38 results found
Lingford-Hughes A, Durant C, Paterson L, et al., 2018, Using baclofen to explore GABA-B receptor function in alcohol dependence: insights from pharmacokinetic and pharmacodynamic measures, Frontiers in Psychiatry, Vol: 9, ISSN: 1664-0640
Background: The role of GABA-B neurotransmission in addiction has recently received increased attention, with clinical trials indicating that baclofen, a GABA-B receptor agonist, may reduce alcohol consumption, craving and promote abstinence. However, the optimal dose to treat alcohol dependence is unclear with patients requesting and tolerating much higher doses of baclofen, compared with other clinical uses. We assessed the pharmacokinetics and pharmacodynamics (PK/PD) of baclofen to provide insight into GABA-B sensitivity in this patient group, relative to controls.Methods: Male healthy volunteers (controls, n = 12) and abstinent alcohol dependent individuals (AD, n = 8) received single oral doses of baclofen or placebo in a 3-way crossover design. Controls received placebo/10 mg/60 mg baclofen in a randomized, double-blind design, AD received placebo/60 mg/90 mg baclofen in a single-blind design. PK/PD measures were recorded at baseline and multiple time-points up to 6 h post-dosing, including plasma baclofen, plasma growth hormone (GH), Subjective High Assessment Scale (SHAS) and biphasic alcohol effects scale (BAES). Repeated measures ANOVA analysis explored “change from baseline” dose, time, group, and interaction effects, t-tests compared peak effects.Results: Dose-dependent effects of baclofen on PK and PD measures were observed in both control and AD groups. Whilst there were no significant group differences in any baclofen PK parameters (t1/2, tmax, Cmax, AUC), marked differences in PD effects were clearly evident. In controls, 60 mg baclofen significantly increased total SHAS and BAES scores, and significantly increased plasma GH levels compared with placebo, with peak effects at 60–120 min, in line with its PK profile. In AD, 60 mg baclofen had limited effects on these parameters; SHAS scores, BAES scores and plasma GH levels were significantly blunted compared with controls (significant group*time interactions P = 0.0014, 0.0015 and P
Tyacke R, Myers J, Venkataraman A, et al., 2018, Evaluation of 11C-BU99008, a positron emission tomography ligand for the Imidazoline2 binding site in human brain, Journal of Nuclear Medicine, Vol: 59, Pages: 1597-1602, ISSN: 1535-5667
The imidazoline2 binding sites (I2BS), are thought to be expressed in glia, and implicated in the regulation of glial fibrillary acidic protein. A positron emission tomography (PET) ligand for this target would be important for the investigation of neurodegenerative and neuroinflammatory diseases. 11C BU99008 has previously been identified as a putative PET radioligand. Here we present the first in vivo characterisation of this PET radioligand in humans and assess its test-retest reproducibility. Methods: 14 healthy male volunteers underwent dynamic PET imaging with 11C BU99008 and arterial sampling. Six subjects were used to assess test-retest and eight were used in the pharmacological evaluation, undergoing a second, or third heterologous competition scan with the mixed I2BS/α2 adrenoceptor drug, idazoxan (n=8; 20, 40, 60 and 80 mg) and the mixed irreversible monoamine oxidase (MAO) A/B inhibitor, isocarboxazid (n=4; 50 mg), respectively. Regional time-activity data were generated from arterial plasma input functions corrected for metabolites using the most appropriate model to derive the outcome measure VT (regional total distribution volume). All image processing and kinetic analysis was performed in MIAKAT™ (www.miakat.org). Results: Brain uptake of 11C BU99008 was good with reversible kinetics and a heterogeneous distribution consistent with known I2BS expression. Model selection criteria indicated that the 2-tissue-compartment was preferred. VT estimates were high in the striatum (105±21 mL cm 3), medium in cingulate cortex (62±10 mL cm 3) and low in the cerebellum (41±7 mL cm 3). Test-retest reliability was found to be reasonable. The uptake was dose-dependently reduced by pre-treatment with idazoxan throughout the brain, with an average block across all regions of ~60% (VT≅30 mL cm 3) at the highest dose (80 mg). The median effective dose (ED50) for idazoxan was calculated as 28 mg. Uptake was not blocked by pre-treatme
Venkataraman A, Keat N, Myers J, et al., 2018, First evaluation of PET-based human biodistribution and radiation dosimetry of 11C-BU99008, a tracer for imaging the imidazoline2 binding site, EJNMMI Research, Vol: 8, ISSN: 2191-219X
