Faculty Bibliography

BACKGROUND:Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE:To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS:This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS:300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION/CONCLUSIONS:Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

We examined the use of a 50-m timed test (50MTT) in an effort to develop objective and easily administered outcome measures for clinical trials in CLN3 disease. Individuals with genetically confirmed CLN3 disease were enrolled from a single institution over a two-year period beginning in August 2019 for baseline assessment. The time to complete independent travel over 50 m was recorded as the outcome of the 50MTT. Performance was measured in a distraction-free hallway with a single turn after 25 m. Data on healthy children were gathered from previous studies by the investigators. A total of 19 children with CLN3 disease (12 males) ranging in age from 66 to 193 months (median 94 months) participated in the study. All children had evidence of vision loss at the time of assessment, and 21.1% had a history of seizures. The 50MTT demonstrated a robust correlation with clinician ratings of gait and overall physical disability based on the Unified Batten Disease Rating Scale (Spearman's rho, Gait r = 0.705, p = 0.001; Physical Symptoms r = 0.876, p < 0.001). When compared to typically developing children, the diagnosis of CLN3 disease was predictive of a 34.98 s increase in the 50MTT (SE = 1.29, p < 0.001) with age as an independent predictor. This study demonstrates preliminary evidence that the 50MTT may be an efficient instrument to capture gross motor functioning in ambulatory individuals with CLN3 disease, and may be a lens for overall physical disability in the condition. As this test may be accomplished with minimal cost and in a shorter amount of time with less reliance on attention or vision as the 6-min walk test, it may be an appealing adjunctive outcome measure in CLN3 clinical trials.
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To derive meaning from sound, the brain must integrate information across many timescales. What computations underlie multiscale integration in human auditory cortex? Evidence suggests that auditory cortex analyses sound using both generic acoustic representations (for example, spectrotemporal modulation tuning) and category-specific computations, but the timescales over which these putatively distinct computations integrate remain unclear. To answer this question, we developed a general method to estimate sensory integration windows-the time window when stimuli alter the neural response-and applied our method to intracranial recordings from neurosurgical patients. We show that human auditory cortex integrates hierarchically across diverse timescales spanning from ~50 to 400 ms. Moreover, we find that neural populations with short and long integration windows exhibit distinct functional properties: short-integration electrodes (less than ~200 ms) show prominent spectrotemporal modulation selectivity, while long-integration electrodes (greater than ~200 ms) show prominent category selectivity. These findings reveal how multiscale integration organizes auditory computation in the human brain.

INTRODUCTION/BACKGROUND:The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. METHODS:An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. RESULTS:Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). CONCLUSIONS:We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.

Objective/UNASSIGNED:To identify and compare patient and procedural variables that are associated with a high radiation dose exposure and worse clinical outcomes between transradial arterial (TRA) and transfemoral arterial (TFA) approaches. Design/UNASSIGNED:This was a retrospective analysis. Setting/UNASSIGNED:A community hospital during the initial phase of adopting a TRA-first approach. Participants/UNASSIGNED:A resultant 215 subjects who only underwent diagnostic cerebral angiograms (DCA) after excluding all therapeutic procedures and patients under 18 years. Interventions/UNASSIGNED:Only DCA from 1 May 2018 to 31 January 2021. Main outcome measures/UNASSIGNED:We compared radiation exposure parameters (total fluoroscopy time (FT), total radiation dose (TD) and dose area product (DAP), number of vessels injected and Patient-Reported Global Health Physical and Mental Outcome Scores (PROGHS) at 30 days postprocedure between groups. Results/UNASSIGNED:FT was significantly greater in TRA compared with TFA (p<0.001). In addition, TRA had a significantly higher TD (p=0.002) and DAP (p=0.005) when compared with TFA. Analysis of only 6-vessel DCAs also showed that TRA had a significantly higher FT, DAP and TD in comparison to TFA. Despite observing a longer FT in TRA, results showed fewer vessels injected and a notably lower success rate in acquiring a 6-vessel DCA using the TRA. Further analysis of the effect of vessel number on FT using general linear models showed that with every increase of one vessel, the FT increases by 2.2 min for TRA (p<0.001; 95% CI 1.03 to 3.36) and by 1.3 min for TFA (p<0.001; 95% CI 0.72 to 1.83). There was no significant difference between groups in PROGHS mental and physical t-scores at 30 days postprocedure, even though our cohort showed a significantly greater percentage of TRA procedures done in the outpatient setting. Conclusions/UNASSIGNED:Adopting a TRA first approach for DCAs may be initially associated with a higher radiation dose for the patient. Better strategies and devices are needed to mitigate this effect.

