Cholinergic enhancement reduces functional connectivity and BOLD variability in visual extrastriate cortex during selective attention
Highlights
► Physostigmine improves performance and alters brain response to cognitive tasks. ► We evaluated cholinergic effects on neural efficiency during selective attention. ► Physostigmine reduced connectivity and BOLD variability in visual areas during task. ► Cholinergic enhancement improves task-specific neural efficiency.
Introduction
Selective attention constitutes the ability to discriminate relevant from irrelevant stimuli (i.e. noise) and to process information within our environment preferentially (Desimone, 1998; Desimone and Duncan, 1995; Kastner et al., 1998). The need for such a selective process arises from a limited attentional capacity of the human brain, which produces a competition for representation at a neural level when multiple stimuli are presented simultaneously (Desimone, 1998; Kastner et al., 1998). The biased competition model of selective attention (Desimone, 1998; Kastner et al., 1998) argues that the processing of stimuli within our environment is based on an interaction between two mechanisms, ‘bottom-up’ processes that act through stimulus-based operations, and ‘top-down’ processes that act through cognitive or executive actions (Desimone, 1998; Duncan, 1998). Thus, the extent to which neural processing is biased toward or away from any particular stimulus in the environment is dependent on the resolution of interactions between these bottom-up and top-down attention mechanisms.
While the cholinergic system is important in multiple cognitive domains, including memory and attention, the literature suggests that the modulation of these functions may occur via stimulus processing mechanisms (Bentley et al., 2011; Furey, 2011). At a behavioral level, cholinergic modulation produced stimulus specific behavioral effects during attention tasks, consistent with the modulation of the relative salience of competing visual stimuli (Bentley et al., 2003a; Furey et al., 2008a). At a neuronal level, the direct application of acetylcholine increased the selectivity of neural response to stimulus orientation in the cat visual cortex (Sillito, 1986; Sillito and Kemp, 1983) consistent with enhancing signal, while cholinergic input to the hippocampus is inhibitory, suggesting a modulation of S/N by reducing response to noise (Buzsaki, 1989). Thus, modulation of S/N may constitute the neural mechanism through which the cholinergic system may establish the relative strengths of stimulus representations. At a regional level, functional brain imaging studies (Bentley et al., 2003a; Freo et al., 2005; Furey et al., 2000c, 1997, 2008b; Ricciardi et al., 2009) demonstrated that enhanced cholinergic activity selectively increased neural responses to task relevant stimuli (i.e. signal) in visual processing cortical regions with reduced or no change in neural responses to task-irrelevant stimuli (i.e. noise), consistent with the hypothesized improvement of S/N ratio.
The enhanced representation of signal together with a reduced representation of noise inherently is reflected in the interaction between top-down and bottom-up mechanisms (Hasselmo et al., 1996; Sarter et al., 2001, 2005; Sarter and Parikh, 2005), and results in shifting a processing bias among the competing stimuli. Functional brain imaging studies have demonstrated that cholinergic enhancement selectively increases neural activity in medial visual processing areas while reducing neural responses in lateral visual extrastriate cortex (Bentley et al., 2003a, Bentley et al., 2003b; Furey et al., 2000c, 2008b; Ricciardi et al., 2009) and in task-relevant prefrontal and parietal cortical regions (Bentley et al., 2004, Bentley et al., 2003a, Bentley et al., 2003b; Freo et al., 2005; Furey et al., 2000c, 1997, 2008b; Ricciardi et al., 2009). As these response modulations were accompanied by improved task performance, we hypothesized that these changes in brain response are associated with an enhanced visual percept that rendered the task easier to perform (Furey, 2011; Furey et al., 2000c). More specifically, the increased processing in medial visual cortex may underlie a superior representation of the stimulus being processed, which renders the task easier to perform and reduces the need to recruit prefrontal cortex.
Temporal variability in BOLD signal is thought to reflect cognitive capacity and integration of information (Garrett et al., 2010, 2011), and changes in BOLD temporal variability potentially could reflect shifts in S/N that reflect improvement in stimulus processing (Mohr and Nagel, 2010; Samanez-Larkin et al., 2010). If the hypothesis that cholinergic enhancement results in more efficient processing is correct, cholinergically mediated decreases in task difficulty may manifest as changes in BOLD temporal variability within task associated brain areas.
Changes in neural activity following cholinergic enhancement extend throughout task-relevant brain regions (Bentley et al., 2004, Bentley et al., 2003a, Bentley et al., 2003b; Freo et al., 2005; Furey et al., 2000c, 1997, 2008b; Ricciardi et al., 2009) and thus suggest that the regional effects are likely not independent, but rather follow changes in communication among task-important brain regions. Cholinergic activity reportedly affects interactions among prefrontal, parietal and sensory brain regions (Golmayo et al., 2003; Nelson et al., 2005), and some specifically have suggested that cholinergic transmission influences anatomically segregated but functionally interconnected regional processes (Bentley et al., 2011; Sarter et al., 2001). Thus our understanding of the neuromodulatory effects of acetylcholine on efficiency of stimulus processing may benefit by investigating changes in interregional connectivity.
Cholinergic potentiation-associated changes in neural activity that are identified based on standard GLM approaches to data analysis are relatively subtle, and are described as simple increases or decreases in neural activity associated with task related brain regions. We anticipate that cholinergically mediated changes in neural response that reflect more efficient processing can be characterized more effectively by using analysis procedures that address both neural efficiency and regional interactions. Our previous findings have lead to the hypothesis that increased cholinergic function produces enhanced visual percepts of critical stimuli, and in this way results in a more efficient processing. In the current manuscript, we explore this hypothesis by assessing functional efficiency as evaluated by the strength of functional connectivity and by indices of BOLD temporal variability in task relevant brain regions following cholinergic modulation.
Section snippets
Subjects
Nine healthy individuals (mean age ± SD = 31 ± 6 years; four females/five males) participated in a randomized, double-blind, placebo-controlled crossover study. All were right-handed, normotensive, had no abnormalities on clinical examination or on laboratory tests (including routine blood and urine tests, EKG, EEG, brain magnetic resonance imaging scan, and chest X-ray), and no history of any relevant medical, neurological, or psychiatric disorder. All were free of medication, including
Behavioral findings
Mean reaction time while performing the selective attention task was significantly faster during the physostigmine as compared to placebo condition (mean RT ± S.D.: physostigmine = 1755 ± 259 s, placebo: 1819 ± 257 s; p = 0.027). No drug-related RT changes occurred during the control task (mean RT ± S.D.: physostigmine = 1284 ± 275 s, placebo: 1267 ± 242 s; p > 0.3). For a detailed report of the behavioral results see Furey et al., 2008a.
Drug-related BOLD response during the selective attention and control tasks
During placebo and physostigmine, significant (p < 0.05
Discussion
The results of the current study support the hypothesis that enhanced cholinergic function may lead to a more efficient stimulus processing, which renders tasks less demanding. Exclusively during the selective attention task, and not during the control condition, cholinergic modulation induced by physostigmine reduced both the strength of connections and the BOLD temporal variability in task-related areas, particularly implicating visual processing extrastriate regions. Cholinergic enhancement
Acknowledgements
We would like to thank James Haxby for collaborative input and Joanna Szczepanik for technical support. This work was supported by the NIMH-IRP.
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