Furman-2021-Augmenting Frontal Dopamine Tone E.pdf Part 1

Acknowledgments: 

This work was supported by funding from the National Institute of Mental Health (R01 112775 to MH & AK) and the Office of Naval Research (MURI N00014-16-1-2832 to DB). The authors thank the research subjects whose generous participation allowed this study to be completed.

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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 randomized, double-blind, placebo-controlled, within-subject fashion to 49 subjects 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 response times across the distribution. 

Resting-state fMRI data demonstrated that the degree to which tolcapone improved performance in individual subjects 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.

Introduction: 

The ability to selectively update the maintained contents of working memory is critical to working memory function (D'Esposito & Postle, 2015). Memoranda must be amenable to change as sensory inputs and goals evolve, but they must also be resistant to distraction; thus, deciding when to update those memoranda, and when to simply maintain them, is essential. 

To render maintenance more responsive to such inputs and goals, past computational modeling has argued for the presence of input and output gating mechanisms (Frank, Loughry, & O'Reilly, 2001; Frank & O'Reilly, 2006). When an input gate is open, the contents of working memory can be updated; when an input gate is closed, those contents are maintained and updates are suppressed. 

Similarly, the opening of an output gate selects an item (or items) maintained in working memory to be emitted to influence behavior. The maintenance process is itself an active one, and this process will complement the gating of memoranda in and out.

Over the past decade, neural evidence for the existence of input and output gates has accumulated (Badre & Frank, 2012; Chatham, Frank, & Badre, 2014; D'Ardenne et al., 2012; Frank & Badre, 2012). Current findings suggest that gating is controlled by the striatum through its connections with the frontal cortex. In particular, activity in the striatum increases when information is gated into working memory areas within the dorsolateral prefrontal cortex (PFC), and transcranial magnetic stimulation of the PFC disrupts this gating of new items into working memory (D'Ardenne et al., 2012). 

Similarly, increases in selection demands from within working memory, as instantiated by output gating, correlate with increases in activity within the caudate, as well as an increase in caudate connectivity with the prefrontal cortex (Chatham et al., 2014). These findings complement results indicating that maintenance is primarily a cortical process (D'Esposito & Postle, 2015). 

Work in both macaques (M. Wang, Vijayraghavan, & Goldman-Rakic, 2004) and humans (Lorenc, Lee, Chen, & D'Esposito, 2015), for example, has demonstrated that causal interventions in specific lateral PFC regions can degrade the performance of working memory maintenance, and more recent work has demonstrated the role of lateral PFC in maintaining representations in posterior cortical regions that encode relevant stimuli (Rose et al., 2016).

These different neural substrates share a link to the neuromodulator dopamine. In computational models that include gating mechanisms, a signal representing the actions of dopamine is responsible for opening and closing the gates (Frank et al., 2001). Moreover, in humans, phasic activity within the dopaminergic midbrain, where the striatal dopaminergic signal presumably originates, correlates with input gating (D'Ardenne et al., 2012). 

Concerning working memory maintenance, neural evidence for the role of cortical dopamine signaling has come from experiments in nonhuman primates in which dopamine agonists and antagonists were infused directly into lateral PFC (Cai & Arnsten, 1997; Vijayraghavan, Wang, Birnbaum, Williams, & Arnsten, 2007; M. Wang et al., 2004; Y. Wang & Goldman-Rakic, 2004). 

Depending on the dose of such infusions, working memory performance could either improve or decline, supporting the now-classic inverted U-shaped influence of dopamine on behavior, such that behavior is optimized for intermediate dopamine tone (Cools & D'Esposito, 2011).

Based on the above findings, the specific locus of dopaminergic effects should determine the nature of their influence on working memory function. In particular, changes in cortical dopamine tone should influence maintenance, but should not differentially impact input and output gating. 

To our knowledge, this hypothesis has not been tested. To address this idea directly, here we take advantage of the unique neuroanatomy and pharmacology of the catechol-O-methyltransferase (COMT) enzyme. 

Dopamine metabolism is regulated differentially in the frontal cortex and striatum: while termination of dopamine's effect in the striatal synapse is predominantly mediated by reuptake via the dopamine transporter, the action of synaptic dopamine in the frontal cortex is terminated primarily via degradation by the COMT enzyme (Chen et al., 2004; Gogos et al., 1998). 

The brain-penetrant COMT inhibitor tolcapone might therefore preferentially augment cortical dopamine tone (Tunbridge, Bannerman, Sharp, & Harrison, 2004) and thereby enhance working memory maintenance, potentially by increasing connectivity of frontal regions with the posterior cortical regions important for representing maintained stimuli (Mueller, Krock, Shepard, & Moore, 2020; Noudoost & Moore, 2011). 

A previous study of tolcapone in humans has shown modest enhancements of working memory (Apud et al., 2007); however, the working memory task employed in that study, the N-back, confounds encoding, maintenance, and retrieval processes on single trials, and therefore cannot easily differentiate input gating, output gating, and maintenance demands. 

Here we propose that tolcapone's effects should be expressed primarily in maintenance, not gating. To test our hypothesis, we take advantage of a paradigm that has previously been used to assess hierarchical working memory maintenance and gating (Chatham et al., 2014) via independent manipulations of working memory load (primarily placing demands on maintenance processes) and task context (primarily impacting gating). 

