Faculty Bibliography

OBJECTIVE:Interictal epileptiform discharges (IEDs) are transients observed on the electroencephalogram (EEG) of patients with epilepsy. IEDs have traditionally been recorded from scalp or intracranial EEG macrocontacts, which coarsely sample neural activity. Here, we investigated the use of flexible, high-resolution microelectrocorticographic (μECoG) arrays for measuring IEDs with greater spatiotemporal precision to test whether there exist microscale patterns of IED activity that may be missed on standard intracranial EEG. METHODS:) to record from seven patients undergoing surgical treatment of epilepsy. We identified IEDs by a combination of expert review and automated detection. We quantified the spatial extent of IEDs, mapped patterns of repeated IED activity, and quantified IED propagation direction using multilinear fit models. We also compared IED detection rates and propagation measurements between μECoG arrays and simulated macroarrays (10-mm spacing, 2.3-mm diameter). RESULTS:We demonstrated successful use of μECoG arrays to map intraoperative microscale patterns of IEDs. The majority of patients (5/7) exhibited elevated IED activity that was highly localized (subcentimeter localization). Across all patients, 40% of detected IEDs were observed within a 4-mm radius of cortex. μECoG arrays also mapped the direction of IED propagation. An average of 39% (range = 4.2%-96.5%, SD = ±36.8%) of the IED events captured by the μECoG arrays were not detectable by simulated macrocontacts. SIGNIFICANCE/CONCLUSIONS:These intraoperative data demonstrate that μECoG arrays can map the microscale spatiotemporal activity of IEDs. These patterns of IEDs may be poorly captured by standard, macroscale recording devices. Our findings support the use of high-resolution, large area coverage μECoG arrays for the presurgical and intraoperative mapping of epileptic cortex.

Childhood adversity is increasingly recognized as a critical modifier of neurologic disorder development and disease severity, including in the neuroimmune disorder multiple sclerosis (MS). While previous studies have linked early-life adversity to increased MS susceptibility and more severe disease, the underlying biological mechanisms remain poorly understood. This study investigated associations between childhood adversity and MS clinical features, with a focus on two potential pathogenic mechanisms: allostatic load and epigenetic modifications. We evaluated 60 consecutively enrolled young adults with MS; 30 with paediatric-onset MS (POMS) and 30 with adult-onset MS (AOMS). At time of enrolment in this cross-sectional study, participants had MS disease duration of 6 years on average. POMS participants were mean 22.09 (2.66) years and AOMS participants were mean 32.41 (2.19) years old. 62% of participants were female. Childhood adversity was defined using a composite index of individual, family and socioeconomic measures captured by the adverse childhood experiences questionnaire, parental education level and estimated household income during childhood. Clinical outcomes included patient-reported SymptoMScreen questionnaire regarding MS symptom burden and MS neurologist-assessed disability using the Expanded Disability Status Scale (EDSS) of the participant's neurologic exam at the time of enrolment. Circulating biomarkers of allostatic load and genome-wide epigenetic profiles (DNA methylation via RRBS; reduced representation bisulfite sequencing) were also assessed. A history of high childhood adversity was associated with significantly greater patient-reported MS symptom burden (P = 0.001) and higher neurologist-reported EDSS disability scores (P = 0.028), independent of disease duration or timing of treatment initiation. There were no differences between childhood adversity and circulating biomarkers of allostatic load. While childhood adversity was not associated with global epigenetic changes across the entire cohort, stratified analysis revealed divergent methylation patterns by age of MS onset: POMS participants with childhood adversity had increased DNA methylation, whereas AOMS participants with childhood adversity showed decreased methylation compared to individuals without childhood adversity. None of the observed clinical and biologic differences were explained by differences in disease duration or the interval between symptom onset and treatment initiation. Our findings suggest that childhood adversity is associated with increased MS symptom burden and neurologic disability in young adults with MS. Childhood adversity may differentially shape the epigenome, depending on the age of MS onset, with potential implications for disease trajectory and therapeutic vulnerability. These results support the biological embedding of childhood adversity in MS and highlight the need for age- and exposure-sensitive approaches to understanding MS pathogenesis across the lifespan.

