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Background: Skill learning engages offline activity in the primary motor cortex (M1). Sensorimotor cortical activity oscillates between excitatory trough and inhibitory peak phases of the mu (8-12 Hz) rhythm. We recently showed that these mu phases influence the magnitude and direction of neuroplasticity induction within M1. However, the contribution of M1 activity during mu peak and trough phases to human skill learning has not been investigated., Objective: To evaluate the effects of phase-dependent TMS during mu peak and trough phases on offline learning of a newly-acquired motor skill., Methods: On Day 1, three groups of healthy adults practiced an explicit motor sequence learning task with their non-dominant left hand. After practice, phase-dependent TMS was applied to the right M1 during either mu peak or mu trough phases. The third group received sham TMS during random mu phases. On Day 2, all subjects were re-tested on the same task to evaluate offline learning., Results: Subjects who received phase-dependent TMS during mu trough phases showed increased offline skill learning compared to those who received phase-dependent TMS during mu peak phases or sham TMS during random mu phases. Additionally, phase-dependent TMS during mu trough phases elicited stronger whole-brain broadband oscillatory power responses than phase-dependent TMS during mu peak phases., Conclusions: We conclude that sensorimotor mu trough phases reflect brief windows of opportunity during which TMS can strengthen newly-acquired skill memories., (Published by Elsevier Inc.)

CLN3 disease is a pediatric neurodegenerative condition wherein seizures are common. The most common disease-causing variant is an ~1-kb deletion in CLN3. We investigated seizure phenotype in relation to genotype and to adaptive behavior, MR spectroscopy and CSF biochemical markers in a CLN3 cohort. We performed seizure phenotyping using clinical history, EEG, and the Unified Batten Disease Rating Scale (UBDRS) seizure score. We assessed correlations of seizure severity with disease severity (UBDRS capability), adaptive behavior composite score (ABC; Vineland-3), glutamate+glutamine+GABA and N-acetylaspartate+N-acetylaspartyl glutamate (MR spectroscopy), and CSF neurofilament light chain (NEFL) levels. In 20 participants, median age was 10.7 years (IQR = 7.8). Eighteen completed baseline EEG; 12 had a 1-year follow-up. Seizures were reported in 14 (8 1-kb deletion homozygotes), with median age at onset of 10.0 (IQR = 6.8). Epileptiform discharges were noted in 15 (9 homozygotes). Bilateral tonic clonic (n = 11) and nonmotor seizures (n = 7) were most common. UBDRS seizure score correlated with age (rp = 0.50; [0.08,0.77]; P = .02), UBDRS capability (rp = -0.57; [-0.81,-0.17]; P = .009) and ABC (rp = -0.66; [-0.85,-0.31]; P = .001) scores, glutamate+glutamine+GABA (rp = -0.54; [-0.80,-0.11]; P = .02) and N-acetylaspartate+N-acetylaspartyl glutamate (rp = -0.54; [-0.80,-0.11]; P = .02), and CSF NEFL (rp = 0.65; [0.29,0.85]; P = .002) levels. After controlling for age, correlations with ABC and CSF NEFL remained significant. In our CLN3 cohort, seizures and epileptiform discharges were frequent and often started by age 10 years without significant difference between genotypes. ABC and CSF NEFL correlate with UBDRS seizure score, reflecting the role of seizures in the neurodegenerative process. Longitudinal evaluations in a larger cohort are needed to confirm these findings., (© 2021 SSIEM.)

