Cutin-Derived Oligomers Induce Hallmark Plant Immune Responses.

The cuticle constitutes the outermost defensive barrier of most land plants. It comprises a polymeric matrix - cutin, surrounded by soluble waxes. Moreover, the cuticle constitutes the first line of defense against pathogen invasion, while also protecting the plant from many abiotic stresses. Aliphatic monomers in cutin have been suggested to act as immune elicitors in plants. This study analyses the potential of cutin oligomers to activate rapid signaling outputs reminiscent of pattern-triggered immunity (PTI) in the model plant Arabidopsis. Cutin oligomeric mixtures led to Ca2+ influx and MAPK activation. Comparable responses were measured for cutin, which was also able to induce a reactive oxygen species (ROS) burst. Furthermore, cutin oligomer treatment resulted in a unique transcriptional reprogramming profile, having many archetypal features of PTI. Targeted spectroscopic and spectrometric analyses of the cutin oligomers suggest that the elicitors compounds consist mostly of two up to three 10,16-dihydroxyhexadecanoic acid monomers linked together through ester bonds. This study demonstrates that cutin breakdown products can act as inducers of early plant immune responses, which underlying mechanisms of perception and potential use in agriculture warrant further investigation.

Redefining migraine prevention: early treatment with anti-CGRP monoclonal antibodies enhances response in the real world.

BACKGROUND: Anti-CGRP monoclonal antibodies (anti-CGRP MAbs) are approved and available treatments for migraine prevention. Patients do not respond alike and many countries have reimbursement policies, which hinder treatments to those who might respond. This study aimed to investigate clinical factors associated with good and excellent response to anti-CGRP MAbs at 6 months. METHODS: European multicentre, prospective, real-world study, including high-frequency episodic or chronic migraine (CM) patients treated since March 2018 with anti-CGRP MAbs. We defined good and excellent responses as ≥50% and ≥75% reduction in monthly headache days (MHD) at 6 months, respectively. Generalised mixed-effect regression models (GLMMs) were used to identify variables independently associated with treatment response. RESULTS: Of the 5818 included patients, 82.3% were females and the median age was 48.0 (40.0-55.0) years. At baseline, the median of MHD was 20.0 (14.0-28.0) days/months and 72.2% had a diagnosis of CM. At 6 months (n=4963), 56.5% (2804/4963) were good responders and 26.7% (1324/4963) were excellent responders. In the GLMM model, older age (1.08 (95% CI 1.02 to 1.15), p=0.016), the presence of unilateral pain (1.39 (95% CI 1.21 to 1.60), p<0.001), the absence of depression (0.840 (95% CI 0.731 to 0.966), p=0.014), less monthly migraine days (0.923 (95% CI 0.862 to 0.989), p=0.023) and lower Migraine Disability Assessment at baseline (0.874 (95% CI 0.819 to 0.932), p<0.001) were predictors of good response (AUC of 0.648 (95% CI 0.616 to 0.680)). These variables were also significant predictors of excellent response (AUC of 0.691 (95% CI 0.651 to 0.731)). Sex was not significant in the GLMM models. CONCLUSIONS: This is the largest real-world study of migraine patients treated with anti-CGRP MAbs. It provides evidence that higher migraine frequency and greater disability at baseline reduce the likelihood of responding to anti-CGRP MAbs, informing physicians and policy-makers on the need for an earlier treatment in order to offer the best chance of treatment success.

µ-Opioid Receptor Activation at the Dorsal Reticular Nucleus Shifts Diffuse Noxious Inhibitory Controls to Hyperalgesia in Chronic Joint Pain in Male Rats.

