Efficacy of Home-Based Transcranial Direct Current Stimulation Over the Primary Motor Cortex and Dorsolateral Prefrontal Cortex in the Disability Due to Pain in Fibromyalgia: A Factorial Sham-Randomized Clinical Study.

This randomized, double-blind, controlled clinical trial compared the effectiveness of home-based-(HB) active transcranial direct current stimulation (a-tDCS) over the left dorsolateral prefrontal cortex (l-DLPFC) or primary motor cortex (M1) with their respective sham-(s)-tDCS to determine whether a-tDCS would be more effective than s-tDCS in reducing pain and improving disability due to pain. The study included 102 patients with fibromyalgia aged 30 to 65 years old randomly assigned to 1 of 4 tDCS groups using a ratio of 2:1:2:1. The groups included l-DLPFC (a-tDCS, n = 34) and (s-tDCS, n = 17), or tDCS on the M1 (a-tDCS, n = 34) or (s-tDCS, n = 17). Patients self-administered 20 sessions of tDCS, with 2 mA for 20 minutes each day under remote supervision after in-person training. The Mixed Model for Repeated Measurements revealed that a-tDCS on DLPFC significantly reduced pain scores by 36.53% compared to 25.79% in s-tDCS. From baseline to the fourth week of treatment, a-tDCS on M1 reduced pain scores by 45.89% compared to 22.92% over s-tDCS. A generalized linear model showed a significant improvement in the disability scale in the groups that received a-tDCS compared to s-tDCS over M1 20.54% versus 2.49% (χ2 = 11.06, df = 1, P < .001]), while on DLPFC the improvement was 14.29% and 5.77%, with a borderline significance (χ2 = 3.19, df = 1, P = .06]), respectively. A higher reduction in serum brain-derived neurotrophic factor from baseline to treatment end was positively correlated with decreased pain scores regardless of the treatment group. The application of a-tDCS over M1 increased the heat pain threshold and the function of the descending pain inhibitory system. PERSPECTIVE: These findings provide important insights: (1) HB-tDCS has effectively reduced pain scores and improved disability due to fibromyalgia. (2) The study provides evidence that HB-a-tDCS is a viable and effective therapeutic approach. (3) HB-a-tDCS over M1 improved the function of the descending pain inhibitory system and increased the heat pain threshold. Finally, our findings also emphasize that brain-derived neurotrophic factor, as an index of neuroplasticity, may serve as a valuable marker associated with changes in clinical pain measures. TRIAL REGISTRATION: Number NCT03843203.

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.

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].

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.

The McGill Quality of Life Questionnaire-Revised (MQOL-R). Psychometric properties and validation of a Brazilian version on palliative care patients: a cross-sectional study.

BACKGROUND: To assess the psychometric properties, including internal consistency, construct validity, criterion validity, criterion-group validity, and responsiveness, the Reviewed McGill Quality of Life Questionnaire (MQOL-R), into Brazilian Portuguese-(BrP). Also, to analyze the relationship of the BrP-MQOL-R with the scores on the Karnofsky Performance Scale (KPS) and on the Numerical Pain Scale (NPS 0-10). METHODS: The BrP-MQOL-R was administered to a sample of 146 adults (men = 78). A team of experts translated the MQOL-R according to international guidelines. Convergent validity and Confirmatory factor analysis (CFA) was performed. RESULTS: The BrP-MQOL-R Cronbach's alpha was 0.85. CFA supported the original four-factor structure, with the following revised model fit-indices: PCLOSE = 0.131, Tucker-Lewis Index (TLI) rho 2 = 0.918, incremental fit index (IFI) delta 2 = 0.936. The convergence validity is supported by a significant correlation between BrP-MQOL-R total scores and their subscales with KPS and with the single item related to the quality of life. And by a converse correlation with the pain scores in the NPS (0-10). Receiver operator characteristics (ROC) analysis showed subjects with KPS equal to or lower than 30% could be discriminated from those with scores on KPS higher than 30% by an area under the curve (AUC) = 0.71, sensitivity = 97%, and specificity = 92%). CONCLUSION: The BrP-MQOL-R proves to be a reliable instrument for assessing the quality of life (QOL) in palliative care (PC), with primary evidence of validity. BrP-MQOL-R presented adequate discriminate properties to identify distinct conditions that impact the QOL in PC.

