Unlearning chronic pain: A randomized controlled trial to investigate changes in intrinsic brain connectivity following Cognitive Behavioral Therapy

Abstract

Chronic pain is a complex physiological and psychological phenomenon. Implicit learning mechanisms contribute to the development of chronic pain and to persistent changes in the central nervous system. We hypothesized that these central abnormalities can be remedied with Cognitive Behavioral Therapy (CBT). Specifically, since regions of the anterior Default Mode Network (DMN) are centrally involved in emotional regulation via connections with limbic regions, such as the amygdala, remediation of maladaptive behavioral and cognitive patterns as a result of CBT for chronic pain would manifest itself as a change in the intrinsic functional connectivity (iFC) between these prefrontal and limbic regions. Resting-state functional neuroimaging was performed in patients with chronic pain before and after 11-week CBT (n = 19), as well as a matched (ages 19-59, both sexes) active control group of patients who received educational materials (n = 19). Participants were randomized prior to the intervention. To investigate the differential impact of treatment on intrinsic functional connectivity (iFC), we compared pre-post differences in iFC between groups. In addition, we performed exploratory whole brain analyses of changes in fractional amplitude of low frequency fluctuations (fALFF). The course of CBT led to significant improvements in clinical measures of pain and self-efficacy for coping with chronic pain. Significant group differences in pre-post changes in both iFC and fALFF were correlated with clinical outcomes. Compared to control patients, iFC between the anterior DMN and the amygdala/periaqueductal gray decreased following CBT, whereas iFC between the basal ganglia network and the right secondary somatosensory cortex increased following CBT. CBT patients also had increased post-therapy fALFF in the bilateral posterior cingulate and the cerebellum. By delineating neuroplasticity associated with CBT-related improvements, these results add to mounting evidence that CBT is a valuable treatment option for chronic pain.

Keywords: CBT; Chronic pain; Default Mode Network; Functional MRI; Functional connectivity.

Fig. 1

Probabailistic independent component analysis. ICA of the entire dataset resulted in a) four Default Mode Networks (DMNs), including anterior DMN (IC7); all ICs are overlaid onto the MNI template at z = 34; b) two salience networks; and c) a single basal ganglia (BG) network. The blue color bar represents the z statistic thresholded at P > 0.5 following alternative hypothesis testing (indicating that the probability of being active exceeds the probability of being noise). All images are displayed in radiological coordinates with left on the right side.

Fig. 2

Decreased connectivity between aDMN and left amygdala and periaqueductal gray after CBT. a) Dual regression of the aDMN network revealed lower connectivity to the left amygdala (L Amg) and periaqueductal gray (PAG) after CBT shown in red (the color bar represents the corrected P value following RANDOMISE and TFCE). Regions of the aDMN are in blue (posterior cingulate cortex, PCC; bilateral hippocampus; and bilateral orbitofrontal cortex, OFC); the blue color bar represents the z statistic thresholded at P > 0.5 for alternative hypothesis testing (indicating that the probability of being active exceeds the probability of being noise).b) The decreased connectivity between aDMN and L Amg correlated with increased Self-Efficacy for Coping with Symptoms; and c) decreased connectivity between aDMN and PAG correlated with increased Self-Efficacy for Pain Management. Panels b and c depict regression lines (blue) as well as individual data points; the CBT group is pink and the EDU group is blue. All images are displayed in radiological coordinates with left on the right side.

Fig. 3

Increased connectivity between basal ganglia and right secondary somatosensory cortex after CBT. a) Dual regression of the basal ganglia (BG) network revealed higher connectivity to the right secondary somatosensory cortex (R S2) after CBT in green (the color bar represents the corrected P value following RANDOMISE and TFCE). Regions of the BG are in blue (nucleus accumbens, NAcc, and putamen); b) the increased connectivity between BG and R S2 correlated with decreased Pain Symptoms; and c) the increased connectivity between BG and R S2 correlated with increased Self-Efficacy for Pain Management. Panels b and c depict regression lines (blue) as well as individual data points; the CBT group is pink and the EDU group is blue. All images are displayed in radiological coordinates with left on the right side.

Fig. 4

Increased fALFF in the cerebellum and the posterior cingulate cortex as well as increased connectivity between the two regions following CBT. a) Whole brain analysis of changes in regional fALFF revealed increased fluctuations in the cerebellum and the posterior cingulate cortex (PCC) (see left panel in blue). When the peak of the cerebellar cluster was used as a seed for connectivity analysis, there was higher connectivity to the PCC after CBT (right panel in red-yellow). Maps are a result of exploratory OLS analysis, cluster corrected for multiple comparisons at P < 0.05. b) The increased fALFF in the cerebellum correlated with increased Self-Efficacy for Pain Management. c) The increased fALFF in the cerebellum also correlated with decreased Total Pain Experience. Panels b and c depict regression lines (blue) as well as individual data points; the CBT group is pink and the EDU group is blue. All images are displayed in radiological coordinates with left on the right side.