BackgroundWe measured whole body distribution of 11C-BU99008, a new PET biomarker for non-invasive identification of the imidazoline2 binding site. The purpose of this phase I study was to evaluate the biodistribution and radiation dosimetry of 11C-BU99008 in healthy human subjects.MethodsA single bolus injection of 11C-BU99008 (296 ± 10.5 MBq) was administered to four healthy subjects who underwent whole-body PET/CT over 120 min from the cranial vertex to the mid-thigh. Volumes of interest were drawn around visually identifiable source organs to generate time-activity curves (TAC). Residence times were determined from time-activity curves. Absorbed doses to individual organs and the whole body effective dose were calculated using OLINDA/EXM 1.1 for each subject.ResultsThe highest measured activity concentration was in the kidney and spleen. The longest residence time was in the muscle at 0.100 ± 0.023 h, followed by the liver at 0.067 ± 0.015 h and lungs at 0.052 ± 0.010 h. The highest mean organ absorbed dose was within the heart wall (0.028 ± 0.002 mGy/MBq), followed by the kidneys (0.026 ± 0.005 mGy/MBq). The critical organ was the heart wall. The total mean effective dose averaged over subjects was estimated to be 0.0056 ± 0.0004 mSv/MBq for an injection of 11C-BU99008.ConclusionsThe biodistribution of 11C-BU99008 has been shown here for the first time in humans. Our dosimetry data showed the total mean effective dose over all subjects was 0.0056 ± 0.0004 mSv/MBq, which would result in a total effective dose of 1.96 mSv for a typical injection of 350 MBq of 11C-BU99008. The effective dose is not appreciably different from those obtained with other 11C tracers.
Turton S, Myers J, Mick I, et al., 2018, Blunted endogenous opioid release following an oral dexamphetamine challenge in abstinent alcohol dependent individuals, Molecular Psychiatry, ISSN: 1359-4184
Addiction has been proposed as a ‘reward deficient’ state, which is compensated for with substance use. There is growing evidence of dysregulation in the opioid system, which plays a key role in reward, underpinning addiction. Low levels of endogenous opioids are implicated in vulnerability for developing alcohol dependence (AD) and high mu-opioid receptor (MOR) availability in early abstinence is associated with greater craving. This high MOR availability is proposed to be the target of opioid antagonist medication to prevent relapse. However, changes in endogenous opioid tone in AD are poorly characterised and are important to understand as opioid antagonists do not help everyone with AD. We used [11C]carfentanil, a selective MOR agonist positron emission tomography (PET) radioligand, to investigate endogenous opioid tone in AD for the first time. We recruited 13 abstinent male AD and 15 control participants who underwent two [11C]carfentanil PET scans, one before and one 3 h following a 0.5 mg/kg oral dose of dexamphetamine to measure baseline MOR availability and endogenous opioid release. We found significantly blunted dexamphetamine-induced opioid release in 5 out of 10 regions-of-interest including insula, frontal lobe and putamen in AD compared with controls, but no significantly higher MOR availability AD participants compared with HC in any region. This study is comparable to our previous results of blunted dexamphetamine-induced opioid release in gambling disorder, suggesting that this dysregulation in opioid tone is common to both behavioural and substance addictions.
Dukart J, Holiga Š, Chatham C, et al., 2018, Cerebral blood flow predicts differential neurotransmitter activity, Scientific Reports, Vol: 8, ISSN: 2045-2322
Application of metabolic magnetic resonance imaging measures such as cerebral blood flow in translational medicine is limited by the unknown link of observed alterations to specific neurophysiological processes. In particular, the sensitivity of cerebral blood flow to activity changes in specific neurotransmitter systems remains unclear. We address this question by probing cerebral blood flow in healthy volunteers using seven established drugs with known dopaminergic, serotonergic, glutamatergic and GABAergic mechanisms of action. We use a novel framework aimed at disentangling the observed effects to contribution from underlying neurotransmitter systems. We find for all evaluated compounds a reliable spatial link of respective cerebral blood flow changes with underlying neurotransmitter receptor densities corresponding to their primary mechanisms of action. The strength of these associations with receptor density is mediated by respective drug affinities. These findings suggest that cerebral blood flow is a sensitive brain-wide in-vivo assay of metabolic demands across a variety of neurotransmitter systems in humans.
