Primary somatosensory cortex and periaqueductal gray functional connectivity as a marker of the dysfunction of the descending pain modulatory system in fibromyalgia.

Background: Resting-state functional connectivity (rs-FC) may aid in understanding the link between pain-modulating brain regions and the descending pain modulatory system (DPMS) in fibromyalgia (FM). This study investigated whether the differences in rs-FC of the primary somatosensory cortex in responders and non-responders to the conditioned pain modulation test (CPM-test) are related to pain, sleep quality, central sensitization, and the impact of FM on quality of life. Methods: This cross-sectional study included 33 females with FM. rs-FC was assessed by functional magnetic resonance imaging. Change in the numerical pain scale during the CPM-test assessed the DPMS function. Subjects were classified either as non-responders (i.e., DPMS dysfunction, n = 13) or responders (n = 20) to CPM-test. A generalized linear model (GLM) and a receiver operating characteristic (ROC) curve analysis were performed to check the accuracy of the rs-FC to differentiate each group. Results: Non-responders showed a decreased rs-FC between the left somatosensory cortex (S1) and the periaqueductal gray (PAG) (P < 0.001). The GLM analysis revealed that the S1-PAG rs-FC in the left-brain hemisphere was positively correlated with a central sensitization symptom and negatively correlated with sleep quality and pain scores. ROC curve analysis showed that left S1-PAG rs-FC offers a sensitivity and specificity of 85% or higher (area under the curve, 0.78, 95% confidence interval, 0.63-0.94) to discriminate who does/does not respond to the CPM-test. Conclusions: These results support using the rs-FC patterns in the left S1-PAG as a marker for predicting CPM-test response, which may aid in treatment individualization in FM patients.

Hyper-connectivity between the left motor cortex and prefrontal cortex is associated with the severity of dysfunction of the descending pain modulatory system in fibromyalgia.

INTRODUCTION: The association between descending pain modulatory system (DPMS) dysfunction and fibromyalgia has been previously described, but more studies are required on its relationship with aberrant functional connectivity (FC) between the motor and prefrontal cortices. OBJECTIVES: The objective of this cross-sectional observational study was to compare the intra- and interhemispheric FC between the bilateral motor and prefrontal cortices in women with fibromyalgia, comparing responders and nonresponders to the conditioned pain modulation (CPM) test. METHODS: A cross-sectional sample of 37 women (23 responders and 14 nonresponders to the CPM test) with fibromyalgia diagnosed according to the American College of Rheumatology criteria underwent a standardized clinical assessment and an FC analysis using functional near-infrared spectroscopy. DPMS function was inferred through responses to the CPM test, which were induced by hand immersion in cold water (0-1°C). A multivariate analysis of covariance for main effects between responders and nonresponders was conducted using the diagnosis of multiple psychiatric disorders and the use of opioid and nonopioid analgesics as covariates. In addition, we analyzed the interaction between the CPM test response and the presence of multiple psychiatric diagnoses. RESULTS: Nonresponders showed increased FC between the left motor cortex (lMC) and the left prefrontal cortex (lPFC) (t = -2.476, p = 0.01) and right prefrontal cortex (rPFC) (t = -2.363, p = 0.02), even when both were considered as covariates in the regression analysis (lMC-lPFC: ß = -0.127, t = -2.425, p = 0.021; lMC-rPFC: ß = -0.122, t = -2.222, p = 0.033). Regarding main effects, a significant difference was only observed for lMC-lPFC (p = 0.035). A significant interaction was observed between the psychiatric disorders and nonresponse to the CPM test in lMC-lPFC (ß = -0.222, t = -2.275, p = 0.03) and lMC-rPFC (ß = -0.211, t = -2.2, p = 0.035). Additionally, a significant interaction was observed between the CPM test and FC in these two region-of-interest combinations, despite the psychiatric diagnoses (lMC-lPFC: ß = -0.516, t = -2.447, p = 0.02; lMC-rPFC: ß = -0.582, t = -2.805, p = 0.008). CONCLUSIONS: Higher FC between the lMC and the bilateral PFC may be a neural marker of DPMS dysfunction in women with fibromyalgia, although its interplay with psychiatric diagnoses also seems to influence this association.

Longer Cortical Silent Period Length Is Associated to Binge Eating Disorder: An Exploratory Study.