BACKGROUND: The dorsal reticular nucleus is a pain facilitatory area involved in diffuse noxious inhibitory control (DNIC) through opioidergic mechanisms that are poorly understood. The hypothesis was that signaling of µ-opioid receptors is altered in this area with prolonged chronic inflammatory pain and that this accounts for the loss of DNICs occurring in this condition. METHODS: Monoarthritis was induced in male Wistar rats (n = 5 to 9/group) by tibiotarsal injection of complete Freund's adjuvant. The immunolabeling of µ-opioid receptors and the phosphorylated forms of µ-opioid receptors and cAMP response element binding protein was quantified. Pharmacologic manipulation of µ-opioid receptors at the dorsal reticular nucleus was assessed in DNIC using the Randall-Selitto test. RESULTS: At 42 days of monoarthritis, µ-opioid receptor labeling decreased at the dorsal reticular nucleus, while its phosphorylated form and the phosphorylated cAMP response element binding protein increased. [d-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate (DAMGO) enhanced DNIC analgesia in normal animals (means ± SD: pre-DNIC: 126.9 ± 7.0 g; DNIC - DAMGO: 147.5 ± 8.0 g vs. DNIC + DAMGO: 198.1 ± 19.3 g; P < 0.001), whereas it produced hyperalgesia in monoarthritis (pre-DNIC: 67.8 ± 7.5 g; DNIC - DAMGO: 70.6 ± 7.7 g vs. DNIC + DAMGO: 32.2 ± 2.6 g; P < 0.001). An ultra-low dose of naloxone, which prevents the excitatory signaling of the µ-opioid receptor, restored DNIC analgesia in monoarthritis (DNIC - naloxone: 60.0 ± 6.1 g vs. DNIC + naloxone: 98.0 ± 13.5 g; P < 0.001), compared to saline (DNIC - saline: 62.5 ± 5.2 g vs. DNIC + saline: 64.2 ± 3.8 g). When injected before DAMGO, it restored DNIC analgesia and decreased the phosphorylated cAMP response element binding protein in monoarthritis. CONCLUSIONS: The dorsal reticular nucleus is likely involved in a facilitatory pathway responsible for DNIC hyperalgesia. The shift of µ-opioid receptor signaling to excitatory in this pathway likely accounts for the loss of DNIC analgesia in monoarthritis.

Neglect scoring modifications in the National Institutes of Health Stroke Scale improve right hemisphere stroke lesion volume prediction.

BACKGROUND: The National Institutes of Health Stroke Scale (NIHSS) does not equitably assess stroke severity in the two cerebral hemispheres. By attributing a maximum of two points for neglect and seven for language, it undervalues right hemisphere deficits. We aimed to investigate if NIHSS equally predicts right hemisphere lesion volumes in patients with and without neglect, and if a modification of the neglect scoring rules could increase its predictive capacity. METHODS: We analyzed a prospective cohort of acute right middle cerebral artery ischemic stroke patients. First, we calculated the correlation between NIHSS scores and lesion volume and analyzed the partial correlation of neglect. Then, we applied different modifications in the neglect scoring rules and investigated how they interfered with lesion volume predictive capacity. RESULTS: A total of 162 ischemic stroke patients were included, 108 with neglect and 54 without. The correlation between lesion volume and NIHSS was lower in patients with neglect (r = 0.540 vs. r = 0.219, p = 0.004) and neglect was a statistically significant covariate in the partial correlation analysis between NIHSS and lesion volume (p = 0.017). With the neglect score tripled and with the duplication or triplication of all neglect modalities, the correlation was significantly higher than with the standard NIHSS (p = 0.043, p = 0.005, p = 0.001, respectively). With these modifications, neglect was no longer a significant covariable in the partial correlation between lesion volume and NIHSS. CONCLUSION: A modification of NIHSS neglect scoring might improve the scale's capacity to predict lesion volume.

Working memory during spontaneous migraine attacks: an fMRI study.

OBJECTIVE: To investigate the neural correlates of working memory during a spontaneous migraine attack compared to the interictal phase, using functional magnetic resonance imaging (fMRI). BACKGROUND: Cognitive disturbances are commonly observed during migraine attacks, particularly in the headache phase. However, the neural basis of these changes remains unknown. METHODS: In a fMRI within-subject test-retest design study, eleven women (32 years of age, average) with episodic migraine were evaluated twice, first during a spontaneous migraine attack, and again in a pain-free period. Each session consisted in a cognitive assessment and fMRI while performing a working memory task (N-back). RESULTS: Cognitive test scores were lower during the ictal session than in the pain-free session. Regions typically associated with working memory were activated during the N-back task in both sessions. A voxel wise between session comparison showed significantly greater activation in the left frontal pole and orbitofrontal cortex during the attack relative to the interictal phase. CONCLUSION: Migraine patients exhibited greater activation of the left frontal pole and orbitofrontal cortex while executing a verbal working memory task during a spontaneous migraine attack when compared to the interictal state. Given the association of these regions with pain processing and inhibitory control, these findings suggest that patients recruit inhibitory areas to accomplish the cognitive task during migraine attacks, a neural signature of their cognitive difficulties.

