Altered prefrontal correlates of monetary anticipation and outcome in chronic pain

Abstract

Chronic pain may alter both affect- and value-related behaviors, which represents a potentially treatable aspect of chronic pain experience. Current understanding of how chronic pain influences the function of brain reward systems, however, is limited. Using a monetary incentive delay task and functional magnetic resonance imaging (fMRI), we measured neural correlates of reward anticipation and outcomes in female participants with the chronic pain condition of fibromyalgia (N = 17) and age-matched, pain-free, female controls (N = 15). We hypothesized that patients would demonstrate lower positive arousal, as well as altered reward anticipation and outcome activity within corticostriatal circuits implicated in reward processing. Patients demonstrated lower arousal ratings as compared with controls, but no group differences were observed for valence, positive arousal, or negative arousal ratings. Group fMRI analyses were conducted to determine predetermined region of interest, nucleus accumbens (NAcc) and medial prefrontal cortex (mPFC), responses to potential gains, potential losses, reward outcomes, and punishment outcomes. Compared with controls, patients demonstrated similar, although slightly reduced, NAcc activity during gain anticipation. Conversely, patients demonstrated dramatically reduced mPFC activity during gain anticipation-possibly related to lower estimated reward probabilities. Further, patients demonstrated normal mPFC activity to reward outcomes, but dramatically heightened mPFC activity to no-loss (nonpunishment) outcomes. In parallel to NAcc and mPFC responses, patients demonstrated slightly reduced activity during reward anticipation in other brain regions, which included the ventral tegmental area, anterior cingulate cortex, and anterior insular cortex. Together, these results implicate altered corticostriatal processing of monetary rewards in chronic pain.

Figure 1. Monetary Incentive Delay Task

Example trials of the monetary incentive delay (MID) task depict both gain and loss, and anticipation and outcome phases. Trial periods were TR-locked so that for each trial TR 1 = Cue (Anticipation), TR 2 = Fixation (Anticipation), TR 3 = Target, TR 4 = Feedback (Outcome), TR(s) 5~7 = Variable Duration Inter-trial Interval. Cues (2 s duration) were circles (potential gains) or squares (potential losses) with monetary values under the shape images. Each fixation period (2 s duration) was followed by a target period (2 s duration) during which a triangle was presented for variable duration (~250 ms) depending on prior accuracy of responses to obtain an average 66% hit rate. Monetary gain or loss values were presented as win/loss feedback (2 s duration) at the end of each trial. Trials were separated by a black screen for a pseudo-randomized inter-trial interval period (2, 4, or 6 s durations).

Figure 2. Ratings of Arousal, Valence, Positive Arousal, Negative Arousal

(A) Across all cues arousal ratings were lower in patients as compared with controls (p = 0.006). Post-hoc t-tests for individual cue between-group differences are marked with asterisks (p<0.05 uncorrected for multiple comparisons). Valence (B), positive arousal (C), and negative arousal (D) ratings were similar in patients and controls. One patient did not provide any ratings, one control subject was missing data for arousal, and a second control subject was missing data for valence; these subjects were excluded from the associated analyses.

Figure 3. Nucleus Accumbens Activity during Reward Anticipation

(A) Bilateral ROI of the NAcc. (B) Raw time course plots of NAcc ROI activity (group means and standard error) to $0 and +$5 anticipation trials. The shaded period of reward anticipation (ant) fMRI BOLD response was estimated to correspond to 4–8 seconds during the raw time course plots [presentation of cue and fixation during TRs 1 and 2 (0–4 seconds) plus 4 seconds to account for hemodynamic response function (HRF) delay]. (C) Contrast (GVNant) beta values extracted from the bilateral ROI for NAcc reward anticipatory activity. (D) Correlation between extracted NAcc GVNant beta values and behavioral drive (BAS drive subscale) for both groups (solid black line) with 95% confidence intervals (gray shading), and correlation in controls only (dashed gray line, confidence intervals not shown). All beta values shown as 10⁻³. BAS, Behavioral Activation System.

Figure 4. Medial Prefrontal Cortex Activity during Reward Anticipation

(A) The bilateral mPFC ROI is shown in red. White boxes denote areas of magnification in sagittal and horizontal planes as depicted in later shown group activation maps. (B) Raw time course plots of the mPFC ROI activity (group means and standard error) to $0 and +$5 anticipation trials. The shaded period of reward anticipation (ant) fMRI BOLD response was estimated to correspond to 4–8 seconds during the raw time course plots [presentation of cue and fixation during TRs 1 and 2 (0–4 seconds) plus 4 seconds to account for hemodynamic response function (HRF) delay]. (C) Contrast (GVNant, +$5 > $0 trials) activation maps of mPFC ROI activity during reward anticipation (p < 0.05, uncorrected). (D) Extracted ROI beta values for mPFC reward anticipatory activity. (E, F, G, H) Correlation between extracted mPFC GVNant beta values and positive affect (PANAS), trait anxiety (STAI Trait), pain severity (BPI), and pain interference (BPI) for both groups (solid black line) with 95% confidence intervals (gray shading). All beta values shown as 10⁻³. PANAS, Positive Affect Negative Affect Schedule; STAI, State-Trait Anxiety Inventory, BPI, Brief Pain Inventory.

Figure 5. Medial Prefrontal Cortex Activity in Response to Reward Gain Outcomes

(A) Raw time course plots of mPFC ROI activity (group means and standard error) split by outcomes (hits or misses) for +$5 anticipation trials. The period of reward outcome (out) fMRI BOLD response is estimated to correspond to 10–14 seconds during the raw time course plots [presentation of outcome and post-outcome during TRs 4 and 5 (6–10 seconds) plus 4 seconds to account for hemodynamic response function (HRF) delay]. (B) Contrast (GVNout) beta values extracted from the ROI for mPFC reward outcome activity.

Figure 6. Medial Prefrontal Cortex Activity in Response to Reward No-Loss Outcomes

(A) Raw time course plots of mPFC ROI activity (group means and standard error) split by outcomes (hits or misses) for −$5 anticipation trials. The period of reward outcome (out) fMRI BOLD response is estimated to correspond to 10–14 seconds during the raw time course plots [presentation of outcome and post-outcome during TRs 4 and 5 (6–10 seconds) plus 4 seconds to account for hemodynamic response function (HRF) delay]. (B) Contrast (NVLout)) activation maps of mPFC ROI during reward outcome (hits versus misses) to −$5 anticipation trials (p < 0.05, uncorrected). (C) Contrast (NVLout) beta values extracted from the ROI for mPFC reward outcome activity. (D, E, F, G) Correlations between mPFC NVLout extracted beta values and trait anxiety (STAI Trait), negative affect (PANAS subscale), mood disturbance (POMS), and fatigue (PROMIS Fatigue) for both groups (solid black lines) with 95% confidence intervals (gray shading), and in patients only (dashed gray line in trait anxiety plot, confidence intervals not shown). All beta values shown as 10⁻³. STAI, State Trait Anxiety Inventory; PANAS, Positive and Negative Affect Schedule; POMS, Profile of Mood States.