Non-invasive brain stimulation on clinical symptoms in multiple sclerosis patients: A systematic review and meta-analysis.

BACKGROUND: Non-invasive brain stimulation (NIBS) has demonstrated mixed effects on the clinical symptoms of multiple sclerosis. This systematic review and meta-analysis aimed to evaluate the effects of NIBS techniques on the most common symptoms of MS. METHODS: A literature search was performed until October 2022 which included randomized controlled trials and quasi-experimental studies that used sham-controlled NIBS in patients with MS. We calculated the Hedge's effect sizes of each domain of interest and their 95% confidence intervals (95% CIs) and performed random effects meta-analyses. RESULTS: A total of 49 studies were included in the systematic review (944 participants). Forty-four eligible studies were included for quantitative analysis, of which 33 applied transcranial direct current stimulation (tDCS), 9 transcranial magnetic stimulation (TMS), and 2 transcranial random noise stimulation (tRNS). We found a significant decrease in fatigue (ES:  - 0.86, 95% CI:  - 1.22 to - 0.51, p < 0.0001), pain (ES: - 1.91, 95% CI, - 3.64 to - 0.19, p=  0.03) and psychiatric symptoms (ES: - 1.44, 95% CI - 2.56 to - 0.32, p = 0.01) in favor of tDCS compared with the sham. On the other hand, there was no strong evidence showing tDCS effectiveness on motor performance and cognition (ES: - 0.03, 95% CI - 0.35 to 0.28, p = 0.83 and ES: 0.71, 95% CI, - 0.09 to 1.52, p = 0.08, respectively). Regarding TMS, we found a significant decrease in fatigue (ES: - 0.45, 95% CI: - 0.84 to -0.07, p = 0.02) and spasticity levels (ES: - 1.11, 95% CI: - 1.48 to - 0.75, p < 0.00001) compared to the sham. However, there was no strong evidence of the effectiveness of TMS on motor performance (ES: - 0.39, 95% CI - 0.95 to 0.16, p = 0.16). Finally, there was no significant evidence showing the effectiveness of tRNS on fatigue levels (ES: - 0.28, 95% CI: - 1.02 to 0.47, p = 0.46) and cognitive improvement (ES: - 0.04, 95% CI: - 0.6, 0.52, p = 0.88) compared with the sham. CONCLUSIONS: Overall, most studies have investigated the effects of tDCS on MS symptoms, particularly fatigue. The symptom that most benefited from NIBS was fatigue, while the least to benefit was motor performance. In addition, we found that disability score was associated with fatigue improvement. Thus, these findings support the idea that NIBS could have some promising effects on specific MS symptoms. It is also important to underscore that studies are very heterogeneous regarding the parameters of stimulation, and this may also have influenced the effects on some specific behavioral domains.

Serum lipid profile in migraine and its association with clinical characteristics.

OBJECTIVES: Migraine is one of the most prevalent and disabling conditions worldwide. Dyslipidemia has become an issue of great importance recently in migraine patients. There is still no consensus on the relationship between specific lipid levels with clinical characteristics of migraine and patients' demographic features. In this study, we investigated each serum lipid level in migraine patients and correlated it with migraine and patients' characteristics to understand the contribution of these factors together. METHODS: In this case-control study, 100 patients with migraine and 76 healthy control subjects were included. Serum lipid levels were calculated and compared with the control group. Also, we analyzed the clinical characteristics of patients and their correlation with lipid levels. Regression analyses were performed to identify the predictors of serum lipid levels. RESULTS: Total cholesterol (TC), triglyceride (TG), and surprisingly high-density lipoprotein (HDL-c) levels were found significantly higher in the migraine group. Also, low-density lipoprotein (LDL-c) level showed a trend of increase and has become significantly higher in the migraine group after adjusting by age. Moreover, there was a positive correlation only between age and TC, LDL-c, and TG levels among the clinical characteristics of migraine and patients' demographic features. DISCUSSIONS: Due to accompanying dyslipidemia, migraine might be considered a risk factor for vascular events regardless of its clinical characteristics. Notwithstanding, elevated HDL-c levels may play a protective role for the vascular events. This dilemma needs to be further explored in future trials to reveal potential biological mechanisms of lipids in migraine patients and to find the optimal therapeutic approach to dyslipidemia.