Real-world effectiveness of fremanezumab for the preventive treatment of migraine: Interim analysis of the pan-European, prospective, observational, phase 4 PEARL study.

BACKGROUND: The ongoing Pan-European Real Life (PEARL) phase 4 study is evaluating fremanezumab effectiveness and safety for the prevention of episodic and chronic migraine. This interim analysis reports primary, secondary and exploratory endpoints from when 500 participants completed at least six months of treatment. METHODS: Adults with episodic migraine or chronic migraine maintaining daily headache diaries were enrolled upon initiation of fremanezumab. Primary endpoint: proportion of participants with ≥50% reduction in monthly migraine days during the six-month period after fremanezumab initiation. Secondary endpoints: mean change from baseline across months 1-12 in monthly migraine days, acute migraine medication use, and headache-related disability. Exploratory endpoint: mean change in headache severity from baseline across months 1-12. Safety was assessed through adverse events reported. RESULTS: Overall, 897 participants were enrolled and 574 included in the effectiveness analyses (episodic migraine, 25.8%; chronic migraine, 74.2%). Of participants with data available, 175/313 (55.9%) achieved ≥50% monthly migraine days reduction during the six-month period post-initiation. Across months 1-12, there were sustained reductions in mean monthly migraine days, acute medication use, disability scores, and headache severity. Few adverse events were reported. CONCLUSION: PEARL interim results support the effectiveness and safety of fremanezumab for migraine prevention in a real-world population across several European countries.Trial registration: encepp.eu: EUPAS35111.

Clinical presentation and neural correlates of stroke-associated spatial delusions.

BACKGROUND AND PURPOSE: Incongruent beliefs about self-localization in space markedly disturb patients' behavior. Spatial delusions, or reduplicative paramnesias, are characterized by a firm conviction of place reduplication, transformation, or mislocation. Evidence suggests they are frequent after right hemisphere lesions, but comprehensive information about their clinical features is lacking. METHODS: We prospectively screened 504 acute right-hemisphere stroke patients for the presence of spatial delusions. Their behavioral and clinical features were systematically assessed. Then, we analyzed the correlation of their duration with the magnitude of structural disruption of belief-associated functional networks. Finally, we described the syndrome subtypes and evaluated whether the clinical categorization would be predicted by the structural disruption of familiarity-associated functional networks using an unsupervised k-means clustering algorithm. RESULTS: Sixty patients with spatial delusions were identified and fully characterized. Most (93%) localized the misidentified places closer to home than the hospital. The median time duration was 3 days (interquartile range = 1-7 days), and it was moderately correlated with the magnitude of structural-functional decoupling of belief-associated functional networks (r = 0.39, p = 0.02; beta coefficient regressing for lesion volume = 3.18, p = 0.04). Each clinical subtype had characteristic response patterns, which were reported, and representative examples were provided. Clustering based on structural disruption of familiarity- and unfamiliarity-associated functional networks poorly matched the clinical categorization (lesion: Rand index = 0.47; structural disconnection: Rand index = 0.51). CONCLUSIONS: The systematic characterization of the peculiar clinical features of stroke-associated spatial delusions may improve the syndrome diagnosis and clinical approaches. The novel evidence about their neural correlates fosters the clarification of the pathophysiology of delusional misidentifications.

Unravelling the Neural Basis of Spatial Delusions After Stroke.

