Faculty Bibliography

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.

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 objective of this pilot study was to assess physical therapists' (PTs) knowledge and needs regarding headache diagnosis and management. BACKGROUND:While there is significant research on physical therapy and cervicogenic headache, studies suggest that migraine is often under-recognized, misdiagnosed, and inadequately treated across society despite its high prevalence and burden. Because migraine commonly includes concurrent neck pain and/or vestibular symptoms, patients with migraine may present to PTs for treatment. Very little is known about PTs' headache and migraine education, knowledge, and clinical practices. METHODS:A team of headache specialists and PTs adapted a previously used headache knowledge and needs assessment survey to help ascertain PTs' knowledge and needs regarding headache treatment. The cross-sectional survey was distributed online via Research Electronic Data Capture (REDCap) to PTs within a large healthcare system in Connecticut. RESULTS:An estimated 50.5% (101/200) of PTs invited to complete the survey did so. Only 37.6% (38/101) of respondents reported receiving any formal headache or migraine education in their professional training, leading to knowledge gaps in differentiating and responding to headache subtypes. Only 45.5% (46/101) were able to identify that migraine is characterized by greater pain intensity than tension-type headache, and 22.8% (23/101) reported not knowing the duration of untreated migraine. When asked about the aspects of care they believe their patients with headache would like to see improved, PTs reported education around prevention and appropriate medication use (61/100 [61.0%]), provider awareness of the degree of disability associated with migraine (51/100 [51.0%]), and diagnostics (47/100 [47.0%]). CONCLUSION/CONCLUSIONS:This sample of PTs from one healthcare system demonstrates knowledge gaps and variations in clinical practice for managing their patients with headache. Future research on integrating additional opportunities for headache education for physical therapists, including evidence-based behavioral therapies, is needed to ascertain whether it is likely to improve patient care.

BACKGROUND:Patients with disabilities face widespread barriers to accessing surgical care given inaccessible health systems, resulting in poor clinical outcomes and perpetuation of health inequities. One barrier is the lack of education, and therefore awareness, among trainees/providers, of the need for reasonable accommodations for surgical patients with disabilities. METHODS:We conducted a scoping review of the literature on the current state of disabilities curricula in medical education and graduate residency curriculum. RESULTS:While the literature does demonstrate a causal link between reasonable accommodation training and positive patient-provider relationships and improved clinical outcomes, in practice, disability-focused curricula are rare and often limited in time and to awareness-based didactic courses in medical education and surgical training. CONCLUSIONS:The absence of structured curricula to educate on anti-ableism and care for patients with disabilities promotes a system of structural "ableism." Expanding disability curricula for medical students and trainees may be an opportunity to intervene and promote better surgical care for all patients.

INTRODUCTION/BACKGROUND:We evaluated whether higher Dietary Inflammatory Index (DII) scores were associated with increased incidence of all-cause dementia and Alzheimer's disease (AD) dementia over 22.3 years of follow-up in the community-based Framingham Heart Study Offspring cohort. METHODS:One thousand four hundred eighty-seven participants (mean ± standard deviation, age in years 69 ± 6) completed food frequency questionnaires (FFQs) and had incident all-cause dementia and AD surveillance data available. RESULTS:Two hundred forty-six participants developed all-cause dementia (including AD, n = 187) over a median follow-up time of 13.1 years. Higher DII scores, averaged across a maximum of three timepoints, were associated with an increased incidence of all-cause dementia and AD after adjustment for demographic, lifestyle, and clinical covariates (hazard ratio [HR] 1.21, 95% confidence interval [CI] 1.10-1.33, P < 0.001; HR 1.20, 95% CI: 1.07-1.34d, P = 0.001, respectively). DISCUSSION/CONCLUSIONS:Higher DII scores were associated with a higher risk of incident all-cause dementia and AD. Although these promising findings need to be replicated and further validated, our results suggest that diets that correlate with low DII scores may prevent late-life dementia. HIGHLIGHTS/CONCLUSIONS:Higher Dietary Inflammatory Index (DII) scores were associated with an increased incidence of all-cause dementia. Higher DII scores were associated with an increased incidence of Alzheimer's disease dementia. Diets that correlate with low DII scores may prevent late-life dementia.

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.

