Faculty Bibliography

The semiology of clinical phenomena is central to neurological reasoning. When clinical manifestations occur in combination (e.g., weakness plus sensory loss), they are traditionally analyzed by considering anatomical localization (e.g., right-sided weakness and aphasia implicate the left cerebral cortex) and disease pattern recognition (e.g., tremor, bradykinesia, and rigidity indicate parkinsonism). The authors introduce a third, complementary approach-phenoconsonance-that relates neurological phenomena to each other not by their anatomical localization or disease pattern recognition but by their shared phenomenology. The authors identify the main components of the description of neurological phenomena in relation to where, what, and how neurological function is affected: examples for "where" include left-arm deficits in left brachial plexopathy or left hemispace neglect in right parietal lesions; examples for "what" include motor strength, visuospatial reasoning, or abstract planning; and examples for "how" include slowness, incoordination, or difficulty with initiation, because either the same function can be disrupted in qualitatively different ways-movement can be slowed or uncoordinated-or the same qualitative abnormality can apply to different functions-slowing may characterize movement, and it may also characterize thinking. The where, what, and how of neurological phenomenology correspond in the authors' synthesis to spatial phenoconsonance, domain phenoconsonance, and qualitative phenoconsonance, respectively. The historical context and conceptual underpinning of the notion of phenoconsonance are reviewed, as is its usefulness for the study of brain-behavior relationships in the evaluation and treatment of individuals with neurological and neuropsychiatric disorders.

AIM/UNASSIGNED:Sensory substitution devices (SSDs) can convert environmental information into an accessible format for people who are blind or have low vision (pBLV). Yet, current SSDs often passively deliver all of the information available with limited user control, potentially leading to confusion and/or cognitive overload. To address this issue, this work proposes a selective, gesture-controlled system intended to improve information relevance and reduce cognitive overload. METHODS/UNASSIGNED:We present Point-To-Tell 2, a system that enables pBLV to privately and efficiently select which information to convey through simple pointing-based gestural control. By integrating a monocular camera with AI-driven pipelines for depth estimation, hand pose tracking, and object detection/segmentation, the system identifies the users' 3D pointing direction and announces the names and distances of objects as they are pointed at, thereby connecting an object's spatial position and identity through hand proprioception. RESULTS/UNASSIGNED:Validation tests in controlled indoor environments show high hand pose tracking accuracy, ensuring reliable ray-casting and object selection despite declining object recognition at longer distances. Distance estimates are stable at close range, though a systematic bias is present. CONCLUSION/UNASSIGNED:This work introduces and technically validates an assistive system designed to improve the usability of assistive technologies by focusing system feedback-potentially reducing users' cognitive load and enhancing their spatial comprehension by leveraging concurrent hand proprioception. Future work will involve user testing and expanding system features to further enhance its practicality across more diverse scenarios.

BACKGROUND:Deep medullary veins (DMVs) play important roles within the cerebrovascular network related to brain drainage and clearance. Although they have been previously correlated with brain volume, it is unknown whether their count is specifically correlated with subcortical or cortical volume changes. PURPOSE/OBJECTIVE:This study aims to better understand the relationship between DMVs, subcortical (lateral ventricle to intracranial volume ratio (ICV)) and cortical atrophy (cortical thickness) to identify whether DMVs can be a predictor of volume changes in these regions. METHODS:We performed a retrospective analysis of 332 cognitively healthy subjects previously followed between 2010 and 2019. Imaging and patient charts were analyzed for baseline demographic and clinical characteristics. Patients underwent a standardized cognitive interview and received a magnetic resonance imaging scan to assess DMVs, cortical thickness, lateral ventricle and global gray matter (GM) volumes, white matter lesions (WMLs) and microbleeds. RESULTS:Among 332 patients (62% female, median age 70), lateral ventricle/ICV was significantly related to DMV count (p<0.001). Similarly, sex stratified analyses confirmed that a larger lateral ventricle/ICV ratio, but not cortical thickness or global GM volumes, was associated with fewer DMVs. In the entire group, subcortical atrophy remained a significant predictor of DMVs even after accounting for baseline characteristics, WMLs, microbleeds and total gray matter volume. CONCLUSIONS:In a large cohort of cognitively unaffected people, subcortical, but not cortical, atrophy was significantly correlated with venous health as measured by DMVs. Reduced DMVs are a strong predictor of ventricular enlargement.

