Individual differences in the proneness to have flow experiences are linked to dopamine D2-receptor availability in the dorsal striatum

Flow is a subjective experience of high but effortless attention, enjoyment, and low self-awareness that can occur during the active performance of challenging tasks. The dispositional proneness to experience flow is associated with personality traits that are known to be influenced by dopaminergic neural systems. Here, for the first time, we investigated relations between flow proneness and dopaminergic function. Specifically, we tested the hypothesis that the availability of dopamine D2-receptors in the striatum is positively associated with flow proneness. Striatal D2-receptor availability was measured in a sample of 25 healthy adults using positron emission tomography and [ 11 C]raclopride. Flow proneness was measured using the Swedish Flow Proneness Questionnaire. As hypothesized, there was a significant correlation (r = .41) between striatal D2-receptor availability and flow proneness. An exploratory analysis of striatal subregions showed that the relation was mainly driven by the dorsal striatum, with a significantly higher correlation in the putamen than in the ventral striatum. The findings constitute the first demonstration of an association between flow proneness and dopaminergic function. We suggest that the proneness to experience flow is related to personality dimensions that are under dopaminergic control and characterized by low impulsiveness, stable emotion, and positive affect

Comparison of D2 dopamine receptor occupancy after oral administration of quetiapine fumarate immediate-release and extended-release formulations in healthy subjects

Quetiapine is an established drug for treatment of schizophrenia, bipolar disorder, and major depressive disorder. While initially manufactured as an immediate-release (IR) formulation, an extended-release (XR) formulation has recently been introduced. Pharmacokinetic studies show that quetiapine XR provides a lower peak and more stable plasma concentration than the IR formulation. This study investigated if the pharmacokinetic differences translate into different time curves for central D2 dopamine receptor occupancy. Eleven control subjects were examined with positron emission tomography (PET) and the radioligand [11C]raclopride. Eight subjects underwent all of the scheduled PET measurements. After baseline examination, quetiapine XR was administered once-daily for 8 d titrated to 300 mg/d on days 5–8, followed by 300 mg/d quetiapine IR on days 9–12. PET measurements were repeated after the last doses of quetiapine XR and IR at predicted times of peak and trough plasma concentrations. Striatal D2 receptor occupancy was calculated using the simplified reference tissue model. Peak D2 receptor occupancy was significantly higher with quetiapine IR than XR in all subjects (50±4% and 32±11%, respectively), consistent with lower peak plasma concentrations for the XR formulation. Trough D2 receptor occupancy was similarly low for both formulations (IR 7±7%, XR 8±6%). The lower peak receptor occupancy associated with quetiapine XR may explain observed pharmacodynamic differences between the formulations. Assuming that our findings in control subjects are valid for patients with schizophrenia, the study supports the view that quetiapine, like the prototype atypical antipsychotic clozapine, may show antipsychotic effect at lower D2 receptor occupancy than typical antipsychotics

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [C-11]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA.Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. </p

Attention-deficit/hyperactivity disorder : Alterations of motor behaviour and dopaminergic transmission

Altered catecholaminergic neurotransmission in the brain has long been thought to be of importance in the regulation of motor behavior and cognitive performance in children who had symptoms of distractability, impulsivity and clumsiness. The dopamine theory of AD/HD has mainly been substantiated by: i) the effects of psychostimulants, which target the dopamine transporter (DAT), and thereby reduce impulsiveness and inattentiveness, increase the striatal cerebral blood flow and functional activity, and ii) the evidence from linkage studies associating the AD/HD syndrome with allelic variations of genes encoding the dopamine transporter and, possibly, the dopamine D4 receptors. However, the central regulatory mechanisms of dopamine neurotransmission in AD/HD have not been established yet. The main aim of this thesis was to examine the dopaminergic system in vivo in children with AD/HD by using positron emission tomography (PET). Twelve adolescents with AD/HD and ten young adults were investigated applying the double-tracer paradigm. Presynaptic and postsynaptic dopamine markers, DAT and dopamine D2 receptors, were mapped using the radioligands [11C]PE2I and [11C]raclopride. In the group of adolescents with ADHD, we also investigated relationship between the central dopamine markers and behavioral/cognitive performance. A new radioligand [11C]PE2I that has a high affinity and selectivity to the central DAT was used. Its favourable signal-to-background ratio enabled us to quantify the DAT density in the human striatum and midbrain; cross-validation of quatification methods of [11C]PE2I binding permitted its application in the clinical study. The PET measurements showed that the DAT and DRD2 density in the striatum did not differ between adolescents and young adults once a correction had been made for age. Thus, the initial findings of increased DAT in the striatum in AD/HD reported in the literature were not confirmed. The decreased regional density of DAT found in the substantia nigra/ventral tegmentum rather suggests a shift in the focus of the pathophysiology of AD/HD to the midbrain structures. In addition, positive correlations between hyperactivity levels and the density of dopamine markers in the striatum support similar reports by other authors and provide evidence for the involvement of the dopamine system in the pathophysiology of AD/HD. The AD/HD syndrome is a heterogenous diagnostic entity, and it is still a matter of debate whether perception and movement coordination problems are a constituent part of it. We investigated movement coordination problems from the perspective of motor control theories with a load lifting task, providing measurements of manipulative movements and associated postural adjustments. Fifty two children were investigated, including an additional control group of younger children, with the intention of addressing the developmental aspects of motor behavior. The results showed that children with AD/HD and developmental coordination disorder, or both, have a deficit in the programming of their motor behavior that is related to the severity/complexity of the syndrome, but which does not correspond to the motor performance of younger children. The deficient parametric control of the motor output, and lack of temporal coordination between the lifting movement and the postural responses limited the adaptation of the motor behavior to the environment