Muscular dystrophies due to heterozygous pathogenic variants in LMNA gene cover a broad spectrum of clinical presentations and severity with an age of onset ranging from the neonatal period to adulthood. The natural history of these conditions is not well defined, particularly in patients with congenital or early onset who arguably present with the highest disease burden. Thus the definition of natural history endpoints along with clinically revelant outcome measures is essential to establishing both clinical care planning and clinical trial readiness for this patient group. We designed a large international cross-sectional retrospective natural history study of patients with genetically proven muscle laminopathy who presented with symptoms before two years of age intending to identify and characterize an optimal clinical trial cohort with pertinent motor, cardiac and respiratory endpoints. Quantitative statistics were used to evaluate associations between LMNA variants and distinct clinical events. The study included 151 patients (median age at symptom onset 0.9   years, range: 0.0-2.0). Age of onset and age of death were significantly lower in patients who never acquired independent ambulation compared to patients who achieved independent ambulation. Most of the patients acquired independent ambulation (n = 101, 66.9%), and subsequently lost this ability (n = 86; 85%). The age of ambulation acquisition (median: 1.2 years, range: 0.8-4.0) and age of ambulation loss (median: 7 years, range: 1.2-38.0) were significantly associated with the age of the first respiratory interventions and the first cardiac symptoms. Respiratory and gastrointestinal interventions occurred during first decade while cardiac interventions occurred later. Genotype-phenotype analysis showed that the most common mutation, p.Arg249Trp (20%), was significantly associated with a more severe disease course. This retrospective natural history study of early onset LMNA -related muscular dystrophy confirms the progressive nature of the disorder, initially involving motor symptoms prior to onset of other symptoms (respiratory, orthopaedic, cardiac and gastrointestinal). The study also identifies subgroups of patients with a range of long-term outcomes. Ambulatory status was an important mean of stratification along with the presence or absence of the p.Arg249Trp mutation. These categorizations will be important for future clinical trial cohorts. Finally, this study furthers our understanding of the progression of early onset LMNA -related muscular dystrophy and provides important insights into the anticipatory care needs of LMNA -related respiratory and cardiac manifestations., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Objectives: To investigate the responsiveness of the motor function measure (MFM) and determine the minimal clinically important difference (MCID) in individuals with 2 common types of congenital muscular dystrophy (CMD)., Design: Observational, prospective, single center, cohort study., Setting: National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH)., Participants: Individuals (N=44) with collagen VI-related dystrophies (COL6-RD, n=23) and 21 individuals laminin alpha2-related muscular dystrophy (LAMA2-RD, n=21) enrolled in a 4-year longitudinal natural history study., Interventions: Not applicable., Main Outcome Measures: Responsiveness of the MFM-32 and the Rasch-scaled MFM-25 and the MCID of the MFM-32 determined from a patient-reported anchor with 2 different methods, within-patient and between-patient., Results: The original MFM-32 and Rasch-scaled MFM-25 performed similarly overall in both the COL6-RD and LAMA2-RD populations, with all subscores (D1, standing and transfers; D2, axial and proximal; D3, distal) showing a significant decrease over time, except MFM D1 and D3 for LAMA2-RD. The MFM D1 subscore was the most sensitive to change for ambulant individuals, whereas the MFM D2 subscore was the most sensitive to change for nonambulant individuals. The MCID for the MFM-32 total score was calculated as 2.5 and 3.9 percentage points according to 2 different methods., Conclusions: The MFM showed strong responsiveness in individuals with LAMA2-RD and COL6-RD. Because a floor effect was identified more prominently with the Rasch-Scaled MFM-25, the use of the original MFM-32 as a quantitative variable with the assumption of scale linearity appears to be a good compromise. When designing clinical trials in congenital muscular dystrophies, the use of MCID for MFM should be considered to determine if a given intervention effects show not only a statistically significant change but also a clinically meaningful change., (Copyright © 2020 American Congress of Rehabilitation Medicine. All rights reserved.)

In an effort to minimize protocol noncompliance in neurological research studies that can potentially compromise patient safety, delay completion of the study, and result in premature termination and added costs, we determined the effect of investigator trainings and site initiation visits (SIVs) on the occurrence of noncompliance events. Results of protocol audits conducted at the National Institute of Neurological Disorders and Stroke from 2003 to 2019 on 97 research protocols were retrospectively analyzed. Based on the depth of auditing and provision of investigator research training, audit data were separated into four arms: 1) Early Period, 2003 to 2012; 2) Middle Period, 2013 to 2016; and Late Period, 2017 to 2019, further divided into 3) Late Period without SIVs; and 4) Late Period with SIVs. Events of noncompliance were classified by the type of protocol deviation, the category, and the cause. In total, 952 events occurred across 1080 participants. Protocols audited during the Middle Period, compared to the Early Period, showed a decrease in the percentage of protocols with at least 1 noncompliance event. Protocols with SIVs had a further decrease in major, minor, procedural, eligibility, and policy events. Additionally, protocols audited during the Early Period had on average 0.46 major deviations per participant, compared to 0.26 events in protocols audited during the Middle Period, and 0.08 events in protocols audited during the Late Period with SIVs. Protocol deviations and noncompliance events in neurological clinical trials can be reduced by targeted investigator trainings and SIVs. These measures have major impacts on the integrity, safety, and effectiveness of human subjects research in neurology., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

