Didier Le Bars

YNIMG Journal 2021 Journal Article

Modeling [11C]yohimbine PET human brain kinetics with test-retest reliability, competition sensitivity studies and search for a suitable reference region

• Chloé Laurencin
• Sophie Lancelot
• Florent Gobert
• Jérôme Redouté
• Inés Mérida
• Thibault Iecker
• François Liger
• Zacharie Irace

C]yohimbine to noradrenergic competition were not evaluated. The objectives of the present study were therefore to fill this gap. METHODS: C]yohimbine 90-minute dynamic scans performed on a PET-MRI scanner. Seven had arterial blood sampling with metabolite assessment and plasmatic yohimbine free fraction evaluation at the first scan to have arterial input function and test appropriate kinetic modeling. The second scan was a simple retest for 6 subjects to evaluate the test-retest reproducibility. For the remaining 7 subjects the second scan was a challenge study with the administration of a single oral dose of 150 µg of clonidine 90 min before the PET scan. Parametric images of α2-ARs distribution volume ratios (DVR) were generated with two non-invasive models: Logan graphical analysis with Reference (LREF) and Simplified Reference Tissue Method (SRTM). Three reference regions (cerebellum white matter (CERWM), frontal white matter (FLWM), and corpus callosum (CC)) were tested. RESULTS: , regional changes have been observed after clonidine administration with a significant increase reported in the amygdala and striatum as well as in several posterior cortical areas as revealed with the voxel-based analysis. CONCLUSION: C]yohimbine PET in the quantitative assessment of α2-ARs occupancy in vivo in the human brain. Trial registration EudraCT 2018-000380-82.

YNICL Journal 2019 Journal Article

Brain processing of pictures of children in men with pedophilic disorder: A positron emission tomography study

• Véronique Fonteille
• Jérôme Redouté
• Pierre Lamothe
• Dominique Straub
• Frank Lavenne
• Didier Le Bars
• Véronique Raverot
• Virginie Moulier

Although structural and functional neuroimaging techniques have recently been used to investigate the mechanisms of sexual attraction to children, a hallmark of pedophilic disorder, the differences in the processing of child sexual stimuli between men attracted to children and those attracted to adults remain unclear. Here, our purpose was to identify through positron emission tomography the brain responses of 15 male outpatients with pedophilic disorder to validated visual sexual stimuli depicting children (VSSc) and to compare them with 15 male healthy controls matched for sexual orientation (to female or male adults), age, and handedness. The patients' sample comprised both offenders and non-offenders. In response to VSSc, the between-groups analysis showed that activation in the right inferior temporal cortex [Brodmann area (BA) 20] was lower in patients than in controls. Moreover, in patients but not in controls, the presentation of VSSc induced an activation in a more caudal region of the right inferior temporal gyrus (BA 37) and in the left middle occipital gyrus (BA 19). In addition, in patients the level of activation in the caudal right inferior temporal gyrus was positively correlated with ratings of sexual arousal elicited by VSSc, whereas this correlation was negative in BA 20. These results implicate the right inferior temporal gyrus as a possible candidate area mediating sexual arousal in patients with pedophilic disorder and suggest that two of its areas play opposite, i.e., activating and inhibitory, roles.

YNIMG Journal 2013 Journal Article

A multi-atlas based method for automated anatomical Macaca fascicularis brain MRI segmentation and PET kinetic extraction

• Bénédicte Ballanger
• Léon Tremblay
• Véronique Sgambato-Faure
• Maude Beaudoin-Gobert
• Franck Lavenne
• Didier Le Bars
• Nicolas Costes