Cost-Effectiveness Analysis to Inform Randomized Controlled Trial Design in Chronic Pain Research: Methods for Guiding Decisions on the Addition of a Run-In Period.

Introduction: Run-In (RI) periods can be used to improve the validity of randomized controlled trials (RCTs), but their utility in Chronic Pain (CP) RCTs is debated. Cost-effectiveness analysis (CEA) methods are commonly used in evaluating the results of RCTs, but they are seldom used for designing RCTs. We present a step-by-step overview to objectively design RCTs via CEA methods and specifically determine the cost effectiveness of a RI period in a CP RCT. Methods: We applied the CEA methodology to data obtained from several noninvasive brain stimulation CP RCTs, specifically focusing on (1) defining the CEA research question, (2) identifying RCT phases and cost ingredients, (3) discounting, (4) modeling the stochastic nature of the RCT, and (5) performing sensitivity analyses. We assessed the average cost-effectiveness ratios and incremental cost effectiveness ratios of varied RCT designs and the impact on cost-effectiveness by the inclusion of a RI period vs. No-Run-In (NRI) period. Results: We demonstrated the potential impact of varying the number of institutions, number of patients that could be accommodated per institution, cost and effectiveness discounts, RCT component costs, and patient adherence characteristics on varied RI and NRI RCT designs. In the specific CP RCT designs that we analyzed, we demonstrated that lower patient adherence, lower baseline assessment costs, and higher treatment costs all necessitated the inclusion of an RI period to be cost-effective compared to NRI RCT designs. Conclusions: Clinical trialists can optimize CP RCT study designs and make informed decisions regarding RI period inclusion/exclusion via CEA methods.

Electroencephalography Signatures for Conditioned Pain Modulation and Pain Perception in Nonspecific Chronic Low Back Pain-An Exploratory Study.

Conditioned pain modulation (CPM) can discriminate between healthy and chronic pain patients. However, its relationship with neurophysiological pain mechanisms is poorly understood. Brain oscillations measured by electroencephalography (EEG) might help gain insight into this complex relationship. OBJECTIVE: To investigate the relationship between CPM response and self-reported pain intensity in non-specific chronic low back pain (NSCLBP) and explore respective EEG signatures associated to these mechanisms. DESIGN: Cross-sectional analysis. PARTICIPANTS: Thirty NSCLBP patients participated. METHODS: Self-reported low back pain, questionnaires, mood scales, CPM (static and dynamic quantitative sensory tests), and resting surface EEG data were collected and analyzed. Linear regression models were used for statistical analysis. RESULTS: CPM was not significantly correlated with self-reported pain intensity scores. Relative power of EEG in the beta and high beta bands as recorded from the frontal, central, and parietal cortical areas were significantly associated with CPM. EEG relative power at delta and theta bands as recorded from the central area were significantly correlated with self-reported pain intensity scores while controlling for self-reported depression. CONCLUSIONS: Faster EEG frequencies recorded from pain perception areas may provide a signature of a potential cortical compensation caused by chronic pain states. Slower EEG frequencies may have a critical role in abnormal pain processing.

Specific Electroencephalographic Signatures for Pain and Descending Pain Inhibitory System in Spinal Cord Injury.

OBJECTIVES: The pain related to spinal cord injury (SCI) is difficult to treat, and it is associated with significant morbidity. One aspect to improve therapeutics is to explore markers of pain and its correlates in SCI. METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 39 patients with SCI were included. We analyzed conditioned pain modulation (CPM) efficiency as the index of the descending pain inhibitory system, EEG variables, and clinical pain levels as measured by the Visual Analogue Scale. Regression analyses were performed to assess the relationship among EEG variables, pain levels, and CPM. RESULTS: We included 39 SCI patients, 74% reported SCI-related pain. We found that (1) less alpha and beta power are related to pain presence, (2) less alpha and beta power are associated with higher pain levels among patients with pain, (3) patients with pain have decreased peak alpha-theta frequency compared to no-pain group, (4) more relative theta power are related to the presence of low CPM efficiency, (5) higher relative theta power is associated with lower CPM efficiency. CONCLUSIONS: Our results confirm and provide additional data on the relationship between decreased alpha and beta frequencies and higher pain levels. One important finding, though, was a specific and different EEG signature for the descending inhibitory pain system, as we showed that increased theta EEG power is related to decreased CPM efficiency; suggesting that, although low CPM efficiency plays a major role in pain in these participants, it does seem to be associated with a specific oscillatory brain rhythm different from clinical pain. These findings have significant implications for future research on EEG-based biomarkers of pain in post-SCI and new interventions as neurofeedback to manage pain in this population.