Turton S, Mick I, Myers J, et al., 2017, Comparing m-opioid receptor availability and opioid/beta-endorphin release between individuals with gambling disorder, alcohol dependence and healthy volunteers using [C-11]carfentanil PET and dexamphetamine challenge, 28th International Symposium on Cerebral Blood Flow, Metabolism and Function / 13th International Conference on Quantification of Brain Function with PET, Publisher: SAGE PUBLICATIONS INC, Pages: 97-97, ISSN: 0271-678X
Mick I, Ramos C, Myers J, et al., 2016, Evidence for GABA-A receptor dysregulation in gambling disorder: correlation with impulsivity., Addiction Biology, Vol: 22, Pages: 1601-1609, ISSN: 1369-1600
Background: As a behavioral addiction, gambling disorder (GD) provides an opportunity to characterize addictive processes without the potentially confounding effects of chronic excessive drug and alcohol exposure. Impulsivity is an established precursor to such addictive behaviours and GD is associated with greater impulsivity. There is also evidence of GABAergic dysregulation in substance addiction and in impulsivity. Methods: This study therefore investigated GABAA receptor availability in 15 individuals with GD and 19 healthy volunteers (HV) using [11C]Ro15-4513, a relatively selective α5 benzodiazepine receptor PET tracer and its relationship with impulsivity. Results: We found significantly higher [11C]Ro15-4513 total distribution volume (VT) in the right hippocampus in the GD group compared with HV. We found higher levels of The ‘Negative Urgency’ construct of impulsivity in GD and these were positively associated with higher [11C]Ro15-4513 VT in the amygdala in the GD group; no such significant correlations were evident in the HV group. Conclusions: These results contrast with reduced binding of GABAergic PET ligands described previously in alcohol and opiate addiction and add to growing evidence for distinctions in the neuropharmacology between substance and behavioral addictions. These results provide the first characterization of GABAA receptors in GD with [11C]Ro15-4513 PET and show greater α5 receptor availability and positive correlations with trait impulsivity. This GABAergic dysregulation is potential target for treatment.
Turton S, Myers J, Mick I, et al., 2016, Alcohol dependent patients have blunted endogenous opioid release measured using [C-11] carfentanil PET and dexamphetamine challenge, 29th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S676-S677, ISSN: 0924-977X
Myers JFM, Comley RA, Gunn RN, 2016, Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans, Journal of Cerebral Blood Flow and Metabolism, Vol: 37, Pages: 2137-2148, ISSN: 1559-7016
[11C]Ro15-4513 has been introduced as a PET radioligand to image the GABAAα5 receptorsubtype thought to be important in learning, memory and addiction. However, the in vivoselectivity of the ligand remains unknown and a full assessment of different analysisapproaches has yet to be performed. Using human heterologous competition data, with[11C]Ro15-4513 and the highly selective GABAAα5 selective negative allosteric modulatorBasmisanil (RG1662), we quantify the GABAAα5 selectivity of [11C]Ro15-4513, assess thevalidity of reference tissues and evaluate the performance of four different kinetic analysismethods. The results show that [11C]Ro15-4513 has high but not complete selectivity forGABAAα5, with α5 representing around 60-70% of the specific binding in α5 rich regions.Competition data indicate that the cerebellum and pons are essentially devoid of α5 signaland might be used as reference regions under certain conditions. Off-target non-selectivebinding to other GABAA subtypes means that the choice of analysis method and theinterpretation of outcome measures must be considered carefully. We discuss the merits oftwo tissue compartmental model analyses to derive both and , band-pass spectralanalysis for estimation of and the simplifified reference tissue model for estimation of BPnd.
