Reward cues readily direct monkeys' auditory performance resulting in broad auditory cortex modulation and interaction with sites along cholinergic and dopaminergic pathways

Abstract

In natural settings, the prospect of reward often influences the focus of our attention, but how cognitive and motivational systems influence sensory cortex is not well understood. Also, challenges in training nonhuman animals on cognitive tasks complicate cross-species comparisons and interpreting results on the neurobiological bases of cognition. Incentivized attention tasks could expedite training and evaluate the impact of attention on sensory cortex. Here we develop an Incentivized Attention Paradigm (IAP) and use it to show that macaque monkeys readily learn to use auditory or visual reward cues, drastically influencing their performance within a simple auditory task. Next, this paradigm was used with functional neuroimaging to measure activation modulation in the monkey auditory cortex. The results show modulation of extensive auditory cortical regions throughout primary and non-primary regions, which although a hallmark of attentional modulation in human auditory cortex, has not been studied or observed as broadly in prior data from nonhuman animals. Psycho-physiological interactions were identified between the observed auditory cortex effects and regions including basal forebrain sites along acetylcholinergic and dopaminergic pathways. The findings reveal the impact and regional interactions in the primate brain during an incentivized attention engaging auditory task.

Figure 1

Auditory task with high or low reward auditory or visual cues: Incentivized Attention Paradigm (IAP). In all conditions, monkeys were required to withhold a response through a wait signal and to respond to an auditory go signal in order to receive a juice reward. In HiRe trials, a large reward (1 ml) was delivered immediately after a correct response. In LoRe trials, a small reward (0.1 ml) was delivered after a 7 s delay. In addition, visual feedback (green or red screen for correct or incorrect responses, respectively) was provided. (A) Four exemplary trials in auditory reward cue experiments (AudCue1 and AudCue2). If the monkey responded to the auditory go signal within a response window of 200–1300 ms in a HiRe trial, then a big juice reward was immediately delivered and the screen turned green. During LoRe trials, a correct response was associated with a delayed small reward and green screen. Note that the LoRe cue was presented until the reward was delivered. A response before the response window (early response) resulted in a red screen and trial termination. A red screen was also shown if the monkey did not respond before the end of the response window (miss). (B) Four exemplary trials in the fMRI experiment with visual reward cues and an auditory wait signal. See text and Table 1 for details.

Figure 2

Performance in the AudCue behavioral experiments. Performance in AudCue1(top) and AudCue2 (bottom). The two leftmost box plots show mean hit rate across each run in the three monkeys for HiRe (blue) and LoRe (gray) trials. The other box plots show the early response rate, miss rate and reaction times (RT) correspondingly. The scale for RT is on the right side. Note that responses were classified as hit, early response or miss (i.e. in each run, HR + ER + MR = 1). Asterisks indicate significant differences between HiRe and LoRe trials [i.e. main effect of reward, *P < 0.05, **P < 0.01 and ***P < 0.001; AudCue: linear mixed model with factors reward (HiRe, LoRe), monkey (M1, M2, M3) and experiment (Audcue1, Audcue2)]. See results and Table 2 for details. The whiskers indicate 1.5 times the interquartile range (IQR) from the first and third quartile. The horizontal line inside the box indicates the sample median. Note that the significance values are for the repeated measures factor (reward cue), thus, for example, the variation in the difference score between HiRe and LoRe RT’s is smaller than one would expect from the box blots.

Figure 3

Performance in the VisCue behavioral experiment. Asterisks indicate significant differences between HiRe and LoRe trials [main effect of reward, *P < 0.05, **P < 0.01 and ***P < 0.001; linear mixed model with factors reward (HiRe, LoRe) and monkey (M1, M2)]. For details see results and Table 2.

Figure 4

Temporal profile of the reward related performance effects. Dashed lines indicate the end of a daily session. Miss rate (MR) during the first 15 runs separately for each monkey with (top) auditory cues (M1, M2: AudCue1; M3: AudCue2) and (bottom) visual cues (see text for details). Error-bars indicate SEM.

Figure 5

Performance during fMRI. Results are illustrated for fMRI_HIGH (Top) and in fMRI_Low (bottom). HiRe trials are depicted in blue, LoRe in gray and NoCue in light gray. Asterisks indicate significant differences between HiRe and LoRe trials (main effect of reward, *P < 0.05, **P < 0.01 and ***P < 0.001; linear mixed model with factors reward (HiRe, LoRe), monkey (M1, M2), and auditory wait signal (fMRI_HIGH, fMRI_LOW)]. For details see text and Table 3.

Figure 6

Brain areas showing stronger activation during HiRe than LoRe trials. Results are shown on inflated cortical surfaces (gyri: light gray; sulci: dark gray). The comparisons (Welch’s v test) were performed in surface space across 1^st level contrast parameter estimates and permutation inference was used to assess statistical significance (red clusters; HiRe vs. baseline and LoRe vs. baseline contrast parameter estimates, the runs of each monkey were treated as a permutation and variance group to accommodate heteroscedasticity, initial cluster-forming Z threshold 2.6, cluster-corrected P < 0.05). Note that the same P-value is attributed to the whole cluster in the PALM analysis, so differential P-value responses mapped to the brain should not be expected. Abbreviations: D dorsal, V ventral, A anterior, P posterior.

Figure 7

Region-of-interest (ROI) analysis of activation differences between HiRe and LoRe trials in monkey STG. The box plots show mean signal magnitudes (two monkeys) in each anatomically-defined STG ROI. To remove outliers, the central 85% of values were included in each case leaving 15–30 runs for M1 and 15–30 runs for M2, depending on the response measure in question. Asterisks indicate significant pair-wise tests comparing signal magnitude between HiRe and LoRe trials in each ROI (permutation-based significance testing using Welch’s v tests, two-sided, 10 000 permutations, FWER corrected across all pair-wise comparisons, *P < 0.05, **P < 0.01 and ***P < 0.001). Note that each test compared activation across HiRe and LoRe trials with identical auditory stimuli and motor responses. The inserts at top show the location of the ROIs. The difference between HiRe and LoRe trials was significant only during the hit and early response trials and the effects were most consistent in the posterior and middle parts of STG.

Figure 8

Brain areas showing significant psycho-physiological interactions (PPI) with the primary auditory cortex (A1, R and RT). These PPIs were analyzed by calculating the interaction between the difference between HiRe and LoRe hit and early response trials and the timeseries of the auditory cortical regions (see Methods). The analysis was performed across 1^st level contrast parameter estimates using permutation inference (10 000 permutations, the runs of each monkey were treated as a permutation and variance group to accommodate heteroscedasticity, initial cluster-forming Z threshold 2.6, cluster-corrected P < 0.05). The results (red clusters) are shown on inflated cortical surfaces (gyri: light gray; sulci: dark gray). We also show three coronal slices registered to a macaque standard brain in stereotactic coordinates. Dashed lines on the lateral surfaces indicate the approximate position of the coronal slices in the brain. Abbreviations: D dorsal, V ventral, A anterior, P posterior, NB nucleus basalis, NA nucleus accumbens.