epilepsy; familial; nicotinic receptor; PET; EEG; nicotine
Garibotto Valentina, Wissmeyer Michael, Giavri Zoi, Ratib Osman, Picard Fabienne (2020), Nicotinic Acetylcholine Receptor Density in the “Higher-Order” Thalamus Projecting to the Prefrontal Cortex in Humans: a PET Study, in Molecular Imaging and Biology
, 22(2), 417-424.
Pichon Swann, Garibotto Valentina, Wissmeyer Michael, Seimbille Yann, Antico Lia, Ratib Osman, Vuilleumier Patrik, Haller Sven, Picard Fabienne (2020), Higher availability of α4β2 nicotinic receptors (nAChRs) in dorsal ACC is linked to more efficient interference control, in NeuroImage
, 214, 116729-116729.
Garibotto Valentina, Corpataux Thibault, Dupuis‐Lozeron Elise, Haller Sven, Fontolliet Timothée, Picard Fabienne (2019), Higher nicotinic receptor availability in the cingulo‐insular network is associated with lower cardiac parasympathetic tone, in Journal of Comparative Neurology
Garibotto Valentina, Wissmeyer Michael, Giavri Zoi, Goldstein Rachel, Seimbille Yann, Seeck Margitta, Ratib Osman, Haller Sven, Picard Fabienne (2019), Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy, in European Journal of Nuclear Medicine and Molecular Imaging
, 46(2), 385-395.
O'Reilly Christian, Chapotot Florian, Pittau Francesca, Mella Nathalie, Picard Fabienne (2018), Nicotine increases sleep spindle activity, in Journal of Sleep Research
Picard Fabienne, Korff Christian (ed.) (2015), Epilepsie et génétique
Kurian Mary, Picard Fabienne (2015), Familial focal epilepsies: the genetic link, in Epileptologie
, 32(2), 139-146.
Baulac Stéphanie, Picard Fabienne (2015), Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations, in Ann Neurol
, 77, 675-683.
Garibotto V, Wissmeyer M, Picard F (2015), Méthodes de médecine nucléaire, in Epilepsie- Bericht Schweiz
Picard Fabienne, Baulac S. (2014), DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy, in Neurology
, 82(23), 2101-2106.
Picard Fabienne, Friston Karl (2014), Predictions, perception, and a sense of self, in Neurology
, 83(12), 1112-1118.
Picard F., Sadaghiani S., Leroy C., Courvoisier D.S., Maroy R., Bottlaender M. (2013), High density of nicotinic receptors in the cingulo-insular network, in Neuroimage
, 79, 42-51.
Garibotto Valentina, Picard Fabienne (2013), Nuclear medicine imaging in epilepsy, in Epileptologie
, 30(2), 109-121.
Picard Fabienne, Scheffer Ingrid (2012), Genetically determined focal epilepsies, in M. Bureau P. Genton C. Dravet A.V. Delgado-Escueta C.A. Tassinari P. Thomas P.Wolf (ed.), John Libbey Eurotext , Montrouge, 349-361.
Picard Fabienne, Bottlaender Michel (2010), More nicotinic receptors in the insular cortex and possible role in NFLE, in Epilepsies
, 22(Supplément), 26-28.
Weckhuysen Sarah, Kurian M, Picard F, Baulac S, Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), Autosomal Dominant Epilepsy with Auditory Features (ADEAF), Familial Mesial Temporal Lobe Epilepsy (FMLTE) and Familial Focal Epilepsy with, in J. Pellock (ed.).
