Pontus Plavén-Sigray

Dopamine D1 receptor availability is related to social behavior: A positron emission tomography study

Dysfunctional interpersonal behavior is thought to underlie a wide spectrum of psychiatric disorders; however, the neurobiological underpinnings of these behavioral disturbances are poorly understood. Previous molecular imaging studies have shown associations between striatal dopamine (DA) D2-receptor binding and interpersonal traits, such as social conformity. The objective of this study was to explore, for the first time, the role of DA D1-receptors (D1-Rs) in human interpersonal behavior. Twenty-three healthy subjects were examined using positron emission tomography and the radioligand [(11)C]SCH23390, yielding D1-R binding potential values. Striatal D1-R binding was related to personality scales selected to specifically assess one dimension of interpersonal behavior, namely a combination of affiliation and dominance (i.e., the Social Desirability, Verbal Trait Aggression and Physical Trait Aggression scales from Swedish Universities Scales of Personality). An exploratory analysis was also performed for extrastriatal brain regions. D1-R binding potential values in the limbic striatum (r = .52; p = .015), associative striatum (r = .55; p = .009), and sensorimotor striatum (r = .67; p = .001) were positively related to Social Desirability scores. D1-R binding potential in the limbic striatum (r = -.51; p = .019) was negatively associated with Physical Trait Aggression scores. For extrastriatal regions, Social Desirability scores showed positive correlations in the amygdala (r = .60; p = .006) and medial frontal cortex (r = .60; p = .004). This study provides further support for the role of DA function in the expression of disaffiliative and dominant traits. Specifically, D1-R availability may serve as a marker for interpersonal behavior in humans. Associations were demonstrated for the same dimension of interpersonal behavior as for D2-R, but in the opposite direction, suggesting that the two receptor subtypes are involved in the same behavioral processes, but with different functional roles.

Research: The readability of scientific texts is decreasing over time

Clarity and accuracy of reporting are fundamental to the scientific process. Readability formulas can estimate how difficult a text is to read. Here, in a corpus consisting of 709,577 abstracts published between 1881 and 2015 from 123 scientific journals, we show that the readability of science is steadily decreasing. Our analyses show that this trend is indicative of a growing use of general scientific jargon. These results are concerning for scientists and for the wider public, as they impact both the reproducibility and accessibility of research findings.

Extrastriatal dopamine D2-receptor availability in social anxiety disorder

Alterations in the dopamine system are hypothesized to influence the expression of social anxiety disorder (SAD) symptoms. However, molecular imaging studies comparing dopamine function between patients and control subjects have yielded conflicting results. Importantly, while all previous investigations focused on the striatum, findings from activation and blood flow studies indicate that prefrontal and limbic brain regions have a central role in the pathophysiology. The objective of this study was to investigate extrastriatal dopamine D2-receptor (D2-R) availability in SAD. We examined 12 SAD patients and 16 healthy controls using positron emission tomography and the high-affinity D2-R radioligand [11C]FLB457. Parametric images of D2-R binding potential were derived using the Logan graphical method with cerebellum as reference region. Two-tailed one-way independent ANCOVAs, with age as covariate, were used to examine differences in D2-R availability between groups using both region-based and voxel-wise analyses. The region-based analysis showed a medium effect size of higher D2-R levels in the orbitofrontal cortex (OFC) in patients, although this result did not remain significant after correction for multiple comparisons. The voxel-wise comparison revealed elevated D2-R availability in patients within OFC and right dorsolateral prefrontal cortex after correction for multiple comparisons. These preliminary results suggest that an aberrant extrastriatal dopamine system may be part of the disease mechanism in SAD.

Reliability of volumetric and surface-based normalisation and smoothing techniques for PET analysis of the cortex: A test-retest analysis using [ 11 C]SCH-23390

ABSTRACT Parametric voxelwise analysis is a commonly used tool in neuroimaging, as it allows for identification of regions of effects in the absence of a strong a‐priori regional hypothesis by comparing each voxel of the brain independently. Due to the inherent imprecision of single voxel measurements, spatial smoothing is performed to increase the signal‐to‐noise ratio of single‐voxel estimates. In addition, smoothing compensates for imprecisions in anatomical registration, and allows for the use of cluster‐based statistical thresholding. Smoothing has traditionally been applied in three dimensions, without taking the tissue types of surrounding voxels into account. This procedure may be suitable for subcortical structures, but is problematic for cortical regions for which grey matter often constitutes only a small proportion of the smoothed signal. New methods have been developed for cortical analysis in which voxels are sampled to a surface, and smoothing is restricted to neighbouring regions along the cortical grey matter in two dimensions. This procedure has recently been shown to decrease intersubject variability and bias of PET data. The aim of this study was to compare the variability, bias and test‐retest reliability of volumetric and surface‐based methods as they are applied in practice. Fifteen healthy young males were each measured twice using the dopamine D1 receptor radioligand [11C]SCH‐23390, and analyses were performed at the level of individual voxels and vertices within the cortex. We found that surface‐based methods yielded higher BPND values, lower coefficient of variation, less bias, better reliability and more precise estimates of parametric binding. All in all, these results suggest that surface‐based methods exhibit superior performance to volumetric approaches for voxelwise analysis of PET data, and we advocate for their use when a ROI‐based analysis is not appropriate. HIGHLIGHTSVolumetric and surface methods were compared for parametric cortical PET analysis.15 healthy controls were each measured twice using [11C]SCH‐23390.Surface methods yielded lower dispersion, less bias, and improved reliability.Surface methods are recommended for cortical analysis when ROIs are not appropriate.

