Furman-2021-Augmenting Frontal Dopamine Tone E.pdf Part 3

Drug x decile effects did not reach statistical significance for any of the other task conditions (CF-S: 0.08±2.9, z = 0.03; CL-S: 2.49±2.3, z=1.08; CL-G: -.33±3.5, z=-0.09), though notably, the trend for CL-S was numerically opposed to that observed for CF-G (i.e., greater slope on tolcapone). 

Tolcapone is a drug called a "dopamine D4 receptor antagonist" that is widely used to treat ADHD, attention deficit disorder, and depression. Compared with other drugs, tolcapone exerts its therapeutic effect mainly by affecting the transmission of dopamine signaling.

However, the role of tolcapone is not limited to the treatment of the above-mentioned diseases. In recent years, more and more studies have shown that tolcapone also has the effect of enhancing memory. In experiments, tolcapone has been found to improve people's memory and learning abilities, especially in cases where memory and cognitive abilities are affected.

According to research by scientists, this memory-enhancing effect of tolcapone is related to its effect on dopamine signaling. Dopamine is an important neurotransmitter that is closely related to various physiological processes such as cognition, emotion, and reward. Tolcapone affects dopamine signaling, thereby producing a series of complex regulatory effects in the body, including enhancing the brain's learning and memory functions.

At the same time, the memory-enhancing effect of tolcapone is also of great significance to human growth and development. With the continuous development of society and technology, the amount of knowledge and information is also increasing day by day. People need to constantly learn and memorize new knowledge to adapt to and cope with the complex and changeable modern life. In this context, the memory-enhancing effect of tolcapone can help us learn and accumulate knowledge better, and improve our competitiveness and adaptability.

Generally speaking, the relationship between tolcapone and memory is positive. This drug has the effect of enhancing memory and learning ability and can help people better process and cope with the increasing amount of knowledge and information, and improve themselves. academic, career, and living standards. Of course, when using tolcapone, you must also fully understand its scope of application and side effects and do personal management and health monitoring to ensure health and safety. It can be seen that we need to improve memory, and Cistanche deserticola can significantly improve memory, because Cistanche deserticola can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors. These substances are very important for memory and learning. In addition, Cistanche deserticola can also improve blood flow and promote oxygen delivery, which can ensure that the brain receives sufficient nutrients and energy, thereby improving brain vitality and endurance.

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Indeed, upon directly comparing drug effects (drug x decile) between task conditions, we found a difference between CL-S and CF-G (8.7±3.05, z=2.73, p = 0.008, Bonferroni adjusted for 6 tests) but no significant difference between any other two conditions. Importantly, these two trial types are matched on working memory load and differ only in selective gating demands (Chatham et al., 2014). 

Thus, this comparison suggests that tolcapone may have opposing effects on the maintenance of information in WM and the ability to selectively gate information out of WM. Further, the specificity of this finding for the CF-G condition argues against a broader effect of tolcapone on some other, more general factor, such as the speed of motor responding. 

Post-hoc examination of the decile2 x drug effect by condition revealed a pattern consistent with that described above: tolcapone decreased the magnitude of the quadratic trend in the CF-G condition but increased it in the CL-S condition. Though the drug did not significantly change the quadratic trend within any condition (CF-S: -1.07±0.72, z=-1.48, p = 0.14; CF-G: -1.26± 0.66, z=-1.91, p=0.06; CL-S: 0.98±0.60, z=1.64, p=0.10; CL-G: -0.25±0.81, z=-0.31, p=0.75), direct comparison between task conditions again demonstrated a significant difference between CL-S and CF-G (2.24±0.84, z=2.69, p=0.04, Bonferroni adjusted for 6 tests). 

To determine whether the significant drug x decile effect on WM maintenance reflected the function of a more stable underlying neural process (i.e. one on the order of minutes or hours rather than seconds), we took advantage of resting state data obtained from the same participants on tolcapone and placebo. Because resting state data are more likely to reflect an underlying state than a task-specific response, we focused on the overall RT slope (i.e., drug x decile parameter from our model), though we also evaluated the additive, more condition-specific effects of RT slope for the CF-G condition (see Methods). 

Brain areas in the lateral frontal cortex that are sensitive to the level of task abstraction and strongly linked to performance on this task, including the dorsal premotor cortex (PMd) and pre-premotor cortex (pPMd) (Badre & D'Esposito, 2009; Badre et al., 2010; Chatham et al., 2014), were used as seed regions for an individual differences analysis of resting state connectivity.
Notably, when evaluating connectivity between left PMd and the rest of the brain, we found changes in connection strength that correlated with the strength of the effect of tolcapone on overall RT slope within brain areas including the left fusiform cortex, right intraparietal sulcus, and the right lateral prefrontal cortex (Figure 3 and Table 2). 

