PET quantification of muscarinic cholinergic receptors with [N‐¹¹C‐methyl]‐benztropine and application to studies of propofol‐induced unconsciousness in healthy human volunteers

Abstract

This work evaluated kinetic analysis methods for estimation of the receptor availability of the muscarinic receptor using dynamic positron emission tomography (PET) studies with [N-(11)C-methyl]-benztropine. The study also investigated the effect of propofol on central muscarinic receptor availability during general anesthesia. Six volunteers were scanned three times, once for baseline while awake, once during unconsciousness, and once after recovery to conscious level. An irreversible two-tissue compartment model was used to estimate the [N-(11)C-methyl]-benztropine specific binding rate constant k(3), a measure of muscarinic receptor availability. Two different estimation methods were used: 1) optimization with positivity constraints on all the parameters; 2) optimization with additional constraints determined from a one-tissue compartment fit to the cerebellum. In regions with low to middle muscarinic receptor density, the k(3) values from method (2) had lower standard errors than that for method (1) and gave a higher correlation with the density of muscarinic receptors measured in human tissue by in vitro studies (r(2) of 0.98 for Method 2 and r(2) of 0.72 for Method 1). But the k(3) values determined by Method 2 had higher errors for regions with high muscarinic receptor density compared to Method 1. For both methods the mean k(3) values during unconsciousness were generally lower than those during awake for most regions evaluated. Therefore, the method with additional constraints derived from the cerebellum (Method 2) was deemed superior for regions with low to middle muscarinic receptor density, while the method with positivity constraint is the better choice in the regions with high muscarinic receptor density. Our results also suggest the existence of propofol-related reductions in muscarinic receptor availability.

Imaging the Effects of Propofol on Human Cerebral Glucose Metabolism Using Positron Emission Tomography

“…4,7 Owing to the complex neural network in the central nervous system, it is difficult to locate precisely these cerebral target regions with traditional means, such as electroencephalography, or study of localized destruction and nerve rupture, however PET technique can provide useful information. 8 Glucose is the only source of energy for brain cells; therefore, study of cerebral glucose metabolism can be used for predicting the state of regional energy metabolism, as well as local neuronal actions. 9 As an isomer of glucose, 18 F-FDG is used as an imaging tracer for the metabolic rate of glucose because it is metabolized in the same way as glucose.…”

Hipnose, imobilidade tônica e eletroencefalograma

“…A existência de uma relação direta entre a capacidade de atenção e a SH tem sido evidenciada, corroborando com a observação de hipniatras e hipnoterapeutas de que quanto maior o domínio do indivíduo sobre sua atenção, mais alta é a sua SH. Essa é uma característica pessoal e um aspecto cognitivo multidimensional que envolve perspectivas peculiares 42,109 . Parece que a condição "hipnotizada" seja caracterizada por uma dissociação funcional dos processos de monitoramento de conflitos e de controle cognitivo, envolvendo áreas do córtex frontal 1 .…”

“…Sabe-se que tal via é envolvida na atenção executiva ou de trabalho 107 . Outra consideração foi que drogas que atuam nessa via, como propofol, podem modular a atenção executiva e induzir uma experiência parecida com a hipnose 108,109 . Usando um protocolo neurofeedback, Batty et al 110 testaram a possibilidade de aumentar a SH em 30 indivíduos e elevar as taxas de teta e alfa no EEG, comparando as técnicas de RPP e auto-hipnose e verificando a importância da relação teta/alfa no aumento.…”

Anaesthesia and PET of the Brain

“…At around the same time, another group found that propofol anaesthesia was associated with a reduction in muscarinic receptor binding by the tracer [ N -11 Cmethyl]-benztropine (Xie et al 2004 ), but this fi nding was diffi cult to interpret. Although it may have indicated binding of propofol to muscarinic receptors, it could also have been the result of a change of affi nity of the receptor for benztropine or an increase in benztropine metabolism caused by propofol.…”