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Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response. In this randomized, double-blind, sham-controlled, single centre trial, we recruited 18 patients with chronic neuropathic pain who did not adequately respond to conventional treatment and had a numerical pain rating scale (NRS) score ≥6. Patients were initially assigned to receive 3 months of active ('on') or sham ('off') stimulation in a double-blind cross-over phase. This was followed by a 3-month single-blind phase, and 6 months of open-label follow-up. A meaningful response in our trial was defined as a ≥30% or 2-point reduction in NRS scores during active stimulation. Using Bayesian statistics, we found a 41.4% probability of response towards on versus off motor cortex stimulation. The probability of improvement during active stimulation (double-blind, single-blind and open-label phases) compared to baseline was 47.2-68.5%. Thirty nine per cent of the patients were considered long-term responders, 71.4% of whom had facial pain, phantom limb pain or complex regional pain syndrome. In contrast, 72.7% of non-responders had either post-stroke pain or pain associated with brachial plexus avulsion. Thirty-nine per cent of patients had a substantial postoperative analgesic effect after electrode insertion in the absence of stimulation. Individuals with diagnoses associated with a good postoperative outcome or those who developed an insertional effect had a near 100% probability of response to motor cortex stimulation. In summary, we found that ∼40% of patients responded to motor cortex stimulation, particularly those who developed an insertional effect or had specific clinical conditions that seemed to predict an appropriate postoperative response.

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BACKGROUND: Motor cortex stimulation (MCS) is routinely used for the treatment of chronic neuropathic pain but its effect on quality of life remains uncertain. OBEJCTIVE: To systematically review the published literature on MCS and quality of life and report the effects of this therapy in a series of patients prospectively followed in our center. METHODS: The systematic literature review was conducted using the search words "motor cortex stimulation and pain and neurosurgery" and "motor cortex stimulation and pain and quality of life." Quality of life in our clinical trial was investigated in a series of 10 patients with chronic neuropathic pain prospectively followed for 12 mo after MCS. RESULTS: Two hundred eighteen nonreplicated articles were pooled for analysis. Of these, 6 described measures of quality of life in the pre- and postoperative period. In these studies, 64 patients with different clinical conditions associated with neuropathic pain were followed for 6 to 84 mo after MCS surgery. Improvement in quality of life ranged from 35% to 85%. In our clinical series, visual analog scale (VAS), SF-12 physical (PhysCS), and mental scores (MenCS) recorded 12 mo after MCS were improved by 60 ± 10% (P = .002), 50 ± 13% (P = .002), and 22 ± 6% (P = .01), respectively. No significant correlation was found between postoperative improvement in pain and either PhysCS (r = 0.18; P = .6) or MenCS (r = -0.24; P = .5). CONCLUSION: MCS improves quality of life in patients with chronic refractory neuropathic pain. Additional factors other than a simple analgesic effect may contribute to these results.

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To evaluate changes in DNA methylation profiles in patients with fibromyalgia (FM) compared to matched healthy controls (HCs). All individuals underwent full clinical and neurophysiological assessment by cortical excitability (CE) parameters measured by transcranial magnetic stimulation. DNA from the peripheral blood of patients with FM (n = 24) and HC (n = 24) were assessed using the Illumina-HumanMethylation450 BeadChips. We identified 1610 differentially methylated positions (DMPs) in patients with FM displaying a nonrandom distribution in regions of the genome. Sixty-nine percent of DMP in FM were hypomethylated compared to HC. Differentially methylated positions were enriched in 5 genomic regions (1p34; 6p21; 10q26; 17q25; 19q13). The functional characterization of 960 genes related to DMPs revealed an enrichment for MAPK signaling pathway (n = 18 genes), regulation of actin cytoskeleton (n = 15 genes), and focal adhesion (n = 13 genes). A gene-gene interaction network enrichment analysis revealed the participation of DNA repair pathways, mitochondria-related processes, and synaptic signaling. Even though DNA was extracted from peripheral blood, this set of genes was enriched for disorders such as schizophrenia, mood disorders, bulimia, hyperphagia, and obesity. Remarkably, the hierarchical clusterization based on the methylation levels of the 1610 DMPs showed an association with neurophysiological measurements of CE in FM and HC. Fibromyalgia has a hypomethylation DNA pattern, which is enriched in genes implicated in stress response and DNA repair/free radical clearance. These changes occurred parallel to changes in CE parameters. New epigenetic insights into the pathophysiology of FM may provide the basis for the development of biomarkers of this disorder.

