Exercising the brain in pain : using fMRI to investigate intrinsic connectivity, cognition and pain regulation in fibromyalgia and how this is affected by physical exercise

The aims of the studies of this thesis were to use functional magnetic resonance imaging (fMRI) to investigate cerebral activation patterns in fibromyalgia (FM) patients and healthy controls (HC) at rest, when performing the stroop colour word test (SCWT) and during pressure pain provocation. Distraction induced analgesia (DIA), performance on the SCWT and pressure pain sensitivity was investigated on the behavioural and psychophysical level. Lastly studies III and IV investigated the effects of a 15-week resistance exercise training intervention on SCWT and pain processing.

The main finding in study I was that FM was associated with decreased connectivity between pain related and sensorimotor brain areas, more specifically between insula and primary sensorimotor areas (S1/M1). Furthermore increased pain sensitivity in both groups correlated to increased connectivity between the insula and thalamus with the default mode network (DMN).

Study II utilised the SCWT were participants are given colour words written in either congruent or incongruent colours. To induce DIA, participants were given two versions of the test, one with congruent words and one with incongruent words, this in order to investigate the impact of cognitive load on pain perception. In the scanner, the stimuli were mixed and presented in an eventrelated fMRI paradigm. The study revealed that DIA functioned the same in FM as it did in HC, and analgesia was not dependant on cognitive load. Performance on the SCWT showed that both groups were slower on the more cognitively demanding task, but interference disrupted performance more in the FM group than in the HC. The fMRI results yielded less activation of the caudate nucleus and hippocampus during SCWT in FM patients. These regions are implicated in learning and reward, suggesting that impaired learning mechanisms can contribute to the cognitive dysfunction often reported by FM patients.

In study III, the SCWT assessments were repeated following the physical exercise intervention. Performance on the SCWT was improved in both groups, in the HC speed of processing had improved significantly, but a specific improvement of cognitive ability was only found in the FM patients. The latter was accompanied by an increased activation of the amygdala following the intervention in the FM group. Regarding DIA, no effects of exercise were found.

Lastly, in study IV fMRI was used to assess pressure pain processing in FM patients and HC before and following the exercise intervention. FM patients were more pain sensitive than HC at both times, but following the intervention pressure pain sensitivity was significantly reduced in the FM group. We found no evidence that the exercise intervention had an effect on cerebral processing of evoked pain in either group. Our data suggest that the reduced pain sensitivity following exercise in FM patients was caused by peripheral mechanisms.

Taken together the results of the four studies all demonstrated aberrations in cerebral activation in FM patients compared to controls, as well as poorer cognitive performance and increased pain sensitivity. However, interestingly, normal function of DIA was found in FM patients. Studies three and four showed that physical exercise was beneficial to FM patients, both regarding cognitive ability and by reducing pain sensitivity.

List of scientific papers

I. Flodin P,. Martinsen S., Löfgren M., Bileviciute-Ljungar I., Kosek E., & Fransson P. (2014). Fibromyalgia Is Associated with Decreased Connectivity Between Pain- and Sensorimotor Brain Areas. Brain Connectivity, 4 (8), 587-594
https://doi.org/10.1089/brain.2014.0274

II. Martinsen S., Flodin P,. Berrebi J., Löfgren M., Bileviciute-Ljungar I., Ingvar M., Fransson P., & Kosek E. (2014). Fibromyalgia Patients Had Normal Distraction Related Pain Inhibition but Cognitive Impairment Reflected in Caudate Nucleus and Hippocampus during the Stroop Color Word Test. PLoS One, 9 (10)
https://doi.org/10.1371/journal.pone.0108637

III. Martinsen S., Flodin P,. Berrebi J., Löfgren M., Bileviciute-Ljungar I., Mannerkorpi, K., Ingvar M., Fransson P., & Kosek E. The role of long-term physical exercise on performance and cortical activation during the Stroop Color Word Task in Fibromyalgia patients. [Manuscript]

IV. Martinsen S., Flodin P,.Löfgren M., Bileviciute-Ljungar I., Mannerkorpi, K., Ingvar M., Fransson P., & Kosek E. Exercise reduces pain sensitivity but does not lead to altered pain related cerebral activation in fibromyalgia patients. [Manuscript]