Burden of epilepsy in Latin America and The Caribbean: a trend analysis of the Global Burden of Disease Study 1990 - 2019.

Background: The epilepsy prevalence in Latin America and the Caribbean (LAC) had remained high over the last 20 years. Data on the burden of epilepsy are needed for healthcare planning and resource allocation. However, no systematic analysis had been performed for epilepsy burden in LAC. Methods: We extracted data of all LAC countries from the Global Burden of Disease (GBD) study from 1990 to 2019. Epilepsy burden was measured as prevalence, mortality, and disability-adjusted life-years (DALYs; defined by the sum of years of life lost [YLLs] for premature mortality and years lived with disability [YLDs]), by age, sex, year, and country. Absolute numbers, rates, and 95% uncertainty intervals were reported. We performed correlational analyses among burden metrics and Socio-demographic Index (SDI). Findings: The burden of epilepsy decreased around 20% in LAC, led by YLLs reduction. In 2019, 6·3 million people were living with active epilepsy of all causes (95% UI 5·3 - 7·4), with 3·22 million (95% UI 2·21 - 4·03) and 3·11 million (95% UI 2·21 to 4·03) cases of epilepsy with identifiable aetiology and idiopathic epilepsy, respectively. The number of DALYs represented the 9·51% (1.37 million, 95% UI 0·99 -1·86) of the global epilepsy burden in 2019. The age-standardized burden was 175·9 per 100 000 population (95% UI 119·4 - 253·3), which tend to have a bimodal age distribution (higher in the youth and elderly) and was driven by high YLDs estimates. The burden was higher in men and older adults, primarily due to high YLLs and mortality. Alcohol use was associated with 17% of the reported DALYs. The SDI estimates significantly influenced this burden (countries with high SDI have less epilepsy burden and mortality, but not prevalence or disability). Interpretation: The epilepsy burden has decreased in LAC over the past 30 years. Even though, LAC is still ranked as the third region with the highest global epilepsy burden. This reduction was higher in children, but burden and mortality increased for older adults. The epilepsy burden is disability predominant; however, the mortality-related estimates are still higher than in other regions. Alcohol consumption and countries' development are important determinants of this burden. There is an urgent need to improve access to epilepsy care in LAC, particularly for older adults. Strengthening primary care with online learning and telemedicine tools, and promoting risk factors modification should be prioritized in the region. Funding: This research was self-funded by the authors.

Recruitment characteristics and non-adherence associated factors of fibromyalgia patients in a randomized clinical trial: A retrospective survival analysis.

INTRODUCTION: Fibromyalgia is a complex pain condition that affects mostly women. Given the disease's lack of understanding, patients report poor adherence to medication and mistrust of medical services. This study aims to describe the recruitment characteristics and non-adherence associated factors of fibromyalgia patients to an RCT. METHODS: We performed a retrospective longitudinal analysis with data from our ongoing RCT. We investigated characteristics of subjects recruited, consented, and randomized. Adherence was studied using survival analysis techniques, and its associated factors were identified using Cox proportional hazards regression model. RESULTS: 524 subjects were contacted, 269 were eligible, 61 consented and 40 subjects were randomized. Thirty-eight percent were non-adherent to the protocol with a median of visits of five. The recruitment survey reported that 90% would likely participate in RCTs, 52% had previous participation, and 19% were aware of RCTs by their physicians. Some barriers were investigator-related (staff's friendliness and receiving the results of their trial participation) and center-related (privacy-confidentiality issues and the institution's reputation), without difference between adherent and non-adherent participants. We report significant factors for non-adherence as VAS anxiety score of 5 or more (5.3 HR, p = 0.01), Body Mass Index (BMI) (0.91 HR, p = 0.041) and Quality of Life (QoL) - Personal development subdomain (0.89 HR, p = 0.046). CONCLUSION: Recruitment and adherence of fibromyalgia patients is a challenge; however, they seem eager to participate in RCTs. We recommend creating a comfortable, friendly and trusting environment to increase the recruitment rate. Higher anxiety, lower BMI and lower quality of life were associated with a higher attrition rate.