OBJECTIVE: Knowing explicitly where we are is an interpretation of our spatial representations. Reduplicative paramnesia is a disrupting syndrome in which patients present a firm belief of spatial mislocation. Here, we studied the largest sample of patients with delusional misidentifications of space (ie, reduplicative paramnesia) after stroke to shed light on their neurobiology. METHODS: In a prospective, cumulative, case-control study, we screened 400 patients with acute right-hemispheric stroke. We included 64 cases and 233 controls. First, lesions were delimited and normalized. Then, we computed structural and functional disconnection maps using methods of lesion-track and network-mapping. The maps were compared, controlling for confounders. Second, we built a multivariate logistic model, including clinical, behavioral, and neuroimaging data. Finally, we performed a nested cross-validation of the model with a support-vector machine analysis. RESULTS: The most frequent misidentification subtype was confabulatory mislocation (56%), followed by place reduplication (19%), and chimeric assimilation (13%). Our results indicate that structural disconnection is the strongest predictor of the syndrome and included 2 distinct streams, connecting right fronto-thalamic and right occipitotemporal structures. In the multivariate model, the independent predictors of reduplicative paramnesia were the structural disconnection map, lesion sparing of right dorsal fronto-parietal regions, age, and anosognosia. Good discrimination accuracy was demonstrated (area under the curve = 0.80 [0.75-0.85]). INTERPRETATION: Our results localize the anatomic circuits that may have a role in the abnormal spatial-emotional binding and in the defective updating of spatial representations underlying reduplicative paramnesia. This novel data may contribute to better understand the pathophysiology of delusional syndromes after stroke. ANN NEUROL 2021;89:1181-1194.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous EEG: Generalizable cross-patient models.

This study describes a generalized cross-patient seizure-forecasting approach using recurrent neural networks with ultra-long-term subcutaneous EEG (sqEEG) recordings. Data from six patients diagnosed with refractory epilepsy and monitored with an sqEEG device were used to develop a generalized algorithm for seizure forecasting using long short-term memory (LSTM) deep-learning classifiers. Electrographic seizures were identified by a board-certified epileptologist. One-minute data segments were labeled as preictal or interictal based on their relationship to confirmed seizures. Data were separated into training and testing data sets, and to compensate for the unbalanced data ratio in training, noise-added copies of preictal data segments were generated to expand the training data set. The mean and standard deviation (SD) of the training data were used to normalize all data, preserving the pseudo-prospective nature of the analysis. Different architecture classifiers were trained and tested using a leave-one-patient-out cross-validation method, and the area under the receiver-operating characteristic (ROC) curve (AUC) was used to evaluate the performance classifiers. The importance of each input signal was evaluated using a leave-one-signal-out method with repeated training and testing for each classifier. Cross-patient classifiers achieved performance significantly better than chance in four of the six patients and an overall mean AUC of 0.602 ± 0.126 (mean ± SD). A time in warning of 37.386% ± 5.006% (mean ± std) and sensitivity of 0.691 ± 0.068 (mean ± std) were observed for patients with better than chance results. Analysis of input channels showed a significant contribution (p < .05) by the Fourier transform of signals channels to overall classifier performance. The relative contribution of input signals varied among patients and architectures, suggesting that the inclusion of all signals contributes to robustness in a cross-patient classifier. These early results show that it is possible to forecast seizures training with data from different patients using two-channel ultra-long-term sqEEG.

Seizure forecasting using minimally invasive, ultra-long-term subcutaneous electroencephalography: Individualized intrapatient models.

OBJECTIVE: One of the most disabling aspects of living with chronic epilepsy is the unpredictability of seizures. Cumulative research in the past decades has advanced our understanding of the dynamics of seizure risk. Technological advances have recently made it possible to record pertinent biological signals, including electroencephalogram (EEG), continuously. We aimed to assess whether patient-specific seizure forecasting is possible using remote, minimally invasive ultra-long-term subcutaneous EEG. METHODS: We analyzed a two-center cohort of ultra-long-term subcutaneous EEG recordings, including six patients with drug-resistant focal epilepsy monitored for 46-230 days with median 18 h/day of recorded data, totaling >11 000 h of EEG. Total electrographic seizures identified by visual review ranged from 12 to 36 per patient. Three candidate subject-specific long short-term memory network deep learning classifiers were trained offline and pseudoprospectively on preictal (1 h before) and interictal (>1 day from seizures) EEG segments. Performance was assessed relative to a random predictor. Periodicity of the final forecasts was also investigated with autocorrelation. RESULTS: Depending on each architecture, significant forecasting performance was achieved in three to five of six patients, with overall mean area under the receiver operating characteristic curve of .65-.74. Significant forecasts showed sensitivity ranging from 64% to 80% and time in warning from 10.9% to 44.4%. Overall, the output of the forecasts closely followed patient-specific circadian patterns of seizure occurrence. SIGNIFICANCE: This study demonstrates proof-of-principle for the possibility of subject-specific seizure forecasting using a minimally invasive subcutaneous EEG device capable of ultra-long-term at-home recordings. These results are encouraging for the development of a prospective seizure forecasting trial with minimally invasive EEG.