Myers J, Comley R, Gunn R, 2016, Quantification of [11C]Ro15-4513 GABAAα5 specific binding and regional selectivity in humans, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 36, Pages: 623-624, ISSN: 0271-678X
Magazzini L, Muthukumaraswamy SD, Campbell AE, et al., 2016, Significant reductions in human visual gamma frequency by the gaba reuptake inhibitor tiagabine revealed by robust peak frequency estimation, Human Brain Mapping, Vol: 37, Pages: 3882-3896, ISSN: 1097-0193
The frequency of visual gamma oscillations is determined by both the neuronal excitation-inhibition balance and the time constants of GABAergic processes. The gamma peak frequency has been linked to sensory processing, cognitive function, cortical structure, and may have a genetic contribution. To disentangle the intricate relationship among these factors, accurate and reliable estimates of peak frequency are required. Here, a bootstrapping approach that provides estimates of peak frequency reliability, thereby increasing the robustness of the inferences made on this parameter was developed. The method using both simulated data and real data from two previous pharmacological MEG studies of visual gamma with alcohol and tiagabine was validated. In particular, the study by Muthukumaraswamy et al.  (Neuropsychopharmacology 38(6):1105-1112), in which GABAergic enhancement by tiagabine had previously demonstrated a null effect on visual gamma oscillations, contrasting with strong evidence from both animal models and very recent human studies was re-evaluated. After improved peak frequency estimation and additional exclusion of unreliably measured data, it was found that the GABA reuptake inhibitor tiagabine did produce, as predicted, a marked decrease in visual gamma oscillation frequency. This result demonstrates the potential impact of objective approaches to data quality control, and provides additional translational evidence for the mechanisms of GABAergic transmission generating gamma oscillations in humans. Hum Brain Mapp, 2016. © 2016 Wiley Periodicals, Inc.
Myers JF, Nutt DJ, Lingford-Hughes AR, 2016, γ-aminobutyric acid as a metabolite: Interpreting magnetic resonance spectroscopy experiments., Journal of Psychopharmacology, Vol: 30, Pages: 422-427, ISSN: 1461-7285
The current rise in the prevalence of magnetic resonance spectroscopy experiments to measure γ-aminobutyric acid in the living human brain is an exciting and productive area of research. As research spreads into clinical populations and cognitive research, it is important to fully understand the source of the magnetic resonance spectroscopy signal and apply appropriate interpretation to the results of the experiments. γ-aminobutyric acid is present in the brain not only as a neurotransmitter, but also in high intracellular concentrations, both as a transmitter precursor and a metabolite. γ-aminobutyric acid concentrations measured by magnetic resonance spectroscopy are not necessarily implicated in neurotransmission and therefore may reflect a very different brain activity to that commonly suggested. In this perspective, we examine some of the considerations to be taken in the interpretation of any γ-aminobutyric acid signal measured by magnetic resonance spectroscopy.
Mick I, Myers J, Ramos AC, et al., 2016, Blunted Endogenous Opioid Release Following an Oral Amphetamine Challenge in Pathological Gamblers, 3rd International Conference on Behavioral Addictions, Publisher: Akadémiai Kiadó, Pages: 30-30, ISSN: 2063-5303
Lingford-Hughes A, Myers J, Watson B, et al., 2016, Using [11C]Ro15 4513 PET to characterise GABA-benzodiazepine receptors in opiate addiction: Similarities and differences with alcoholism, Neuroimage, Vol: 132, Pages: 1-7, ISSN: 1095-9572
The importance of the GABA-benzodiazepine receptor complex and its subtypes are increasingly recognised inaddiction. Using the α1/α5 benzodiazepine receptor PET radioligand [ 23 11C]Ro15 4513, we previously showed reducedbinding in the nucleus accumbens and hippocampus in abstinent alcohol dependence. We proposed that 24reduced [ 25 11C]Ro15 4513 binding in the nucleus accumbens was a marker of addiction whilst the reduction in hippocampusand positive relationship with memory was a consequence of chronic alcohol abuse. To examine this 26further we assessed [ 27 11C]Ro15 4513 binding in another addiction, opiate dependence, and used spectral analysisto estimate contributions of α1 and α5 subtypes to [ 28 11C]Ro15 4513 binding in opiate and previously acquired alcohol-dependentgroups. Opiate substitute maintained opiate-dependent men (n = 12) underwent an [ 29 11C]Ro154513 PET scan and compared with matched healthy controls (n = 13). We found a significant reduction in 30[ 31 11C]Ro15 4513 binding in the nucleus accumbens in the opiate-dependent compared with the healthy controlgroup. There was no relationship between [ 32 11C]Ro15 4513 binding in the hippocampus with memory. Wefound that reduced [ 33 11C]Ro15 4513 binding was associated with reduced α5 but not α1 subtypes in the opiate-dependentgroup. This was also seen in an alcohol-dependent group where an association between memory 34performance and [ 35 11C]Ro15 4513 binding was primarily driven by α5 and not α1 subtype. We suggest that reducedα5 levels in the nucleus accumbens are associated with addiction since we have now shown this in depen- 36dence to two pharmacologically different substances, alcohol and opiates.