A longstanding debate has surrounded the role of the motor system in speech perception, but progress in this area has been limited by tasks that only examine isolated syllables and conflate decision-making with perception. Using an adaptive task that temporally isolates perception from decision-making, we examined an EEG signature of motor activity (sensorimotor μ/beta suppression) during the perception of auditory phonemes, auditory words, audiovisual words, and environmental sounds while holding difficulty constant at two levels (Easy/Hard). Results revealed left-lateralized sensorimotor μ/beta suppression that was related to perception of speech but not environmental sounds. Audiovisual word and phoneme stimuli showed enhanced left sensorimotor μ/beta suppression for correct relative to incorrect trials, while auditory word stimuli showed enhanced suppression for incorrect trials. Our results demonstrate that motor involvement in perception is left-lateralized, is specific to speech stimuli, and it not simply the result of domain-general processes. These results provide evidence for an interactive network for speech perception in which dorsal stream motor areas are dynamically engaged during the perception of speech depending on the characteristics of the speech signal. Crucially, this motor engagement has different effects on the perceptual outcome depending on the lexicality and modality of the speech stimulus.

Introduction: The absence of an ischemic lesion on MRI fluid-attenuated inversion recovery (FLAIR) is helpful in predicting stroke onset within 4.5 h. However, some ischemic strokes become visible on FLAIR within 4.5 h. We hypothesized that the early lesion visibility on FLAIR may predict stroke outcome 90 days after intravenous (IV) thrombolysis, independent of time., Materials and Methods: We analyzed data from acute ischemic stroke patients presenting over the last 10 years who were screened with MRI and treated with IV thrombolysis within 4.5 h from onset. Three independent readers assessed whether ischemic lesions seen on diffusion-weighted imaging were also FLAIR positive based on visual inspection. Multivariable regression analyses were used to obtain an adjusted odds ratio of favorable clinical and radiological outcomes based on FLAIR positivity., Results: Of 297 ischemic stroke patients, 25% had lesion visibility on initial FLAIR. The interrater agreement for the FLAIR positivity assessment was 84% (κ = 0.604, 95% CI: 0.557-0.652). Patients with FLAIR-positive lesions had more right hemispheric strokes (57 vs. 41%, p = 0.045), were imaged later (129 vs. 104 min, p = 0.036), and had less frequent favorable 90-day functional outcome (49 vs. 63%, p = 0.028), less frequent early neurologic improvement (30 vs. 58%, p = 0.001), and more frequent contrast extravasation to the cerebrospinal fluid space (44 vs. 26%, p = 0.008)., Conclusions: Early development of stroke lesion on FLAIR within 4.5 h of onset is associated with reduced likelihood of favorable 90-day outcome after IV thrombolysis., (Published by S. Karger AG, Basel.)

Background: Interpersonal trauma (IPT) is highly prevalent among HIV-positive (HIV+) individuals, but its relationship with brain morphology and function is poorly understood., Setting: This cross-sectional analysis evaluated the associations of IPT with cognitive task performance, daily functioning, magnetic resonance imaging (MRI) brain cortical thickness, and bilateral volumes of 4 selected basal ganglia regions in a US-based cohort of aviremic HIV+ individuals, with (HIV+ IPT+) and without IPT exposure (HIV+ IPT-), and sociodemographically matched HIV-negative controls with (HIV- IPT+) and without IPT exposure (HIV- IPT-)., Methods: Enrollees completed brain MRI scans, a semistructured psychiatric interview, a neurocognitive battery, and 3 measures of daily functioning. Demographic and clinical characteristics of the 4 groups were described, and pairwise between-group comparisons performed using χ tests, analysis of variance, or t-tests. Linear or Poisson regressions evaluated relationships between group status and the outcomes of interest, in 6 pairwise comparisons, using Bonferroni correction for statistical significance., Results: Among 187 participants (mean age 50.0 years, 63% male, 64% non-white), 102 were HIV+ IPT+, 35 were HIV+ IPT-, 26 were HIV- IPT-, and 24 were HIV- IPT+. Compared with the remaining 3 groups, the HIV+ IPT+ group had more activities of daily living declines, higher number of impaired Patient's Assessment of Own Functioning Inventory scores, and lower cortical thickness in multiple cerebral regions. Attention/working memory test performances were significantly better in HIV- IPT- compared with the HIV+ IPT+ and HIV+ IPT- groups. Basal ganglia MRI volumes were not significantly different in any between-group comparisons., Conclusion: IPT exposure and HIV infection have a synergistic effect on daily functioning and cortical thickness in aviremic HIV+ individuals.

