High-beta oscillations at EEG resting state and hyperconnectivity of pain circuitry in fibromyalgia: an exploratory cross-sectional study.

Background: Electroencephalography (EEG) has identified neural activity in specific brain regions as a potential indicator of the neural signature of chronic pain. This study compared the lagged coherence connectivity between regions of interest (ROIs) associated with the pain connectome in women with fibromyalgia (FM) and healthy women (HC). Methods: We evaluated 64 participants (49 FM and 15 HC) during resting-state EEG sessions under both eyes open (EO) and eyes closed (EC) conditions. In addition to EEG measurements, we assessed clinical and psychological symptoms and serum levels of brain-derived neurotrophic factor (BDNF). The connectivity between eight ROIs was computed across eight different EEG frequencies. Results: The FM group demonstrated increased connectivity between the left dorsolateral prefrontal cortex (DLPFC) and right anterior cingulate cortex (ACC), specifically in the beta-3 frequency band (t = 3.441, p = 0.044). When comparing the EO and EC conditions, FM patients exhibited heightened interhemispheric connectivity between insular areas (t = 3.372, p = 0.024) and between the left insula (INS) and right DLPFC (t = 3.695, p = 0.024) within the beta-3 frequency band. In the EC condition, there was a negative correlation between pain disability and connectivity in the beta-3 frequency band between the left ACC and the left primary somatosensory cortex (SI; r = -0.442, p = 0.043). In the EO condition, there was a negative correlation between central sensitization severity and lagged coherence connectivity in the alpha-2 frequency band between the right ACC and left SI (r = 0.428, p = 0.014). Moreover, in the EO-EC comparison, the lagged coherence connection between the left DLPFC and right INS, indexed by the gamma frequency band, showed a negative correlation with serum BDNF levels (r = -0.506, p = 0.012). Conclusion: These findings indicate that increased connectivity between different pain processing circuits, particularly in the beta-3 frequency band during rest, may serve as neural biomarkers for the chronic pain brain signature associated with neuroplasticity and the severity of FM symptoms.

Peripheral body temperature rhythm as a marker of the severity of depression symptoms in fibromyalgia.

BACKGROUND: Circadian rhythm alterations have been reported in fibromyalgia (FM) and depression. Peripheral body temperature (PBT) is a reliable measure of the circadian system, so we compared the PBT rhythm between persons with FM and controls. We evaluated PBT correlation with depression symptoms and pain severity in women with FM. METHODS: We included 101 women aged 30-65 with FM diagnosis (FM group, n = 83) and controls (n = 18). Twenty-four-hour PBT was assessed by actigraphy. For the analysis, in the FM group, the PBT measurement was divided into four periods: morning (6 a.m.-noon), afternoon (noon-6 p.m.), evening (6 p.m.-midnight), and night (midnight-6 a.m.). According to their scores on the Hamilton Depression Rating Scale (HDRS), participants were classified as having mild or moderate to severe depression symptoms. RESULTS: There was no difference in PBT between FM and controls. Subjects with FM and moderate to severe depression symptoms showed a higher PBT (p = .003) during the evening period (p = .004). The analysis of PBT rhythm revealed an interaction between time and group according to mild or moderate to severe depression symptoms (χ2 (3) = 12.79, p < .005). The pain severity was positively correlated with PBT (ß=0.22, [CI 95%, 0.07-0.37], p = .003). CONCLUSIONS: PBT rhythm was not a sensitive measure for discriminating persons with FM from controls. In FM, PBT is related to the severity of depression symptoms and pain intensity.

The effect of home-based transcranial direct current stimulation in cognitive performance in fibromyalgia: A randomized, double-blind sham-controlled trial.

