Faculty Bibliography

Studies of epilepsy patients provide insight into the neuroscience of human memory. Patients with remote memory deficits may learn new information but have difficulty recalling events from years past. The processes underlying remote memory impairment are unclear and likely result from the interaction of multiple factors, including hippocampal dysfunction. The hippocampus likely has a continued role in remote semantic and episodic memory storage over time, and patients with mesial temporal lobe epilepsy (TLE) are at particular risk for deficits. Studies have focused on lateralization of remote memory, often with greater impairment in left TLE, which may relate to verbal task demands. Remote memory testing is restricted by methodological limitations. As a result, deficits have been difficult to measure. This review of remote memory focuses on evidence for its underlying neurobiology, theoretical implications for hippocampal function, and methodological difficulties that complicate testing in epilepsy patients.

Since the outbreak of the COVID-19 pandemic, races across academia and industry have been initiated to identify and develop disease modifying or preventative therapeutic strategies has been initiated. The primary focus has been on pharmacological treatment of the immune and respiratory system and the development of a vaccine. The hyperinflammatory state ("cytokine storm") observed in many cases of COVID-19 indicates a prognostically negative disease progression that may lead to respiratory distress, multiple organ failure, shock, and death. Many critically ill patients continue to be at risk for significant, long-lasting morbidity or mortality. The human immune and respiratory systems are heavily regulated by the central nervous system, and intervention in the signaling of these neural pathways may permit targeted therapeutic control of excessive inflammation and pulmonary bronchoconstriction. Several technologies, both invasive and non-invasive, are available and approved for clinical use, but have not been extensively studied in treatment of the cytokine storm in COVID-19 patients. This manuscript provides an overview of the role of the nervous system in inflammation and respiration, the current understanding of neuromodulatory techniques from preclinical and clinical studies and provides a rationale for testing non-invasive neuromodulation to modulate acute systemic inflammation and respiratory dysfunction caused by SARS-CoV-2 and potentially other pathogens. The authors of this manuscript have co-founded the International Consortium on Neuromodulation for COVID-19 to advocate for and support studies of these technologies in the current coronavirus pandemic.

OBJECTIVE/UNASSIGNED:Little is known about psychiatric symptoms among patients with migraine and newly diagnosed focal epilepsy. The investigators compared symptoms of depression, anxiety, and suicidality among people with newly diagnosed focal epilepsy with migraine versus without migraine. METHODS/UNASSIGNED:The Human Epilepsy Project is a prospective multicenter study of patients with newly diagnosed focal epilepsy. Depression (measured with the Center for Epidemiologic Studies Depression Scale), anxiety (measured with the 7-item Generalized Anxiety Disorder scale), and suicidality scores (measured with the Columbia-Suicide Severity Rating Scale [C-SSRS]) were compared between participants with versus without migraine. Data analysis was performed with the Kolmogorov-Smirnov test for normality assessment, the Mann-Whitney U test, chi-square test, and linear regression. RESULTS/UNASSIGNED:Of 349 patients with new-onset focal epilepsy, 74 (21.2%) had migraine. There were no differences between the patients without migraine versus those with migraine in terms of age, race, and level of education. There were more women in the group with migraine than in the group without migraine (75.7% vs. 55.6%, p=0.0018). The patients with epilepsy and comorbid migraine had more depressive symptoms than the patients with epilepsy without migraine (35.2% vs. 22.7%, p=0.031). Patients with epilepsy with comorbid migraine had more anxiety symptoms than patients with epilepsy without migraine, but this relation was mediated by age in logistic regression, with younger age being associated with anxiety. Comorbid migraine was not associated with C-SSRS ideation or behavior. CONCLUSIONS/UNASSIGNED:Among a sample of patients with newly diagnosed focal epilepsy, 21.2% had migraine. Migraine comorbidity was associated with higher incidence of depressive symptoms. Future studies should be performed to better assess these relationships and possible treatment implications.