Background: Functional movement disorders (FMDs), part of the wide spectrum of functional neurological disorders (conversion disorders), are common and often associated with a poor prognosis. Nevertheless, little is known about their neurobiological underpinnings, particularly with regard to the contribution of genetic factors. Because FMD and stress-related disorders share a common core of biobehavioural manifestations, we investigated whether variants in stress-related genes also contributed, directly and interactively with childhood trauma, to the clinical and circuit-level phenotypes of FMD., Methods: Sixty-nine patients with a 'clinically defined' diagnosis of FMD were genotyped for 18 single-nucleotide polymorphisms (SNPs) from 14 candidate genes. FMD clinical characteristics, psychiatric comorbidity and symptomatology, and childhood trauma exposure were assessed. Resting-state functional connectivity data were obtained in a subgroup of 38 patients with FMD and 38 age-matched and sex-matched healthy controls. Amygdala-frontal connectivity was analysed using a whole-brain seed-based approach., Results: Among the SNPs analysed, a tryptophan hydroxylase 2 ( TPH2 ) gene polymorphism-G703T-significantly predicted clinical and neurocircuitry manifestations of FMD. Relative to GG homozygotes, T carriers were characterised by earlier FMD age of onset and decreased connectivity between the right amygdala and the middle frontal gyrus. Furthermore, the TPH2 genotype showed a significant interaction with childhood trauma in predicting worse symptom severity., Conclusions: This is, to our knowledge, the first study showing that the TPH2 genotype may modulate FMD both directly and interactively with childhood trauma. Because both this polymorphism and early-life stress alter serotonin levels, our findings support a potential molecular mechanism modulating FMD phenotype., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We compared resting state (RS) functional connectivity and task-based fMRI to lateralize language dominance in 30 epilepsy patients (mean age = 33; SD = 11; 12 female), a measure used for presurgical planning. Language laterality index (LI) was calculated from task fMRI in frontal, temporal, and frontal + temporal regional masks using LI bootstrap method from SPM12. RS language LI was assessed using two novel methods of calculating RS language LI from bilateral Broca's area seed based connectivity maps across regional masks and multiple thresholds (p < .05, p < .01, p < .001, top 10% connections). We compared LI from task and RS fMRI continuous values and dominance classifications. We found significant positive correlations between task LI and RS LI when functional connectivity thresholds were set to the top 10% of connections. Concordance of dominance classifications ranged from 20% to 30% for the intrahemispheric resting state LI method and 50% to 63% for the resting state LI intra- minus interhemispheric difference method. Approximately 40% of patients left dominant on task showed RS bilateral dominance. There was no difference in LI concordance between patients with right-sided and left-sided resections. Early seizure onset (<6 years old) was not associated with atypical language dominance during task-based or RS fMRI. While a relationship between task LI and RS LI exists in patients with epilepsy, language dominance is less lateralized on RS than task fMRI. Concordance of language dominance classifications between task and resting state fMRI depends on brain regions surveyed and RS LI calculation method., (Published [2020]. This article is a U.S. Government work and is in the public domain in the USA.)