In eukaryotes, each ribosomal subunit includes a ribosomal protein (RP) that is encoded as a fusion protein with ubiquitin (Ub). In yeast, each Ub-RP fusion requires processing by deubiquitylating enzymes (DUBs) to generate ribosome assembly-competent RPs and contribute to the cellular Ub pool. However, how Ub-RP fusions are processed by DUBs in human cells remains unclear. Here, we discovered that Ub-RPs are substrates of the Ub-fusion degradation (UFD) pathway in human cells via lysine 29 and 48 (K29/K48)-specific ubiquitylation and proteasomal degradation. We identified a pool of DUBs that catalytically process Ub-RPs, as well as DUBs that physically occlude Ub-RP interaction with UFD pathway Ub E3 ligases to prevent their degradation in a non-catalytic manner. Our results suggest that DUBs both process and stabilize Ub-RPs, whereas the UFD pathway regulates levels of Ub-RPs that cannot be fully processed by DUBs to fine-tune protein homeostasis.

BACKGROUND/UNASSIGNED:There is a greater risk of complications from severe COVID-19 in immunocompromised patients with multiple sclerosis (pwMS) treated with certain disease-modifying therapies (DMTs), as well as a diminished vaccine response. METHODS/UNASSIGNED:In this exploratory, observational study, we recruited 28 patients with Relapsing Remitting MS (RRMS, n=24) or Secondary Progressive MS (SPMS, n=4), that were receiving treatment with either natalizumab or fumarates (diroximel or dimethyl) prior to baseline sample collection. Blood samples were collected before vaccination (baseline), between 4 weeks and 6 months post vaccination, and post booster administration. A multiplex bead immunoassay (MBI) was used to measure anti-Spike IgG, while IFNγ and IL-2 ELISpot assays were used to determine T cell activation. A 35-color spectral flow cytometry panel was used to phenotype bulk B and T cells and SARS-CoV-2-specific T cells, while dimensionality reduction was performed for further phenotypic analysis. RESULTS/UNASSIGNED:We observed a significantly increased absolute lymphocyte count (ALC) (p=0.0003) in natalizumab-treated pwMS when compared to fumarate-treated pwMS primarily due to increased circulating CD19+ B cells. Fumarate-treated pwMS exhibited a diminished Th1/Th2 ratio when compared to natalizumab-treated pwMS (p=0.0004) or healthy controls (p=0.0745), while natalizumab treatment marginally increased the Th1/Th2 ratio compared to healthy controls (p=0.1311). The observed increase in B cells in natalizumab-treated pwMS were predominantly memory B cells, and double negative (DN) B cells. However, no significant differences between the treatment groups were seen in terms of Spike IgG titers following the initial vaccination course or booster dose, nor in SARS-CoV-2-specific CD4+ responses, all of which remained robust for at least 6 months post-vaccination. The magnitude of humoral and cellular immune responses in both treatment groups were comparable to vaccinated healthy controls. Additionally, SARS-CoV-2 spike-specific CD4+ T cell phenotyping revealed a Th2 dominant response to booster dose in natalizumab-treated pwMS (p=0.0485) but not fumarate-treated pwMS. CONCLUSION/UNASSIGNED:pwMS treated with natalizumab or fumarates exhibit similarly robust and durable SARS-CoV-2 specific T cell and humoral responses following vaccination and booster dose. DMT-treated pwMS showing comparable responses to healthy individuals following initial vaccination supports the notion that treatment with these specific DMTs does not diminish strong, long-lasting immunity conferred by COVID-19 vaccination, despite the phenotypic differences modulated by each therapy.

