Faculty Bibliography

Neurologic conditions are a leading cause of morbidity and mortality within the United States and worldwide. Brain health is a global concern, and the American Academy of Neurology's Brain Health Initiative promises to drive progress in this field over the next decades. Neurologists with detailed training and insight into brain function are uniquely positioned to apply emerging preventive health data to promote healthy brain development and maintain optimal brain function throughout the lifespan. The neurologist's role in promoting brain health is also vital in patients with active neurologic disease, in whom preventive measures may reduce recurrence or slow progression of disease and may enhance quality of life and overall function. In this Emerging Issues in Neurology article, we present the factors that may protect brain function and frame a practical approach to screening assessments and preventive interventions that neurology clinicians may consider to improve the brain health of patients at all life stages.

T cell-based immunotherapies have demonstrated effectiveness in treating diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (FL) but predicting response and understanding resistance remains a challenge. To address this, we developed syngeneic models reflecting the genetics, epigenetics, and immunology of human FL and DLBCL. We show that EZH2 inhibitors reprogram these models to re-express T cell engagement genes and render them highly immunogenic. EZH2 inhibitors do not harm tumor-controlling T cells or CAR-T cells. Instead, they reduce regulatory T cells, promote memory chimeric antigen receptor (CAR) CD8 phenotypes, and reduce exhaustion, resulting in a decreased tumor burden. Intravital 2-photon imaging shows increased CAR-T recruitment and interaction within the tumor microenvironment, improving lymphoma cell killing. Therefore, EZH2 inhibition enhances CAR-T cell efficacy through direct effects on CAR-T cells, in addition to rendering lymphoma B cells immunogenic. This approach is currently being evaluated in two clinical trials, NCT05934838 and NCT05994235, to improve immunotherapy outcomes in B cell lymphoma patients.

Adolescents and young adults (AYAs; ages 15-39 years) are a vulnerable population facing challenges in oncological care, including access to specialized care, transition of care, unique tumor biology, and poor representation in clinical trials. Brain tumors are the second most common tumor type in AYA, with malignant brain tumors being the most common cause of cancer-related death. The 2021 WHO Classification for central nervous system (CNS) Tumors highlights the importance of integrated molecular characterization with histologic diagnosis in several tumors relevant to the AYA population. In this position paper from the Society for Neuro-Oncology (SNO), the diagnosis and management of CNS tumors in AYA is reviewed, focusing on the most common tumor types in this population, namely glioma, medulloblastoma, ependymoma, and CNS germ cell tumor. Current challenges and future directions specific to AYA are also highlighted. Finally, possible solutions to address barriers in the care of AYA patients are discussed, emphasizing the need for multidisciplinary and collaborative approaches that span the pediatric and adult paradigms of care, and incorporating advanced molecular testing, targeted therapy, and AYA-centered care.

Mobile health (mHealth) tools can be used to deliver nonpharmacologic therapies to patients with migraine. However, mHealth studies often report poor treatment adherence. Neuroscience Education Therapy (NET), behavioral economics, and Digital Navigators have the potential to increase treatment adherence and thereby improve remote migraine self-management. We conducted a 6-month prospective pilot randomized controlled trial testing if a multi-component package of behavioral interventions increased treatment adherence among patients using one of two different mHealth migraine self-management programs (low-intensity program consisting only of a headache diary versus high-intensity program consisting of a headache diary and behavioral exercises). Our outcomes were the number of diary entries and behavioral exercises completed/week captured via back-end analytics of the mHealth application. We also compared our adherence data at 90-days (a secondary endpoint to assess the durability of the effect) with adherence data from similar published studies without the adherence-enhancing package. We enrolled 26 participants (n = 15 low intensity group, n = 11 high-intensity group). During the 6-week intervention period, we had a median of 7 headache diary entries/week in both groups and a median of 6 days/week of behavioral exercises in the high-intensity group. The rate of adherence with the adherence-enhancing package included was 2.9-8x higher compared to the median rates of the behavioral exercises to historical controls. With use of NET, behavioral economics, and digital navigators, participants achieved higher levels of adherence to both self-management programs compared to prior remote migraine self-management studies. Therefore, these tools may be beneficial to improving adherence to migraine self-management programs.