SARS-CoV-2 infection has been associated with increased autoimmune disease risk. Past studies have not aligned regarding the most prevalent autoimmune diseases after infection, however. Furthermore, the relationship between infection severity and new autoimmune disease risk has not been well examined. We used RECOVER's electronic health record (EHR) networks, N3C, PCORnet, and PEDSnet, to estimate types and frequency of autoimmune diseases arising after SARS-CoV-2 infection and assessed how infection severity related to autoimmune disease risk. We identified patients of any age with SARS-CoV-2 infection between April 1, 2020 and April 1, 2021, and assigned them to a World Health Organization COVID-19 severity category for adults or the PEDSnet acute COVID-19 illness severity classification system for children (<age 21). We collected baseline covariates from the EHR in the year pre-index infection date and followed patients for 2 years for new autoimmune disease, defined as ≥ 2 new ICD-9, ICD-10, or SNOMED codes in the same concept set, starting >30 days after SARS-CoV-2 infection index date and occurring ≥1 day apart. We calculated overall and infection severity-stratified incidence ratesper 1000 person-years for all autoimmune diseases. With least severe COVID-19 severity as reference, survival analyses examined incident autoimmune disease risk. The most common new-onset autoimmune diseases in all networks were thyroid disease, psoriasis/psoriatic arthritis, and inflammatory bowel disease. Among adults, inflammatory arthritis was the most common, and Sjögren's disease also had high incidence. Incident type 1 diabetes and hematological autoimmune diseases were specifically found in children. Across networks, after adjustment, patients with highest COVID-19 severity had highest risk for new autoimmune disease vs. those with least severe disease (N3C: adjusted Hazard Ratio, (aHR) 1.47 (95%CI 1.33-1.66); PCORnet aHR 1.14 (95%CI 1.02-1.26); PEDSnet: aHR 3.14 (95%CI 2.42-4.07)]. Overall, severe acute COVID-19 was most strongly associated with autoimmune disease risk in three EHR networks.

INTRODUCTION/UNASSIGNED:White matter hyperintensity (WMH) is a hallmark imaging biomarker of cerebral small vessel disease and are strongly associated with vascular cognitive impairment in the elderly. Morphological changes in large extracranial brain-feeding arteries, such as the internal carotid (ICA) and vertebral arteries (VA), may alter intracranial hemodynamics and contribute to WMH development. This study examined the relationship between arterial tortuosity and WMHs using magnetic resonance angiography (MRA). METHODS/UNASSIGNED:Seventy-eight participants underwent time-of-flight (TOF) MRA and phase-contrast (PC) MRI to assess arterial morphology and blood flow. After excluding three for poor image quality, 75 subjects were analyzed. Arterial tortuosity was quantified using the inflection count metric (ICM) and ICA angle. Global cerebral blood flow (CBF) was estimated with PC-MRI and compared against pseudo-continuous arterial spin labeling (pCASL) to determine whether it could be a reliable surrogate measurement to reflect intracranial blood supply. RESULTS/UNASSIGNED:Participants with severe WMHs (Fazekas ≥2) demonstrated greater tortuosity (higher ICM and larger ICA angles) and lower blood flow than those with mild WMHs. Females showed more tortuous arteries, greater WMH burden, and higher susceptibility to hypoperfusion. Correlation analyses revealed a positive association between tortuosity and WMH volume. DISCUSSION/UNASSIGNED:These findings highlight the role of extracranial arterial tortuosity in WMH burden and reveal sex-specific differences in vascular vulnerability. The results underscore the need for further investigation into how age-related vascular remodeling contributes to WMH development and cognitive decline.

BACKGROUND/UNASSIGNED:that requires emergent postoperative MR confirmation of the classical "white cord" (i.e., high intrinsic T2W MR cord signal reflecting edema/swelling). METHODS/UNASSIGNED:Most frequently, postoperative MR studies in newly paretic/injured patients following cervical operations will show evidence of direct intraoperative ("iatrogenic") spinal cord injury. Less frequently, findings may include new non-operative vs. operative pathology (i.e., hematomas/hematomyelia, graft extrusions/malpositioning, new/residual/recurrent disc/stenosis/Ossification of the Posterior Longitudinal Ligament (OPLL), and other pathology). RESULTS/UNASSIGNED:WCS/RI after cervical spine surgery is extremely rare, being reported in only 17 cases as of 2020, and cannot be diagnosed based on "clinical judgment" alone; rather, it requires a STAT corroborate postoperative MR to demonstrate the classical "white cord". However, most likely postoperative MR studies document "iatrogenic" cord injuries, and less likely show new non-surgical and/or new surgical compressive pathology warranting reoperations to remediate the extent/severity of neurological injuries. CONCLUSION/UNASSIGNED:that requires STAT postoperative MR documentation of the classical swollen/edematous "white cord".