Functional MRI detection of pharmacologically induced memory impairment

Abstract

To examine alterations in brain activation associated with pharmacologically induced memory impairment, we used functional MRI (fMRI) to study the effects of lorazepam and scopolamine on a face–name associative encoding paradigm. Ten healthy young subjects were scanned on four occasions, 2 weeks apart; they were administered i.v. saline during two placebo-scanning sessions and then alternately administered i.v. lorazepam (1 mg) or scopolamine (0.4 mg) in a double-blind, randomized, cross-over design. Both the extent and magnitude of activation within anatomic regions of interest (ROIs) were examined to determine the reproducibility of activation in the placebo sessions and the regional specificity of the pharmacologic effects. Activation within all ROIs was consistent across the two placebo scans during the encoding of novel face–name pairs (compared with visual fixation). With the administration of either lorazepam or scopolamine, significant decreases were observed in both the extent and magnitude of activation within the hippocampal, fusiform, and inferior prefrontal ROIs, but no significant alterations in activation in the striate cortex were found. Both medications impaired performance on postscan memory measures, and significant correlations between memory performance and extent of activation were found in hippocampal and fusiform ROIs. These findings suggest that pharmacologic effects can be detected with fMRI by using a reproducible experimental paradigm and that medications that impair memory also diminish activation in specific brain regions thought to subserve complex memory processes.

Cholinergic Stimulation Enhances Neural Activity Associated with Encoding but Reduces Neural Activity Associated with Retrieval in Humans

“…Under placebo, there was no such effect, resulting in a significant interaction effect between pharmacological condition and spatial context encoding. These data provide direct evidence for an enhancing effect of cholinergic stimulation on encoding at the neural level in humans and complement previous findings that cholinergic inhibition by administration of the muscarinic receptor antagonist scopolamine reduces neural activity during encoding in the hippocampus and parahippocampal gyrus (Sperling et al, 2002;Schon et al, 2005). It is important to note that the application of physostigmine generally elevated ACh-levels and thus affected both nicotinic and muscarinic receptors.…”

Scopolamine Reduces Persistent Activity Related to Long-Term Encoding in the Parahippocampal Gyrus during Delayed Matching in Humans

“…These results are consistent with previous pharmacological neuroimaging studies that revealed decreased activation in the left fusiform gyrus during delayed recognition of abstract shapes (Rosier et al, 1999), decreased activation in both extent and magnitude of fusiform gyrus and hippocampus during face-name association learning (Sperling et al, 2002), and decreased activation during repetition priming in the left fusiform cortex (Thiel et al, 2002) after injection of scopolamine at encoding. In the present study, we used a subsequent memory paradigm that allowed us to investigate directly whether the fMRI response to novel stimuli was correlated with long-term encoding.…”

“…Behavioral studies in monkeys (Aigner et al, 1991;Tang et al, 1997) and humans Mewaldt, 1975, 1977;Rosier et al, 1998;Atri et al, 2004) have shown that injection of the muscarinic cholinergic antagonist scopolamine before encoding, but not before retrieval, impairs performance on memory tasks. A recent fMRI study showed that scopolamine reduces hippocampal, fusiform, and inferior prefrontal activity in individuals performing a longterm associative encoding task (Sperling et al, 2002). Similarly, a positron emission tomography study demonstrated that the in-fluence of scopolamine at encoding reduces recognition-related activity in the fusiform gyrus (FG) (Rosier et al, 1999).…”

Alterations in Memory Networks in Mild Cognitive Impairment and Alzheimer's Disease: An Independent Component Analysis

“…The associative memory task consisted of novel faces (faces unfamiliar to the participants) paired with fictional first names (Sperling et al, 2001(Sperling et al, , 2002(Sperling et al, , 2003b. Participants were explicitly instructed to try to remember the name associated with each face, and to make a decision regarding whether they thought the name "fit" the face (i.e., "was a good name for that face") or not.…”