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Journal of Cerebral Blood Flow and... Jun 2022We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified...
We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified reference tissue model (SRTM) by incorporating a non-zero dissociation time constant from the specifically bound compartment. The forward computational approach avoided errors associated with noisy and nonorthogonal basis functions using an inverse linear model. Compared to analysis by a multilinear single-compartment reference tissue model (MRTM), fFTRM provided improved accuracy for estimation of binding potentials at early times in the scan, with no worse reproducibility across sessions. To test the model's ability to identify small focal changes in binding potential using a within-scan challenge, we employed a nonhuman primate model of focal dopamine release elicited by deep brain microstimulation remote to ventral striatum (VST) during imaging by simultaneous PET and fMRI. The new model reported an unambiguously lateralized response in VST consistent with fMRI, whereas the MRTM-derived response was not lateralized and was consistent with simulations of model bias. The proposed model enabled better accuracy in PET [C]raclopride displacement studies and may also facilitate challenges sooner after injection, thereby recovering some sensitivity lost to radioactive decay of the PET tracer.
Topics: Animals; Brain; Positron-Emission Tomography; Raclopride; Radionuclide Imaging; Radiopharmaceuticals; Reproducibility of Results
PubMed: 34894821
DOI: 10.1177/0271678X211065212 -
JCI Insight May 2021Bariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors...
Bariatric surgery is the most effective method for weight loss in morbid obesity. There is significant individual variability in the weight loss outcomes, yet factors leading to postoperative weight loss or weight regain remain elusive. Alterations in the μ-opioid receptor (MOR) and dopamine D2 receptor (D2R) systems are associated with obesity and appetite control, and the magnitude of initial brain receptor system perturbation may predict long-term surgical weight loss outcomes. We tested this hypothesis by studying 19 morbidly obese women (mean BMI 40) scheduled to undergo bariatric surgery. We measured their preoperative MOR and D2R availabilities using positron emission tomography with [11C]carfentanil and [11C]raclopride, respectively, and then assessed their weight development association with regional MOR and D2R availabilities at 24-month follow-up. MOR availability in the amygdala consistently predicted weight development throughout the follow-up period, but no associations were found for D2R. This is the first study to our knowledge to demonstrate that neuroreceptor markers prior to bariatric surgery are associated with postoperative weight development. Postoperative weight regain may derive from dysfunction in the opioid system, and weight loss outcomes after bariatric surgery may be partially predicted based on preoperative brain receptor availability, opening up new potential for treatment possibilities.
Topics: Adult; Bariatric Surgery; Brain; Female; Humans; Middle Aged; Neuroimaging; Obesity, Morbid; Positron-Emission Tomography; Preoperative Period; Receptors, Dopamine D2; Receptors, Opioid, mu; Weight Gain; Weight Loss
PubMed: 33848266
DOI: 10.1172/jci.insight.147820 -
Human Brain Mapping Aug 2021Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for...
Although striatal dopamine neurotransmission is believed to be functionally linked to the formation of the corticostriatal network, there has been little evidence for this regulatory process in the human brain and its disruptions in neuropsychiatric disorders. Here, we aimed to investigate associations of striatal dopamine transporter (DAT) and D receptor availabilities with gray matter (GM) volumes in healthy humans. Positron emission tomography images of D receptor (n = 34) and DAT (n = 17) captured with the specific radioligands [ C]raclopride and [ F]FE-PE2I, respectively, were acquired along with T1-weighted magnetic resonance imaging data in our previous studies, and were re-analyzed in this work. We quantified the binding potentials (BP ) of these radioligands in the limbic, executive, and sensorimotor functional subregions of the striatum. Correlations between the radioligand BP and regional GM volume were then examined by voxel-based morphometry. In line with the functional and anatomical connectivity, [ C]raclopride BP in the limbic striatum was positively correlated with volumes of the uncal/parahippocampal gyrus and adjacent temporal areas. Similarly, we found positive correlations between the BP of this radioligand in the executive striatum and volumes of the prefrontal cortices and their adjacent areas as well as between the BP in the sensorimotor striatum and volumes of the somatosensory and supplementary motor areas. By contrast, no significant correlation was found between [ F]FE-PE2I BP and regional GM volumes. Our results suggest unique structural and functional corticostriatal associations involving D receptor in healthy humans, which might be partially independent of the nigrostriatal pathway reflected by striatal DAT.
