Association of major depressive disorder with altered functional brain response during anticipation and processing of heat pain

Abstract

Context: Chronic pain and depression are highly comorbid conditions, yet little is known about the neurobiological basis of pain processing in major depressive disorder (MDD).

Objective: To examine the neural substrates underlying anticipation and processing of heat pain in a group of unmedicated young adults with current MDD.

Design: Functional magnetic resonance neuroimaging data were collected during an event-related factorial experimental pain paradigm. Painful and nonpainful heat stimuli were applied to the left volar forearm while different color shapes explicitly signaled the intensity of the upcoming stimulus.

Setting: University brain imaging center. Patients Fifteen (12 female) young adults with current MDD and 15 (10 female) healthy subjects with no history of MDD were recruited and matched for age and level of education. The Structured Clinical Interview for DSM-IV was administered to all participants by a board-certified psychiatrist. Main Outcome Measure Between-group differences in blood oxygen level-dependent functional magnetic resonance neuroimaging signal change to anticipation and processing of painful vs nonpainful temperature stimuli.

Results: Subjects with MDD compared with healthy controls showed (1) increased activation in the right anterior insular region, dorsal anterior cingulate, and right amygdala during anticipation of painful relative to nonpainful stimuli, (2) increased activation in the right amygdala and decreased activation in periaqueductal gray matter and the rostral anterior cingulate and prefrontal cortices during painful stimulation relative to nonpainful stimulation, and (3) greater activation in the right amygdala during anticipation of pain, which was associated with greater levels of perceived helplessness.

Conclusions: These findings suggest that increased emotional reactivity during the anticipation of heat pain may lead to an impaired ability to modulate pain experience in MDD. Future studies should examine the degree to which altered functional brain response during anticipatory processing affects the ability to modulate negative affective states in MDD, which is a core characteristic of this disorder.

Figure 1. Experimental Paradigm

All subjects completed the paradigm in the scanner. In order to ensure similar engagement between the groups, subjects were asked to engage in the continuous performance task (CPT) [circle - LEFT, square - RIGHT button, 1 trial / 2 secs]. The stimuli change color (red - anticipate pain, green - anticipate warmth, 4-8 seconds) for the anticipation condition. The stimulus condition consists of a hot-painful or warm-non-painful stimulus for 5 seconds. The four experimental conditions are: A. Painful heat stimulus is given during CPT; B. Painful heat stimulus is given alone; C. Non-painful warm stimulus is given during CPT; D. Non-painful warm stimulus is given alone. There are two regressors of interest for each task condition (anticipation: A1, B1, C1, D1) and (stimulus: A2, B2, C2, D2). Two linear contrasts of interest were obtained: [(A1+B1)-(C1+D1)] to examine group differences during pain anticipation; and [(A2+B2)-(C2+D2)] to examine group differences during painful stimulation.

Figure 2. Average Post-Scan Subjects’ Ratings of Temperature Stimuli

Subjects reported the average intensity and unpleasantness of non-painful heat and non-painful warm stimuli following each functional run to ensure similar perceptual ratings between the groups. The intensity of painful and non-painful temperatures was rated on two separate 11-point Likert scales (see Methods). No significant group differences in the subjective ratings of painful heat intensity, painful heat unpleasantness, and non-painful warm intensity were observed (p’s > 0.2). MDD subjects reported higher unpleasantness ratings to non-painful warm stimuli (p=0.03).

Figure 3. Significant Group Differences during Anticipation (A) and Stimulation (B) Periods

Bar graphs show % BOLD changes for the (Painful Heat - Non-painful warmth) contrast for MDD and CON groups. C.f. Table 2 for details. Images are shown in neurological orientation. dACC- dorsal anterior cingulate cortex, R. AI - right anterior insular region, DLPFC - dorso-lateral prefrontal cortex, PAG - periaqueductal grey

Figure 4. Brain-behavior Correlations

A) Right amygdala showed significantly higher BOLD signal change in MDD versus CON individuals during pain anticipation (c.f. Table 2 for details). Extracted % signal changes within amygdala showed significant positive correlation with helplessness scores in MDD subjects during pain anticipation (r = 0.65, p <0.05), which was specific to this disorder; B) Right dorso-lateral prefrontal cortex (DLPFC) showed lower BOLD signal change in MDD versus CON individuals during pain experience (c.f. Table 2 for details). Extracted % signal change within right DLPFC showed significant negative correlation with post-scan subjects’ ratings of pain intensity in MDD, CON and in the combined group (r’s>0.5, p’s<0.05).