Prognosis of headache in children: a 25-year follow-up.

AIM: To describe the natural history, evaluate the long-term prognosis, and identify predictors of a favorable outcome of childhood migraines in a cohort of children who had been diagnosed with migraine 25 years before. METHODS: One hundred eighteen children with headache (ages 2 to 15), observed in a headache outpatient clinic of a University Hospital in 1994, by one of the authors, were revaluated in 2019/2020 by a standardized telephone interview specifying headache characteristics, treatment, precipitants, and family history. Headache diagnosis at follow-up was based on ID-Migraine and confirmed by a semistructured interview. RESULTS: Revaluation was achieved for 88 (75%) patients (43 with migraine), 47 women and age average 41.2 ± 3.2. Over the follow-up (average 25.5 years), 33% of the patients had experienced remission, 41% maintained the same diagnosis, and 26% evolved into a different headache. Sixty six percent reported an improvement. Only eight patients were attending regular consultations because of headache. Male sex came out as the only predictor of a favorable outcome. CONCLUSION: Most patients (66%) with pediatric headache continue to experience headache although reporting a significant improvement. Boys tended to remit more often than girls. This data suggests that age, genetics, and hormonal factors may play an important role in migraine phenotypic expression.

Pain Modulation from the Locus Coeruleus in a Model of Hydrocephalus: Searching for Oxidative Stress-Induced Noradrenergic Neuroprotection.

Pain transmission at the spinal cord is modulated by noradrenaline (NA)-mediated actions that arise from supraspinal areas. We studied the locus coeruleus (LC) to evaluate the expression of the cathecolamine-synthetizing enzyme tyrosine hydroxylase (TH) and search for local oxidative stress and possible consequences in descending pain modulation in a model of hydrocephalus, a disease characterized by enlargement of the cerebral ventricular system usually due to the obstruction of cerebrospinal fluid flow. Four weeks after kaolin injection into the cisterna magna, immunodetection of the catecholamine-synthetizing enzymes TH and dopamine-ß-hydroxylase (DBH) was performed in the LC and spinal cord. Colocalization of the oxidative stress marker 8-OHdG (8-hydroxyguanosine; 8-OHdG), with TH in the LC was performed. Formalin was injected in the hindpaw both for behavioral nociceptive evaluation and the immunodetection of Fos expression in the spinal cord. Hydrocephalic rats presented with a higher expression of TH at the LC, of TH and DBH at the spinal dorsal horn along with decreased nociceptive behavioral responses in the second (inflammatory) phase of the formalin test, and formalin-evoked Fos expression at the spinal dorsal horn. The expression of 8-OHdG was increased in the LC neurons, with higher co-localization in TH-immunoreactive neurons. Collectively, the results indicate increased noradrenergic expression at the LC during hydrocephalus. The strong oxidative stress damage at the LC neurons may lead to local neuroprotective-mediated increases in NA levels. The increased expression of catecholamine-synthetizing enzymes along with the decreased nociception-induced neuronal activation of dorsal horn neurons and behavioral pain signs may indicate that hydrocephalus is associated with alterations in descending pain modulation.

Obtaining Aromatic Extracts from Portuguese Thymus mastichina L. by Hydrodistillation and Supercritical Fluid Extraction with CO2 as Potential Flavouring Additives for Food Applications.

Humans often respond to sensory impulses provided by aromas, and current trends have generated interest in natural sources of fragrances rather than the commonly used synthetic additives. For the first time, the resulting aroma of a selected culture of Thymus mastichina L. was studied as a potential food ingredient. In this context, dried (DR) and fresh (FR) samples were submitted to carbon dioxide (CO2) supercritical extraction (SFE) and hydrodistillation (HD) methods. The extracts were characterised according to their volatile composition by GC-MS, cytotoxicity against a non-tumour cell culture, and sensory attributes (odour threshold and olfactive descriptors). The most abundant aromas were quantified, and the analysis performed by GC-MS revealed an abundance of terpenoids such as thymol chemotype, followed by the precursors α-terpinene and p-cymene. DR and FR extracts (EX) obtained from SFE-CO2 show the highest content of thymol, achieving 52.7% and 72.5% of the isolated volatile fraction. The DR essential oil (EO) contained the highest amount of terpenoids, but it was also the most cytotoxic extract. In contrast, SFE-CO2 products showed the lowest cytotoxic potential. Regarding FR-OE, it had the lowest extraction yield and composition in aroma volatiles. Additionally, all samples were described as having green, fresh and floral sensory notes, with no significant statistical differences regarding the odour detection threshold (ODT) values. Finally, FR-EX of T. mastichina obtained by SFE-CO2 presented the most promising results regarding food application.

