Nicotinic acetylcholine receptors (nAChRs) are involved in a familial form of frontal lobe epilepsy, autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). In several ADNFLE families, mutations were identified in the nAChR alpha4 or beta2 subunit, which together compose the main cerebral nAChR. Electrophysiological assessment using in vitro expression systems indicated a gain of function of the mutant receptors. However the precise mechanisms by which they contribute to the pathogenesis of a focal epilepsy remain obscure, especially since alpha4beta2 nAChRs are known to be widely distributed within the entire brain. PET study using [18F]-F-A-85380, a high affinity agonist at the alpha4beta2 nAChRs, allows the determination of the regional distribution and density of the nAChRs in healthy volunteers and in ADNFLE patients, thus offering a unique opportunity to investigate some in vivo consequences of the molecular defect. We have assessed nAChR distribution in eight non-smoking ADNFLE patients (from five families) bearing an identified mutation in nAChRs and in seven age-matched non-smoking healthy volunteers using PET and [(18)F]-F-A-85380. Parametric images of volume of distribution (Vd) were generated as the ratio of tissue to plasma radioactivities. The images showed a clear difference in the pattern of the nAChR density in the brains of the patients compared to the healthy volunteers. Vd values revealed a significant increase (between 12 and 21%, P < 0.05) in the ADNFLE patients in the mesencephalon, the pons and the cerebellum when compared to control subjects. Statistical parametric mapping (SPM) was then used to better analyse subtle regional differences. This analysis 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. In five patients who underwent an additional [(18)F]-fluorodeoxyglucose (FDG) PET experiment, hypometabolism was observed in the neighbouring area of the right orbitofrontal cortex. The demonstration of a regional nAChR density decrease in the prefrontal cortex, despite the known distribution of these receptors throughout the cerebral cortex, is consistent with a focal epilepsy involving the frontal lobe. We also propose 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 inhibition of cerebral monoamine oxidases (MAOs) by cigarette smoke components could participate to the tobacco addiction. However, the actual extent of this inhibition in vivo in smokers is still poorly known. We investigated cerebral MAO-A availability in 7 tobacco-dependent subjects and 6 healthy nonsmokers, using positron emission tomography (PET) and the MAO-A selective radioligand [C]befloxatone. In comparison to nonsmokers, smokers showed a significant overall reduction of [C]befloxatone binding potential (BP) in cortical areas (average reduction, -60%) and a similar trend in caudate and thalamus (-40%). Our findings confirm a widespread inhibition of cerebral MAO-A in smokers. This mechanism may contribute to tobacco addiction and for a possible mood-modulating effect of tobacco.

Under the conditions of this study, food increases the rate and the extent of mefloquine absorption. It is reasonable to recommend that mefloquine be administered with food in travellers receiving chemoprophylaxis and in patients on recovery receiving curative treatment. In acutely ill patients, mefloquine should be taken as soon as possible and administration with or shortly after meals should be attempted as soon as feasible.

We used behavioral and functional magnetic resonance imaging (fMRI) methods to probe the cerebral organization of a simple logical deduction process. Subjects were engaged in a motor trial-and-error learning task, in which they had to infer the identity of an unknown 4-key code. The design of the task allowed subjects to base their inferences not only on the feedback they received but also on the internal deductions that it afforded (autoevaluation). fMRI analysis revealed a large bilateral parietal, prefrontal, cingulate, and striatal network that activated suddenly during search periods and collapsed during ensuing periods of sequence repetition. Fine-grained analyses of the temporal dynamics of this search network indicated that it operates according to near-optimal rules that include 1) computation of the difference between expected and obtained rewards and 2) anticipatory deductions that predate the actual reception of positive reward. In summary, the dynamics of effortful mental deduction can be tracked with fMRI and relate to a distributed network engaging prefrontal cortex and its interconnected cortical and subcortical regions.

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