Noninvasive Neuromodulation in Headache: An Update.

Background: Migraine is a common disabling primary headache condition. Although strives have been made in treatment, there remains an unmet need for safe, effective acute, and preventative treatments. The promising concept of neuromodulation of relevant neuronal targets in a noninvasive fashion for the treatment of primary headache disorders has led to the trial of numerous devices over the years. Objective: We aimed to review the evidence on current neuromodulation treatments available for the management of primary headache disorders. Methods: Randomized controlled trial as well as open-label and real-world studies on central and peripheral cephalic and noncephalic neuromodulation modalities in primary headaches were critically reviewed. Results: The current evidence suggests a role of single-pulse transcranial magnetic stimulation, supraorbital nerve stimulation, and remote noncephalic electrical stimulation as migraine abortive treatments, with stronger evidence in episodic rather than in chronic migraine. Single-pulse transcranial magnetic stimulation and supraorbital nerve stimulation also hold promising evidence in episodic migraine prevention and initial positive evidence in chronic migraine prevention. More evidence should clarify the therapeutic role of the external vagus nerve stimulation and transcranial direct current stimulation in migraine. However, external vagus nerve stimulation may be effective in the acute treatment of episodic but not chronic cluster headache, in the prevention of hemicrania continua and paroxysmal hemicrania but not of short-lasting neuralgiform headache attacks. The difficulty in setting up sham-controlled studies has thus far prevented the publication of robust trials. This limitation along with the cost of these therapies has meant that their use is limited in most countries. Conclusion: Neuromodulation is a promising nonpharmacological treatment approach for primary headaches. More studies with appropriate blinding strategies and reduction of device cost may allow more widespread approval of these treatments and in turn increase clinician's experience in neuromodulation.

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine.

With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene-related peptide-targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain-binary toxin-AA (BiTox/AA)-cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.

Cortical Mechanisms of Single-Pulse Transcranial Magnetic Stimulation in Migraine.

Single-pulse transcranial magnetic stimulation (sTMS) of the occipital cortex is an effective migraine treatment. However, its mechanism of action and cortical effects of sTMS in migraine are yet to be elucidated. Using calcium imaging and GCaMP-expressing mice, sTMS did not depolarise neurons and had no effect on vascular tone. Pre-treatment with sTMS, however, significantly affected some characteristics of the cortical spreading depression (CSD) wave, the correlate of migraine aura. sTMS inhibited spontaneous neuronal firing in the visual cortex in a dose-dependent manner and attenuated L-glutamate-evoked firing, but not in the presence of GABAA/B antagonists. In the CSD model, sTMS increased the CSD electrical threshold, but not in the presence of GABAA/B antagonists. We first report here that sTMS at intensities similar to those used in the treatment of migraine, unlike traditional sTMS applied in other neurological fields, does not excite cortical neurons but it reduces spontaneous cortical neuronal activity and suppresses the migraine aura biological substrate, potentially by interacting with GABAergic circuits.

Medication-overuse headache: a widely recognized entity amidst ongoing debate.

Medication overuse in primary headache disorders is a worldwide phenomenon and has a role in the chronification of headache disorders. The burden of disease on individuals and societies is significant due to high costs and comorbidities. In the Third Edition of the International Classification of Headache Disorders, medication-overuse headache is recognized as a separate secondary entity next to mostly primary headache disorders, although many clinicians see the disease as a sole complication of primary headache disorders. In this review, we explore the historical background of medication-overuse headache, its epidemiology, phenomenology, pathophysiology and treatment options. The review explores relevant unanswered questions and summarizes the current debates in medication-overuse headache.

Highly parallel direct RNA sequencing on an array of nanopores.

Sequencing the RNA in a biological sample can unlock a wealth of information, including the identity of bacteria and viruses, the nuances of alternative splicing or the transcriptional state of organisms. However, current methods have limitations due to short read lengths and reverse transcription or amplification biases. Here we demonstrate nanopore direct RNA-seq, a highly parallel, real-time, single-molecule method that circumvents reverse transcription or amplification steps. This method yields full-length, strand-specific RNA sequences and enables the direct detection of nucleotide analogs in RNA.

Cancer Chemotherapy in Early Life Significantly Alters the Maturation of Pain Processing.