Topics: Adult; Dopamine Plasma Membrane Transport Proteins; Gray Matter; Humans; Magnetic Resonance Imaging; Male; Neostriatum; Positron-Emission Tomography; Prefrontal Cortex; Radiopharmaceuticals; Receptors, Dopamine D2; Ventral Striatum; Young Adult
PubMed: 34014611
DOI: 10.1002/hbm.25538 -
Molecules (Basel, Switzerland) Jan 2020Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the gene. As a result, intranuclear inclusions of mutant huntingtin... (Review)
Review
Huntington's disease (HD) is a fatal neurodegenerative disease caused by a CAG expansion mutation in the gene. As a result, intranuclear inclusions of mutant huntingtin protein are formed, which damage striatal medium spiny neurons (MSNs). A review of Positron Emission Tomography (PET) studies relating to HD was performed, including clinical and preclinical data. PET is a powerful tool for visualisation of the HD pathology by non-invasive imaging of specific radiopharmaceuticals, which provide a detailed molecular snapshot of complex mechanistic pathways within the brain. Nowadays, radiochemists are equipped with an impressive arsenal of radioligands to accurately recognise particular receptors of interest. These include key biomarkers of HD: adenosine, cannabinoid, dopaminergic and glutamateric receptors, microglial activation, phosphodiesterase 10 A and synaptic vesicle proteins. This review aims to provide a radiochemical picture of the recent developments in the field of HD PET, with significant attention devoted to radiosynthetic routes towards the tracers relevant to this disease.
Topics: Biomarkers; Brain; Cannabinoid Receptor Agonists; Carbon Radioisotopes; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Fluorine Radioisotopes; GABA Antagonists; Humans; Huntington Disease; Microglia; Phosphodiesterase Inhibitors; Positron-Emission Tomography; Purinergic P1 Receptor Antagonists; Radiopharmaceuticals
PubMed: 31979301
DOI: 10.3390/molecules25030482 -
Journal of Pain Research 2021It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered...
PURPOSE
It has been suggested that reward system dysfunction may account for emotion and pain suffering in migraine. However, there is a lack of evidence whether the altered reward system connectivity is directly associated with clinical manifestations, including negative affect and ictal pain severity and, at the molecular level, the dopamine (DA) D2/D3 receptors (D2/3Rs) signaling implicated in encoding motivational and emotional cues.
PATIENTS AND METHODS
We acquired resting-state functional MRI from interictal episodic migraine (EM) patients and age-matched healthy controls, as well as positron emission tomography (PET) with [C]raclopride, a selective radiotracer for DA D2/3Rs, from a subset of these participants. The nucleus accumbens (NAc) was seeded to measure functional connectivity (FC) and DA D2/3Rs availability based on its essential involvement in pain-related aversive/reward functions. Associations of the brain measures with positive/negative affect and ictal pain severity were also assessed.
RESULTS
Compared with controls, the EM group showed weaker right NAc connectivity with areas implicated in pain and emotional regulation, such as the amygdala, rostral anterior cingulate cortex, hippocampus, and thalamus; but showed stronger left NAc connectivity with the dorsolateral prefrontal cortex and lingual gyrus. Moreover, among the altered NAc connectivities, only right NAc-amygdala connectivity was inversely correlated with DA D2/3Rs availability in migraine patients (diagnostic group-by-D2/3Rs interaction p < 0.007). At a clinical level, such weaker NAc-amygdala connectivity was associated with lower interictal positive affect and greater ictal pain severity over the head and facial extension area (pain area and intensity number summation, PAINS).
CONCLUSION
Together, our findings suggest that altered reward system connectivity, specifically between the NAc and amygdala, might be affected by endogenous DA D2/3Rs signaling, and such process might be a neural mechanism that underlies emotional and pain suffering in episodic migraineurs.
PubMed: 33727857
DOI: 10.2147/JPR.S296540 -
Translational Psychiatry May 2021Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the...
Obesity is a growing burden to health and the economy worldwide. Obesity is associated with central µ-opioid receptor (MOR) downregulation and disruption of the interaction between MOR and dopamine D receptor (DR) system in the ventral striatum. Weight loss recovers MOR function, but it remains unknown whether it also recovers aberrant opioid-dopamine interaction. Here we addressed this issue by studying 20 healthy non-obese and 25 morbidly obese women (mean BMI 41) eligible for bariatric surgery. Brain MOR and DR availability were measured using positron emission tomography (PET) with [C]carfentanil and [C]raclopride, respectively. Either Roux-en-Y gastric bypass or sleeve gastrectomy was performed on obese subjects according to standard clinical treatment. 21 obese subjects participated in the postoperative PET scanning six months after bariatric surgery. In the control subjects, MOR and DR availabilities were associated in the ventral striatum (r = .62) and dorsal caudate (r = .61). Preoperatively, the obese subjects had disrupted association in the ventral striatum (r = .12) but the unaltered association in dorsal caudate (r = .43). The association between MOR and DR availabilities in the ventral striatum was recovered (r = .62) among obese subjects following the surgery-induced weight loss. Bariatric surgery and concomitant weight loss recover the interaction between MOR and DR in the ventral striatum in the morbidly obese. Consequently, the dysfunctional opioid-dopamine interaction in the ventral striatum is likely associated with an obese phenotype and may mediate excessive energy uptake. Striatal opioid-dopamine interaction provides a feasible target for pharmacological and behavioral interventions for treating obesity.