IMPORTANCE/UNASSIGNED:A substantial number of individuals worldwide experience long COVID, or post-COVID condition. Other postviral and autoimmune conditions have a female predominance, but whether the same is true for long COVID, especially within different subgroups, is uncertain. OBJECTIVE/UNASSIGNED:To evaluate sex differences in the risk of developing long COVID among adults with SARS-CoV-2 infection. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study used data from the National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER)-Adult cohort, which consists of individuals enrolled in and prospectively followed up at 83 sites in 33 US states plus Washington, DC, and Puerto Rico. Data were examined from all participants enrolled between October 29, 2021, and July 5, 2024, who had a qualifying study visit 6 months or more after their initial SARS-CoV-2 infection. EXPOSURE/UNASSIGNED:Self-reported sex (male, female) assigned at birth. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Development of long COVID, measured using a self-reported symptom-based questionnaire and scoring guideline at the first study visit that occurred at least 6 months after infection. Propensity score matching was used to estimate risk ratios (RRs) and risk differences (95% CIs). The full model included demographic and clinical characteristics and social determinants of health, and the reduced model included only age, race, and ethnicity. RESULTS/UNASSIGNED:Among 12 276 participants who had experienced SARS-CoV-2 infection (8969 [73%] female; mean [SD] age at infection, 46 [15] years), female sex was associated with higher risk of long COVID in the primary full (RR, 1.31; 95% CI, 1.06-1.62) and reduced (RR, 1.44; 95% CI, 1.17-1.77) models. This finding was observed across all age groups except 18 to 39 years (RR, 1.04; 95% CI, 0.72-1.49). Female sex was associated with significantly higher overall long COVID risk when the analysis was restricted to nonpregnant participants (RR, 1.50; 95%: CI, 1.27-1.77). Among participants aged 40 to 54 years, the risk ratio was 1.42 (95% CI, 0.99-2.03) in menopausal female participants and 1.45 (95% CI, 1.15-1.83) in nonmenopausal female participants compared with male participants. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this prospective cohort study of the NIH RECOVER-Adult cohort, female sex was associated with an increased risk of long COVID compared with male sex, and this association was age, pregnancy, and menopausal status dependent. These findings highlight the need to identify biological mechanisms contributing to sex specificity to facilitate risk stratification, targeted drug development, and improved management of long COVID.

IMPORTANCE/UNASSIGNED:Antiseizure medications (ASMs) are potential teratogens commonly prescribed for multiple indications. ASM fetal exposure can impair neurodevelopment. Folate improves pregnancy outcomes, but higher doses may pose risks. OBJECTIVES/UNASSIGNED:To compare the outcomes of 6-year-old children of women with epilepsy (WWE) vs those of healthy women (HW), and assess the association of outcomes to third-trimester ASM exposures. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:After informed consent, pregnant WWE and HW were enrolled from 2012 through 2016 in this prospective, multicenter, nonrandomized clinical trial. Children were assessed at 6 years of age (2019-2022). Participants were recruited from 20 US epilepsy centers. Study data were analyzed from August 2023 to August 2024. EXPOSURES/UNASSIGNED:Fetal ASM exposures. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The a priori main neurodevelopmental outcome was the blindly assessed Verbal Index Score in 6-year-old children. The Verbal Index Score is calculated as the mean of the scores from the Word Definitions and Verbal Similarities subtests from the Differential Ability Scales, Expressive One-Word Picture Vocabulary Test, Phonological Processing, Comprehension of Instructions, and Sentence Repetition subtests from the Neuropsychological Assessment and Peabody Picture Vocabulary Test. The 2 primary analyses (1) compared children of WWE and HW using linear regression and (2) examined the outcomes of fetal exposure via ASM blood concentrations. Analyses were adjusted for multiple potential confounding factors. Other outcomes and folate exposure-related outcomes were assessed. RESULTS/UNASSIGNED:A total of 1123 pregnant women were screened, and 456 were enrolled (426 did not meet criteria, and 241 chose not to participate). A total of 298 children of WWE (mean [SD] age, 6.4 [4.2] years; 158 female [53.0%]; 140 male [47.0%]) vs 89 children of HW (mean [SD] age, 6.4 [4.2] years; 41 female [46.1%]; 48 male [53.9%]) did not differ on Verbal Index Score (parameter estimate, -0.6; 95% CI, -3.2 to 1.9; P = .64). Exposure-dependent outcomes differed across ASMs. Assessment of other ASMs was limited because 232 of 298 WWE (78%) were taking lamotrigine or levetiracetam alone or in combination. Folate supplementation during the first 12 weeks of pregnancy had positive associations with cognition and behavior with no signal for risks at higher folate doses. CONCLUSIONS AND RELEVANCE/UNASSIGNED:Results of this prospective nonrandomized clinical trial suggest that verbal abilities in children of WWE vs HW did not differ. Exposure-dependent outcomes of ASMs highlight the importance of dosing high enough to protect the mother and fetus from seizures but low enough to protect the fetus. Folate supplementation early in pregnancy including higher doses was associated with improved cognitive and behavioral outcomes. Additional research is needed for ASMs with inadequate information on fetal exposure risks. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT01730170.