MRI templates and digital atlases are needed for automated and reproducible quantitative analysis of non-human primate PET studies. Segmenting brain images via multiple atlases outperforms single-atlas labelling in humans. We present a set of atlases manually delineated on brain MRI scans of the monkey Macaca fascicularis. We use this multi-atlas dataset to evaluate two automated methods in terms of accuracy, robustness and reliability in segmenting brain structures on MRI and extracting regional PET measures. Methods Twelve individual Macaca fascicularis high-resolution 3DT1 MR images were acquired. Four individual atlases were created by manually drawing 42 anatomical structures, including cortical and sub-cortical structures, white matter regions, and ventricles. To create the MRI template, we first chose one MRI to define a reference space, and then performed a two-step iterative procedure: affine registration of individual MRIs to the reference MRI, followed by averaging of the twelve resampled MRIs. Automated segmentation in native space was obtained in two ways: 1) Maximum probability atlases were created by decision fusion of two to four individual atlases in the reference space, and transformation back into the individual native space (MAXPROB). 2) One to four individual atlases were registered directly to the individual native space, and combined by decision fusion (PROPAG). Accuracy was evaluated by computing the Dice similarity index and the volume difference. The robustness and reproducibility of PET regional measurements obtained via automated segmentation was evaluated on four co-registered MRI/PET datasets, which included test–retest data. Results Dice indices were always over 0. 7 and reached maximal values of 0. 9 for PROPAG with all four individual atlases. There was no significant mean volume bias. The standard deviation of the bias decreased significantly when increasing the number of individual atlases. MAXPROB performed better when increasing the number of atlases used. When all four atlases were used for the MAXPROB creation, the accuracy of morphometric segmentation approached that of the PROPAG method. PET measures extracted either via automatic methods or via the manually defined regions were strongly correlated, with no significant regional differences between methods. Intra-class correlation coefficients for test–retest data were over 0. 87. Conclusions Compared to single atlas extractions, multi-atlas methods improve the accuracy of region definition. They also perform comparably to manually defined regions for PET quantification. Multiple atlases of Macaca fascicularis brains are now available and allow reproducible and simplified analyses.

YNIMG Journal 2010 Journal Article

Primate brain template image and reference atlas creation for voxel-based functional analysis of PET in Macaca fascicularis

• Nicolas Costes
• Vincent Leviel
• Léon Tremblay
• Véronique Sgambato-Faure
• Franck Lavenne
• Jean-Christophe Comte
• Didier Le Bars
• Bénédicte Ballanger

YNIMG Journal 2009 Journal Article

Association between triallelic polymorphism of the serotonin transporter and [18F]MPPF binding potential at 5-HT1A receptors in healthy subjects

• Amélie Lothe
• Claudette Boni
• Nicolas Costes
• Philip Gorwood
• Sandrine Bouvard
• Didier Le Bars
• Franck Lavenne
• Philippe Ryvlin

Previous [11C]WAY100-635 PET studies have demonstrated that the short (S) and long (L) alleles of the serotonin transporter gene-linked polymorphic region (5-HTTLPR) were associated with distinct patterns of 5-HT1A receptor distribution in human. However, these studies reported discordant findings and did not take into account the recent description of two functional variants of the L allele (LA/LG). To further explore this issue, we investigated the triallelic functional polymorphism of the 5-HTTLPR in 38 healthy volunteers who underwent a [18F]MPPF PET study of 5-HT1A receptors. We used a simplified reference tissue model to generate parametric images of [18F]MPPF binding potential (BPND), and compared these data among the different genotypes using statistical parametric mapping and region of interest of the raphe nuclei. Homozygote carriers of the S allele demonstrated greater [18F]MPPF BPND than carriers of the LA allele, but this association was only found in women. Differences in [18F]MPPF BPND between women with and without LA allele were observed over large clusters encompassing the right and left temporal lobes, cingulate and perisylvian regions, as well as the right precuneus and frontal dorso-lateral cortex, and the left orbitofrontal cortex. In contrast, no difference was found between groups in the raphe nuclei. The greater [18F]MPPF BPND observed in women homozygote carriers of the S allele could either reflect a greater 5-HT1A receptor density or a lower extracellular concentration of 5-HT. Our data suggest that any future PET studies of 5-HT1A receptors should incorporate the 5-HTTLPR polymorphism status of the population studied.

YNIMG Journal 2007 Journal Article

Functional anatomy of motor urgency

• Stéphane Thobois
• Bénédicte Ballanger
• Pierre Baraduc
• Didier Le Bars
• Franck Lavenne
• Emmanuel Broussolle
• Michel Desmurget