Topics: Analgesics, Opioid; Bariatric Surgery; Dopamine; Female; Humans; Obesity, Morbid; Positron-Emission Tomography; Receptors, Dopamine D2; Weight Loss
PubMed: 33934103
DOI: 10.1038/s41398-021-01370-2 -
Neuropathology and Applied Neurobiology Feb 2023CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in...
AIMS
CYP2C19 transgenic mouse expresses the human CYP2C19 gene in the liver and developing brain, and it exhibits altered neurodevelopment associated with impairments in emotionality and locomotion. Because the validation of new animal models is essential for the understanding of the aetiology and pathophysiology of movement disorders, the objective was to characterise motoric phenotype in CYP2C19 transgenic mice and to investigate its validity as a new animal model of ataxia.
METHODS
The rotarod, paw-print and beam-walking tests were utilised to characterise the motoric phenotype. The volumes of 20 brain regions in CYP2C19 transgenic and wild-type mice were quantified by 9.4T gadolinium-enhanced post-mortem structural neuroimaging. Antioxidative enzymatic activity was quantified biochemically. Dopaminergic alterations were characterised by chromatographic quantification of concentrations of dopamine and its metabolites and by subsequent immunohistochemical analyses. The beam-walking test was repeated after the treatment with dopamine receptor antagonists ecopipam and raclopride.
RESULTS
CYP2C19 transgenic mice exhibit abnormal, unilateral ataxia-like gait, clasping reflex and 5.6-fold more paw-slips in the beam-walking test; the motoric phenotype was more pronounced in youth. Transgenic mice exhibited a profound reduction of 12% in cerebellar volume and a moderate reduction of 4% in hippocampal volume; both regions exhibited an increased antioxidative enzyme activity. CYP2C19 mice were hyperdopaminergic; however, the motoric impairment was not ameliorated by dopamine receptor antagonists, and there was no alteration in the number of midbrain dopaminergic neurons in CYP2C19 mice.
CONCLUSIONS
Humanised CYP2C19 transgenic mice exhibit altered gait and functional motoric impairments; this phenotype is likely caused by an aberrant cerebellar development.
Topics: Humans; Mice; Animals; Adolescent; Mice, Transgenic; Cytochrome P-450 CYP2C19; Ataxia; Cerebellum; Cerebellar Diseases; Neurodegenerative Diseases; Atrophy; Disease Models, Animal
PubMed: 36536486
DOI: 10.1111/nan.12867 -
Frontiers in Neuroscience 2022The linear parametric neurotransmitter positron emission tomography (lp-ntPET) kinetic model can be used to detect transient changes (activation) in endogenous...
The linear parametric neurotransmitter positron emission tomography (lp-ntPET) kinetic model can be used to detect transient changes (activation) in endogenous neurotransmitter levels. Preclinical PET scans in awake animals can be performed to investigate neurotransmitter transient changes. Here we use the spatiotemporal kernel reconstruction (Kernel) for noise reduction in dynamic PET, and lp-ntPET kinetic modeling. Kernel is adapted for motion correction reconstruction, applied in awake rat PET scans. We performed 2D rat brain phantom simulation using the ntPET model at 3 different noise levels. Data was reconstructed with independent frame reconstruction (IFR), IFR with HYPR denoising, and Kernel, and lp-ntPET kinetic parameters ( : efflux rate, γ: activation magnitude, : activation onset time, and : activation peak time) were calculated. Additionally, significant activation magnitude (γ) difference with respect to a region with no activation (rest) was calculated. Finally, [C]raclopride experiments were performed in anesthetized and awake rats, injecting cold raclopride at 20 min after scan start to simulate endogenous neurotransmitter release. For simulated data at the regional level, IFR coefficient of variation (COV) of , γ, and was reduced with HYPR denoising, but Kernel showed the lowest COV (2 fold reduction compared with IFR). At the pixel level the same trend is observed for , γ, and COV, but reduction is larger with Kernel compared with IFR (10-14 fold). Bias in γ with respect with noise-free values was additionally reduced using Kernel (difference of 292, 72.4, and -6.92% for IFR, IFR+KYPR, and Kernel, respectively). Significant difference in activation between the rest and active region could be detected at a simulated activation of 160% for IFR and IFR+HYPR, and of 120% for Kernel. In rat experiments, lp-ntPET parameters have better confidence intervals using Kernel. In the γ, and parametric maps, the striatum structure can be identified with Kernel but not with IFR. Striatum voxel-wise γ, and values have lower variability using Kernel compared with IFR and IFR+HYPR. The spatiotemporal kernel reconstruction adapted for motion correction reconstruction allows to improve lp-ntPET kinetic modeling noise in awake rat studies, as well as detection of subtle neurotransmitter activations.