PEARLS. Closure of Mandibular Spaces During Retention.

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Rapid treatment-induced brain changes in pediatric CRPS.

To date, brain structure and function changes in children with complex regional pain syndrome (CRPS) as a result of disease and treatment remain unknown. Here, we investigated (a) gray matter (GM) differences between patients with CRPS and healthy controls and (b) GM and functional connectivity (FC) changes in patients following intensive interdisciplinary psychophysical pain treatment. Twenty-three patients (13 females, 9 males; average age ± SD = 13.3 ± 2.5 years) and 21 healthy sex- and age-matched controls underwent magnetic resonance imaging. Compared to controls, patients had reduced GM in the primary motor cortex, premotor cortex, supplementary motor area, midcingulate cortex, orbitofrontal cortex, dorsolateral prefrontal cortex (dlPFC), posterior cingulate cortex, precuneus, basal ganglia, thalamus, and hippocampus. Following treatment, patients had increased GM in the dlPFC, thalamus, basal ganglia, amygdala, and hippocampus, and enhanced FC between the dlPFC and the periaqueductal gray, two regions involved in descending pain modulation. Accordingly, our results provide novel evidence for GM abnormalities in sensory, motor, emotional, cognitive, and pain modulatory regions in children with CRPS. Furthermore, this is the first study to demonstrate rapid treatment-induced GM and FC changes in areas implicated in sensation, emotion, cognition, and pain modulation.

Fear and Reward Circuit Alterations in Pediatric CRPS.

In chronic pain, a number of brain regions involved in emotion (e.g., amygdala, hippocampus, nucleus accumbens, insula, anterior cingulate, and prefrontal cortex) show significant functional and morphometric changes. One phenotypic manifestation of these changes is pain-related fear (PRF). PRF is associated with profoundly altered behavioral adaptations to chronic pain. For example, patients with a neuropathic pain condition known as complex regional pain syndrome (CRPS) often avoid use of and may even neglect the affected body area(s), thus maintaining and likely enhancing PRF. These changes form part of an overall maladaptation to chronic pain. To examine fear-related brain circuit alterations in humans, 20 pediatric patients with CRPS and 20 sex- and age-matched healthy controls underwent functional magnetic resonance imaging (fMRI) in response to a well-established fearful faces paradigm. Despite no significant differences on self-reported emotional valence and arousal between the two groups, CRPS patients displayed a diminished response to fearful faces in regions associated with emotional processing compared to healthy controls. Additionally, increased PRF levels were associated with decreased activity in a number of brain regions including the right amygdala, insula, putamen, and caudate. Blunted activation in patients suggests that (a) individuals with chronic pain may have deficits in cognitive-affective brain circuits that may represent an underlying vulnerability or consequence to the chronic pain state; and (b) fear of pain may contribute and/or maintain these brain alterations. Our results shed new light on altered affective circuits in patients with chronic pain and identify PRF as a potentially important treatment target.

Habenula functional resting-state connectivity in pediatric CRPS.

The habenula (Hb) is a small brain structure located in the posterior end of the medial dorsal thalamus and through medial (MHb) and lateral (LHb) Hb connections, it acts as a conduit of information between forebrain and brainstem structures. The role of the Hb in pain processing is well documented in animals and recently also in acute experimental pain in humans. However, its function remains unknown in chronic pain disorders. Here, we investigated Hb resting-state functional connectivity (rsFC) in patients with complex regional pain syndrome (CRPS) compared with healthy controls. Twelve pediatric patients with unilateral lower-extremity CRPS (9 females; 10-17 yr) and 12 age- and sex-matched healthy controls provided informed consent to participate in the study. In healthy controls, Hb functional connections largely overlapped with previously described anatomical connections in cortical, subcortical, and brainstem structures. Compared with controls, patients exhibited an overall Hb rsFC reduction with the rest of the brain and, specifically, with the anterior midcingulate cortex, dorsolateral prefrontal cortex, supplementary motor cortex, primary motor cortex, and premotor cortex. Our results suggest that Hb rsFC parallels anatomical Hb connections in the healthy state and that overall Hb rsFC is reduced in patients, particularly connections with forebrain areas. Patients' decreased Hb rsFC to brain regions implicated in motor, affective, cognitive, and pain inhibitory/modulatory processes may contribute to their symptomatology.