BACKGROUND:Patients with headache often seek urgent medical care to treat pain and associated symptoms that do not respond to therapeutic options at home. Urgent Cares (UCs) may be suitable for the evaluation and treatment of such patients but there is little data on how headache is evaluated in UC settings and what types of treatments are available. We conducted a study to evaluate the types of care available for patients with headache presenting to UCs. DESIGN/METHODS:Cross-Sectional. METHODS:Headache specialists across the United States contacted UCs to collect data on a questionnaire. Questions asked about UC staffing (e.g. number and backgrounds of staff, hours of operation), average length of UC visits for headache, treatments and tests available for patients presenting with headache, and disposition including to the ED. RESULTS:Data from 10 UC programs comprised of 61 individual UC sites revealed: The vast majority (8/10; 80%) had diagnostic testing onsite for headache evaluation. A small majority (6/10; 60%) had the American Headache Society recommended intravenous medications for acute migraine available. Half (5/10) had a headache protocol in place. The majority (6/10; 60%) had no follow up policy after UC discharge. CONCLUSIONS:UCs have the potential to provide expedited care for patients presenting for evaluation and treatment of headache. However, considerable variability exists amongst UCs in their abilities to manage headaches. This study reveals many opportunities for future research including the development of protocols and professional partnerships to help guide the evaluation, triage, and treatment of patients with headache in UC settings.

BACKGROUND:Although coma is commonly encountered in critical care, worldwide variability exists in diagnosis and management practices. We aimed to assess variability in coma definitions, etiologies, treatment strategies, and attitudes toward prognosis. METHODS:As part of the Neurocritical Care Society Curing Coma Campaign, between September 2020 and January 2021, we conducted an anonymous, international, cross-sectional global survey of health care professionals caring for patients with coma and disorders of consciousness in the acute, subacute, or chronic setting. Survey responses were solicited by sequential emails distributed by international neuroscience societies and social media. Fleiss κ values were calculated to assess agreement among respondents. RESULTS:The survey was completed by 258 health care professionals from 41 countries. Respondents predominantly were physicians (n = 213, 83%), were from the United States (n = 141, 55%), and represented academic centers (n = 231, 90%). Among eight predefined items, respondents identified the following cardinal features, in various combinations, that must be present to define coma: absence of wakefulness (81%, κ = 0.764); Glasgow Coma Score (GCS) ≤ 8 (64%, κ = 0.588); failure to respond purposefully to visual, verbal, or tactile stimuli (60%, κ = 0.552); and inability to follow commands (58%, κ = 0.529). Reported etiologies of coma encountered included medically induced coma (24%), traumatic brain injury (24%), intracerebral hemorrhage (21%), and cardiac arrest/hypoxic-ischemic encephalopathy (11%). The most common clinical assessment tools used for coma included the GCS (94%) and neurological examination (78%). Sixty-six percent of respondents routinely performed sedation interruption, in the absence of contraindications, for clinical coma assessments in the intensive care unit. Advanced neurological assessment techniques in comatose patients included quantitative electroencephalography (EEG)/connectivity analysis (16%), functional magnetic resonance imaging (7%), single-photon emission computerized tomography (6%), positron emission tomography (4%), invasive EEG (4%), and cerebral microdialysis (4%). The most commonly used neurostimulants included amantadine (51%), modafinil (37%), and methylphenidate (28%). The leading determinants for prognostication included etiology of coma, neurological examination findings, and neuroimaging. Fewer than 20% of respondents reported routine follow-up of coma survivors after hospital discharge; however, 86% indicated interest in future research initiatives that include postdischarge outcomes at six (85%) and 12 months (65%). CONCLUSIONS:There is wide heterogeneity among health care professionals regarding the clinical definition of coma and limited routine use of advanced coma assessment techniques in acute care settings. Coma management practices vary across sites, and mechanisms for coordinated and sustained follow-up after acute treatment are inconsistent. There is an urgent need for the development of evidence-based guidelines and a collaborative, coordinated approach to advance both the science and the practice of coma management globally.