OBJECTIVE:To compare clinical and imaging features of multiple sclerosis (MS) severity between Black Americans (BA) and White Americans (WA) and evaluate the role of socioeconomic status. METHODS:We compared BA and WA participants in the Multiple Sclerosis Partners Advancing Technology Health Solutions (MS PATHS) cohort with respect to MS characteristics including self-reported disability, objective neurologic function assessments, and quantitative brain MRI measurements, after covariate adjustment (including education level, employment, or insurance as socioeconomic indicators). In a subgroup, we evaluated within-race, neighborhood-level indicators of socioeconomic status (SES) using 9-digit ZIP codes. RESULTS:Of 1,214 BAs and 7,530 WAs with MS, BAs were younger, had lower education level, and were more likely to have Medicaid insurance or be disabled or unemployed than WAs. BAs had worse self-reported disability (1.47-fold greater odds of severe vs. mild disability, 95% CI 1.18, 1.86) and worse performances on tests of cognitive processing speed (-5.06 fewer correct, CI -5.72, -4.41), walking (0.66 seconds slower, 95% CI 0.36, 0.96) and manual dexterity (2.11 seconds slower, 95% CI 1.69, 2.54). BAs had more brain MRI lesions and lower overall and gray matter brain volumes, including reduced thalamic (-0.77 mL, 95% CI -0.91, -0.64), cortical (-30.63 mL, 95% CI -35.93, -25.33), and deep (-1.58 mL, 95% CI -1.92, -1.23) gray matter volumes. While lower SES correlated with worse neuroperformance scores in WAs, this association was less clear in BA. CONCLUSION/CONCLUSIONS:We observed a greater burden of disease in BAs with MS relative to WAs with MS, despite adjustment for SES indicators. Beyond SES, future longitudinal studies should also consider roles of other societal constructs (e.g., systemic racism). Such studies will be important for identifying prognostic factors and optimal treatment strategies among BAs with MS is warranted.

BACKGROUND:Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that has been neuropathologically diagnosed in brain donors exposed to repetitive head impacts, including boxers and American football, soccer, ice hockey, and rugby players. CTE cannot yet be diagnosed during life. In December 2015, the National Institute of Neurological Disorders and Stroke awarded a seven-year grant (U01NS093334) to fund the "Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy (DIAGNOSE CTE) Research Project." The objectives of this multicenter project are to: develop in vivo fluid and neuroimaging biomarkers for CTE; characterize its clinical presentation; refine and validate clinical research diagnostic criteria (i.e., traumatic encephalopathy syndrome [TES]); examine repetitive head impact exposure, genetic, and other risk factors; and provide shared resources of anonymized data and biological samples to the research community. In this paper, we provide a detailed overview of the rationale, design, and methods for the DIAGNOSE CTE Research Project. METHODS:The targeted sample and sample size was 240 male participants, ages 45-74, including 120 former professional football players, 60 former collegiate football players, and 60 asymptomatic participants without a history of head trauma or participation in organized contact sports. Participants were evaluated at one of four U.S. sites and underwent the following baseline procedures: neurological and neuropsychological examinations; tau and amyloid positron emission tomography; magnetic resonance imaging and spectroscopy; lumbar puncture; blood and saliva collection; and standardized self-report measures of neuropsychiatric, cognitive, and daily functioning. Study partners completed similar informant-report measures. Follow-up evaluations were intended to be in-person and at 3 years post-baseline. Multidisciplinary diagnostic consensus conferences are held, and the reliability and validity of TES diagnostic criteria are examined. RESULTS:Participant enrollment and all baseline evaluations were completed in February 2020. Three-year follow-up evaluations began in October 2019. However, in-person evaluation ceased with the COVID-19 pandemic, and resumed as remote, 4-year follow-up evaluations (including telephone-, online-, and videoconference-based cognitive, neuropsychiatric, and neurologic examinations, as well as in-home blood draw) in February 2021. CONCLUSIONS:Findings from the DIAGNOSE CTE Research Project should facilitate detection and diagnosis of CTE during life, and thereby accelerate research on risk factors, mechanisms, epidemiology, treatment, and prevention of CTE. TRIAL REGISTRATION:NCT02798185.

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.

Objective/UNASSIGNED:At the time of multiple sclerosis (MS) diagnosis, identifying those at risk for poorer health-related quality of life and emotional well-being can be a critical consideration for treatment planning. This study aimed to test whether adverse childhood experiences predict MS patients' health-related quality of life and emotional functioning at time of diagnosis and initial course of disease. Methods/UNASSIGNED:We recruited patients at the time of new MS diagnosis to complete self-report surveys at baseline and a one-year follow-up. Questionnaires included the Adverse Childhood Experiences (ACEs), as well as the MS Knowledge Questionnaire (MSKQ), the 36-Item Short Form Health Survey (SF-36), and Self-Management Screening (SeMaS). Results/UNASSIGNED: Conclusions/UNASSIGNED:Childhood adversity predicts health-related quality of life and emotional well-being at time of MS diagnosis and over the initial course of the disease. Measured using a brief screening inventory (ACEs), routine administration may be useful for identifying patients in need of increased supportive services.