Augmenting Frontal Dopamine Tone Enhances Maintenance over Gating Processes in Working Memory

Abstract

The contents of working memory must be maintained in the face of distraction, but updated when appropriate. To manage these competing demands of stability and flexibility, maintained representations in working memory are complemented by distinct gating mechanisms that selectively transmit information into and out of memory stores. The operations of such dopamine-dependent gating systems in the midbrain and striatum and their complementary dopamine-dependent memory maintenance operations in the cortex may therefore be dissociable. If true, selective increases in cortical dopamine tone should preferentially enhance maintenance over gating mechanisms. To test this hypothesis, tolcapone, a catechol- O-methyltransferase inhibitor that preferentially increases cortical dopamine tone, was administered in a randomized, double-blind, placebo-controlled, within-subject fashion to 49 participants who completed a hierarchical working memory task that varied maintenance and gating demands. Tolcapone improved performance in a condition with higher maintenance requirements and reduced gating demands, reflected in a reduction in the slope of RTs across the distribution. Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual participants correlated with increased connectivity between a region important for first-order stimulus response mappings (left dorsal premotor cortex) and cortical areas implicated in visual working memory, including the intraparietal sulcus and fusiform gyrus. Together, these results provide evidence that augmenting cortical dopamine tone preferentially improves working memory maintenance.

Predicted Utility Modulates Working Memory Fidelity in the Brain

“…Importantly, a subset of these models emphasize the action of the neurotransmitter dopamine to explain how WM might be modulated based on value (Badre & Frank, 2012; Braver & Cohen, 2000; Frank et al, 2001; Frank & Badre, 2012; Frank & O’Reilly, 2006; Hazy et al, 2007). Evidence in both animals and humans has linked cortical dopamine to improved accuracy in WM tasks and maintenance that is more robust to distraction (Durstewitz & Seamans, 2002; Frank & Fossella, 2011; Furman et al, 2020; Wiecki & Frank, 2013). In essence, dopamine increases the signal-to-noise ratio (SNR) in cortex, which may be in line with our observation of progressively reduced entropy for higher predicted utility items.…”

Working memory, cortical dopamine tone, and frontoparietal brain recruitment in post-traumatic stress disorder: a randomized controlled trial

“…A pioneering study that administered tolcapone while subjects performed the N-back, a canonical working memory task, showed improvements in working memory processing, primarily in subjects with presumptively lower dopamine tone (as assessed by COMT genotype); and corresponding BOLD effects were interpreted as improved neural efficiency in lateral prefrontal cortex [26]. More recent data has shown that tolcapone might improve maintenance processes in visual working memory circuits [27]. Similarly, tolcapone has demonstrated significant effects on affective-motivational behaviors.…”

Impact and centrality of attention dysregulation on cognition, anxiety, and low mood in adolescents

“…Attention has been described as a design feature for efficient goal-directed action 6 and is a central neural control feature subserving agential efficacy. Consequently, the impairments characteristic of attention dysregulation could involve dysfunctional input-gating mechanisms for filtering contextually relevant information, failures of dopamine to maintain task representations in working memory 44 , or inefficient output-gating mechanisms precipitating the impulsivity component, frequently manifested as sub-optimal premature responding.…”