Advances in pediatric cancer treatment have led to a ten year survival rate greater than 75%. Platinum-based chemotherapies (e.g. cisplatin) induce peripheral sensory neuropathy in adult and pediatric cancer patients. The period from birth through to adulthood represents a period of maturation within nociceptive systems. Here we investigated how cisplatin impacts upon postnatal maturation of nociceptive systems. Neonatal Wistar rats (Postnatal day (P) 7) were injected (i.p.) daily with either vehicle (PBS) or cisplatin (1mg/kg) for five consecutive days. Neither group developed mechanical or thermal hypersensitivity immediately during or after treatment. At P22 the cisplatin group developed mechanical (P < 0.05) and thermal (P < 0.0001) hypersensitivity versus vehicle group. Total DRG or dorsal horn neuronal number did not differ at P45, however there was an increase in intraepidermal nerve fiber density in cisplatin-treated animals at this age. The percentage of IB4+ve, CGRP+ve and NF200+ve DRG neurons was not different between groups at P45. There was an increase in TrkA+ve DRG neurons in the cisplatin group at P45, in addition to increased TrkA, NF200 and vGLUT2 immunoreactivity in the lumbar dorsal horn versus controls. These data highlight the impact pediatric cancer chemotherapy has upon the maturation of pain pathways and later life pain experience.

Deaths among drivers and right-front passengers in frontal collisions: redesigned air bags relative to first-generation air bags.

OBJECTIVE: After automakers were allowed the option of using sled tests for unbelted male dummies to certify the frontal crash performance of vehicles, most frontal air bags were depowered, starting in model year 1998, to reduce deaths and serious injuries arising from air bag deployments. Concern has been expressed that depowering air bags could compromise the protection of adult occupants. This study aimed to determine the effects of changes in air bag designs on risk of death among front-seat occupants. METHODS: Deaths among drivers and right-front passengers per involvement in frontal police-reported crashes during calendar years 1998-2004 were compared among vehicles with sled-certified air bags (model years 1998-2004) and first-generation air bags (model years 1994-97). Frontal crash deaths were identified from the Fatality Analysis Reporting System. National estimates of police-reported crashes were derived from the National Automotive Sampling System/General Estimates System. Sled certification status for model years 1998-2004 was ascertained from published federal data and a survey of automobile manufacturers. Passenger cars, pickup trucks, sport utility vehicles, and minivans were studied. Stratified analyses were done to compute risk ratios (RR) and 95% confidence intervals (95% CI) for driver and right-front passenger deaths by air bag generation and crash, vehicle, and driver characteristics. RESULTS: In frontal crashes, overall RRs were 0.89 for driver deaths (95% CI = 0.74-1.08) and 0.89 for right-front passenger deaths (95% CI = 0.74-1.07) in sled-certified vehicles compared with first-generation air bag-equipped vehicles. Child right-front passengers (ages 0-4, 5-9) in vehicles with sled-certified air bags had statistically significant reductions in risk of dying in frontal collisions, including a 65% reduced risk among ages 0-4 (RR = 0.35; 95% CI = 0.21-0.60). No differences in effects of sled-certified air bags were observed between drivers ages 15-59 and 60-74 in sled-certified vehicles, both of whom had RRs slightly below 0.90 (non-significant). Among occupants killed in sled-certified vehicles, police-reported belt use was somewhat higher than in first-generation vehicles. CONCLUSIONS: No differences in risk of frontal crash deaths were observed between adult occupants with sled-certified and first-generation air bags. Consistent with reports of decreases in air bag-related deaths, this study observed significant reductions in frontal deaths among child passengers seated in the right-front position in sled-certified vehicles. Higher restraint use rates among children in sled-certified vehicles and other vehicle design changes might have contributed partially to these reductions.

Using head-on collisions to compare risk of driver death by frontal air bag generation: a matched-pair cohort study.

US air bag regulations were changed in 1997 to allow tests of unbelted male dummies in vehicles mounted and accelerated on sleds, resulting in longer crash pulses than rigid-barrier crashes. This change facilitated depowering of frontal air bags and was intended to reduce air bag-induced deaths. Controversy ensued as to whether sled-certified air bags could increase adult fatality risk. A matched-pair cohort study of two-vehicle, head-on, fatal collisions between drivers involving first-generation versus sled-certified air bags during 1998-2005 was conducted by using Fatality Analysis Reporting System data. Sled certification was ascertained from public information and a survey of automakers. Conditional Poisson regression for matched-pair cohorts was used to estimate risk ratios adjusted for age, seat belt status, vehicle type, passenger car size, and model year for driver deaths in vehicles with sled-certified air bags versus first-generation air bags. For all passenger-vehicle pairs, the adjusted risk ratio was 0.87 (95% confidence interval: 0.77, 0.98). In head-on collisions involving only passenger cars, the adjusted risk ratio was 1.04 (95% confidence interval: 0.85, 1.29). Increased fatality risk for drivers with sled-certified air bags was not observed. A borderline significant interaction between vehicle type and air bag generation suggested that sled-certified air bags may have reduced the risk of dying in head-on collisions among drivers of pickup trucks.