Midazolam decreases cerebral blood flow in the left prefrontal cortex in a dose-dependent fashion

Abstract

Midazolam, a short-lived benzodiazepine producing sedation and reversible anterograde amnesia, was administered intravenously to 14 healthy male volunteers. Regional cerebral blood flow (rCBF) was measured using positron emission tomography (PET) with intravenous H215O at either a 'high' midazolam EEG effect (EEG signs of stage 2 sleep), or 'low' midazolam EEG effect (increase in EEG beta power only). Memory tests administered following PET scans showed significant drug-induced impairment in learning and retrieval at the same drag concentration at which PET images were acquired. Statistical parametric mapping was used to identify regions where rCBF changes after drug administration were significantly different in the high- vs. low-effect groups. Dose x condition interactions were found in the left dorsolateral prefrontal cortex [Brodmann's areas (BA) 9 and 46], bilateral orbital-frontal cortex (BA 47), the left middle temporal gyms (BA 22) and the right hippocampus. The predominantly left frontal rCBF decreases occur in a region associated with semantic processing, working memory, and encoding of verbal material, a process preferentially affected by midazolam. Our interpretation is that rCBF changes in the hippocampus are unlikely to mediate the anterograde amnesia produced by midazolam. Although in the present study PET images were acquired during the resting state rather than during memory processing, these results underscore the need for further investigation relating to the interaction of midazolam with specific cognitive operations in these brain regions.