Chronic pain and the emotional brain: specific brain activity associated with spontaneous fluctuations of intensity of chronic back pain

Abstract

Living with unrelenting pain (chronic pain) is maladaptive and is thought to be associated with physiological and psychological modifications, yet there is a lack of knowledge regarding brain elements involved in such conditions. Here, we identify brain regions involved in spontaneous pain of chronic back pain (CBP) in two separate groups of patients (n = 13 and n = 11), and contrast brain activity between spontaneous pain and thermal pain (CBP and healthy subjects, n = 11 each). Continuous ratings of fluctuations of spontaneous pain during functional magnetic resonance imaging were separated into two components: high sustained pain and increasing pain. Sustained high pain of CBP resulted in increased activity in the medial prefrontal cortex (mPFC; including rostral anterior cingulate). This mPFC activity was strongly related to intensity of CBP, and the region is known to be involved in negative emotions, response conflict, and detection of unfavorable outcomes, especially in relation to the self. In contrast, the increasing phase of CBP transiently activated brain regions commonly observed for acute pain, best exemplified by the insula, which tightly reflected duration of CBP. When spontaneous pain of CBP was contrasted to thermal stimulation, we observe a double-dissociation between mPFC and insula with the former correlating only to intensity of spontaneous pain and the latter correlating only to pain intensity for thermal stimulation. These findings suggest that subjective spontaneous pain of CBP involves specific spatiotemporal neuronal mechanisms, distinct from those observed for acute experimental pain, implicating a salient role for emotional brain concerning the self.

Figure 1.

Ratings of fluctuations of spontaneous pain of CBP can be parceled into distinct phases, and each phase has a different time length distribution. A, Top, Example rating of spontaneous fluctuations of pain in one CBP patient. The bottom panel shows two vectors derived from such ratings to search for brain activity BOLD signal. The first vector (blue) corresponds to time periods when the subjective rating (experience) of spontaneous pain intensity is high. It is the binarized high–low pain rating, relative to mean pain. The second vector (red) corresponds to time periods where ratings are rapidly increasing, which may correspond to increased nociceptive input to the brain. The right inset shows relationships between the three time-curves at a higher time resolution. B, The length of the two vectors exhibit different distributions across all 13 CBP patients. The left panel is for time periods when spontaneous pain is high (n = 161 events; mean, 22.5 s; mode, 10.5 s; SD, 22.1 s), and the right panel is for time periods when spontaneous pain is increasing (n = 866 events; mean, 5.3 s; mode, 3.5 s; SD, 3.1 s).

Figure 2.

Brain activity for spontaneous CBP shows two distinct patterns: one for phases identified as high pain and another for increasing pain phases. A, Random-effects average brain activity in CBP patients for time periods in which spontaneous pain is high. Activity is limited mainly to the mPFC and rACC. B, Fixed-effects analysis yields additional activations bilaterally in posterior thalamus, amygdala, and ventral striatum (VS). C, BOLD response for peak activations in rACC (10, 22, 28) and mPFC (18, 60, 12) for periods when spontaneous pain is high. Across-subject mean and SEMs are shown. D, Random-effects analysis for periods when spontaneous pain is increasing. Brain activity does not overlap with A and is primarily located in right anterior insula, mACC, and supplementary motor area (SMA), left primary somatosensory (S1), and motor (M1) regions, right secondary somatosensory cortex (S2), and cerebellum. Fixed-effect analysis did not reveal additional brain activity (data not shown). E, BOLD response for peak activations in the mACC (0, 3, 46), right insula (54, 16, −4) and right S2 (46, −20, 28) for time period when spontaneous pain is increasing. Across-subject mean and SEMs are shown. A complete list of activations is found in supplemental tables 2 and 3, available at www.jneurosci.org as supplemental material. Activity maps are presented in MNI space, x, y, and z coordinates in millimeters.

Figure 3.

Intensity and duration of CBP are correlated with distinct brain areas and for different phases of spontaneous fluctuations of CBP. A, Covariate analysis between pain intensity (mean rating of pain during scan) and brain activity for phases when spontaneous pain is high results in a single cluster in mPFC, maximum across-subject correlation is at (−36, 44, 18) (R² = 0.81; p < 0.01). B, Covariate analysis between pain duration (in years) and brain activity for phases when spontaneous pain is increasing results in right anterior insular cluster, with maximum correlation at (58, 8, −2) (R² = 0.80; p < 0.01). C, Time courses for peak activations in mPFC (red) and insula (black) for periods when spontaneous pain is high (left) and when spontaneous pain is increasing (right). Across-subject mean and SEMs are shown. Activity maps are presented in MNI space, x, y, and z coordinates in millimeters.

Figure 4.

Activity in right and left DLPFC locations with peak atrophy in CBP (Apkarian et al., 2004b), during high pain, show an inverse relationship between mPFC but not with insula. A, Across-subject correlations between brain activity for right and left DLPFC locations with peak atrophy in CBP are negatively correlated with mPFC activity (p < 0.01), and uncorrelated to insula activity (p > 0.64), for periods when spontaneous pain is high. B, BOLD responses show early transient DLPFC activity, which become deactivated in the period in which mPFC activity increases. Across-subject mean and SEMs are shown. C, Brain regions and correlations are depicted on the brain. Note that these relations are only true during high pain phase. All four areas are significantly positively correlated with each other during increasing phase of spontaneous CBP.

Figure 5.

Brain activity for spontaneous pain of CBP does not show any overlap with that of thermal pain in CBP and healthy normal subjects. A, Average pain ratings for thermal stimulus applied to the back in CBP patients (n = 11) and matched normal controls (n = 11). There is no significant difference in pain ratings between the two groups. Bottom shows temperature profile of the stimulus applied to the back. B, Random-effects average brain activity for high pain of spontaneous CBP includes mPFC and rostral parts of the anterior cingulate. It is similar to the brain activity pattern observed for spontaneous pain in study 1 (compare Fig. 1A) and does not encompass brain areas activated for noxious heat in CBP (middle) and matched healthy controls (right). C, Similar brain activity patterns are seen for noxious heat applied to the back in CBP (orange) and in healthy normal subjects (blue). It includes the bilateral insular cortex, medial ACC, and supplementary motor areas, in addition to cerebellum and somatosensory regions. Activity maps are presented in MNI space, x, y, and z coordinates in millimeters. Detailed activity maps for B and complete lists of activated areas are found in supplemental Figure 1 and Table 4, available at www.jneurosci.org as supplemental material.

Figure 6.

Pain intensity for spontaneous CBP and thermal pain are encoded in different brain regions. A, Pain intensity for spontaneous pain of CBP (mean rating of pain during scan) exhibits a significant positive correlation with mPFC activity (p < 0.001, replicating the result shown in Fig. 3A) and is uncorrelated with insular activity. B, Pain intensity for thermal pain in both CBP patients and normal subjects is best correlated with insular activity (p < 0.01) and shows no correlation with mPFC activity (x, y, and z coordinates in millimeters).