Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Former American football players exposed to repetitive head impacts (RHI) are at a risk of chronic traumatic encephalopathy (CTE), but chronic pain, polypharmacy, and extensive orthopedic surgeries may also contribute to cognitive and behavioral symptoms. This study evaluated associations between chronic pain, centrally acting medications (CAMs), and orthopedic surgeries with cognitive and behavioral symptoms among former American football players. METHODS:The sample included former professional (PRO) and collegiate (COL) football players and unexposed, asymptomatic men (UE) from DIAGNOSE CTE. Number of CAMs, orthopedic surgeries, and average pain scores were compared between the groups. Among former football players, logistic regression tested associations between CAMs, average pain score, and orthopedic surgeries with diagnoses of cognitive impairment and neurobehavioral dysregulation (NBD) using traumatic encephalopathy syndrome (TES) research criteria. Linear regression tested associations between CAMs, average pain score, and orthopedic surgeries with the Montreal Cognitive Assessment (MoCA) and behavioral and mood symptom scales. Covariates included age, education, race, and total years of football. RESULTS:The study included 236 men (120 PRO, 60 COL, 56 UE). The mean ages were 59.1 (PRO), 53.5 (COL) and 59.6 (UE) years. PRO and COL used more CAMs (mean PRO = 0.76, COL = 1.14, UE = 0.14), had higher average pain scores (PRO = 4.22, COL = 3.21, UE = 1.05), and more orthopedic surgeries than the UE (mean PRO = 2.76, COL = 1.22, UE = 0.34). CAMs and average pain scores were associated with increased odds of consensus diagnosed NBD (CAMs OR = 2.15, 95% CI 1.53 to 3.26; average pain score OR = 1.55, 95% CI 1.32 to 1.85). CAMs and average pain scores were associated with increased measures of impulsivity, depression, anxiety, behavioral regulation, and aggression. CAMs and average pain scores were not associated with consensus diagnosed cognitive impairment, but CAMs were negatively associated with MoCA score (estimate = -0.47, 95% CI -0.81 to -0.13). There was no association between number of orthopedic surgeries and cognition or NBD. DISCUSSION/CONCLUSIONS:CAMs and chronic pain are associated with NBD and CAMs are associated with reduced MoCA scores in former American football players.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Patients with epilepsy (PWE), especially temporal lobe epilepsy (TLE), experience impaired memory for personally experienced events. However, current assessments of episodic memory are limited in their ecological validity with a potential to miss detection of subtle cognitive decline. We conducted an exploratory study to determine whether a naturalistic film-viewing task with open-ended spoken recall could detect memory differences between TLE patients and healthy controls (HCs). METHODS:TLE patients (ages 18-60, fluent in English, not legally blind) were recruited from a Level 4 Epilepsy Center (2018-2024). TLE diagnosis was based on seizure semiology, MRI Brain, and EEG. TLE patients scored 22/30 on the Montreal Cognitive Assessment (MOCA); HCs scored 26/30. Subjects watched 6 short films and then freely recalled film details. Spoken responses were recorded, transcribed, segmented, and scored for film- and event-level recall. Recall order was assessed using the Damerau-Levenshtein distance. Semantic and causal centrality were quantified using sentence embeddings and rater-identified causal links, respectively. Beta regression with cluster-robust standard errors assessed group and centrality effects on recall probability. Beta regression evaluated the influence of age, MOCA, and testing platform on sequence recall error. RESULTS:We recruited 51 subjects (27 TLEs; 24 HCs, 70.1% F, mean 29.9 ±8.3 years). TLE patients and HCs showed similar recall of films (HC 89% ±11% vs TLE 88% ±18%, p = 0.54), coarse-grained events (HC 50% ±16% vs TLE 44% ±18%, p = 0.19) and fine-grained events (HC 25%±10% vs. TLE 22%±12%, p=0.17). Both groups recalled high causal centrality events better. However, TLE patients showed significantly greater fine-grained event sequence deviations at recall than HCs (HC 15% ±13% vs TLE 23% ±18%, p = 0.02, Hedges' g = 0.85, Cliff's δ = 0.51), with RTLE demonstrating more sequence deviations than HCs (15%±13 vs. 29%±21% p = 0.021) Age, education, MOCA, and performance on standard verbal and visual memory tasks were unrelated to film, event, and sequence recall performance. DISCUSSION/CONCLUSIONS:We demonstrate that a short film task with spontaneous spoken recall can identify group level differences in episodic memory. TLE patients demonstrate impaired sequence memory despite intact film- and event-level recall compared to healthy controls. Sequence memory may represent a subtle manifestation of memory impairment that is not detected by standard cognitive testing.

