INVESTIGATING THE CHOLINERGIC REGULATION OF HUMAN LEARNING AND MEMORY USING FUNCTIONAL MAGNETIC RESONANCE SPECTROSCOPY

Abstract

Current theories consider the effects of acetylcholine neuromodulation in neuronal ensembles as a bidirectional network modulator: increased levels set network dynamics to process external stimuli, and decreased levels set network dynamics to process information that has been previously stored. Accordingly, invasive measurements in animal models have shown that acetylcholine drives neural activity increases during tasks of memory encoding and attention. Using noninvasive proton magnetic resonance spectroscopy (1H-MRS) while subjects performed a configural working memory task, our first study aimed to be the first to measure increases in cholinergic neurotransmission during memory encoding in human medial temporal lobe. We found that changes in choline-containing compounds over minute-long task blocks correlated with the subjective difficulty of the task across subjects.

More recent animal work during tasks of attention have shown that increases in acetylcholine appear on much faster timescales than had previously been considered; these phasic increases occur in coordination with learned behavioral responses to sensory stimuli and last for only seconds. In addition, research employing pharmacological functional magnetic resonance imaging (fMRI) in human subjects have indicated that acetylcholine may not only activate areas required for external focus, but also decrease ongoing neural activity in brain areas that may interfere with task performance. Converging these lines of evidence, our next experiments collected fMRI and 1H-MRS measurements in ventromedial prefrontal cortex while subjects performed a sustained attention task. The results show that stimulus-based phasic cholinergic activity coincides with phasic reductions in neural activity. Together, these findings support the theory that acetylcholine works in a coordinated manner on both tonic and phasic timescales to control a global brain-state switch between the processing of externally generated and internally generated information.