Signal quality and power spectrum analysis of remote ultra long-term subcutaneous EEG.

OBJECTIVE: Ultra long-term subcutaneous electroencephalography (sqEEG) monitoring is a new modality with great potential for both health and disease, including epileptic seizure detection and forecasting. However, little is known about the long-term quality and consistency of the sqEEG signal, which is the objective of this study. METHODS: The largest multicenter cohort of sqEEG was analyzed, including 14 patients with epilepsy and 12 healthy subjects, implanted with a sqEEG device (24/7 EEG™ SubQ), and recorded from 23 to 230 days (median 42 days), with a median data capture rate of 75% (17.9 hours/day). Median power spectral density plots of each subject were examined for physiological peaks, including at diurnal and nocturnal periods. Long-term temporal trends in signal impedance and power spectral features were investigated with subject-specific linear regression models and group-level linear mixed-effects models. RESULTS: sqEEG spectrograms showed an approximate 1/f power distribution. Diurnal peaks in the alpha range (8-13Hz) and nocturnal peaks in the sigma range (12-16Hz) were seen in the majority of subjects. Signal impedances remained low, and frequency band powers were highly stable throughout the recording periods. SIGNIFICANCE: The spectral characteristics of minimally invasive, ultra long-term sqEEG are similar to scalp EEG, whereas the signal is highly stationary. Our findings reinforce the suitability of this system for chronic implantation on diverse clinical applications, from seizure detection and forecasting to brain-computer interfaces.

Undergraduate neurology teaching: Comparison of an inpatient versus outpatient clinical setting.

BACKGROUND: Neurology is often perceived as a difficult discipline by medical students, yet it is an essential part of medical training. While the most common disorders of the nervous system can be observed in the outpatient setting, positive neurological signs are more likely to be found in neurology wards. We aimed to compare the impact of a neurology outpatient versus inpatient rotation setting on the grades obtained by medical students as a proxy measure of the learning outcomes. METHODS: We compared the results obtained by fourth year medical students in practical (OSCE) and multiple choice question (MCQ) exams in neurology, between students whose main (total of 24 h contact) teaching allocation was either the outpatient or inpatient setting, controlling for students' gender, teacher, academic year and student' previous achievement (measured by their scores on practical evaluation). RESULTS: A total of 1127 students were included, of whom 644 (57.14%) were allocated mainly to the neurology ward and 483 (42.86%) to the outpatient clinic. Students assigned to the ward obtained significantly higher grades in the OSCE and MCQ exams than those placed in the outpatient clinic. Teaching setting was an independent predictor of both classifications after adjustment. CONCLUSIONS: The teaching setting had a significant impact on the learning outcomes. This may be due to a higher likelihood of observing abnormal neurological signs or to more student-centered teaching on the ward. These results highlight the importance of a balanced distribution of students by different clinical settings.

Headache Gauge: a real-life calendar-based tool for headache monitoring.

