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.
Highlights
Disruption to cholinergic neurotransmission – whether by targeted lesions, toxins, drugs, aging or disease –induces impairments in a range of functions, including perception (Erskine et al, 2004), attention (Robbins et al, 1989), memory and learning (Kopelman, 1986), emotion (Kamboj and Curran, 2006), and sleep (Kim and Jeong, 1999)
The discussion focuses on those results where pro-cholinergic drugs suppress task-specific frontoparietal activity, while the fourth attempts to explain why in other circumstances, the opposite profile is seen: i.e. frontoparietal hyper-activation secondary to pro-cholinergic therapies. These accounts can be summarised as follows: (1) procholinergic reductions in parietal activity are associated with reduced attentional orienting; (2) pro-cholinergic reductions in frontal activity may occur due to enhanced sensory processing, or via other efficiency-enhancing mechanisms, thereby requiring less ‘attentional effort’; (3) pro-cholinergic reductions in activity of a predominantly medially located, resting-state network suggest a shift from internal to external processing; and (4) pro-cholinergic increases in activity, especially of a dorsolateral frontoparietal network, may reflect increased recruitment of attentional-executive processes
Taken together with the observations made at the start of this subsection, these results indicate that cholinergic stimulation may suppress top-down enhancement of subtle inputs, by favouring a state in which bottom-up inputs compete for attention by virtue of their salience
Summary
Disruption to cholinergic neurotransmission – whether by targeted lesions, toxins, drugs, aging or disease –induces impairments in a range of functions, including perception (Erskine et al, 2004), attention (Robbins et al, 1989), memory and learning (Kopelman, 1986), emotion (Kamboj and Curran, 2006), and sleep (Kim and Jeong, 1999) This broad cognitivebehavioural profile reflects in part the pan-cortical and subcortical reach of cholinergic neurons (Mesulam and Geula, 1991). By favouring stronger, at the expense of weaker, inputs (Krnjevicet al., 1971; McCormick and Prince, 1986), or by selective strengthening of input-driven synapses (Huerta and Lisman, 1993), the cholinergic system may bias particular modes of attentional or memory processing, respectively (Hasselmo and McGaughy, 2004) To reconcile these two roles – as a general modulator of cortical activity, and as a mediator of highly specific regional processing effects – several models have emerged that embrace both perspectives
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