Systematic review: Effects of cholinergic signaling on cognition in human pharmacological studies

Acetylcholine (ACh) is one of the main neurotransmitters in central nervous systems across species. It has been extensively studied in animal models, and is known for its profound role in attention processes and adaptive responses to changing environments. Recent theories propose that this occurs by modulating the relative influence of top-down and bottom-up inputs during perceptual inference and regulating cue-validity updating in uncertain environments. However, the role of ACh in human cognition has mostly been investigated in memory and is less well established in other domains. Here we provide a systematic review of human studies investigating effects of ACh on cognitive functions using pharmacological modulators, with a focus on the cognitive processes needed for acute behavioural adaptation to situational changes. Results revealed that ACh is involved in sustained attention, perceptual detection, the updating of cue-response relationships and the speed of information processing, with differential cognitive effects associated with muscarinic and nicotinic modulators. This supports a role of ACh in prioritizing top-down and bottom-up information in humans, potentially enabling rapid updating of behavioural responses to situational changes. However, efforts to parse out the molecular roles of ACh signaling with pharmacological methodologies may be limited by their relative nonspecificity and an inability to mimic signaling dynamics. Integration of pharmacological findings with neuroimaging data such as functional magnetic resonance spectroscopy may be helpful to identify the effects of cholinergic modulators on whole-brain pharmacodynamics.