Barriers and facilitators for clinical trial participation of underrepresented and non-underrepresented fibromyalgia patients: A cross-sectional internet survey.

BACKGROUND: There is a need of well-powered randomized clinical trials in fibromyalgia. However, challenges for recruitment are presented. This study aims to describe and assess the perception of barriers and facilitators and the associated factors for the participation of underrepresented and non-underrepresented fibromyalgia patients. METHODS: We performed an online survey through REDCap (Research Electronic Data Capture) targeting fibromyalgia patients from April 7 to July 3, 2020 during the COVID-19 stay home mandate and it was restricted to the United States of America. We described and compared the survey characteristics between underrepresented and non-underrepresented participants, and we performed logistic regression models to assess the associated factors with clinical trial participation. RESULTS: In total, 481 completed the survey including 168 underrepresented fibromyalgia patients. Only (1) 11.09 % reported previous participation in clinical trials and the significant perceived barriers were investigator-related (lack of friendliness of research staff and the opportunity to receive the results) and center-related (privacy and confidentiality policies, and the institution's reputation); (2) the participation rate and perceived barriers and facilitators were similar between underrepresented and non-underrepresented patients; and was positively associated with low income, higher age, and clinical trial awareness from their physician; and negatively associated with the perception of investigator-related barriers; and (4) for the underrepresented population, the presence of emotional support. CONCLUSION: Our findings suggest low rates of participation, regardless of underrepresented population status. Strategies as involving their physician as liaison to increase the awareness of clinical trials, as well as improving patient-researcher communication should be considered in this population.

IMPORTANCE trial: a provisional study-design of a single-center, phase II, double-blinded, placebo-controlled, randomized, 4-week study to compare the efficacy and safety of intranasal esketamine in chronic opioid refractory pain.

Background:  Cancer is the second leading cause of death globally. Up to 86% of advanced cancer patients experience significant pain, while 10-20% live in chronic pain. Besides, increasing prescription of opioids resulted in 33,000 deaths in the US in 2015. Both reduce patients' functional status and quality of life. While cancer survival rates are increasing, therapeutic options for chronic opioid refractory pain are still limited. Esketamine is the s-enantiomer of ketamine, with superior analgesic effect and less psychotomimetic side effects. Intranasal esketamine was approved by the FDA for treatment-resistant depression. However, its use in chronic cancer pain has never been tested. Therefore, we propose a phase II, randomized, placebo-controlled trial to evaluate the efficacy and safety of intranasal esketamine in chronic opioid refractory cancer pain. Methods and analysis: We will recruit 120 subjects with chronic opioid refractory pain, defined as pain lasting more than 3 months despite optimal therapy with high dose opioids (>60 mg morphine equivalent dose/day) and optimal adjuvant therapy. Subjects will be randomized into two groups: intranasal esketamine (56mg) and placebo. Treatment will be administered twice a week for four consecutive weeks. The primary outcome is defined as reduction in the Numeric Pain Rating Scale (NPRS) after first application. Secondary outcomes include NPRS reduction after four weeks, the number of daily morphine rescue doses, functional status and satisfaction, and depression. Conclusion: This study may extend therapeutic options in patients with chronic pain, thus improving their quality of life and reducing opioid use. Trial registration: Clinical Trials.gov, NCT04666623. Registered on 14 December 2020.

EEG modulation by different transcranial direct current stimulation (tDCS) montages: a randomized double-blind sham-control mechanistic pilot trial in healthy participants.

Background: Based on our Phantom study on transcranial direct current stimulation (tDCS), we hypothesized that EEG band power and field confinement would be greater following left dorsolateral prefrontal cortex (DLPFC - F3) tDCS using circular vs. rectangular electrodes.Methods: Double-blind-randomized trial comparing tDCS with anode over left DLPFC (groups: rectangular electrodes, circular electrodes, sham) and 2 active subgroup references (right shoulder vs. right DLPFC).Results: Twenty-four randomized participants were assessed. We indeed found higher average EEG power spectral density (PSD) across bands for circular vs. rectangular electrodes, largely confined to F3 and there was a significant increase at AF3 for low alpha (p = 0.037). Significant differences included: increased PSD in low beta (p = 0.024) and theta bands (p = 0.021) at F3, and in theta (p = 0.036) at FC5 for the right DLPFC vs. shoulder with no coherence changes. We found PSD differences between active vs. sham tDCS at Fz for alpha (p = 0.043), delta (p = 0.036), high delta (p = 0.030); and at FC1 for alpha (p = 0.031), with coherence differences for F3-Fz in beta (p = 0.044), theta (p = 0.044), delta (p = 0.037) and high delta (p = 0.009).Conclusion: This pilot study despite low statistical power given its small sample size shows that active left DLPFC tDCS modulates EEG frontocentrally and suggests that electrode shapes/reference locations affect its neurophysiological effects, such as increased low alpha power at AF3 using circular vs. rectangular electrodes. Further research with more participants is warranted.