Neuroimaging studies have implicated left temporal lobe regions in audiovisual integration of speech and inferior parietal regions in temporal binding of incoming signals. However, it remains unclear which regions are necessary for audiovisual integration, especially when the auditory and visual signals are offset in time. Aging also influences integration, but the nature of this influence is unresolved. We used a McGurk task to test audiovisual integration and sensitivity to the timing of audiovisual signals in two older adult groups: left hemisphere stroke survivors and controls. We observed a positive relationship between age and audiovisual speech integration in both groups, and an interaction indicating that lesions reduce sensitivity to timing offsets between signals. Lesion-symptom mapping demonstrated that damage to the left supramarginal gyrus and planum temporale reduces temporal acuity in audiovisual speech perception. This suggests that a process mediated by these structures identifies asynchronous audiovisual signals that should not be integrated., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Only a few small studies have previously reported episodes of hypoglycemia in children with neuromuscular diseases; however, there has been no broader investigation into the occurrence of hypoglycemia in children with congenital muscle disease (CMD)., Methods: Pediatric patients enrolled in the CMD International Registry (CMDIR) with a history of hypoglycemia were included in this retrospective review. Hypoglycemic episodes and associated clinical and biochemical characteristics were characterized., Results: Ten patients with CMD (5 with LAMA2-related muscular dystrophy) reported at least one episode of hypoglycemia beginning at an average age of 3.5 years. Predominant symptoms included altered mental status and nausea/vomiting, and laboratory studies demonstrated metabolic acidosis and ketonuria, consistent with ketotic hypoglycemia., Conclusion: Patients with CMD may have an increased risk of hypoglycemia during fasting, illness, or stress due to their relatively low muscle mass and hence, paucity of gluconeogenic substrate. Clinicians should therefore maintain a high index of suspicion for hypoglycemia in this high-risk patient population and caregivers should routinely be trained to recognize and treat hypoglycemia.

Objective: To identify the rate of change of clinical outcome measures in children with 2 types of congenital muscular dystrophy (CMD), COL6-related dystrophies (COL6-RDs) and LAMA2-related dystrophies (LAMA2-RDs)., Methods: Over the course of 4 years, 47 individuals (23 with COL6-RD and 24 with LAMA2-RD) 4 to 22 years of age were evaluated. Assessments included the Motor Function Measure 32 (MFM32), myometry (knee flexors and extensors, elbow flexors and extensors), goniometry (knee and elbow extension), pulmonary function tests, and quality-of-life measures. Separate linear mixed-effects models were fitted for each outcome measurement, with subject-specific random intercepts., Results: Total MFM32 scores for COL6-RDs and LAMA2-RDs decreased at a rate of 4.01 and 2.60 points, respectively, each year ( p < 0.01). All muscle groups except elbow flexors for individuals with COL6-RDs decreased in strength between 1.70% ( p < 0.05) and 2.55% ( p < 0.01). Range-of-motion measurements decreased by 3.21° ( p < 0.05) at the left elbow each year in individuals with LAMA2-RDs and 2.35° ( p < 0.01) in right knee extension each year in individuals with COL6-RDs. Pulmonary function demonstrated a yearly decline in sitting forced vital capacity percent predicted of 3.03% ( p < 0.01) in individuals with COL6-RDs. There was no significant change in quality-of-life measures analyzed., Conclusion: Results of this study describe the rate of change of motor function as measured by the MFM32, muscle strength, range of motion, and pulmonary function in individuals with COL6-RDs and LAMA2-RDs., (© 2019 American Academy of Neurology.)

Background : Neuroinflammation and human endogenous retroviruses (HERV) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term antiretroviral therapy (ART), Triumeq (abacavir, lamivudine, and dolutegravir) exposure in patients with ALS, and efficacy against biomarkers of disease progression. Methods : Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centers. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75 ECD levels, neurophysiological parameters, and clinical indicators. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered (NCT02868580). Findings : 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favorable response on HERV-K expression levels was observed, accompanied by a decline in ALSFRS-R progression rate of 21.8% (95% CI -4.8%-48.6%) and the amount of urinary p75 ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation : Long-term Triumeq exposure was safe and well tolerated in this cohort. There was suggestive indication for a possible biological response in some pharmacodynamic and clinical biomarkers. A larger international phase 3 trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom, and GSK. ViiV Healthcare provided the Triumeq.

