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NeuroImage Jan 2021To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and...
To minimize motion-related distortion of reconstructed images, conventional positron emission tomography (PET) measurements of the brain inevitably require a firm and tight head restraint. While such a restraint is now a routine procedure in brain imaging, the physiological and psychological consequences resulting from the restraint have not been elucidated. To address this problem, we developed a restraint-free brain PET system and conducted PET scans under both restrained and non-restrained conditions. We examined whether head restraint during PET scans could alter brain activities such as regional cerebral blood flow (rCBF) and dopamine release along with psychological stress related to head restraint. Under both conditions, 20 healthy male participants underwent [O]HO and [C]Raclopride PET scans during working memory tasks with the same PET system. Before, during, and after each PET scan, we measured physiological and psychological stress responses, including the State-Trait Anxiety Inventory (STAI) scores. Analysis of the [O]HO-PET data revealed higher rCBF in regions such as the parahippocampus in the restrained condition. We found the binding potential (BP) of [C]Raclopride in the putamen was significantly reduced in the restrained condition, which reflects an increase in dopamine release. Moreover, the restraint-induced change in BP was correlated with a shift in the state anxiety score of the STAI, indicating that less anxiety accompanied smaller dopamine release. These results suggest that the stress from head restraint could cause unsolicited responses in brain physiology and emotional states. The restraint-free imaging system may thus be a key enabling technology for the natural depiction of the mind.
Topics: Adult; Anxiety; Brain; Carbon Radioisotopes; Cerebrovascular Circulation; Dopamine; Functional Neuroimaging; Head; Healthy Volunteers; Humans; Male; Memory, Short-Term; Oxygen Radioisotopes; Positron-Emission Tomography; Putamen; Raclopride; Restraint, Physical; Stress, Physiological; Stress, Psychological; Young Adult
PubMed: 33039616
DOI: 10.1016/j.neuroimage.2020.117434 -
Materials (Basel, Switzerland) Jan 2023In this work, we developed a novel approach to purify [C]Raclopride ([C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition...
In this work, we developed a novel approach to purify [C]Raclopride ([C]RAC), an important positron emission tomography radiotracer, based on tailored shape-recognition polymers, with the aim to substitute single-pass HPLC purification with an in-flow trap & release process. Molecular imprinting technology (MIT) applied to solid phase extraction (MISPE) was investigated to develop a setting able to selectively extract [C]RAC in a mixture containing a high amount of its precursor, (S)-O-Des-Methyl-Raclopride (DM-RAC). Two imprinted polymers selective for unlabeled RAC and DM-RAC were synthesized through a radical polymerization at 65 °C using methacrylic acid and trimethylolpropane trimethacrylate in the presence of template molecule (RAC or DM-RAC). The prepared polymer was characterized by scanning electron microscopy and Fourier transform infrared spectroscopy and tested in MISPE experiments. The polymers were used in testing conditions, revealing a high retention capacity of RAC-MISPE to retain RAC either in the presence of similar concentrations of RAC and DM-RAC precursor (96.9%, RSD 6.6%) and in the presence of a large excess of precursor (90%, RSD 4.6%) in the loading solution. Starting from these promising results, preliminary studies for selective purification of [C]Raclopride using this RAC-MISPE were performed and, while generally confirming the selectivity capacity of the polymer, revealed challenging applicability to the current synthetic process, mainly due to high backpressures and long elution times.
PubMed: 36770098
DOI: 10.3390/ma16031091 -
Neuropsychopharmacology : Official... May 2024The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced... (Randomized Controlled Trial)
Randomized Controlled Trial
The rewarding effects of stimulant drugs such as methylphenidate (MP) depend crucially on how fast they raise dopamine in the brain. Yet how the rate of drug-induced dopamine increases impacts brain network communication remains unresolved. We manipulated route of MP administration to generate fast versus slow dopamine increases. We hypothesized that fast versus slow dopamine increases would result in a differential pattern of global brain connectivity (GBC) in association with regional levels of dopamine D1 receptors, which are critical for drug reward. Twenty healthy adults received MP intravenously (0.5 mg/kg; fast dopamine increases) and orally (60 mg; slow dopamine increases) during simultaneous [C]raclopride PET-fMRI scans (double-blind, placebo-controlled). We tested how GBC was temporally associated with slow and fast dopamine increases on a minute-to-minute basis. Connectivity patterns were strikingly different for slow versus fast dopamine increases, and whole-brain spatial patterns were negatively correlated with one another (rho = -0.54, p < 0.001). GBC showed "fast>slow" associations in dorsal prefrontal cortex, insula, posterior thalamus and brainstem, caudate and precuneus; and "slow>fast" associations in ventral striatum, orbitofrontal cortex, and frontopolar cortex (p < 0.05). "Fast>slow" GBC patterns showed significant spatial correspondence with D1 receptor availability (estimated via normative maps of [C]SCH23390 binding; rho = 0.22, p < 0.05). Further, hippocampal GBC to fast dopamine increases was significantly negatively correlated with self-reported 'high' ratings to intravenous MP across individuals (r = -0.68, p = 0.015). Different routes of MP administration produce divergent patterns of brain connectivity. Fast dopamine increases are uniquely associated with connectivity patterns that have relevance for the subjective experience of drug reward.