We also found changes in left PMd <-> right fusiform cortex connectivity that were more specifically correlated with the drug-related change in CF-G behavior (Figure 3, right panel, and Table 2). 

No significant changes in connectivity between our PFC ROIs and the striatum were found for either analysis or the comparable analyses with decile2 parameters. These results were not driven by outliers;tolcapone-induced increases in connectivity values, as shown for right middle intraparietal sulcus (mIPS; overall RT slope) and right fusiform gyrus (Figure 3, bottom; RT slope for the CF-G condition), correlated with tolcapone-induced flattening of RT slope across a broad range of connectivity values. (Data were very similar for the other significant regions listed in Table 2). 

No significant relationships emerged for the right PMd ROI. In a secondary analysis, we also evaluated changes in connectivity between a more anterior prefrontal region linked to performance on this task, the pre-PMd (Chatham et al., 2014), and the rest of the brain. We observed a significant change in connectivity between the left prePMd and bilateral primary somatomotor cortex that tracked the behavioral effect of tolcapone on overall RT slope; connectivity with a subset of left PSMC voxels was also sensitive to the drug-related change in RT slope for the CF-G condition (Figure 4 and Table 3). 

These changes were also not driven by outliers; tolcapone-induced increases in connectivity values between left pre-PMd and left precentral gyrus, as well as the left supplementary motor area (SMA), correlated with tolcapone-induced flattening of overall RT slope across a broad range of connectivity values. (Data were very similar for the other regions in Table 3). In contrast, suprathreshold regions in a connectivity analysis of right pre-PMd were driven by outlier subjects (data not shown) and thus were unrevealing. Lastly, no significant findings were seen for the decile 2 parameters.

Discussion: Here we present convergent evidence that tolcapone significantly improves working memory maintenance without demonstrable effects on gating. Specifically, tolcapone reduces RT slope in a task condition that maximizes maintenance requirements and minimizes selective input and output gating demands (CF-G) but has no statistically significant effect on other task conditions. Moreover, this effect in CF-G is significantly different from the condition that most heavily taxes output gating (CL-S). Across subjects, the degree to which tolcapone reduces overall RT slope (i.e., collapsed across conditions) correlates directly with increases in connectivity between left PMd, a prefrontal region important for linking stimulus with response (Badre & D'Esposito, 2009), and posterior cortical areas previously implicated in visual working memory function, including the intraparietal sulcus and fusiform cortex. 

In complementary fashion, the degree to which tolcapone reduces RT slope across conditions also correlates with increases in connectivity between a prefrontal region important for more abstract task representations, left pre-PMd, and motor areas including the bilateral primary somatomotor cortex. No individual differences in the functional correlations between these cortical regions and the striatum were found to significantly track drug effects on behavior, as might be expected if gating function were affected. 

Together these results substantiate the hypothesis that cortical dopamine preferentially supports working memory maintenance rather than gating processes, consistent with theoretical and empirical accounts of working memory function (Cools & D'Esposito, 2011; D'Esposito & Postle, 2015; Frank & Badre, 2012; Frank & O'Reilly, 2006; M. Wang et al., 2004). As noted above, tolcapone appears to primarily improve the efficiency of maintenance rather than gating. However, the context last (CL) conditions, which preferentially increase demands on output gating, also include a maintenance component and yet did not show any effect of the drug. The most likely explanation has to do with the relative influence of maintenance and gating on overall reaction time. 

On placebo, increased maintenance demands alone, when gating demands are minimal and constant, increase reaction time (as seen in the RT difference between the "context first" conditions, CF-S and CF-G; Table 1). However, stronger gating demands, and specifically output gating demands, drive a significantly larger increase in reaction time (Chatham et al., 2014): both conditions in which the context is presented last (CLS, CL-G) have significantly longer reaction times than either of the context first conditions. 

In addition, the efficiency of output gating directly impacts the motor report used to infer the success of maintenance. Thus, while CL-S and CL-G also have relatively high maintenance requirements, the greater demands on output gating, especially in the selective (CL-S) condition, likely obscure any effects that tolcapone might have on maintenance. As a result, the effect of tolcapone is only significant in the CF-G condition. Alternatively, the tolcapone-induced increase in cortical dopamine tone might actively interfere with the function of the striatally-mediated output gate. 

In this case, the gate would function more inefficiently, and the effects of tolcapone on maintenance may be indistinguishable in these conditions, regardless of other task manipulations. Consistent with this possibility, we show a significant difference between the effects of tolcapone on the CF-G and CL-S conditions, reducing RT slope in the former but relatively increasing it in the latter (Figure 2B and Table 1). Notably, in this task, we do not strongly distinguish between the maintenance of context and the maintenance of content. Previous work has demonstrated that subjects can access the contents of working memory via distinct mechanisms, supporting the differentiation of context from content (Gehring, Bryck, Jonides, Albin, & Badre, 2003). 