PubMed: 35645721
DOI: 10.3389/fnins.2022.901091 -
Neuropsychopharmacology : Official... Apr 2020Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human...
Impaired cognitive flexibility in visual reversal-learning tasks has been observed in a wide range of neurological and neuropsychiatric disorders. Although both human and animal studies have implicated striatal D-like and D-like receptors (D2R; D1R) in this form of flexibility, less is known about the contribution they make within distinct sub-regions of the striatum and the different phases of visual reversal learning. The present study investigated the involvement of D2R and D1R during the early (perseverative) phase of reversal learning as well as in the intermediate and late stages (new learning) after microinfusions of D2R and D1R antagonists into the nucleus accumbens core and shell (NAcC; NAcS), the anterior and posterior dorsomedial striatum (DMS) and the dorsolateral striatum (DLS) on a touchscreen visual serial reversal-learning task. Reversal learning was improved after dopamine receptor blockade in the nucleus accumbens; the D1R antagonist, SCH23390, in the NAcS and the D2R antagonist, raclopride, in the NAcC selectively reduced early, perseverative errors. In contrast, reversal learning was impaired by D2R antagonism, but not D1R antagonism, in the dorsal striatum: raclopride increased errors in the intermediate phase after DMS infusions, and increased errors across phases after DLS infusions. These findings indicate that D1R and D2R modulate different stages of reversal learning through effects localised to different sub-regions of the striatum. Thus, deficits in behavioral flexibility observed in disorders linked to dopamine perturbations may be attributable to specific D1R and D2R dysfunction in distinct striatal sub-regions.
Topics: Animals; Discrimination, Psychological; Male; Neostriatum; Nucleus Accumbens; Rats; Receptors, Dopamine D1; Receptors, Dopamine D2; Reversal Learning; Visual Perception
PubMed: 31940660
DOI: 10.1038/s41386-020-0612-4 -
Proceedings of the National Academy of... Jan 2021The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's...
The link between synaptic plasticity and reorganization of brain activity in health and disease remains a scientific challenge. We examined this question in Parkinson's disease (PD) where functional up-regulation of postsynaptic D receptors has been documented while its significance at the neural activity level has never been identified. We investigated cortico-subcortical plasticity in PD using the oculomotor system as a model to study reorganization of dopaminergic networks. This model is ideal because this system reorganizes due to frontal-to-parietal shifts in blood oxygen level-dependent (BOLD) activity. We tested the prediction that functional activation plasticity is associated with postsynaptic dopaminergic modifications by combining positron emission tomography/functional magnetic resonance imaging to investigate striatal postsynaptic reorganization of dopamine D receptors (using C-raclopride) and neural activation in PD. We used covariance (connectivity) statistics at molecular and functional levels to probe striato-cortical reorganization in PD in on/off medication states to show that functional and molecular forms of reorganization are related. D binding across regions defined by prosaccades showed increased molecular connectivity between both caudate/putamen and hyperactive parietal eye fields in PD in contrast with frontal eye fields in controls, in line with the shift model. Concerning antisaccades, parietal-striatal connectivity dominated in again in PD, unlike frontal regions. Concerning molecular-BOLD covariance, a striking sign reversal was observed: PD patients showed negative frontal-putamen functional-molecular associations, consistent with the reorganization shift, in contrast with the positive correlations observed in controls. Follow-up analysis in off-medication PD patients confirmed the negative BOLD-molecular correlation. These results provide a link among BOLD responses, striato-cortical synaptic reorganization, and neural plasticity in PD.
Topics: Aged; Brain Mapping; Case-Control Studies; Caudate Nucleus; Dopamine; Dopamine Antagonists; Female; Frontal Lobe; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Neuronal Plasticity; Neurons; Oxygen; Parietal Lobe; Parkinson Disease; Positron-Emission Tomography; Putamen; Raclopride; Receptors, Dopamine D2; Saccades; Synapses
PubMed: 33431672
DOI: 10.1073/pnas.2013962118