A simulation and comparison of dynamic functional connectivity methods

There is a current interest in quantifying brain dynamic functional connectivity (DFC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for DFC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exists many DFC methods it is difficult to assess differences in dynamic brain connectivity between studies. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating DFC (sliding window, tapered sliding window, temporal derivative, spatial distance and jackknife correlation). In particular, we were interested in each methods’ ability to track changes in covariance over time, which is a key property in DFC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future DFC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. In this paper, we present dfcbenchmarker, which is a Python package where researchers can easily submit and compare their own DFC methods to evaluate its performance.

Accuracy and reliability of [11C]PBR28 specific binding estimated without the use of a reference region

[11C]PBR28 is a positron emission tomography radioligand used to estimate the expression of 18kDa translocator protein (TSPO). TSPO is expressed on glial cells and can function as a marker for immune activation. Since TSPO is expressed throughout the brain, no true reference region exists. For this reason, an arterial input function is required for accurate quantification of [11C]PBR28 binding and the most common outcome measure is the total distribution volume (VT). Notably, VT reflects both specific binding and non-displaceable binding (VND). Therefore, estimates of specific binding, such as binding potentials (e.g., BPND) and specific distribution volume (VS) should theoretically be more sensitive to underlying differences in TSPO expression. It is unknown, however, if unbiased and accurate estimates of these measures are obtainable for [11C]PBR28. The Simultaneous Estimation (SIME) method uses time-activity-curves from multiple brain regions with the aim to obtain a brain-wide estimate of VND, which can subsequently be used to improve the estimation of BPND and VS. In this study we evaluated the accuracy of SIME-derived VND, and the reliability of resulting estimates of specific binding for [11C]PBR28, using a combination of simulation experiments and in vivo studies in healthy humans. The simulation experiments showed that VND values estimated using SIME were both precise and accurate. Data from a pharmacological competition challenge showed that SIME provided VND values that were on average 19% lower than those obtained using the Lassen plot, but similar to values obtained using the Likelihood-Estimation of Occupancy technique. Test-retest data showed that SIME-derived VS values exhibited good reliability and precision, while larger variability was observed in SIME-derived BPND values. The results support the use of SIME for quantifying specific binding of [11C]PB28, and suggest that VS can be used in preference to, or as a complement to the conventional outcome measure VT. Additional studies in patient cohorts are warranted.

Dopamine D1 receptor availability is not associated with delusional ideation measures of psychosis proneness

The dopamine D1 receptor (D1R) is thought to play a role in psychosis and schizophrenia, however the exact nature of this involvement is not clear. Positron emission tomography studies comparing D1R between patients and control subjects have produced inconsistent results. An important confounding factor in most clinical studies is previous exposure to antipsychotic treatment, which is thought to influence the density of D1R. To circumvent some of the limitations of clinical studies, an alternative approach for studying the relationship between D1R and psychosis is to examine individuals at increased risk for psychotic disorders, or variation in subclinical psychotic symptoms such as delusional ideation within the general population, referred to as psychosis proneness traits. In this study, we investigated whether D1R availability is associated with delusional ideation in healthy controls using data from 76 individuals measured with PET using [11C]SCH23390 and 217 individuals who completed delusional ideation questionnaires, belonging to three different study cohorts. We first performed exploratory, hypothesis-generating, analyses by creating and evaluating a new measure of delusional ideation (n=132 and n=27), which was then found to show a negative association with D1R availability (n=24). Next, we performed confirmatory analyses using Bayesian statistical modelling, in which we first attempted to replicate this result (n=20), and then evaluated the association of Peters Delusion Inventory scores with D1R availability in two independent cohorts (n=41 and 20). Collectively, we found strong evidence that there is little to no linear association between delusional ideation and D1R availability in healthy controls. If differences in D1R can be confirmed in drug-naive schizophrenia patients compared to controls, further studies are needed to ascertain whether these changes occur at the onset of psychotic symptoms or if they are associated with specific behavioural or genetic aspects of psychosis proneness other than delusional ideation.