Clinical decision-making often simplifies continuous risk data into discrete levels using round-number thresholds. These simplifications can distort risk assessments. To systematically uncover these distortions, we develop an interpretable machine learning model that identifies anomalies caused by threshold-based practices. Through simulations, real-world data, and longitudinal studies, we demonstrate how round-number thresholds can lead to discontinuities and counter-causal paradoxes in mortality risk. Despite advances in medicine, these anomalies persist, underscoring the need for dynamic and nuanced risk assessment methods in healthcare. Our findings suggest continuous reassessment of clinical protocols, especially in critical settings like intensive care, to improve patient outcomes by aligning thresholds with the continuous nature of risk.

Epilepsy in the Child-Bearing Ages through Menopause is an international consortium of clinicians dedicated to improving the health of women with epilepsy across the lifespan. Epilepsy in the Child-Bearing Ages through Menopause's Adolescent and Young Adult Committee addresses quality of care for female youth with epilepsy. The Committee developed a literature review and expert opinion guidance for child neurologists on performing optimal counseling about epilepsy and reproductive health for female youth with epilepsy. To do so, we identified and voted on key topics essential for this counseling, then conducted comprehensive literature reviews for each topic, iteratively developed key statements about counseling content and style for each topic and voted on final content for inclusion. The included topics were teratogenesis, folic acid supplementation, pregnancy and fertility, contraception, heritability of epilepsy, menstrual and hormonal disorders, catamenial epilepsy, and taking a sexual history. This review provides a clear, novel framework for pediatric neurologists to counsel adolescent and young adult women with epilepsy about their reproductive health, supporting improvement in practices recommended by professional organization such as the American Academy of Neurology and Child Neurology Foundation.

Large Language Models (LLMs) offer a framework for understanding language processing in the human brain. Unlike traditional models, LLMs represent words and context through layered numerical embeddings. Here, we demonstrate that LLMs' layer hierarchy aligns with the temporal dynamics of language comprehension in the brain. Using electrocorticography (ECoG) data from participants listening to a 30-minute narrative, we show that deeper LLM layers correspond to later brain activity, particularly in Broca's area and other language-related regions. We extract contextual embeddings from GPT-2 XL and Llama-2 and use linear models to predict neural responses across time. Our results reveal a strong correlation between model depth and the brain's temporal receptive window during comprehension. We also compare LLM-based predictions with symbolic approaches, highlighting the advantages of deep learning models in capturing brain dynamics. We release our aligned neural and linguistic dataset as a public benchmark to test competing theories of language processing.

Neuroinflammation involving glial cell activation and BBB dysfunction has increasingly been recognized as a key feature of neuropsychiatric disorders. In vivo imaging methods, particularly translocator protein positron emission tomography (TSPO-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have advanced our understanding of glial activation and BBB permeability in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease, schizophrenia, and depression. We present key findings from the clinical application of these imaging modalities and highlight critical methodological challenges-including variability in study protocols, tracer selection, input function derivation, and parameter estimation-that currently limit cross-study comparability and clinical translation. TSPO-PET and DCE-MRI provide valuable clinical insights on the inflammatory mechanisms contributing to CNS disease at various disease stages. Future methodological standardization, co-localization studies, and longitudinal multi-modal applications will be crucial for using these tools as markers of disease in the context of immune interventions in at-risk populations.

PURPOSE OF REVIEW/OBJECTIVE:Antithrombotic-associated intracerebral hemorrhage (ICH) is associated with high rates of morbidity and mortality. Rapid and effective antithrombotic reversal is critical for mitigating risk of hemorrhage expansion and neurological deterioration. This review provides an overview of the most recent advances in emergency antithrombotic reversal in ICH. RECENT FINDINGS/RESULTS:Rapid coagulopathy reversal within the first 60-90 min of hospital presentation may limit massive ICH expansion and improve outcomes. Current data suggests reversal of vitamin K antagonists with intravenous vitamin K and 4-factor prothrombin complex concentrates (4f-PCC), reversal of dabigatran with idarucizumab, and reversal or direct oral factor Xa inhibitors with either 4f-PCC or andexanet-alfa. While platelet transfusion is not suggested for antiplatelet-associated ICH, DDAVP may be reasonable, and a new reversal agent is under development for ticagrelor. Rapid reversal of antithrombotic-associated coagulopathy in the context of ICH may prevent ICH expansion and improve neurological outcomes.