Oscillatory activity within sensorimotor networks is characterized by time-varying changes in phase and power. The influence of interactions between sensorimotor oscillatory phase and power on human motor function, like corticospinal output, is unknown. We addressed this gap in knowledge by delivering transcranial magnetic stimulation (TMS) to the human motor cortex during electroencephalography recordings in 20 healthy participants. Motor evoked potentials, a measure of corticospinal excitability, were categorized offline based on the mu (8-12 Hz) and beta (13-30 Hz) oscillatory phase and power at the time of TMS. Phase-dependency of corticospinal excitability was evaluated across a continuous range of power levels using trial-by-trial linear mixed-effects models. For mu, there was no effect of PHASE or POWER (P > 0.51), but a significant PHASE × POWER interaction (P = 0.002). The direction of phase-dependency reversed with changing mu power levels: corticospinal output was higher during mu troughs versus peaks when mu power was high while the opposite was true when mu power was low. A similar PHASE × POWER interaction was not present for beta oscillations (P > 0.11). We conclude that the interaction between sensorimotor oscillatory phase and power gates human corticospinal output to an extent unexplained by sensorimotor oscillatory phase or power alone., (Published by Oxford University Press 2018.)

Objective: We aimed to predict language deficits after epilepsy surgery. In addition to evaluating surgical factors examined previously, we determined the impact of the extent of functional magnetic resonance imaging (fMRI) activation that was resected on naming ability., Method: Thirty-five adults (mean age 37.5 ± 10.9 years, 13 male) with temporal lobe epilepsy completed a preoperative fMRI auditory description decision task, which reliably activates frontal and temporal language networks. Patients underwent temporal lobe resections (20 left resection). The Boston Naming Test (BNT) was used to determine language functioning before and after surgery. Language dominance was determined for Broca and Wernicke area (WA) by calculating a laterality index following statistical parametric mapping processing. We used an innovative method to generate anatomic resection masks automatically from pre- and postoperative MRI tissue map comparison. This mask provided the following: (a) resection volume; (b) overlap between resection and preoperative activation; and (c) overlap between resection and WA. We examined postoperative language change predictors using stepwise linear regression. Predictors included parameters described above as well as age at seizure onset (ASO), preoperative BNT score, and resection side and its relationship to language dominance., Results: Seven of 35 adults had significant naming decline (6 dominant-side resections). The final regression model predicted 38% of the naming score change variance (adjusted r 2  = 0.28, P = 0.012). The percentage of top 10% fMRI activation resected (P = 0.017) was the most significant contributor. Other factors in the model included WA LI, ASO, volume of WA resected, and WA LI absolute value (extent of laterality)., Significance: Resection of fMRI activation during a word-definition decision task is an important factor for postoperative change in naming ability, along with other previously reported predictors. Currently, many centers establish language dominance using fMRI. Our results suggest that the amount of the top 10% of language fMRI activation in the intended resection area provides additional predictive power and should be considered when planning surgical resection., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: The objective of this study was to evaluate the methods by which neurology physician-scientists are quantified through applying author-level metrics to commonly used definitions when discussing funding efforts aimed at the attrition of the physician-scientist workforce., Methods: Neurology residency alumni from institutions with the highest National Institute of Neurological Disorders and Stroke funding were identified for 2003-2005, and their funding records, publishing history, and impact factor ( h -index) were obtained via the NIH Research Portfolio Online Reporting Tools and Scopus Author Profile. The group differences of total publications, yearly publication rate, and h- index between R01-funded, non-R01-funded, and nonfunded individuals were analyzed via analysis of variance models, and a publications-per-research hour rate was calculated and similarly compared across groups., Results: From 15 programs, and from a total of 252 neurologists, 186 were identified as having demonstrated an interest in research. The mean h- index, yearly publication rate, and cumulative number of publications were significantly higher in those who eventually received an R01 grant compared to those without R01 funding and those with no research funding. Within the top 50 performers by yearly publication rate, there was an equal mix of the 3 groups of neurologists: R01 (19, 38%), non-R01 (15, 30%), and nonfunded (16, 32%). Those who were nonfunded (10% research effort) had an estimated 4.9 publications per 1,000 research hours compared to 3.0 for those with non-R01 (40% research effort) funding and 3.2 for those with R01 funding (80% research effort)., Conclusions: While eventual R01 grant and early career funding pathways were confirmed as important components of higher h -index and larger publication numbers, the classic definition of a physician-scientist was questioned through these findings. Those presumed to be without funding and generally excluded from the physician-scientist pool because of lack of protected research time, in some instances, outperformed their R01-funded colleagues and had a higher publications-per-research hour than those with an R01 and those with non-R01 funding, when estimating a 10% research effort. This reflects a potentially erroneous assumption and indicates the important contribution of these neurologists., (© 2018 American Academy of Neurology.)