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

Background The positron emission tomography radioligand (R)-[11C]PK11195 can be used to quantify the expression of translocator protein (TSPO), which is considered a marker for activation of glial cells. TSPO is expressed throughout the brain, and for this reason no true reference region exists. When a radioligand does not have a reference region, an arterial input function (AIF) is usually required in order to quantify binding. However, obtaining an AIF can be difficult as well as uncomfortable for participants. Alternative methods have therefore been proposed with the aim of estimating (R)-[11C]PK11195 binding without arterial measurements, such as standardized uptake values (SUVs), supervised-cluster analysis (SVCA), or the use of a pseudo-reference region. The objective of this study was to evaluate the test-retest reliability and convergent validity of these techniques. Methods Data from a previously published (R)-[11C]PK11195 test-retest study in six healthy male subjects were reanalysed. Non-displaceable binding potential (BPND) was calculated for a set of cortical and subcortical brain regions using the simplified reference tissue model, with either cerebellum as reference region or a reference input derived using SVCA. SUVs were estimated for the time interval of 40-60 minutes. For comparison, total distribution volume (VT), specific distribution volume (VS) and BPND were estimated from the two-tissue-compartment model (2TCM) using AIF. Test-retest reliability was then assessed for all outcome measures. Convergent validity was examined by correlating all measures derived without an AIF to those derived using 2TCM. Results Test-retest reliability for BPND estimates were poor (80% of all regional ICCs<0.5). SUVs showed, on average, moderate reliability. BPND estimates derived without an AIF were not correlated with VT, VS or BPND from the 2TCM (all R2<12%). SUVs were not correlated with any other outcome (all R2<9%). Discussion BPND estimated using cerebellum or SVCA as reference input showed poor reliability and little to no convergent validity with outcomes derived using an AIF. SUVs showed moderate reliability but no convergent validity with any other outcome. Caution is warranted for interpreting patient-control comparisons employing (R)-[11C]PK11195 outcome measures obtained without an AIF.

Is dopamine D1 receptor availability related to social behavior? A positron emission tomography replication study

Background Associations between dopamine receptor levels and pro- and antisocial behavior have previously been demonstrated in human subjects using positron emission tomography (PET) and self-rated measures of personality traits. So far, only one study has focused on the dopamine D1-receptor (D1-R), finding a positive correlation with the trait social desirability, which is characterized by low dominant and high affiliative behavior, while physical aggression showed a negative correlation. The aim of the present study was to replicate these previous findings using a new independent sample of subjects. Materials and methods Twenty-six healthy males were examined with the radioligand [11C]SCH-23390, and completed the Swedish universities Scales of Personality (SSP) which includes measures of social desirability and physical trait aggression. The simplified reference tissue model with cerebellum as reference region was used to calculate BPND values in the whole striatum and limbic striatum. The two regions were selected since they showed strong association between D1-R availability and personality scores in the previous study. Pearson’s correlation coefficients and replication Bayes factors were then employed to assess the replicability and robustness of previous results. Results There were no significant correlations (all p values > 0.3) between regional BPND values and personality scale scores. Replication Bayes factors showed strong to moderate evidence in favor no relationship between D1-receptor availability and social desirability (striatum BF01 = 12.4; limbic striatum BF01 = 7.2) or physical aggression scale scores (limbic striatum BF01 = 3.3), compared to the original correlations. Discussion We could not replicate the previous findings of associations between D1-R availability and either pro- or antisocial behavior as measured using the SSP. Rather, there was evidence in favor of failed replications of associations between BPND and scale scores. Potential reasons for these results are restrictive variance in both PET and personality outcomes due to high sample homogeneity, or that the previous findings were false positives.

Simulations to benchmark time-varying connectivity methods for fMRI

There is a current interest in quantifying time-varying connectivity (TVC) based on neuroimaging data such as fMRI. Many methods have been proposed, and are being applied, revealing new insight into the brain’s dynamics. However, given that the ground truth for TVC in the brain is unknown, many concerns remain regarding the accuracy of proposed estimates. Since there exist many TVC methods it is difficult to assess differences in time-varying connectivity between studies. In this paper, we present tvc_benchmarker, which is a Python package containing four simulations to test TVC methods. Here, we evaluate five different methods that together represent a wide spectrum of current approaches to estimating TVC (sliding window, tapered sliding window, multiplication of temporal derivatives, spatial distance and jackknife correlation). These simulations were designed to test each method’s ability to track changes in covariance over time, which is a key property in TVC analysis. We found that all tested methods correlated positively with each other, but there were large differences in the strength of the correlations between methods. To facilitate comparisons with future TVC methods, we propose that the described simulations can act as benchmark tests for evaluation of methods. Using tvc_benchmarker researchers can easily add, compare and submit their own TVC methods to evaluate its performance.