The cognitive neuroscience of sustained attention: where top-down meets bottom-up (Sarter, Givens, Bruno; 2001)

The basal forebrain corticopetal cholinergic projections terminate in practically all areas and layers of the cortex (for review see Ref. [87]). For several decades, human and animal psychopharmacological experiments on the effects of nicotine and muscarinic receptor antagonists (such as scopolamine and atropine) have strongly implicated cholinergic systems in sustained attention. Beginning with the demonstration of the effects of excitotoxic lesions of the basal forebrain on rats’ performance in the five-choice reaction time and other tasks and on the performance of monkeys in a version of Posner’s overt orientation task (e.g., Refs. [7,59,79,102]), the crucial dependency of attentional abilities on the integrity of this system has been extensively explored. Collectively, the available evidence from studies on the effects of loss of cortical cholinergic inputs demonstrates the following: (1) selective lesions of the basal forebrain corticopetal cholinergic projections, produced by infusions of the cholinoimmunotoxin 192 IgG-saporin into the region of the nucleus basalis of Meynert and the substantia innominata in the basal fore- brain, are sufficient to produce profound impairments in sustained attention [50]. (2) The lesion-induced impair- ment in performance is restricted to signal trials while correct rejections remain unaffected, reflecting the absence of the normally augmenting effects of cortical acetyl- choline (ACh) on the processing of sensory inputs (e.g., Refs. [54,62,98,103]. Moreover, such lesions decrease the vigilance levels and augment the vigilance decrement [50]. (3) Loss of cortical cholinergic inputs alone, as opposed to loss of all basal forebrain cholinergic efferents, suffices to produce such impairments [53]. (4) The impairments in sustained attention observed following cortical cholinergic deafferentation are persistent and do not recover, even following extended periods of daily practice of perform- ance [50]. (5) The extent of the impairments in sustained attention is tightly correlated with the degree of loss of cortical cholinergic inputs, particularly in fronto–dorsal cortical areas [50].

Selective Effects of Cholinergic Modulation on Task Performance during Selective Attention

The cholinergic neurotransmitter system is critically linked to cognitive functions including attention. The current studies were designed to evaluate the effect of a cholinergic agonist and an antagonist on performance during a selective visual attention task where the inherent salience of attended/unattended stimuli was modulated. Two randomized, placebo-controlled, crossover studies were performed, one (n ¼ 9) with the anticholinesterase physostigmine (1.0 mg/h), and the other (n ¼ 30) with the anticholinergic scopolamine (0.4 mc/kg). During the task, two double-exposure pictures of faces and houses were presented side by side. Subjects were cued to attend to either the face or the house component of the stimuli, and were instructed to perform a matching task with the two exemplars from the attended category. The cue changed every 4–7 trials to instruct subjects to shift attention from one stimulus component to the other. During placebo in both studies, reaction time (RT) associated with the first trial following a cued shift in attention was longer than RT associated with later trials (po0.05); RT also was significantly longer when attending to houses than to faces (po0.05). Physostigmine decreased RT relative to placebo preferentially during trials greater than one (po0.05), with no change during trial one; and decreased RT preferentially during the attention to houses condition (po0.05) vs attention to faces. Scopolamine increased RT relative to placebo selectively during trials greater than one (po0.05), and preferentially increased RT during the attention to faces condition (po0.05). The results suggest that enhancement or impairment of cholinergic activity preferentially influences the maintenance of selective attention (ie trials greater than 1). Moreover, effects of cholinergic manipulation depend on the selective attention condition (ie faces vs houses), which may suggest that cholinergic activity interacts with stimulus salience. The findings are discussed within the context of the role of acetylcholine both in stimulus processing and stimulus salience, and in establishing attention biases through top-down and bottom-up mechanisms of attention.