Topics: Humans; Male; Adult; Female; Brain; Positron-Emission Tomography; Magnetic Resonance Imaging; Dopamine; Methylphenidate; Double-Blind Method; Young Adult; Raclopride; Central Nervous System Stimulants; Receptors, Dopamine D1; Neural Pathways; Dopamine Antagonists; Brain Mapping
PubMed: 38326458
DOI: 10.1038/s41386-024-01803-8 -
Communications Biology Feb 2023Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat...
Dopamine facilitates cognition and is implicated in reward processing. Methylphenidate, a dopamine transporter blocker widely used to treat attention-deficit/hyperactivity disorder, can have rewarding and addictive effects if injected. Since methylphenidate's brain uptake is much faster after intravenous than oral intake, we hypothesize that the speed of dopamine increases in the striatum in addition to its amplitude underly drug reward. To test this we use simulations and PET data of [C]raclopride's binding displacement with oral and intravenous methylphenidate challenges in 20 healthy controls. Simulations suggest that the time-varying difference in standardized uptake value ratios for [C]raclopride between placebo and methylphenidate conditions is a proxy for the time-varying dopamine increases induced by methylphenidate. Here we show that the dopamine increase induced by intravenous methylphenidate (0.25 mg/kg) in the striatum is significantly faster than that by oral methylphenidate (60 mg), and its time-to-peak is strongly associated with the intensity of the self-report of "high". We show for the first time that the "high" is associated with the fast dopamine increases induced by methylphenidate.
Topics: Humans; Methylphenidate; Dopamine; Raclopride; Brain; Attention Deficit Disorder with Hyperactivity; Dopamine Antagonists
PubMed: 36765261
DOI: 10.1038/s42003-023-04545-3 -
Brain, Behavior, and Immunity Nov 2022Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain... (Randomized Controlled Trial)
Randomized Controlled Trial
Immune-brain interactions influence the pathophysiology of addiction. Lipopolysaccharide (LPS)-induced systemic inflammation produces effects on reward-related brain regions and the dopamine system. We previously showed that LPS amplifies dopamine elevation induced by methylphenidate (MP), compared to placebo (PBO), in eight healthy controls. However, the effects of LPS on the dopamine system of tobacco smokers have not been explored. The goal of Study 1 was to replicate previous findings in an independent cohort of tobacco smokers. The goal of Study 2 was to combine tobacco smokers with the aforementioned eight healthy controls to examine the effect of LPS on dopamine elevation in a heterogenous sample for power and effect size determination. Eight smokers were each scanned with [C]raclopride positron emission tomography three times-at baseline, after administration of LPS (0.8 ng/kg, intravenously) and MP (40 mg, orally), and after administration of PBO and MP, in a double-blind, randomized order. Dopamine elevation was quantified as change in [C]raclopride binding potential (ΔBP) from baseline. A repeated-measures ANOVA was conducted to compare LPS and PBO conditions. Smokers and healthy controls were well-matched for demographics, drug dosing, and scanning parameters. In Study 1, MP-induced striatal dopamine elevation was significantly higher following LPS than PBO (p = 0.025, 18 ± 2.9 % vs 13 ± 2.7 %) for smokers. In Study 2, MP-induced striatal dopamine elevation was also significantly higher under LPS than under PBO (p < 0.001, 18 ± 1.6 % vs 11 ± 1.5 %) in the combined sample. Smoking status did not interact with the effect of condition. This is the first study to translate the phenomenon of amplified dopamine elevation after experimental activation of the immune system to an addicted sample which may have implications for drug reinforcement, seeking, and treatment.
