Functional connectivity response to acute pain assessed by fNIRS is associated with BDNF genotype in fibromyalgia: an exploratory study.

Fibromyalgia is a heterogenous primary pain syndrome whose severity has been associated with descending pain modulatory system (DPMS) function and functional connectivity (FC) between pain processing areas. The brain-derived neurotrophic factor (BDNF) Val66Met single nucleotide polymorphism has been linked to vulnerability to chronic pain. In this cross-sectional imaging genetics study, we investigated fibromyalgia, the relationship between BDNF Val66Met heterozygous genotypes (Val/Met), and the functional connectivity (FC) response pattern to acute pain stimulus in the motor (MC) and prefrontal (PFC) cortex assessed by near-infrared spectroscopy (fNIRS) before and after a cold pressor test utilizing water (0-1 °C). Also, we assessed the relationship between this genotype with the DPMS function and quality of life. We included 42 women (Val/Val = 30; Val/Met = 12) with fibromyalgia, ages 18-65. The MANCOVA comparing Val/Met to Val/Val genotypes showed higher ΔFC between left(l)-PFC-l-MC (ß = 0.357, p = 0.048), l-PFC-right(r)-PFC (ß = 0.249, p = 0.012), l-PFC-r-MC (ß = 0.226, p = 0.022), and l-MC-r-PFC (ß = 0.260, p = 0.016). Val/Met genotypes showed higher efficiency of the DPMS and lower disability due to pain. Here we show that fibromyalgia patients carrying the Val/Met BDNF genotype presented an increased ΔFC across MC and PFC in response to acute pain associated with differences in acute pain perception and fibromyalgia symptoms.

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.

Impact of Bifrontal Home-Based Transcranial Direct Current Stimulation in Pain Catastrophizing and Disability due to Pain in Fibromyalgia: A Randomized, Double-Blind Sham-Controlled Study.

This randomized, double-blind trial tested the hypothesis that 20 sessions of home-based anodal(a)-transcranial direct current stimulation (tDCS) (2mA for 20 minutes) bifrontal, with anodal on the left dorsolateral prefrontal cortex (l-DLPFC) would be better than sham-(s)-tDCS to reduce scores on Pain Catastrophizing Scale and disability-related to pain assessed by the Profile of Chronic Pain: Screen (primary outcomes). Secondary outcomes were depressive symptoms, sleep quality, heat pain threshold , heat pain tolerance , and serum brain-derived-neurotrophic-factor (BDNF). Forty-eight women with fibromyalgia, 30 to 65 years-old were randomized into 2:1 groups [a-tDCS (n = 32) or s-tDCS (n = 16)]. Post hoc analysis revealed that a-tDCS reduced the Pain Catastrophizing Scale total scores by 51.38% compared to 26.96% in s-tDCS, and a-tDCS reduced Profile of Chronic Pain: Screen total scores by 31.43% compared to 19.15% in s-tDCS. The a-tDCS improved depressive symptoms, sleep quality and increased the heat pain tolerance. The delta-value in the serum BDNF (mean post treatment end minus pretreatment) was conversely correlated with the a-tDCS effect in pain catastrophizing. In contrast, the a-tDCS impact on reducing the disability-related to pain at the treatment end was positively associated with a reduction in the serum BDNF and improvement of depressive symptoms, sleep quality and pain catastrophizing symptoms. PERSPECTIVE: Home-based bifrontal tDCS with a-tDCS on the l-DLPFC are associated with a moderate effect size (ES) in the following outcomes: 1) Decreased rumination and magnification of pain catastrophizing. 2) Improved the disability for daily activities due to fibromyalgia symptoms. Overall, these findings support the feasibility of self-applied home-based tDCS on DLPFC to improve fibromyalgia symptoms.

Evoked potentials as biomarkers of hereditary spastic paraplegias: A case-control study.

INTRODUCTION: The Hereditary Spastic Paraplegias (HSP) are a group of genetic diseases that lead to slow deterioration of locomotion. Clinical scales seem to have low sensitivity in detecting disease progression, making the search for additional biomarkers a paramount task. This study aims to evaluate the role of evoked potentials (EPs) as disease biomarkers of HSPs. METHODS: A single center cross-sectional case-control study was performed, in which 18 individuals with genetic diagnosis of HSP and 21 healthy controls were evaluated. Motor evoked potentials (MEP) obtained with transcranial magnetic stimulation and somatosensory evoked potentials (SSEP) were performed in lower (LL) and upper limbs (UL). RESULTS: Central motor conduction time in lower limbs (CMCT-LL) was prolonged in HSP subjects, with marked reductions in MEP-LL amplitudes when compared to the control group (p<0.001 for both comparisons). CMCT-UL was 3.59ms (95% CI: 0.73 to 6.46; p = 0.015) prolonged and MEP-UL amplitudes were reduced (p = 0.008) in the HSP group. SSEP-LL latencies were prolonged in HSP subjects when compared to controls (p<0.001), with no statistically significant differences for upper limbs (p = 0.147). SSEP-UL and SSEP-LL latencies presented moderate to strong correlations with age at onset (Rho = 0.613, p = 0.012) and disease duration (Rho = 0.835, p<0.001), respectively. Similar results were obtained for the SPG4 subgroups of patients. CONCLUSION: Motor and somatosensory evoked potentials can adequately differentiate HSP individuals from controls. MEP were severely affected in HSP subjects and SSEP-LL latencies were prolonged, with longer latencies being related to more severe disease. Future longitudinal studies should address if SSEP is a sensitive disease progression biomarker for HSP.

Spectral Power Density analysis of the resting-state as a marker of the central effects of opioid use in fibromyalgia.

Spectral power density (SPD) indexed by electroencephalogram (EEG) recordings has recently gained attention in elucidating neural mechanisms of chronic pain syndromes and medication use. We compared SPD variations between 15 fibromyalgia (FM) women in use of opioid in the last three months (73.33% used tramadol) with 32 non-users. EEG data were obtained with Eyes Open (EO) and Eyes Closed (EC) resting state. SPD peak amplitudes between EO-EC were smaller in opioid users in central theta, central beta, and parietal beta, and at parietal delta. However, these variations were positive for opioid users. Multivariate analyses of variance (ANOVAs) revealed that EO-EC variations in parietal delta were negatively correlated with the disability due to pain, and central and parietal beta activity variations were positively correlated with worse sleep quality. These clinical variables explained from 12.5 to 17.2% of SPD variance. In addition, central beta showed 67% sensitivity / 72% specificity and parietal beta showed 73% sensitivity/62% specificity in discriminating opioid users from non-users. These findings suggest oscillations in EEG might be a sensitive surrogate marker to screen FM opioid users and a promising tool to understand the effects of opioid use and how these effects relate to functional and sleep-related symptoms.