The literature is rich with evidence of the involvement of the cholinergic system in attention mechanisms (Everitt and Robbins, 1997; Hasselmo and McGaughy, 2004; Himmelhe- ber et al, 2000; Robbins, 1997; Sarter and Bruno, 2000; Sarter et al, 2003, 2005b; Yu and Dayan, 2002). Researchers have hypothesized that attentional processes are mediated through cholinergic mechanisms that facilitate the proces- sing of sensory information (Robbins, 1997) and some evidence exists to support this idea (Furey et al, 2000b; Sillito and Kemp, 1983a). Furthermore, evidence indicates that the cholinergic system is recruited through both bottom-up, stimulus driven mechanisms and by top-down, goal-directed mechanisms suggesting that cholinergic in- volvement in stimulus processing reflects the combined influence of both bottom-up and top-down attentional processes (reviewed by Sarter et al, 2005a). In general, the cholinergic neurons of the basal forebrain that projects throughout neocortex are thought to enhance signal-to-noise (S/N) ratios for neural processing (Murphy and Sillito, 1991; Sato et al, 1987). Sillito (Sillito and Kemp, 1983b) demonstrated that the direct application of acet- ylcholine to cat visual cortex increased the selectivity of the cell’s response to stimulus orientation, consistent with the hypothesis that acetylcholine increases S/N. Similarly, Buzsaki (1989) showed that cholinergic input to hippocam- pus is inhibitory, suggesting that acetylcholine may enhance S/N in hippocampus by reducing the response to noise. The cholinergic influence on S/N may constitute the neural mechanism through which the cholinergic system influ- ences selective attention, and may establish the relative strengths of the neural representations of competing stimuli. For example, a functional imaging study (Furey et al, 2000b) demonstrated that enhanced cholinergic activity selectively increased neural responses to task- relevant stimuli (ie signal) with reduced or no change in neural responses to task-irrelevant stimuli (ie noise), consistent with a selective enhancement for target stimuli via S/N processing. The modulation of S/N processing in the context of the neural representation of competing stimuli may alter the stimulus bias established between attended and unattended stimuli.

Acetylcholine also has other effects on excitability of neurons. Its presence causes a slow depolarization by blocking a tonically-active K+ current, which increases neuronal excitability. It appears to be a paradox, however, that ACh increases spiking activity in inhibitory interneurons while decreasing strength of synaptic transmission from those cells. This decrease in synaptic transmission also occurs selectively at some excitatory cells: For instance, it has an effect on intrinsic and associational fibers in layer Ib of piriform cortex, but has no effect on afferent fibers in layer Ia. Similar laminar selectivity has been shown in dentate gyrus and region CA1 of the hippocampus. One theory to explain this paradox interprets acetylcholine neuromodulation in the neocortex as modulating the estimate of expected uncertainty, acting counter to norepinephrine (NE) signals for unexpected uncertainty. Both would then decrease synaptic transition strength, but ACh would then be needed to counter the effects of NE in learning, a signal understood to be 'noisy'.

The purpose of the current study was to evaluate the influence of cholinergic modulation on behavioral performance of a selective attention task. The task required the alternation of attention between two object categories present in each stimulus, thus the task required the shifting of goal-directed attention between two competing stimuli. The two object categories differed in the level of inherent salience (faces and houses), and thus as the task required the shift in directed attention, the salience of the unattended stimulus changed. We expected that acetylcholine is central to establishing the processing bias among competing stimuli. We were interested specifically in evaluating the influence of cholinergic modulation on goal-directed performance, and predicted that performance would change differentially depending on the inherent salience of the unattended stimulus so that changes in performance would reflect any shift in stimulus bias among the competing stimuli. A stimulus category bias would be reflected by the difference in reaction times (RTs) when attending to each of the two stimulus categories, and the larger this RT difference the greater the bias toward the stimulus category with the fastest RT. Two separate studies were conducted, one evaluating the enhancement of cholinergic activity using the anticholinesterase and physostigmine, and the other investigating the inhibition of cholinergic function using scopolamine.