Magnetoencephalography in migraine and headache disorders: A review of its use to date

Background and Significance: Migraines are a leading cause of disability and suffering in the United States affecting 1 in 6 adults (Peters, 2019), and costing $32 billion per year in medical treatments and lost productivity (Bonafede et al., 2018). Migraines are also the most common reason for consultation to the neurologist (Callaghan et al., 2018). Migraine headaches are the greatest cause of disability in patients under the age of 50, affecting more females than males (3:1) (Pomes et al., 2019). The origin of migraine pathophysiology is still contentious. Vasogenic theory of migraine suggests that migraine attacks are caused by vasoconstriction followed by vasodilation of the meningeal vessels (Silberstein, 2004). However, the theory was disapproved due to the lack of correlation between the phases of migraine and alterations in cerebral blood flow. The neurogenic theory proposed that migraine is primarily a neuronal dysfunction caused by cortical sensory depolarization or depression (CSD) that leads to hyperexcitability of cortex and vascular changes (Charles and Baca, 2013). The theory gained popularity when CSD (Richter and Lehmenkuhler, 2008) originating from the visual cortex was found to be a physiological correlate of migraine aura (visual disturbances that accompanies headache) by some initial breakthrough studies (Barkley et al., 1990; Bowyer et al., 2001) that used Magnetoencephalography (MEG), a brain imaging tool. However, this finding did not provide evidence in support of CSD in migraine patients that doesn’t experience aura, leading to speculation that CSD in these patients could be asymptomatic occurring through other mechanisms that cannot be mapped by MEG (Hadjikhani and Vincent, 2019). Ever since these initial promising findings from the early 1990s, many studies have set out to investigate the cortical hyperexcitability phenomena in migraine and other headache disorders using MEG. However, studies have been mixed in their design, population characteristics and phenotypes. In addition, the state of the MEG has also evolved from a few induction coil magnetometer sensors from the 1900s to a more sophisticated multichannel SQUID devices with hundreds of sensors that we have today. As a result, analysis techniques have evolved making it possible to study deeper subcortical structures, in addition to cortical sources. This has caused additional variability to the reported datasets and its interpretation. MEG studies in migraine and headache disorders can be categorized into one of these three types, 1. Resting state, 2. Sensory evoked (visual, auditory, somatosensory) and 3) motor evoked. Majority of studies have investigated cortical evoked fields or cortical rhythms in various frequency bands from alpha-gamma bands. A few studies have investigated connectivity of different brain areas in the resting state or in a hyperexcitable state. Given the advancements in MEG, combining MEG with computational models is an upcoming technique and holds great promise to further our mechanistic understanding of brain dynamics in health and disease (Gross, 2019). Going beyond local activity, MEG combined with computational models (e.g., dynamic causal models) allows inference on latent states within a Bayesian framework based on brain activity. Given that migraine is not a purely sensory abnormality, but involves a significant behavioral and/or psychological components (e.g., fear avoidance) (Rogers et al., 2020), computationally driven MEG techniques hold promise to correlate task-related changes in brain activity more directly to latent cognitive processes. In this systematic review, we would like to present the current state of MEG in migraine and headache disorders, and accumulate evidence for the lack of computationally driven studies in MEG that can shed light into behavioral manifestations that inadvertently exacerbate pain, suffering and contribute to functional impairment. Barkley GL, Tepley N, Nagel-Leiby S, Moran JE, Simkins RT, Welch KM (1990) Magnetoencephalographic studies of migraine. Headache 30:428-434. Bonafede M, Sapra S, Shah N, Tepper S, Cappell K, Desai P (2018) Direct and Indirect Healthcare Resource Utilization and Costs Among Migraine Patients in the United States. Headache 58:700-714. Bowyer SM, Aurora KS, Moran JE, Tepley N, Welch KM (2001) Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Annals of neurology 50:582-587. Callaghan BC, Burke JF, Kerber KA, Skolarus LE, Ney JP, Magliocco B, Esper GJ (2018) The association of neurologists with headache health care utilization and costs. Neurology 90:e525-e533. Charles AC, Baca SM (2013) Cortical spreading depression and migraine. Nature reviews Neurology 9:637-644. Gross J (2019) Magnetoencephalography in Cognitive Neuroscience: A Primer. Neuron 104:189-204. Hadjikhani N, Vincent M (2019) Neuroimaging clues of migraine aura. J Headache Pain 20:32. Peters GL (2019) Migraine overview and summary of current and emerging treatment options. Am J Manag Care 25:S23-S34. Pomes LM, Guglielmetti M, Bertamino E, Simmaco M, Borro M, Martelletti P (2019) Optimising migraine treatment: from drug-drug interactions to personalized medicine. J Headache Pain 20:56. Richter F, Lehmenkuhler A (2008) [Cortical spreading depression (CSD): a neurophysiological correlate of migraine aura]. Schmerz 22:544-546, 548-550. Rogers DG, Protti TA, Smitherman TA (2020) Fear, Avoidance, and Disability in Headache Disorders. Current pain and headache reports 24:33. Silberstein SD (2004) Migraine pathophysiology and its clinical implications. Cephalalgia : an international journal of headache 24 Suppl 2:2-7

Mentored peer review of standardized manuscripts as a teaching tool for residents: a pilot randomized controlled multi-center study

Abstract Background There is increasing need for peer reviewers as the scientific literature grows. Formal education in biostatistics and research methodology during residency training is lacking. In this pilot study, we addressed these issues by evaluating a novel method of teaching residents about biostatistics and research methodology using peer review of standardized manuscripts. We hypothesized that mentored peer review would improve resident knowledge and perception of these concepts more than non-mentored peer review, while improving review quality. Methods A partially blinded, randomized, controlled multi-center study was performed. Seventy-eight neurology residents from nine US neurology programs were randomized to receive mentoring from a local faculty member or not. Within a year, residents reviewed a baseline manuscript and four subsequent manuscripts, all with introduced errors designed to teach fundamental review concepts. In the mentored group, mentors discussed completed reviews with residents. Primary outcome measure was change in knowledge score between pre- and post-tests, measuring epidemiology and biostatistics knowledge. Secondary outcome measures included level of confidence in the use and interpretation of statistical concepts before and after intervention, and RQI score for baseline and final manuscripts. Results Sixty-four residents (82%) completed initial review with gradual decline in completion on subsequent reviews. Change in primary outcome, the difference between pre- and post-test knowledge scores, did not differ between mentored (−8.5%) and non-mentored (−13.9%) residents (p = 0.48). Significant differences in secondary outcomes (using 5-point Likert scale, 5 = strongly agree) included mentored residents reporting enhanced understanding of research methodology (3.69 vs 2.61; p = 0.001), understanding of manuscripts (3.73 vs 2.87; p = 0.006), and application of study results to clinical practice (3.65 vs 2.78; p = 0.005) compared to non-mentored residents. There was no difference between groups in level of interest in peer review (3.00 vs 3.09; p = 0.72) or the quality of manuscript review assessed by the Review Quality Instrument (RQI) (3.25 vs 3.06; p = 0.50). Conclusions We used mentored peer review of standardized manuscripts to teach biostatistics and research methodology and introduce the peer review process to residents. Though knowledge level did not change, mentored residents had enhanced perception in their abilities to understand research methodology and manuscripts and apply study results to clinical practice