Faculty Bibliography

OBJECTIVE:NF2-related schwannomatosis (NF2-SWN) is an autosomal dominant genetic disorder characterized by the development of schwannomas, meningiomas, and spinal ependymomas. Treatment with bevacizumab, a monoclonal antibody against VEGF, has been shown to result in decreased vestibular schwannoma size and hearing improvement in ~50% of NF2-SWN patients. It is unknown whether the same degree of benefit is seen in younger patients compared with older patients. The objective of this study is to determine the association between age and bevacizumab treatment outcomes in NF2-SWN. STUDY DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary referral center. PATIENTS/METHODS:Thirty-seven patients with NF2-SWN. INTERVENTIONS/METHODS:Bevacizumab. MAIN OUTCOME MEASURES/METHODS:Change in tumor size of 20% or more. RESULTS:This study includes 37 patients with NF2-SWN who were treated with bevacizumab at our institution between 2014 and 2024. They were divided into 2 groups: 22 adults over the age of 25 (26 to 71 y) and 15 adolescent and young adult (AYA) patients under the age of 25 (12 to 24 y). The median treatment duration was 2.1 years. A significantly higher proportion of AYA schwannomas (37.5%, n=9) exhibited radiographic tumor progression during the treatment period compared with those of the older patient group (11.9%, n=5) (P=0.026), despite similar pre-treatment growth rates. There was no significant difference in the proportion of older and younger patients with hearing decline, improvement, or stability (P>0.05). CONCLUSIONS:AYA patients were significantly more likely to exhibit progression of tumor growth during bevacizumab treatment compared with older patients, though no significant differences were detected in hearing outcomes.

Recent research demonstrates that large language models can predict neural activity recorded via electrocorticography during natural language processing. To predict word-by-word neural activity, most prior work evaluates encoding models within individual electrodes and participants, limiting generalizability. Here we analyze electrocorticography data from eight participants listening to the same 30-min podcast. Using a shared response model, we estimate a common information space across participants. This shared space substantially enhances large language model-based encoding performance and enables denoising of individual brain responses by projecting back into participant-specific electrode spaces-yielding a 37% average improvement in encoding accuracy (from r = 0.188 to r = 0.257). The greatest gains occur in brain areas specialized for language comprehension, particularly the superior temporal gyrus and inferior frontal gyrus. Our findings highlight that estimating a shared space allows us to construct encoding models that better generalize across individuals.

Carotid webs are increasingly recognized as an underdiagnosed etiology of ischemic stroke, especially in young, otherwise healthy patients. These fibrous intimal protrusions create regions of flow stasis within the internal carotid artery, predisposing to thromboembolism. Diagnosis remains challenging due to their subtle radiographic appearance and underappreciation in clinical practice. While antiplatelet therapy or anticoagulation used to be the cornerstone of management, medical therapy alone has been found to be insufficient for stroke prevention in symptomatic patients. Definitive intervention includes carotid artery stenting or carotid endarterectomy; both have demonstrated excellent safety and efficacy. Risk stratification for symptomatic and asymptomatic carotid webs remains an area of active research, with emerging evidence suggesting that specific anatomic features, termed the carotid web angioarchitecture, may help predict stroke risk. Further studies are needed to determine the role of preventative intervention. A deeper understanding of carotid web pathogenesis, natural history, and hemodynamic impact is critical for guiding clinical decision-making.

