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

Evidence for Thalamic Involvement in the Thermal Grill Illusion: An fMRI Study

Perceptual illusions play an important role in untangling neural mechanisms underlying conscious phenomena. The thermal grill illusion (TGI) has been suggested as a promising model for exploring percepts involved in neuropathic pain, such as cold-allodynia (pain arising from contact with innocuous cold). The TGI is an unpleasant/painful sensation from touching juxtapositioned bars of cold and warm innocuous temperatures.To develop an MRI-compatible TGI-unit and explore the supraspinal correlates of the illusion, using fMRI, in a group of healthy volunteers.We constructed a TGI-thermode allowing the rapid presentation of warm(41°C), cold(18°C) and interleaved(41°C+18°C = TGI) temperatures in an fMRI-environment. Twenty volunteers were tested. The affective-motivational (“unpleasantness”) and sensory-disciminatory (“pain-intensity”) dimensions of each respective stimulus were rated. Functional images were analyzed at a corrected α-level <0.05.The TGI was rated as significantly more unpleasant and painful than stimulation with each of its constituent temperatures. Also, the TGI was rated as significantly more unpleasant than painful. Thermal stimulation versus neutral baseline revealed bilateral activations of the anterior insulae and fronto-parietal regions. Unlike its constituent temperatures the TGI displayed a strong activation of the right (contralateral) thalamus. Exploratory contrasts at a slightly more liberal threshold-level also revealed a TGI-activation of the right mid/anterior insula, correlating with ratings of unpleasantness(rho = 0.31).To the best of our knowledge, this is the first fMRI-study of the TGI. The activation of the anterior insula is consistent with this region's putative role in processing of homeostatically relevant feeling-states. Our results constitute the first neurophysiologic evidence of thalamic involvement in the TGI. Similar thalamic activity has previously been observed during evoked cold-allodynia in patients with central neuropathic pain. Our results further the understanding of the supraspinal correlates of the TGI-phenomenon and pave the way for future inquiries into if and how it may relate to neuropathic pain

Fibromyalgia patients had normal distraction related pain inhibition but cognitive impairment reflected in caudate nucleus and hippocampus during the Stroop Color Word Test.

The mechanisms causing cognitive problems in chronic pain patients are not well understood. We used the Stroop color word task (SCWT) to investigate distraction-induced analgesia, cognitive performance, and cerebral activation patterns in 29 fibromyalgia (FM) patients (mean age 49.8 years, range 25-64 years) and 31 healthy controls (HC) (mean age 46.3 years, range 20-63 years). In the first study, SCWT was used to investigate distraction-induced analgesia in FM patients. Two versions of the task were applied, one with only congruent color-word images and one with incongruent images. Pressure pain thresholds were assessed using a pressure algometer before, during, and following SCWT. In the second study, reaction times (RTs) were assessed and functional magnetic resonance imaging (fMRI) was used to investigate cerebral activation patterns in FM patients and HC during the SCWT. An event-related task mixing incongruent and congruent images was used. In study one, we found reduced pressure pain sensitivity during SCWT in both groups alike and no statistically significant differences were seen between the incongruent and congruent conditions. The study two revealed longer RTs during the incongruent compared to the congruent condition in both groups. FM patients had longer RTs than HC in both conditions. Furthermore, we found a significant interaction between group and congruency; that is, the group differences in RTs were more pronounced during the incongruent condition. This was reflected in a reduced activation of the caudate nucleus, lingual gyrus, temporal areas, and the hippocampus in FM patients compared to HC. In conclusion, we found normal pain inhibition during SWTC in FM patients. The cognitive difficulties seen in FM patients, reflected in longer RTs, were related to reduced activation of the caudate nucleus and hippocampus during incongruent SCWT, which most likely affected the mechanisms of cognitive learning in FM patients

The translocator protein gene is associated with symptom severity and cerebral pain processing in fibromyalgia

