author(s):  
Richard Hampl ◽  
Martin Hill ◽  
Luboslav Stárka
Keyword(s):  
Healthy Subjects ◽  
Serum Levels ◽  
Body Fluids ◽  
Gas Chromatography Mass Spectrometry ◽  
Specific Radioimmunoassay ◽  
Order Of Magnitude ◽  
Three Body ◽  
First Time ◽  
Nanomolar Range ◽  
Detection And Quantification

3β,7α-Dihydroxyandrost-5-en-17-one (1) (7α-OH-DHEA) and its 7β-hydroxy epimer 2 (7β-OH-DHEA) - 7α- and 7β-hydroxydehydroepiandrosterone - were detected and quantified in three human body fluids: in blood serum, saliva and ejaculate. Specific radioimmunoassay and gas chromatography-mass spectrometry have been used. For the first time the data on changes of these dehydroepiandrosterone metabolites are reported for a representative group of healthy subjects of both sexes (172 females and 217 males) during the life span. The serum levels of both 7-hydroxydehydroepiandrosterone epimers in serum and also in semen were in the low nanomolar range, while concentrations by one order of magnitude lower were found in saliva, but still within the detection limit. The results will serve as a basis for comparative studies of 7-hydroxydehydroepiandrosterone levels under various pathophysiological conditions, with a particular respect to autoimmune disorders.

Methylphenidate reduces orienting bias in healthy individuals

2021 ◽  
pp. 026988112199688
Author(s):  
Leehe Peled-Avron ◽  
Hagar Gelbard Goren ◽  
Noa Brande-Eilat ◽  
Shirel Dorman-Ilan ◽  
Aviv Segev ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Asymmetric Effect ◽  
Healthy Individuals ◽  
Double Blind ◽  
Spatial Orienting ◽  
Individual Trait ◽  
Neurological Patients ◽  
Dopamine Signaling ◽  
First Time ◽  
Neural Effect

Background: Healthy individuals show subtle orienting bias, a phenomenon known as pseudoneglect, reflected in a tendency to direct greater attention toward one hemispace. Accumulating evidence indicates that this bias is an individual trait, and attention is preferentially directed contralaterally to the hemisphere with higher dopamine signaling. Administration of methylphenidate (MPH), a dopamine transporter inhibitor, was shown to normalize aberrant spatial attention bias in psychiatric and neurological patients, suggesting that the reduced orienting bias following administration of MPH reflects an asymmetric effect of the drug, increasing extracellular dopamine in the hemisphere with lower dopamine signaling. Aim: We predicted that, similarly to its effect on patients with brain pathology, MPH will reduce the orienting bias in healthy subjects. Methods: To test this hypothesis, we examined the behavioral effects of a single dose (20 mg) of MPH on orienting bias in 36 healthy subjects (18 females) in a randomized, double-blind placebo-controlled, within-subject design, using the greyscales task, which has been shown to detect subtle attentional biases in both patients and healthy individuals. Results/outcomes: Results demonstrate that healthy individuals vary in both direction and magnitude of spatial orienting bias and show reduced magnitude of orienting bias following MPH administration, regardless of the initial direction of asymmetry. Conclusions/interpretations: Our findings reveal, for the first time in healthy subjects, that MPH decreases spatial orienting bias in an asymmetric manner. Given the well-documented association between orienting bias and asymmetric dopamine signaling, these findings also suggest that MPH might exert a possible asymmetric neural effect in the healthy brain.

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.

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