INTRODUCTION/BACKGROUND:Though brain fog is common in Long-coronavirus disease 2019 (Long-COVID), the incidence of mild cognitive impairment (MCI) is unknown. METHODS:In an observational cohort study, recovered COVID-positive, Long-COVID, and COVID-negative subjects underwent blinded evaluation using National Alzheimer's Coordinating Center (NACC) and National Institute on Aging (NIA) -Alzheimer's Association diagnostic criteria for dementia and MCI. The cumulative incidence of MCI was calculated for each group, and the hazard of MCI was compared between groups. RESULTS:Among 260 subjects, the cumulative incidence of MCI over 4.4 years was higher with Long-COVID (27%) versus recovered-COVID (5%) or COVID-negative status (1%). There was a higher hazard of MCI for patients with Long-COVID compared to those without (hazard ratio [HR] 3.93, 95% confidence interval [CI] 1.86-8.31, p < 0.001), and specifically for the Alzheimer's disease (AD) -related MCI subtype (HR 3.20, 95% confidence interval [CI] 1.14-9.00, p = 0.027). DISCUSSION/CONCLUSIONS:The cumulative incidence and adjusted hazard of MCI (and specifically AD-related MCI) at 4.4 years was significantly higher among Long-COVID patients compared to recovered-COVID and COVID-negative controls.

PURPOSE OF REVIEW/UNASSIGNED:Alzheimer disease (AD) and epilepsy are major causes of neurologic disability and are reciprocally related: epileptiform discharges, subclinical seizures, and epilepsy are more prevalent in patients with AD compared with controls; progressive cognitive impairment commonly afflicts epilepsy patients; and late-onset epilepsy patients have higher rates of new-onset dementia. RECENT FINDINGS/UNASSIGNED:Epidemiologic studies support shared risk factors (e.g., genetic variants, vascular disease, sleep disorders, microbiome) with notable divergences. AD and epilepsy have some overlapping anatomic (e.g., hippocampus, entorhinal, and association cortex), clinical (e.g., memory, attentional, and executive) impairments, and neuropathologic (e.g., amyloid, tau, neurofibrillary tangles) features. Shared clinical and translational challenges include underlying mechanisms (e.g., genetic variants, neuroinflammation, metabolic and mitochondrial dysfunction, excitatory/inhibitory imbalance, microbiome, and sociodemographic factors) and identifying valid and reliable biomarkers (e.g., total tau and phosphorylated tau (p-tau), amyloid deposition, Aβ42/Aβ40 ratio) to assess disease progression, predict outcomes, and assess potentially disease-modifying interventions. SUMMARY/UNASSIGNED:Identifying convergences and divergences between epilepsy and AD may inform our understanding. The clinical, neurophysiologic, neuropathologic, and molecular pathologic changes in AD and epilepsy may reveal pathophysiologic insights and therapeutic opportunities.

OBJECTIVE:To assess whether object relations theory (ORT) formulations generated by large language models (LLMs) enhance resident education in psychodynamic psychiatry. METHODS:This institutional review board (IRB)-approved observational study was conducted at a single academic program from January to March 2025. Eleven postgraduate year (PGY) 3 and 4 residents submitted de-identified psychotherapy case narratives to a GPT-4 model using a standardized ORT prompt. Residents evaluated accuracy, clarity, and educational value using a 10-item, 5-point Likert scale and provided free-text feedback. Descriptive statistics were calculated. Thematic analysis was used to identify key perceptions. RESULTS:Ten residents completed the rating process. Mean scores ranged from 3.5 to 4.2 across all items, with the highest ratings for identification of objects, affective tone, and educational value. Qualitative analysis identified five themes: (1) improved clarity and structure, (2) stronger conceptual anchoring to ORT, (3) risk of overgeneralization, (4) maternal emphasis bias, and (5) importance of faculty oversight. Residents characterized the outputs as concise and clinically applicable, although they noted occasional factual inaccuracies and misalignments with specific case details. CONCLUSIONS:With appropriate supervision, AI-generated ORT formulations may serve as a valuable adjunct to psychodynamic education by standardizing terminology and supporting conceptual development. Future controlled studies are needed to evaluate effects on Milestone-aligned assessment and applicability to additional psychotherapy models.