Decreased neural inhibitory state in fibromyalgia pain: A cross-sectional study.

OBJECTIVES: Chronic pain is one of the most common and challenging symptoms in fibromyalgia (FM). Currently, self-reported pain is the main criterion used by clinicians assessing patients with pain. However, it is subjective, and multiple factors can affect pain levels. In this study, we investigated the neural correlates of FM pain using conditioned pain modulation (CPM), electroencephalography (EEG), and transcranial magnetic stimulation (TMS). METHODS: In this cross-sectional neurophysiological analysis of a randomized, double-blind controlled trial, 36 patients with fibromyalgia were included. We analyzed CPM, EEG variables and TMS measures and their correlation with pain levels as measured by a visual analog scale. Univariate and multivariate linear regression analyses were performed to identify the predictors of pain severity. RESULTS: We found: (1) no association between pain levels and CPM; (2) an association between reduced alpha and beta power over the central region in resting-EEG and higher pain levels; (3) an association between smaller event-related desynchronization (ERD) responses in theta and delta bands over the central region and higher pain levels; (4) an association between smaller ERD responses in theta and delta bands and smaller intracortical inhibition and higher intracortical facilitation ratios; (5) an association between smaller ERD responses in delta band and reduced CPM. CONCLUSIONS: Our results do not support CPM as a biomarker for pain intensity in FM. However, our specific EEG findings showing the relationship between pain, CPM and TMS measures suggest that FM leads to a disruption of inhibitory neural modulators and thus support CPM as a likely predictive marker of disrupted pain modulation system. These neurophysiological markers need to be further explored in potential future trials as to find novel targets for the treatment of FM.

Beta-band oscillations as a biomarker of gait recovery in spinal cord injury patients: A quantitative electroencephalography analysis.

OBJECTIVE: The gait recovery in spinal cord injury (SCI) seems to be partially related to the reorganization of cerebral function; however, the neural mechanisms and the respective biomarkers are not well known. This study tested the hypothesis that enhanced beta-band oscillations may be a marker of compensatory neural plasticity during the recovery period in SCI. We tested this hypothesis at baseline in SCI subjects and also in response to cortical stimulation with transcranial direct current stimulation (tDCS) combined with robotic-assisted gait training (RAGT). METHODS: In this neurophysiological analysis of a randomized controlled trial, thirty-nine patients with incomplete SCI were included. They received 30 sessions of either active or sham anodal tDCS over the primary motor area for 20 min combined with RAGT. We analyzed the Electroencephalography (EEG) power spectrum and task-related power modulation of EEG oscillations, and their association with gait function indexed by Walk Index for Spinal Cord Injury (WISCI-II). Univariate and multivariate linear/logistic regression analyses were performed to identify the predictors of gait function and recovery. RESULTS: Consistent with our hypothesis, we found that in the sensorimotor area: (1) Anodal tDCS combined with RAGT can modulate high-beta EEG oscillations power and enhance gait recovery; (2) higher high-beta EEG oscillations power at baseline can predict baseline gait function; (3) high-beta EEG oscillations power at baseline can predict gait recovery - the higher power at baseline, the better gait recovery; (4) decreases in relative high-beta power and increases in beta power decrease during walking are associated with gait recovery. CONCLUSIONS: Enhanced EEG beta oscillations in the sensorimotor area in SCI subjects may be part of a compensatory mechanism to enhance local plasticity. Our results point to the direction that interventions enhancing local plasticity such as tDCS combined with robotic training also lead to an immediate increase in sensorimotor cortex activation, improvement in gait recovery, and subsequent decrease in high-beta power. These findings suggest that beta-band oscillations may be potential biomarkers of gait function and recovery in SCI. SIGNIFICANCE: These findings are significant for rehabilitation in SCI patients, and as EEG is a portable, inexpensive, and easy-to-apply system, the clinical translation is feasible to follow better the recovery process and to help to individualize rehabilitation therapies of SCI patients.

