Granville James Matheson

Diurnal and seasonal variation of the brain serotonin system in healthy male subjects

The mammalian circadian clock underlies both diurnal and seasonal changes in physiology, and its function is thought to be disturbed in both seasonal and non-seasonal depression. In humans, molecular imaging studies have reported seasonal changes in the serotonin system. Despite the role of the circadian clock in generating seasonal physiological changes, however, diurnal variation of serotonin receptors and transporters has never been directly studied in humans. We used positron emission tomography to examine diurnal and seasonal changes in the serotonin 5-HT1A receptor and serotonin transporter in two large cohorts of healthy male subjects, employing a cross-sectional design. In 56 subjects measured with [(11)C]WAY-100635, we observed diurnal increases in the availability of 5-HT1A receptors in the cortex. In 40 subjects measured with [(11)C]MADAM, a decrease in 5-HTT was observed in the midbrain across the day. We also found seasonal changes in the 5-HT1A receptor in serotonin projection regions, with higher availability on days with a longer duration of daylight. Our observation that serotonin receptor and transporter levels may change across the day in humans is corroborated by experimental research in rodents. These findings have important implications for understanding the relationship between the circadian and serotonin systems in both the healthy brain and in affective disorders, as well as for the design of future molecular imaging studies.

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.

Contribution of non-genetic factors to dopamine and serotonin receptor availability in the adult human brain

The dopamine (DA) and serotonin (5-HT) neurotransmission systems are of fundamental importance for normal brain function and serve as targets for treatment of major neuropsychiatric disorders. Despite central interest for these neurotransmission systems in psychiatry research, little is known about the regulation of receptor and transporter density levels. This lack of knowledge obscures interpretation of differences in protein availability reported in psychiatric patients. In this study, we used positron emission tomography (PET) in a twin design to estimate the relative contribution of genetic and environmental factors, respectively, on dopaminergic and serotonergic markers in the living human brain. Eleven monozygotic and 10 dizygotic healthy male twin pairs were examined with PET and [11C]raclopride binding to the D2- and D3-dopamine receptor and [11C]WAY100635 binding to the serotonin 5-HT1A receptor. Heritability, shared environmental effects and individual-specific non-shared effects were estimated for regional D2/3 and 5-HT1A receptor availability in projection areas. We found a major contribution of genetic factors (0.67) on individual variability in striatal D2/3 receptor binding and a major contribution of environmental factors (pairwise shared and unique individual; 0.70–0.75) on neocortical 5-HT1A receptor binding. Our findings indicate that individual variation in neuroreceptor availability in the adult brain is the end point of a nature–nurture interplay, and call for increased efforts to identify not only the genetic but also the environmental factors that influence neurotransmission in health and disease.

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.

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.

We need to talk about reliability: Making better use of test retest studies for study design and interpretation

Positron emission tomography (PET), along with many other fields of clinical research, is both timeconsuming and expensive, and recruitable patients can be scarce. These constraints limit the possibility of large-sample experimental designs, and often lead to statistically underpowered studies. This problem is exacerbated by the use of outcome measures whose accuracy is sometimes insufficient to answer the scientific questions posed. Reliability is usually assessed in validation studies using healthy participants, however these results are often not easily applicable to clinical studies examining different populations. I present a new method and tools for using summary statistics from previously published test-retest studies to approximate the reliability of outcomes in new samples. In this way, the feasibility of a new study can be assessed during planning stages, and before collecting any new data. An R package called relfeas also accompanies this article for performing these calculations. In summary, these methods and tools will allow researchers to avoid performing costly studies which are, by virtue of their design, unlikely to yield informative conclusions.

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.

Serotonin 5-HT1A receptor binding and self-transcendence in healthy control subjects - a replication study using Bayesian hypothesis testing

Objective A putative relationship between markers for the serotonin system and the personality scale self-transcendence (ST) and its subscale spiritual acceptance (SA) has been demonstrated in a previous PET study of 5-HT1A receptor binding in healthy control subjects. The results could however not be replicated in a subsequent PET study at an independent centre. In this study, we performed a replication of our original study in a larger sample using Bayesian hypothesis testing to evaluate relative evidence both for and against this hypothesis. Methods Regional 5-HT1A receptor binding potential (BPND) was examined in 50 healthy male subjects using PET with the radioligand [11C]WAY100635. 5-HT1A availability was calculated using the simplified reference tissue model (SRTM) yielding regional BPND. ST and SA were measured using the Temperament and Character Inventory (TCI) questionnaire. Correlations between ST/SA scores and 5-HT1A BPND in frontal cortex, hippocampus and raphe nuclei were examined by calculation of default correlation Bayes factors (BFs) and replication BFs. Results There were no significant correlations between 5-HT1A receptor binding and ST/SA scores. Rather, five of six replication BFs provided moderate to strong evidence for no association between 5-HT1A availability and ST/SA, while the remaining BF provided only weak evidence. Conclusion We could not replicate our previous findings of an association between 5-HT1A availability and the personality trait ST/SA. Rather, the Bayesian analysis provided evidence for a lack of correlation. Further research should focus on whether other components of the serotonin system may be related to ST or SA. This study also illustrates how Bayesian hypothesis testing allows for greater flexibility and more informative conclusions than traditional p-values, suggesting that this approach may be advantageous for analysis of molecular imaging data.