Background: Transcranial Direct Current Stimulation (tDCS) is a promising approach to improving fibromyalgia (FM) symptoms, including cognitive impairment. So, we evaluated the efficacy and safety of home-based tDCS in treating cognitive impairment. Besides, we explored if the severity of dysfunction of the Descendant Pain Modulation System (DPMS) predicts the tDCS effect and if its effect is linked to changes in neuroplasticity as measured by the brain-derived neurotrophic factor (BDNF). Methods: This randomized, double-blind, parallel, sham-controlled clinical trial, single-center, included 36 women with FM, aged from 30 to 65 years old, assigned 2:1 to receive a-tDCS (n = 24) and s-tDCS (n = 12). The primary outcome was the Trail Making Test's assessment of executive attention, divided attention, working memory (WM), and cognitive flexibility (TMT-B-A). The secondary outcomes were the Controlled Oral Word Association Test (COWAT), the WM by Digits subtest from the Wechsler Adult Intelligence Scale (WAIS-III), and quality of life. Twenty-minute daily sessions of home-based tDCS for 4 weeks (total of 20 sessions), 2 mA anodal-left (F3) and cathodal-right (F4) prefrontal stimulation with 35 cm2 carbon electrodes. Results: GLM showed a main effect for treatment in the TMT-B-A [Wald χ2 = 6.176; Df = 1; P = 0.03]. The a-tDCS improved cognitive performance. The effect size estimated by Cohen's d at treatment end in the TMT-B-A scores was large [-1.48, confidence interval (CI) 95% = -2.07 to-0.90]. Likewise, the a-tDCS effects compared to s-tDCS improved performance in the WM, verbal and phonemic fluency, and quality-of-life scale. The impact of a-tDCS on the cognitive tests was positively correlated with the reduction in serum BDNF from baseline to treatment end. Besides, the decrease in the serum BDNF was positively associated with improving the quality of life due to FM symptoms. Conclusion: These findings revealed that daily treatment with a home-based tDCS device over l-DLPFC compared to sham stimulation over 4 weeks improved the cognitive impairment in FM. The a-tDCS at home was well-tolerated, underlining its potential as an alternative treatment for cognitive dysfunction. Besides, the a-tDCS effect is related to the severity of DPMS dysfunction and changes in neuroplasticity state. Clinical trial registration: [www.ClinicalTrials.gov], identifier [NCT03843203].

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.

Association between descending pain modulatory system and cognitive impairment in fibromyalgia: A cross-sectional exploratory study.

Background: The successful regulation of sensory input to the central nervous system depends on the descending pain modulatory system (DPMS). For the effective regulation of sensory input to the central nervous system and behavioral responses to pain, the DPMS is required. Its connection to fibromyalgia (FM)-related cognitive dysfunction has not yet been investigated. Therefore, this study tested whether measures of verbal fluency, sustained attention, and short-term and working memory could distinguish FM patients from healthy controls (HC). Additionally, it investigated, using a standardized paradigm, the link between cognitive ability and the function of the DPMS in responders and non-responders to the conditioned pain modulation test (CPM-test). Materials and methods: We enrolled 21 HC women and 69 FM patients, all of whom ranged in age from 30 to 65. We employed scores from the Trail Making Test (TMTB-A) (sustained and divided attention), the Controlled Oral Word Association Test (COWAT) (orthographic and semantic fluency), and the Digits subtest of the Wechsler Adult Intelligence Scale (WAIS-III) as dependent variables. Results: A generalized linear model (GLM) adjusted by educational level revealed significantly lower scores in FM than HC on the Span digits forward, COWAT-orthographic, and TMTB-A. For FM patients, multilevel MANCOVA revealed that the cognitive performance of non-responders compared to responders to CPM-test showed lower adjusted scores in Span digits forward (Partial-η2 = 0.358, P = 0.001), Span digits backward (Partial-η2 = 0.358, P = 0.001), COWAT-orthographic (Partial-η2 = 0.551, P = 0.001), COWAR-semantic (Partial-η2 = 0.355, P = 0.001), and TMTB-A (Partial-η2 = 0.360, P = 0.001). The association between the cognitive tests and the DPMS is moderated by the serum level of brain-derived neurotrophic factor (BDNF). Additionally, these cognitive assessments had a positive correlation with antidepressant use and pain threshold. The cognitive assessments, on the other hand, were conversely associated with a life of quality. Conclusion: Based on these findings, it can be shown that HC performed substantially better on cognitive exams than FM did. They demonstrated a link between clinical complaints about attention and memory and decreased DPMS effectiveness. Additionally, they demonstrated that the BDNF is a moderating element in a potential relationship between the severity of cognitive impairment and DPMS dysfunction.