Objective: To examine the diaphragm and chest wall dynamics with cine breathing magnetic resonance imaging (MRI) in ambulatory boys with Duchenne muscular dystrophy (DMD) without respiratory symptoms and controls., Methods: In 11 DMD boys and 15 controls, cine MRI of maximal breathing was recorded for 10 sec. The lung segmentations were done by an automated pipeline based on a Holistically-Nested Network model (HNN method). Lung areas, diaphragm, and chest wall motion were measured throughout the breathing cycle., Results: The HNN method reliably identified the contours of the lung and the diaphragm in every frame of each dataset (~180 frames) within seconds. The lung areas at maximal inspiration and expiration were reduced in DMD patients relative to controls ( P  =   0.02 and <0.01, respectively). The change in the lung area between inspiration and expiration correlated with percent predicted forced vital capacity (FVC) in patients ( r s  = 0.75, P  =   0.03) and was not significantly different between groups. The diaphragm position, length, contractility, and motion were not significantly different between groups. Chest wall motion was reduced in patients compared to controls ( P  <   0.01)., Interpretation: Cine breathing MRI allows independent and reliable assessment of the diaphragm and chest wall dynamics during the breathing cycle in DMD patients and controls. The MRI data indicate that ambulatory DMD patients breathe at lower lung volumes than controls when their FVC is in the normal range. The diaphragm moves normally, whereas chest wall motion is reduced in these boys with DMD.

Objective: To evaluate the associations among diffusion-weighted imaging (DWI) lesions, blood pressure (BP) dysregulation, MRI markers of small vessel disease, and poor outcome in a large, prospective study of primary intracerebral hemorrhage (ICH)., Methods: The Ethnic/Racial Variations of Intracerebral Hemorrhage (ERICH) study is a multicenter, observational study of ICH among white, black, and Hispanic patients., Results: Of 600 patients, mean (±SD) age was 60.8 ± 13.6 years, median (interquartile range) ICH volume was 9.1 mL (3.5-20.8), and 79.6% had hypertension. Overall, 26.5% of cases had DWI lesions, and this frequency differed by race/ethnicity (black 33.8%, Hispanic 24.9%, white 20.2%, overall p = 0.006). A logistic regression model of variables associated with DWI lesions included lower age (odds ratio [OR] 0.721, p = 0.002), higher first recorded systolic BP (10-unit OR 1.12, p = 0.002), greater change in mean arterial pressure (MAP) prior to the MRI (10-unit OR 1.10, p = 0.037), microbleeds (OR 1.99, p = 0.008), and higher white matter hyperintensity (WMH) score (1-unit OR 1.16, p = 0.002) after controlling for race/ethnicity, leukocyte count, and acute in-hospital antihypertensive treatment. A second model of variables associated with poor 90-day functional outcome (modified Rankin Scale scores 4-6) included DWI lesion count (OR 1.085, p = 0.034) as well as age, ICH volume, intraventricular hemorrhage, Glasgow Coma Scale score, WMH score, race/ethnicity, acute in-hospital antihypertensive treatment, and ICH location., Conclusions: These results support the hypotheses that acute BP dysregulation is associated with the development of DWI lesions in primary ICH and that DWI lesions are, in turn, associated with poor outcomes., (© 2017 American Academy of Neurology.)