Additional experiments have shown that context and content can be accessed relatively independently (Linares & Pelegrina, 2018), or that they may be retrieved together, as composites (Bialkova & Oberauer, 2010). Here, context (the number) is presented explicitly in each trial along with the target/nontarget (letter and/or symbol). Our neural hypothesis – that maintenance operations are based in the cortex – does not directly speak to the context/content distinction. Similarly, our work does not speak to whether tolcapone influences a particular subprocess instantiated during maintenance or the overall maintenance state per se. Future work (e.g. to determine the cortical locus for each of these context and content representations, or to place differential demands on hypothesized maintenance subprocesses) might address to what extent these factors are linked neurally. 

Additionally, complementing differences in the type of maintained information with parametric gating demands – e.g. by increasing variability in the number of items to be selected from working memory – would further clarify how different corticostriatal circuits support working memory function. A second particularity of our results concerns the influence of increased frontal dopamine tone on the RT distribution (slope across deciles), but not the mean RT. Given that the lateral frontal cortex is thought to exert top-down control to maintain stimulus representations within posterior structures (D'Esposito & Postle, 2015; Rose et al., 2016), one potential explanation concerns the efficiency of this control. Because task demands are identical for all CF-G trials, but RTs in the last decile are more than 1.5 times the RTs in the first decile (Figure 2A), something other than external task demands must explain the discrepancy. 

Increased frontal dopamine tone may increase the efficiency of this top-down communication, stabilizing trialwise top-down control and thereby increasing the proportion of trials for which control is optimized. Such a mechanism would reduce the frequency of trials in which top-down communication is inefficient, decreasing the number of RTs at the slower end of the distribution and leading to a decline in RT slope. More generally, previous work suggests that a reduction in intra-individual variability can be linked to the optimization of both frontal and dopaminergic function (MacDonald, Li, & Backman, 2009). 

In a seminal study of patients with brain lesions of various etiologies, Stuss and colleagues demonstrated that lateral frontal lesions increase intra-individual RT variability in a visual shape selection task (Stuss, Murphy, Binns, & Alexander, 2003). Macdonald and colleagues subsequently showed that, in a task pitting number identity against number position, diminished D1 receptor binding in the dorsolateral prefrontal cortex, parietal cortex, and anterior cingulate cortex is likewise associated with increasing intra-individual RT variability for incongruent trials (MacDonald, Karlsson, Rieckmann, Nyberg, & Backman, 2012). 

Perhaps most directly, in a study linking behavior with the function of the COMT gene, Stefanis and colleagues (Stefanis et al., 2005) found that subjects with greater Met loading at the COMT Val158Met polymorphism demonstrated reduced intra-individual RT variability in the identical pairs version of the continuous performance task (CPT). Because the Met allele for this polymorphism reduces the dopamine metabolizing activity of the enzyme, it is thought to increase dopamine tone; thus, COMT inhibition by tolcapone would also be predicted to reduce intraindividual RT variability, as was seen here. 

As demonstrated by the resting state functional MRI data, the behavioral effect of tolcapone, indexed by the model's overall RT slope parameter for each subject, is reflected in connectivity changes within networks that differ across the lateral frontal cortex. Specifically, drug-related changes in functional connectivity between the pMD, implicated in linking stimulus with response, and left fusiform cortex, right IPS, and right inferior frontal gyrus were correlated with changes in overall RT slope, such that greater enhancement of connectivity tracked greater reduction of RT slope by tolcapone. 

The combination of the fusiform cortex and IPS is frequently seen in the context of visual working memory tasks, in which visual association regions (such as the fusiform gyrus) and frontoparietal control regions (including the IPS) are co-active (D'Esposito & Postle, 2015; Xu, 2017). Although consistent, these findings are only suggestive given that a direct link to visual working memory activity is not possible with resting state data (as it would be with task-active fMRI of a working memory task). Caution should thus be used in extrapolating from brain region to cognitive process (Poldrack, 2011). 

Nonetheless, changes induced by dopamine in frontal networks have been well-established in previous resting state data (Dang, O'Neil, & Jagust, 2012; Kahnt & Tobler, 2017; Kelly et al., 2009), and we add to the functional relevance of such changes here. Irrespective of their specific function, however, it is curious that dopaminergic changes in the functional connectivity of a more anterior prefrontal region, pre-PMd, involved brain areas typically associated with motor function – i.e. bilateral primary somatomotor cortex. One might instead expect, given the nature of our task and the observed effect of the drug, that tolcapone would alter the more anterior lateral frontal region's association with those supporting working memory maintenance, and the more posterior lateral frontal region's association with those subserving its motor implementation. A potential explanation is based on the nature of the task itself. 

