Serotonergic gene-to-gene interaction is associated with mood and GABA concentrations but not with pain-related cerebral processing in fibromyalgia subjects and healthy controls.

The neurotransmitter serotonin, involved in the regulation of pain and emotion, is critically regulated by the 5-HT1A autoreceptor and the serotonin transporter (5-HTT). Polymorphisms of these genes affect mood and endogenous pain modulation, both demonstrated to be altered in fibromyalgia subjects (FMS). Here, we tested the effects of genetic variants of the 5-HT1A receptor (CC/G-carriers) and 5-HTT (high/intermediate/low expression) on mood, pain sensitivity, cerebral processing of evoked pain (functional MRI) and concentrations of GABA and glutamate (MR spectroscopy) in rostral anterior cingulate cortex (rACC) and thalamus in FMS and healthy controls (HC). Interactions between serotonin-relevant genes were found in affective characteristics, with genetically inferred high serotonergic signalling (5-HT1A CC/5-HTThigh genotypes) being more favourable across groups. Additionally, 5-HT1A CC homozygotes displayed higher pain thresholds than G-carriers in HC but not in FMS. Cerebral processing of evoked pressure pain differed between groups in thalamus with HC showing more deactivation than FMS, but was not influenced by serotonin-relevant genotypes. In thalamus, we observed a 5-HT1A-by-5-HTT and group-by-5-HTT interaction in GABA concentrations, with the 5-HTT high expressing genotype differing between groups and 5-HT1A genotypes. No significant effects were seen for glutamate or in rACC. To our knowledge, this is the first report of this serotonergic gene-to-gene interaction associated with mood, both among FMS (depression) and across groups (anxiety). Additionally, our findings provide evidence of an association between the serotonergic system and thalamic GABA concentrations, with individuals possessing genetically inferred high serotonergic signalling exhibiting the highest GABA concentrations, possibly enhancing GABAergic inhibitory effects via 5-HT.

Evidence of fatigue, disordered sleep and peripheral inflammation, but not increased brain TSPO expression, in seasonal allergy: A [11C]PBR28 PET study.

Allergy is associated with non-specific symptoms such as fatigue, sleep problems and impaired cognition. One explanation could be that the allergic inflammatory state includes activation of immune cells in the brain, but this hypothesis has not been tested in humans. The aim of the present study was therefore to investigate seasonal changes in the glial cell marker translocator protein (TSPO), and to relate this to peripheral inflammation, fatigue and sleep, in allergy. We examined 18 patients with severe seasonal allergy, and 13 healthy subjects in and out-of pollen season using positron emission tomography (n = 15/13) and the TSPO radioligand [11C]PBR28. In addition, TNF-α, IL-5, IL-6, IL-8 and IFN-γ were measured in peripheral blood, and subjective ratings of fatigue and sleepiness as well as objective and subjective sleep were investigated. No difference in levels of TSPO was seen between patients and healthy subjects, nor in relation to pollen season. However, allergic subjects displayed both increased fatigue, sleepiness and increased percentage of deep sleep, as well as increased levels of IL-5 and TNF-α during pollen season, compared to healthy subjects. Allergic subjects also had shorter total sleep time, regardless of season. In conclusion, allergic subjects are indicated to respond to allergen exposure during pollen season with a clear pattern of behavioral disruption and peripheral inflammatory activation, but not with changes in brain TSPO levels. This underscores a need for development and use of more specific markers to understand brain consequences of peripheral inflammation that will be applicable in human subjects.

Resistance exercise improves muscle strength, health status and pain intensity in fibromyalgia--a randomized controlled trial.

INTRODUCTION: Fibromyalgia (FM) is characterized by persistent widespread pain, increased pain sensitivity and tenderness. Muscle strength in women with FM is reduced compared to healthy women. The aim of this study was to examine the effects of a progressive resistance exercise program on muscle strength, health status, and current pain intensity in women with FM. METHODS: A total of 130 women with FM (age 22-64 years, symptom duration 0-35 years) were included in this assessor-blinded randomized controlled multi-center trial examining the effects of progressive resistance group exercise compared with an active control group. A person-centred model of exercise was used to support the participants' self-confidence for management of exercise because of known risks of activity-induced pain in FM. The intervention was performed twice a week for 15 weeks and was supervised by experienced physiotherapists. Primary outcome measure was isometric knee-extension force (Steve Strong®), secondary outcome measures were health status (FIQ total score), current pain intensity (VAS), 6MWT, isometric elbow-flexion force, hand-grip force, health related quality of life, pain disability, pain acceptance, fear avoidance beliefs, and patient global impression of change (PGIC). Outcomes were assessed at baseline and immediately after the intervention. Long-term follow up comprised the self-reported questionnaires only and was conducted after 13-18 months. Between-group and within-group differences were calculated using non-parametric statistics. RESULTS: Significant improvements were found for isometric knee-extension force (p = 0.010), health status (p = 0.038), current pain intensity (p = 0.033), 6MWT (p = 0.003), isometric elbow flexion force (p = 0.02), pain disability (p = 0.005), and pain acceptance (p = 0.043) in the resistance exercise group (n = 56) when compared to the control group (n = 49). PGIC differed significantly (p = 0.001) in favor of the resistance exercise group at post-treatment examinations. No significant differences between the resistance exercise group and the active control group were found regarding change in self-reported questionnaires from baseline to 13-18 months. CONCLUSIONS: Person-centered progressive resistance exercise was found to be a feasible mode of exercise for women with FM, improving muscle strength, health status, and current pain intensity when assessed immediately after the intervention. TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT01226784, Oct 21, 2010.

Fibromyalgia is associated with decreased connectivity between pain- and sensorimotor brain areas.

Fibromyalgia (FM) is a syndrome characterized by chronic pain without known peripheral causes. Previously, we have reported dysfunctional pain inhibitory mechanisms for FM patients during pain administration. In this study we employed a seed correlation analysis, independent component analysis (ICA), and an analysis of fractional amplitude of low frequency fluctuations (fALFF) to study differences between a cohort of female FM patients and an age- and sex-matched healthy control group during a resting-state condition. FM patients showed decreased connectivity between thalamus and premotor areas, between the right insula and primary sensorimotor areas, and between supramarginal and prefrontal areas. Individual sensitivity to painful pressure was associated with increased connectivity between pain-related regions (e.g., insula and thalamus) and midline regions of the default mode network (including posterior cingulate cortex and medial prefrontal cortex) among patients and controls. However, neither ICA nor fALFF revealed any group differences. Our findings suggest that abnormal connectivity patterns between pain-related regions and the remaining brain during rest reflect an impaired central mechanism of pain modulation in FM. Weaker coupling between pain regions and prefrontal- and sensorimotor areas might indicate a less efficient system level control of pain circuits. Moreover, our results show that multiple, complementary analytical approaches are valuable for obtaining a more comprehensive characterization of deviant resting-state activity. In conclusion, our findings show that FM primarily is associated with decreased connectivity, for example, between several pain-related areas and sensorimotor regions, which could reflect a deficiency in pain regulation.

Evidence for thalamic involvement in the thermal grill illusion: an FMRI study.

BACKGROUND: 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. AIM: To develop an MRI-compatible TGI-unit and explore the supraspinal correlates of the illusion, using fMRI, in a group of healthy volunteers. METHODS: 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. RESULTS: 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). CONCLUSION/SIGNIFICANCE: 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.