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.

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.

Transcranial Direct Current Stimulation to Improve the Dysfunction of Descending Pain Modulatory System Related to Opioids in Chronic Non-cancer Pain: An Integrative Review of Neurobiology and Meta-Analysis.

Background: Opioid long-term therapy can produce tolerance, opioid-induced hyperalgesia (OIH), and it induces dysfunction in pain descending pain inhibitory system (DPIS). Objectives: This integrative review with meta-analysis aimed: (i) To discuss the potential mechanisms involved in analgesic tolerance and opioid-induced hyperalgesia (OIH). (ii) To examine how the opioid can affect the function of DPIS. (ii) To show evidence about the tDCS as an approach to treat acute and chronic pain. (iii) To discuss the effect of tDCS on DPIS and how it can counter-regulate the OIH. (iv) To draw perspectives for the future about the tDCS effects as an approach to improve the dysfunction in the DPIS in chronic non-cancer pain. Methods: Relevant published randomized clinical trials (RCT) comparing active (irrespective of the stimulation protocol) to sham tDCS for treating chronic non-cancer pain were identified, and risk of bias was assessed. We searched trials in PubMed, EMBASE and Cochrane trials databases. tDCS protocols accepted were application in areas of the primary motor cortex (M1), dorsolateral prefrontal cortex (DLPFC), or occipital area. Results: Fifty-nine studies were fully reviewed, and 24 with moderate to the high-quality methodology were included. tDCS improved chronic pain with a moderate effect size [pooled standardized mean difference; -0.66; 95% confidence interval (CI) -0.91 to -0.41]. On average, active protocols led to 27.26% less pain at the end of treatment compared to sham [95% CI; 15.89-32.90%]. Protocol varied in terms of anodal or cathodal stimulation, areas of stimulation (M1 and DLPFC the most common), number of sessions (from 5 to 20) and current intensity (from 1 to 2 mA). The time of application was 20 min in 92% of protocols. Conclusion: In comparison with sham stimulation, tDCS demonstrated a superior effect in reducing chronic pain conditions. They give perspectives that the top-down neuromodulator effects of tDCS are a promising approach to improve management in refractory chronic not-cancer related pain and to enhance dysfunctional neuronal circuitries involved in the DPIS and other pain dimensions and improve pain control with a therapeutic opioid-free. However, further studies are needed to determine individualized protocols according to a biopsychosocial perspective.

Cognitive effects of transcranial direct current stimulation combined with working memory training in fibromyalgia: a randomized clinical trial.

Cognitive dysfunction in fibromyalgia has been reported, especially memory. Anodal transcranial direct current stimulation (tDCS) over the dorsolateral prefrontal cortex (DLPFC) has been effective in enhancing this function. We tested the effects of eight sessions of tDCS and cognitive training on immediate and delayed memory, verbal fluency and working memory and its association with brain-derived neurotrophic factor (BDNF) levels. Forty females with fibromyalgia were randomized to receive eight sessions of active or sham tDCS. Anodal stimulation (2 mA) was applied over the DLPFC and online combined with a working memory training (WMT) for 20 minutes. Pre and post-treatment neurocognitive tests were administered. Data analysis on deltas considering years of education and BDNF as covariates, indicated active-tDCS + WMT significantly increased immediate memory indexed by Rey Auditory Verbal Learning Test score when compared to sham. This effect was dependent on basal BDNF levels. In addition, the model showed active stimulation increased orthographic and semantic verbal fluency scores (Controlled Oral Word Association Test) and short-term memory (Forward Digit Span). The combination of both techniques seemed to produce effects on specific cognitive functions related to short-term and long-term episodic memory and executive functions, which has clinical relevance for top-down treatment approaches in FM.