BACKGROUND: This study aimed to validate a semi-quantitative composite score tool, "Headache Gauge" (HG), to monitor the treatment effect in primary headaches in everyday clinic practice, adjustable to any chosen timeframe. METHOD: A cohort validation study of HG was performed in primary headache patients, recovering their clinical data and patient-related outcome measures (PROMs) for headache (HIT-6, MIDAS, HURT), work impact (WPAIQ), quality-of-life (SF-12), and mood (STAI, ZUNG). HG score distribution, its relation to clinical variables, its internal consistency, and its convergent validity were determined. RESULTS: HG was plotted in 233 patients: 90.1% females, age average 37 years, 86% with migraine, 27% with chronic headaches, and 28% with medication overuse. HG ranged from 0.21 to 58.3 in this sample, higher in chronic headaches (HG 16) and medication overuse (HG 15). HG presented good concurrent validity, significantly correlating with HIT-6 (p < 0.0001), SF-12 (p = 0.001), WPAIQ (p < 0.0001), MIDAS (p < 0.0001), and HURT (p < 0.0001). Good sensitivity to change (p < 0.001) and moderate test-retest reliability (p = 0.001) were calculated after reassessment of 147 patients (63.1% of the initial sample). CONCLUSIONS: Headache Gauge is a clinical data-based outcome measure that conceptually translates the percentage of lost time to headache in any given timeframe. It relates to headache impact, therefore bearing the potential to be relevant in real-life clinical monitoring.

Serotoninergic pain modulation from the rostral ventromedial medulla (RVM) in chemotherapy-induced neuropathy: The role of spinal 5-HT3 receptors.

Chemotherapy-induced neuropathy (CIN) is a common complication of cancer treatment. Although CIN is treated with antidepressants that act at serotonin (5-HT) reuptake, the mechanisms of serotoninergic modulation of nociceptive transmission during CIN remain unknown, namely as to the involvement of the rostroventromedial medulla (RVM) and the role of spinal 5-HT3 receptors (5-HT3R). Male Wistar rats were injected with the cytostatic paclitaxel or vehicle solution. One month after CIN induction, we first studied the activation of RVM neurons, and then the activation of the local serotoninergic neurons. Immunostaining of phosphorylated extracellular signal-regulated kinase (pERK) indicated increased activation in paclitaxel-injected animals. The double immunohistochemistry of pERK and tryptophan hydroxylase (TpH) showed higher expression of TpH and increased co-localization of TpH and pERK of paclitaxel-injected animals, indicating that CIN is associated with increased activation of serotoninergic RVM neurons. The 5-HT content at the spinal dorsal horn assessed by HPLC was higher in paclitaxel-injected animals. The immunohistochemical analysis of 5-HT also showed increased expression at the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The levels of 5-HT3R detected by immunohistochemistry were higher in the superficial dorsal horn (laminae I-II) of paclitaxel-injected animals. The intrathecal administration of the 5-HT3R antagonist ondansetron reversed mechanical and cold hypersensitivity in the von Frey and cold plate tests, respectively. The results indicate that CIN is associated with increased recruitment of descending 5-HT-mediated modulation from the RVM which affects the spinal serotoninergic system and probably accounts for pain hypersensitivity due to the pronociceptive role of spinal 5-HT3R.

Shift of µ-opioid Receptor Signaling in the Dorsal Reticular Nucleus Is Implicated in Morphine-induced Hyperalgesia in Male Rats.

BACKGROUND: Increased descending pain facilitation accounts for opioid-induced hyperalgesia, but the underlying mechanisms remain elusive. Given the role of µ-opioid receptors in opioid-induced hyperalgesia in animals, the authors hypothesized that the dorsal reticular nucleus, a medullary pain facilitatory area, is involved in opioid-induced hyperalgesia through altered µ-opioid receptor signaling. METHODS: The authors used male Wistar rats (n = 5 to 8 per group), chronically infused with morphine, to evaluate in the dorsal reticular nucleus the expressions of the µ-opioid receptor and phosphorylated cAMP response element-binding, a downstream marker of excitatory µ-opioid receptor signaling. The authors used pharmacologic and gene-mediated approaches. Nociceptive behaviors were evaluated by the von Frey and hot-plates tests. RESULTS: Lidocaine fully reversed mechanical and thermal hypersensitivity induced by chronic morphine. Morphine-infusion increased µ-opioid receptor, without concomitant messenger RNA changes, and phosphorylated cAMP response element-binding levels at the dorsal reticular nucleus. µ-opioid receptor knockdown in morphine-infused animals attenuated the decrease of mechanical thresholds and heat-evoked withdrawal latencies compared with the control vector (von Frey [mean ± SD]: -17 ± 8% vs. -40 ± 9.0%; P < 0.001; hot-plate: -10 ± 5% vs. -32 ± 10%; P = 0.001). µ-opioid receptor knockdown in control animals induced the opposite (von Frey: -31 ± 8% vs. -17 ± 8%; P = 0.053; hotplate: -24 ± 6% vs. -3 ± 10%; P = 0.001). The µ-opioid receptor agonist (D-ALA2,N-ME-PHE4,GLY5-OL)-enkephalin acetate (DAMGO) decreased mechanical thresholds and did not affect heat-evoked withdrawal latencies in morphine-infused animals. In control animals, DAMGO increased both mechanical thresholds and heat-evoked withdrawal latencies. Ultra-low-dose naloxone, which prevents the excitatory signaling of the µ-opioid receptor, administered alone, attenuated mechanical and thermal hypersensitivities, and coadministered with DAMGO, restored DAMGO analgesic effects and decreased phosphorylated cAMP response element-binding levels. CONCLUSIONS: Chronic morphine shifted µ-opioid receptor signaling from inhibitory to excitatory at the dorsal reticular nucleus, likely enhancing descending facilitation during opioid-induced hyperalgesia in the rat.

