Abstracts

Rationale: Mutations in the ?4?2 neuronal nicotinic acetylcholine receptors (nAChRs) have been identified in a familial form of epilepsy, the autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In vitro electrophysiological studies have suggested that these nAChR mutations are all gain-of-function mutations that increase the receptor sensitivity to ACh, however the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since ?4?2 nAChRs are known to be widely distributed within the entire cortex. While the epileptogenic focus was long thought to be located in the orbitofrontal or the mesial prefrontal area, in the familial as well as the sporadic forms of NFLE, subsequent studies using intracerebral stereo-EEG recordings converged toward a possible insular or operculo-insular origin of the nocturnal frontal lobe epilepsies in addition to a frequent origin in the cingulate cortex. We consequently postulated that the operculo-insular cortex and the cingulate cortex could be particularly rich in nAChRs. Methods: We assessed the distribution of the ?4?2 nAChRs in the normal human cortex in a group of seven non-smoking healthy subjects, using 2-[18F]F-A-85380 PET with volumes of interest (VOIs) analysis and partial volume effect correction. The 2-[18F]F-A-85380 tracer has a high affinity for heteromeric nAChRs which include ?2 subunits, particularly the major ?4?2 subtype. The analysis included 82 cortical VOIs.Results: The density was not homogenous across different parts of the cortex. Compared to the median density of all cortical regions, the nAChR density was significantly higher in both hemispheres by about 20% in the insula and the anterior cingulate cortex, and 18% in the mid-cingulate cortex (p<0.05).Conclusions: The insular and cingulate cortices are particularly rich in nAChRs. The insula and the cingulate cortex are highly interconnected and constitute the so-called cortical salience network, which is thought to relate emotional value to internal and external stimuli and to generate appropriate autonomic arousal. We propose that the insular and cingulate nAChRs play an important role in normal central autonomic functions, and in the neurobiological processes of disorders such as nocturnal frontal lobe epilepsy. The finding of a neurochemical link between nocturnal frontal lobe epilepsy and the insula supports the need to include this structure among the regions investigated during the presurgical evaluation of pharmacoresistant non lesional nocturnal frontal lobe epilepsies.