The 2024 revised McDonald criteria for multiple sclerosis recognize the optic nerve as a topography for dissemination in space. Optical coherence tomography-derived inter-eye differences in peri-papillary retinal nerve fiber layer or ganglion cell-inner plexiform layer thicknesses (≥6μm or ≥4μm, respectively) are proposed for identifying unilateral optic nerve involvement. However, the value of combining inter-eye difference measures and optimal temporal-quadrant peri-papillary retinal nerve fiber layer inter-eye differences remains unclear. We investigated the diagnostic performance of combined inter-eye differences, optimal temporal-quadrant peri-papillary retinal nerve fiber layer inter-eye differences, and examined the effects of time, prior optic neuritis frequency, sex, and race on inter-eye differences. Retinal optical coherence tomography images from all study participants underwent rigorous quality control. Receiver operating characteristic analyses and area under the receiver operating characteristic curves (AUC) were used to determine optimal inter-eye differences of individual and combined measures to distinguish eyes with, from without, prior optic neuritis in people with multiple sclerosis. Mixed-effects models were used to assess impact of time, prior optic neuritis events, sex, and race on inter-eye differences. An independent multiple sclerosis cohort from a second center was examined for external validation. Among 1854 people with multiple sclerosis, optimal inter-eye difference thresholds for identifying unilateral optic nerve involvement were 6μm for peri-papillary retinal nerve fiber layer (AUC=0.80), 4μm for ganglion cell-inner plexiform layer (AUC=0.83), and 8μm for temporal-quadrant peri-papillary retinal nerve fiber layer (AUC=0.71) thicknesses. Peri-papillary retinal nerve fiber layer inter-eye differences ≥6μm or ganglion cell-inner plexiform layer inter-eye differences ≥4μm yielded 87.6% sensitivity, 70.0% specificity, and 64.0% positive predictive value. Concurrent inter-eye differences at lower thresholds (≥5μm peri-papillary retinal nerve fiber layer, ≥3μm ganglion cell-inner plexiform layer) reduced sensitivity to 72.5%, but improved specificity (86.6%) and positive predictive value (76.7%), while maintaining accuracy and negative predictive value. Temporal-quadrant peri-papillary retinal nerve fiber layer inter-eye differences did not improve diagnostic performance. Over a median of 5.1 years, ganglion cell-inner plexiform layer and peri-papillary retinal nerve fiber layer inter-eye differences remained stable. Prior optic neuritis counts and sex did not affect inter-eye differences. Although Black Americans had higher inter-eye differences than White Americans, optimal thresholds were comparable across races. The validation cohort comprising 254 people with multiple sclerosis confirmed these findings. In conclusion, concurrent peri-papillary retinal nerve fiber layer (≥5μm) and ganglion cell-inner plexiform layer inter-eye differences (≥3μm) improve unilateral optic nerve involvement detection versus either alone (≥6μm or ≥4μm, respectively), while temporal-quadrant peri-papillary retinal nerve fiber layer inter-eye differences offer limited benefit. Inter-eye differences remain stable longitudinally and unaffected by prior optic neuritis frequency.

A transient ischemic attack is an acute neurologic event caused by focal ischemia affecting the brain, eye, or spinal cord, resolving quickly without infarction on magnetic resonance imaging (MRI) diffusion-weighted imaging (DWI). It is a tissue-based diagnosis, highlighting the need for prompt recognition and risk stratification. Evaluation in the emergency department includes detailed history, risk assessment, neurologic examination, and initial noncontrast computed tomography (CT) to rule out other conditions, with MRI DWI as the gold standard for confirming no infarction. Vascular imaging, echocardiography, electrocardiogram (ECG), and laboratories help identify underlying causes. Central retinal artery occlusion (CRAO) requires urgent diagnosis and ophthalmology consultation to prevent permanent vision loss.

INTRODUCTION/AIMS/OBJECTIVE:There is a lack of information about startle reflex (SR) in primary lateral sclerosis (PLS). This study examined the presence and prevalence of SR in PLS and compared findings with amyotrophic lateral sclerosis (ALS). METHODS:46 PLS and 54 ALS participants were assessed through structured interviews in this cross-sectional study. Fisher's exact test was used to compare reported SR prevalence. Multivariable linear regression was utilized to study associations between disease group and SR frequency in response to sudden stimuli. RESULTS:SR differed markedly between the two groups, with a higher prevalence in PLS (93.5%) than ALS (20.4%; p < 0.001). Among ALS patients, SR was present in all upper motor neuron (UMN)-predominant cases, which accounted for 54.5% of the SR-positive ALS group, but only 10.4% of probable/definite ALS cases. In SR-positive patients, response frequency to sudden stimuli exceeded 60% in both ALS and PLS, most often triggered by auditory stimuli. Younger age, shorter disease duration, and PLS diagnosis were associated with more frequent SR. DISCUSSION/CONCLUSIONS:SR is significantly more common in PLS than in ALS. Notably, UMN-predominant ALS, although limited in number, showed a higher prevalence of SR (6 out of 6, 100%), indicating that predominant UMN involvement may be a key determinant of SR across both conditions. These hypothesis-generating findings suggest that SR may serve as a novel clinical marker in PLS and UMN-predominant ALS, warranting further validation through prospective studies.

IMPORTANCE/UNASSIGNED:Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. OBJECTIVE/UNASSIGNED:To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. INTERVENTIONS/UNASSIGNED:Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. MAIN OUTCOMES AND MEASURES/UNASSIGNED:Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. RESULTS/UNASSIGNED:A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, -0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, -0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, -0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. CONCLUSIONS AND RELEVANCE/UNASSIGNED:This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. TRIAL REGISTRATION/UNASSIGNED:ClinicalTrials.gov Identifier: NCT05965739.