Optimised transcranial direct current stimulation (tDCS) for fibromyalgia-targeting the endogenous pain control system: a randomised, double-blind, factorial clinical trial protocol.

INTRODUCTION: Fibromyalgia (FM) is a common debilitating condition with limited therapeutic options. Medications have low efficacy and are often associated with adverse effects. Given that FM is associated with a defective endogenous pain control system and central sensitisation, combining interventions such as transcranial direct current stimulation (tDCS) and aerobic exercise (AE) to modulate pain-processing circuits may enhance pain control. METHODS AND ANALYSIS: A prospective, randomised (1:1:1:1), placebo-controlled, double-blind, factorial clinical trial will test the hypothesis that optimised tDCS (16 anodal tDCS sessions combined with AE) can restore of the pain endogenous control system. Participants with FM (n=148) will undergo a conditioning exercise period and be randomly allocated to one of four groups: (1) active tDCS and AE, (2) sham tDCS and AE, (3) active tDCS and non-aerobic exercise (nAE) or (4) sham tDCS and nAE. Pain inhibitory activity will be assessed using conditioned pain modulation (CPM) and temporal slow pain summation (TSPS)-primary outcomes. Secondary outcomes will include the following assessments: Transcranial magnetic stimulation and electroencephalography as cortical markers of pain inhibitory control and thalamocortical circuits; secondary clinical outcomes on pain, FM, quality of life, sleep and depression. Finally, the relationship between the two main mechanistic targets in this study-CPM and TSPS-and changes in secondary clinical outcomes will be tested. The change in the primary efficacy endpoint, CPM and TSPS, from baseline to week 4 of stimulation will be tested with a mixed linear model and adjusted for important demographic variables. ETHICS AND DISSEMINATION: This study obeys the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Partners Healthcare under the protocol number 2017P002524. Informed consent will be obtained from participants. Study findings will be reported in conferences and peer-reviewed journal publications. TRIAL REGISTRATION NUMBER: NCT03371225.

Colour vision in juvenile myoclonic epilepsy.

To determine the integrity of colour perception, related to photic sensitivity, in patients with juvenile myoclonic epilepsy. Twenty-four patients with photoparoxysmal response, 27 patients without photoparoxysmal response, and 32 healthy individuals were investigated using the Farnsworth Munsell-100 Hue test to calculate error scores for total colour, blue/yellow, and red/green. No significant differences were observed regarding blue/yellow, red/green or total error score between juvenile myoclonic epilepsy patients with or without photoparoxysmal response. However, the data for all three scores were significantly higher in both patient groups compared to the healthy control group. In both patient groups, the blue/yellow error score was significantly higher than the red/green error score. We were unable to identify a relationship between photoparoxysmal response and colour vision in patients with juvenile myoclonic epilepsy. We believe that the underlying reason why juvenile myoclonic epilepsy patients had significantly higher blue/yellow, red/green, and total error score compared to the healthy control group may be due to GABA dysfunction, which is considered to play a role in the pathophysiology of this disease as well as the physiology of colour vision.

Methylation of cation-chloride cotransporters NKCC1 and KCC2 in patients with juvenile myoclonic epilepsy.

The etiology of juvenile myoclonic epilepsy (JME) is still unknown and the process of elaboration of multiple genetic mechanisms is ongoing. The aim of this study was to investigate the potential role of NKCC1 (SCL12A2) and KCC2 (SCL12A5) in JME by comparing their DNA methylation status in patients with JME versus healthy controls. Forty-nine patients with JME and 39 healthy individuals were compared for DNA methylation at the 5CpG islands. A total of 71 (81%) samples were found to have methylation in the NKCC1 gene, 36 (73%) from patients and 35 (90%) from healthy individuals. Out of the KCC2 samples, 50 (57%) were found to have methylation, 33 (67%) from patients and 17 (44%) from healthy individuals. In patients with JME, methylation of NKCC1 (73%) was lower than its methylation in the controls (90%) (p = 0.047). On the other hand, methylation of KCC2 in patients with JME (67%) was greater than the methylation in the controls (44%) (p = 0.022). Twenty-eight patients were treated with VPA and ongoing medications were not found to be associated with methylation (p > 0.05). In the present study, we determined significantly lower NKCC1 DNA methylation and significantly higher KCC2 DNA methylation levels in patients with JME compared with the healthy controls. This implies that NKCC1 expression can be higher and KCC2 expression can be reduced in affected people. Further studies that investigate the potential effect of DNA methylation mechanisms regulating gene expression on seizure activity and how they change JME network activity will be helpful.

