Project

Back to overview

PET and EEG study of the nicotinic system in epilepsy

English title PET and EEG study of the nicotinic system in epilepsy
Applicant Picard Fabienne
Number 127608
Funding scheme Project funding (Div. I-III)
Research institution Hôpitaux Universitaires de Genève Service de Neurologie
Institution of higher education University of Geneva - GE
Main discipline Neurology, Psychiatry
Start/End 01.09.2010 - 30.11.2015
Approved amount 330'234.00
Show all

Keywords (6)

epilepsy; familial; nicotinic receptor; PET; EEG; nicotine

Lay Summary (English)

Lead
Lay summary
Mutations have been identified in neuronal nicotinic acetylcholine receptors (nAChRs) 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, at the time of arousals from sleep. 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 a4b2 nicotinic receptors, the main human nAChR. The study 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 nAChR density in the patients in the ventral mesencephalon, and decreased nAChR density in the right dorsolateral prefrontal region. Based on the known biochemical and cellular circuits in the brainstem, these results suggested 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 present project 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. We aim to study a group of control subjects, of patients with a non lesional diurnal partial epilepsy, of patients with an idiopathic generalized epilepsy, and of patients with nocturnal frontal lobe epilepsy.In parallel, as another mean to understand the generation of nocturnal epileptic seizures in case of mutated nAChRs, we will study the effect of nicotine on some physiological transient synchronized electroencephalographical (EEG) rhythms called "sleep spindles", which appear repetitively during non-REM sleep stage 2, by comparing sleep EEG recordings with and without a nicotine patch in a group of healthy non-smoking control subjects. 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.
Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Nicotinic Acetylcholine Receptor Density in the “Higher-Order” Thalamus Projecting to the Prefrontal Cortex in Humans: a PET Study
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.
Higher availability of α4β2 nicotinic receptors (nAChRs) in dorsal ACC is linked to more efficient interference control
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.
Higher nicotinic receptor availability in the cingulo‐insular network is associated with lower cardiac parasympathetic tone
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, cne.24726-cne.24726.
Nicotinic receptor abnormalities as a biomarker in idiopathic generalized epilepsy
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.
Nicotine increases sleep spindle activity
O'Reilly Christian, Chapotot Florian, Pittau Francesca, Mella Nathalie, Picard Fabienne (2018), Nicotine increases sleep spindle activity, in Journal of Sleep Research, e12800-e12800.
Epilepsie et génétique
Picard Fabienne, Korff Christian (ed.) (2015), Epilepsie et génétique.
Familial focal epilepsies: the genetic link
Kurian Mary, Picard Fabienne (2015), Familial focal epilepsies: the genetic link, in Epileptologie, 32(2), 139-146.
Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations
Baulac Stéphanie, Picard Fabienne (2015), Familial focal epilepsy with focal cortical dysplasia due to DEPDC5 mutations, in Ann Neurol, 77, 675-683.
Méthodes de médecine nucléaire
Garibotto V, Wissmeyer M, Picard F (2015), Méthodes de médecine nucléaire, in Epilepsie- Bericht Schweiz .
DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy
Picard Fabienne, Baulac S. (2014), DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy, in Neurology, 82(23), 2101-2106.
Predictions, perception, and a sense of self
Picard Fabienne, Friston Karl (2014), Predictions, perception, and a sense of self, in Neurology, 83(12), 1112-1118.
High density of nicotinic receptors in the cingulo-insular network
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.
Nuclear medicine imaging in epilepsy
Garibotto Valentina, Picard Fabienne (2013), Nuclear medicine imaging in epilepsy, in Epileptologie, 30(2), 109-121.
Genetically determined focal epilepsies
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.
More nicotinic receptors in the insular cortex and possible role in NFLE
Picard Fabienne, Bottlaender Michel (2010), More nicotinic receptors in the insular cortex and possible role in NFLE, in Epilepsies, 22(Supplément), 26-28.
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
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.).

Collaboration

Group / person Country
Types of collaboration
Faculty of Psychology and Educational Sciences, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Neuroscience Colloquium, Dpt of Neurosciences, St. Olav University Hospital, Trondheim Individual talk Sleep-related hypermotor epilepsy 13.06.2017 Tronheim, Norway Picard Fabienne;
Focal Epilepsy Conference Faroe Islands Talk given at a conference Genetic aspects of nicotinic receptor mutations in focal epilepsies 24.05.2017 Faroe Islands, Denmark Picard Fabienne;
Friday Colloquium, Max Planck Institute for Biological Cybernetics Individual talk Epilepsy and insula 23.10.2015 Tübingen, Germany Picard Fabienne;
Consensus Conference on NFLE (Nocturnal Frontal Lobe Epilepsy) Talk given at a conference Nocturnal frontal lobe epilepsy: pathophysiological mechanisms 30.08.2014 Bologna, Italy Picard Fabienne;
2nd SFCNS Congress (Swiss Federation of Clinical Neuro-Societies) Poster Special richness of nicotinic receptors in the cingulo-insular network. 05.06.2013 Montreux, Switzerland Picard Fabienne;
5ème Journée Romande d’Epileptologie (JRE) Individual talk Mécanismes physio-pathologiques des épilepsies frontales nocturnes 24.01.2013 Lausanne, Switzerland Picard Fabienne;
European College of Neuropsychopharmacology. Targeted Expert Meeting on Epilepsy and Psychiatry. Talk given at a conference member of the Scientific Advisory Panel 12.10.2012 Vienne, Austria Picard Fabienne;
American Epilepsy Society (AES) Poster Special richness of the insular cortex in nicotinic receptors - Implications for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). 02.12.2011 Baltimore, United States of America Picard Fabienne;
13èmes Journées Françaises contre l’Epilepsie (JFE) Poster Richesse de l’insula et du cortex cingulaire en récepteurs nicotiniques 11.11.2010 Grenoble, France Picard Fabienne;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
ScienceComm’14. « Science et art » et « Visualisation scientifique » Talk 18.09.2014 Sursee / Beromünster, Switzerland Picard Fabienne;
Conférences et ateliers formation continue universitaire, direction Prof. Golay Performances, exhibitions (e.g. for education institutions) 14.05.2014 Genève, Switzerland Picard Fabienne;


Communication with the public

Communication Title Media Place Year
Media relations: radio, television Neurosciences, épilepsie Radio Cité Genève Western Switzerland 2014
Talks/events/exhibitions Journée Rencontre d’Epilepsie-France (Journée Nationale d'épilepsie), Lyon International 2013

Abstract

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.
-