Cholinergic modulation of cognition: insights from human pharmacological functional neuroimaging

Abstract

Evidence from lesion and cortical-slice studies implicate the neocortical cholinergic system in the modulation of sensory, attentional and memory processing. In this review we consider findings from sixty-three healthy human cholinergic functional neuroimaging studies that probe interactions of cholinergic drugs with brain activation profiles, and relate these to contemporary neurobiological models. Consistent patterns that emerge are: (1) the direction of cholinergic modulation of sensory cortex activations depends upon top-down influences; (2) cholinergic hyperstimulation reduces top-down selective modulation of sensory cortices; (3) cholinergic hyperstimulation interacts with task-specific frontoparietal activations according to one of several patterns, including: suppression of parietal-mediated reorienting; decreasing 'effort'-associated activations in prefrontal regions; and deactivation of a 'resting-state network' in medial cortex, with reciprocal recruitment of dorsolateral frontoparietal regions during performance-challenging conditions; (4) encoding-related activations in both neocortical and hippocampal regions are disrupted by cholinergic blockade, or enhanced with cholinergic stimulation, while the opposite profile is observed during retrieval; (5) many examples exist of an 'inverted-U shaped' pattern of cholinergic influences by which the direction of functional neural activation (and performance) depends upon both task (e.g. relative difficulty) and subject (e.g. age) factors. Overall, human cholinergic functional neuroimaging studies both corroborate and extend physiological accounts of cholinergic function arising from other experimental contexts, while providing mechanistic insights into cholinergic-acting drugs and their potential clinical applications.

Fig. 1

Model that links effects of acetylcholine on sensory cortex as appreciated from non-human electrophysiological studies, with effects observed in human functional imaging paradigms following systemic cholinergic stimulation or antagonism. (A) Schematic configuration of neocortical cholinergic system showing how sensory cortex receives cholinergic modulation both directly and indirectly via cholinergic modulation of frontoparietal processing. (B) Effects of ACh on the sensory cortical circuits are known for ex vivo slices, often with selective layer IV input activation, that are arguably most representative of passive-stimulation paradigms when top-down inputs are relatively low. In these situations, ACh application causes net neural suppression, that corresponds with findings from human functional imaging paradigms in which pro-cholinergic drugs result in sensory cortex suppression (or vice versa for scopolamine). (C) Task-driven selective activation of sensory or parietal cortex (e.g. as guided by the rule: X not Y) is found in non-human studies to be acetylcholine dependent. Correspondingly, cholinergic antagonists decrease task-relevant sensory cortex activations under attention-demanding conditions in human functional imaging studies. In Alzheimer's disease, where task-driven sensory cortex activations are abnormally low, and a cortical cholinergic deficit exists, administration of physostigmine increases selective sensory cortex activations. (D) Cholinergic hyperstimulation increases activity in both task-relevant and task-irrelevant units, in non-human electrophysiological recordings. If task-relevant units are already close to maximal firing, then this may lead to a greater increment in task-irrelevant units, explaining why in hypercholinergic states there may be an actual reduction in task-driven selective activation of sensory cortex, as seen in human functional imaging paradigms under ChEI or nicotine. Abbreviations: ACh, acetylcholine; Glu, glutamate; GABA, gamma-amino butyric acid; ChEI, cholinesterase inhibitor.

Fig. 2

Explanations for modulations of frontoparietal activations in cholinergic-functional imaging studies. (A) Decreases in parietal activation during re-orienting trials secondary to pro-cholinergic drugs (especially nicotine) may occur indirectly because of a hypercholinergic-induced reduction in spatial biasing. (B) Decreases in frontoparietal activation secondary to pro-cholinergic drugs may also be secondary to direct effects of cholinergic stimulation in sensory cortical regions, which result in heightened efficiency, and thus less ongoing need for executive control. (C) Decreases in medial frontal–parietal activations secondary to pro-cholinergic drugs overlap with a recognised resting-state network, which together with drug-induced reciprocal increases in activity in dorsolateral regions, suggests a state change from internally focused feedback-predominant mode to externally directed feedforward mode. (D) Increases in frontoparietal activations secondary to pro-cholinergic drugs, specifically during demanding task conditions, and sometimes with performance improvement, suggest recruitment of additional executive-attentional processes. Note that thick arrows are intended to show possible order by which processes are modulated, and not anatomical connectivity.

Fig. 3

Overview of memory-related processes modulated by cholinergic drugs as revealed by cholinergic-functional imaging studies, and relationship with theoretical models in which high ACh levels facilitate encoding while suppressing retrieval (Hasselmo and McGaughy, 2004) as well as potentiate top-down control of sensory processing (Sarter et al., 2006). (A) Sensory regions, especially fusiform cortex, show enhanced activations with pro-cholinergic drugs (and vice versa with anti-cholinergics) during attention-demanding periods, including during encoding phases of working memory tasks, which correlates with subsequent memory. Sensory regions also demonstrate cholinergic sensitivity in several memory-related processes elicitable by functional imaging – sustained-activity, repetition decreases, and conditioning-induced sensory remapping. (B) Medial temporal regions show enhanced activation with pro-cholinergic therapies during encoding, but suppression during retrieval (or vice versa for anti-cholinergic therapies) – this profile corresponding to the discussed computational model of memory function. (C) Prefrontal regions show a similar pattern of responses as medial temporal regions: anti-cholinergic therapies decreasing activations during encoding or working memory paradigms, but increasing or not modulating activations during retrieval (and vice versa for pro-cholinergic therapies except in the case of one working memory paradigm* that was interpreted as increased efficiency – see Fig. 2B).

Fig. 4

Modulations of functional imaging activations by cholinergic drugs often correspond to an inverted-U shaped pattern, depending upon both relative task demands (A) and subject-specific factors (B). In many cases, there is also a concordant effect on performance, e.g. in Alzheimer's disease where physostigmine increases task-related activations, reaction time and memory, or in healthy subjects where scopolamine decreases the same three parameters.