In the task, subjects are required to maintain one or two stimuli – a letter, a symbol, or both – across a trial, based on a context cue (a number) that can be provided either before or after the other items. 

We hypothesize that tolcapone should lead to the greatest behavioral improvements when the demand for memory maintenance is greater. Moreover, we argue that this effect should be most prominent when output gating demands are low, thereby reducing response time variability induced by context-contingent selection from working memory. 

Thus, we specifically predict that we will find behavioral improvement when maintenance demands are high but gating demands are low. Similarly, the administration of tolcapone should have limited effects on performance as a function of gating demands when maintenance demands are held constant.

Methods: 60 healthy subjects with no history of medical, psychiatric, or neurological contraindications were recruited and ultimately eligible to participate in the study. All subjects gave written informed consent by the Declaration of Helsinki and the Committee for the Protection of Human Subjects at the University of California, San Francisco, and the University of California, Berkeley; they were compensated for their participation. 

Subjects first underwent a history and physical exam, as well as blood testing for liver function and urine screening for drugs of abuse, to ensure there were no medical contraindications to tolcapone use or magnetic resonance imaging (MRI) scanning. All subjects were right-handed and had normal or corrected-to-normal vision. Before testing sessions, subjects were trained on the task to familiarize them with task procedures. Subjects then underwent two separate behavioral sessions, each consisting of 180 task trials, as well as resting-state functional MRI (fMRI) that was part of a larger study. 

For those sessions, subjects were randomized in a double-blind, counterbalanced, placebo-controlled fashion to receive either a single 200mg dose of tolcapone or a matched placebo on their first visit, and the alternative treatment on their second visit. The tolcapone dose was based on our previously published findings that a single 200mg dose has measurable behavioral effects (Kayser, Allen, Navarro-Cebrian, Mitchell, & Fields, 2012; Kayser, Mitchell, Weinstein, & Frank, 2015; Saez, Zhu, Set, Kayser, & Hsu, 2015). 

Overall, 11 subjects were excluded before the final behavioral data analysis: four because they only participated in one day of behavioral testing, four because they did not complete all study procedures within each testing day, and three because their task accuracy did not exceed the chance. The remaining 49 subjects contributed to all behavioral data. Ages ranged from 18-33 years old (mean 21.6  3.1 (sd)); 26 of 49 were women. An additional four subjects were removed from the resting state data set because of excessive motion (translation greater than 3 mm), leaving 45 subjects for imaging analyses.

Task. Details of the task have been published elsewhere (Chatham & Badre, 2013; Chatham et al., 2014). Briefly, each trial of the task consisted of three separate visual stimuli – a number (1, 2, or 3), a letter (A or B), and a symbol (a snowflake or a Sun) – that could be presented sequentially in any order (Figure 1). 

Each of the first two stimuli for that trial was presented for 0.5 seconds, separated by an inter-stimulus interval (ITI) of 1.5 – 5.0 seconds (drawn from a uniform distribution). Following a second ITI, the final stimulus remained on the screen until the subject had chosen one of the two accompanying response options (see below). Subjects were required to maintain both the context, as cued by the number, and at least one of the letter and symbol stimuli across the trial. 

Specifically, numbers served as a "context" that conveyed information about which of the two other stimuli was relevant for a given trial: for the number 1, subjects were required to selectively remember the symbol ("selective" context); for the number 2, subjects were required to selectively remember the letter ("selective" context); and for the number 3, subjects were required to remember both the symbol and the letter ("global" context). 

Trials in which both the letter and the symbol were admitted into working memory were considered to be high-load trials, while those trials in which only one of the two was maintained were considered to be low-load trials (Figure 1). 

Accompanying the third visual stimulus (whether number, letter, or symbol) were two choices consisting of both a letter and a symbol; subjects were required to make a left or right button press to identify the choice with the appropriate memorandum/a. For global trials, subjects were informed that the two choice options could share one of the memoranda, requiring subjects to remember both items to make the correct decision.

Gating demands were manipulated by varying the order in which the three stimuli were presented. Trials in which the number was presented first placed primary demands on input gating: subjects needed to select the appropriate visual stimulus/stimuli to input and maintain across the delay, but output gating demands were reduced, as all maintained memoranda were behaviorally relevant. 

In contrast, trials in which the number was presented last not only placed demands on input gating, but also placed significantly greater demands on output gating: subjects updated and maintained all visually presented stimuli in working memory, because the identity of the behaviorally relevant stimuli was not yet specified, but they then needed to select for output only the appropriate choice from the contents of working memory. 

For these trials in which the number was presented last, note that output gating demands were higher for the "selective" contexts, compared with the "global" context, because working memory contained items that were not behaviorally relevant. Lastly, trials in which the context (i.e. the number) was presented as the second of the three visual stimuli were included in the behavioral task for completeness, to ensure that subjects needed to attend to all stimulus positions equally. 

However, because these trials more strongly confound input gating, output gating, and maintenance demands, they were not analyzed further. In sum, four task conditions were analyzed: context first, selective (CF-S); context first, global (CF-G); context last, selective (CL-S); and context last, global (CL-G).

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