Background: Reliable imaging biomarkers of response to therapy in acute stroke are needed. The final infarct volume and percent of early reperfusion have been used for this purpose. Early fluctuation in stroke size is a recognized phenomenon, but its utility as a biomarker for response to therapy has not been established. This study examined the clinical relevance of early change in stroke volume and compared it with the final infarct volume and percent of early reperfusion in identifying early neurologic improvement (ENI)., Methods: Acute stroke patients, enrolled between 2013 and 2014 with serial magnetic resonance imaging (MRI) scans (pretreatment baseline, 2 h post, and 24 h post), who received thrombolysis were included in the analysis. Early change in stroke volume, infarct volume at 24 h on diffusion, and percent of early reperfusion were calculated from the baseline and 2 h MRI scans were compared. ENI was defined as ≥4 point decrease in National Institutes of Health Stroke Scales within 24 h. Logistic regression models and receiver operator characteristics analysis were used to compare the efficacy of 3 imaging biomarkers., Results: Serial MRIs of 58 acute stroke patients were analyzed. Early change in stroke volume was significantly associated with ENI by logistic regression analysis (OR 0.93, p = 0.048) and remained significant after controlling for stroke size and severity (OR 0.90, p = 0.032). Thus, for every 1 mL increase in stroke volume, there was a 10% decrease in the odds of ENI, while for every 1 mL decrease in stroke volume, there was a 10% increase in the odds of ENI. Neither infarct volume at 24 h nor percent of early reperfusion were significantly associated with ENI by logistic regression. Receiver-operator characteristic analysis identified early change in stroke volume as the only biomarker of the 3 that performed significantly different than chance (p = 0.03)., Conclusions: Early fluctuations in stroke size may represent a more reliable biomarker for response to therapy than the more traditional measures of final infarct volume and percent of early reperfusion., (© 2017 S. Karger AG, Basel.)

Rationale: Whether sleep-disordered breathing (SDB) severity and diminished lung function act synergistically to heighten the risk of adverse health outcomes remains a topic of significant debate., Objectives: The current study sought to determine whether the association between lower lung function and mortality would be stronger in those with increasing severity of SDB in a community-based cohort of middle-aged and older adults., Methods: Full montage home sleep testing and spirometry data were analyzed on 6,173 participants of the Sleep Heart Health Study. Proportional hazards models were used to calculate risk for all-cause mortality, with FEV 1 and apnea-hypopnea index (AHI) as the primary exposure indicators along with several potential confounders., Measurements and Main Results: All-cause mortality rate was 26.9 per 1,000 person-years in those with SDB (AHI ≥5 events/h) and 18.2 per 1,000 person-years in those without (AHI <5 events/h). For every 200-ml decrease in FEV 1 , all-cause mortality increased by 11.0% in those without SDB (hazard ratio, 1.11; 95% confidence interval, 1.08-1.13). In contrast, for every 200-ml decrease in FEV 1 , all-cause mortality increased by only 6.0% in participants with SDB (hazard ratio, 1.06; 95% confidence interval, 1.04-1.09). Additionally, the incremental influence of lung function on all-cause mortality was less with increasing severity of SDB (P value for interaction between AHI and FEV 1 , 0.004)., Conclusions: Lung function was associated with risk for all-cause mortality. The incremental contribution of lung function to mortality diminishes with increasing severity of SDB.

Background: We sought to investigate the frequency of microbleed development following intracerebral hemorrhage in a predominantly African-American population and to identify predictors of new microbleed formation., Aims And/or Hypothesis: To investigate the frequency and predictors of new microbleeds following intracerebral hemorrhage., Methods: The DECIPHER study was a prospective, longitudinal, magnetic resonance-based cohort study designed to evaluate racial/ethnic differences in risk factors for microbleeds and to evaluate the prognostic impact of microbleeds in this intracerebral hemorrhage population. We evaluated new microbleed formation in two time periods: from baseline to 30 days and from 30 days to year 1., Results: Of 200 subjects enrolled in DECIPHER, 84 had magnetic resonance imaging at all required time points to meet criteria for this analysis. In the baseline to day 30 analysis, 11 (13·1%) had new microbleeds, compared with 25 (29·8%) in the day 30 to year 1 analysis. Logistic regression analysis demonstrated that baseline number of microbleeds [odds ratio 1·05 (95% confidence interval 1·01, 1·08), P = 0·01] was associated with new microbleed formation at 30 days. A logistic regression model predicting new microbleed at one-year included baseline number of microbleeds [odds ratio 1·05 (1·00, 1·11), P = 0·046], baseline age [odds ratio 1·05 (1·00, 1·10), P = 0·04], and white matter disease score [odds ratio 1·18 (0·96, 1·45). P = 0·115]. Overall, 28 of 84 (33·3%) intracerebral hemorrhage subjects formed new microbleeds at some point in the first year post-intracerebral hemorrhage., Conclusions: We found that one-third of intracerebral hemorrhage subjects in this cohort surviving one-year developed new microbleeds, which suggests a dynamic and rapidly progressive vasculopathy. Future studies are needed to examine the impact of new microbleed formation on patient outcomes., (© 2015 World Stroke Organization.)