PURPOSE/OBJECTIVE:The Unified Multiple System Atrophy Rating Scale (UMSARS) is widely used as an outcome measure in MSA trials, but it has limitations for clinical trial use. To address these, we developed the Multiple System Atrophy Combined Outcome Assessment (MuSyCA), a comprehensive multimodal tool for disease-modifying MSA trials. The purpose of this manuscript is to describe the development and validation plan for MuSyCA, with emphasis on its structure, intended use, and assessment of reliability, validity, and sensitivity in tracking disease progression. METHODS:The development of MuSyCA followed a multistep process. Candidate outcome assessments were identified through systematic literature review and analysis of longitudinal data from large MSA cohorts. Content was refined through multiple Delphi-like consensus rounds involving MSA experts, patient advocacy groups representatives, and industry stakeholders. Cognitive interviews conducted in 20  patients with MSA evaluated the clarity and clinical relevance of patient- and clinician-reported outcomes; feedback was incorporated into a subsequent version of the MuSyCA. Validation is ongoing and includes assessment of construct validity, internal consistency, test-retest reliability, and responsiveness. Longitudinal analyses to determine sensitivity to change over time are ongoing. RESULTS:MuSyCA combines patient- and clinician-reported outcomes, biomarkers (neurofilament light chain, neuroimaging), and performance-based measures to capture subjective and objective aspects of MSA progression, enhancing its utility  to detect treatment effects in clinical trials. MuSyCa is not intended to be used in clinical practice. CONCLUSIONS:MuSyCA offers a multidimensional approach to MSA assessment, supporting precise, disease-relevant evaluations in trials of putative disease-modifying therapies. Its validation will provide a standardized multimodal outcome measure, advancing MSA therapeutic development.

OBJECTIVE:To compare seizure outcomes during pregnancy in women with epilepsy (WWE) by history of catamenial patterns. BACKGROUND:Catamenial patterns are defined as increased seizure frequency during certain phases of the menstrual cycle (perimenstrual, peri-ovulatory, or luteal in anovulatory cycles). Animal studies suggest seizure improvement occurs with higher progesterone and allopregnanolone concentrations and lower estrogen concentrations. Prior human studies also reported that WWE with catamenial patterns were more likely to have improved seizure frequency during pregnancy, presumably due to higher sensitivity to fluctuations in sex steroid hormones. DESIGN/METHODS/METHODS:Women with epilepsy (WWE), ages 18-40yo, were enrolled in a longitudinal, prospective cohort study at time of attempting conception to compare fertility outcomes to healthy controls. Once enrolled, WWE used a daily diary app for menstrual and seizure tracking from preconception through delivery. For this secondary analysis, participants were excluded if they chose to discontinue the study, if they did not become pregnant, were seizure free preconception, if their diary data was inadequate (defined as <80 % of the days tracked), or if they had <1 month of seizure data tracked prior to conception. Prospective diary data was used to determine if participants met criteria for observed catamenial patterns. Seizure frequency during pregnancy was compared to preconception frequency. RESULTS:Among 89 participants, 13 became pregnant with seizure tracking; 6 (46 %) met criteria for catamenial epilepsy. Focal epilepsy was less common than generalized epilepsy in the catamenial group (33 %) vs the non-catamenial group (86 %, p = 0.10). No significant differences in seizure frequency change from preconception to pregnancy were observed between groups (p = 0.42). During pregnancy, 33 % of the catamenial group and 43 % of the non-catamenial group became seizure-free (p = 0.99). Seizure improvement or stability occurred in 67 % and 86 %, respectively (p = 0.56). CONCLUSIONS:In patients who had preconception seizures, seizure control during pregnancy was generally favorable: many patients' seizure frequency improved or achieved seizure freedom. There was no clear evidence that a pre-conception catamenial pattern immediately before pregnancy altered prognosis. Further research is needed to guide counseling and treatment during pregnancy.