Neuronal ceroid lipofuscinosis type 8 (CLN8) disease is an ultra-rare autosomal recessive lysosomal disorder that results in epilepsy, vision loss, and developmental regression. Due to limited information on the natural history of CLN8 disease, we analyzed disease features and progression as part of gene therapy clinical trial readiness. We performed an international cross-sectional study using semi-structured interviews, as well as measures of adaptive functioning and a motor-language scale adapted from CLN2 disease. The interviews were conducted with parents of children with CLN8 disease from January to May 2020. The cohort included 6 individuals with CLN8 disease (4 males, 2 females) of which the median age was 9.9 years (IQR 6.0-12.9) among the 5 living children. The median age of onset of symptoms was 4.1 years (IQR 3.8-5.4), onset of seizures was 4.5 years (IQR 4.3-5.4), onset of vision loss was 6.5 years (IQR 6.0-7.6), and age at diagnosis was 6.6 years (IQR 4.8-8.3). Initial symptoms were seizures (n = 2), language decline (n = 2), motor decline (n = 1), and dementia (n = 1). The most common seizure types were tonic-clonic and myoclonic (n = 4 each). Of those with three or more timepoints of decline in motor and language summary scores, there was a rapid median annual rate of decline of 1.4 score units (IQR 1.1-2.0) from initial decline, where 6 represents normal function and 0 represents no verbal or motor skills. The cohort demonstrated impaired adaptive functioning on the Vineland-III with a median composite score of 65 (IQR 39-65). CLN8 disease is often, but not always, a late infantile form of neuronal ceroid lipofuscinosis in which seizures typically occur earlier than vision loss. Measurable and rapid progression of motor and language functioning was demonstrated in the majority of the cohort, informing clinical trial design.
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BACKGROUND AND OBJECTIVE/OBJECTIVE:Loneliness is common and its prevalence is rising. The relationship of loneliness with subsequent dementia and the early preclinical course of Alzheimer disease and related dementia (ADRD) remains unclear. Thus, the primary objective of this study was to determine the association of loneliness with 10-year all-cause dementia risk and early cognitive and neuroanatomic imaging markers of ADRD vulnerability. METHODS:Retrospective analysis of prospectively collected data from the population-based Framingham Study cohorts (09/09/1948-12/31/2018). Eligible participants had loneliness assessed and were dementia-free at baseline. Loneliness was recorded using the Center for Epidemiologic Studies Depression Scale; defined conservatively as feeling lonely ≥3 days in the past week. The main outcomes were incident dementia over a 10-year period, cognition, and MRI brain volumes and white-matter injury. RESULTS:Of 2308 participants (mean age, 73 [SD, 9] years; 56% women) who met eligibility in the dementia sample, 14% (329/2308) developed dementia; 6% (144/2308) were lonely. Lonely (versus not lonely) adults had higher 10-year dementia risk (age-, sex-, and education-adjusted hazard ratio, 1.54; 95% CI, 1.06-2.24). Lonely participants younger than age 80 without APOE ε4 alleles had a three-fold greater risk (adjusted hazard ratio, 3.03; 95% CI, 1.63-5.62). Among 1875 persons without dementia who met eligibility in the cognition sample (mean age, 62 [SD, 9] years; 54% women), loneliness associated with poorer executive function, lower total cerebral volume, and greater white-matter injury. DISCUSSION/CONCLUSIONS:Over 10 years of close clinical dementia surveillance in this cohort study, loneliness was associated with increased dementia risk; this tripled in adults whose baseline risk would otherwise be relatively low based on age and genetic risk, representing a majority of the US population. Loneliness was also associated with worse neurocognitive markers of ADRD vulnerability, suggesting an early pathogenic role. These findings may have important clinical and public health implications given observed loneliness trends. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class I evidence that loneliness increases the 10-year risk of developing dementia.

Two studies examined genetic and environmental influences on traits proposed by the revised Reinforcement Sensitivity Theory (rRST) of personality. Both quantitative and molecular behavioral genetic methods were applied considering the effects of COMT, DRD2, HTR1A and TPH2 single nucleotide polymorphisms (SNPs). Study one included 274 monozygotic and 154 dizygotic twins for the quantitative behavioral study; and in study two there were 431 twins for the molecular genetic study. The Reinforcement Sensitivity Questionnaire was used to assess basic personality traits defined by the rRST. Univariate biometric modeling suggested that genetic influences accounted for 34-44% of variance of Behavioral Approach System (BAS), Behavioral Inhibition System (BIS) and Fight-Fligh-Freeze System. Molecular genetic analyses proposed the significant main effect of COMT SNP on the BAS and TPH2 SNP on the BIS, and pointed out epistatic effects of COMT x DRD2 on BAS and HTR1A x TPH2 on Fight. Results demonstrated substantial heritability for all rRST constructs, as well as for differences in the molecular genetic basis of both approach-related and avoidance-related dimensions.