Faculty Bibliography

[Figure: see text].

PURPOSE OF REVIEW/OBJECTIVE:Patent foramen ovale (PFO) is widely prevalent and studies have suggested an association with ischemic stroke. In this review, we aim to highlight current management of patients with ischemic stroke in the setting of PFO and discuss some areas of controversy. RECENT FINDINGS/RESULTS:Upon reviewing the literature, we have found that the evidence regarding the management of patients with cryptogenic stroke and PFO has come a long way in the past several years, and many uncertainties remain in clinical practice. The Risk of Paradoxical Embolism (RoPE) score helps to predict the probability of a pathogenic PFO, and recent trial data confirms the benefit of closure in carefully selected patients. The benefit of closure in older patients and in patients with alternate, competing mechanisms is still uncertain, and the long-term risks of closure are not known. Finally, the efficacy of direct oral anticoagulants (DOACs) in this patient population as compared to other medical therapy or mechanical closure has not yet been investigated. Randomized data is needed to help answer these questions. PFO closure is a safe and effective strategy in reducing stroke risk in carefully selected patients with cryptogenic stroke in the setting of a PFO. More studies are needed to test optimal medical treatment strategies and the safety and efficacy of PFO closure in patient subgroups not included in prior PFO closure trials.

From August 27-28, 2020 the Epilepsy Foundation hosted the Pipeline Conference, exploring emerging issues related to antiepileptic drug and device development. The conference featured epilepsy therapeutic companies and academic laboratories developing drugs for focal epilepsies, innovations for rare and ultra-rare diseases, and devices both in clinical trials and approved for use. In this paper, we outline the virtual presentations by the authors, including novel data from their development pipeline.

In the adult mammalian brain, Gli1 expressing neural stem cells reside in the subventricular zone and their progeny are recruited to sites of demyelination in the white matter where they generate new oligodendrocytes, the myelin forming cells. Remarkably, genetic loss or pharmacologic inhibition of Gli1 enhances the efficacy of remyelination by these neural stem cells. To understand the molecular mechanisms involved, we performed a transcriptomic analysis of this Gli1-pool of neural stem cells. We compared murine NSCs with either intact or deficient Gli1 expression from adult mice on a control diet or on a cuprizone diet which induces widespread demyelination. These data will be a valuable resource for identifying therapeutic targets for enhancing remyelination in demyelinating diseases like multiple sclerosis.

PURPOSE OF REVIEW:Behavioral therapies are proven treatments for many neurologic conditions. However, the COVID-19 pandemic has posed significant challenges for conducting behavioral research. This article aims to (1) highlight the challenges of running behavioral clinical trials during the pandemic, (2) suggest approaches to maximize generalizability of pandemic-era studies, and (3) offer strategies for successful behavioral trials beyond the pandemic. RECENT FINDINGS:Thousands of clinical trials have been impacted by the COVID-19 pandemic, from undergoing protocol revisions to suspension altogether. Furthermore, for ongoing trials, recruitment of diverse populations has suffered, thereby exacerbating existing inequities in clinical research. Patient adherence and retention have been affected by a myriad of pandemic-era restraints, and medical, psychiatric, and other complications from the pandemic have the potential to have long-term effects on pandemic-era study results. In the development of post-pandemic study protocols, attention should be given to designing studies that incorporate successful aspects of pre-pandemic and pandemic-era strategies to (1) broaden recruitment using new techniques, (2) improve access for diverse populations, (3) expand protocols to include virtual and in-person participation, and (4) increase patient adherence and retention.

Staphylococcus aureus bi-component pore-forming leukocidins are secreted toxins that directly target and lyse immune cells. Intriguingly, one of the leukocidins, Leukocidin AB (LukAB), is found associated with the bacterial cell envelope in addition to secreted into the extracellular milieu. Here, we report that retention of LukAB on the bacterial cells provides S. aureus with a pre-synthesized active toxin that kills immune cells. On the bacteria, LukAB is distributed as discrete foci in two distinct compartments: membrane-proximal and surface-exposed. Through genetic screens, we show that a membrane lipid, lysyl-phosphatidylglycerol (LPG), and lipoteichoic acid (LTA) contribute to LukAB deposition and release. Furthermore, by studying non-covalently surface-bound proteins we discovered that the sorting of additional exoproteins, such as IsaB, Hel, ScaH, and Geh, are also controlled by LPG and LTA. Collectively, our study reveals a multistep secretion system that controls exoprotein storage and protein translocation across the S. aureus cell wall.

OBJECTIVES/OBJECTIVE:Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH. METHODS:A sample of 547 subjects completed a headache diagnostic interview, the SF-12 to calculate physical (PCS) and mental (MCS) health component scores, depression (major depression inventory [MDI]) and neuroticism (Eysenck Personality Questionnaire) measures. We defined the following headache diagnosis categories: pure TTH, pure migraine, and coexistent headache (TTH + migraine). Cases were further classified into chronic (≥15) or episodic (<15 headache days/month). RESULTS:Using generalized linear models (GLM) adjusted for age, sex and education, both PCS-12 and MCS-12 scores varied in groups distinguished by migraine and TTH status; scores were lower for individuals with coexistent headache (TTH + migraine; n=83), followed by pure TTH (n=97) and pure migraine (n=43) compared to the no headache group (n=324) (p≤0.001). In analyses considering chronicity, PCS-12 scores were lower in chronic coexistent headache followed by pure chronic TTH (CTTH), episodic migraine +/- episodic TTH (ETTH) and pure ETTH than in the no headache group (p≤0.001). MCS-12 scores were lower in pure CTTH, followed by chronic coexistent headache, episodic migraine +/- ETTH and pure ETTH compared to the no headache group (p≤0.001). Multiple regression models showed that in TTH, lower PCS-12 scores were associated with age (p=0.04), female sex (p=0.02), and poor self-rated health (p≤0.001). Lower MCS-12 scores in TTH were associated with depression (p≤0.001). CONCLUSIONS:In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL.

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has triggered a global effort to rapidly develop and deploy effective and safe coronavirus disease 2019 (COVID-19) vaccinations. Vaccination has been one of the most effective medical interventions in human history, although potential safety risks of novel vaccines must be monitored, identified, and quantified. Adverse events must be carefully assessed to define whether they are causally associated with vaccination or coincidence. Neurologic adverse events following immunizations are overall rare but with significant morbidity and mortality when they occur. Here, we review neurologic conditions seen in the context of prior vaccinations and the current data to date on select COVID-19 vaccines including mRNA vaccines and the adenovirus-vector COVID-19 vaccines, ChAdOx1 nCOV-19 (AstraZeneca) and Ad26.COV2.S Johnson & Johnson (Janssen/J&J).

Mapping the structural and functional connectivity of the central nervous system has become a key area within neuroimaging research. While detailed network structures across the entire brain have been probed using animal models, non-invasive neuroimaging in humans has thus far been dominated by cortical investigations. Beyond the cortex, subcortical nuclei have traditionally been less accessible due to their smaller size and greater distance from radio frequency coils. However, major neuroimaging developments now provide improved signal and the resolution required to study these structures. Here, we present an overview of the connectivity between the amygdala, brainstem, cerebellum, spinal cord and the rest of the brain. While limitations to their imaging and analyses remain, we also provide some recommendations and considerations for mapping brain connectivity beyond the cortex.