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHI). In CTE, hyperphosphorylated tau (p-tau) aggregates are found in neurons at the depth of cortical sulci close to the gray matter/white matter (GM/WM) boundary. To date, CTE can only be diagnosed postmortem by neuropathological examination. Traumatic encephalopathy syndrome (TES) is the clinical syndrome purported to be associated with CTE pathology. The aim of this study is to investigate microstructural properties at the GM/WM boundary in individuals with a history of exposure to RHI and clinical features of CTE (i.e., TES). Diffusion magnetic resonance imaging (dMRI), TES diagnoses, and cerebrospinal fluid (CSF) biomarkers were acquired from 165 male former American football players (age: 57.29 ± 8.23 years) from the DIAGNOSE CTE Research Project, a multicenter, observational cohort study. Fractional anisotropy (FA) was measured at the GM/WM boundary of the whole brain. In addition, a widely used method (tract-based spatial statistics [TBSS]) was applied to measure FA of central WM. We used analyses of covariance to test associations between FA and TES. Furthermore, we used linear regressions to test associations between FA and nine CSF biomarkers (i.e., p-tau-181, -217, -231, total tau, amyloid β [Aβ]_1-40, Aβ_1-42, glial fibrillary acidic protein [GFAP], neurofilament light [NfL], and soluble triggering receptor expressed on myeloid cells-2 [sTREM2]). We report an association between higher FA at the GM/WM boundary and higher levels of certainty for CTE pathology (F(1, 147) = 5.781, 95% confidence interval (CI) = 0.0003-0.003, p = 0.035) as well as neurobehavioral dysregulation (F(1, 148) = 7.559, 95% CI = 0.001-0.009, p = 0.020), and functional dependence/dementia (F(1, 148) = 5.046, 95% CI = 0.0004-0.006, p = 0.039). In addition, we report an association between higher FA at the GM/WM boundary and higher CSF p-tau-181 (β = 0.272, 95% CI = 0.078-0.466, p = 0.029) and p-tau-217 (β = 0.295, 95% CI = 0.102-0.488, p = 0.027). FA of the central WM was not associated with TES diagnoses. Taken together, these findings suggest that dMRI at the GM/WM boundary could be used to investigate microstructural alterations suggestive of tau pathology-associated neurodegeneration in individuals with TES, the clinical presentation of CTE. Future studies are needed to validate this approach and to identify clinically useful cutoff values for dMRI metrics.

OBJECTIVE:People with migraine have a higher prevalence and severity of insomnia. We examined the relationship between insomnia severity and migraine-related disability (MIDAS) and migraine-specific quality of life (MSQv2.1). METHODS:We conducted a post-hoc analysis of a pilot randomized controlled study assessing the RELAXaHEAD application in those with insomnia and comorbid migraine. Descriptive statistics were used to summarize demographic and clinical characteristics. Linear mixed model analysis was conducted to evaluate Insomnia Severity Index (ISI) as a predictor of each MSQv2.1 domain and MIDAS. RESULTS:Forty-two participants completed baseline and at least one follow-up survey. Mean age was 43.8 years (SD 12.6) and the majority (85.7%) were female. Most participants (81.0%) had severe migraine-related disability (median baseline MIDAS, 32 (IQR 52)). Over half (54.8%) of participants had moderate clinical insomnia (mean baseline ISI, 18.5 (SD 4.6)). Baseline median MSQv2.1 scores were 44.3 (IQR 31.4) for Role Function-Restrictive (RFR), 65.0 (IQR 45.0) for Role Function-Preventive (RFP), and 46.7 (IQR 46.7) for Emotional Function (EF). The effect of ISI on MIDAS was statistically significant (rate ratio (RR)=1.10, p < 0.05, 95%CI [1.028, 1.171], meaning each one-point increase in ISI was associated with a 10% higher MIDAS score). Additionally, a 1-point increase in ISI was associated with a decrease of 1.2 points in MSQ-RFR (B=-1.205, p = 0.001),1.0 point in MSQ-RFP (B=-0.981, p = 0.020), and 1.4 points in MSQ-EF (B=-1.66, p = 0.001). CONCLUSIONS:Our study revealed significant associations between insomnia severity and migraine-related disability and quality of life, highlighting the importance of prevention and sleep intervention for patients with migraine.