Catecholaminergic neuromodulation and selective attention jointly shape perceptual decision making

Reviewer #1 (Public Review):

The authors aimed to contrast the effects of pharmacologically enhanced catecholamine and acetylcholine levels versus the effects of voluntary spatial attention on decision making in a standard spatial cueing paradigm. Meticulously reported, the authors show that atomoxetine, a norepinephrine reuptake inhibitor, and cue validity both enhance model-based evidence accumulation rate, but have several distinct effects on EEG signatures of pre-stimulus cortical excitability, evoked sensory EEG potentials and perceptual evidence accumulation. The results are based on a reasonable sample size (N=28) and state-of-the art modeling and EEG methods.

Although the authors draw a few partial conclusions that are not fully supported by the data (see below), I think that the authors' EEG findings provide sufficient support for the overall conclusion that "selective attention and neuromodulatory systems shape perception largely independently and in qualitatively different ways". This is an important conclusion because neuromodulatory systems and selective spatial attention are both known to regulate the neural gain of task-relevant single neurons and neural networks. Apparently, these effects on neural gain affect decision making in dissociable ways.

The effects of donepezil, a cholinesterase inhibitor, were generally less strong than those of atomoxetine, and in various analyses went in the opposite direction. The authors fairly conclude that more work is necessary to determine the effects of cholinergic neuromodulation on perceptual decision making.

1. I believe that the following partial conclusions are not fully supported by the data:

a) In the results section on page 6, the authors conclude that "Attention and ATX both enhanced the rate of evidence accumulation towards a decision threshold, whereas cholinergic effects were negligible." I believe "negligible" is wrong here: the corresponding effects of donepezil had p-values of .09 (effect of donepezil on drift rate), .07 (effect of donepezil on the cue validity effect on drift rate) and .09 (effect of donepezil on non-decision time), and were all in the same direction as the effects of atomoxetine, and would presumably have been significant with a somewhat larger sample size. I would say the effects of donepezil were "in the same direction but less robust" (or at the very least "less robust") instead of "negligible".

b) "In the results section on page 8, the authors conclude that "Summarizing, we show that drug condition and cue validity both affect the CPP, but they do so by affecting different features of this component (i.e. peak amplitude and slope, respectively)."
This conclusion is a bit problematic for two reasons. First, drug condition had a significant effect not only on peak amplitude but also on slope. Second, cue validity had a significant effect not only on slope but also on peak amplitude. It may well be that some effects were more significant than others, but I think this does not warrant the authors' conclusion.

c) In the discussion section on page 11, the authors conclude that "First, although both attention and catecholaminergic enhancement affected centro-parietal decision signals in the EEG related to evidence accumulation (O'Connell et al., 2012; Twomey et al., 2015), attention mainly affected the build-up rate (slope) whereas ATX increased the amplitude of the CPP component (Figure 3D-F)."
As I wrote above, I believe it is not correct that "attention mainly affected the build-up rate or slope", given that the effect of cue-validity on CPP slope was also significant. Also, while the authors' data do support the conclusion that ATX increased the amplitude and not the slope of the CPP component, a previous study in humans found the opposite: ATX increased the slope but did not affect the peak amplitude of the CPP (Loughnane et al 2019, JoCN, https://pubmed.ncbi.nlm.nih.gov/30883291/). Although the authors cite this study (as from 2018 instead of 2019), they do not draw attention to this important discrepancy between the two studies. I encourage the authors to dedicate some discussion to these conflicting findings.

1. On page 12 and page 14 the authors suggest a selective effect of ATX on *tonic* catecholamine activity, but to my knowledge the exact effects of ATX on phasic vs. tonic catecholamine activity are unknown. Although microdialysis studies have shown that a single dose of atomoxetine increases catecholamine concentrations in rodents, it is unknown whether this reflects an increase in tonic and/or phasic activity, due to the limited temporal resolution of microanalysis. Thus, atomoxetine may affect tonic and/or phasic catecholamine activity, and which of these two effects dominates is still unknown, I think.