Developing an optimized strategy with transcranial direct current stimulation to enhance the endogenous pain control system in fibromyalgia.

INTRODUCTION: Fibromyalgia affects more than 5 million people in the United States and has a detrimental impact on individuals' quality of life. Current pharmacological treatments provide limited benefits to relieve the pain of fibromyalgia, along with a risk of adverse effects; a scenario that explains the increasing interest for multimodal approaches. A tailored strategy to focus on this dysfunctional endogenous pain inhibitory system is transcranial direct current stimulation (tDCS) of the primary motor cortex. By combining tDCS with aerobic exercise, the effects can be optimized. Areas covered: The relevant literature was reviewed and discussed the methodological issues for designing a mechanistic clinical trial to test this combined intervention. Also, we reviewed the neural control of different pathways that integrate the endogenous pain inhibitory system, as well as the effects of tDCS and aerobic exercise both alone and combined. In addition, potential neurophysiological assessments are addressed: conditioned pain modulation, temporal slow pain summation, transcranial magnetic stimulation, and electroencephalography in the context of fibromyalgia. Expert commentary: By understanding the neural mechanisms underlying pain processing and potential optimized interventions in fibromyalgia with higher accuracy, the field has an evident potential of advancement in the direction of new neuromarkers and tailored therapies.

A novel biomarker for prediction of atrial fibrillation susceptibility in patients with celiac disease.

BACKGROUND: Celiac disease (CD), a serious autoimmune disorder that occurs in people who are genetically predisposed, is induced by dietary gluten intake and affects primarily the small intestine. Many studies have identified an increased risk of cardiovascular problems in patients with CD. Moreover, these patients are susceptible to certain liver diseases, as well as fibrosis. OBJECTIVE: The aim of this study was to assess the presence of fibrosis using the De Ritis ratio, determining its effect on the electromechanical features of the left atrium and its susceptibility to atrial fibrillation (AF) in patients with CD. METHODS: A total of 97 patients diagnosed with CD by antibody test and biopsy were included in this prospective study. Two groups were created from these patients, a fibrosis-prone (FP) group and a non-fibrosis-prone (NFP) group, according to the cut-off value, as defined in previously published reports, for the AST/ALT ratio. Electrocardiographic and echocardiographic examinations were performed as part of the study. RESULTS: There were no differences in the baseline characteristics and conventional echocardiographic parameters of the defined groups. However, the patients in the FP group, as compared to those in the NFP group, had significantly increased PWD (56.68±6.48 ms vs. 37.49±6.22 ms, P<0.001). Additionally, significantly higher interatrial (60.50±13.05 ms vs. 29.40±11.55 ms, P<0.001), intra-left atrial (44.18±14.12 ms vs. 21.02±11.99 ms, P<0.001), and intra-right atrial (15.61±8.91 ms vs. 8.38±4.50 ms, P<0.001) EMD was found among the patients in the FP group compared to that of the NFP group. CONCLUSION: It is believed that the susceptibility to AF cited in previous studies may be related to fibrosis. Our study is the first to examine the possible effects of fibrosis on AF susceptibility in patients with CD, whereby we propose a new biomarker for prediction of AF susceptibility of these patients.

Reversible Splenial Lesion Syndrome After Intravenous Immunoglobulin Treatment for Guillain-Barre Syndrome.

Reversible corpus callosum splenial (CCS) lesions have been described in patients with varied etiologies. The most common causes of previously reported reversible focal lesions of the CCS are viral encephalitis, antiepileptic drug toxicity/withdrawal, and metabolic disorders. Intravenous immunoglobulin (IVIG) therapy is used for different immune-mediated diseases. It is generally safe, and serious adverse reactions are uncommon. We presented a rare case of disturbed consciousness with reversible CCS lesions after IVIG therapy for Guillain-Barre syndrome in an adult woman. In this case, we believe that IVIG therapy caused reversible CCS lesions with encephalopathy and probably result of cytotoxic edema and/or cerebral arterial vasospasm.