Test-retest reliability and convergent validity of (R)-[11C]PK11195 outcome measures without arterial input function

Purpose: The PET radioligand (R)-[C-11]PK11195 is used to quantify the 18-kDa translocator protein (TSPO), a marker for glial activation. Since there is no brain region devoid of TSPO, an arterial input function (AIF) is ideally required for quantification of binding. However, obtaining an AIF is experimentally demanding, is sometimes uncomfortable for participants, and can introduce additional measurement error during quantification. The objective of this study was to perform an evaluation of the test-retest reliability and convergent validity of techniques used for quantifying (R)-[C-11]PK11195 binding without an AIF in clinical studies. Methods: Data from six healthy individuals who participated in two PET examinations, 6weeks apart, were analyzed. Regional non-displaceable binding potential (BPND) values were calculated using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using supervised cluster analysis (SVCA). Standardized uptake values (SUVs) were estimated for the time interval of 40-60min. Results: Test-retest reliability for BPND estimates were poor (80% of ICCs &lt;0.5). BPND estimates derived without an AIF were not correlated with BPND, total or specific distribution volume from the 2TCM using an AIF (all R-2&lt;12%). SUVs showed moderate reliability but no correlation to any other outcome measure. Conclusions: Caution is warranted when interpreting patient-control comparisons employing (R)-[C-11]PK11195 outcome measures obtained without an AIF

Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease:A Positron Emission Tomography Study with [¹¹C]PBR28 and Machine Learning Analysis

Background The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. Objective In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. Methods We analyzed [C-11]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. Results We observed a conspicuous pattern of elevated regional [C-11]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. Conclusions We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an alpha-synucleinopathy that remains strikingly incurable. (c) 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Societ

Effects of age, BMI and sex on the glial cell marker TSPO : a multicentre [11C]PBR28 HRRT PET study

Purpose The purpose of this study was to investigate the effects of ageing, sex and body mass index (BMI) on translocator protein (TSPO) availability in healthy subjects using positron emission tomography (PET) and the radioligand [C-11]PBR28. Methods [C-11]PBR28 data from 140 healthy volunteers (72 males and 68 females; N = 78 with HAB and N = 62 MAB genotype; age range 19-80 years; BMI range 17.6-36.9) were acquired with High Resolution Research Tomograph at three centres: Karolinska Institutet (N = 53), Turku PET centre (N = 62) and Yale University PET Center (N = 25). The total volume of distribution (V-T) was estimated in global grey matter, frontal, temporal, occipital and parietal cortices, hippocampus and thalamus using multilinear analysis 1. The effects of age, BMI and sex on TSPO availability were investigated using linear mixed effects model, with TSPO genotype and PET centre specified as random intercepts. Results There were significant positive correlations between age and V-T in the frontal and temporal cortex. BMI showed a significant negative correlation with V-T in all regions. Additionally, significant differences between males and females were observed in all regions, with females showing higher V-T. A subgroup analysis revealed a positive correlation between V-T and age in all regions in male subjects, whereas age showed no effect on TSPO levels in female subjects. Conclusion These findings provide evidence that individual biological properties may contribute significantly to the high variation shown in TSPO binding estimates, and suggest that age, BMI and sex can be confounding factors in clinical studies