Reviewer #2 (Public Review):

The authors attempt to show distinct contributions of selective attention and neuromodulators (both cholinergic and catecholaminergic) during a spatial attention task. To do this, they had participants perform a Posner cueing task using random dot motion stimuli, with a typical 80/20 split of valid to invalidly cued trials. In addition, they designed a within-subjects paradigm wherein participants took placebo (PLA), Donepezil (DNP), or Atomoxetine (ATX). Both behaviour and EEG measures were taken in order to investigate the interaction or lack thereof of Drug and Cue factors with respect to these measures, and relative timing of EEG differences to derive potential neuromechanistic similarities/differences. In this context, an interaction of Drug and Cue factors (e.g. faster valid vs invalid RTs in ATX vs PLA) might indicate a role of that neuromodulator in the mechanisms of spatial attention. This is in fact not what they found, rather most findings pointed towards a lack of interaction of Drug and Cue, hence the central thesis of the paper of distinct contributions of neuromodulator and selective attention.

Strengths:
- The experimental design is well done, especially the blinding of the drug taken in each session. However, it is an important caveat to any results that participants were obviously aware they had taken an active drug in ATX condition (Supp Info).
- The analyses are in general quite solidly performed, with most analysis choices relating to behaviour and EEG making sense, albeit with exceptions below.
- The research question and how it relates to the experiment is very interesting, and the question worthy of consideration.

Weaknesses:
- The main weakness of the paper lies in the strength of evidence provided, and how the results tally with each other. To begin with, there are a lot of significance tests performed here, increasing the chances of false positives. Multiple comparison testing is only performed across time in the EEG results, and not across post-hoc comparisons throughout the paper. In and of itself, it does not invalidate any result per se, but it does colour the interpretation of any results of weak significance, of which there are quite a few. For example, the effect of Drug on d' and subsequent post-hoc comparisons, also effect of ATX on CPP amplitude and others.
- The lack of an overall RT effect of Drug leaves any DDM result a little underwhelming. How do these results tally? One potential avenue for lack of RT effect in ATX condition is increased drift rate but also increased non-decision time, working against each other. However, it may be difficult to validate these results theoretically.
- There is an interaction between ATX and Cue in terms of drift rate, this goes against the main thesis of the paper of distinct and non-interacting contributions of neuromodulators and attention. This finding is then ignored. There is also a greater EDAN later for ATX compared to PLA later in the results, which would also indicate interaction of neuromodulators and attention but this is also somewhat ignored.
- The CPP results are somewhat unclear. Although there is an effect of ATX on drift rate algorithmically, there is no effect of ATX on CPP slope. On the other hand, even though there is no effect of DNP on drift rate, there is an effect of DNP on CPP slope. Perhaps one may say that the effect of DNP on drift rate trended towards significance, but overall the combination of effects here is a little unconvincing. In addition, there is an effect of ATX on CPP amplitude, but how does this tally with behaviour? Would you expect greater CPP amplitude to lead to faster or slower RTs? The authors do recognise this discrepancy in the Discussion, but discount it by saying the relationship between algorithmic and CPP parameters in terms of DDM is unclear, which undermines the reasoning behind the CPP analyses (and especially the one correlating CPP slope with DDM drift rate).
- The posterior component effects are problematic. The main issue is the lack of clarification of and justification for the choice of posterior component. The analysis is introduced in the context of the target selection signal the N2pc/N2c, but the component which follows is defined relative to Cue, albeit post-target. Thus this analysis tells us the effect of Cue on early posterior (possibly) visual ERP components, but it is not related to target selection as it is pooled across target/distractor. Even if we ignore this, the results themselves wrt Drug lack context. There is a trending lower amplitude for ATX at later latencies at temporo-parietal electrodes, and more positive for DNP, relative to PLA. Is this what one would expect given behaviour? This is where the issue of correct component identification becomes critical in order to inform any priors on expected ERP results given behaviour.

Given the issues above; mainly a) weak statistical evidence, b) contradictory behavioural and EEG evidence, and c) lack of theoretical background to inform priors on what to expect from the EEG results in order to develop a coherent narrative, I would say that what remains is moderate/incomplete evidence towards the thesis of the paper. This work is however a very fruitful effort at approaching the research question as to whether there is an interaction of neuromodulators and spatial attention. I commend the authors on a transparent and rigorous analysis of the current data.