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LESSONS LEARNED: Pregabalin is a medication that can decrease neuronal hyperexcitability, relieve neuropathic pain, and reach stable plasma levels after a titration period of only a few days.Its use during oxaliplatin infusions was not able to decrease the incidence of chronic, oxalipaltin-related neuropathic pain, compared with placebo. BACKGROUND: Patients with colorectal cancer (CRC) receiving oxaliplatin (OXA) develop acute and chronic painful oxaliplatin-induced peripheral neuropathy (OXAIPN). Acute and chronic OXA-related neuropathies have different pathophysiological bases, but both lead to a common phenomenon: central sensitization (CS) of nociceptive neuronal networks, leading to increased sensitivity (hyperlgesia, allodynia) in the somatosensory system, the common ground of chronic neuropathic pain. Because CS is related to increased risk of painful OXAIPN, we hypothesized that preemptive use of the anti-hyperalgesic drug pregabaline (known to decrease CS) during OXA infusions would decrease the incidence of chronic OXAIPN. METHODS: Pain-free, chemotherapy-naïve CRC patients receiving at least one cycle of modified-FLOX [5-FU(500 mg/m2)+leucovorin(20 mg/m2)/week for] 6 weeks+oxaliplatin(85 mg/m2) at weeks 1-3-5 every 8 weeks] were randomized (1:1) into the study. Patients received either pregabalin or placebo for 3 days before and 3 days after each OXA infusion and were followed for up to 6 months. Clinical assessments were performed at baseline, at the end of chemotherapy, and after the follow-up period. The main outcome was average pain at the last visit assessed by the visual analogic scale (0-10) item of the Brief Pain Inventory (BPI). Secondary endpoints were presence of neuropathic pain according to the Douleur Neuropathique-4 (DN-4), pain dimensions (short- form McGill Pain Questionnaire [MPQ]), Neuropathic Pain Symptom Inventory (NPSI), and changes in nerve conduction studies (NCS) and side effect profile. RESULTS: One hundred ninety-nine patients (57.0 ± 10.7 years old, 98 female, 101 male) were randomized. Data from 56 patients were not included in the analyses (as they did not receive at least one full cycle of modified FLOX). Data from 78 patients in the pregabalin group and 65 patients in the placebo group were retained for analyses. At the last visit, pain intensity in the pregabalin group was 1.03 (95% confidence interval [CI] = 0.79-1.26), and 0.85 (95% CI = 0.64-1.06) in the placebo group, which did not reach significance. Scores from the BPI, MPQ, DN-4, NPSI, and NCS and side-effect profiles and incidence of death did not differ between groups. Quality of life (QoL) score did not differ between groups (placebo = 76.9 ± 23.1, pregabalin group 79.4 ± 20.6). Mood scores were not significantly different between groups (placebo 9.7 [8.1-11.2]; pregabalin 6.8 [5.6-8.0]). CONCLUSION: The preemptive use of pregabalin during OXA infusions was safe, but did not decrease the incidence of chronic pain related to OXAIPN.

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INTRODUCTION: The assessment of cortical excitability (CE) measurements has been increasingly used in neuropsychiatric research. However, there is scant information on the normative values of these measurements, as well as the possible effect of hemisphere laterality, gender and age on these variables. OBJECTIVES: To obtain normative data for CE measurements by transcranial magnetic stimulation, to assess inter-/intra-investigator variability and the influence of sex, age and oral contraception use. METHODS: A sample of 216 healthy volunteers matched according to age and gender was evaluated. Bilateral rest motor thresholds, motor evoked potentials (MEP), intracortical inhibition and facilitation were measured in the first dorsal interosseous muscle area representation of the primary motor cortex with a circular transcranial magnetic stimulation coil delivering biphasic pulses. Normative data were obtained for 200 participants (in a 1:1 male:female ratio) in a balanced proportion between five age groups (18-30; 31-40; 41-50; 51-60; >60 years). Inter/intra-investigator variability was assessed in 20 healthy volunteers in two sessions performed within a 30-minute interval. Measurements were also performed in a subgroup of 16 healthy female volunteers, using oral contraception and during the menstrual phase. RESULTS: Age had a dichotomous effect on CE measurements, providing significantly different normative data for subjects <50 and >50 years old, with smaller MEP's and intracortical inhibition in older individuals. There were no differences between genders or between left and right hemispheres. Also, CE parameters did not significantly differ with use of contraceptive treatment compared to the menstrual phase of the cycle. The inter-/intra-investigator reliability assessment showed some variability that may not be clinically significant. CONCLUSIONS: Age had a non-linear effect on CE. There were non-significant differences between genders, hemispheres or with use of oral contraceptives. There was good inter-/intra-investigator correlation for rest motor thresholds and motor evoked potentials while intracortical inhibition and facilitation had low correlations but acceptable reliability.

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