Hypoxic cancer cells resist many antineoplastic therapies and can seed recurrence^1,2. We previously found that either deficiency or inhibition of protein-tyrosine phosphatase (PTP1B) promotes human epidermal growth factor receptor 2-positive breast cancer cell death in hypoxia by activation of RNF213 (ref. ³), a large protein with multiple AAA-ATPase domains and two ubiquitin ligase domains (RING and RZ) implicated in Moyamoya disease, lipotoxicity and innate immunity⁴. Here we report that PTP1B and ABL1/2 reciprocally control RNF213 tyrosine phosphorylation and, consequently, its oligomerization and RZ domain activation. The RZ domain ubiquitylates and induces the degradation of the major NF-κB regulator CYLD/SPATA2. Decreased CYLD/SPATA2 levels lead to NF-κB activation and induction of the NLRP3 inflammasome which, together with hypoxia-induced endoplasmic reticulum stress, triggers pyroptotic cell death. Consistent with this model, CYLD deletion phenocopies, whereas NLRP3 deletion blocks, the effects of PTP1B deficiency on human epidermal growth factor receptor 2-positive breast cancer xenograft growth. Reconstitution studies with RNF213 mutants confirm that the RZ domain mediates tumour cell death. In concert, our results identify a unique, potentially targetable PTP1B-RNF213-CYLD-SPATA2 pathway critical for the control of inflammatory cell death in hypoxic tumours, provide new insights into RNF213 regulation and have potential implications for the pathogenesis of Moyamoya disease, inflammatory disorders and autoimmune disease.

Perceptual awareness results from an intricate interaction between external sensory input and the brain's spontaneous activity. Pre-stimulus ongoing activity influencing conscious perception includes both brain oscillations in the alpha (7 to 14 Hz) and beta (14 to 30 Hz) frequency ranges and aperiodic activity in the slow cortical potential (SCP, <5 Hz) range. However, whether brain oscillations and SCPs independently influence conscious perception or do so through shared mechanisms remains unknown. Here, we addressed this question in 2 independent magnetoencephalography (MEG) data sets involving near-threshold visual perception tasks in humans using low-level (Gabor patches) and high-level (objects, faces, houses, animals) stimuli, respectively. We found that oscillatory power and large-scale SCP activity influence conscious perception through independent mechanisms that do not have shared variance. In addition, through mediation analysis, we show that pre-stimulus oscillatory power and SCP activity have different relations to pupil size-an index of arousal-in their influences on conscious perception. Together, these findings suggest that oscillatory power and SCPs independently contribute to perceptual awareness, with distinct relations to pupil-linked arousal.

OBJECTIVE:The goal is to provide an overview of artificial intelligence (AI) and machine learning (ML) methodology and appraisal tailored to clinicians and researchers in the headache field to facilitate interdisciplinary communications and research. BACKGROUND:The application of AI to the study of headache and other healthcare challenges is growing rapidly. It is critical that these findings be accurately interpreted by headache specialists, but this can be difficult for non-AI specialists. METHODS:This paper is a narrative review of the fundamentals required to understand ML/AI headache research. Using guidance from key leaders in the field of headache medicine and AI, important references were reviewed and cited to provide a comprehensive overview of the terminology, methodology, applications, pitfalls, and bias of AI. RESULTS:We review how AI models are created, common model types, methods for evaluation, and examples of their application to headache medicine. We also highlight potential pitfalls relevant when consuming AI research, and discuss ethical issues of bias, privacy and abuse generated by AI. Additionally, we highlight recent related research from across headache-related applications. CONCLUSION/CONCLUSIONS:Many promising current and future applications of ML and AI exist in the field of headache medicine. Understanding the fundamentals of AI will allow readers to understand and critically appraise AI-related research findings in their proper context. This paper will increase the reader's comfort in consuming AI/ML-based research and will prepare them to think critically about related research developments.