This PET H2 15O study uses a reaching task to determine the neural basis of the unconscious motor speed up observed in the context of urgency in healthy subjects. Three conditions were considered: self-initiated (produce the fastest possible movement toward a large plate, when ready), externally-cued (same as self-initiated but in response to an acoustic cue) and temporally-pressing (same as externally-cued with the plate controlling an electromagnet that prevented a rolling ball from falling at the bottom of a tilted ramp). Results show that: (1) Urgent responses (Temporally-pressing versus Externally-cued) engage the left parasagittal and lateral cerebellar hemisphere and the sensorimotor cortex (SMC) bilaterally; (2) Externally-driven responses (Externally-cued versus Self-initiated) recruit executive areas within the contralateral SMC; (3) Volitional responses (Self-initiated versus Externally-cued) involve prefrontal cortical areas. These observations are discussed with respect to the idea that neuromuscular energy is set to a submaximal threshold in self-determined situations. In more challenging tasks, this threshold is raised and the first answer of the nervous system is to optimize the response of the lateral (i. e. crossed) corticospinal tract (contralateral SMC) and ipsilateral cerebellum. In a second step, the anterior (i. e. uncrossed) corticospinal tract (ipsilateral SMC) and the contralateral cerebellum are recruited. This recruitment is akin to the strategy observed during recovery in patients with brain lesions.

YNIMG Journal 2006 Journal Article

Increased serotonin receptor availability in human sleep: Evidence from an [18F]MPPF PET study in narcolepsy

• Christopher Derry
• Christopher Benjamin
• Peter Bladin
• Didier Le Bars
• Henri Tochon-Danguy
• Samuel F. Berkovic
• Luc Zimmer
• Nicolas Costes

Data from animal studies suggest that serotonin release promotes wakefulness and suppresses REM sleep, but there are dangers in extrapolating these findings to humans. Binding of the radioligand [18F]MPPF to 5HT1A receptors is sensitive to levels of endogenous serotonin. In this study, we aimed to demonstrate changes in serotonin receptor availability in the human brain in wakefulness and sleep using [18F]MPPF and positron emission tomography. 14 subjects with narcolepsy cataplexy underwent [18F]MPPF PET scans in wakefulness and in sleep. Subjects who used the stimulant methylphenidate took their normal medication for the wake scan but omitted it prior to the sleep scan. The change in binding potential (BP) between the sleep and wake scans was examined using paired t test. Methylphenidate is thought to have little or no effect on serotonergic neurotransmission, and in order to confirm the absence of an effect on [18F]MPPF binding, a concurrent study was performed using a β-microprobe technique to examine the effect of methylphenidate administration on [18F]MPPF binding in Sprague–Dawley rats. The human study showed a significant increase in [18F]MPPF binding in sleep compared to wakefulness in the whole brain and all regions of interest examined (temporal cortex, mesial temporal region and cingulate cortex). The β-microprobe study confirmed that methylphenidate administration had no effect on [18F]MPPF binding. These findings indicate that serotonin receptor availability is increased in sleep compared to wakefulness in narcoleptic humans.

YNIMG Journal 2004 Journal Article

Statistical parametric mapping of 5-HT1A receptor binding in temporal lobe epilepsy with hippocampal ictal onset on intracranial EEG

• Isabelle Merlet
• Philippe Ryvlin
• Nicolas Costes
• Damien Dufournel
• Jean Isnard
• Isabelle Faillenot
• Karine Ostrowsky
• Franck Lavenne

Experimental data in animals show that 5-HT1A receptors are predominantly located in limbic areas and suggest that serotonin, via these receptors, mediates an antiepileptic and anticonvulsant effect. In this PET study, we used an antagonist of the 5-HT1A receptor, [18F]MPPF, to assess the extent of 5-HT1A receptor binding changes in a group of seven temporal lobe epilepsy (TLE) patients with hippocampal ictal onset demonstrated by intracerebral EEG recording. On the basis of MRI-measured hippocampal volumes (HV), patients were classified into “normal HV” or “hippocampal atrophy” (HA). Voxel-based analyses (SPM99) were performed to objectively assess the differences in [18F]MPPF binding potential (BP) between patients (taken as a group or as individuals) and a database of 48 controls subjects. In the full group of patients, a significant decreased BP was detected ipsilateral to the epileptogenic zone in the hippocampus, temporal pole, insula, and temporal neocortex. This result was confirmed in the subgroup of patients with HA. In patients with normal HV, the BP decrease was restricted to the temporal pole. TLE patients also demonstrated an increased BP in various regions contralateral to the epileptogenic zone. These data suggest that in TLE patients with hippocampal seizure onset, the decrease in 5-HT1A receptor binding partly reflects hippocampal neuronal loss, but is also observed in various regions involved in temporo-limbic epileptogenic networks that appeared normal on MRI. Further studies are warranted to evaluate the clinical usefulness of [18F]MPPF-PET as compared to other established PET tracers in drug resistant TLE.