Introduction: Although binge eating disorder (BED) is an eating disorder and obesity is a clinical disease, it is known that both conditions present overlapped symptoms related to, at least partially, the disruption of homeostatic and hedonistic eating behavior pathways. Therefore, the understanding of neural substrates, such as the motor cortex excitability assessed by transcranial magnetic stimulation (TMS), might provide new insights into the pathophysiology of BED and obesity. Objectives: (i) To compare, among BED, obesity, ex-obese, and HC (healthy control) subjects, the cortical excitability indexed by TMS measures, such as CSP (cortical silent period; primary outcome), SICI (intracortical inhibition), and ICF (intracortical facilitation; secondary outcome). (ii) To explore the relationship of the CSP, eating behavior (e.g., restraint, disinhibition, and hunger), depressive symptoms, and sleep quality among the four groups (BED, obesity, ex-obese, and HC). Methods: Fifty-nine women [BED (n = 13), obese (n = 20), ex-obese (n = 12), and HC (n = 14)] comprise the total sample for this study. Assessments: cortical excitability measures (CSP, SICI, and ICF), inhibition response task by the Go/No-go paradigm, and instruments to assess the eating psychopathology (Three-Factor Eating Questionnaire, Eating Disorder Examination Questionnaire, and Binge Eating Scale) were used. Results: A MANCOVA analysis revealed that the mean of CSP was longer in the BED group compared with other three groups: 24.10% longer than the obesity group, 25.98% longer than the HC group, and 25.41% longer than the ex-obese group. Pearson's correlations evidenced that CSP was positively associated with both eating concern and binge eating scores. Conclusion: The findings point out that BED patients present longer CSP, which might suggest an upregulation of intracortical inhibition. Additionally, CSP was positively correlated with Binge Eating Scale and eating concern scores. Further studies are needed.

The Fear of Pain Questionnaire: psychometric properties of a Brazilian version for adolescents and its relationship with brain-derived neurotrophic factor (BDNF).

OBJECTIVES: The primary aim was to assess the psychometric properties (including internal consistency, construct validity, criterion validity, criterion-group validity and responsiveness) of the Fear of Pain Questionnaire (FOPQ) for adolescents (FOPQ-A) and parents (FOPQ-P) translated to Brazilian Portuguese (BrP). The secondary aim was to analyze the factor structures and their ability to identify subjects with chronic pain conditions and identify the relationship of the BrP FOPQ-A with saliva brain-derived neurotrophic-factor (BDNF). METHODS: A cross-sectional study was conducted with 286 adolescents aged 11 to 18 (257 healthy adolescents [157 females] and 29 adolescents with chronic pain [16 females]). Parents and adolescents completed the BrP-FOPQ. A team of experts translated the FOPQ according to international guidelines. Convergent validity and factor analysis were performed. Later, a subsample (n=146) was used to correlate the BrP-FOPQ-A with saliva BDNF. RESULTS: The BrP-FOPQ for adolescents and parents presented strong psychometric properties (Cronbach's α equal to 0.92 and 0.91, respectively). BrP-FOPQ-A confirmatory factor analysis yielded a two-factor structure while the factorial analyses of BrP-FOPQ-P demonstrated that the best solution was a three-structure factorial. The BrP-FOPQ-P scores in healthy adolescents and those in chronic pain conditions was 34.13 (16.71) vs 43.14 (18.08), respectively. A generalized mixed model demonstrated that the scores in the BrP-FOPQ-A are higher in those with chronic pain conditions compared to healthy subjects (29.20 [12.77] vs 33.80 [10.76], respectively; Wald χ2= 17.80; df=1, P<0.0001). The model revealed that the BDNF was positively correlated with the score of BrP-FOPQ-A and subjects with chronic pain showed higher levels of BDNF. CONCLUSION: The BrP-FOPQ scores for adolescents and parents were found to be psychometrically robust and reliable instruments, with primary evidence of validity. Higher scores on the BrP-FOPQ-A were correlated positively with saliva BDNF and permitted the identification of subjects with chronic pain conditions.

Functional Spectroscopy Mapping of Pain Processing Cortical Areas During Non-painful Peripheral Electrical Stimulation of the Accessory Spinal Nerve.

Peripheral electrical stimulation (PES), which encompasses several techniques with heterogeneous physiological responses, has shown in some cases remarkable outcomes for pain treatment and clinical rehabilitation. However, results are still mixed, mainly because there is a lack of understanding regarding its neural mechanisms of action. In this study, we aimed to assess its effects by measuring cortical activation as indexed by functional near infrared spectroscopy (fNIRS). fNIRS is a functional optical imaging method to evaluate hemodynamic changes in oxygenated (HbO) and de-oxygenated (HbR) blood hemoglobin concentrations in cortical capillary networks that can be related to cortical activity. We hypothesized that non-painful PES of accessory spinal nerve (ASN) can promote cortical activation of sensorimotor cortex (SMC) and dorsolateral prefrontal cortex (DLPFC) pain processing cortical areas. Fifteen healthy volunteers received both active and sham ASN electrical stimulation in a crossover study. The hemodynamic cortical response to unilateral right ASN burst electrical stimulation with 10 Hz was measured by a 40-channel fNIRS system. The effect of ASN electrical stimulation over HbO concentration in cortical areas of interest (CAI) was observed through the activation of right-DLPFC (p = 0.025) and left-SMC (p = 0.042) in the active group but not in sham group. Regarding left-DLPFC (p = 0.610) and right-SMC (p = 0.174) there was no statistical difference between groups. As in non-invasive brain stimulation (NIBS) top-down modulation, bottom-up electrical stimulation to the ASN seems to activate the same critical cortical areas on pain pathways related to sensory-discriminative and affective-motivational pain dimensions. These results provide additional mechanistic evidence to develop and optimize the use of peripheral nerve electrical stimulation as a neuromodulatory tool (NCT03295370- www.clinicaltrials.gov).