Lingford-Hughes AR, Mick I, Myers J, et al., 2015, Blunted endogenous opioid release following an oral amphetamine challenge in pathological gamblers, Neuropsychopharmacology, Vol: 41, Pages: 1742-1750, ISSN: 1740-634X
Pathological gambling is a psychiatric disorder and the first recognized behavioral addiction, with similarities to substance use disorders but without the confounding effects of drug-related brain changes. Pathophysiology within the opioid receptor system is increasingly recognized in substance dependence, with higher mu-opioid receptor (MOR) availability reported in alcohol, cocaine and opiate addiction. Impulsivity, a risk factor across the addictions, has also been found to be associated with higher MOR availability. The aim of this study was to characterize baseline MOR availability and endogenous opioid release in pathological gamblers (PG) using [¹¹C]carfentanil PET with an oral amphetamine challenge. 14 PG and 15 healthy volunteers (HV) underwent two [¹¹C]carfentanil PET scans, before and after an oral administration of 0.5 mg/kg of d-amphetamine. The change in [¹¹C]carfentanil binding between baseline and post-amphetamine scans (ΔBPND) was assessed in 10 regions of interest (ROI). MOR availability did not differ between PG and HV groups. As seen previously, oral amphetamine challenge led to significant reductions in [¹¹C]carfentanil BPND in 8/10 ROI in HV. PG demonstrated significant blunting of opioid release compared with HV. PG also showed blunted amphetamine-induced euphoria and alertness compared with HV. Exploratory analysis revealed that impulsivity positively correlated with caudate baseline BPND in PG only. This study provides the first evidence of blunted endogenous opioid release in PG. Our findings are consistent with growing evidence that dysregulation of endogenous opioids may play an important role in the pathophysiology of addictions.
Nutt D, Wilson S, Lingford-Hughes A, et al., 2015, Differences between magnetoencephalographic (MEG) spectral profiles of drugs acting on GABA at synaptic and extrasynaptic sites: A study in healthy volunteers, NEUROPHARMACOLOGY, Vol: 88, Pages: 155-163, ISSN: 0028-3908
Quelch D, De Santis V, Strege A, et al., 2015, Influence of Agonist Induced Internalization on [H-3]Ro15-4513 Binding-An Application to Imaging Fluctuations in Endogenous GABA With Positron Emission Tomography, SYNAPSE, Vol: 69, Pages: 60-65, ISSN: 0887-4476
Mick I, Myers J, Stokes PRA, et al., 2014, Amphetamine induced endogenous opioid release in the human brain detected with [C-11]carfentanil PET: replication in an independent cohort, INTERNATIONAL JOURNAL OF NEUROPSYCHOPHARMACOLOGY, Vol: 17, Pages: 2069-2074, ISSN: 1461-1457
Watson BJ, Taylor LG, Reid AG, et al., 2014, Investigating expectation and reward in human opioid addiction with [C-11]raclopride PET, ADDICTION BIOLOGY, Vol: 19, Pages: 1032-1040, ISSN: 1355-6215
Mick I, Myers J, Stokes P, et al., 2014, Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [C-11]carfentanil PET study, 27th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S699-S700, ISSN: 0924-977X
Stokes PRA, Myers JF, Kalk NJ, et al., 2014, Acute increases in synaptic GABA detectable in the living human brain: A [C-11]Ro15-4513 PET study, NEUROIMAGE, Vol: 99, Pages: 158-165, ISSN: 1053-8119
Myers JFM, Evans CJ, Kalk NJ, et al., 2014, Measurement of GABA Using J-Difference Edited H-1-MRS Following Modulation of Synaptic GABA Concentration with Tiagabine, SYNAPSE, Vol: 68, Pages: 355-362, ISSN: 0887-4476