Topics: Central Nervous System Stimulants; Corpus Striatum; Dopamine; Humans; Inflammation; Lipopolysaccharides; Methylphenidate; Positron-Emission Tomography; Raclopride; Smokers
PubMed: 36058419
DOI: 10.1016/j.bbi.2022.08.016 -
NeuroImage Feb 2021Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological... (Randomized Controlled Trial)
Randomized Controlled Trial
Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test-retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [C]raclopride and [C]FLB 457 to assess the correlation in binding potential (BP) in extrastriatal brain regions. BP was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BP values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [C]raclopride and [C]FLB 457 BP extrastriatally (Pearson's R: 0.30-0.56), in contrast to very strong correlations between repeated [C]FLB 457 measurements (Pearson's R: 0.82-0.98). In comparison, correlations between repeated [C]raclopride measurements were low to moderate (Pearson's R: 0.28-0.75). These results are likely related to low signal to noise ratio of [C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [C]raclopride should be interpreted with caution.
Topics: Brain; Brain Mapping; Carbon Radioisotopes; Dopamine Antagonists; Female; Humans; Male; Middle Aged; Positron-Emission Tomography; Pyrrolidines; Raclopride; Radioligand Assay; Radiopharmaceuticals; Receptors, Dopamine D2; Salicylamides
PubMed: 33144221
DOI: 10.1016/j.neuroimage.2020.117523 -
Human Brain Mapping Dec 2023Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported... (Meta-Analysis)
Meta-Analysis
Feeding induces dopamine release in the striatum, and a dysfunction of the dopaminergic reward system can lead to overeating, and obesity. Studies have reported inconsistent findings of dopamine receptor (DR) positron emission tomography scans in obesity. Here we investigated the association between DR availability and overweight/obesity using Bayesian and frequentist meta-analysis. We performed a systematic search of Embase, Medline, Scopus and Web of Science for studies that compared striatal DR availability between lean subjects and overweight/obese subjects. The standardized mean difference (Hedge's g) of DR availability was calculated after extraction of data from each study. Studies were divided into two groups according to the definition of overweight/obese subjects (body mass index [BMI] cutoff of 25 and 30 kg/m ). Both Bayesian and frequentist meta-analysis was done in R Statistical Software version 4.2.2 (The R Foundation for Statistical Computing). Nine studies were eligible for inclusion in this study. Three studies with C11-raclopride, one with C11-PNHO, two with F18-fallypride, one with I123-IBZM, one with C11-NMB and one with both C11-raclopride and C11-PNHO were included. In Bayesian meta-analysis, the standardized mean difference of DR availability between lean and overweight/obese subjects markedly overlapped with zero regardless of BMI cutoff for obesity. In frequentist meta-analysis, the pooled standardized mean difference of DR availability did not show the significant difference between lean and overweight/obese subjects. There was an effect of the radiopharmaceutical on the standardized mean difference of DR availability in meta-analysis of BMI cutoff of 25 kg/m . In conclusion, brain DR availability is not different between lean and overweight/obese subjects. However, the effect is dependent on the radiopharmaceutical and the degree of obesity. Further studies with multi-radiopharmaceutical in the same individuals are needed to understand the association between DR and obesity.
Topics: Humans; Overweight; Raclopride; Bayes Theorem; Radiopharmaceuticals; Receptors, Dopamine D2; Obesity; Brain; Dopamine; Body Mass Index
PubMed: 37950852
DOI: 10.1002/hbm.26534 -
Annals of Clinical and Translational... Nov 2019The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with...
OBJECTIVE
The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age-related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive.
METHODS
The present work used magnetic resonance imaging and positron emission tomography with C-raclopride to jointly examine vascular parameters (white-matter lesions and perfusion), DA D2-receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging (COBRA) study.
RESULTS
Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White-matter lesion burden was negatively correlated with caudate DA D2-receptor availability and white-matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2-receptor availability, white-matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey-matter volumes, a larger number of white-matter lesions, and lower episodic memory performance.
INTERPRETATION
Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age-sensitive cognitive functions, with emphasis on DA integrity.
Topics: Aged; Aging; Brain; Cardiovascular Diseases; Cognition; Dopamine; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Positron-Emission Tomography
PubMed: 31663685
DOI: 10.1002/acn3.50927 -
EJNMMI Physics Apr 2022There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [C]raclopride with older data. This typically means...
