Faculty Bibliography

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.

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.

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.

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.

BACKGROUND/UNASSIGNED:High intensity focused ultrasound (HiFU) is a relatively new incisionless intervention used for treatment of essential tremor and Parkinson's disease tremor. Understanding the indications, benefits, risks and limitations of HiFU, as well as how it compares to deep brain stimulation (DBS), is important in guiding appropriate recommendations for prospective patients. METHODS/UNASSIGNED:Current literature on efficacy and safety of HiFU in essential tremor and Parkinson's disease was reviewed. We additionally reviewed data on the patients who presented to our center for HiFU consultation, including outcomes of patients with low skull density ratios, and distances traveled for the procedure. RESULTS/DISCUSSION/UNASSIGNED:HiFU is an effective and generally well-tolerated treatment for tremor. Adverse events, especially gait instability, are typically temporary but should be discussed with patients. The risk of tremor recurrence in certain patients with Parkinson's disease is also of note. Identifying appropriate candidates for either intervention remains crucial and involves considering each patient's circumstances and preferences, potential adverse effects, and practical aspects like access to follow-up and expectations. Data on bilateral HiFU lesioning, use of HiFU in patients with low skull density ratios, and emerging targets like the pallidothalamic tract are discussed as well.

Monitoring representative fractions of neurons from multiple brain circuits in behaving animals is necessary for understanding how different brain regions interact. Using multishank, high-density recording silicon probes (up to 1,024 sites), we describe the main characteristic LFP patterns in the hippocampus, including sharp wave-ripples (SPW-Rs), dentate spikes (DSs), theta, and gamma oscillations. Our novel observations primarily relate to the distinction between subclasses of SPW-Rs and DSs, as well as their neuronal spiking correlations. In addition to the classical SPW-Rs, initiated in the CA2-3 recurrent collateral system and characterized by a large negative sharp wave (sink) in the mid-CA1 stratum radiatum (SPW-R^Rad), a small subset of ripples, associated with a sink in CA1 str. lacunosum-moleculare was also observed (SPW-R^LM). The two types of ripple events differed in frequency, magnitude, and neuronal correlates. CA3 pyramidal neurons were strongly active during SPW-R^Rad but not during (SPW-R^LM). DSs could also be grouped further based on their excitatory inputs from the medial and lateral entorhinal cortex (DS^MEC and DS^LEC), by their impact on their physiological targets, and by the brain states into which they were embedded. Overall, our experiments demonstrate the utility and need for high-density recording of both LFP and spiking activity for the appropriate classification of seemingly similar events. These distinctions relate not only to their neurogenesis but also to their behavioral-cognitive contributions.

Flickering light is a new promising, fully non-invasive brain stimulation technique that utilizes intermittent sensory stimulation to induce brainwave synchronization (entrainment). While the effects of 40 Hz externally induced neural entrainment have been extensively described, little is known about 60 Hz entrainment in humans. This study presents preliminary observations on the neural and somatic response to flickering 60 Hz light in healthy volunteers over a 3-week period. Fourteen volunteers were randomized to receive either 60 Hz flickering white light or constant light as sham (30-min sessions, 3 weeks, 5 days/week on weekdays). Neural entrainment was assessed with EEG on days 1, 5 and 19. Salivary cortisol and C-reactive protein (CRP) levels, measured with ELISA, assessed the somatic response to stimulation. Side effects and well-being were monitored via questionnaires. EEG recordings showed neural entrainment and synchrony in response to 60 Hz flickering light across multiple cortical regions, including occipital, central, temporal, and frontal areas. The entrainment power and synchronization between different cortical regions declined significantly by day 19 compared to day 1, indicating possible neural habituation. Cortisol and CRP salivary levels were unchanged, and minor side effects were reported with equal frequency in the active and sham groups. Our findings show that 60 Hz flickering light can induce significant neural entrainment and synchrony in healthy adults and is well tolerated. The decline in entrainment strength and neural synchrony observed with repeated 60 Hz stimulations suggests plastic changes in the cortex. To the best of our knowledge, this is the first study to characterize neural and somatic responses to repeated 60 Hz flickering visual stimuli. Given the well-known connection between 60 Hz brain oscillations and cognition, neuroplasticity, and their role in neuropsychiatric disorders, additional research in both preclinical and clinical settings is warranted.

BACKGROUND/UNASSIGNED:Most patients with cervical synovial cysts (CSC) present with radiculopathy and/or myelopathy. MR studies are the gold standard for diagnosing CSC, and typically show hypointense T1/hyperintense T2 lesions, with occasional cyst-wall enhancement and additional cyst-wall calcification. Surgery typically warrants focal cyst resection/ decompression with/without an instrumented fusion. Here, we reviewed the diagnosis/treatment of a 76-year-old male with a CSC, and C5-C6/C6-C7 , and C7-T1 stenosis. We further provided a select review of the literature. METHODS/UNASSIGNED:For 3 months, a 76-year-old-male experienced progressive bilateral/arm pain (i.e., radiculopathy), and one week of increased right upper/right lower extremity weakness with loss of balance (i.e., myelopathy). The MR with/without contrast and non contrast CT studies documented moderate C5-C6/C6-C7 stenosis and a large, likely synovial cyst filling the right-side of the spinal canal at the C7-T1 level (i.e, 12 mm x 9 mmx 19 mm). RESULTS/UNASSIGNED:The patient urgently underwent excision of the large right C7-T1 synovial cyst, along with a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. At 4-postoperative months, the patient was neurologically intact. The repeated X-rays performed at 2, 6, and 12 weeks postoperatively documented maintained alignment, while the MR scan confirmed adequate cord decompression without myelomalacia. CONCLUSION/UNASSIGNED:A 76-year-old male with increased right-sided myeloradiculopathy, successfully underwent resection of a right-sided C7-T1 synovial cyst filling the spinal canal, a C6-T2 laminectomy for stenosis, and a C4-T4 instrumented fusion. Four months postoperatively, the patient was neurologically intact, with postoperative X-rays showing stable alignment. Further, the follow-up MR documented no residual cord/root compression, or myelomalacia. Here, we have provided a review of this case and select literature regarding the diagnosis and surgery for CSC.