Attention and the Cholinergic System: Relevance to Schizophrenia

Abstract

Traditional methods of drug discovery often rely on a unidirectional, "bottom-up" approach: A search for molecular compounds that target a particular neurobiological substrate (e.g., a receptor type), the refinement of those compounds, testing in animal models using high-throughput behavioral screening methods, and then human testing for safety and effectiveness. Many attempts have found the "effectiveness" criterion to be a major stumbling block, and we and others have suggested that success may be improved by an alternative approach that considers the neural circuits mediating the effects of genetic and molecular manipulations on behavior and cognition. We describe our efforts to understand the cholinergic system's role in attention using parallel approaches to test main hypotheses in both rodents and humans as well as generating converging evidence using methods and levels of analysis tailored to each species. The close back-and-forth between these methods has enhanced our understanding of the cholinergic system's role in attention both "bottom-up" and "top-down"-that is, the basic neuroscience identifies potential neuronal circuit-based mechanisms of clinical symptoms, and the patient and genetic populations serve as natural experiments to test and refine hypotheses about its contribution to specific processes. Together, these studies have identified (at least) two major and potentially independent contributions of the cholinergic system to attention: a neuromodulatory component that influences cognitive control in response to challenges from distractors that either make detection more difficult or draw attention away from the distractor, and a phasic or transient cholinergic signal that instigates a shift from ongoing behavior and the activation of cue-associated response. Right prefrontal cortex appears to play a particularly important role in the neuromodulatory component integrating motivational and cognitive influences for top-down control across populations, whereas the transient cholinergic signal involves orbitofrontal regions associated with shifts between internal and external attention. Understanding how these two modes of cholinergic function interact and are perturbed in schizophrenia will be an important prerequisite for developing effective treatments.

Thalamic cholinergic innervation makes a specific bottom-up contribution to signal detection: Evidence from Parkinson’s disease patients with defined cholinergic losses

“…Instead, cortical, and especially fronto-parietal, cholinergic activity are hypothesized to support “attentional effort” – the motivated activation of top-down attention to stabilize task representations, especially when performance is challenged (Lustig & Sarter, 2016; Raizada & Poldrack, 2008; Sarter et al, 2006). Fronto-parietal cholinergic activity increases reliably from baseline to the SAT, and further in response to the dSAT condition or other challenges (see Kozak et al, 2006); even placing trained animals in the operant chamber or simply testing them at the same time every day can lead to increases in frontoparietal cholinergic activity suggesting a readiness to engage in the task (Paolone et al, 2012).…”

What do phasic cholinergic signals do?

“…Degeneration of the cholinergic system therefore is expected to disrupt both the learning of associations between signals and the response rules needed to interact with the outside world and the use of (learned) signals to guide the retrieval of associative frameworks guiding action selection (e.g., Mesulam, 2004; Sarter, Albin, Kucinski, & Lustig, 2014). Furthermore, ill-timed cholinergic transients, due to abnormalities in the organization of corticosubcortical circuitry, may cause false detections or inappropriate attention and response to behaviorally-insignificant signals and therefore support psychopathological states (Lustig & Sarter, 2016). …”

Distinct Frontoparietal Networks Underlying Attentional Effort and Cognitive Control

“…Effort has been defined as the motivated activation of task-set representations in response to reduced performance or other indicators of increased task difficulty due to external or internal factors (e.g., the flickering described above, fatigue, advanced age) (Sarter, Gehring, & Kozak, 2006). The right prefrontal cortex (RPFC) has been proposed as a critical locus for interactions between control, motivation, and effort (e.g., Lustig & Sarter, 2016; Watanabe & Sakagami, 2007). However, as Botvinick and Braver note, the neural correlates of effort remain relatively unexplored.…”

“…Supporting the role of BA 9 in directing these functions, it is highly connected with sensory, motor, parietal, and other PFC regions as well as midbrain and limbic structures (Alexander, DeLong, & Strick, 1986; Bates & Goldman-Rakic, 1993; Miller & Cohen, 2001). In a recent review, we noted that it serves as a common locus for increased activation in response to control demands in young adults, putatively compensational increases in activation during control-demanding tasks in older adults, and abnormal function during working memory tasks in schizophrenia (Lustig & Sarter, 2016, their Figure 3). …”

“…This inverted-U pattern may reflect increased recruitment of motivated attention until a “crunch point” (Reuter-Lorenz & Lustig, 2005), after which demand exceeds the subject’s ability to maintain performance. It is not yet clear whether drops in performance and activation reflect loss of motivation, abandoning the current task set to explore alternatives, or some combination of cognitive-motivational processes (Lustig & Sarter, 2016). …”