Using arterial spin labeling perfusion MRI to explore how midazolam produces anterograde amnesia

Abstract

While our previous work suggests that the midazolam-induced memory impairment results from the inhibition of new association formation, little is known about the neural correlates underlying these effects beyond the effects of GABA agonists on the brain. We used arterial spin-labeling perfusion MRI to measure cerebral blood flow changes associated with the effects of midazolam on ability to learn arbitrary word-pairs. Using a double-blind, within-subject cross-over design, subjects studied word-pairs for a later cued-recall test while they were scanned. Lists of different word-pairs were studied both before and after an injection of either saline or midazolam. As expected, recall was severely impaired under midazolam. The contrast of MRI signal before and after midazolam administration revealed a decrease in CBF in the left dorsolateral prefrontal cortex (DLPFC), left cingulate gyrus and left posterior cingulate gyrus/precuneus. These effects were observed even after controlling for any effect of injection. A strong correlation between the midazolam-induced changes in neural activity and memory performance was found in the left DLPFC. These findings provide converging evidence that this region plays a critical role in the formation of new associations and that low functioning of this region is associated with anterograde amnesia.

Disruption of cortical integration during midazolam‐induced light sedation

“…After completion of the pre‐injection section, participants were given ani.v. injection of either midazolam (0.03 mg/kg of the participant's body mass, to a maximum of 2.5 mg) diluted to a total volume of 10 ml or a matching volume of saline through the intravenous cannula within a 2‐min period [Liang et al, ; Nyhus and Curran, ; Park et al, ; Reder et al, ]. The drug administration procedure was double‐blinded, thus neither the participants nor the experimenter was told which drug the participants were being given.…”

Effects of anesthesia on cerebral blood flow, metabolism, and neuroprotection

“…224 Regional CBF alteration has been observed with the largest declines in areas of the brain involved in memory formation, attention, and arousal; while the location of these changes correlates with the areas of the brains associated with the clinical effects observed following administration of benzodiazepines, a causal relationship has not yet been established. 225,226 Interestingly, unlike the sedative effects, the reduction of CBF following midazolam administration is not reversed by doses of flumazenil, an observation that may be explained by direct vasoconstriction mediated by flumazenil. 227,228 This effect though is controversial as some reports describe a recovery of CBF following administration of flumazenil following midazolam.…”

Midazolam: an essential palliative care drug

“…Midazolam can cause prolonged anterograde amnesia. [75][76][77] Clinical applications of midazolam in palliative care…”