Brain state monitoring for the future prediction of migraine attacks.

BACKGROUND: Migraine attacks are unpredictable, precluding preemptive interventions and leading to lack of control over individuals' lives. Although there are neurophysiological changes 24-48 hours before migraine attacks, so far, they have not been used in patients' management. This study evaluates the applicability and the ability to identify pre-attack changes of daily "at home" electroencephalography obtained with a portable system for migraine patients. METHODS: Patients with episodic migraine fulfilling ICHD-3 beta criteria used a mobile system composed of a wireless EEG device (BrainStation®, Neuroverse®, Inc., USA) and mobile application (BrainVitalsM®, Neuroverse®, Inc., USA) to self-record their neural activity daily at home while resting and while performing an attention task, over the course of 2 weeks. Standard EEG spectral analysis and event-related brain potentials (ERP) methods were used and recordings were grouped by time from migraine attacks (i.e. "Interictal day", "24 h Before Migraine", "Migraine day" and "Post Migraine"). RESULTS: Twenty-four patients (22 women) recorded an average of 13.3 ± 1.9 days and had 2 ± 0.9 attacks. Twenty-four hours before attack onset, there was a statistically significant modulation of relative power in the delta (decrease) and beta (increase) frequency bands, at rest, and a significant reduction of the amplitude and inter-trial coherence measures of an attention event-related brain potential (P300). CONCLUSIONS: This proof-of-concept study shows that brain state monitoring, utilising an easy-to-use wearable EEG system to track neural modulations at home, can identify physiological changes preceding a migraine attack enabling valuable pre-symptom prediction and subsequent early intervention.

Attenuation of the Diffuse Noxious Inhibitory Controls in Chronic Joint Inflammatory Pain Is Accompanied by Anxiodepressive-Like Behaviors and Impairment of the Descending Noradrenergic Modulation.

The noradrenergic system is paramount for controlling pain and emotions. We aimed at understanding the descending noradrenergic modulatory mechanisms in joint inflammatory pain and its correlation with the diffuse noxious inhibitory controls (DNICs) and with the onset of anxiodepressive behaviours. In the complete Freund's adjuvant rat model of Monoarthritis, nociceptive behaviors, DNICs, and anxiodepressive-like behaviors were evaluated. Spinal alpha2-adrenergic receptors (a2-AR), dopamine beta-hydroxylase (DBH), and noradrenaline were quantified concomitantly with a2-AR pharmacologic studies. The phosphorylated extracellular signal-regulated kinases 1 and 2 (pERK1/2) were quantified in the Locus coeruleus (LC), amygdala, and anterior cingulate cortex (ACC). DNIC was attenuated at 42 days of monoarthritis while present on days 7 and 28. On day 42, in contrast to day 28, noradrenaline was reduced and DBH labelling was increased. Moreover, spinal a2-AR were potentiated and no changes in a2-AR levels were observed. Additionally, at 42 days, the activation of ERKs1/2 was increased in the LC, ACC, and basolateral amygdala. This was accompanied by anxiety- and depressive-like behaviors, while at 28 days, only anxiety-like behaviors were observed. The data suggest DNIC is attenuated in prolonged chronic joint inflammatory pain, and this is accompanied by impairment of the descending noradrenergic modulation and anxiodepressive-like behaviors.