These last years mutations in neuronal nicotinic acetylcholine receptors (nAChRs) have been identified in a form of familial partial epilepsy, the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), characterized by the occurrence of seizures with hypermotor symptoms during the non-rapid eye movement (non-REM) sleep stage 2. NAChRs are largely distributed throughout the whole cortex and the thalamus. Most nAChRs are presynaptic and play a neuromodulator role, allowing to increase the release of various neurotransmitters. Despite the demonstration of a gain of function of the mutated receptors, by electrophysiological studies conducted in vitro, the precise mechanisms leading to this nocturnal epilepsy are still unknown. In 2006 we studied the nAChR cerebral distribution in a group of patients with ADNFLE carrying a nAChR mutation, by a PET-scan using [18F]-F-A-85380, a ligand with a high affinity and specificity for ?4?2 nicotinic receptors, the main human nAChR. The study of regions of interest showed a different pattern of brain distribution of the radiotracer in the ADNFLE patients when compared to a group of control subjects, with a significant increase of nicotinic receptor density in the patients in mesencephalon, pons and cerebellum. Statistical parametric mapping (SPM) confirmed clear regional differences between patients and controls: patients had increased nAChR density in the epithalamus, ventral mesencephalon and cerebellum, but decreased nAChR density in the right dorsolateral prefrontal region (Picard et al., Brain 2006). Based on the known biochemical and cellular circuits in the brainstem, these results suggest that the nAChR density increase in mesencephalon is involved in the pathophysiology of ADNFLE through the role of brainstem ascending cholinergic systems in arousal. The follow-up step consists of extending this examination to other forms of epilepsy, in order to verify the specificity of the hyperfixation pattern for ADNFLE, and search for a potential involvement of nicotinic receptors in other forms of epilepsy.While the first study was performed in the Commissariat à l'Energie Atomique (CEA, Orsay, France), this follow-up study will take place at the University Hospital of Geneva since we have developed an automated process, that fully complies GMP requirements, for the production of [18F]-F-A-85380 using the TracerLab MXFDG synthesizer (funded by a grant “Projet de Recherche et de Développement (PRD)” in 2007, Dr Y. Seimbille and Dr F. Picard; “D. Lukic, C. Tamburella, F. Picard, Y. Seimbille. Automated production of [18F]F-A-85380 using TracerLab MXFDG synthesizer. 18th International Symposium on Radiopharmaceutical Sciences, July 12-17, 2009, Edmonton, Canada”). We aim to study 4 groups of subjects: control subjects (Group 1, 12 subjects); patients with a non lesional partial epilepsy and a predominance of diurnal seizures (Group 2, 8 subjects); patients with an idiopathic generalized epilepsy (Group 3, 8 subjects); and patients with nocturnal frontal lobe epilepsy (Group 4, 8 subjects). For each patient, a cerebral MRI, [18F]-fluorodeoxyglucose (FDG) PET/CT and [18F]-F-A-85380 PET/CT examinations are planned. We will perform data analyses on volume of distribution (Vd) parametric images which will be based on the ratio of brain tissue to unchanged F-A-85380 plasma at equilibrium. Statistical parametric mapping (SPM2) will be used to further study the parametric PET images. This study is primarily dedicated to demonstrate that the pattern of hyperfixation that was obtained in ADNFLE patients is specific for this disorder and does not constitute a common pattern to various forms of epilepsy. However, by establishing the regional distribution of nicotinic receptors in patients with other epilepsies, we will also search for a possible involvement of the nAChRs in other forms of epilepsy.In parallel, as another mean to understand the generation of nocturnal epileptic seizures in case of mutated nAChRs, we plan to study the effect of nicotine on some physiological transient synchronized electroencephalographical (EEG) rhythms of 11-15 Hz frequency called “sleep spindles”, which appear repetitively during non-REM sleep stage 2. These oscillations are generated in the thalamus and transmitted to the cortex, and interestingly have been involved in memory consolidation (Clemens et al., 2006; Schmidt et al., 2006; Schabus et al., 2008). We already showed that the duration of the last sleep spindle immediately preceding the nocturnal frontal lobe epilepsy (NFLE) seizures was increased compared with all the other sleep spindles, suggesting that the thalamic nAChRs play a role in the pathophysiology of the disorder (Picard et al., 2007). We aim to study the effect of nicotine on sleep spindles (density, duration, frequency, amplitude and localization) in a group of 12 healthy non-smoking control subjects, by comparing sleep EEG recordings using a 256 channel-system, with and without a nicotine patch. A well-recognized system of automatic sleep spindle detection and waveforms analysis (PRANA, Phi Tools) will be used, as well as the electrical source imaging tools available in Christoph Michel’s laboratory (CMU, Geneva). This will help to better understand the relationships between nAChRs and the thalamocortical loops at an electrophysiological level, and their relation to sleep and epilepsy at a clinical level.