IMPORTANCE/UNASSIGNED:In vivo biomarkers for detecting neuropathologies from repetitive head impacts (RHI), including chronic traumatic encephalopathy (CTE), are needed. OBJECTIVE/UNASSIGNED:To evaluate the utility of plasma phosphorylated tau 217 (p-tau217), assess its performance as a beta-amyloid (Aβ) biomarker in participants with RHI exposure at risk for CTE, and explore concordance with CTE neuropathology in a postmortem subsample. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This longitudinal, multicenter, case-control study used data from the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of CTE (DIAGNOSE CTE) Research Project, collected from September 2016 to October 2023. Participants were former American football players (case participants) and asymptomatic men unexposed to RHI (control participants). A subsample had available neuropathologic data. EXPOSURES/UNASSIGNED:RHI, traumatic encephalopathy syndrome (TES) diagnoses, and levels of CTE certainty. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Plasma p-tau217 (classified as positive [≥0.63 pg/mL], intermediate [0.40-0.62 pg/mL], and negative [<0.40 pg/mL]), Aβ-positron emission tomography (PET; 18F-florbetapir; with Aβ-positive defined as a standardized uptake value ratio [SUVR] ≥1.10), and tau-PET (18F-flortaucipir). TES diagnoses were assigned by multidisciplinary consensus conference. Analyses of postmortem brains controlled for age, race, and APOE ε4 status. RESULTS/UNASSIGNED:Among 231 participants (mean [SD] age, 57.75 [8.25] years), 177 were former football players (117 professional and 60 college) and 54 were unexposed participants. Former football players had higher baseline mean (SD) p-tau217 concentrations than unexposed participants (0.35 [0.26] pg/mL vs 0.27 [0.14] pg/mL; P = .008), although this was driven by a higher proportion of Aβ-PET-positive participants among former players. Plasma p-tau217 increased over time across the sample (B = 0.207 [95% CI, 0.117-0.298]; P < .001), with no significant time × exposure group interactions. Among football players, p-tau217 showed no time × group interactions with TES diagnosis, TES-CTE certainty, or RHI metrics. Higher p-tau217 concentration correlated with higher global Aβ-PET SUVR (B = 0.058 [95% CI, 0.053-3.501; P = .01), with a few discordant cases (5 participants were p-tau217-negative and Aβ-PET-positive; 7 participants were p-tau217-positive and Aβ-PET-negative). P-tau217 had similar areas under the curve for projecting Aβ-PET positivity as cerebrospinal fluid (CSF) p-tau181/Aβ42 and CSF Aβ40/42 measures (p-tau217: AUC, 0.88 [95% CI, 0.80-0.96]; CSF p-tau181/Aβ42: AUC, 0.89 [95% CI, 0.79-1.00]; CSF Aβ40/42: AUC, 0.85 [95% CI, 0.72-0.98]). Among 9 brain donors, 6 had CTE (stages II-IV; none with Alzheimer disease). Seven had negative or intermediate p-tau217, concordant with Aβ-PET. Two p-tau217 outliers with stage III CTE had normal concentrations upon additional testing. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of this study suggest that plasma p-tau217 concentration is unlikely to be useful for the detection of CTE, but it does show utility for ruling out Aβ pathology in participants at risk for CTE.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Direct electrocortical stimulation (DES) is the gold standard for mapping eloquent cortex, yet existing functional atlases are limited by sampling biases and density-based methods that obscure a region's true functional probability. Consequently, interpatient variability and the functional contributions of nontraditional language areas, such as the middle frontal gyrus, remain poorly characterized, particularly in epilepsy populations where functional reorganization is common. We therefore developed a probabilistic functional atlas of extraoperative DES and applied data-driven methods to characterize the functional organization of language, motor, and sensory cortex. METHODS:This was a retrospective observational study of patients undergoing intracranial monitoring for drug-resistant epilepsy (2008-2023). Electrical stimulation was delivered to intracranial electrodes during language tasks, and language, motor, and sensory findings were recorded. Positive and negative stimulation sites were analyzed in standard patient space and using the Human Connectome Project parcellation atlas. A multilevel statistical framework, including probability mapping, bootstrapped region-of-interest analyses, and kernel density estimation, defined structure-function relationships. Generalized linear mixed-effects models assessed the influence of clinical variables on language disruption. RESULTS:= 0.003) independently predicted a lower probability of language disruption in the temporal lobe. DISCUSSION/CONCLUSIONS:This extraoperative DES atlas provides a comprehensive benchmark for understanding functional cortical organization in epilepsy. We add evidence to the growing literature that language and motor systems are more distributed and variable than classically described. Substantial interpatient variability underscores the necessity of individualized mapping to guide safe neurosurgical planning. Limitations include the retrospective design and sampling bias inherent to electrode placement.

The goal of this study was to clarify the contribution of prefrontal cortex activity to men's appraisals, affect states, and decision making in the context of hypothetical heterosexual dating scenarios lacking clear consent. Transcranial direct stimulation (tDCS) was applied to the prefrontal cortex to examine whether it would modify and reduce the likelihood of hypothetical dating violence. Participants (n = 102) responded to first-person vignettes wherein a woman responded either ambiguously or with a refusal to their sexual advance. While responding to the vignettes, participants received sham or active tDCS to modulate prefrontal cortex-mediated responding. Neuromodulation interacted with the communication response type of the woman in the vignette (e.g. ambiguous vs. refusal responses) to influence participants' reports of negative affect (F = 9.57, P = 0.002, Cohen's f²