Mick I, Myers J, Stokes P, et al., 2014, Endogenous opioid release in pathological gamblers after an oral amphetamine challenge: a [C-11]carfentanil PET study, ECNP Workshop for Junior Scientists in Europe, Publisher: ELSEVIER SCIENCE BV, Pages: S62-S63, ISSN: 0924-977X
Hamandi K, Myers J, Muthukumaraswamy S, 2014, Tiagabine-induced stupor — More evidence for an encephalopathy, Epilepsy & Behavior, Vol: 31, Pages: 196 - 197-196 - 197, ISSN: 1525-5050
Muthukumaraswamy SD, Myers JFM, Wilson SJ, et al., 2013, Elevating Endogenous GABA Levels with GAT-1 Blockade Modulates Evoked but Not Induced Responses in Human Visual Cortex, NEUROPSYCHOPHARMACOLOGY, Vol: 38, Pages: 1105-1112, ISSN: 0893-133X
Mendez MA, Horder J, Myers J, et al., 2013, The brain GABA-benzodiazepine receptor alpha-5 subtype in autism spectrum disorder: A pilot [C-11]Ro15-4513 positron emission tomography study, NEUROPHARMACOLOGY, Vol: 68, Pages: 195-201, ISSN: 0028-3908
Stokes PRA, Benecke A, Myers J, et al., 2013, History of cigarette smoking is associated with higher limbic GABAA receptor availability, Neuroimage, Vol: 69, Pages: 70-77
Cigarette smoking presents a significant worldwide healthcare challenge. Preclinical, genetic association and clinical trials studies provide considerable evidence for the involvement of the human γ-aminobutyric acid (GABA) system in the neurobiology of nicotine addiction. However there are few human GABA neurochemical imaging studies of nicotine addiction. We investigated limbic GABAA receptor availability in volunteers with a history of cigarette smoking using [11C]Ro15 4513 positron emission tomography (PET). Eight [11C]Ro15 4513 PET scans from volunteers with a history of cigarette smoking were compared to twelve scans from volunteers who were non-smokers. Total, α1 and α5 GABAA receptor subtype [11C]Ro15 4513 VT values were quantified using spectral analysis of limbic regions implicated in nicotine addiction. Spectral analysis allows quantification of the overall [11C]Ro15 4513 spectral frequency as well as α1 and α5 GABAA receptor subtype specific spectral frequency components. Volunteers with a history of cigarette smoking showed significantly higher total [11C]Ro15 4513 VT values in the presubgenual cingulate and parahippocampal gyrus, and at a trend level in the insula, nucleus accumbens and subgenual cingulate. In six abstinent previous smokers (‘ex-smokers’), total [11C]Ro15 4513 binding was significantly higher in all limbic regions studied, with higher α5 availability in the amygdala, anterior cingulate, nucleus accumbens and presubgenual cingulate. These results suggest that limbic GABAA receptor availability is higher in volunteers with a history of cigarette smoking which may reflect either higher expression of GABAA receptors or lower endogenous GABA levels. The findings in ex-smokers suggest that higher GABAA receptor availability continues with abstinence indicating that this may be a trait marker for nicotine addiction or that alterations in GABA function associated with cigarette smoking persist.
Muthukumaraswamy SD, Myers JFM, Wilson SJ, et al., 2013, The effects of elevated endogenous GABA levels on movement-related network oscillations, NEUROIMAGE, Vol: 66, Pages: 36-41, ISSN: 1053-8119
Lingford-Hughes A, Myers JF, Watson B, et al., 2012, Imaging GABA-benzodiazepine receptor subtypes in addiction, 25th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Publisher: ELSEVIER SCIENCE BV, Pages: S133-S133, ISSN: 0924-977X
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