Task performance across the conditions is not distinguished by more abstract control requirements, but rather by load and gating demands. As a result, working memory demands are instead placed on the particular stimulus (e.g. the letter or the symbol) necessary for the response; the demands placed on more abstract task representations (e.g. of the context, as represented by the number) are consistent across tasks and are necessary only to the extent that they lead to the appropriate motor response. As a caveat, while our primary behavioral result concerns an interaction between drug, decile, and condition, behavioral correlations with resting state fMRI data were primarily driven by the drug x decile parameter, collapsed across conditions. 

Because resting state functional connectivity is more likely to reflect an underlying state or process than a task-specific response, the overall RT slope parameter may better capture changes in this process (e.g. working memory maintenance) because it includes this change across all task conditions, even though the behavioral change only reaches significance for CF-G. That said, we did identify more focused areas of resting state connectivity that significantly correlated with the RT slope effect specific to the CF-G condition, suggesting that condition-specific effects may be present, though perhaps with less power. Future fMRI data obtained during task performance both on and off tolcapone would be better able to address the condition-specific nature of connectivity changes. 

Given that these results demonstrate an effect of tolcapone on working memory maintenance, future work might also focus on complementary drug manipulations that more strongly impact input and output gating. While many mechanisms have been proposed for global gates that can update all items (or no items) to working memory, selective gating, whether at input or output, is thought to benefit most from striatal mechanisms (Chatham & Badre, 2015). As a result, striatally-acting D2 receptor agonists such as bromocriptine or cabergoline, in contrast to tolcapone, would be expected to impact selective input and output gating. 

More speculatively, the different posterior areas demonstrating tolcapone-induced changes in functional connectivity with left PMd and left pre-PMd suggest that disruption of activity in either of these two lateral frontal regions – e.g. by transcranial magnetic stimulation – might differentially diminish cognitive control, and thus task performance. If TMS of left PMd disrupts working memory maintenance, for example, accuracy should decrease in CF-G. On the other hand, if TMS of left pre-PMd disrupts motor activity, accuracy should remain unchanged, while RT should increase across all conditions. Together, an improved understanding of the brain networks responsible for optimizing working memory maintenance and gating may provide a better foundation for understanding their intermittent impairments in both control and patient populations. Figure 1. Task A. In this task, numbers define the context of each trial. 

The numbers 1 and 2 indicate that only the symbols or the letters, respectively, are relevant to the response. These "selective" contexts are differentiated from the "global" context defined by the number 3, which indicates that both symbols and letters are relevant to the response. B-E. All trials conclude with a screen containing two response options, one of which includes the correct item (for the selective contexts) or the correct items (for the global context). In all cases, only one of the two responses is correct, here indicated by the check mark. Importantly, the order of presentation of the three stimuli in each trial can vary. When the number representing the context is presented first (panels B and C), subjects can update working memory with only the relevant item(s), thereby taxing only input gating. 

In contrast, when the context is presented last, subjects must have already gated both memoranda into working memory, placing greater demands on the selection of the relevant output from memory and more strongly taxing output gating. F. The four trial types differ in both the strategy required and the number of encoded stimuli. Our prediction that tolcapone's effect should be most visible in conditions with increased maintenance requirements and decreased gating demands suggests that behavioral effects should be seen most clearly in the CF-G condition (highlighted). Figure 2. Behavior A. 

Collapsed across drug conditions, the raw RTs divided by decile demonstrate differences in both offset and slope for the four task conditions. B. The decline in RT slope on tolcapone versus placebo is evident in the model-free data for CF-G (* p < 0.05). Figure 3. Resting-state fMRI results: left dorsal premotor cortex The strength of connectivity between seed in the left dorsal premotor cortex (L PMd; green region, upper left image) and every voxel in the brain was correlated with the subject-wise estimate of tolcapone's effect on overall RT slope (left panel) or RT slope for the CF-G condition (right panel). Significant regions (p < 0.001, corrected) for the former analysis include the right inferior frontal gyrus (IFG), right middle intraparietal sulcus (IPS), and the left fusiform cortex; for the latter analysis, the right fusiform cortex was found. Representative plots of the data points for two regions, right mIPS, and right fusiform cortex, are shown to demonstrate that outliers do not drive these effects. Figure 4. Resting-state fMRI results: left pre-premotor cortex The strength of connectivity between seed in the left pre-premotor cortex (L pPMd; yellow region, upper left image) and every voxel in the brain was correlated with the subject-wise estimate of tolcapone's effect on overall RT slope. 

Significant regions (p < 0.001, corrected) for the overall effect of RT slope (left panel) include areas extending over the precentral and postcentral gyri bilaterally (primary somatomotor cortex, or PSMC). A subset of the L PSMC voxels was correlated with the RT slope for the CF-G condition. Representative plots of the data points for two regions, right PSMC and left PSMC, are shown to demonstrate that outliers do not drive these effects.

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