BACKGROUND
There has been an ongoing need to compare and combine the results of new PET imaging studies conducted with [C]raclopride with older data. This typically means harmonizing data across different scanners. Previous harmonization studies have utilized either phantoms or human subjects, but the use of both phantoms and humans in one harmonization study is not common. The purpose herein was (1) to use phantom images to develop an inter-scanner harmonization technique and (2) to test the harmonization technique in human subjects.
METHODS
To develop the harmonization technique (Experiment 1), the Iida brain phantom was filled with F-18 solution and scanned on the two scanners in question (HRRT, HR+, Siemens/CTI). Phantom images were used to determine the optimal isotropic Gaussian filter to harmonize HRRT and HR+ images. To evaluate the harmonization on human images (Experiment 2), inter-scanner variability was calculated using [C]raclopride scans of 3 human subjects on both the HRRT and HR+ using percent difference (PD) in striatal non-displaceable binding potential (BP between HR+ and HRRT (with and without Gaussian smoothing). Finally, (Experiment 3), PD was calculated for test-retest (T/RT) variability of striatal BP for 8 human subjects scanned twice on the HR+.
RESULTS
Experiment 1 identified the optimal filter as a Gaussian with a 4.5 mm FWHM. Experiment 2 resulted in 13.9% PD for unfiltered HRRT and 3.71% for HRRT filtered with 4.5 mm. Experiment 3 yielded 5.24% PD for HR+.
CONCLUSIONS
The PD results show that the variability of harmonized HRRT is less than the T/RT variability of the HR+. The harmonization technique makes it possible for BP estimates from the HRRT to be compared to (and/or combined with) those from the HR+ without adding to overall variability. Our approach is applicable to all pairs of scanners still in service.
PubMed: 35416555
DOI: 10.1186/s40658-022-00457-z -
Molecular Pharmaceutics Mar 2020The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D receptor antagonists were used to...
The interaction of dopaminergic and cholinergic neurotransmission in, e.g., Parkinson's disease has been well established. Here, D receptor antagonists were used to assess changes in [F]-FEOBV binding to the vesicular acetylcholine transporter (VAChT) in rodents using positron emission tomography (PET). After pretreatment with either 10 mg/kg haloperidol, 1 mg/kg raclopride, or vehicle, 90 min dynamic PET scans were performed with arterial blood sampling. The net influx rate () was obtained from Patlak graphical analysis, using a metabolite-corrected plasma input function and dynamic PET data. [F]-FEOBV concentration in whole-blood or plasma and the metabolite-corrected plasma input function were not significantly changed by the pretreatments (adjusted > 0.07, Cohen's 0.28-1.89) while the area-under-the-curve (AUC) of the parent fraction of [F]-FEOBV was significantly higher after haloperidol treatment (adjusted = 0.022, Cohen's = 2.51) than in controls. Compared to controls, the AUC of [F]-FEOBV, normalized for injected dose and body weight, was nonsignificantly increased in the striatum after haloperidol (adjusted = 0.4, Cohen's = 1.77) and raclopride (adjusted = 0.052, Cohen's = 1.49) treatment, respectively. No changes in the AUC of [F]-FEOBV were found in the cerebellum (Cohen's 0.63-0.74). Raclopride treatment nonsignificantly increased in the striatum 1.3-fold compared to control rats (adjusted = 0.1, Cohen's = 1.1) while it reduced in the cerebellum by 28% (adjusted = 0.0004, Cohen's = 2.2) compared to control rats. Pretreatment with haloperidol led to a nonsignificant reduction in in the striatum (10%, adjusted = 1, Cohen's = 0.44) and a 40-50% lower than controls in all other brain regions (adjusted < 0.0005, Cohen's = 3.3-4.7). The changes in induced by the selective D receptor antagonist raclopride can in part be quantified using [F]-FEOBV PET imaging. Haloperidol, a nonselective D/σ receptor antagonist, either paradoxically decreased cholinergic activity or blocked off-target [F]-FEOBV binding to σ receptors. Hence, further studies evaluating the binding of [F]-FEOBV to σ receptors using selective σ receptor ligands are necessary.
Topics: Animals; Cerebellum; Corpus Striatum; Dopamine D2 Receptor Antagonists; Fluorine Radioisotopes; Haloperidol; Kinetics; Male; Parkinson Disease; Piperidines; Positron-Emission Tomography; Protein Binding; Raclopride; Radiopharmaceuticals; Rats; Rats, Wistar; Receptors, sigma; Vesicular Acetylcholine Transport Proteins
PubMed: 32011892
DOI: 10.1021/acs.molpharmaceut.9b01129