The translocator protein (TSPO) is upregulated during glia activation in chronic pain patients. TSPO constitutes the rate-limiting step in neurosteroid synthesis, thus modulating synaptic transmission. Related serotonergic mechanisms influence if pro- or anti-nociceptive neurosteroids are produced. This study investigated the effects of a functional genetic polymorphism regulating the binding affinity to the TSPO, thus affecting symptom severity and cerebral pain processing in fibromyalgia patients. Gene-to-gene interactions with a functional polymorphism of the serotonin transporter gene were assessed. Fibromyalgia patients (n = 126) were genotyped regarding the polymorphisms of the TSPO (rs6971) and the serotonin transporter (5-HTTLPR/rs25531). Functional magnetic resonance imaging (n = 24) was used to study brain activation during individually calibrated pressure pain. Compared to mixed/low TSPO affinity binders, the high TSPO affinity binders rated more severe pain (p = 0.016) and fibromyalgia symptoms (p = 0.02). A significant interaction was found between the TSPO and the serotonin transporter polymorphisms regarding pain severity (p amp;lt; 0.0001). Functional connectivity analyses revealed that the TSPO high affinity binding group had more pronounced pain-evoked functional connectivity in the right frontoparietal network, between the dorsolateral prefrontal area and the parietal cortex. In conclusion, fibromyalgia patients with the TSPO high affinity binding genotype reported a higher pain intensity and more severe fibromyalgia symptoms compared to mixed/low affinity binders, and this was modulated by interaction with the serotonin transporter gene. To our knowledge this is the first evidence of functional genetic polymorphisms affecting pain severity in FM and our findings are in line with proposed glia-related mechanisms. Furthermore, the functional magnetic resonance findings indicated an effect of translocator protein on the affective-motivational components of pain perception. (C) 2016 The Authors. Published by Elsevier Inc.Funding Agencies|Swedish Rheumatism Association; Stockholm County Council; Swedish Foundation for Strategic Research [2012-0179]; Swedish Research Council [K2013-52X-22199-01-3, K2015-99x-21874-05-4, 2011-4807, K2009-52P-20943-03-2]; AFA insurance; Karolinska Institutet Foundation; Karolinska Institutet; European Union [602919]</p

Representation of cerebral activation when contrasting HC>FM for incongruent >congruent stimuli.

<p>Results are reported at threshold setting of p<0.001, p values are at peak voxel, not corrected for multiple comparisons. Smallest reported cluster-size is 20 voxels.</p><p>Representation of cerebral activation when contrasting HC>FM for incongruent >congruent stimuli.</p

Average normalized PPTs ± SEM during a) congruent and b) incongruent SCWT in FM patients and HC.

<p>PPTs increased in both groups alike during congruent as well as incongruent SCWT. There were no statistically significant differences between congruent and incongruent SCWT regarding the modulation of PPTs. * = p<0.05, ** = p<0.01, *** = p<0.001. The normalization was performed as follows: each PPT value was divided with the individual’s first PPT at baseline and the curves were adjusted (by adding a coefficient) so that the baseline value always corresponded to 1.</p

Main areas of interest representing cerebral activation when contrasting incongruent >congruent stimuli for FM patients (n = 23) and HC (n = 28) together.

<p>Results are reported at p<0.05, FWE corrected for multiple comparisons. A: dorsal anterior cingulate cortex (dACC), B: posterior cingulate cortex (PCC), C: precuneus, D: cerebellum, E: Insula (bilateral) and F: dorsolateral prefrontal cortex (dlPFC).</p

Representation of cerebral activation when contrasting incongruent >congruent stimuli for FM patients and HC together.

<p>Results are reported at p<0.05, FWE corrected for multiple comparisons at cluster level.</p><p>Representation of cerebral activation when contrasting incongruent >congruent stimuli for FM patients and HC together.</p

Average reaction times (s) ± SEM during congruent and incongruent SCWT.

<p>FM patients had longer reaction times than controls in both conditions (congruent p = 0.027, incongr p = 0.005), but the difference was more pronounced during incongruent SCWT (p = 0.023).</p